The New

S|ogren's
Syndrome
Handbook
EDITOR

DANIEL ). WALLACE, MD

ASSOCIATE EDITORS

Evelyn J. Bromet, PHD

Arthur Grayzel, MD
Katherine Morland Hammitt, MA
Stuart S. Kassan, MD
Frederick B. Vivino, MD

A publication of the SJOGREN'S SYNDROME FOUNDATION

 The New
Sjogren's
Syndrome
Handbook
REVISED AND EXPANDED THIRD EDITION

OXFORD
UNIVERSITY PRESS

2005
 OXTORD
UNIVERSITY PRESS

Oxford New York

Auckland Bangkok Buenos Aires Cape Town Chennai
Dar es Salaam Delhi Hong Kong Istanbul Karachi Kolkata
Kuala Lumpur Madrid Melbourne Mexico City Mumbai Nairobi
Sao Paulo Shanghai Taipei Tokyo Toronto

Copyright © 2005 by The Sjogren's Syndrome Foundation

Published by Oxford University Press, Inc.
198 Madison Avenue, New York, New York 10016
www.oup.com

Oxford is a registered trademark of Oxford University Press

All rights reserved. No part of this publication may be reproduced,

stored in a retrieval system, or transmitted, in any form or by any means,
electronic, mechanical, photocopying, recording, or otherwise,
without the prior permission of Oxford University Press.
Library of Congress Cataloging-in-Publication Data
The new Sjogren's syndrome handbook / editor, Daniel J. Wallace;
associate editors, Evelyn J. Bromet... [et al.]—3rd ed., rev. and expanded
p. cm.
"A publication of the Sjogren's Syndrome Foundation"
Includes bibliographical references and index
ISBN 0-19-517228-0
1. Sjogren's syndrome—Popular works.
I. Wallace, Daniel J. (Daniel Jeffrey), 1949-
II. Bromet, Evelyn J.
III. Sjogren's Syndrome Foundation.
RC 647.5.S5 N49 2005
616.7V5—dc22 2003027681

135798642
Printed in the United States of America
on acid-free paper
CONTENTS

Preface Evelyn J. Bromet ix

List of Contributors xi
Introduction: Why Write a Book on Sjogren's Syndrome?
Daniel J. Wallace xv

PART 1: INTRODUCTION AND DEFINITIONS

1 The History of Sjogren's Syndrome 3
Norman Total
2 What Is Sjogren's Syndrome? 5
Arthur Grayzel
3 Who Develops Sjogren's Syndrome? 10
Daniel J. Wallace

PART 11: THE PATHOLOGY OF SJOGREN'S SYNDROME

4 What Leads to Dryness? 15
Janine Smith, Serena Morrison
5 Sjogren's Syndrome: A Genetic and Immunologic
Perspective 24
Lama Hashish, Amr Sawalha, John B. Harley, Robert Fox

PART 111: WHERE AND HOW CAN THE BODY BE AFFECTED

BY SJOGREN'S?
6 Generalized Symptoms and Signs of Sjogren's
Syndrome 35
Nehad R. Soloman, Steven E. Carsons

V
CONTENTS
vi

7 The Dry Eye 41

Abha Gulati, Reza Dana
8 The Salivary Glands, Ears, Nose, and Larynx 52
Robert S. Lebovics
9 The Dry Mouth: A Dental Perspective on Sjogren's 58
Ava J. Wu, Troy E. Daniels
10 The Internal Organs in Sjogren's 68
Fotini C. Soliotis, Stuart S. Kassan,
Haralampos M. Moutsopoulos
11 Manifestations of Connective Tissue Diseases Seen in
Secondary Sjogren 's 81
Frederick B. Vivino
12 Useful Studies: Blood Tests, Imaging, Biopsies, and
Beyond 97
Roger A. Levy, Veronica S. Vilela, Mirhelen M. Abreu
13 How Can I Be Sure It's Really Sjogren's? 106
Robert F. Spiera, Harry Spiera

PART IV: THE MANAGEMENT OF SJOGREN'S SYNDROME

14 Treatment of Dry Eye 115
Michael A. Lemp
15 Treatment of Dry Mouth 121
Philip C. Fox
16 Systemic Therapies in Sjogren's 130
Aikaterini D. Chrysochou, Fotini C. Soliotis, Stuart S.
Kassan, Haralampos M. Moutsopoulos
17 Taming Sjogren's: Fighting Fatigue, Lifestyle Factors, and
Nondrug Management 145
Jeanne L. Melvin
18 Conquering Sjogren's 159
Joan E. Broderick, Evelyn /. Bromet
19 Complementary and Alternative Therapies for Sjogren's
Syndrome 175
Swamy Venuturupalli
 CONTENTS
Vll

20 How Are Drugs Tested for Sjogren's? 186

Stanley R. Pillemer
21 Adjunctive Measures, Comorbidities, and Reproductive
Issues in Sjogren's 193
Marilyn Solsky, Michael H. Weisman

PART V: OUTCOMES AND FUTURE DIRECTIONS

22 Can I Work? 207
David S. Hallegua
23 What Will Happen to Me? 215
Clio P. Mavragani, Stuart S. Kassan,
Haralampos M. Moutsopoulos
24 Is There Hope for a Cure? 219
Arthur Grayzel

PART VI: APPENDICES

1. For Further Reading 225
2. Resource Materials 232
Katherine Morland Hammitt
3. Products for Sjogren's patients 238
Bonnie T. Litton, Joan Manny,
Katherine Morland Hammitt
4. Glossary 250
Index 259
This page intentionally left blank
PREFACE

SJOGREN'S SYNDROME is an autoimmune disorder that afflicts women

and men of all ages, with perimenopausal women representing the
highest-risk group. Because it is a disorder that can manifest itself in
many different ways, Sjogren's syndrome may go undetected and undi-
agnosed for years, which in turn can lead to physical damage, disability,
and emotional suffering. This was the situation facing Elaine Harris in
1983 when she founded the Sjogren's Syndrome Foundation (SSF). Mrs.
Harris recognized that patients need to be knowledgeable about Sjo-
gren's syndrome if they are to successfully navigate the medical care
system to get the proper diagnosis and best possible treatment. Hence
in 1989, she spearheaded the effort within the SSF to produce the first
Sjogren's Syndrome Handbook. The first volume was soon followed by
a second edition, The New Sjogren's Syndrome Handbook, edited by
Steven Carsons, MD, and Elaine Harris, that took into account new
insights from research about this complex, multifaceted disease.
This new book, edited by Dr. Daniel J. Wallace in collaboration with
members of the foundation's medical and scientific advisory board, sub-
stantially expands and updates medical information on the causes and
consequences of Sjogren's syndrome. The various chapters incorporate
discoveries from recent cutting-edge investigations about the origins and
treatments of Sjogren's syndrome. There are chapters on the various or-
gan systems that can be affected, on possible psychological impacts, and
on various treatment options, as well as an appendix enumerating the
resources available for patients with the disease. The book also addresses
the concerns of many patients with Sjogren's syndrome who also have

ix
PREFACE
X

other chronic health problems, such as rheumatoid arthritis, chronic fa-

tigue syndrome, fibromyalgia, diabetes, high blood pressure, and osteo-
porosis. Thus, this book offers a comprehensive glimpse into the many
faces of Sjogren's and the patterns and consequences of comorbid
conditions.
It's no secret that if you don't ask the right questions, you won't get
the right answers. This book is specifically intended to give patients a
comprehensive vehicle from which to launch questions and evaluate
answers.
Sjogren's patients are all too aware that the disorder encompasses
more symptoms than just dry eyes and dry mouth. But many doctors
and health care providers are not aware of all of its potential somatic
sequelae. This book is thus intended to be a resource that patients can
share with their doctor and other health care providers so that they have
the most up-to-date information on diagnosis and treatment. And make
sure that family and friends read this book as well, so that they too
will better understand what their loved ones are experiencing from day
to day.
For the SSF, this new Handbook has special significance because ed-
ucating patients and their families about Sjogren's syndrome and increas-
ing public and professional awareness are two of our primary missions.
The SSF also has a third mission—that of promoting research into new
treatments and a cure. As an epidemiologist and Sjogren's patient, I am
optimistic that this new edition of the Handbook will stimulate clinical
investigators by exposing them to the diverse manifestations of the dis-
ease and by increasing their awareness of its public health impact.
Lastly, I hope that this book will be read and studied by the general
public, clinicians, psychologists, epidemiologists, and biomedical scien-
tists worldwide. We all have to work together to develop effective inter-
ventions to alleviate or avert the symptoms and—sooner rather than
later, I hope—to develop the means to prevent its occurrence.

Evelyn J. Bromet, PhD

Past chair, Sjogren's Syndrome Foundation Publications Committee
Professor of Psychiatry and Preventive Medicine
State University of New York, Stony Brook
CONTRIBUTORS

MIRHELEN MENDES ABREU, MD Rheumatology Discipline, Faculdade

de Ciencias Medicas, Universidade do Estado do Rio de Janeiro
JOAN E. BRODERICK, PhD Assistant Professor of Psychiatry and Behav-
ioral Science, Program Director, Applied Behavioral Medical Research Insti-
tute, State University of New York, Stony Brook
EVELYN J. BROMET, PhD Professor of Psychiatry and Preventive Medi-
cine, State University of New York, Stony Brook
STEVEN CARSONS, MD Chief, Division of Rheumatology, Allergy and
Immunology, Winthrop University Hospital, Mineola, New York
AKATERINI D. CHRYSOCHOU, MD Registrar in Rheumatology, De-
partment of Pathophysiology, School of Medicine, National University of
Athens
TROY E. DANIELS, DDS, MS Professor of Oral Medicine and Pathology,
Schools of Dentistry and Medicine, University of California, San Francisco
REZA DANA, MD, MPH Associate Professor of Ophthalmology, Harvard
University School of Medicine, Boston
PHILIP C. FOX, DDS President, P. C. Fox Consulting, LLC, and Visiting
Scientist, Carolinas Medical Center, Charlotte, North Carolina
ROBERT I. FOX, MD, PhD Department of Rheumatology, Scripps Me-
morial Hospital and Research Foundation, La Jolla, California
ARTHUR GRAYZEL, MD, MACR Emeritus Professor of Medicine, New
York University, and Past President, Sjogren's Syndrome Foundation
ABHA GULATI, MD Postdoctoral Research Fellow, Harvard University
School of Medicine, Boston

xi
CONTRIBUTORS
Xll

DAVID S. HALLEGUA, MD Clinical Instructor, Cedars-Sinai/UCLA School

of Medicine, Los Angeles
KATHERINE MORLAND HAMMTTT, MA Director of Research Devel-
opment and Public Policy, Sjogren's Syndrome Foundation, Bethesda,
Maryland
JOHN HARLEY, MD Professor of Medicine, University of Oklahoma Col-
lege of Medicine, Oklahoma City
LAMA HASHISH, MD Fellow in Rheumatology, University of Oklahoma
Health Sciences Center, Oklahoma City
STUART S. KASSAN, MD, FACP, FACR Clinical Professor of Medicine,
University of Colorado Health Sciences Center, Denver
ROBERT S. LEBOVICS, MD, FACS Head and Neck Surgical Group, New
York, and Surgical Consultant, National Institutes of Health, Bethesda,
Maryland
MICHAEL A. LEMP, MD Clinical Professor of Ophthalmology, George-
town and George Washington University Schools of Medicine, Washington,
DC
ROGER ABRAMINO LEVY, MD Rheumatology Discipline, Faculdade de
Ciencias Medicas, Universidade do Estado do Rio de Janeiro
CLIO P. MAVRAGANI, MD Fellow in Rheumatology, Department of Path-
ophysiology, School of Medicine, National University of Athens
JEANNE L. MELVESf, MS, OTR/L, FAOTA Past Program Manager, Fibro-
myalgia and Chronic Pain Program, Cedars-Sinai Medical Center, Los An-
geles; Private Practice, Beverly Hills, California
SERENA MORRISON, MD National Eye Institute, National Institutes of
Health, Bethesda, Maryland
HARALAMPOS M. MOUTSOPOULOS, MD, FACP, FRCP (Edin) Profes-
sor and Chairman, Department of Pathophysiology, School of Medicine,
National University of Athens
STANLEY R. PILLEMER, MD Sjogren's Syndrome Clinic, Gene Therapy
and Therapeutics Branch, National Institute of Dental and Craniofacial Re-
search, National Institutes of Health, Bethesda, Maryland
AMR SAWALHA, MD Rheumatology Fellow, University of Michigan, Ann
Arbor
JANINE SMITH, MD Deputy Clinical Director, National Eye Institute, Na-
tional Institutes of Health, Bethesda, Maryland
FOTINI C. SOLIOTIS, MD, MRCP (UK) Specialist Registrar in Rheuma-
tology, Royal Free Hospital, London, and Visiting Rheumatology Fellow,
 CONTRIBUTORS
xiii

Department of Pathophysiology, School of Medicine, National University of

Athens
NEHAD R. SOLOMAN, MD Rheumatology Fellow, Winthrop University
Hospital—Nassau University Medical Center, Mineola, New York
MARILYN A. SOLSKY, MD Attending Physician, Cedars-Sinai Medical
Center, Los Angeles
HARRY SPIERA, MD Clinical Professor of Medicine, Mount Sinai School
of Medicine, New York
ROBERT F. SPIERA, MD Associate Clinical Professor of Medicine, Albert
Einstein College of Medicine, Director of Rheumatology, Beth Israel Medical
Center, New York
NORMAN TALAL, MD Adjunct Professor of Medicine, New York Uni-
versity School of Medicine
SWAMY VENUTURUPALLI, MD Clinical Instructor, Cedars-Sinai Medical
Center, David Geffen School of Medicine at the University of California, Los
Angeles
VERONICA SILVA VILELA, MD Rheumatology Discipline, Faculdade de
Ciencias Medicas, Universidade do Estado do Rio de Janeiro
FREDERICK B. VTVTNO, MD, FACR Chief, Division of Rheumatology,
University of Pennsylvania Medical Center—Presbyterian, Penn Sjogren's
Syndrome Center, Philadelphia
DANIEL J. WALLACE, MD Clinical Professor of Medicine, Cedars-Sinai
Medical Center, David Geffen School of Medicine at the University of Cal-
ifornia, Los Angeles
MICHAEL H. WEISMAN, MD Director, Division of Rheumatology,
Cedars-Sinai Medical Center, David Geffen School of Medicine at the Uni-
versity of California, Los Angeles
AVA J. WU, DDS Associate Clinical Professor of Oral Medicine, University
of California, San Francisco School of Dentistry
This page intentionally left blank
Introduction:
Why Write a Book on
Sjogren's Syndrome?

ONE AMERICAN IN 70 has a mysterious eponymous condition known as

Sjogren's syndrome. Named after a Swedish ophthalmologist who de-
scribed its salient features 70 years ago, until recently Sjogren's resided
in a nosologic purgatory, with its manifestations misunderstood, under-
appreciated, and ignored. An international consensus has finally been
derived regarding what the term Sjogren's refers to. Now that organized
science has finally come to terms (literally) with this syndrome, a number
of insights elucidated by Sjogrenologists has been rapidly forthcoming.
The collective wisdom of these investigators has recently resulted in the
publication of prescient findings that serve to emphasize the importance
of research into this area and will have implications far beyond the syn-
drome itself. The Sjogren's Syndrome Foundation has endeavored to col-
lect the most relevant facts relating to the condition and publish them
in this handbook. It is our hope that researchers, clinicians, physicians,
allied health professionals, and dentists, as well as patients and their
families, will be able to use this resource.
Why should we write a book on Sjogren's? Sjogren's is an autoim-
mune condition that affects the whole body, especially musculoskeletal
and glandular tissues. It can exist as a primary condition or be a con-
comitant feature of rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, or other rheumatic disorders. According to the National
Institutes of Health, between 14 million and 22 million Americans have
an autoimmune condition, and 120 such conditions have been identified

xv
INTRODUCTION
XVI

to date. Approximately 20 percent of this group have Sjogren's syn-

drome. Sjogren's is perceived incorrectly as being rare and does not re-
ceive a strong focus in medical education. Its symptoms are subtle and
can be intermittent or nonspecific. It has been estimated that symptoms
are present for a mean of six years before it is properly diagnosed. This
is unfortunate, because a delayed diagnosis drastically alters quality of
life. For example, up to 50 percent of individuals with Sjogren's report
some degree of social isolation due to their symptoms, 62 percent have
serious dental complications (e.g., caries), and 38 percent report signif-
icant musculoskeletal impairments. Most importantly, approximately 5-
10 percent of those with primary Sjogren's develop a lymphoproliferative
malignancy. Sjogren's is almost unique among autoimmune disorders in
its ability to result in lymphoma in certain cases. This link could be
exploited by researchers to help us understand many of the common
immunologic features shared by cancer and autoimmune disorders.
Although Sjogren's is the second most common autoimmune condi-
tion affecting the musculoskeletal system, it ranks eighth in terms of
research funding. Studies aimed at finding the cause of and cure for this
syndrome will ultimately save taxpayers billions of dollars in lost wages
and productivity, as well as improve lifestyle for many. We hope that
our efforts will result in increased awareness and improved understand-
ing of this underappreciated syndrome. This especially applies to pa-
tients, their families, and physicians and allied health professionals as-
sisting in patient care.
This editor gratefully acknowledges the help of Katherine Hammitt,
Director of Research and Public Policy for the Sjogren's Syndrome Foun-
dation, for rounding up difficult-to-access statistics on the impact of the
syndrome in the United States. The sources supporting this data are
available from the national office upon request.

Daniel J. Wallace, MD
Clinical Professor of Medicine
Cedars-Sinai Medical Center
David Geffen School of Medicine at the
University of California, Los Angeles
November 2003
 PARTI

Introduction
and Definitions

The term Sjogren's does not tell the casual reader much about what the
syndrome is. In this section, we will learn that although its features have
been observed for hundreds of years, the first comprehensive description
of the syndrome did not take place until 1933. The publication of sta-
tistically validatable criteria for Sjogren's has finally enabled investiga-
tors to not only define what it consists of but elucidate who develops
the syndrome and how it is classified.
This page intentionally left blank
 Norman Talal, MD

1 The History of
Sjogren's Syndrome

THE FIRST CASE REPORT describing what we now know to be Sjogren's

syndrome appeared in 1882, when the German physician Theodor Leber
described filamentary keratitis (mucous strands that attach to and in-
flame the cornea). In 1888, surgeon Johann Mikulicz presented to the
Society for Scientific Medicine at Konigsberg the case of a 42-year-old
East Prussian farmer with painless parotid, lacrimal, and submandibular
gland swelling. The term Mikulicz's syndrome was commonly used to
describe other conditions associated with parotid gland swelling, such
as tuberculosis and lymphoma. Later that year, the London physician
W. B. Hadden presented to the Clinical Society the case of a 65-year-old
female with dry mouth and inability to tear whose condition responded
to tincture of jaborandi (pilocarpine).
It took 30 more years for evidence of a "syndrome" to emerge. In
1926, Henri Gougerot in Paris described three patients with salivary
gland enlargement and mucous membrane and vulvar atrophy and dry-
ness. In 1927, Houwer connected filamentary keratitis with arthritis.
And in 1933, the ophthalmologist Henrik Sjogren published his seminal
monograph (not translated into English until 1943) in which he de-
scribed a series of 19 patients with dry eye and dry mouth, of whom 13
also had arthritis. He coined the term keratoconjunctivitis sicca and used
rose bengal staining to study the ocular surface for abnormalities due to
dryness. Sjogren would go on to publish 15 more papers on the subject
and practice ophthalmology; he retired in 1965 and died in 1986.
In 1953, William Morgan and Benjamin Castleman rediscovered and

3
THE NEW SJOGREN'S SYNDROME HANDBOOK
4

popularized Sjogren's work (which had received little attention) and

elaborated upon its histopathologic features. Kurt Bloch and colleagues
noted that Sjogren's could exist by itself or be secondary to other au-
toimmune disorders in 1955. In the 1950s and 1960s, Joseph Bunim,
Norman Talal, and their students were instrumental in publishing the
clinical presentation, natural history, and laboratory features of large
numbers of Sjogren's patients and associating the syndrome with lym-
phoma. Even though Sjogren's antibodies (anti-Ro/SSA and anti-La/SSB)
were discovered in the late 1960s, it took another 30 years for auto-
immune Sjogren's to be differentiated from other causes of dry eye and
dry mouth, such as HIV infection and hepatitis, in official classifications.
This finally allowed clinical trials of medications for the treatment of
Sjogren's syndrome to be undertaken.
 Arthur Grayzel, MD

2 What Is Sjogren's
Syndrome?

IN THIS CHAPTER Sjogren's syndrome will be described and classified by

means of its signs, symptoms, autoimmune features, and autoantibodies.
This material is intended to be an overview, with both the concepts and
specific findings to be explained in more detail in the following chapters.

Definitions: Is Sjogren's Syndrome a Disease?

Why isn't Sjogren's syndrome a disease? It really is when viewed from
a current perspective. A syndrome, as defined in the Random House
Dictionary, is "a group of symptoms that characterizes a disease,"
whereas a disease, according to Stedman's Medical Dictionary, is "a
pathologic entity characterized by two of these criteria: a recognized
etiologic agent, an identifiable group of signs and symptoms, or consis-
tent anatomical alterations." Sjogren's syndrome has an identifiable
group of signs and symptoms and consistent anatomical alterations.

Signs and Symptoms

What are the signs and symptoms of Sjogren's syndrome? The most
distinctive ones, and those originally described by Henrik Sjogren, are
dry eye and dry mouth due to a lack of tear production and a lack of
saliva. The actual symptoms in the eye include a gritty sensation, the
sense of a foreign body in the eye, or itching; redness; and an increased
sensitivity to light that may make reading or watching television difficult.
The symptoms of lack of saliva may include difficulty chewing, swal-
lowing, and speaking, and severe, progressive dental caries. Patients

5
THE NEW SJOGREN'S SYNDROME HANDBOOK
6

TABLE 2.1 DISEASES ASSOCIATED

WITH SECONDARY SJOGREN'S

Rheumatoid arthritis
Systemic lupus erythematosus
Scleroderma
Vasculitis
Polymyositis/dermatomyositis
Primary biliary cirrhosis

find they are continually sipping water. These distinctive symptoms

have also been called the sicca syndrome (from the Latin siccus, meaning
"dry").
Other organs in the body that secrete moist material, usually as a
form of mucus, can also participate in this sicca syndrome and produce
troublesome symptoms in patients with Sjogren's. Among these organs
are the lungs, the upper airways such as the nose and throat, the vagina,
and the skin. These symptoms, however, are not used to define the
disease.
Finally, since Sjogren's is, as we shall see, a chronic inflammatory
disease, patients complain of symptoms common to all inflammatory
diseases, such as chronic and profound fatigue, as well as symptoms
common to all chronic diseases, such as depression. These symptoms,
while real and often disabling, are too nonspecific to define the disease.

Primary and Secondary Sjogren's

Henrik Sjogren also reported that 13 of the original 19 patients he
described had arthritis. Arthritis in patients with Sjogren's resembles
rheumatoid arthritis, but there is usually less swelling. On the other
hand, 15-30 percent of patients with unequivocal rheumatoid arthritis
may develop Sjogren's syndrome. This situation can be the source of
much confusion and has led to the concept of primary and secondary
Sjogren's. Patients have secondary Sjogren's when they also have another
autoimmune disease—most commonly rheumatoid arthritis (RA) or sys-
temic lupus erythematosus (SLE), but a large number of other autoim-
mune diseases qualify as well (Table 2.1).
 WHAT is SJOGREN'S SYNDROME?
7

Inflammation of the Glands

Patients with Sjogren's may have enlarged or swollen lacrimal or sal-
ivary glands. When one biopsies such glands and examines the tissue
microscopically, one sees that the glands are infiltrated by white blood
cells. These cells include B cells or antibody-producing lymphocytes, ac-
tivated T lymphocytes, and macrophages. Together these cells produce
a localized inflammation that is ultimately capable of destroying the
gland. This inflammatory process is similar, if not identical, to that in-
volving the islets of the pancreas in type 1 diabetes mellitus, the synovial
membrane lining the joints in rheumatoid arthritis, and the tissues spe-
cifically involved in the other autoimmune diseases. The inflammatory
infiltration of white blood cells can also be seen in the very small salivary
glands that line the lower lip. These minor salivary glands are very easy
to biopsy and are very helpful in making the diagnosis of Sjogren's. It
is useful to make the diagnosis early because glands that have been in-
vaded but not yet destroyed have enough residual glandular tissue to
respond to medication that stimulates salivary flow.

Autoimmunity
Autoimmune diseases are so named because in these diseases the B
lymphocytes produce antibodies to, and the T lymphocytes are activated
by, proteins or protein-nucleic acid complexes that are a normal com-
ponent of the body's own cells. The underlying reason for this abnormal
immune response is not completely known, nor in the case of Sjogren's
has the specific protein in the glandular tissue been identified for certain,
but enough is known to definitely classify Sjogren's as an autoimmune
disease. A hallmark of autoimmune diseases is the production of anti-
bodies circulating in the blood that are characteristic for the specific
autoimmune disease in question. This is true in Sjogren's, in which anti-
bodies to one or both of two protein-RNA complexes, called Ro/SSA
and La/SSB, are present in more than 60 percent and 40 percent, respec-
tively, of the serum from patients with Sjogren's. These autoantibodies
are also commonly found in the serum of patients with SLE, thereby
strengthening the concept of Sjogren's as an autoimmune disease.

The International Classification Criteria for Sjogren's

As one can see, Sjogren's fulfills the definition of a disease. It has a
definite and almost unique set of sicca symptoms, a definite anatomic-
THE NEW SJOGREN'S SYNDROME HANDBOOK
8

TABLE 2.2 REVISED EUROPEAN-AMERICAN CRITERIA FOR THE

CLASSIFICATION OF SJOGREN'S SYNDROME

1. Ocular symptoms (1 of 3)
• Dry eyes for longer than three months
• Sensation of a foreign body in the eye
• Use of artificial tears more often than three times a day
2. Oral symptoms (1 of 3)
• Dry mouth for longer than three months
• Swollen salivary glands
• Need liquids to swallow
3. Ocular tests (1 of 2)
• Unanesthetized Schirmer's «s 5 mm/5 minutes
• Vital dye staining
4. Positive lip biopsy (focus score 2* 1/4 mm2)
5. Oral tests (1 of 3)
• Unstimulated salivary flow rate ^ 0.1 ml/minute
• Abnormal parotid sialography
• Abnormal salivary scintigraphy
6. Positive anti-SSA and/or SSB

Diagnosis of primary Sjogren's syndrome requires 4 of 6 criteria, including item

4 or item 6. Diagnosis of secondary Sjogren's syndrome requires established con-
nective tissue disease and one sicca symptom plus 2 of 3 objective tests for dry
mouth and dry eye (items 3-5). Diagnosis of Sjogren's syndrome can be made in
patients who have no sicca symptoms if 3 of the 4 objective tests are fulfilled (items
3-6).
Modified from Ann Rheum Dis, 2002; 61:554-558.

pathologic basis, and a well-defined pair of autoantibodies. Still, Sjo-

gren's is not easy to diagnose and until very recently was not easy to
define in a way that would enable patients with Sjogren's to be studied
as a uniform group. Thus an international committee of experts was
assembled, under the auspices of the Sjogren's Syndrome Foundation, to
formulate diagnostic criteria so that patients who could be universally
considered to have Sjogren's could be entered into clinical trials and
other forms of research (Table 2.2). These classification criteria, pub-
lished in 2002, now define how one decides that a patient has unequiv-
ocal Sjogren's. Early in the disease, patients who actually have Sjogren's
may not meet all of the criteria, so bear in mind that the diagnosis and
treatment of any individual patient is a matter of clinical judgment.
It is important to rule out diseases that might also produce typical
Sjogren's findings. These conditions include:
 WHAT is SJOGREN'S SYNDROME?
9

• Previous radiation to the head and neck

• Lymphoma
• Sarcoidosis
• Hepatitis C infection
• HIV infection (AIDS)
• Graft-versus-host disease
• Medications that can cause dryness

Summing Up
Sjogren's is a relatively common and serious autoimmune disease that
involves an inflammatory immune destruction of the lacrimal and sali-
vary glands, producing a well-defined set of symptoms connected with
dry mouth and dry eye. Constitutional symptoms such as fatigue, joint
pain, and depression are also common.
 Daniel). Wallace, MD

3 Who Develops
Sjogren's Syndrome?

SINCE SJOGREN'S is A SYNDROME and a disease, ascertaining how many

people have it and elucidating its epidemiologic features have proven to
be difficult undertakings. Although there are a variety of reasons for this,
the most important is that an international consensus on how to define
Sjogren's has only recently been agreed upon. This chapter will review
how many people have Sjogren's and the principal identifying features
of those individuals, as well as issues relating to genetic predisposition.

How Many People Have Sjogren's?

Most professionals trained in estimating the numbers of people with
a disorder do so in terms of prevalence or incidence. Prevalence is defined
as the number of individuals per 100,000 people with a condition, while
incidence is the number per 100,000 who are diagnosed in a given year.
Some papers have published figures based upon self-reported dry eye or
dry mouth with arthritis. Others have relied upon older definitions of
Sjogren's, which could include dry eye, dry mouth, and arthritis as a
consequence of viral infections such as AIDS or hepatitis. If we restrict
ourselves to autoimmune Sjogren's, the Sjogren's Syndrome Foundation
estimates that 4 million people in the United States (out of 280 million)
have it. This breaks down to one person in 70.
Where did these numbers come from? In the United States, approx-
imately 0.5 percent of the population, or 1 person in 200, meets the
criteria for primary Sjogren's. To these 1.4 million Americans, we next
add the numbers who fulfill the criteria for other autoimmune conditions

10
 WHO DEVELOPS SJOGREN'S SYNDROME?
11

and who also have Sjogren's. Since approximately 30 percent overall

with rheumatoid arthritis (3 million), systemic lupus erythematosus (1
million), and scleroderma-related disorders and other musculoskeletal
conditions that are autoimmune diseases (1 million) also fulfill defini-
tions for Sjogren's, 1.5 million of these 5 million bring the total to 2.9
million. How does one account for the remaining 1.1 million? Simply
because Sjogren's is underreported. Many people (especially with mild
Sjogren's) never bother to complain to their doctor about their symp-
toms, or their health care professional lacks the education and experi-
ence to make a diagnosis.

Age, Race, Geography, Sex, and the Environment

The mean age of onset of Sjogren's is in the early 50s. Less than 5
percent of Sjogren's patients are under the age of 20, and nearly all of
these have anti-Ro/SSA antibodies. Sjogren's syndrome is probably found
in all races and ethnicities to a similar extent, although this has not been
well studied. In the last decade, published studies estimating the preva-
lence of the syndrome in China, Spain, Slovenia, Finland, Greece, and
the United States have demonstrated strikingly similar results. In all these
surveys, 90-95 percent of people with primary Sjogren's were female.
The percentage is slightly lower in secondary disease, but for all practical
purposes signs and symptoms of Sjogren's in males and females are the
same. Hormonal influences no doubt play a role in female predominance
of the syndrome, but this issue has not been adequately explored.
While chemical or environmental exposures play a role in other rheu-
matic disorders associated with Sjogren's syndrome, except for sun sen-
sitivity (which is directly related to antibodies to anti-Ro/SSA), no spe-
cific chemical or occupational endeavor correlates with its presence. One
exception would be increased symptoms of Sjogren's syndrome among
individuals residing in regions with a dry climate.

Primary and Secondary Sjogren's

Patients with primary Sjogren's by definition lack the obvious distin-
guishing features of rheumatoid arthritis, systemic lupus erythematosus,
or scleroderma (see Chapter 11). These include deforming arthritis, dis-
coid rashes, and tight skin. However, compared to individuals with sec-
ondary Sjogren's, there are certain features noted more commonly in
primary Sjogren's. These consist of Raynaud's phenomenon (color
THE NEW SJOGREN'S SYNDROME HANDBOOK
12

changes in the hands with cold exposure), salivary gland enlargement,

swollen lymph nodes, anti-Ro/SSA and anti-La/SSB positivity, central
nervous system dysfunction, and the potential for developing lymphoma
(44 times greater than in healthy individuals).

SJogren's, Genetics, and Other Autoimmune Diseases

Sjogren's syndrome can run in families. One Sjogren's patient in eight
will have a relative (usually female) with the condition. Only a handful
of reports of identical twins with Sjogren's have been published; clearly
the genetics of the syndrome are complex and multifactorial. A first-
degree relative (parent, sibling, or child) of someone with Sjogren's has
a 1-3 percent risk of developing the syndrome. Actually, these relatives
have a much higher risk for being diagnosed with autoimmune thyroid
disease or lupus than Sjogren's. In some studies, up to 30 percent of
Sjogren's patients have Hashimoto's thryoiditis or are hypothyroid.
Other autoimmune conditions found in 1-30 percent of Sjogren's pa-
tients include lupus, rheumatoid arthritis, scleroderma, inflammatory
myositis, type 1 diabetes, and multiple sclerosis. Occasionally, family
members of Sjogren's patients have antinuclear antibodies, rheumatoid
factor, and anti-Ro/SSA on blood testing without any symptoms of or
evidence for autoimmune disease. A variety of genetic markers on the
surface of cells known as human leukocyte antigen (HLA) haplotypes
also predispose individuals to Sjogren's. These are reviewed in Chapters
4 and 5.

Summing Up
One American in 70 has Sjogren's, evenly divided between primary
and secondary disease. This population is overwhelmingly female and
middle-aged. Sjogren's patients present an increased risk of having an-
other autoimmune disorder, a family member with autoimmune disease,
and lymphoma. No geographic, racial, environmental, or ethnic risk fac-
tors have been associated with primary Sjogren's syndrome.
 PART II

The Pathology of
Sjogren's Syndrome

What goes awry in our body that creates the symptoms and signs of
Sjogren's syndrome? In this section, we learn that Sjogren's results from
a dysfunctional immune system, which leads to inflammation and the
formation of autoantibodies. This is compounded by a pathologic pro-
cess resulting in dryness.
This section of the handbook is not an easy read. Indeed, many rheu-
matologists and immunologists have difficulty grappling with these con-
cepts. However, we have tried to present complex concepts in a relatively
easy-to-understand fashion.
This page intentionally left blank
 Janine Smith, MD
Serena Morrison, MD

4 What Leads to Dryness?

SJOGREN'S SYNDROME affects the exocrine glands, which produce saliva

and tears. Two of the key features of Sjogren's syndrome are dry eye
(also called keratoconjunctivitis sicca or KCS) and dry mouth (also called
xerostomia). What is the cause of this dryness? In this chapter, the nor-
mal function and disease-related dysfunction of the lacrimal and salivary
glands affected in Sjogren's syndrome will be discussed. Then theories
about the cause of the dryness will be considered.

The Lacrimal Gland

Since the source of human tears is the lacrimal gland, it is important
to know its normal anatomy and structure. The lacrimal gland is located
underneath the upper eyelid on the outer side near the temple. There are
two lobes of the lacrimal gland, the palpebral and the orbital. Some
smaller, accessory lacrimal glands are located on the conjunctiva (the
transparent membrane that covers the white part of the eye and which
gets red when irritated) (Table 4.1).
The lacrimal glands should constantly be producing tears while we
are performing our normal activities. Their purpose is to lubricate and
protect the surface of the eye. We are usually unaware of these tears,
called basal tears. Reflex or emergency tears are produced to flush and
lubricate the eye quickly if a particle or chemical gets into the eye, or
by emotion. Some people with dry eye have painful episodes due to
decreased amounts of basal tears, but because their lacrimal gland is not
completely damaged, they can still produce a normal amount of reflex
tears. They may even think they have excess tearing when in fact they
have dry eye. This is because as their eyes dry out from a lack of basal

15
THE NEW SJOGREN'S SYNDROME HANDBOOK
16

TABLE 4.1 EXOCRINE GLANDS

1. Lacrimal glands (produces tears)

a. Consists of palpebral lobe, orbital lobe, and accessory glands
b. Tear film layers: mucous, aqueous, lipid
2. Salivary glands (produces saliva)
a. Consists of parotid, submandibular, and sublingual glands
b. Secretions (mucous and serous)

tears, their eyes start to hurt, and this triggers a large amount of emer-
gency tears. One of the signs of severe damage to the lacrimal gland is
an inability to cry emotional or emergency tears.
In Sjogren's syndrome, the lacrimal gland does not produce a suffi-
cient volume of tear fluid. In addition, the tears produced are abnormal
in their consistency and do not lubricate or protect the surface of the
eye well. For example, the tears are unstable and often evaporate faster
than normal, leaving dry spots on the surface of the eye (see "Tear Film
Layers," below); people often feel as though their eyes are driest at the
end of the day. In addition, when reading or concentrating (such as when
working on a computer), people blink less, which allows the tear film
to evaporate more readily. Dry eye can result in a decreased ability to
read for extended periods of time.

Tear Film Maintenance

Before delving into the components of the tears, it is important to
mention the role of the eyelids and cornea in maintaining the tear layer.
Blinking spreads the tears over the eye and pushes debris toward the
inner corner of the eye so that it can drain into the nose through a small
opening in the eyelid, called the punctum. This is why mucus collects in
the corner of the eye.
Any malfunction in eyelid movement or decreased frequency of blink-
ing (as occurs with tasks that require visual attention, such as reading
or using the computer) can worsen dry eye symptoms. The cornea is like
the crystal on a watch. It is the transparent covering of the center portion
of the outer surface of the eye. Along with the tears, the cornea functions
as a lens to make vision sharp and clear. If the cornea is not smooth—
say, because of dryness—the tears are not well distributed, and blurred
vision can result.
 WHAT LEADS TO DRYNESS?
17

Tear Film Layers

Tears have three major components: mucous, aqueous (or liquid),
and lipid (or oily). These contents are arranged in layers, and the com-
ponents of each layer must be healthy and in balance for the tears to
function properly.
The mucous layer is the tear layer that is closest to the eye surface.
Special cells that are found in the conjunctiva, called goblet cells, create
mucin, which makes up this layer. This layer makes the tears slippery
and anchors them loosely to the surface of the cornea for protection. It
also helps prevent infection by keeping bacteria from sticking to the
surface of the eye.
The aqueous layer is the liquid component of the tears and hydrates
the mucous layer to form a sort of tear gel. This layer is produced by the
lacrimal gland and also lubricates and enhances the spreadability of the
tear film. The aqueous layer contains proteins such as lysozyme and
lactoferrin, which act like antibiotics and protect the eye from bacteria.
Tiny sebaceous (oil-producing) glands, called Meibomian glands, are
located along the margin of the eyelids, adjacent to the lashes. They
produce the lipid layer of the tear film, which enhances tear stability and
retards evaporation of the tears. If the lipid layer is completely removed,
the rate of evaporation is increased fourfold.

Salivary Glands
Sjogren's syndrome also affects the salivary glands. The principal
glands of salivation are the parotid, submandibular, and sublingual
glands, which are located in the cheek, under the chin, and under the
tongue, respectively. When these glands are functioning well, they can
produce 800-1,500 milliliters of saliva each day.
These glands produce two major types of secretions. The first is the
serous secretion, which contains ptyalin. Ptyalin is an enzyme that helps
digest starches. The second type is the mucous secretion, which contains
mucin for lubricating and protection.
So what is so important about saliva? The mouth is loaded with
bacteria that can cause infection, destroy tissue, and promote cavities
(dental caries). The saliva helps wash away the bacteria and food par-
ticles that the bacteria require to survive. Several factors within the saliva
even destroy bacteria.
Both the eye and the mouth encounter bacteria and environmental
THE NEW SJOGREN S SYNDROME HANDBOOK
18

irritants on an ongoing basis. Both the eyes and mouth need lubrication,
since they are constantly in motion. Saliva and tears contain all the nec-
essary elements to protect and lubricate the surfaces of the eyes and
mouth.

Theories of How Sjogren's Syndrome Develops

The production of tears and saliva is complicated. There are many
steps involved in the production of these complex fluids, and disruption
of this process can reduce the amount of the secretions and alter their
composition. Nerve fibers going into the glands, the acinar gland cells
(which are the cells that produce the fluid), the stromal cells (which
support the acinar cells), and even sex hormones all play a major role
in the production of saliva and tears. All aspects of these systems need
to be functioning and in concert with each other for normal tear and
saliva production.

Decrease in Glandular Cell Output

The lacrimal and salivary glands are exocrine glands. This means that
they have special cells, acinar cells, that empty into the body through
ducts that produce secretions. In order for the acinar cells to make liquid,
their relationship with the supporting stromal cells needs to be just right.
If this relationship is disrupted, secretion will decline.
Damage to these special gland cells can occur with an autoimmune
event. In these cases, for some unknown reason, the body's lymphocytes
(the body's immune defense cells) are attracted to the salivary and lac-
rimal glands. Once the lymphocytes gather in the exocrine glands, they
multiply and become the focus of inflammation. This inflammation is an
attack by the body on itself. For example, the lymphocytes release com-
pounds called cytokines that can injure the acinar cells and can even
cause the stromal cells to dysfunction and fail to support the acinar cells.
As a result, the gland cells become sick and can even die. When an acinar
cell dies, it releases its contents, which are recognized as foreign, and the
process can lead to even more inflammation. Sick gland cells do not
produce normal amounts or quality of fluid secretions.

Nerve Destruction
Normally messages sent through the nerve fibers to an exocrine gland
cause it to produce fluid. Damage to or dysfunction of the nerves can
 WHAT LEADS TO DRYNESS?
19

lead to surface dryness by disturbing the fluid production and release.

The salivary and lacrimal glands have a direct link to the brain through
these nerve fibers. Think of the brain as central command and the nerves
that link the brain and the glands as the messengers.
In one scenario, the central command (brain) gets confused; even
though it senses that tears or saliva need to be produced, it sends out
the wrong signal, and the tears and saliva are not made. Drugs can also
cause this confusion at the brain level. That is why many medicines often
have the side effect of dry mouth and dry eye.
The second situation is that the central command knows exactly what
needs to happen and sends the correct message through the messengers
(nerves), but it is the messengers that are confused this time. One pos-
sibility is that products of inflammation called cytokines cause paralysis
in these nerves. The result is that the glands that are supposed to be
stimulated fail to receive the message to make tears and saliva, although
they are capable of doing so.
A third possibility involves the cornea (the surface of the eye) and its
connection to the neural centers. If for some reason the cornea's nerves
are not working well, then no message will be sent to the brain that
tears are needed. Without the message that a problem exists, the brain
does not know to send a message to the lacrimal gland to increase se-
cretions. Any interruption of this feedback loop, which some researchers
call a servomechanism, can decrease the amount of secretions.

Sex Hormones
Another factor to be considered is the role of sex hormones. It is
known that autoimmunity is more prevalent in women than men. Could
this be because of the sex hormones? Women normally have higher levels
of estrogen and lower levels of androgens than men, and eye tissue has
components that specifically bind to sex hormones. It has been found
that with a decrease in local androgens, the inflammation mentioned
above goes unchecked. A certain amount of androgens are required to
maintain a noninflamed state in exocrine glands. For example, andro-
gens decrease the production of autoantibodies, and estrogens tend to
promote inflammation. Some studies have even found that hormone re-
placement therapy (with estrogen and progestin) is associated with dry
eye in postmenopausal women.
THE NEW SJOGREN'S SYNDROME HANDBOOK
20

Autoimmune Theories
In the foregoing section, we talked about how damage to the lacrimal
and salivary glands, a problem with the nervous system, or a disturbance
in the level or balance of sex hormones could result in dryness. One
prevalent theme for the cause of the damage is autoimmunity. But what
triggers the autoimmunity? Scientists are investigating many theories:
that the cause of Sjogren's syndrome may be an infectious trigger, a
genetic factor, a combination of factors, or a cause that we have not
even considered.

Extension of the Inflammatory Theory: Apoptosis

Apoptosis is the process by which a cell is programmed to self-
destruct. If the cells do not die when they are supposed to, problems
result. Cells that keep growing and dividing can become tumors and may
be malignant. What does this have to do with Sjogren's syndrome? In
Sjogren's, when the lymphocytes arrive at the fluid-producing lacrimal
or salivary gland, instead of just passing through, they are activated and
signal the immune system to initiate an attack. That is a problem in
itself. The second problem is that the lymphocytes are supposed to die
at some point but sometimes do not undergo natural death or apoptosis.
The lymphocytes accumulate in the glands and keep stimulating the im-
mune system to attack the glands. An accumulation of lymphocytes,
called a focus of inflammation, is characteristic in exocrine glands of
people with Sjogren's syndrome. This focus is what is found when a lip
biopsy of a minor salivary gland is performed in the diagnosis of Sjo-
gren's syndrome. An increased risk for Sjogren's syndrome may exist in
people whose cells are resistant to apoptosis.

Infections: Viral, Epstein-Barr-like, or H. pylori

Infection with viruses such as hepatitis C, human lymphotrophic leu-
kemia virus (HTLV-1), and human immunodeficiency virus (HIV) has
been known to cause dry eye. Therefore, viral infection in general (not
necessarily with the above viruses) has been identified as a potential
pathogenic mechanism for Sjogren's syndrome.
When viruses enter a person's body they can change the surfaces of
the normal cells so that the cells look like foreign invaders such as bac-
teria. As a result of changes in these markers, the cells are no longer
 WHAT LEADS TO DRYNESS?
21

recognized as self, and the body's defenses attack them as if they were
a foreign invader.
Another mechanism involves invading microbes, which sneak past
the body's defenses by disguising themselves as native cells. If the de-
fenses figure out this plan, they attack the invaders. Unfortunately, the
native cells are so similar to the microbes that the defense cells cannot
differentiate and therefore attack the native cells as well.
Epstein-Barr virus (EBV) is implicated as a contributor to Sjogren's
syndrome. The picture is not clear, and the only evidence is indirect.
EBV is a very common virus in the herpes family, and almost everyone
has had it at some point. Usually EBV infection is very mild. Most people
get flulike symptoms and swollen parotid glands but quickly recover. A
few people get more serious symptoms from EBV such as fatigue and
swollen lymph glands (including the spleen). This type of infection with
EBV is a condition called infectious mononucleosis. The virus enters the
salivary glands, which swell and can become painful.
The interesting part about EBV is that after its initial infection, it
quiets down and hides away. It tends to be dormant in the salivary gland.
Once in a while the EBV can be reactivated. This often happens only
when the person has immune system suppression (e.g., a patient who
chemotherapy and does not have normal defenses). If the virus reacti-
vates, it can trigger chronic inflammation (by revving up the immune
system), and an example of uncontrolled inflammation could be Sjo-
gren's syndrome. No conclusive evidence proves this theory correct, but
it is a possibility. Questions remain: since most people have EBV, why
do some reactivate, and why does this reactivation trigger inflammation?
Genetic background may be an important factor in determining who is
susceptible to a viral infection triggering an abnormal inflammatory
response.
Some researchers are looking for an association between Helicobacter
pylori and Sjogren's syndrome. H. pylori is more commonly known as
the bacterium that causes stomach ulcers. Interestingly, H. pylori is being
recognized as the cause of infections in many other parts of the body as
well.
A lot of controversy exists as to whether H. pylori plays any role in
the development of Sjogren's syndrome. Some studies found an increased
prevalence of H. pylori infections in Sjogren's syndrome patients, but
THE NEW SJOGREN'S SYNDROME HANDBOOK
22

other studies could not confirm this. The trouble with this research is
that once H. pylori triggers an infection, it is often difficult to detect at
a later time. Further research into the role of H. pylori infection in Sjo-
gren's syndrome is ongoing.

Genetics
As mentioned above, the environment (such as viruses and bacteria)
is a consideration for the cause of Sjogren's syndrome, but another big
factor is the person's genetic background. Does something about the
genetic makeup of someone with Sjogren's syndrome make that person
more susceptible to autoimmune disease? For unknown reasons, some
patterns of genes make certain people more susceptible than others to
autoimmune diseases such as Sjogren's syndrome. When a certain mix
occurs between the genes and the environment, then autoimmune dis-
eases can be triggered.
For example, each gland cell has a protein on its surface: a human
leukocyte antigen (HLA). Think of this as the gland cell's identification
card. People have a certain type of HLA on all of their cells, including
those in the exocrine glands. These HLA types have been labeled as
HLA-DR1, HLA-DR2, and so on. All the different HLA types should
signal that the gland cell is friendly to the lymphocyte. But for some
unknown reason, the lymphocytes sometimes get confused when reading
the HLA-DR3 gene in Caucasians, which results in a higher incidence
of Sjogren's syndrome in this race. The HLA-DR3 antigen is most often
found in patients who develop antibodies to Ro/SSA or La/SSB. Inter-
estingly, HLA-DR3 in other races does not seem to have the same effect;
other HLA-DR genes trigger Sjogren's syndrome in other races.

ICA-69
As another example, ICA-69 is a recently identified self-antigen, or
component of a specific tissue or cell that is being mistakenly recognized
as foreign by the immune system. The actual function of ICA-69 is un-
known, but it is known to act as a self-antigen in the salivary glands,
lacrimal glands, pancreatic cells, and nervous system tissue. It may have
been altered by infection or inflammation or it may be in its natural
form. An example of this was mentioned above in the virus section. As
a virus invades the body, it can cause changes in native cells and create
 WHAT LEADS TO DRYNESS?
23

a self-antigen. The native cells are then no longer recognized by the

body's defense system, a fact that leads to self-attack.
Of interest is that some patients with Sjogren's syndrome develop
complications involving the nervous system. Autoimmune targeting of
ICA-69 may play a role in this process, since ICA-69 is also expressed
in nervous tissue.

Summing Up
In this chapter the normal function of the exocrine glands affected
by Sjogren's syndrome has been detailed. An intricate pathway exists to
create the right amount, components and consistency of tears and saliva.
If this process is disrupted in any way, the production and components
of the secretions can be altered. We know an autoimmune process is
involved, but many possibilities exist as to why Sjogren's syndrome starts
and how it damages the body. The cause of the body's attack on itself
remains unclear, and a combination of infection and genetics is being
investigated as a potential disease-inducing factor.
With further research, the answer may be revealed to be one of the
proposed theories, but more likely it will be some combination of these
factors. Inflammation clearly results in malfunction of the fluid-
producing glands, but the cause of the inflammation is unclear. For now,
the exact cause of the Sjogren's syndrome remains unknown.
 Lama Hashish, MD
Amr Sawalha, MD
John B. Hariey, MD, PhD
Robert Fox, MD, PhD

5 Sjogren's Syndrome:
A Genetic and
Immunologic
Perspective

SJOGREN'S SYNDROME is an autoimmune disorder that presents when

one's genetic predisposition combines with environmental or infectious
factors. Further, there are neural and hormonal influences. This chapter
reviews how these factors interact with the immune system to produce
Sjogren's syndrome.

The Genetics of Sjogren's

Several genetic and environmental factors are involved in the path-
ogenesis of primary Sjogren's syndrome. Indeed, interaction between sus-
ceptibility genes and the various environmental factors are thought to
define the conditions that make this disease possible. Similar to many
other autoimmune disorders, Sjogren's syndrome appears to be a com-
plicated disease with many different susceptibility genes and environ-
mental factors, most of which are unknown.
The evidence for genetic susceptibility was first recognized in a family
that had Sjogren's syndrome involving three generations at once; the case
was published in 1937. More recent advances in genetics research
methodology have allowed the identification of strong associations with
human histocompatibility antigen (HLA) as well as other genes. (The
HLA allele associations that have been replicated, and thus confirmed,
include HLA-DRB1*0301, HLA-DRB1*1501, HLA-DQA1*0103,
HLA-DQA1*0501, HLA-DQB 1*0201, and HLA-DQB 1*0601.)

24
 A GENETIC AND IMMUNOLOGIC PERSPECTIVE
_ _
25

TABLE 5.1 IMPORTANT COMPONENTS OF THE IMMUNE

SYSTEM IN SJOGREN'S SYNDROME

1. White blood cells

a. Granulocytes—promote acute inflammation
b. Lymphocytes—promote chronic inflammation
i. T cells (memory cells)
ii. B cells (promote production of autoantibodies)
2. Proteins
a. Albumin—carrier proteins, decreased in chronic disease
b. Globulin—levels increased in inflammation
i. Alpha globulins
ii. Beta globulins
iii. Gamma globulins—IgG, IgM, IgD, IgA, and IgE
3. Important autoantibodies in Sjogren's
a. Anti-Ro/SSA
b. Anti-La/SSB
c. Rheumatoid factor
d. Antinuclear antibody
e. Anti-muscarinic receptor antibody

Mutations in various cytokines (which act as cell messengers) and

related genes have also been associated with primary Sjogren's syn-
drome. Examples include interleukin-10 (IL-10) and interleukin-6 (IL-
6). Other genetic associations reported include polymorphisms in the
complement component mannose-binding lectin (MBL), tumor necrosis
factor-alpha (TNF-ct), and transporters associated with antigen process-
ing (TAP2). In addition, mutations in Ro52 and glutathione S-transferase
Ml (GSTMl) genes have been reported. The individual role of each of
these genes in Sjogren's syndrome is yet to be understood.

The Pathogenic Role of Autoantibodies in Sjogren's

It is thought that the pathogenesis of this disorder includes two pro-
cesses. There is a T-lymphocyte-mediated process that leads to direct cell
destruction and a B-lymphocyte activation process that leads to the pro-
duction of the autoantibodies (see Table 5.1 and Figure 5.1).
Destruction of the salivary and lacrimal glands and other target tis-
sues is attributed to focal lymphocytic infiltration, which involves pri-
marily T-lymphocytes (a kind of white blood cell that plays a role in
immune system function).
There are a number of different kinds of autoantibodies in Sjogren's
syndrome. Antibodies are proteins that we make to defend against all
Figure 5.1. The immune response in Sjogren's syndrome
 A GENETIC AND IMMUNOLOGIC PERSPECTIVE
27

kinds of different infections. They are also called immunoglobulins and

have a few major types: IgG, IgM, IgA, and IgE. (Immunoglobulin E
causes many kinds of allergy.) Antibodies are not usually supposed to
bind to something that we are made of. When they do, they are called
autoantibodies. Most of the known autoantibodies in Sjogren's are of
the IgG type, though at least some are IgA.
Autoantibodies have names that tell us what they bind to, but this
does not reveal what they do or how they work. Anti-Ro/SSA, anti-La/
SSB, rheumatoid factor, antinuclear antibody, and anti-muscarinic recep-
tor are found in the bloodstream of a substantial fraction of Sjogren's
syndrome patients. The rinding of an autoantibody is frequently an in-
dication that the immune system may be involved in the disease process.
There is some evidence that these autoantibodies are important patho-
genic factors in damage to target organs as well as the extraglandular
manifestations.
The antibodies most commonly looked for are the antinuclear anti-
body (ANA) and the Sjogren's-associated antibodies, anti-Ro/SSA and
anti-La/SSB; the latter two are even used in the recent diagnostic criteria.
However, there is a great deal of confusion about the meaning of a
positive antibody (especially if it is weak) and if Sjogren's can exist if
the antibody is negative. There is a common misunderstanding that an-
tinuclear antibodies are both sensitive and specific. In fact, there is a
relatively high frequency of antinuclear autoantibodies in otherwise
healthy individuals, patients with liver disease, and patients with carci-
noma. The frequency of ANA in putatively normal individuals can be
as high as 31.7 percent of individuals at a 1:40 serum dilution, 13.3
percent at 1:80, 5.0 percent at 1:160, and 3.3 percent at 1:320. However,
it has been calculated that the risk of an individual with ANA 1:320
developing systemic lupus erythematosus or Sjogren's during a ten-year
follow-up period is less than 5 percent.
The role of antibodies against nuclear antigens (ANA) as well as anti-
Ro/SSA and anti-La/SSB in the pathogenesis of Sjogren's has always been
puzzling, since these antigens are found in all nucleated cells. The pur-
pose of the immune system has always been assumed to distinguish self
from non-self in a strict manner. Until relatively recently, it was assumed
that the body did not generate antibodies against its own antigens. How-
ever, we now recognize that the body continually makes an initial re-
sponse against many self-antigens, but at a low level. This is reflected in
the high frequency of low-titer autoantibodies described above and the
THE NEW SJOGREN'S SYNDROME HANDBOOK
28

observation that most patients with a higher-titer ANA (such as ANA

1:320) do not actually go on to get Sjogren's or lupus. The key question
then becomes why some of these anti-self responses escalate and con-
tribute to disease, while other anti-self immune reactions just go away.
Anti-muscarinic receptor antibody is the most interesting from the
perspective of current thinking. This antibody is thought to block the
action of the nerves that go to the salivary and lacrimal glands, thereby
reducing the production of saliva and tears. The detection of anti-
muscarinic receptor antibodies is very difficult and is performed in only
a few research laboratories around the world.
The primary cause of Sjogren's syndrome has not been identified, but
as noted above, several factors are thought to contribute to the patho-
genesis of this disorder. Those factors are genetic and environmental,
including hormone effects and viral infections.

Hormonal Influences
Estrogen activity may be involved in developing dry mouth and dry
eye symptoms because of the following factors:

• Sjogren's affects women much more frequently than men.

• The symptoms of dry mouth and dry eye are more prevalent in pa-
tients who are receiving hormone replacement therapy than those
who are not.

Viruses, the Immune System, and Sjogren's

It is thought that some viral infections could have a role in the path-
ogenesis of Sjogren's syndrome by the following mechanism. After a vi-
rus or bacterium enters the body, an immune reaction is almost always
activated. (Parasitic infections are less of a threat to us than they were
to our forebears.) Thankfully, the infection is almost always defeated
and the person returns to normal health. Sometimes this initial response
against the virus or bacterium becomes chronic because the body cannot
clear the infection, and sometimes the immune response heads off in
the direction of autoimmunity. Examples of infections that can cause
chronic problems include streptococci (a bacterium that can cause rheu-
matic fever), human immunodeficiency virus (HIV), and hepatitis C virus
(chronic hepatitis). Indeed, hepatitis C virus can cause dry eye, dry
mouth, and arthritis, all symptoms found in Sjogren's syndrome.
 A GENETIC AND IMMUNOLOGIC PERSPECTIVE
29

Epstein-Barr Virus
Epstein-Barr virus has been suggested as a possible activator or co-
factor in the development of Sjogren's syndrome. Once we are infected
with this virus, we remain infected for the rest of our lives, and nearly
everyone is infected. The evidence for this virus being important in Sjo-
gren's syndrome has not yet convinced most scientists, and it remains an
idea that is not generally accepted.

Hepatitis C
Chronic hepatitis C can cause symptoms that are similar to Sjogren's
syndrome (dry mouth, dry eye, and arthritis, occurring in association
with an enlarged parotid gland with lymphocytic infiltration). Anti-Ro/
SSA and anti-La/SSB, which are present in the sera of Sjogren's syndrome
patients, are typically absent in the sera of the patient with chronic hep-
atitis C infection, as are the usual pathologic findings of autoimmune
Sjogren's syndrome. Most experts in Sjogren's syndrome lean toward
including hepatitis C as one of the differential diagnoses of dry eye-dry
mouth syndrome, as other features distinguish it.

Retroviruses
Two retroviruses, human immunodeficiency virus (HIV) and human
T-cell leukemia virus (HTLV-1), are known to be causes of a syndrome
that presents with a clinical picture similar to that seen in Sjogren's syn-
drome. Those viruses affect males more than females, and the autoan-
tibodies that define Sjogren's syndrome have not been found in the pa-
tients who carry those viruses. HLTV-1 may cause muscle deterioration
and causes a condition with the unattractive name of tropical spastic
paraparesis. This virus is endemic in some parts of the world.
The medical literature now has many, many reports describing the
dry eye and mouth associated with HIV infection. Both Sjogren's and
HIV infection have diffuse lymphocyte infiltration in the affected tissues.
However, the kind of lymphocyte that dominates in HIV-infected pa-
tients tends to be different than those that dominate in Sjogren's syn-
drome. The characteristic autoantibodies, anti-Ro/SSA and anti-La/SSB,
are typically not found in HIV-infected patients. There are other gene-
related differences as well. Consequently, HIV-infected patients are not
usually considered to have Sjogren's syndrome, but there is some dis-
agreement among doctors on this point.
THE NEW SJOGREN'S SYNDROME HANDBOOK
30

Figure 5.2. Normal Tearing or Salivation Secretion requires a functional unit

Background: The Functional Circuit That Links Ocular/

Oral Symptoms and Secretory Function
In order to understand the spectrum of disorders that contribute to
dry eye and mouth, it is important to recognize that these symptoms
result from an imbalance in a functional circuit that controls lacrimal
and salivary function. The functional circuit can be considered to start
at the mucosal membrane (either the ocular surface or buccal mucosal
surface) where the patient has decreased aqueous secretions (Figure 5.2).
These highly innervated surfaces send unmyelinated nerves to specific
regions of the midbrain, termed the lacrimatory and salvatory nuclei.
This midbrain region sends signals to the cortex, where dryness is sensed,
and receives input from cortical centers that reflect input such as de-
pression or stress reactions associated with dryness. The clearest evidence
of these cortical inputs is the classical Pavlovian response of salivation
in response to other cortical stimuli. After the midbrain receives input
from the mucosa and higher cortical centers, efferent (outgoing) nerves
that innervate the glands using cholinergic neurotransmitters (especially
acetylcholine and vasoactive intestinal peptide) and blood vessels using
adrenergic (adrenalin-containing) neurotransmitters are activated. The
presence of inflammatory infiltrates in the glands contributes to inade-
 A GENETIC AND IMMUNOLOGIC PERSPECTIVE
31

Figure 5.3. A salivary gland seen in a patient with Sjogren's syndrome demon-
strating inflammation (A), as compared with a normal gland (B).

quate secretory response not only by destruction of glandular elements

but also by interfering with effective release of neurotransmitters by the
nerves in the end organ and the response of the glandular cells at the
level of post-receptor signaling. As a result, there is decreased activation
of the receptors that subsequently produce the energy source for water
transport. Thus, a key point in the pathogenesis of Sjogren's is the ob-
servation that the salivary and lacrimal glands are not totally destroyed
and local immune-generated release of cytokines, autoantibodies, and
other chemicals leads to dysfunction of the residual glands.
Although rheumatologists are talking about autoantibodies and acute
phase reactants, the patient has complaints about dry, painful eyes and
mouth. In the initial stages of the disorder, patients are describing in-
creased friction as the upper eyelid traverses the globe or the tongue
moves over the buccal mucosa. For example, the upper eyelid normally
traverses the globe on a carpet of lubricating tear film, composed of a
mixture of aqueous and mucous secretions. When the aqueous tear or
saliva component is deficient, the patient senses increased friction. The
friction between the upper lids can be great enough so the surface com-
ponents of the conjunctiva adhere to the upper lid and are torn off by
upper-lid motion. Defects of the surface mucin layer are detected by the
retention of rose bengal, which is a characteristic test for keratocon-
junctivitis sicca (dry eye). The ocular surface becomes a site of chronic
THE NEW SJOGREN'S SYNDROME HANDBOOK
32

inflammation, similar to a wound. From these regions arise unmyelin-

ated afferent (incoming) nerves, which eventually end in specific regions
of the midbrain, including the lacrimatory/salvatory nuclei. Neural sig-
nals are subsequently sent to the cortex, where pain is sensed.
In summary, symptoms of dryness can result from disruption of any
portion of the functional circuit. In Sjogren's syndrome, the dryness in
part results from autoimmune destruction of the salivary gland (which we
see as an abnormal Sjogren's lip biopsy in Figure 5.3). However, dryness
can also result from increased evaporative loss from the surface of the eye
(termed non-Sjogren's keratoconjunctivitis sicca), or a sensation of dry-
ness that originates from imbalance of neurotransmitters within the cen-
ters of the brain that control tear and/or saliva function. The latter causes
of dryness, termed central, can include drugs with anti-cholinergic side ef-
fects, including over-the-counter cold remedies (e.g., antihistamines) and
sleeping aids as well as medications used for conditions of depression or
neuropathy (including amitriptyline or nortriptyline), for muscle spasm,
for blood pressure, or to control seizures. Also, a variety of poorly under-
stood processes that may influence the production of neurotransmitters in
the brain including demyelinating disorders such as multiple sclerosis, de-
pression, the process of aging, and even Alzheimer's disease, and the
symptom complex termed fibromyalgia may lead to dryness by affecting
the centers of the brain that control salivation and tearing or the sensation
of these problems by the higher brain cortical centers.

Summing Up
Sjogren's syndrome results from the interaction of genetic and envi-
ronmental factors. It is likely that multiple genes interact to predispose
an individual to Sjogren's syndrome. However, even when all of the
genes are present (as in identical twins), it is clear that other (presumed)
environmental factors play a role, since less than 20 percent of identical
twins are concordant for the disorder. No single environmental agent
has been identified despite an intensive 20-year search. It is more likely
that many different agents can stimulate the innate immune system,
which is a primitive immune system, and thus prime the more sophis-
ticated acquired immune system to perpetuate the autoimmune process.
The molecules that define the innate system and the acquired immune
system and that link the two systems are the subject of intensive research.
It is hoped that an understanding of these molecular events will lead to
a new generation of therapies for patients.
 PART HI

Where and How

Can the Body
be Affected
by Sjogren's?

Sjogren's syndrome can affect just about any part of the body. Although
most patients are aware of its impact on the eyes, ears, nose, and throat,
pathologic changes occur in the heart, lung, kidney, liver, skin, and
joints. Sjogren's is also associated with other rheumatic conditions. Part
3 takes the reader on a tour of the body and shows how Sjogren's can
affect different tissues. This is followed by an exploration of the testing
that can confirm the diagnosis, and a discussion of conditions that mimic
Sjogren's.
This page intentionally left blank
 Nehad R. Soloman, MD
Steven E. Carsons, MD

6 Generalized Symptoms
and Signs of Sjogren's
Syndrome

IT HAS BEEN LONG realized that Sjogren's syndrome is a complex disease,

with the principal symptoms being dry eye and dry mouth. Over the
course of many years it has been realized that there are a myriad of
extraglandular symptoms encompassed by this disorder. These may in-
clude constitutional symptoms such as fatigue, achiness, fever, adeno-
pathy (swollen glands), myalgias (muscle pain), and weight loss. Dryness
in this disease is predominantly of the eyes and mouth, but it is not
limited to these areas and commonly occurs in the skin, respiratory tract,
and vaginal lining. Patients with Sjogren's syndrome may also suffer
from shortness of breath, cough, joint pain and swelling, rashes, reflux,
muscle weakness, urinary dysfunction, peripheral or central nervous sys-
tem disease, thyroid disease, and even depression. This chapter will pro-
vide a brief overview, with focus on the various extraglandular signs and
symptoms associated with Sjogren's syndrome (Table 6.1), whereas the
next chapters will focus on specific organ manifestations.
Constitutional symptoms are common in Sjogren's syndrome and
may be in part due to the general immune response and persistent in-
flammation. High levels of autoantibodies circulating in the body me-
diate this inflammatory immune response.

Skin Problems
The skin is a common site for signs of Sjogren's syndrome. Some
symptoms and signs involving the skin include dry skin as well as a

35
THE NEW SJOGREN'S SYNDROME HANDBOOK
36

TABLE 6.1 GENERAL EXTRAGLANDULAR

SYMPTOMS AND SIGNS OF
SJOGREN'S SYNDROME

Symptoms Signs

Fatigue Adenopathy
Myalgias Rash
Fever Mouth sores
Cough Raynaud's phenomenon
Shortness of breath Weight loss
Dysphagia Synovitis
Reflux Diminished reflexes
Neuropathy Purpura
Vaginal dryness Cracked skin
Dysuria Hives
Achiness Vasculitis
Joint pain Pneumonitis
Muscle weakness Hypokalemia
Numbness
Tingling
Depression
Itchy skin
Epigastric pain
Nocturia
Renal colic
Painful intercourse

whole host of rashes and discoloration. When the glands in the skin are
affected by Sjogren's syndrome, the result is dryness, which may occur
in about 50 percent of patients. This dryness can often lead to cracking
and fissuring. This may result in infection, with areas of the skin becom-
ing reddened and itchy. When blood vessels in the skin become inflamed
due to white blood cells infiltrating and destroying their walls, the result
is vasculitis. This is a rash that resembles red pinpoint spots located over
the lower parts of the extremities, particularly the legs. Vasculitis usually
occurs over the course of several years following the diagnosis of Sjo-
gren's syndrome. Occasionally the rash may be raised, purple, and pain-
ful. This is referred to as palpable purpura. Hypergammaglobulinemic
purpura is another type of skin rash; its orange-brown color results from
high levels of immunoglobulin circulating in the blood, causing the
blood to be thicker than normal and the red blood cells to leak through
 GENERALIZED SYMPTOMS AND SIGNS OF SJOGREN'S SYNDROME
37

the superficial blood vessels of the skin. Urticaria or hives can also occur
in some patients with Sjogren's syndrome and generally do not itch.

Raynaud's Phenomenon
Another common sign seen in Sjogren's syndrome is Raynaud's phe-
nomenon, which is a three-part response that classically occurs when
extremities are exposed to the cold. Generally, the fingers will initially
turn white with constriction of blood vessels, then turn blue as a result
of pooling of blood in the veins, and finally red when fresh blood reen-
ters the region. Raynaud's phenomenon is seen not only in Sjogren's
syndrome but also in a variety of other connective tissue disorders.

Airway Problems
The upper airway, which includes the mouth, nose, and throat, and
the lower airway, including the windpipe and lungs, are commonly in-
volved in Sjogren's syndrome. The internal linings of the upper and
lower airways, which contain mucus glands, get flooded with lympho-
cytes (white blood cells) and fail to function properly, leading to dryness.
Mucus gland dysfunction may result in laryngotracheobronchitis, which
is a chronic inflammatory condition involving the voice box, windpipe,
and bronchial tubes. As a result of this inflammation, patients often
experience a dry cough. An inability to clear the mucus may result in
pneumonia, with fever, chills, and cough being the predominant symp-
toms of this illness. In addition to pneumonia, patients with Sjogren's
syndrome may experience shortness of breath due to a condition known
as interstitial pneumonitis. This is an inflammation of the supporting
tissue around the alveoli (air sacs) of the lungs. It is important to note
that this is a slow process that occurs over years. This type of lung
involvement is usually found on X-rays and pulmonary function testing.

Arthritis
Approximately 50 percent of patients with Sjogren's syndrome will
experience episodes of arthritis during the course of their disease. These
episodes may present as symptoms of arthralgia (joint pain), morning
stiffness, or synovitis (intermittent swelling of the joints). X-rays gener-
ally tend not to show destructive changes. Some patients with primary
Sjogren's syndrome will develop a rheumatoid-like arthritis before the
THE NEW SJOGREN'S SYNDROME HANDBOOK
38

onset of classic Sjogren's symptoms, while true rheumatoid arthritis can

also be complicated by the development of dry eye and dry mouth,
termed secondary Sjogren's syndrome. In fact, when Henrik Sjogren first
described the symptoms of dryness, it was in a group of patients who
had an established diagnosis of rheumatoid arthritis. Not surprisingly,
the two disorders are sometimes difficult to tell apart.

Gastrointestinal Problems
Sjogren's syndrome may also involve the gastrointestinal tract, lead-
ing to symptoms of reflux and dysphagia. Reflux, which is the regurgi-
tation of acid into the esophagus, is thought to result from the inappro-
priate relaxation of the lower esophageal sphincter. This may be due in
part to a dysfunction in the autonomic nervous system, which controls
the valve. Lymphocytes infiltrating the nerves may be the cause of this
dysfunction. The clinical symptom of reflux is a burning or discomfort
in the epigastric area (mid-chest). Excessive acid in the mouth in addition
to the existing dryness can also commonly result in mouth sores. Dys-
phagia (difficulty swallowing) is thought to occur by one of two mech-
anisms. The first is due to dryness of the pharynx and esophagus, leading
to functional inability to swallow. The second mechanism may be due
to an actual dysfunction in the movements of the esophagus controlled
by the autonomic nervous system. The resultant clinical symptoms in-
clude nausea and epigastric pain.
Inflammation of the pancreas has rarely been reported in association
with Sjogren's syndrome. Symptoms of this manifestation include nau-
sea, fever, and burning abdominal pain with a radiation to the back.
Liver disease has also been reported in some patients with Sjogren's syn-
drome. Such diseases include autoimmune hepatitis and primary biliary
cirrhosis. Patients with these diseases are frequently without symptoms
and are diagnosed by routine laboratory testing. With progression of
liver disease, some signs and symptoms include pruritis (itching), pre-
dominantly of the palms and soles, jaundice (yellowing of skin) and
malabsorption of fat.

Kidney Problems
Patients who have kidney involvement present with symptoms of
muscle weakness as a result of an electrolyte imbalance known as hy-
 GENERALIZED SYMPTOMS AND SIGNS OF SJOGREN'S SYNDROME
39

pokalemia (low potassium). This electrolyte imbalance often leads to the

development of kidney stones, which often cause symptoms of renal
colic. Renal colic is recurrent, sharp back pain in the area of the kidney.
Interstitial cystitis, which is a nonbacterial (sterile) inflammation of the
bladder, can also been seen in Sjogren's syndrome and presents with
symptoms such as frequent nighttime urination, suprapubic pain, and
dysuria (pain on urination).

Nerve Problems
In rare instances, the nervous system may be involved in Sjogren's
syndrome. Symptoms of peripheral neuropathy include numbness, tin-
gling, and burning of the extremities. This may also on rare occasion
lead to difficulty with balance. Peripheral neuropathy can also result in
symptoms of muscle weakness or abnormal body movements. On phys-
ical exam, reflexes may be absent. Cranial neuropathy may also be seen
in primary Sjogren's syndrome. One of the most common nerves to be
affected is the trigeminal nerve, which supplies sensation to the face and
the surface of the eyes as well as to the organs of taste and smell. When
this nerve is affected, the result is facial pain or a loss of sensation, taste,
or smell. On very rare occasion the central nervous system may also be
involved with symptoms resembling those of multiple sclerosis, such as
difficulty with speech, balance, blurry vision, movement, and coordina-
tion, as well as fine motor skills.

Lymphoma
Lymphoma is another serious disease that can develop in Sjogren's
syndrome patients. It manifests as persistent fever, weight loss, and ad-
enopathy of the glands of the neck, armpits, or groin, or swelling and
induration of the salivary glands. Benign lymphoproliferative disease
(abnormally increased white blood cells in blood or tissue) can often
lead to similar symptoms of gland swelling without true lymphoma.

Thyroid Disease
Thyroid disease may also accompany Sjogren's syndrome. The com-
mon symptoms of a hypofunctional thyroid include weight gain, cold
intolerance, deepening of the voice, coarse hair, excessive fatigue, and
depression. Hyperfunctional thyroid disease, known as Graves' disease,
THE NEW SJOGREN'S SYNDROME HANDBOOK
40

can also occur, with symptoms of sweating, palpitations, thinning of the

hair, and weight loss. It is important to note that thyroid disease may
also occur independently of Sjogren's syndrome.

Vaginal Symptoms
As mentioned previously, dryness is the hallmark of this disease. This
dryness can occur on the vaginal surface, thereby decreasing the amount
of natural lubrication and resulting in painful intercourse and vaginal
burning. Excessive vaginal dryness can also result in various infections.

Depression
Depression has not been studied in Sjogren's syndrome, though it is
frequently reported. In a recent survey devised by the Sjogren's Syndrome
Foundation, depression was reported in about 29 percent of patients
who responded to the survey. This depression is thought to be indepen-
dent of thyroid disease or fibromyalgia.

Summing Up
It can be seen that Sjogren's syndrome involves more than just dry
eye and dry mouth; rather, it is a whole array of symptoms encompassing
the entire body. These symptoms may significantly impair a patient's
quality of life. However, with prompt recognition and proper treatment,
this can be ameliorated.
 Abha Gulati, MD
Reza Dana, MD, MPH

7 The Dry Eye

DRY EYE SYNDROME, also called keratoconjunctivitis sicca (KCS), is a

component of the dryness (sicca) that characterizes Sjogren's syndrome.
The ocular surface consists of the conjunctiva (the mucous membrane
covering the outside of the eyeball and the lining of the lids) and the
cornea (the central transparent part of the eyeball that allows the light
rays to pass through). Dry eye syndrome includes a variety of disorders
that affect the ocular surface (both conjunctiva and cornea).
Early diagnosis of dry eye and timely therapy usually help in averting
complications, which may be severe; if inadequately treated, it may lead
to severe damage to the ocular surface.

The Tear Film

The tear film that covers the surface of the eye consists of three layers:
(1) the superficial lipid layer, (2) the middle aqueous layer, and (3) the
deep mucin layer (Figure 7.1). The aqueous layer forms the greatest bulk
of the tear film and is secreted by the lacrimal (tear-producing) glands
(Figure 7.2). The aqueous layer contains water-soluble factors and elec-
trolytes. It helps to wet the conjunctival and corneal surface and causes
mechanical flushing of debris and organisms. It acts as a barrier to the
entry of toxic substances and microorganisms, and its constituents help
inhibit the growth of these microorganisms on the ocular surface. The
aqueous layer also contains essential growth factors for the ocular sur-
face cells. See Chapter 4 for more details.

What Changes Occur on the Eye Surface In Dry Eye?

Tears are necessary for the continued health of the ocular surface and
for the lubrication required for movement of the lids on the globe. In

41
THE NEW SJOGREN'S SYNDROME HANDBOOK
42

Figure 7.1. Diagram showing three layers of the tear film: the superficial lipid
layer, the middle aqueous layer, and the deep mucin layer.

the presence of a. compromised tear film, the lubricating ability of the

tear film is reduced, resulting in greater blink-induced shear force. This
blink-induced shear force may be enough to cause changes in the cells
of the ocular surface. Moreover, the normal tear film contains essential
growth factors that are required for epithelial healing, and deficiency of
these factors contributes to impaired healing of the damaged ocular sur-
face in dry eye patients.
The cornea is often more resistant than the conjunctiva to disease in
dry eye. The corneal epithelium (the most superficial cell layer) forms a
protective barrier between the environment and underlying ocular struc-
tures. In moderate to severe dry eye, there is increasing loss of corneal
epithelial cells, which are replaced by smaller corneal epithelial cells, or
there may be persistent epithelial defects, since the normal healing pro-
cess is impaired. In severe cases of dry eye, the corneal epithelial defects
may enlarge and produce corneal ulcers associated with corneal thin-
ning. These ulcers are initially sterile but may get secondarily infected
due to poor healing. In more severe cases, the cornea can thin out con-
 THE DRY EYE
43

Cross-Section of the Eye and Tear Film Producing Structures

Figure 7.2. Diagram of cross-section of the eye showing tear-film-producing

structures.

siderably ("melt") and even perforate, even though the eye often remains
white and appears quiet. "Melting" in the context of dry eye is most
commonly seen in patients who have rheumatoid arthritis.

How Does a Patient with Dry Eye Present?

The patient's history is extremely important in diagnosing dry eye.
Most symptoms in patients with KCS result from an abnormal and in-
adequately lubricative ocular surface that increases shear forces under
the eyelids and diminishes the ability of the ocular surface to respond
normally to environmental challenges. Symptoms vary from one patient
to another depending on the severity of the dryness, the ability of the
diminished tear film to moisten the ocular surface, and the patient's tol-
erance for ocular discomfort. Patients often use the term dryness to de-
scribe their condition but will have difficulty defining exactly what it
means. The term discomfort may be a more accurate summation of all
the patient's symptoms. Other frequently encountered symptoms in pa-
tients with dry eye are the sensation of a foreign body in the eye or a
THE NEW SJOGREN'S SYNDROME HANDBOOK
44

sandy sensation, burning, and photophobia (difficulty opening eyes in

light).
The principal function of the tear film is to maintain a smooth, clear,
refractive corneal surface in a hostile external environment. Any adverse
effect on the corneal regularity and clarity will interfere with vision. Thus
blurred vision may also be one of the initial complaints in a dry eye
patient. It is somewhat like looking through a dirty windshield. If the
dry eye is due to excessive evaporation, then the patient may feel better
by blinking frequently. Patients may also complain of itching, excessive
secretion of mucus, heaviness of the eyelids, tight eyelids, and inability
to produce tears. Associated inflammation of the surface of the eye may
cause pain and redness. Pain may also be due to the filaments (described
later) that may form on the surface of the cornea in severe dry eye.
Dry eye patients are highly sensitive to drafts and winds. Often they
volunteer information regarding their intolerance to air-conditioning or
driving in the car with the windows rolled down. Reading is often dif-
ficult for dry eye sufferers. This difficulty probably occurs because the
blink frequency decreases during tasks requiring concentration, such as
reading or staring at a computer screen. Some patients complain that
awakening is the worst part of their day. Sleep (like general anesthesia)
decreases tear production. If the eye is already compromised with regard
to tear flow, further reduction during sleep may be enough to produce
nocturnal symptoms. Smoke is almost universally intolerable to severely
tear-deficient patients. Since smoke is actually a suspension of solids in
air, the particulate bombardment of the ocular surface produces discom-
fort. Determining whether symptoms are worse or better indoors or out-
doors, at work or at home, will aid in identifying environments that
need to be modified to improve a patient's symptoms.
Patients should be asked whether they are able to produce irritant
and emotional tears. Inability to cry while peeling onions and when
feeling sad or hurt are suggestive of very severe lacrimal gland involve-
ment. Information should be obtained regarding lubricants and medi-
cations, including drops as well as ointments. Most patients with KCS
improve with topical lubricant therapy. However, excessive use of arti-
ficial tears that contain preservatives may worsen the symptoms. Fur-
thermore, any topical medication may be potentially toxic due to the
patient's inability to dilute the medication because of a lack of aqueous
tear secretion. Some systemic medications such as antiallergics and
 THE DRY EYE
45

antidepressants may worsen dry eye symptoms by decreasing tear

production.
It is important to determine whether the patient has any other as-
sociated systemic signs or symptoms of dryness. Important questions
should be directed toward detecting a history of dry mouth. Patients
with severe dry mouth will have difficulty swallowing bread or meat
without additional fluids. Patients with Sjogren's syndrome and dry
mouth are at greater risk of dental and gum disease owing to lack of
saliva. Women may experience a noticeable decrease in vaginal secre-
tions, which can lead to sexual dysfunction. A family history should be
taken to see whether there is any blood relative with dry eye, Sjogren's
syndrome, collagen vascular disease, or other eye diseases.

Clinical Examination

Non-ocular Examination
The facial skin must be inspected for evidence of acne rosacea, which
is a condition commonly associated with Meibomian gland dysfunction.
Salivary gland enlargement may be seen in patients with Sjogren's syn-
drome. The thyroid gland should be examined for enlargement and nod-
ules, as thyroid disorders are commonly seen in patients with Sjogren's
syndrome.

Ocular Examination
Patients with Sjogren's syndrome may have enlarged lacrimal glands.
The size of the lacrimal gland may be evaluated by asking the patient
to look down while the upper eyelid is pulled up, but in practice this is
not a reliable way of determining lacrimal pathology. In moderate to
severe dry eye, the eye appears red due to the presence of inflammation.
A detailed eye examination is performed under magnification using
the slit lamp. In dry eye, the conjunctiva and the cornea lose their normal
luster. These are seen as a distorted light reflex on the eye surface. Dry
eye patients often have excessive tear debris, which probably has two
origins. Some of the debris is dead epithelial cells that have fallen off
the surface of the cornea, and some are small fibrils of lipid-
contaminated mucin that have rolled up and been pushed into the space
between the eyeball and the eyelid by the shearing action of the lids.
Another characteristic finding that may be seen in patients with severe
THE NEW SJOGREN'S SYNDROME HANDBOOK
46

dry eye is corneal filaments. Unlike the debris and mucus described
above, filaments are actually stuck to the cornea and are not free-
floating. It is likely that when the cornea dries to a point that is incom-
patible with a healthy epithelial layer, some surface cells become desic-
cated and are shed. As a result, a small pit on the corneal surface
appears, to which mucus can attach and serve as a site for adherence of
surface epithelial cells, leading to filament formation. Because filaments
are anchored to epithelial cells, pulling on them can be very painful.
Unfortunately, this is exactly what happens during blinking, with the
resultant symptoms not unlike those produced by a foreign body. This
form of dry eye is known as filamentary keratitis.
Paralleling the decrease in tear secretion in the lacrimal glands, there
is a decrease in certain enzymatic constituents of tears (e.g., lysozyme
and lactoferrin, among others), as well as the normal secreted antibodies
that protect the eyes from infection. Absence of these protective enzymes
and antibodies results in decreased resistance of the eye to infection. Dry
eye patients who wear contact lenses are at higher risk of developing
contact-lens-associated infections, presumably due to the higher propen-
sity of bacteria to adhere to their contact lenses and ocular surface.
The health of the Meibomian glands must also be assessed. Thick,
turbid secretions or the presence of oil or foam suggest Meibomian gland
dysfunction. The eyelid margins should be examined for thickening, ir-
regularity, increased blood vessels, and broken and missing eyelashes,
which are found in cases of chronic blepharitis (eyelid inflammation).

Tear Secretion Tests

Schirmer Testing
The Schirmer test is the simplest test used for assessing aqueous tear
production. Small strips of filter paper, 35 mm long, are used for this
test. The strip is placed at the junction of the middle and lateral third
of the lower eyelid in both eyes (Figure 7.3). The patient is told to blink
normally. Strips are removed after five minutes, and the wetting is re-
corded in millimeters. The Schirmer test may be done with the eyes open
or closed. Less than 6 mm of wetting after five minutes indicates a di-
agnosis of tear deficiency, although the reliability of this test may be
affected by environmental conditions such as temperature or humidity.
 THE DRY EYE
47

figure 7.3. Schirmer test. The amount of wetting of the paper strip is a measure
of tear secretion.

Rose Bengal Stain

Rose bengal is a red vegetable dye that is used to stain cells that have
lost their normal mucin coating. Rose bengal application is a valuable
test in the diagnosis of dry eye. It has one disadvantage in that it causes
irritation on instillation. The irritation seems to be directly related to the
amount of epithelial damage present on the corneal surface and to some
extent the size of the drop of dye used. Alternatively, rose bengal strip
may be used. A drop of anesthetic may be instilled in the eye before the
test to reduce irritation. An alternative to rose bengal is the lissamine
green dye test. The dyeing quality of lissamine green is the same as that
of rose bengal, and it has the advantage of causing little or no irritation
on instillation.
It is important to remember that in dry eye the pattern of the stain,
not merely its presence, is important. The stained area corresponds to
the exposed surface of the eye. In severe dry eye, the entire cornea tends
to stain.
THE NEW SJOGREN S SYNDROME HANDBOOK
_
48

Figure 7.4. Fluorescein staining of cornea showing characteristic of staining of

the exposed area of ocular surface in dry eye.

Fluorescein Staining
Fluorescein is a vegetable dye that is used to stain the surface of the
eye. It is an orange dye that fluoresces green when excited by blue light.
It is typically applied to the eyes with a fluorescein-impregnated strip
wetted with a drop of sterile, nonpreserved saline. Fluorescein is able to
permeate through a disrupted epithelial layer and diffuse among the in-
tercellular spaces. Thus it gives an indication of the areas on the surface
of the eye that have rubbed off due to dryness (Figure 7.4). Fluorescein
staining is a standard method used to demonstrate ocular surface dam-
age. Fluorescein instillation is very well tolerated and causes minimal
irritation.

Tear Breakup Time

Fluorescein is also useful in staining tears to detect how well the
cornea remains continuously covered with a tear film. Tear breakup time
(TBUT) tests how well the cornea remains moistened between blinks.
After the moistened fluorescein strip is applied to the eye, the patient is
 THE DRY EYE
49

asked to blink two or three times to distribute the dye. The test is per-
formed at the slit lamp by asking the patient to stare straight ahead and
not blink. Without touching the patient's eyelids, the examiner scans the
cornea with the cobalt-blue light of the slit lamp, watching for an area
of tear film rupture manifested by a black island within the green sea of
fluorescein. The TBUT is the time in seconds between the last blink and
the appearance of the first random dry spot. A normal TBUT is consid-
ered to be 10 seconds or more, while TBUT is reduced in dry eye.

Laboratory Tests
The following tests for dry eye are most often used in research
settings.

Tear Osmolarity
Tear osmolarity tests measure the particle concentration in the tear
film. For proper functioning, body fluids normally contain a certain con-
centration of solutes. Tear osmolarity is a measure of this concentration,
which in dry eye patients is hypertonic (elevated osmolarity). Elevated
tear osmolarity indicates an imbalance between the rate of tear secretion
and the rate of evaporation, in which a decrease in the former or an
increase in the latter, or both, is sufficient to disturb the normal balanc-
ing mechanisms. Tear hyperosmolarity probably plays an important role
in the ocular surface damage in dry eye disease. There are various types
of osmometers available for measuring tear osmolarity.

Tear Lysozyme and Lactoferrin

The tear lysozyme test measures lysozyme, which is an enzyme nor-
mally present in human tears. Several assay systems are available to
determine the level of lysozyme in tears. Normal tear lysozyme levels are
between 2 and 4 mg/ml. Patients with Sjogren's syndrome have decreased
lysozyme production. Lactoferrin is a stable antibacterial enzyme in tears
that can also be measured using multiple tests.

Tear Protein Analysis

Tear protein analysis is based on the rationale that tears from dry
eye patients may contain altered protein composition. Tear proteins are
measured with the enzyme-linked immunosorbent assay (ELISA), which
uses antibodies directed against them. Electrophoresis is a method that
THE NEW SJOGREN'S SYNDROME HANDBOOK
50

can separate various proteins in tears, using their electric gradients. De-
creased levels of the goblet-cell-specific mucin MUC5AC have been dem-
onstrated in tears of patients with Sjogren's syndrome.

Conjunctival Impression Cytology

Conjunctival impression cytology is performed using a certain type
of filter paper, which is placed on the conjunctiva in order to obtain the
impression of the Conjunctival epithelium. This test has been used to
assay goblet cells in normal subjects and dry eye patients. Reduction in
the number of goblet cells is found in dry eye patients.

Conditions That Mimic Dry Eye

Certain eye conditions may be associated with a sensation of dryness.
Blepharitis is a common condition that may mimic dry eye. Patients with
blepharitis present with symptoms of burning that are worse on awak-
ening, better within an hour or so, and worse again later in the day.
There is only modest response to artificial lubricants, but eyelid hygiene
done on a regular basis improves symptoms. It is important to emphasize
that blepharitis and dry eye can coexist.
In allergic conjunctivitis, symptoms are primarily that of itching. A
history of hay fever or atopic dermatitis can be present. Mucin debris
may be seen in the tear film. There is usually no rose bengal or fluores-
cein staining present. It is important to appreciate that allergy and dry
eye often coexist. This can be attributed to the fact that in KCS lack of
tears and decreased tear turnover may result in an inability to dilute or
wash out allergens, increasing the likelihood of allergic conjunctivitis.
Conversely, systemic antiallergy medications can exacerbate dryness, and
preservatives present in topical antiallergy medicines can also worsen the
dry-eye-related eye surface damage.
A variety of conditions in which the surface of the eye may be dis-
rupted may be perceived as dryness. Such conditions include viral infec-
tions, contact lens irritation, and medication-induced irritation. The lack
of aqueous tear secretion in KCS results in an inability to dilute or wash
out substances that the eye comes in contact with, either purposely in
the form of topical lubricants or medications, or inadvertently by the
application of cosmetics to the face and eyelids. Inability to dilute or
wash out potentially toxic substances can cause epithelial and tear film
abnormalities. Patients present with symptoms of burning, the sensation
 THE DRY EYE
51

of a foreign body, and photophobia, which are present all the time and
worsen with continued use of the offending agent.

Social Aspects of Dry Eye

Dry eye is characterized by chronic symptoms of ocular dryness and
discomfort that can be debilitating; when severe, they may affect psy-
chological health and the ability to work. Because of the chronic nature
of the problem, most patients go through periods of despondency and
depression. Ophthalmologists must recognize this part of the illness and
actively encourage their patients to continue to pursue their normal ac-
tivities, remain hopeful, and comply with recommended treatments. The
patients should also be asked to stay away from unproven "cures," many
of which are touted over the Internet.
 Robert S. Lebovics, MD FACS

8 The Sali ary Glands,

Ears, Nose, and Larynx

SJOGREN'S SYNDROME IN ITS primary form, also known as the sicca

syndrome, is a multisystem disease with a multiplicity of target organs
and clinical effects. Understanding the otolaryngologic manifestations of
this disease can best be appreciated with a brief introduction to the anat-
omy of the upper airways and alimentary tract (Figure 8.1).

Anatomy
The lining of the nose, also known as the nasal mucosa, is a moist,
fluid-producing organ that is rich in glandular material. In the average
adult, the nose and paranasal sinuses secrete about one quart of thin,
clear, mucoid fluid a day, which as part of our normal physiology is
passed and eventually swallowed. In many disease states, Sjogren's syn-
drome being a prime example, this physiology is altered, with several
manifestations. In the simplest sense, treatment is directed at restoring
this mucociliary flow and facilitating the cleansing of the inner tubes and
passageways of the head and neck.
A rich network of glandular structures are present on direct exami-
nation of the nasal cavity. Laterally in both sides of the nose are the
nasal turbinates (passages), which are rich in glands secreting fluid as
well as being actively involved in humidification of the airflow and reg-
ulating temperature. The secretions often contain various enzymes such
as lactoferrin and lysozyme in addition to several types of immunoglob-
ulins, specifically certain subclasses of the IgG molecule as well as the
secretory form of the IgA molecule. In a sense, the paranasal sinuses are

52
Figure 8.1. Salivary glands important in Sjogren's Syndrome. Reprinted from
Sichel and DuBrul, Oral Anatomy, Mosby, 1975.
THE NEW SJOGREN'S SYNDROME HANDBOOK
54

a reservoir for producing these secretions as well as acting as a capacitor

for the storage of warmth and/or cold as well as humidity. There are
probably hundreds of minor salivary glands in the nose as well as the
nasopharynx, oral cavity, hypopharynx, and larynx.
As one progresses down the nasopharyngeal tube, one gets to the
back of the nose, which in reality is the top of the throat. While the
lining here becomes more squamous rather than respiratory in nature,
the basic functions of humidification, clearing of particles, and mainte-
nance of immunity are still paramount. Additionally, the eustachian tube
orifices exit into the nasopharynx, and this is a conduit for draining the
middle ear space and by extension the mastoid air cells. Inflammation
or disease at this point may have otologic implications. As one continues
back down the nasopharynx, the tongue base can be visualized as well
as the larynx, where both vocal cords are easily visualized, and one can
often see clear, thin fluid coming up from the tracheobronchial tree,
which is the lower-airway equivalent of the secretions that begin in the
nose and sinuses passages. The hypopharynx also acts as a point or a
separate conduit for entering the alimentary tract, that is, the esophagus.
A change occurs here, and the lining again is much more squamous and
rich in glands such that saliva can be secreted to aid in the early digestion
of food particles. Of course, we all know that the oral cavity and the
oral tongue are the main inflow point for nutritional support in addition
to a bypass mechanism for respiration. A basic understanding of the
anatomy therefore is critical to understanding the ear, nose, and throat
manifestations of Sjogren's syndrome and by extension its treatments.

Nasal Manifestations
As the autoimmune process within the nasal cavity progresses, one
may see the clinical consequences of this destructive process. The de-
structive, crust-like pattern is often referred to as atrophic rhinitis. A
foul smell, crusts, and even nasal bleeding can be seen. As secretions
become thick and occasionally foul-smelling, secondary infection may
appear. This can cause further local destruction of the glandular tissue
and sometimes even the nasal septum. It is not uncommon to see a
perforation of the cartilaginous portion of the nasal septum due to this
inflammatory process, with or without secondary bacterial infection.
The paranasal sinuses drain through the various ostia (openings) into
the nasal cavity, and with the exception of the sphenoid sinus, they drain
 THE SALIVARY GLANDS, EARS, NOSE, AND LARYNX
55

from under one of the nasal turbinates. As the inflammatory process

proceeds, one may see obstruction of the middle or superior meatus,
thus causing secondary outflow problems from the maxillary, ethmoid,
and/or frontal sinuses. The narrowest portion of the sinonasal tract in
terms of drainage is at the ostiomeatal complex, which is anatomically
close to the middle meatus. Even mild local inflammation can cause sinus
infections. Symptoms include pain, headache, and occasional fever, in
addition to the atrophic symptoms. Many patients will complain of an-
osmia (loss of smell) and a sense of fullness inside the nose. Secondary
infections of the paranasal sinuses need to be treated medically.
My personal bias in treating Sjogren's of the nose and sinus tract
revolves around humidification and replacement of what is lost. Specif-
ically, water in all its forms is critical for reversing the atrophic/inflam-
matory destruction and for allowing the passage of thick, crusty material
down into the oral cavity so that it can eventually be swallowed or spit
out through the mouth. The overriding principle here is one of humid-
ification using clean, balanced saline solutions. There are various brands
of over-the-counter saline sprays, and I have no preference for any par-
ticular one. The critical point here is constant and prophylactic humid-
ification and saline replacement. Recently, a longer-acting form of nasal
lubricant is available that is glycol-based (trade name Rhinaris). It comes
both as a mist and as a gel, with the latter being particularly useful for
longer-term lubrication and hydration, particularly while sleeping. The
use of topical intranasal steroids is often suggested, although its efficacy
has yet to be clearly demonstrated.
Additionally, some people with severe crusting need to irrigate with
a WaterPik, and various nasal attachments exist that help to facilitate
nasal hygiene. Other devices such as a Netti Pot may have value, as do
hot, steamy showers. For all patients with Sjogren's syndrome, the use
of concurrent medications that can facilitate dryness needs to be avoided;
this particularly is important with respect to antihistamines and systemic
decongestants.

How Is the Ear Affected in Sjogren's?

Hearing loss as a result of Sjogren's disease is uncommon but does
occur. Some autoimmune diseases have clearly been linked with a sen-
sorineural (nerve-type) deafness; however, this does not appear to be the
case here. There are patients, however, who occasionally complain of
THE NEW SJOGREN'S SYNDROME HANDBOOK
56

either tinnitus, hearing loss, or otalgia in small degrees; this can be as

high as one-quarter of all patients. Because the middle-ear fluid needs to
drain into the back of the nose through the eustachian tube orifice, dis-
ease with severe inflammation in the nasal cavity could potentially block
the eustachian tube or cause an inflammatory condition resulting in a
conductive hearing loss. Fortunately, this is easily treated with either
ventilating tubes, amplification devices, or local hygiene. Sometimes, in-
creased doses of immunosuppressives or steroids may have value.

How Is the Mouth Affected in Sjogren's?

See Chapter 9.

How Is the Larynx Affected in Sjogren's?

The larynx or voice box is involved in protecting the airway from
foreign bodies and promoting good airflow into the tracheobronchial
tree. It is also involved in diverting food to the alimentary tract (esoph-
agus), and it is the most critical organ in terms of our ability to phonate.
Laryngeal disorders in Sjogren's are often manifested by coughing and
occasionally hoarseness. Voice changes may be present, as the glands
below the vocal cords and the trachea are also affected in addition to
the minor salivary glands from above. Patients infrequently develop res-
piratory symptoms attributable to Sjogren's; however, professional sing-
ers or people who use their voice frequently during the day are at in-
creased risk for chronic laryngitis and its sequelae. Inspissation
(thickening) of mucus and other secretions can cause a foul smell and
occasionally a sense of blockage in one's airway. As in treating disease
in the mouth, vigorous oral hydration is the primary treatment in ad-
dition to systemic immune system modulation with either steroids or
glandular stimulation with drugs such as cevimeline and pilocarpine.
Other treatments include voice rest and occasionally guaifenesin-
containing products to help thin mucus, not only in the nasal tract but
also in the tracheobronchial tree.

Summing Up
The otolaryngologic (ear, nose, and throat) manifestations of Sjo-
gren's disease are significant and varied. It is critical to remind patients
and their physicians to limit drugs that can dry the mucous membranes
 THE SALIVARY GLANDS, EARS, NOSE, AND LARYNX
57

within the upper airways. Antihistamines and decongestants are but two
of the medications that have these effects. Oral hydration and replace-
ment with artificial saliva have value, as does replacing sinonasal secre-
tions with saline or glycol-based nose sprays. Guaifenesin is useful in
helping the larynx to clear itself.
 Ava |. Wu, DPS
Troy E. Daniels, DOS, MS

9 The Dry Mouth:

A Dental Perspective
On Sjogren's

SOMETIMES A DENTIST is the first to diagnose Sjogren's. Dry mouth is a

common complaint that can have many causes. This symptom is often
referred to as xerostomia. It is usually caused by a decrease in the
amount and quality of saliva, but because it is a subjective perception,
abnormalities in salivary function may not be observed in all patients
with this complaint. Almost all Sjogren's syndrome patients experience
some degree of dry mouth.

Causes of Dry Mouth

The most common cause of dry mouth is from the use of certain
types of drugs. Hundreds of drugs in several categories are known to
cause dry mouth as a side effect (Table 9.1). Clinical experience suggests
also that interactions may occur between different drugs not usually as-
sociated with dry mouth, causing that symptom. In most cases, the drugs
causing dry mouth do so through their effect on nerves that regulate
salivary function.
Sjogren's syndrome is a systemic autoimmune disease that causes dry
mouth by way of lymphocytes (a type of white blood cell) infiltrating
the salivary glands. These infiltrating cells replace the normal salivary
gland cells that produce the secretion (acinar cells) and affect the func-
tion of duct cells that convey the secretion to the mouth. Recent research
also shows that Sjogren's patients may produce an antibody in their

58
 THE DRY MOUTH: A DENTAL PERSPECTIVE ON SJOGREN'S
59

TABLE 9.1 DRUGS COMMONLY ASSOCIATED WITH DRY MOUTH*

Antianxiety: alprazolam
Antihypertensive: clonidine; methyldopa
Antidepressant: amitriptyline (+ + +);** buproprion (0); citalopram (0/+);
doxepin (++); fluoxetine (0/+); imipramine (++); mirtazapine (0); nefazodone
(0/+); nortriptyline (++); paroxetine (+); sertraline (0); venlafaxine (0/+)
Antihistamine/antiemetic: brompheniramine (++); cetirizine (0/+);
chlorpheniramine (++); diphenhydramine (+ + +); hydroxyzine (++);
loratadine (0/+); perchlorperazine (++); promethazine (+ + ++)
Antipsychotic: chlorpromazine (++); clozapine (+ + +); fluphenazine (+);
haloperidol (0/+); loxapine (+); molindone (+); olanzapine (+); quetiapine (+);
risperidone (0/+); thioridazine (+ ++); thiothixene (+); trifluoperazine (+);
ziprasidone (0/+)
Anti-Parkinson's: benztropine; selegiline; trihexyphenidyl
Antiacne: isotretinoin
Decongestant: pseudoephedrine
Bronchodilator: ipratropium; albuterol
Muscle relaxant: cyclobenzaprine

Rating of anticholinergic (drying) effects: 0 none; 0/+ very low; + low; + +

moderate; + + + high
*For consistency and clarity, all drugs are listed by their generic names, alpha-
betically. There are hundreds of drugs associated with dry mouth, but with most
of them, the symptom is generally mild, occurs in a small minority of patients taking
the drug, or the drug is not prescribed for chronic use. This list includes the cate-
gories of drugs that most commonly cause significant dry mouth, but it is not all
inclusive. When questions arise, patients should consult with their physician or a
reliable drug information source.
Source: Anderson PO, Knoben JE, Troutman WG, Handbook of Clinical Drug
Data, 10th ed. McGraw-Hill, 2002.

bloodstream that can affect the nerves regulating salivary function. The
onset of dry mouth symptoms in patients with Sjogren's is very gradual,
and most patients cannot determine exactly when it began. It may pro-
gress gradually until little or no saliva is produced, but more commonly,
patients' symptoms and salivary dysfunction progress to some interme-
diate point and do not progress further.
As mentioned previously, the use of prescription drugs can play a
significant role in causing or exacerbating the sensation of dry mouth.
Accordingly, patients with Sjogren's must review with their physicians
any prescription drugs they are taking, to ensure that those drugs are
not increasing their dry mouth. Often, there are alternative and equiv-
alent drugs available that are not as drying (Table 9.1).
Dry mouth can also be caused by other chronic diseases such as
THE NEW SJOGREN'S SYNDROME HANDBOOK
60

TABLE 9.2 CAUSES OF DRY MOUTH

Temporary dry mouth

• Effects of short-term drug use (e.g., antihistamines)
• Virus infections* (e.g., mumps)
• Dehydration (e.g., heat or injury)
• Psychogenic conditions (e.g., anxiety)

Chronic dry mouth

• Effects of chronically administered drugs (see Table 9.1)
• Chronic diseases
• Sjogren's syndrome*
• Sarcoidosis*
• HIV* or hepatitis C infection
• Depression
• Diabetes mellitus, uncontrolled
• Amyloidosis (primary or secondary)
• Central nervous system diseases
• Rarely, absent or malformed glands
• Other effects of treatment
• Therapeutic radiation to the head and neck
• Graft-versus-host disease (following bone marrow transplantation)

*These conditions may also cause major salivary gland enlargement

sarcoidosis, HIV or hepatitis C infection, uncontrolled diabetes, or de-

pression. Previous medical treatments such as radiation therapy to the
head and neck, bone marrow transplantation (graft-versus-host disease),
or chemotherapy for treating malignancies can damage the salivary
glands and cause decreased salivation (Table 9.2). The effects of such
treatment can be either temporary or permanent, depending on the type
and intensity of treatment.
Temporary symptoms of dry mouth, such as when taking over-the-
counter drugs for treating cold symptoms, are not important. However,
if dry mouth and diminished salivation continues for many weeks or
months, regardless of the cause, detrimental changes will begin to occur
to the teeth and oral function.

The Functions of Saliva

Saliva is an essential body fluid whose critical role in oral comfort
and function is seldom appreciated until there is not enough of it. It is
created by three pairs of major salivary glands, the parotid, submandib-
 _
THE DRY MOUTH: A DENTAL PERSPECTIVE ON SJOGREN'S
61

ular, and sublingual glands, and by hundreds of minor glands located in

many areas of the mouth. All of these glands can be affected by Sjo-
gren's. Saliva is composed mostly of water but includes small amounts
of many substances that have important roles in protecting and preserv-
ing the teeth, oral soft tissues, and oral function. These roles include:

" Protecting, lubricating and cleansing the oral mucosa. Saliva coats
tissues of the mouth and ingested food allowing the food to pass
smoothly over the teeth and oral soft tissue. This coating facilitates
chewing and swallowing and acts as a barrier to irritating and harmful
substances contained in food. The salivary coating inside the mouth also
facilitates speech.
• Protecting against dental caries (decay). As discussed below, dental
caries results from the exposure of teeth to acid produced by adhering
bacterial plaques. Saliva contains several chemical systems, called buf-
fers, that can neutralize the acidity of foods and beverages to maintain
a neutral pH (a measure of the chemical balance between acidic and
alkaline). Saliva also contains reservoirs of calcium and phosphate ions
that replenish those elements as they are gradually lost from teeth. Se-
cretory IgA is a unique antibody found in saliva that can coat many oral
bacteria, interfering with their ability to adhere to teeth.
• Protecting against infection by bacteria, yeasts, and viruses. There
are several protein components in saliva (for example, lactoferrin, per-
oxidase, histatins, and secretory leukocyte protease) that have antibac-
terial, antifungal, and antiviral properties.
• Aiding digestion and taste. Initial stages of digestion occur in the
mouth by way of enzymes contained in saliva. Taste buds, which are
located in the mouth, can only respond to dissolved substances; saliva
enhances the sense of taste by both dissolving and digesting solid foods.
The solvent and digestive roles of saliva allow the taste buds to convey
food flavors that enhance enjoyment of any meal.

Oral Problems Caused by Chronic Dry Mouth

Clearly, saliva is important for the quality of life. Progressive loss of
saliva production correspondingly erodes the beneficial and protective
effects of saliva listed above. The most severely affected patients with
THE NEW SJOGREN'S SYNDROME HANDBOOK
62

Sjogren's do not produce measurable amounts of saliva, but most pa-

tients retain residual salivary gland function, ranging from a small
amount to almost normal.

Dry Mouth Symptoms

The critical damage threshold for decreased salivary function has not
yet been defined. It has been shown, however, that the sensation of dry
mouth does not occur for an individual until saliva production drops to
approximately one-half that person's baseline value. The feeling of in-
traoral dryness associated with Sjogren's often develops over a period of
months or years. Sudden onset of oral dryness is rare in Sjogren's. Oc-
casionally, an individual is not aware of being dry until asked if he or
she can swallow a cracker without water. The severity of oral dryness
in patients with Sjogren's may fluctuate, but it usually does not include
periods of time during the day where their mouth feels normal.
Normally, little saliva is produced during sleep, so it is common for
all individuals to feel some oral dryness in the morning or on awakening
during the night. This symptom may be more severe for patients with
Sjogren's and should be managed with small amounts of a commercial
saliva substitute or a secretogogue, instead of water, to avoid sleep dis-
ruption caused by the urge to urinate.

Dental Caries
The process of tooth decay is caused by interactions between several
types of bacteria commonly found in the mouth and particular sugars
present in the diet of most individuals. These bacteria form plaques,
coating the teeth so rapidly that they can be seen by the unaided eye
after only a day or two without tooth brushing. If an individual's diet
includes sucrose (common table sugar) or other sugars that can be meta-
bolized by these bacteria, the organisms grow rapidly in number and
produce increasing amounts of acid from their metabolism of the sugar.
The acid in turn progressively dissolves the mineral content of the teeth
(called decalcification), to which the organisms adhere.
For individuals who have a deficient amount of saliva, dental caries
progresses more rapidly and in different dental locations, even in those
with good oral hygiene. The pattern of dry mouth caries is distinctive.
Caries is located on the necks of teeth near the gum line, the cusp tips
of back teeth, or the biting edges of front teeth. This is in contrast to
 THE DRY MOUTH: A DENTAL PERSPECTIVE ON SJOGREN's
63

dental caries in individuals with normal saliva but inadequate oral hy-
giene, where caries occur between teeth and in pits and fissures on the
chewing surfaces of back teeth. In addition, dry mouth patients often
exhibit recurrent caries along the margins of existing dental restorations,
ultimately causing the restorations to fail.
Insufficient saliva contributes to increased dental decay in several
ways: (1) a decreased ability to buffer acids that are ingested or produced
by bacteria adhering to teeth, (2) an insufficient reservoir of calcium and
phosphate ions to replenish that naturally lost from teeth, (3) a reduction
of antimicrobial proteins, and (4) reduced oral cleansing from lower
salivary flow.
Dental caries usually causes no symptoms until it penetrates through
the surface enamel of the tooth into the dentin. Dental enamel is very
dense and composed almost entirely of nonorganic material, like ivory,
while dentin is like bone, with many organic components, including
nerves. After caries enters the dentin, that tooth usually becomes sensi-
tive to heat or cold. If untreated, caries can progress through the dentin
into the pulp, where the bacteria infect the dental pulp, causing increased
pain (pulpitis). From the pulp, invading bacteria can expand into the
bone adjacent to the root tip, causing a painful abscess. Early dental
caries appears as a flat, whitish spot on a tooth's surface (decalcification).
As the process continues, there is progressive loss of tooth structure, and
a cavity appears that can be tan to black in color.

Fungal Infection
About one-third of patients with chronic salivary deficiency have
symptoms of burning in their tongue or elsewhere in their mouth and/
or intolerance to acidic or spicy foods. These symptoms are usually
caused by localized infection of the lining the mouth (stomatopyrosis)
by different species of the fungus Candida. This organism is often a nor-
mal inhabitant of the oral flora, but in susceptible patients with deficient
saliva, Candida can proliferate and cause those symptoms. Where this
has occurred, the tongue appears red, loses its normal carpet-like surface
texture, and may develop surface grooves. Other affected areas develop
well-defined or diffuse red areas caused by thinning of the mucosa (called
atrophy). These intraoral changes are often associated with redness or
crusting at the corners of the lips, called angular cheilitis. This combi-
nation of clinical features is called erythematous candidiasis. Effective
THE NEW SJOGREN'S SYNDROME HANDBOOK
64

treatment with antifungal drugs will lead to complete restoration of the

mucosal changes and elimination of the symptoms, despite ongoing sal-
ivary deficiency. However, in susceptible patients, this condition often
recurs, necessitating retreatment, which can be repeated as often as
necessary.

Oral Functional Problems

It is common for patients with Sjogren's to have difficulty swallowing
dry foods because they have insufficient saliva to adequately moisten the
bolus of food. They may also have difficulty speaking because the tongue
and lips have insufficient salivary lubrication. As noted in Chapter 15,
these can be overcome by frequent sips of water and/or use of secret-
ogogues. Sjogren's patients wearing complete dentures often experience
progressive difficulty because deficient oral lubrication may cause the
tongue to continually move the lower denture. Where it is possible to
do so, implants surgically imbedded within the lower jaw may provide
a means to stabilize the lower denture.

Periodontal Disease
It is often argued that in Sjogren's increased amounts of bacterial
plaque will develop on teeth, which should cause greater gum inflam-
mation (gingivitis). However, most research papers that have addressed
the question of whether patients with Sjogren's have more severe gum
disease than the general population have found no difference between
the groups. Perhaps patients with Sjogren's are more aware of the ben-
eficial effect of careful hygiene and have better oral hygiene than the
general population, which could play a role in investigators' inability to
find more severe periodontal disease in Sjogren's patients.

Halitosis (Bad Breath)

Halitosis can occur when there is an overgrowth of certain types of
odor-causing bacteria. These bacteria can be the result of active dental
caries or periodontal disease, inadequate oral hygiene, or deficient saliva
such as in Sjogren's. This problem is managed by appropriate dental or
periodontal treatment to eradicate underlying disease along with regular
and careful oral hygiene.
 THE DRY MOUTH; A DENTAL PERSPECTIVE ON SJOGREN S
65

Salivary Gland Enlargement

Salivary gland enlargement or swelling occurs in about one-third of
patients with Sjogren's, while the majority of Sjogren's patients never
experience this change. The enlargement is gradual in onset and without
symptoms or with only mild symptoms of discomfort. It can slowly re-
gress and recur over periods of many months or become chronic. In rare
cases of Sjogren's, these enlargements can transform into a malignant
condition, usually lymphoma. In patients experiencing this enlargement,
it may be appropriate to consider other causes of the enlargement by
way of magnetic resonance imaging, fine-needle aspiration for cytology,
or salivary gland biopsy.

Diagnostic Testing of Dry Mouth

Dry mouth from Sjogren's and other causes is diagnosed by both
dentists and physicians with a combination of methods.

Symptoms and Follow-up Questions

The range of symptoms experienced by patients with Sjogren's is dis-
cussed in the section above. In patients complaining of dry mouth, it is
also helpful to know if their mouth feels dry while eating, if they need
water for swallowing solid foods, or if they need water to chew and
swallow dry foods. Positive responses to these questions have a signifi-
cant association with decreased saliva production.

Salivary and Oral Examination

In examining patients suspected of having Sjogren's, the major sali-
vary glands should be palpated for evidence of tenderness, changes in
consistency, or enlargement. Saliva expressed from the major salivary
ducts intraorally should be visually assessed for its clarity, viscosity, and
wetting ability. The oral mucosa should be assessed for its lubricity (nor-
mally wet and slippery versus dry and sticky) and its color. The extent
and pattern of dental caries must be noted, as described in the section
above.

Salivary Flow Rate Measurement (Sialometry)

Salivary gland function is most easily assessed by collecting saliva
over a specified period of time. The collection can be made from separate
THE NEW SJOGREN'S SYNDROME HANDBOOK
66

glands, such as the parotid, using special collectors, or of whole saliva

collected simply by expectoration (spitting). These collections can be
made under conditions that stimulate salivary secretion (for example,
while chewing or tasting) or without stimulation, yielding quite different
results with different diagnostic potential. These are all painless, non-
invasive tests that are useful to assess the presence and severity of sali-
vary dysfunction and to monitor patients' disease progress over time and
the effects of treatment. There is no universally accepted measure that
defines abnormal salivary function, but an unstimulated whole salivary
flow rate of less than 1 ml/10 minutes is widely accepted as a threshold
of abnormal function. Reductions in salivary flow rate are caused by
many different conditions, and none are diagnostically specific.

Scintigraphy
This test measures the rate at which a small amount of injected ra-
dioactive material is taken up from the blood into the salivary glands
and secreted into the mouth. It is another method to measure salivary
gland function that may be helpful for evaluating individuals with severe
salivary dysfunction.

Sialography
This technique uses a liquid radiographic contrast medium injected
into a salivary duct followed by X-ray images of that gland to exhibit
its ductal structure. The technique is useful to explore duct obstructions
and distinguish between chronic inflammatory changes and neoplasms,
but it is limited in its ability to provide diagnostically specific informa-
tion about Sjogren's. Sialography in patients with significant salivary
hypofunction must be done with water-based contrast media to avoid
the risk of chronic foreign body reaction from use of oil-based media.

Ultrasound and Magnetic Resonance Imaging (MRI)

These are non-invasive imaging techniques that can examine salivary
glands for structural changes. Ultrasound examination may be helpful
in identifying vascular or cystic lesions in salivary glands. MRI is an
excellent technique for imaging masses in salivary glands, particularly as
part of presurgical evaluation. There have been only a few studies ex-
amining these techniques in the context of Sjogren's. The possibility of
 THE DRY MOUTH; A DENTAL PERSPECTIVE ON SJOGREN S
67

diagnostic applications for Sjogren's have been suggested, but evidence

of their usefulness is inconclusive at this time.

Sialochemistry
These techniques examine saliva for the presence and amount of par-
ticular substances. Sialochemistry has been applied to compare saliva
samples from normal individuals to those from Sjogren's patients with
the hope of identifying differences that can be used as diagnostic criteria
for Sjogren's. Differences between normal and Sjogren's saliva have been
identified, but many of those differences are caused by reduced salivary
function, not specifically by Sjogren's.

Minor Salivary Gland Biopsy

This test, also commonly referred to as a lip biopsy, is currently con-
sidered the gold standard for diagnosing the salivary component of Sjo-
gren's. Using local anesthesia, a small, shallow incision is made on the
inner surface of the lower lip to directly visualize and remove at least
four of these small glands. There are hundreds of these minor salivary
glands located throughout the mouth, which are between Vie and Vs inch
(1 and 3 mm) in diameter. This technique is preferable to the punch
biopsy technique, which is a blind procedure; it usually does not yield
a sufficient sample of minor glands and may endanger sensory nerves in
the area. A pathologist then examines the glands for the presence of
changes characteristic of the salivary component of Sjogren's, or occa-
sionally of other diseases.

Summing Up
The symptom of dry mouth can be the result of diverse causes. It is
important to determine if it is the result of decreased salivary function
from a disease such as Sjogren's, from the chronic use of a drug known
to cause dry mouth, or from a combination of both. With this knowl-
edge, preventive measures can be taken to minimize the effects of this
potentially important physiological change.
 Fotinl C Sollotis, MD
Stuart S. Kassan, MD
Haralampos Moutsopoulos, MD

10 The Internal Organs

in Sjogren's

IN SJOGREN'S SYNDROME the immune system primarily targets the sali-

vary and lacrimal glands. However, less commonly the same immune
process can also affect the major organs of the body, such as the lungs,
the heart, the gut, the liver, the kidney, and the nervous system. Major
organ disease is only seen in one-third of primary Sjogren's patients and
can be divided into two categories depending on whether it manifests
itself early (that is, together with the symptoms of dry eye and dry
mouth) or later on, sometimes years after the diagnosis of Sjogren's has
been made.
Manifestations of lung and liver disease as well as one type of kidney
disease (interstitial nephritis) occur early, around the time of diagnosis
of Sjogren's, and are unlikely to occur later on. These diseases are char-
acterized by a common immune process: an infiltration of the affected
organ by a group of white cells called lymphocytes.
On the other hand, the less common type of kidney disease, glome-
rulonephritis, and the involvement of the peripheral nerves often occur
later in the disease process and are not present at the time of diagnosis
of Sjogren's. These two diseases are also characterized by a common
immune process: inflammation of blood vessels, known as vasculitis,
caused by the deposition of immune complexes (structures made up of
antibodies) on the vessel walls.
Although disease of the major body organs is rarely severe or life-
threatening in Sjogren's, it should nevertheless be diagnosed promptly so
that effective treatment is given. This is one of the reasons why Sjogren's
patients should be monitored by their physician on a regular basis.

68
 THE INTERNAL ORGANS IN SJOGREN's
69

The Resplratoiy Tract

The entire respiratory tract may be affected in Sjogren's. Starting
from the nose, thinning of the mucous membrane of the nose, or
atrophic rhinitis, can occur, giving rise to nasal dryness. Moving down
the airway, the voice box (larynx), windpipe (trachea), and bronchial
tubes can become inflamed; this is known as laryngotracheobronchitis.
The main symptoms of this condition are hoarseness of the voice, dry
cough, wheezing and shortness of breath.
Because there is less mucus produced in the airway, Sjogren's patients
have difficulty clearing foreign material that has been inhaled into the
respiratory tract. This can also contribute to the chronic inflammation
of the bronchi and can predispose the patient to bacterial infections.
Also, mucus can become stuck in the small bronchi, blocking the ven-
tilation of a small segment of the lung. This can lead to the collapse of
that lung segment (known as atelectasis).
Inflammation of the trachea and bronchi (tracheobronchitis) can be
diagnosed by performing breathing tests known as pulmonary function
tests. The patient blows into a tube connected to a machine that mea-
sures the flow of air in the bronchi. In this way the reduced flow of air
in the bronchial tubes can be detected. In tracheobronchitis a standard
chest X-ray can be normal.
The use of room humidifiers can be of help in relieving the symptoms
of mild tracheobronchitis. Also, prescribed nebulizers, which can deliver
tiny water droplets into the small airways, may be useful. If the patient
is wheezing or if the pulmonary function tests confirm blockage of air-
flow in the bronchi, then inhalers containing medications that dilate the
bronchi can be prescribed. However, these are only partially effective, as
they cannot clear the mucus blocking the bronchi. In this respect, drugs
that break down mucus (mucolytics) may be of some benefit.
The lung itself can also become inflamed in Sjogren's (interstitial lung
disease, ILD). As the bronchi branch out they end up in small air sacs
known as the alveoli, where carbon dioxide is exchanged for oxygen.
Around the alveoli there is supporting tissue known as the interstitium.
This contains small blood vessels that take up the oxygen from the al-
veoli. If there is inflammation and scarring within the interstitium, then
less oxygen can enter the blood within the lungs.
The symptoms of interstitial lung disease vary depending on the se-
verity of the disease. In the early stages patients may have no symptoms
THE NEW SJOGREN'S SYNDROME HANDBOOK
70

or may complain of a dry cough and mild shortness of breath on exer-

tion. In the late stages of severe ILD, which is rare, patients may have
disabling breathlessness on exertion.
The chest X-ray may show a lacy or honeycomb type of shadowing
within the lungs. Pulmonary function tests show impairment of gas
transfer from the alveoli into the blood vessels and a reduced volume of
air in the lungs. High-resolution computed tomography scans (HRCT)
of the lungs are very useful in confirming the diagnosis. When looking
at HRCT films, areas of inflammation appear as patches of white
"ground glass" within the dark lungs. However, other lung conditions
can mimic interstitial lung disease associated with Sjogren's, and
therefore further investigations are sometimes necessary in order to con-
firm the diagnosis. In a procedure known as bronchoscopy, a tube can
be inserted from the nose inside the lungs with the patient awake. Then
a sample of bronchial secretions can be obtained and examined under
the microscope. In ILD associated with Sjogren's, fluid from bronchial
secretions typically contains numerous lymphocytes, which are cells in-
volved in inflammation. Sometimes a lung biopsy, done either during
bronchoscopy or through a chest incision under local anesthetic (open-
lung biopsy), is needed to make the diagnosis. The standard treatment
for ILD is corticosteroids given either by mouth or intravenously. De-
pending on the response and on the severity of the disease, it may also
be necessary to add other immunosuppressive drugs such azathioprine
or cyclophosphamide. If treated early, ILD does not cause any long-term
disability.
Inflammation of the lining around the lung (pleurisy) can occur in
Sjogren's. This condition is usually seen in patients with secondary Sjo-
gren's syndrome and particularly in those suffering from systemic lupus
erythematosus or rheumatoid arthritis. Pleurisy usually causes chest pain
on breathing. Fluid can sometimes accumulate in the pleural space (pleu-
ral effusion) causing shortness of breath. Pleurisy is treated with non-
steroidal anti-inflammatory drugs or corticosteroids. Also, drainage of
the pleural effusion may sometimes be necessary.
Very rarely Sjogren's patients develop an abnormally high pressure
in the pulmonary arteries, the vessels that carry blood from the heart to
the lungs. This is known as pulmonary hypertension. The main symptom
of pulmonary hypertension is shortness of breath on exertion. In Sjo-
gren's, pulmonary hypertension can develop in isolation or as a result
 THE INTERNAL ORGANS IN SJOGREN'S
71

of ILD and lung scarring (fibrosis). Pulmonary hypertension can be di-

agnosed on a routine cardiac echocardiogram. To obtain an accurate
measurement of the pulmonary artery pressure, the patient undergoes
cardiac catheterization. Under local anesthetic, a thin wire is guided from
the artery in the leg into the main aorta and then into the right side of
the heart so that measurements of pressure can be taken. If left un-
treated, severe pulmonary hypertension can cause heart failure. Treat-
ment of any underlying interstitial lung disease can help improve the
degree of pulmonary hypertension. The use of intravenous epoprostenol
and anticoagulants has greatly improved the life expectancy of patients
with severe pulmonary hypertension. More recently a new oral drug,
bosentan, has also been shown to be an effective treatment.

Kidneys
The kidneys remove waste products from the blood and form urine.
The most common kidney problem in patients with Sjogren's syndrome
is inflammation of the tissue around the kidney filters, known as inter-
stitial nephritis. Interstitial nephritis is found early in the disease and has
a benign course. It generally causes mild deterioration in kidney func-
tion, manifested as a mild elevation in the plasma creatinine concentra-
tion. This usually requires no treatment. Progression to end-stage renal
disease is a rare event. When there is progressive deterioration of kidney
function in a patient with Sjogren's syndrome, a kidney biopsy is often
done. This involves taking a small piece of kidney tissue with a needle
while the patient is awake, under local anesthetic. The tissue is examined
under the microscope, and if the diagnosis of interstitial nephritis is
made, a course of corticosteroids is given as treatment. Kidney function
usually improves within a few weeks unless irreversible scarring in the
kidneys has already occurred.
Interstitial nephritis can cause abnormalities in the kidney tubules,
which are part of the kidney filtering mechanism. One such abnormality
is renal tubular acidosis (RTA). In RTA the kidney tubules are unable
to excrete acid in the urine. This can occur in up to 25 percent of patients
with Sjogren's syndrome. As a result, the urine becomes more alkaline
(high urine pH) and the blood becomes more acidic (low blood pH).
This can lead to low levels of potassium in the blood and can give rise
to kidney stones. Patients with RTA usually have no symptoms. Rarely,
when the blood potassium level is very low, muscle weakness or even
THE NEW SJOGREN'S SYNDROME HANDBOOK
72

paralysis can occur. Also, recurrent pain in the loin area, caused by kid-
ney stones, can sometimes be the presenting symptom. The treatment of
RTA depends on its severity. If the potassium level is very low, then the
patient is given potassium supplements to take in the form of tablets.
Alkaline agents (sodium bicarbonate) are given to correct the acidity of
the blood so as to prevent the formation of renal stones.
Another rare abnormality of the renal tubules in Sjogren's syndrome
is nephrogenic diabetes insipidus. In this condition the renal tubules be-
come insensitive to the effects of anti-diuretic hormone and as a result
cannot concentrate the urine. Patients with nephrogenic diabetes insi-
pidus complain of thirst and of passing large amounts of urine fre-
quently. The diagnosis is suspected if the urine remains dilute when the
patient is deprived of water (when a normal person becomes dehydrated
the kidneys try to save water by concentrating the urine). Nephrogenic
diabetes insipidus can be treated by a number of means, including the
use of diuretics, non-steroidal anti-inflammatory drugs, and a low-salt,
low-protein diet.
The glomeruli, which also form part of the kidney filtering mecha-
nism, are rarely affected in Sjogren's syndrome. Antibodies produced by
the immune system become deposited on the glomeruli and cause in-
flammation (glomerulonephritis). As a result, the function of the kidneys
deteriorates. This can be picked up on routine testing of a sample of
urine and by looking at the blood tests and observing a deterioration of
kidney function. Symptoms include high blood pressure and leg swelling
due to water retention (edema). Glomerulonephritis is rare in patients
with Sjogren's and occurs mainly in those patients who also have other
overlapping conditions such as systemic lupus erythematosus, cryoglob-
ulinemia (a condition whereby protein complexes circulating in the
blood become deposited during cold weather), and vasculitis (inflam-
mation of blood vessels). If left untreated, glomerulonephritis may lead
to severe kidney failure. Therefore in a patient with suspected glome-
rulonephritis a kidney biopsy should be performed to confirm the di-
agnosis and assess the severity of the kidney disease. Treatment is then
given in the form of corticosteroids as well as other immunosuppressive
drugs (cyclophosphamide).
Inflammation of the bladder, known as interstitial cystitis, can occur
in patients with Sjogren's. The symptoms are frequent urination and pain
in the lower abdomen over the bladder area.
 THE INTERNAL ORGANS IN SJOGREN S
73

The Gastrointestinal Tract

In Sjogren's the exocrine glands of the gastrointestinal tract can also
be affected. The cells lining the esophagus produce less mucus, and the
esophagus becomes dry like the mouth. This can lead to difficulty in
swallowing. Difficulty in swallowing can also be caused by abnormal
contractions of the esophagus or by a lack of the normal contractions
that move the food down the esophagus to the stomach. This condition,
which can affect up to one-third of patients with Sjogren's, is known as
esophageal dysmotility.
The diagnosis of dysmotility is made by measuring the pressure inside
the wall of the esophagus during swallowing (manometry). When the
wall of the esophagus contracts abnormally, treatment is aimed at relax-
ing the smooth muscle of the esophagus. Nitroglycerin and calcium
channel blockers may be helpful.
On the other hand, when the muscle tone in the wall of the esophagus
is reduced, gastric juice moves up the esophagus, producing a burning
sensation behind the breastbone (heartburn) and chest pain. This is
known as gastro-esophageal reflux. Prolonged reflux of acid results in
chronic irritation of the esophagus (esophagitis). Mild reflux can be
treated by the use of antacids. Antacids form a "raft" that floats on the
surface of the stomach contents to reduce reflux and protect the lining
of the esophagus. Severe gastro-esophageal reflux and esophagitis are
best treated by the use of drugs that reduce acid production by the stom-
ach. These include H2-receptor antagonists (ranitidine) and proton pump
inhibitors (omeprazole).
However, a proportion of patients with Sjogren's have reduced acid
secretion by the stomach. This is a result of long-standing inflammation
that destroys the cells that produce acid (chronic atrophic gastritis), an
immune process similar to the one that destroys the salivary glands.
Atrophic gastritis can cause indigestion (dyspepsia) and pain over the
upper part of the abdomen. Diagnosis is made by endoscopy. This is
performed by a gastroenterologist with the patient awake but slightly
sedated. The stomach is visualized by inserting an elastic tube with a
camera at its end (fiber-optic endoscope) inside the stomach. A biopsy
is often taken to confirm the diagnosis. Unfortunately, once the acid-
producing cells of the stomach are damaged, it is often too late to give
any treatment.
However, other conditions associated with atrophic gastritis can be
THE NEW SJOGREN'S SYNDROME HANDBOOK
74

prevented. Destruction of the cells that produce acid in the stomach can
prevent absorption of vitamin B12, important in the production of red
blood cells. Its deficiency can result in a form of anemia known as per-
nicious anemia. Pernicious anemia can be diagnosed by a simple blood
test and can be successfully treated by B12 injections (see Chapter 16).
In Sjogren's, involvement of other exocrine glands such as the pan-
creas can sometimes occur. Most of the time this does not cause any
symptoms. However, in some cases the pancreas cannot secrete its di-
gestive enzymes, and then the symptoms are diarrhea and steatorrhea
(floating, fatty stools). Pancreatic enzyme insufficiency can be treated by
the regular administration of oral pancreatic enzymes.
Acute inflammation of the pancreas, known as pancreatitis, has been
rarely described in Sjogren's patients. It presents with abdominal pain,
nausea, and vomiting. Laboratory tests show elevation of amylase, an
enzyme measured in the serum. Amylase is produced by the salivary
glands as well as by the pancreas. A quarter of patients with Sjogren's
may have a raised serum amylase due to salivary gland inflammation
rather than due to acute pancreatitis.

The Liver
In studies of Sjogren's patients, approximately 6 percent are found to
have autoimmune liver disease. The main two conditions associated with
Sjogren's are chronic active hepatitis and primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a chronic disease that affects mainly
middle-aged women. It is caused by inflammation around the channels
that transport bile from the liver into the intestine, the bile ducts. As a
result, these ducts become blocked, and bile builds up in the liver and
spills into the blood. In the late stages of the disease the liver becomes
scarred. This is known as cirrhosis. In the early stages, the main symp-
toms of PBC are due to the accumulation of bile acids and salts in the
blood. Patients complain of generalized itching and tiredness. Later on
in the disease they develop jaundice (yellow tinge of the skin and the
eyes), pale stools, and dark urine. In the late stages, cirrhosis can cause
accumulation of fluid in the abdomen (ascites) and internal bleeding
from buildup of pressure in the veins of the esophagus (esophageal
varices).
The diagnosis is suspected when a patient with Sjogren's has the
above symptoms and abnormal liver function tests. There is also a very
 THE INTERNAL ORGANS IN SJOGREN'S
75

specific blood test for the diagnosis of PBC, the presence of anti-
mitochondrial antibodies. However, a liver biopsy is usually necessary
to confirm the diagnosis and to evaluate if the disease is in its early or
late stages. This involves taking a small piece of liver, using a needle,
under a local anesthetic.
The lack of bile salts in the intestine results in reduced absorption of
fat and the fat-soluble vitamins A, D, E, and K. Vitamin D deficiency
can result in weakening of the bones (osteoporosis) and fractures. Vi-
tamin K deficiency can result in problems with blood clotting. Therefore
patients with PBC benefit from taking calcium plus vitamin D supple-
ments to strengthen their bones, as well as vitamins A, E, and K.
Because the cause of PBC is not known, there is no curative treatment
for the disease. The only definite treatment is liver transplantation. How-
ever, the prognosis of PBC varies greatly from one patient to another.
Many patients lead active lives with few symptoms for 10 to 20 years.
In some patients, however, the condition progresses more rapidly and
liver failure may occur in just a few years.
Ursodeoxycholic acid may delay the progression of the disease. In
large trials, it has been shown to improve liver function as well as sur-
vival of patients with PBC. Treatment of pruritis is often a challenge in
PBC. The mainstay is cholestyramine, a resin that forms a complex with
bile acids in the intestine, promoting their excretion in the stools.
In chronic active hepatitis (CAH), the immune system continuously
attacks the liver cells, and as a result, scarring of the liver (cirrhosis) can
occur. In general, CAH can be caused by hepatitis viruses, by drugs, or
by an unknown mechanism that dysregulates the immune system. The
last of these is the case in Sjogren's patients. CAH is suspected in a
patient with Sjogren's when liver function tests become abnormal with-
out the patient taking any new drugs. Evidence pointing toward an au-
toimmune active hepatitis is the finding of antibodies in the blood
against smooth muscle or liver/kidney microsomes. Typical symptoms
are fatigue, malaise, fever, and loss of appetite. The diagnosis is con-
firmed by liver biopsy. CAH can be treated by the use of steroids and
other immunosuppressive drugs such as azathioprine.

The Heart
Involvement of the heart is very rare in primary Sjogren's. Some Sjo-
gren's patients have been found to have a small amount of fluid around
THE NEW SJOGREN'S SYNDROME HANDBOOK
76

the heart, known as pericardial effusion. This is caused by inflammation

of the lining around the heart (pericarditis). It is usually picked up by
chance on routine ultrasound scanning of the heart, as most patients are
asymptomatic. Patients with secondary Sjogren's who have lupus are
more likely to develop pericarditis that gives rise to symptoms. This
usually occurs during a lupus flare. The symptoms are typically of left-
sided chest pain that changes with posture. When the patient is examined
using a stethoscope, a characteristic sound, known as a "rub," can be
heard at the left edge of the sternum. An electrocardiogram may show
typical changes of pericarditis, and visualization of the heart using ech-
ocardiography reveals fluid around the heart. Lupus patients mostly de-
velop small to medium collections of fluid around the heart that have
no bearing on the heart function. However, very rarely, if there is a large
amount of fluid around the heart, it can impede the pumping action of
the heart, and the patient can develop heart failure. Patients with rheu-
matoid arthritis and secondary Sjogren's can also develop pericardial
effusions during a flare of the rheumatoid arthritis. However, it has been
estimated that during the course of their disease, less than 10 percent of
rheumatoid arthritis patients have a clinical episode of pericarditis.
Steroids are given to treat small to medium pericardial effusions,
whereas in the case of large effusions, draining of the fluid using a needle
may be necessary.

Congenital Heart Block

When the fetus is inside the womb, its heart beats regularly as a result
of its natural pacemaker. However, there is a condition whereby this
pacemaker fails and the heart rate drops dangerously low. This is known
as congenital heart block. There are two types of congenital heart block,
incomplete and complete. In complete heart block, insertion of an arti-
ficial pacemaker is necessary after delivery.
All babies born with congenital heart block have mothers who carry
anti-Ro/SSA antibodies, whereas 75 percent have mothers with anti-La/
SSB antibodies. Most of these mothers have these antibodies without
having any symptoms of an autoimmune disease. These antibodies are
thought to cross the placenta and bind onto the fetal heart, preventing
the normal development of the pacemaker.
Up to 75 percent of Sjogren's patients have anti-Ro/SSA antibodies
and up to 40 percent have anti-La/SSB antibodies. However, if a woman
 THE INTERNAL ORGANS IN SJOGREN S
77

who has Sjogren's and anti-Ro/SSA antibodies becomes pregnant, the

risk of having a fetus with congenital heart block is only 1-2 percent.
The risk is much higher if she has previously given birth to another baby
with congenital heart block. For this reason, the fetuses of anti-Ro/SSA-
and anti-La/SSB-positive mothers need to be closely monitored after the
18th week of gestation for signs of heart block (see also pages 196-198).
If heart block is detected and is of the reversible form, treatment can be
given with steroids that cross the placenta (dexamethasone).

The Nervous System

Patients with Sjogren's syndrome can have disease of the nervous
system. The peripheral nerves that control sensation can be damaged by
the immune system. This is known as sensory neuropathy. Patients with
sensory neuropathy initially complain of numbness or tingling at the tips
of their toes. Also, they may notice alterations in the appreciation of
pain and temperature, and a burning sensation. The problem is usually
symmetrical. It can progress very slowly to involve the fingers of both
hands. In most patients the symptoms are mild and non-disabling. Ap-
proximately 40 percent of patients improve spontaneously.
The diagnosis is usually made by examination of the peripheral
nerves. Patients may have reduced sensation in the hands and feet in a
"glove and stocking" pattern. The reflexes may also be absent. However,
the physical examination can be normal. The diagnosis is confirmed by
electrical stimulation tests, called nerve conduction studies. As most pa-
tients have mild symptoms, no specific treatment is usually given for
peripheral sensory neuropathy in Sjogren's. For patients with severe
symptoms, treatment may prove difficult. There are some therapies that
can be tried, such as intravenous immunoglobulin or plasmapheresis.
Sometimes an individual nerve that controls the movement of one
muscle can be affected, and this can result in weakness of the muscle.
One such example is if a patient suddenly develops foot drop on one
side. This is known as mononeuritis. The cause of this problem is in-
flammation in the blood vessel supplying the individual nerve or vas-
culitis. Vasculitis can be treated by the use of steroids or other drugs
that suppress the immune system. If the treatment is given early, the
nerve can recover from the damage and the muscle weakness can resolve.
The cranial nerves, that is, the nerves supplying the face, can also
be affected in Sjogren's. Most commonly the sensory branch of the
THE NEW SJOGREN'S SYNDROME HANDBOOK
78

trigeminal nerve is affected. This supplies the sensation around the eyes,
the nose, the cheeks, and the mouth. In Sjogren's, the symptoms of tri-
geminal neuropathy are numbness or tingling around the mouth and the
cheeks. The area around the eye is less commonly involved. Pain may
be present but usually is not severe.
In carpal tunnel syndrome, a common complication in Sjogren's, in-
flamed tissue in the forearm presses against the median nerve, causing
pain, numbness, tingling, and sometimes muscle weakness in the thumb
and index and middle fingers. The symptoms are often worse at night.
The diagnosis is confirmed by nerve conduction studies. Night splints
can help alleviate the symptoms. Also, steroid injections into the carpal
tunnel can give temporary relief for up to few months. Steroid injections
can be repeated once or twice, but if the symptoms persist, surgery may
be necessary. The surgical procedure, known as carpal tunnel decom-
pression, involves making a small cut on the inside of the wrist to free
the tissues that press the median nerve. This can be done under local
anesthetic on an outpatient basis. It is usually very successful.
Sjogren's has been reported to affect the brain. However, this point
will remain controversial until further studies are done. In studies of
Sjogren's patients all over the world, a variety of neurological symptoms
originating from the brain have been recorded. For example, some pa-
tients have been noted to have symptoms of epilepsy, stroke, multiple
sclerosis, or Parkinson's disease. However, there is no consensus as to
the proportion of Sjogren's patients affected by diseases of the brain.
Although these neurological diseases are noted to occur in Sjogren's pa-
tients, they may not necessarily be caused by Sjogren's.
Some Sjogren's patients have been noted to have memory or concen-
tration problems or symptoms of anxiety and depression. Again, the
percentages quoted in studies vary (7 to 80 percent). Part of the problem
is that the symptoms can be quite subtle and not easily recognized. Mem-
ory or concentration problems can also sometimes be a manifestation of
anxiety or depression, so patients have to be carefully evaluated by a
psychologist or psychiatrist. If anxiety or depression is confirmed, ther-
apy in the form of psychological counseling or drugs (antidepressants)
may be of benefit. Also, patients with isolated memory or concentration
problems may improve with the help of mental exercises prescribed by
specially trained psychologists.
 THE INTERNAL ORGANS IN SJOGREN S
79

TABLE 10.1 ORGAN INVOLVEMENT IN PATIENTS WITH PRIMARY

SJOGREN'S

Percentage of patients with

primary Sjogren's also
Organ Complication affected by this complication

Lung Interstitial lung disease 6 percent

Lung Small-airway disease 23 percent
Lung Pleurisy 2 percent
Kidney Interstitial nephritis 9 percent
Esophagus Esophageal dysmotility 36 percent
Heart Pericarditis 2 percent
Liver Primary biliary cirrhosis 4 percent
Nerves Carpal tunnel syndrome 12 percent
Nerves Peripheral neuropathy 2 percent

Summing Up
The major body organs can be affected in one-third of primary Sjo-
gren's patients. Involvement of the lungs usually produces mild symp-
toms not requiring other than symptomatic treatment. Interstitial lung
disease occurs rarely and requires treatment with steroids and immu-
nosuppressive drugs. Involvement of the kidneys can manifest itself as
interstitial nephritis which is usually benign and requires no treatment.
Very rarely it may cause kidney damage, which can be reversed if treated
early with steroids. More severe disease such as glomerulonephritis can
sometimes occur, requiring treatment with steroids and immunosuppres-
sive drugs. Esophageal dysmotility can cause difficulty in swallowing as
well as acid reflux. The latter can be treated with drugs that reduce acid
production by the stomach. More rarely, indigestion can be due to
atrophic gastritis. This can result in pernicious anemia that can be
treated with regular vitamin B12 injections.
Primary biliary cirrhosis can rarely occur in association with Sjogren's
and has a variable prognosis. Ursodeoxycholic acid can delay the pro-
gression of the disease. Chronic active hepatitis can also rarely occur,
and it can be treated with steroids and immunosuppressive drugs. Peri-
carditis usually occurs in patients with secondary Sjogren's and systemic
lupus erythematosus and can be successfully treated with steroids. The
most common disease of the peripheral nerves in Sjogren's is carpal tun-
THE NEW SJOGREN'S SYNDROME HANDBOOK
80

nel syndrome. It can be treated with steroid injections or surgery. Pe-

ripheral sensory neuropathy can occur in Sjogren's and is usually mild
and non-disabling. Very rarely vasculitis can result in mononeuritis, and
this can be reversed after treatment with steroids and immunosuppres-
sive drugs. Involvement of the brain is controversial. A variety of symp-
toms such as memory problems, anxiety, and depression are more com-
mon in Sjogren's patients. Other more severe symptoms of epilepsy,
stroke, and multiple sclerosis have been reported and may possibly be
caused by Sjogren's (see Table 10.1).
 Frederick B. VMno, MD, MS, FACR

11 Manifestations of
Connective Tissue
Diseases Seen in
Secondary Sjogren's

MANY PATIENTS WITH A VARIETY of autoimmune conditions demonstrate

manifestations of Sjogren's syndrome. This chapter briefly reviews these
and shows how Sjogren's relates with and interacts with them.

Definitions and Terms

The term connective tissue disorders, also known as collagen vascular
diseases, refers to a group of chronic, autoimmune, rheumatic, and sys-
temic inflammatory diseases characterized by the production of auto-
antibodies in the blood and inflammation of the connective tissues (what
holds us together). Common symptoms include arthritis, musculoskeletal
pain, Raynaud's phenomenon (see below), skin rashes, fatigue, intersti-
tial lung disease (scarring of the lungs), esophageal dysmotility (disor-
dered contraction of the esophagus), and reflux. Other internal organs
may also be affected. The most important connective tissue disorders
besides Sjogren's include rheumatoid arthritis, systemic lupus erythe-
matosus, scleroderma, polymyositis, dermatomyositis, mixed connective
tissue disease, undifferentiated connective tissue disease, and vasculitis,
and will be briefly discussed in this chapter.
When a previously healthy person develops dry eye and dry mouth
associated with autoantibodies in the blood or a positive lip biopsy,
he or she will be diagnosed with primary Sjogren's syndrome. When a

81
THE NEW SJOGREN'S SYNDROME HANDBOOK
82

person has a known connective tissue disease (e.g., rheumatoid arthritis

for five years) and then later develops dry eye and dry mouth as a further
complication, we call it secondary Sjogren's syndrome (i.e., secondary to
another connective tissue disease). The ratio of patients with primary
and secondary Sjogren's is roughly 1:1. Other autoimmune disorders
that primarily affect a single organ system may coexist with primary
Sjogren's syndrome but are not strictly classed among the connective
tissue diseases. These include Hashimoto's thyroiditis, Raynaud's, and
antiphospholipid antibody syndrome.

Rheumatoid Arthritis
Rheumatoid arthritis (RA) is the most common autoimmune rheu-
matic disease and may affect up to 1-1.5 percent of the North American
population. It occurs most often in people 40-60 years old but may
develop at any age, even in children. The female-to-male ratio is 2.5 to
1. As the name implies, the target organ for inflammation in RA is the
joint, particularly the joint lining or synovium. Rheumatoid arthritis pa-
tients typically develop painful swelling of small and large joints over a
period of weeks to months. A symmetrical polyarthritis develops over
time. In rare cases this process occurs more acutely. The proximal inter-
phalangeal (PIP) and metacarpalphalangeal (MCP) joints (the knuckles
closest to the wrist) of the hands, the wrists, elbows, shoulders, hips,
knees, ankles, and feet are usually affected. The arthritis is associated
with fatigue and generalized morning stiffness. The daily stiffness often
limits patient mobility and lasts 45-60 minutes or longer before maximal
improvement. In some cases, subcutaneous nodules (rheumatoid nod-
ules) develop around the elbows or at pressure points in the extremities.
The diagnosis of RA is based on clinical findings and results of lab-
oratory studies, X-rays, and joint fluid analysis. The latter test is per-
formed by aspirating synovial fluid from a swollen joint to look for
inflammation (i.e., WBC count > 2,000/mm3) and to exclude infectious
causes of arthritis and the presence of crystals as seen in polyarticular
gout and pseudorheumatoid pseudogout, two disorders that can mimic
RA. Diagnosis of RA requires the presence of symptoms and signs for
at least six weeks (Table 11.1). Serum rheumatoid factor is positive in
70-80 percent of patients at onset and 90 percent of patients in ad-
vanced cases. Although helpful in diagnosis, serum rheumatoid factor is
 MANIFESTATIONS OF CONNECTIVE TISSUE DISEASES
83

TABLE 11.1 CRITERIA FOR THE CLASSIFICATION OF

RHEUMATOID ARTHRITIS

1. Morning stiffness > 1 hour

2. Arthritis of ^ 3 joint areas
3. Arthritis of hand joints (PIPs, MCPs) or wrists
4. Symmetric arthritis
5. Rheumatoid nodules
6. Serum rheumatoid factor
7. Radiographic changes (erosions, periarticular demineralization)

Note: Criteria 1-4 must be present for at least 6 weeks. Clas-

sification or diagnosis as RA requires 4 of 7 criteria.
Source: Modified from Arthritis Rheum 1988; 31;315-324.

not specific for the disease and may occur in primary Sjogren's syndrome
and other connective tissue diseases. X-rays show symmetric narrowing
of joint spaces due to cartilage loss, thinning of bone around inflamed
joints (periarticular demineralization), and erosions. Erosions (little holes
at the edges of the bone ends) develop as early as one year after onset
and exemplify the destructive nature of RA. Patients with primary Sjo-
gren's can also develop a rheumatoid-like arthritis, but erosions are not
typically observed.
In a subset of patients the inflammation spreads to other organs and
causes secondary Sjogren's syndrome and other problems. The most
common morbidities include scleritis and episcleritis (inflammation of
the outer layers of the ocular surface), interstitial lung disease, pleural
and pericardial effusions (fluid around the lungs or heart), cutaneous
vasculitis (inflammation of blood vessels), carpal tunnel syndrome, pe-
ripheral neuropathy, and cervical subluxation with myelopathy (spinal
cord injury due to unstable neck bones).
Most cases of rheumatoid arthritis require aggressive treatment, in-
cluding multiple medications and physical therapy, to prevent disability,
deformity, and other complications. Non-steroidal anti-inflammatory
drugs (NSAIDs) (e.g., ibuprofen), oral and intraarticular steroids, hy-
droxychloroquine, methotrexate, and the TNF-oc inhibitors (etanercept,
infliximab, adalimumab) are the most commonly used treatments. Pa-
tients who fail medical therapy eventually may require joint replacement
surgery.
THE NEW SJOGREN'S SYNDROME HANDBOOK
84

TABLE 11.2 CRITERIA FOR THE CLASSIFICATION OF

SYSTEMIC LUPUS ERYTHEMATOSUS

1. Malar rash
2. Discoid rash
3. Photosensitivity
4. Oral ulcers
5. Arthritis
6. Serositis
7. Renal disorder
8. Neurologic disorder
9. Hematologic disorder
10. Abnormal immunology test
11. Antinuclear antibody positivity

Note: Classification as SLE requires that 4 of 11 criteria be met.

Source: Modified from Arthritis Rheum 1982, 25;1271-7.

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune rheu-
matic disorder characterized by immune complex (antigen-antibody
complex) deposition in various tissues, causing multiple organ disease
and/or failure in association with anti-nuclear antibody (ANA) produc-
tion in the blood. In North America lupus affects approximately 0.05
percent of the general population and preferentially strikes young
women (the female-to-male ratio is 8:1) in the 15-40 age group, espe-
cially African Americans. Less commonly SLE occurs among men, pe-
diatric patients, and older adults. Lupus often runs in families.
Because lupus patients may manifest a myriad of medical problems,
diagnosis can be challenging. However, the American College of Rheu-
matology has advanced a set of research classification criteria that also
provide a useful framework for diagnosis (Table 11.2). The criteria rec-
ognize the high prevalence of mucocutaneous manifestations and auto-
antibody production in the disease. Four of eleven criteria must be sat-
isfied either simultaneously or sequentially for classification as SLE. Since
some patients don't exhibit the full-blown syndrome at disease onset,
the diagnosis of lupus is sometimes suspected but not unequivocally con-
firmed until months or years later.
Lupus causes a variety of skin rashes, including hives, blisters, a
measles-like rash, and a rash that resembles psoriasis. The most char-
acteristic skin and mucous membrane abnormalities, however, include
 MANIFESTATIONS OF CONNECTIVE TISSUE DISEASES
85

the malar rash, discoid rash, skin photosensitivity, oral ulcers, or nasal
ulcers. The malar or butterfly rash looks like a red patch over the nasal
bridge, nose, and cheeks in the shape of a butterfly and heals without
scarring. In contrast, discoid lupus causes raised, red plaques on the head
and extremities. These plaques are often associated with scaling and fol-
licular plugging, and heal with loss of pigmentation, scarring, and/or
loss of hair. In some instances patients with lupus develop severe skin
rashes in sun-exposed areas (photosensitive rashes) following brief ex-
posure to the sun or ultraviolet light. Painless or painful oral and nasal
ulcers can also occur, especially in individuals with active skin disease.
The diagnostic hallmark of SLE is the presence of antinuclear anti-
bodies (ANAs), found in up to 95 percent of patients when tested by
indirect immunofluorescence using the Hep-2 cell substrate. Cases of
ANA-negative lupus (i.e., patients with clinical lupus but a negative test)
can be diagnosed by testing for anti-Ro/SSA and anti-La/SSB using a
different assay system. This is because the marker autoantibodies for
Sjogren's syndrome, anti-La/SSB and anti-Ro/SSA, are also found in 15-
45 percent of SLE patients. Anti-Sm antibodies are most specific for SLE
but are found in < 30 percent of patients. Anti-double-stranded-DNA
antibodies occur in < 60 percent of patients and correlate best with
disease activity, especially lupus kidney disease. Titers tend to rise with
disease flares and fall toward normal with improvement. In contrast,
levels of complement (immune mediator proteins) C3, C4, and CH50
tend to fall with disease exacerbations (as immune complexes are formed
and bind complement) but rise with remissions. Lupus patients also form
antibodies to phospholipids, and this will sometimes cause a false posi-
tive RPR or VDRL blood test for syphilis. The ANA and other immu-
nologic tests are two of the necessary four criteria for diagnosis.
Constitutional symptoms in lupus include fevers, weight loss, malaise,
and fatigue. Internal organ involvement in SLE also causes serious and
sometimes life-threatening complications. Interstitial lung disease, pleu-
risy (inflammation of the lining around the lung), pleural effusions, in-
flammatory pneumonitis (pneumonia), and pulmonary hemorrhage all
cause shortness of breath and, in the most severe cases, lead to respi-
ratory failure. Pericarditis (inflammation of the heart lining) and peri-
cardial effusions cause chest pain and shortness of breath. Heart failure,
valvular heart disease, and accelerated coronary atherosclerosis also
occur. Acute or chronic kidney inflammation (lupus nephritis) due to
THE NEW SJOGREN'S SYNDROME HANDBOOK
86

glomerulonephritis (inflammation of the kidney filtration units) or inter-

stitial nephritis (inflammation of the tissues surrounding the glomeruli)
leads to loss of kidney function and the appearance of protein, cells,
and/or casts in the urine. In the most severe cases lupus nephritis may
rapidly progress and necessitate prompt diagnosis and treatment to pre-
vent the need for dialysis or even patient demise.
Critical complications can also develop with central nervous system
involvement. Lupus can cause seizures, psychosis, coma, stroke, mini-
stroke, mood disorders, confusion, cognitive dysfunction, chorea (move-
ment disorders), transverse myelitis (spinal cord damage due to inflam-
mation), and abnormalities of the cranial nerves. Peripheral neuropathies
also occur. The musculoskeletal manifestations of lupus include arthral-
gias and myalgias (joint and muscle pain) along with polyarthritis. The
arthritis of SLE can cause deformities similar to those seen in rheumatoid
arthritis but rarely causes erosions. Hematologic abnormalities in lupus
include autoimmune hemolytic anemia and thrombocytopenia (low
platelets). In these conditions the body forms antibodies against its own
red blood cells or platelets, and patients develop fatigue, shortness of
breath, or bleeding.
The ten-year survival rate in lupus is approximately 90 percent, and
many patients have mild cases (e.g., skin rashes, joint pain) that do not
require treatment with toxic drugs. Skin rashes, hair loss, and oral ulcers
can be effectively managed with hydroxychloroquine, other anti-malarial
drugs, and/or topical steroids. Hydroxychloroquine and NSAIDs alle-
viate arthritis and joint and muscle pain. Use of oral steroids (e.g., pred-
nisone), intravenous steroids, and/or more toxic immunosuppressives
(e.g., azathioprine, cyclophosphamide) is indicated in patients who fail
more conservative measures or develop life-threatening problems such
as hemolytic anemia, severe thrombocytopenia, or disease of the heart,
lungs, kidneys, or central nervous system.

Antiphospholipid Antibody Syndrome

Antiphospholipid antibody syndrome (APS) is an autoimmune dis-
order characterized by recurrent arterial and venous thromboses (blood
clots) and/or recurrent spontaneous abortions (miscarriages) associated
with the presence of antibodies to phospholipids. It can occur by itself
as a primary disorder (primary APS) or in association with connective
 MANIFESTATIONS OF CONNECTIVE TISSUE DISEASES
87

tissue disease (secondary APS), most notably lupus. Its occurrence in

primary Sjogren's syndrome is infrequent. It most commonly causes deep
venous thromboses in the arms and legs, pulmonary emboli (clots in the
lungs), strokes, mini-strokes or recurrent miscarriages (usually in the sec-
ond or third trimester). Blood clots must be documented by objective
medical testing, and antibody presence is demonstrated when one or
more of the following blood tests is positive: anticardiolipin antibodies,
lupus anticoagulant, or anti-beta-2-glycoprotein I. Mild thrombocyto-
penia also occurs in APS but doesn't prevent clots. The major treatment
is lifelong anticoagulation with blood thinners such as heparin or war-
farin. Other causes of blood clots and pregnancy loss must always be
excluded in the diagnostic evaluation. The antibodies may occasionally
occur in normal people and don't always cause clots when present.

Scleroderma
As the name implies, scleroderma, or systemic sclerosis, is a multi-
system autoimmune rheumatic disease characterized by progressive
thickening and induration of the skin in association with fibrosis (scar-
ring) of the internal organs and thickening of small blood vessels. It
affects a small percentage of the general population (0.02-0.075 per-
cent), with peak occurrence at ages 35-65 years and a female prepon-
derance. In early stages it causes puffiness of the hands, later followed
by skin thickening on the fingers and toes. The skin on the digits be-
comes tight and shiny like leather (sclerodactyly), and this process grad-
ually spreads up the arms and legs to involve the face and occasionally
the trunk as well. Diagnosis can be made by skin biopsy or documen-
tation of skin involvement and typical features by an experienced clini-
cian. Diagnosis of scleroderma requires the presence of one major and
two minor criteria (Table 11.3).
Patients are classified into disease subsets and prognostic categories
according to the degree of clinically involved skin and autoantibody pro-
file. People with limited scleroderma have cutaneous thickening of the
distal limbs (below the elbows and knees) without truncal involvement
and are typically anti-centromere antibody positive (40-50 percent). The
CREST syndrome (calcinosis, Raynaud's, esophageal dysmotility, scler-
odactyly, telangiectasias) falls within the classification scheme of limited
systemic sclerosis. People with diffuse scleroderma have skin thickening
THE NEW SJOGREN'S SYNDROME HANDBOOK
88

TABLE 11.3 CRITERIA FOR THE CLASSIFICATION OF SYSTEMIC SCLEROSIS

A. Major: Symmetric thickening, tightening and induration of skin above the

metacarpal-phalangeal joints (where the fingers join the hands) or metatarsal-
phalangeal joints (where the toes join the feet)
B. Minor:
1. Sclerodactyly
2. Scarring of finger tips or loss of finger pads
3. Chest X-ray scarring at the base of both lungs

Note: Classification of scleroderma requires one major or two minor criteria.

Source: Modified from Arthritis Rheum, 1980, 23;581-590.

above and below the elbows, knees, and/or trunk. They are typically
anti-scleroderma or anti-Scl-70 antibody positive (20-30 percent) and
carry a worse prognosis due to greater internal organ disease. Raynaud's
phenomenon (cold-induced color changes in the fingers) is discussed fur-
ther below and may predate the onset of scleroderma by months to
years.
When the skin thickening begins, patients can also develop itching,
malaise, fatigue, arthritis, and musculoskeletal pain. Scarring of the gas-
trointestinal tract causes difficulty swallowing due to esophageal dys-
motility (disordered contractions of the esophagus) and severe gastro-
esophageal reflux disease (GERD). Interstitial fibrosis and pulmonary
hypertension (high blood pressure in the lungs) lead to progressive short-
ness of breath, especially during exertion. Pericarditis, pericardial effu-
sions, heart rhythm abnormalities, and heart failure result from inflam-
mation and scarring of cardiac tissue. Hypertension associated with
acute renal failure, also called scleroderma renal crisis, is a medical emer-
gency that may necessitate dialysis or cause patient demise. Muscle
weakness due to myositis (muscle inflammation) can also occur.
Symptomatic treatments are available and used according to organ
involvement. Some patients will note spontaneous improvement of skin
thickening over time or following use of medications such as D-
penicillamine or methotrexate. Reflux is treated by diet and use of pro-
ton pump inhibitors (e.g., omeprazole). Angiotensin-converting enzyme
(ACE) inhibitors (e.g., captopril) can control blood pressure and preserve
kidney function if initiated early in scleroderma renal crisis.
 MANIFESTATIONS OF CONNECTIVE TISSUE DISEASES
89

Raynaud's Phenomenon
Raynaud's phenomenon is defined as cold-induced color changes of
the fingers, toes, nose, or earlobes that result from spasm and/or thick-
ening of small arteries at involved sites. It can exist as an isolated prob-
lem (primary Raynaud's disease) or in association with any of the con-
nective tissue disorders including Sjogren's (secondary Raynaud's). It
causes the worst problems among individuals with scleroderma. Patients
typically develop blanching of part of the fingers or involved areas after
exposure to cold, followed by cyanosis (bluing) and later erythema (red-
ness) upon rewarming. Occasionally, episodes can be induced by nicotine
from cigarette smoke or emotional stress. Primary Raynaud's disease
usually affects young women and may be annoying to the patient but
seldom causes significant discomfort or permanent damage. In contrast,
secondary Raynaud's may cause ischemic pain and/or numbness fol-
lowed eventually by complications such as digital ulcers, infections, loss
of the fingertip pads or bone, and digital gangrene. Patients are treated
with calcium channel blockers (e.g., nifedipine) to relax the blood vessels
and with anti-platelet agents (e.g., aspirin) to prevent clots. The most
severe cases will require use of intravenous medications, nerve blocks,
or surgical amputation.

Polymyositis and Dermatomyosltis

Polymyositis and dermatomyositis comprise a group of autoimmune
rheumatic diseases that cause skeletal muscle weakness and inflamma-
tion (myositis). Dermatomyositis also causes a characteristic rash. These
disorders affect 0.05-0.08 percent of the population with peak age at
onset of 10-15 years in children and 45-60 years in adults. The female-
to-male ratio is 2:1. Polymyositis is more common than dermatomyositis
in adults, and the reverse is true for children.
Patients insidiously develop symmetric weakness of proximal muscles
around the shoulders and hips over a three- to- six-month period. This
may cause difficulty getting up from a chair, climbing stairs, walking, or
raising an arm to comb the hair or hang up a coat. The myositis may
spread to muscles that control breathing or swallowing and cause short-
ness of breath or dysphagia (difficulty swallowing). Other problems in-
clude fatigue, arthritis, joint and muscle pain, Raynaud's, interstitial lung
disease, GERD, esophageal dysmotility, and heart failure. Secondary
THE NEW SJOGREN S SYNDROME HANDBOOK
90

Sjogren's can also complicate polymyositis and dermatomyositis, and

myositis can occasionally be a manifestation of primary Sjogren's.
People with dermatomyositis exhibit one or more of several charac-
teristics rashes. These include the heliotrope rash (lilac discoloration of
the eyelids), Gottron's sign (a scaly, red rash over the knuckles), shawl
sign (redness of the posterior shoulders and neck), and the V-sign (red-
ness of the anterior neck and upper chest). Children with dermato-
myositis often develop ectopic calcifications (painful calcium deposits of
the skeletal muscle and subcutaneous tissues). The diagnosis of poly-
myositis or dermatomyositis is suspected when the skeletal muscle en-
zymes, creatine phosphokinase (CPK) and aldolase, are elevated in the
blood of a patient who is weak. An electromyographic or EMG study
will demonstrate abnormal electrical activity of the muscles and help
eliminate a neuropathy as the cause of the weakness. The diagnosis is
confirmed by biopsy of an involved muscle that shows damage and in-
filtration of muscle fibers by lymphocytes and other inflammatory cells.
Although not found in the majority of patients, the presence of cer-
tain myositis-specific autoantibodies suggests disease correlates. Anti-Jo
1 antibodies denote a subset of polymyositis patients with the anti-
synthetase syndrome (fever, Raynaud's, interstitial lung disease, polyar-
thritis), while anti-SRP (signal recognition particle) antibodies in poly-
myositis suggest a poor prognosis and response to treatment. Anti-PM-1
(or anti-PM-Scl) antibodies are found in patients with a scleroderma-
myositis overlap syndrome, while anti-Mi-2 antibodies are observed in
patients with classic dermatomyositis.
Most patients with polymyositis or dermatomyositis respond to treat-
ment with high-dose oral and/or intravenous steroids followed by phys-
ical therapy for gait training and muscle strengthening. Patients who fail
steroids or develop unacceptable side effects may be treated with other
immunosuppressive agents, including methotrexate, azathioprine, cy-
closporine, and intravenous gamma globulin.

Mixed Connective Tissue Disease

Mixed connective tissue disease, as originally described, denotes a
subset of connective tissue disease patients whose blood contains high
titers of anti-RNP (ribonucleoprotein) antibodies. Antinuclear antibodies
and rheumatoid factor are also observed. Patients typically manifest fea-
tures of several different connective tissue diseases, including RA, SLE,
 MANIFESTATIONS OF CONNECTIVE TISSUE DISEASES
91

scleroderma, and polymyositis or dermatomyositis. Secondary Sjogren's

may also occur. The most common signs and symptoms include puffy
hands, sclerodactyly, Raynaud's, skin rashes, pleurisy, polyarthritis, dys-
phagia, reflux, myalgias, and myositis. Most patients evolve into classic
lupus or scleroderma over time, and autoantibody profiles may change.
When patients meet diagnostic criteria for two different collagen vas-
cular diseases at the time of diagnosis, the term overlap syndrome is
preferred.

Undifferentiated Connective Tissue Disease

This term describes a group of individuals who exhibit signs and
symptoms of connective tissue disease and are ANA positive but anti-
RNP negative. These patients fail to meet the diagnostic criteria for any
one specific disorder. They may complain of sicca symptoms, but lip
biopsies are typically negative. In some cases, a change over time in
clinical features or autoantibody profile may yield a specific diagnosis.

Vasculttis
Vasculitis is a broad term that describes a heterogeneous group of
collagen vascular disorders that cause blood vessel inflammation with
subsequent damage to the vessel wall, tissue necrosis from ischemia
(poor blood supply), and in some cases eventual organ failure. Its clinical
manifestations vary according to the site of involvement. It can be lo-
calized to a single organ or cause systemic disease. Vasculitis can exist
as a primary disorder (e.g., polyarteritis nodosa) or occur as a compli-
cation of another connective tissue disease, including Sjogren's syn-
drome. It can sometimes be precipitated by infections or medication side
effects. Vasculitic disorders are grouped according to (1) the size and
type of vessel involved, (2) the type of cells that cause the vessel inflam-
mation, (3) etiology, and (4) affected organs.
The subset of Sjogren's syndrome patients with extraglandular man-
ifestations (i.e., serious internal organ disease; see Chapter 10) are also
the individuals at greatest risk for the development of vasculitis. Labo-
ratory clues may include the appearance of cryoglobulins in the blood
(proteins that precipitate out in the cold); high titers of anti-Ro/SSA
antibodies; elevation of serum IgG, gamma globulins, or the erythrocyte
sedimentation rate; low levels of complement C3 or C4; or positive anti-
neutrophil cytoplasmic (ANCA) antibodies. However, as with other
THE NEW SJOGREN'S SYNDROME HANDBOOK
92

patient groups, the definitive diagnosis of vasculitis in Sjogren's can only

be made by biopsy of an involved organ or by doing an arteriogram.
The biopsy should show invasion and/or damage of blood vessel walls
by inflammatory cells. The arteriogram is performed by injecting radio-
opaque contrast dye into an artery to look for abnormalities of vessel
shape, including aneurysms, segmental narrowing, or dilatation.
The skin is the most frequent site of vasculitis in Sjogren's syndrome.
Cutaneous vasculitis affects small vessels (arterioles, capillaries, venules)
and typically causes raised reddish purple spots on the legs, called pal-
pable purpura. These lesions may be painful or pruritic. Other vasculitic
rashes in Sjogren's include urticaria (hives), skin ulcers, or erythema mul-
tiforme (red spots of variable size and shape). Vasculitic involvement of
small to medium arteries in Sjogren's syndrome will occasionally affect
the nervous system and cause strokes, mini-strokes, or peripheral neu-
ropathies. A particular type of peripheral neuropathy, mononeuritis mul-
tiplex, is highly suggestive of vasculitis and is suspected when the patient
develops foot drop associated with patchy loss of sensation in the lower
extremities. The diagnosis is confirmed by performing an EMG/nerve
conduction study of the legs followed by biopsy of the sural nerve. Vas-
culitis of the medium-sized arteries of abdominal organs is rare in Sjo-
gren's syndrome but can cause life-threatening complications. The di-
agnosis is proven by arteriogram or examination of tissue specimens
obtained during emergency surgery.
Treatments for vasculitis vary with the organs involved but in some
cases prove to be long, difficult, and extremely toxic. Therefore, every
effort should be made to obtain a proper diagnosis at the time of initial
presentation and exclude other disorders that cause similar symptoms
but require different treatments.

Secondary Sjogren's Syndrome: Clinical

Manifestations, Diagnosis, and Prevalence
The onset of secondary Sjogren's syndrome among connective tissue
disease patients is highly variable (1-40 years) but occurs in the majority
of people about 5-10 years after diagnosis of the primary, underlying
disorder. Sicca symptoms in secondary Sjogren's are generally milder
than those of primary Sjogren's. It remains unclear whether this phe-
nomenon reflects lesser severity or earlier diagnosis facilitated as a ben-
efit of rheumatologic care for other problems. Clearly, however, the prev-
alence of salivary gland swelling, adenopathy (swelling of the lymph
 MANIFESTATIONS OF CONNECTIVE TISSUE DISEASES
93

nodes), and lymphomas in secondary Sjogren's is diminished compared

to its primary counterpart.
Some studies suggest that dry eye occurs more commonly than dry
mouth in lupus and RA patients with secondary Sjogren's, while in scle-
roderma patients with secondary Sjogren's, the reverse seems true. In-
terestingly, in scleroderma, secondary Sjogren's occurs more commonly
among the limited variant than the diffuse form of the disease. Treat-
ments for these patient groups are typically directed toward the under-
lying disease. However, symptomatic patients with secondary Sjogren's
may also benefit from therapy with secretogogues and other measures,
as discussed in Chapters 14 and 15.
At the present time, the diagnosis of secondary Sjogren's is most eas-
ily accomplished by utilizing the revised European-American classifica-
tion criteria that were recently adopted by the Sjogren's Syndrome Foun-
dation (see Table 2.2). These require that patients have an established
connective tissue disease, at least one sicca symptom, and two out of
three objective tests for dry eye and dry mouth.
The prevalence of secondary Sjogren's in other collagen vascular dis-
orders remains controversial and depends on how this diagnosis is made.
When older diagnostic criteria were applied to large patient populations,
prevalence figures for secondary Sjogren's of 31 percent, 20 percent, and
20 percent were reported in patients with rheumatoid arthritis, lupus,
and scleroderma, respectively. According to one survey, anti-Ro/SSA and
anti-La/SSB are normally present in primary Sjogren's and lupus, as de-
scribed above, but become more prevalent in all patient groups with the
development of secondary Sjogren's: rheumatoid arthritis (24 percent/6
percent), lupus (73 percent/46 percent), and scleroderma (33 percent/18
percent). Studies of positive lip biopsies in the same patient groups sug-
gest prevalence figures that are even higher: RA 35 percent, SLE 18-90
percent, and scleroderma 17-51 percent. Interestingly, the proportion of
patients with positive biopsies in these studies was always substantially
higher than the number of patients with symptoms. Perhaps future stud-
ies of prevalence utilizing the new classification criteria will settle this
controversy.

How Sjogren's Syndrome May Influence the

Expression of Other Connective Tissue Diseases
The influence of secondary Sjogren's on the course of other con-
nective tissue diseases has not been closely examined. In rheumatoid
THE NEW SJOGREN'S SYNDROME HANDBOOK
94

arthritis patients the coexistence of secondary Sjogren's reportedly has

little effect on the course of arthritis or other clinical manifestations.
However, dryness of the gastrointestinal tract from Sjogren's syndrome
could potentially exacerbate a variety of problems common to these dis-
orders, including reflux, dysphagia, dyspepsia (upset stomach), and con-
stipation. Respiratory dryness from Sjogren's could not only aggravate
chronic cough due to interstitial lung disease but also predispose to re-
current respiratory infections. In lupus, two studies suggest that second-
ary Sjogren's is associated with an increased incidence of erosive po-
lyarthritis, an uncommon complication of SLE. In scleroderma, a study
of over 800 people reported that patients with systemic sclerosis and
secondary Sjogren's (particularly the CREST variant) were at increased
risk of developing vasculitis. Another study reported that autoimmune
liver disease, particularly primary biliary cirrhosis, was more prevalent
in scleroderma patients with secondary Sjogren's compared to sclero-
derma patients alone. Further studies will shed additional light on these
observations.

Evolution of Sjogren's Syndrome into

Other Disorders
As alluded to previously, patients with various connective tissue dis-
orders, including Sjogren's syndrome, share overlapping clinical and lab-
oratory features and are sometimes difficult to tell apart. Rheumatoid
arthritis, for example, may be complicated by secondary Sjogren's, and
the initial manifestations of primary Sjogren's can include a rheumatoid-
like polyarthritis with rheumatoid factor in the blood. Sjogren's syn-
drome was once thought to be a benign variant of lupus, and the pres-
ence of anti-Ro/SSA and anti-La/SSB antibodies in both diseases suggests
a common pathogenetic mechanism. Reports also exist in the medical
literature of patients who met criteria for both diseases at the time of
presentation and were therefore felt to have an SLE-Sjogren's overlap
syndrome. Not surprisingly, there are even reports of individuals who
started with one disease and evolved into another.
One study from France described 55 patients who presented with
sicca symptoms, anti-Ro/SSA or anti-La/SSB, and other manifestations
of connective tissue disease and who fulfilled the European diagnostic
criteria for primary Sjogren's. Other autoantibodies tested negative. Dur-
ing a subsequent period of 12-14 years, four patients developed new
 MANIFESTATIONS OF CONNECTIVE TISSUE DISEASES
95

signs and symptoms (malar rash, pleuropericarditis, glomerulonephritis)

thought to be atypical for Sjogren's. Follow-up testing revealed the pres-
ence of anti-Sm (two patients) and anti-double-stranded DNA (two pa-
tients) antibodies, and these patients were eventually diagnosed with lu-
pus according to the American College of Rheumatology criteria. In
another report a patient with primary Sjogren's syndrome (dry eye, dry
mouth, anti-Ro/SSA, anti-La/SSB) turned anti-centromere positive about
three years after he developed parotid swelling and renal tubular acidosis
(failure of the kidneys to excrete acid form the blood). He was eventually
diagnosed with the CREST variant of scleroderma following the onset
of Raynaud's phenomenon, digital ischemia, nail fold capillary dropout,
and telangiectasias (dilated small vessels in the skin that cause red spots).
Thus, in clinical situations where new symptoms cannot be explained by
a previous diagnosis, further evaluation and consideration of a new di-
agnosis may be necessary.

Other Autoimmune Disorders Associated with

Sjogren's Syndrome
Any patient with known autoimmune disease is at increased risk for
developing a second autoimmune disorder. This must also be considered
when new health problems occur. Other autoimmune disorders found
in Sjogren's syndrome patients include celiac sprue, primary biliary cir-
rhosis, chronic active autoimmune hepatitis, myasthenia gravis, perni-
cious anemia, multiple sclerosis, Addison's disease, Graves' disease, and
Hashimoto's thyroiditis. Hashimoto's thyroiditis most commonly coex-
ists with Sjogren's syndrome and causes goiter and hypothyroidism. It
can be difficult to diagnose because symptoms begin insidiously and
overlap with those of primary Sjogren's. These may include fatigue, dry
skin, coarse hair, constipation, headaches, arthralgias, myalgias, facial
swelling, cognitive dysfunction, and hoarseness. Hypothyroidism is di-
agnosed by blood tests (high TSH, low or normal free T4) and may
also occur coincidentally in a Sjogren's patient due to other causes. The
diagnosis of Hashimoto's is confirmed by the presence of one or more
thyroid autoantibodies in the blood, including anti-microsomal and
anti-thyroid peroxidase antibodies. It is treated with thyroid hormone
replacement, and frequent monitoring of thyroid function tests is
required.
THE NEW SJOGREN'S SYNDROME HANDBOOK
96

Summing Up
Between 20 and 40 percent of patients with rheumatoid arthritis,
lupus, and scleroderma and to a lesser extent other autoimmune disor-
ders also have Sjogren's syndrome. Each of these conditions presents
unique challenges that impact the diagnosis and management of the
syndrome.
 Roger A. Levy
Veronica S. Vllela, MD
Mlrhelen M. Abreu, MD

12 Useful Studies:
Blood Tests, Imaging,
Biopsies, and Beyond

THE REVISED EUROPEAN DIAGNOSTIC criteria of primary Sjogren's syn-

drome includes anti-Ro/SSA and/or anti-La/SSB antibodies as one of the
six items. The antinuclear antibody (ANA) test is a commonly performed
serologic assay for aiding in the diagnosis of a few systemic autoimmune
diseases, such as systemic lupus erythematosus (SLE), scleroderma,
mixed connective tissue disease, and Sjogren's. The test is based on an
immune fluorescent technique and is in most instances dependent on a
subjective analysis. When ANA is positive, it does not mean that an
autoimmune disease is present; it can occur in relatives of patients with
a definite diagnosis and in healthy individuals (usually in the lower titer
range), and it can also be induced by certain drugs (such as the anti-
hypertension agent hydralazine or the psychiatric drug chlorpromazine).
When anti-Ro/SSA and/or anti-La/SSB antibodies are present in the se-
rum, the ANA displays a speckled pattern in the cell nuclei. In addition
to anti-Ro/SSA and/or anti-La/SSB antibodies, several other laboratory
tests are used in the diagnostic investigation of Sjogren's. Once the di-
agnosis is confirmed, laboratory tests are important in the clinical
follow-up of Sjogren's patients and help the rheumatologist and other
specialists caring for the Sjogren's patient to evaluate if the disease is
flaring up; in addition, some have prognostic value. Since there has been
rapid progress in the sensitivity and specificity of several tests and the
replacement of a few "old favorites," such as LE cell detection and im-
print ANA, it is crucial for the modern clinician to be up to date with

97
THE NEW SJOGREN'S SYNDROME HANDBOOK
98

TABLE 12.1 BLOOD TESTING IN SJOGREN'S SYNDROME

Group Test

Acute phase reactants CRP, alpha-1-acid GP, erythrocyte sedimentation

rate.
Hematologic tests CBC, platelet count.
Non-specific immune tests Total serum IgG and IgM, cryoglobulins, protein
electrophoresis.
Non-specific autoantibodies Rheumatoid factor, ANA, anti-Ro/SSA, anti-La/SSB.
Specific autoantibodies Anti-M3, anti-fodrin.

Key to abbreviations: CRP = C-reactive protein, alpha-1 acid GP = alpha-1 acid

glycoprotein, CBC = complete blood count, ANA = antinuclear antibodies

the most recent tests and methods that the clinical laboratory has to offer.
In order to facilitate explanation of the different laboratory tests, they are
subdivided according to the methodology applied and their specificity. In
certain cases it may be difficult to differentiate primary Sjogren's from
SLE, and a laboratory test profile may be useful (Table 12.1).

Acute Phase Reactants

The measurement of acute phase reactants or proteins reflects a sys-
temic inflammatory reaction. These proteins are elevated in response to
the systemic inflammatory stimulus and are initially depicted by an in-
crease in the erythrocyte sedimentation rate, a nonspecific test in which
values are increased in all inflammatory conditions. The sedimentation
rate is often used as a follow-up tool; it is a cheap and easy-to-perform
test that can be done without much sophistication and shows increased
values when there are more acute phase reactants circulating in the
blood. It is important to recall that the sedimentation rate is higher when
the patient has significant anemia; this should not be understood as in-
creased production of acute phase reactants. The most commonly mea-
sured acute phase reactants nowadays are C-reactive protein (CRP),
alpha-1 acid glycoprotein (alpha-1 acid-GP) and serum amyloid A
(SAA); these are the first ones to increase after an inflammatory stimulus
and to drop once treatment is started or the stimulus is blocked. Other
acute phase reactants that can also be measured to evaluate systemic
inflammation are immunoglobulins, haptoglobin, fibrinogen, factor VIII,
and complement system proteins. Most laboratories around the world
 BLOOD TESTS, IMAGING, BIOPSIES, AND BEYOND
99

are currently performing specific determination of acute phase reactants

by more sensitive techniques, such as nephelometry and turbidimetry.
These ultrasensitive methodologies used for measuring CRP, alpha-1 acid
GP, and SAA make them a reliable tool not only for the initial diagnostic
investigation, but also during follow-up for evaluating systemic flare-ups.
The protein electrophoresis technique separates proteins according to
their molecular weights, and different clones can be depicted clearly. The
fractions to where the bands of protein migrate in the gel are named
with Greek letters, and while albumin, due to its larger size, appears in
the first portion, called alpha, most of the acute phase reactants and
proteins involved in the inflammatory response migrate to the gamma
region. When many proteins are found in increased amounts in the
gamma region, it is called polyclonal hypergammaglobulinemia; the con-
dition indicates that several autoantibodies are being formed, along with
increased amounts of circulating acute phase reactants. A monoclonal
band indicates an uncontrolled expansion of a certain cell type.

Cryoglobulins
Cryoglobulins are proteins involved in the immune response that are
separated through a precipitation under cold temperatures. These pro-
teins can be further analyzed by electrophoresis and other immunolog-
ical and biochemical techniques and then classified according to their
characteristics. Cryoglobulins are related to infection with the hepatitis
C virus, cutaneous vasculitis, and hypocomplementemia. Polyclonal and
monoclonal mixed cryoglobulinemia (type II) can be found in up to 60
percent of primary Sjogren's patients. The most commonly found pro-
teins are IgG polyclonal and IgM K monoclonal. During follow-up, a
switch to type I (monoclonal) cryoglobulinemia might be indicative of
the appearance of lymphoma.

Hematologic Alterations
The hematologic alterations found in primary Sjogren's, although
nonspecific, might add useful information during the initial investigation.
During follow-up of primary Sjogren's these parameters are important
in evaluating disease activity as well as drug toxicity. In a recent study
by Ramos-Casals and colleagues, with 360 patients (93 percent women)
followed from 1994 to 2000, anemia was detected in 20 percent, leu-
copenia in 16 percent, thrombocytopenia in 13 percent, eosinophilia in
THE NEW SJOGREN S SYNDROME HANDBOOK
100

TABLE 12.2 LABORATORY TESTS HELPFUL FOR THE DIAGNOSTIC

DIFFERENTIATION OF PRIMARY SJOGREN'S AND SLE

Frequency in primary Frequency in

Test Sjogren's (%) SLE (%)

Antinuclear antibodies (ANA) 80 98

Rheumatoid factor 70 20
Anti-dsDNA — 60
Anti-Sm — 30
Anti-RNP 30-40 >5
Anti-Ro/SSA 70 30
Anti-La/SSB 60 15
Anti-ribosomal P protein — 20
Anti-cardiolipin 14 30-40

12 percent, lymphopenia in 9 percent, elevated sedimentation rate in 22

percent, hypergammaglobulinemia (> 25 percent) in 22 percent, hypo-
gammaglobulinemia (< 15 percent) in 15 percent, reduced IgG in 8
percent, antiphospholipid antibodies in 13 percent, and monoclonal IgM
gammopathy in 22 percent.
Sometimes the diagnosis of secondary Sjogren's within the context of
a disease such as SLE, scleroderma, or rheumatoid arthritis (RA) is easy
to make, but this is not always the case in the initial differential diagnosis
workup to distinguish between primary Sjogren's and other systemic
connective tissue disorders. Some laboratory findings, such as ANA,
anti-Ro/SSA, and anti-La/SSB, are common to primary Sjogren's and SLE
(Table 12.2) and sometimes scleroderma. But there are other antibodies
that are specific to SLE, such as anti-dsDNA and anti-Sm, and those that
are typical of scleroderma, such as anti-topoisomerase I (Scl-70) and the
nucleolar pattern of ANA. We have to bear in mind the notion that a
positive ANA (especially in low titers) is not a disease marker and can
be found in 5 to 30 percent of the normal population. Rheumatoid fac-
tor can be found both in primary Sjogren's or its secondary form and
also in RA without Sjogren's.

Rheumatoid Factor
Rheumatoid factor (RF) is a type of autoantibody that binds to the
Fc portion of IgG and are important in the immune response. B-cells
 _
BLOOD TESTS, IMAGING, BIOPSIES, AND BEYOND
101

that produce exist in the circulating lymphocyte pool in a high frequency

(approximately 1-2 percent) in normal individuals and in patients with
pathological conditions associated with the sustained levels of circulating
RF, such as rheumatoid arthritis (RA), Sjogren's, and mixed cryoglobu-
linemia, associated with hepatitis C virus infection. RFs are induced by
many infectious entities (viruses, bacteria, parasites) as a consequence of
a secondary immune response to the pathogen, but usually the response
in these conditions is transient. RF might be found persistently in 50-
70 percent of primary Sjogren's patients, it can be of any of the three
major immunoglobulin classes, IgG, IgA or IgM, and it is related to the
presence of cryoglobulins. Even though it is a nonspecific finding in Sjo-
gren's, the presence of RF is predictive of systemic organ involvement.
Because RF titers do not correlate with disease activity, unlike the acute
phase reactants, RFs are not used to monitor disease activity or treat-
ment response. IgA RF is directly related to the extension of the inflam-
matory infiltrate. The variation of RF frequency in primary Sjogren's
among different series may be due to differences in patient population
selection, in the classification criteria applied, and in the method used
for RF detection. Like the appearance of a monoclonal band in the pro-
tein electrophoresis, the disappearance of previously found circulating
RF and presence of elevated beta-2-microglobulin in the serum have a
predictive value for the detection of lymphoma.

ANA, Anti-Ro/SSA, and Anti-La/SSB

Antinuclear antibodies are detected by immune-fluorescent technique
in more than 70 percent of the cases of primary Sjogren's and hence
serve as a screening tool in diagnosis. ANAs are found also in the sec-
ondary forms of Sjogren's and in other connective tissue disorders with-
out Sjogren's, so they are not specific or highly sensitive for primary
Sjogren's. The ANA result is expressed in serum dilution titer, and the
immune fluorescence pattern has to be described. The substrate most
commonly used for the reaction is the HEp2 cell line, as it has a large
nucleus that facilitates the fluorescence reading and it has been stan-
dardized in most parts of the world. A finely speckled pattern is asso-
ciated with anti-Ro/SSA with or without anti-La/SSB, which should be
investigated by a more specific methodology, such as counterimmune
electrophoresis, immune precipitation, or hemagglutination. Although
these two autoantibodies are part of the classification criteria of primary
THE NEW SJOGREN'S SYNDROME HANDBOOK
102

Sjogren's, they are not specific. The reactivity against Ro/SSA and La/
SSB can also be found in subacute cutaneous SLE and in mothers and
infants with so-called neonatal lupus syndrome. A coarse speckled pat-
tern might be related to anti-RNP with or without anti-Sm antibodies,
the presence of which should also be confirmed by specific techniques
such as the above. In an entity called mixed connective tissue disease
(MCTD), anti-RNP antibodies are the only type of autoantibodies
found, and the clinical picture is composed of signs and symptoms of
SLE, scleroderma, RA, and dermatopolymyositis. When a rim pattern is
found around the nucleus there is a suggestion that anti-dsDNA is pres-
ent. Antibodies related to SLE, such as anti-dsDNA and anti-Sm, have
to be looked at when there is a suspicion of this diagnostic hypothesis.
In a study of 72 patients with primary Sjogren's, decreased salivary flow
(according to the European classification criteria) correlated with the
presence of ANA, anti-Ro/SSA, and anti-La/SSB. No such correlation
was seen for the lacrimal flow, and there was no mutual correlation
between lacrimal and salivary flow.

Anti-Alpha-Fodrin, Anti-Acetylcholine Muscarinic

Receptor M3 Antibodies, and Other Recently
Described Autoantibodies
Anti-alpha-fodrin (a 120kD extracellular matrix protein) seems to be
a good candidate for the role of a major autoantigen in Sjogren's, as it
was found to play an important role in the P53 knockout mouse
model—it was more common in juvenile forms, its pathogenic role was
suggested, and it might have a prognostic value. Anti-alpha-fodrin was
not specific for Sjogren's, since it was also found in a lower frequency
in patients with SLE without Sjogren's. The anti-acetylcholine muscarinic
receptors inhibit muscarinic receptors on parasympathetic neurotrans-
mission and are a new marker for diagnosis for primary and secondary
Sjogren's. Autoantibodies against anti-acetylcholine muscarinic receptors
may be considered among the serum factors implicated in the patho-
physiology of the development of primary Sjogren's dry eye; they are
related to an accelerated loss of glandular function and could be a new
marker to differentiate Sjogren's dry eye from non-Sjogren's dry eye.
These findings from the physiopathogenic point of view would classify
Sjogren's as a type of disease process mediated by an autoantibody tar-
geting a neurotransmitter receptor, as in myasthenia gravis. Antibodies
directed to the amino-terminal fragment of alpha-fodrin were frequently
 BLOOD TESTS, IMAGING, BIOPSIES, AND BEYOND
103

detected in Sjogren's patients compared with rheumatic disease patients

without Sjogren's or healthy controls (70 versus 12 percent or 4 percent;
p <0.00001). These recently described autoantibodies are rapidly mov-
ing from the basic sciences lab bench to the clinical pathology laboratory,
and their role will certainly develop further in the near future. They may
also become new treatment targets in this era of biologic therapy.

Hormonal Changes
Hormonal changes such as prolactin elevation have been reported in
up to 46 percent of the primary Sjogren's patients, more commonly in
younger ones. The assessment of prolactin and other hormonal altera-
tions in Sjogren's is crucial for proper patient handling. Prolactin is the
hormone responsible for lactation stimulus; it also acts as a cellular and
humoral immune modulator, mostly enhancing the immune response.
Like many other proteins that act in the immune system, the gene for
prolactin is encoded in the short arm of chromosome 6; it is produced
in many sites, such as the pituitary gland, central nervous system cells,
and lymphocytes. Its receptors are structurally similar to cytokine recep-
tors, and there is a marked similarity in transduction pathways and sig-
naling. Molecules structurally similar to prolactin are produced by glan-
dular cells of Sjogren's patients, but not in controls, and are related to
the presence of anti-Ro/SSA antibodies. Prolactin levels are altered in 4
to 46 percent of the patients; patient selection and study design variation
account for this wide range, but as in other series, prolactin was more
frequently increased in younger patients. It is of clinical interest that
increased prolactin levels were related to disease activity. Thyroid au-
toimmune syndromes such as Graves's disease and Hashimoto's thyroid-
itis may coexist with Sjogren's. Primary autoimmune thyroiditis was seen
in 15 percent, anti-TPO antibodies were found in 25 percent, and anti-
thyroglobulin was discovered in 24 percent. ACTH and cortisol were
found to have decreased basal concentration when compared to normal
controls; patients also displayed a decreased response to stimulus. The
female sex hormones LH, FSH, and GnRH were found to be in lower
concentration when compared to normal controls.
Laboratory results may vary among different series mainly due to
study design and patient population selection. But most importantly, the
rheumatologist or the clinician who cares for Sjogren's patients must be
aware of the methodological differences and variations in specificity and
sensibility of the different laboratory techniques used. Determinations
THE NEW SJOGREN S SYNDROME HANDBOOK
?04

that used to be semiquantitative are quickly becoming ultrasensitive due

to methodological progresses that are rapidly being adopted by clinical
laboratory. This has a good side and a bad side: we are able to use some
markers as disease evaluation tools, but on the other hand, some estab-
lished knowledge has to change when a newer, more sensitive method
replaces another one with a higher specificity. Predictors of neoplasic
transformation have to be looked at with extreme care.

Labial Salivary Gland Biopsy

The expected histopathologic picture of Sjogren's is of glandular lym-
phocytic infiltration frequently forming lymphocytic aggregates. Salivary
glands are the best tissues for histologic examination in Sjogren's, as they
are affected in the majority of patients and are easily accessible for bi-
opsy procedures. In 1966 Caiman and Reifman reported for the first
time the involvement of minor labial salivary glands (LSGs) in a single
patient with Sjogren's. The histologic picture was similar to major sali-
vary gland findings in patients with Sjogren's. A minor LSG biopsy is
done by performing a small elliptic section in the mucous membrane of
the lower lip, achieving the glandular tissue and avoiding the thin mus-
cular layer. The procedure is done under topical anesthesia with lido-
caine. The sample obtained is fixed in formalin and stained with he-
matoxilin/eosin. The histologic findings in earlier phases of Sjogren's are
periductal and perivascular lymphocytic infiltration. The key feature for
the diagnosis is the lymphocytes clusters of focal infiltrates. Specimens
from non-Sjogren's patients may have scattered lymphocytes, but focal
infiltrates are not characteristic. Focal lymphocytic infiltrates are evalu-
ated according to scoring systems.
Even though salivary gland biopsy is part of the diagnostic criteria
for Sjogren's, it is still a controversial procedure. The LSG biopsy has a
sensitivity of 70 to 83 percent, depending on the scoring system used.
Patients with Sjogren's confirmed by other tests may have normal LSG
in a minority of cases. Some authors question the high specificity of the
biopsy. Focal lymphocytic infiltrates were also encountered in other dis-
orders not related to Sjogren's. Therefore, a positive LSG biopsy should
be considered carefully together with clinical symptoms and diagnostic
tests. In patients with symptoms of oral and ocular dryness, positive
ocular tests and positive serology for anti-Ro/SSA and anti-La/SSB, LSG
biopsy is probably unnecessary, as these findings are enough to establish
the diagnosis. If the patient has the symptoms of oral and ocular dryness,
 BLOOD TESTS, IMAGING, BIOPSIES, AND BEYOND
105

positive ocular and oral signs, and negative serology, a biopsy would
probably be helpful, because if the results are positive, the patient will
meet the criteria and the diagnosis will be concluded. Nevertheless, ex-
perienced pathologists must evaluate the biopsies, and grading systems
should be used. Higher scores are more specific for Sjogren's. The biopsy
results must be considered along with other tests; while an LSG biopsy
would be positive in 87 percent of Sjogren's cases; in some it might add
little or no information.

Salivary Gland Scintigraphy

The oral component of Sjogren's may also be evaluated by salivary
gland scintigraphy. Salivary gland scintigraphy is a noninvasive nuclear
medicine technique for the assessment of major salivary glands. A ra-
dionuclide, pertechnetium m99, is infused intravenously; after sixty
minutes images of major salivary glands are captured by a nuclear cham-
ber and transmitted to a computer. The uptake of pertechnetium by the
glands is observed as well as the amount of saliva containing the radio-
nuclide. Measuring the uptake after salivary stimulation with lemon can
complement the method; delayed or diminished uptake is suggestive of
Sjogren's. Scintigraphy is a tool for the evaluation of the oral component
in the European criteria for Sjogren's. It is a noninvasive, qualitative,
and dynamic test and has the advantage of evaluating the four major
salivary glands (bilateral parotids and submandibulary glands) simulta-
neously; thus it can complement labial gland biopsy, which examines
only the minor salivary glands. Scintigraphy of salivary glands is highly
sensitive for Sjogren's but has a low specificity. The pertechnetium up-
take of m99 is frequently diminished in normal controls and in patients
with other connective tissue diseases. Reduced uptake by scintigraphy
correlates with reduced salivary flow by sialometry and with abnormal
ocular tests. Therefore patients with diminished salivary flow on sialo-
metry and positive rose bengal test will probably have abnormal salivary
gland scintigraphy.

Summing Up
Blood testing can be very useful in diagnosing primary and secondary
Sjogren's syndrome, identifying clinical subsets, and assessing inflam-
matory activity. Infrequently, a biopsy of tissue or imaging studies may
be needed to assist in localizing or better characterizing a pathologic
process.
 Robert F. Spiera
Harry Spiera

13 How Can I Be Sure It's

Really Sjogren's?

IN THIS CHAPTER, we will explore the differential diagnosis of Sjogren's

syndrome and the occurrence of sicca (dryness) and other Sjogren's fea-
tures in other, nonautoimmune conditions that can mimic Sjogren's.
It is important to be as accurate as possible in the diagnosis of Sjo-
gren's for several reasons. At times, the clinical features being addressed
may have an easily treatable alternative explanation, so diagnostic ac-
curacy allows true resolution of the problem rather than just further
management of the problem, which of course is often imperfect. The
diagnosis of Sjogren's can also have prognostic implications beyond just
the experienced subjective complaints, so erroneously assigning the di-
agnosis can burden the patient with concerns (such as the increased risk
of lymphoproliferative disease) that may indeed be misplaced. Finally,
Sjogren's may be mimicked by other potentially dangerous health con-
ditions in which earlier diagnosis may allow for improved clinical
outcome.

Environmental Factors
The hallmark features of Sjogren's—dryness of the eyes and mouth—
can be seen in many other medical conditions (Table 13.1). Outside
influences can also play a major role. Simple environmental factors such
as very dry heat in the winter months might contribute to a subjective
sense of dryness, but it would be unusual for that to result in compli-
cations of dryness (such as corneal abrasions or cavities) or even measur-
able severe dryness on objective testing such as Schirmer's testing of eye

106
 __
HOW CAN I BE SURE IT'S REALLY SJOGREN'S?
107

TABLE 13.1 NON-AUTOIMMUNE

CAUSES OF DRYNESS

Environment
Age
Medications
• Antidepressants
• Antipsychotics
• Neuroleptics
• Anticholinergics
• Antihista mines
• Diuretics
• Estrogens (dry eye)
Metabolic
• Diabetes
• Hypothyroidism

moisture. Medications can be an important cause of sicca symptoms and

should always be considered carefully in evaluation of the patient com-
plaining of dryness. Antidepressants, particularly the tricyclic class, are
notorious for causing dryness, particularly of the mouth, which in some
individuals may be severe. These medications are used to treat not just
depression but also sleep disorders and even chronic pain and therefore
are widely used in the general population. Hormone replacement therapy
in postmenopausal women has been shown to increase the risk of de-
veloping significant dry eye symptoms, possibly related to an effect on
the quality of the tear film. Diuretics, used to treat high blood pressure
and/or edema (fluid retention), can be drying, particularly when used at
high doses. Often routine laboratory studies such as electrolytes can offer
a clue that this side effect is manageable, and should be evaluated par-
ticularly in patients with sicca complaints being treated with these med-
ications. Other medications that can have significant drying effects in-
clude anticholinergic medications, often used to treat bladder conditions
or gastrointestinal motility disorders. Many of the antipsychotic medi-
cations used to treat psychiatric disease as well as medications used to
treat Parkinson's disease similarly have significant anticholinergic effects,
resulting in dryness. Antihistamines are widely used to treat allergies and
are a cause of dryness. These drugs are now available over the counter,
and patients therefore may not even think of including them in their list
of medications when consulting a physician for evaluation. They never-
THE NEW SJOGREN'S SYNDROME HANDBOOK
108

theless can be a major factor contributing to the development of sicca.

Meticulous review of medications is therefore imperative in evaluating
patients for the possibility of Sjogren's. Often the identified culprit can
be withdrawn or another, less drying medication substituted. Moreover,
even in patients with well-established Sjogren's, use of these medications
may exacerbate the dryness and should be considered.

Age
Another consideration in evaluating dryness is advancing age. As
people get older, there is a tendency to have less robust ocular and oral
moisture, often on a degenerative rather than an autoimmune basis. Ap-
proximately one-third of elderly patients complain of significant dryness,
and of course in only a minority of these is Sjogren's syndrome the cul-
prit. Furthermore, as people age they are more likely to have a myriad
of other medical problems, such as hypertension, bladder difficulties, or
depression, that may be treated with the aforementioned medications.
This can further exacerbate the sicca complaints, as discussed above. It
is important, however, to recognize that advanced age does not preclude
a diagnosis of Sjogren's, but rather should lead to some pause in making
the diagnosis, particularly in the absence of serological support for the
diagnosis.

Infections
A variety of infections can also cause features mimicking Sjogren's
syndrome. Parotid enlargement, oral dryness, and fatigue can occur in
the context of mumps infection, but in that setting it is usually a self-
limiting problem. Bacterial infection of parotid glands can occur, but
generally it is more of an acute illness and tends not to be confused
diagnostically with Sjogren's syndrome. Tuberculosis or even leprosy,
however, can be unusually infectious causes of parotitis and cause sys-
temic symptoms such as fever and fatigue, and should be considered in
the differential diagnosis in a patient who might be at risk for those
infections.
HIV infection has been associated with a syndrome that appears clin-
ically similar to Sjogren's, diffuse infiltrative lymphocytosis syndrome
(DILS). Similar to primary Sjogren's patients, OILS patients can have
significant sicca complaints, may demonstrate salivary gland enlarge-
ment (including both the parotid and minor salivary glands), and may
 HOW CAN I BE SURE IT'S REALLY SJOGREN'S?
109

have other nonspecific complaints such as joint pain and fatigue. Even
biopsy of affected glands may not distinguish this syndrome from Sjo-
gren's, as there can be a similar tissue appearance. Specialized staining
of the biopsy tissue, however, shows that the immune cells infiltrating
the glandular tissues are different from those that are seen in Sjogren's
patients (T8 or suppressor T cells in DILS, versus T4 or helper T cells
in Sjogren's syndrome). Patients with DILS and HIV are much less likely
to have the typical autoantibodies of Sjogren's such as anti-Ro/SSA, anti-
La/SSB, or rheumatoid factor. HIV infection should therefore be consid-
ered, particularly in patients with seronegative Sjogren's, and risk factors
for HIV should be considered in anyone diagnosed with Sjogren's.
Relatively recently, hepatitis C has been recognized as the most com-
mon cause of non-A, non-B hepatitis, affecting perhaps as much as 1
percent of the population. Investigators have questioned whether hepa-
titis C infection may be associated with the development of Sjogren's,
although studies have yielded conflicting results. There may be a subset
of Sjogren's syndrome appearing in association with hepatitis C infec-
tion, although given the relatively common occurrence of hepatitis C
infection in the general population, it is hard to establish cause and
effect. Like patients with Sjogren's syndrome, patients with hepatitis C
seem to be at increased risk for lymphoma compared to the general
population. Even serologically the issue can be confusing, as patients
with hepatitis C virus infection (or any chronic liver condition, for that
matter) can develop positive rheumatoid factor, commonly encountered
in patients with Sjogren's syndrome. In patients with fatigue, joint pain,
and a positive rheumatoid factor without other supporting Sjogren's se-
rologies such as SSA and SSB antibodies, it may be prudent to screen
for hepatitis C infection, which can be done by a simple blood test.

Metabolic Disorders
Metabolic disorders may also mimic Sjogren's syndrome. Patients
with diabetes often complain of excessive thirst and a subjective sense
of dryness. Fatigue is also common with poorly controlled blood sugar.
Other symptoms such as very frequent urination or blurred vision may
help guide the physician to the more appropriate diagnosis of diabetes.
Even the very most basic laboratory testing usually includes determina-
tion of blood sugar levels, and diabetes is therefore not often a hard
diagnosis to make. Another endocrine disorder that can be associated
THE NEW SJOGREN'S SYNDROME HANDBOOK
110

with Sjogren's-like features is thyroid disease. Underactive thyroid can

result in dryness of the mouth, vagina, skin, and hair. Fatigue is often a
major complaint, and joint and muscle pain is common. Routine phys-
ical exam will usually reveal abnormal reflexes that might point to the
diagnosis. Blood tests can confirm the diagnosis of an underactive thy-
roid gland but must be specifically ordered. Underactive thyroid is easily
treatable; more importantly, it can be dangerous if left unrecognized and
untreated. Interestingly, thyroid abnormalities are more common in pa-
tients with Sjogren's syndrome and other autoimmune diseases as well,
so when there are symptoms of increasing fatigue and musculoskeletal
pain, even in a patient with well-established Sjogren's, it is worthwhile
to check for the presence of thyroid function test abnormalities.

Hbromyalgia and Chronic Fatigue Syndrome

Other, less well defined generalized disorders may also be confused
with Sjogren's syndrome or, conversely, can complicate the course of
Sjogren's syndrome. Fibromyalgia is a rheumatic disorder characterized
by widespread musculoskeletal pain, often more of muscles than joints
themselves, without an inflammatory or recognized autoimmune basis
to the subjective complaints. Fatigue can be a prominent component of
this syndrome as well. There is a strong association with poor sleep, and
nonrestorative sleep is felt to be a contributing factor in the development
of this syndrome. Other medications used to treat fibromyalgia have
significant drying effects, including pain medications such as narcotic
analgesics, or antidepressant medications, which may be used to aid
sleep, to treat chronic pain, or of course to treat underlying depression,
which often occurs in fibromyalgia. Hence these patients may have the
constellation of symptoms—sicca features, fatigue, and pain—that often
is associated with Sjogren's syndrome. Immunomodulatory interventions
such as antimalarial medications or corticosteroids, however, do not help
fibromyalgia patients, and therefore it is important to recognize fibro-
myalgia as a potential alternative cause of the symptoms in patients
being evaluated for Sjogren's syndrome. Patients with fibromyalgia typ-
ically do not have the lab test abnormalities that are associated with
Sjogren's syndrome. Conversely, patients with well-established Sjogren's
often have disordered sleep habits related to frequent nocturnal urina-
tion (a result of increased fluid intake while awake), as well as stress
and anxiety related to the underlying rheumatic disease, all of which
 HOW CAN I BE SURE IT'S REALLY SJOGREN'S?
Ill

increase their risk for developing secondary fibromyalgia. This must be

considered in evaluating new complaints of pain and fatigue, even in a
patient with well-established Sjogren's, so that effective therapy can be
instituted or—just as important—inappropriate immunomodulatory or
immunosuppressive interventions not be initiated for what is not an in-
flammatory or autoimmune-based constellation of symptoms.
Chronic fatigue syndrome is a related syndrome with many features
that overlap with those of fibromyalgia. Patients with chronic fatigue
syndrome often report that from a functional standpoint, fatigue is a
more limiting feature than muscle or joint pain. Like fibromyalgia, no
underlying inflammatory or autoimmune abnormality has been well de-
fined, but questions have been raised regarding relationships to various
viral infections. Mild lymph gland enlargement has been described in
association with this syndrome as well, but not the robust enlargement
or parotid enlargement that can be seen in Sjogren's syndrome. The
symptoms tend not to respond to immunomodulatory interventions such
as corticosteroids. Although chronic fatigue can be a very prominent
complaint in the context of Sjogren's, fatigue alone in the absence of
objective evidence of significant dryness or other serological abnormal-
ities would argue more for the diagnosis of chronic fatigue syndrome
than Sjogren's per se.

Other Autoimmune Conditions

It is recognized that there is much overlap between the various au-
toimmune diseases. The distinction between primary and secondary Sjo-
gren's has been addressed in Chapter 11. Other immune-mediated con-
ditions, however, may be associated with Sjogren's-like complaints but
represent different disease entities. Sarcoidosis is an inflammatory con-
dition that can result in parotid and other glandular enlargement, sicca
symptoms, often significant eye inflammation, joint pain, and most com-
monly lung inflammation. Biopsies of affected tissue reveal granuloma,
a different finding than would be seen in tissue specimens from patients
with Sjogren's syndrome. Patients with sarcoidosis generally do not de-
velop the autoantibodies seen in Sjogren's syndrome. Autoimmune liver
disease can also be associated with Sjogren's-like features. In particular,
primary biliary cirrhosis is an autoimmune liver condition with a high
rate of subjective sicca complaints, joint pain, and even joint swelling
as well as fatigue. Many of these patients do indeed have Sjogren's
THE NEW SJOGREN'S SYNDROME HANDBOOK
112

syndrome, and biopsy of salivary glands reveals changes typical of Sjo-

gren's syndrome. Conversely, patients with Sjogren's syndrome can de-
velop autoimmune liver disease consistent with primary biliary cirrhosis.
It therefore becomes largely semantic whether we call the disorder pri-
mary Sjogren's complicated by primary biliary cirrhosis, or primary bil-
iary cirrhosis with secondary Sjogren's syndrome. The main practical
point is that chronic liver disease can be associated with Sjogren's syn-
drome, and that measurement of liver function tests should be included
in laboratory testing of patients suspected of having Sjogren's syndrome.

Summing Up
Sjogren's syndrome refers to a constellation of clinical features that
share an autoimmune basis. Many of the features, however, such as dry-
ness, fatigue, pain, and even glandular enlargement can occur as the
result of non-autoimmune conditions such as medications, age, meta-
bolic abnormalities, or infection. These alternative explanations must be
considered when making the diagnosis of Sjogren's, particularly when
the typical blood test abnormalities (serologies) are not present. Just as
important, in patients with well-established Sjogren's an exacerbation or
change in symptoms may be related to these other nonautoimmune fac-
tors. It is vital to consider these, particularly when making therapeutic
decisions.
 PART IV

The Management of
Sjogren's Syndrome

There are four approaches toward treating Sjogren's syndrome. First,

physical measures include exercise and attention to environmental fac-
tors such as sleep, climate, and geography. Next, since the "head bone"
is connected to the "Sjogren's bone," emotional support as well as mea-
sures taken to create an optimal atmosphere to promote healing can be
ameliorative. Third, medications exist that modulate the immune system
or provide symptomatic treatment for symptoms such as dryness. Finally,
surgical options such as biopsies may be needed under certain circum-
stances. This section will review how a practitioner manages patients
with Sjogren's syndrome.
This page intentionally left blank
 Michael A. Lemp, MD

14 Treatment of Dry Eye

THE EYES ARE FREQUENTLY affected in Sjogren's syndrome, with dry eye
one of the most common manifestations. Because vision connects us to
the outside world, disruption of visual perceptions has a profound im-
pact on our relationship to the world and our sense of well-being.
Dry eye occurs frequently in the general population. Recent studies
suggest that as many as 40 million to 60 million Americans may be
affected. Estimates of 3 million to 8 million patients with moderate to
severe dry eye in the United States have been reported recently. Of these,
about 2 million to 4 million will have Sjogren's syndrome. Chapters 4
and 6 discuss the cause and diagnosis of dry eye in great detail. A review
follows as a prelude to a discussion of its management.

A Brief Review of Dry Eye

The most common symptoms associated with dry eye involve dis-
comfort—sensations of dryness, irritation, itching, burning, a foreign
body in the eye, grittiness, or sandiness. In addition, it is now known
that symptoms of eye fatigue, which are common in Sjogren's, are prob-
ably related to problems maintaining clear vision between blinks. In an
unconscious attempt to maintain a smooth tear film there is a tendency
to blink more frequently; over time this causes ocular fatigue. While only
a small percentage of patients with Sjogren's have dryness severe enough
to threaten permanent visual loss, it is important to have an ophthal-
mologic examination with an initial diagnosis and periodic follow-up
examinations.

Diagnosis of Dry Eye

The ophthalmologist will perform a complete eye examination, which
will include a measure of vision both with and without correction

115
THE NEW SJOGREN'S SYNDROME HANDBOOK
116

(glasses or contact lenses) and an examination of the front part of the

eye using a special microscope called a slit lamp. This enables the doctor
to check the surface of the eye, the lids and tear glands, and the interior
of the eye up to the lens (the location of cataracts). Further tests include
an exam of the retina and vitreous humor, which occupy the back of the
eye. This exam usually requires the use of dilating drops, which allow
for a full view of retinal tissue.
In addition, other tests may be performed. In patients complaining
of ocular irritation and suspected of having dry eye, a Schirmer test is
commonly performed. This involves a small strip of filter paper folded
over the lower lid, inserted into the tear film, and left in place for five
minutes. The length of the strip that is wetted is a measure of the amount
of tears present. Other tests may include the instillation of special dyes
into the eye (rose bengal, lissamine green, fluorescein). These dyes stain
surface cells damaged from dryness or inflammation. Abnormal insta-
bility of the tear film is a hallmark of dry eye; this is measured by the
tear film breakup test. A small amount of fluorescein dye is instilled in
the tears to help visualize them. Using a special filter in the slit lamp
that lights up the fluorescein, the doctor can measure how rapidly the
tear film is breaking up. Some doctors also use this dye to estimate how
rapidly tears are exiting into the drainage pathways (tear clearance test);
this is a reflection of how rapidly new tears are being produced. New
research is under way to develop a simple, reliable tests (e.g., tear ly-
sozyme, tear lactoferrin, tear osmolarity) that will provide additional
information on ocular surface conditions and be suitable for widespread
use in clinics and physicians' offices.

Treatment of Dry Eye

The use of artificial tears to supplement natural tear production and
replace tears lost to evaporation has been the mainstay of treatment of
dry eye (Table 14.1). These products are available without prescription
at pharmacies. All of them contain water, salts, polymers (thickening
agents), stabilizers, and pH buffers. In addition, many of the tear sub-
stitutes contain preservatives to protect against infection. Unfortunately,
most preservatives used in artificial tear solutions are toxic to the surface
of the eye when used more than four times a day. Over the last decade
most companies have introduced tear substitutes without preservatives;
these products are packaged in small, one-time-use dispensers, and once
TABLE 14.1 ARTIFICIAL TEAR PREPARATIONS

Major Concentration
Component(s) (%) Trade Name Preservative/EDTA*

Carboxymethyl 0.5% Refresh Plus None

cellulose Refresh Tears Purite
1% Celluvisc None
0.25% Theratears None

Glycerin 0.3% Moisture Eyes Benzalkonium chloride

Benzalkonium chloride, EDTA
1 .0% Computer Eye
Drops

Hydroxyprophyl 5 mg/insert Lacrisert (biode- None

cellulose gradable insert)

Hydroxypropyl 0.2%-0.3% GenTeal Sodium perborate

methylcellulose GenTeal Gel Sodium perborate
GenTeal Mild Sodium perborate
0.5% Tearisol Benzalkonium chloride, EDTA

Hydroxypropyl Blon Tears None

methylcellulose, Lacritears Benzalkonium chloride, EDTA
dextran 70 Benzalkonium chloride, EDTA
Tears Renewed

Hydroxypropyl Clear Eyes CLR Sorbic acid, EDTA

methylcellulose, Visine for Contacts Potassium sorbate, EDTA
glycerin

Hydroxypropyl Tears Naturale Polyquad

methylcellulose, Forte
glycerin, dextran 70 Tears Naturale Free None

Hydroxypropyl meth- Visine Tears Benzalkonium chloride

ylcellulose, glyc- None
erin, PEG-400 Visine Preservative
Free

Methylcellulose 1% Murocel Methyl-, propylparabens

Polycarbophll, PEG- AquaSite EDTA

400, dextran 70 AquaSite multi- EDTA, Sorbic acid
dose

Polyvinyl alcohol 1 .4% AKWA Tears Benzalkonium chloride, EDTA

Polyvinyl alcohol, 1% HypoTears Benzalkonium chloride, EDTA

PEG-400, dextrose EDTA
HypoTears PF

Polyvinyl alcohol, 1 .4% Murine Tears Benzalkonium chloride, EDTA

povidone

*EDTA = ethylenediaminetetraaceticacid.
THE NEW SJOGREN'S SYNDROME HANDBOOK
775

TABLE 14.2 OCULAR LUBRICANTS

1. Lanolin-free products
Ointments: Hypotears, Moisture Eyes PM, Puralube, Tears Renewed
Gel: Gen Teal
2. Lanolin-containing products
Ointments: Artificial Tears, Akwa tears, Dry Eyes, Duratears Naturale,
Lacrilube NP, Lacrilube SOP, Lubritears, Refresh PM

the seal is broken they should not be used again. Tear substitutes provide
moisture to the eye and increase lubrication between the lids and the
surface of the eye. The major limitation of artificial tears is their short
duration of action. Nonetheless, they provide relief for most patients
suffering from dry eye. Several new products contain ingredients that
limit tear evaporation or stabilize the tear film. Ocular lubricants are
usually applied at bedtime (see Table 14.2). For more information see
Appendix 3.
Punctal occlusion involves closing of the tear drainage openings lo-
cated at the inner edges of the lids. This can be accomplished by inserting
a small plug that blocks the outflow of tears and serves to thicken the
tear film. Punctal plugs are either temporary (they dissolve) or permanent
(that is, they do not dissolve, but they can become dislodged). Alterna-
tively, permanent blockage of the outflow channels can be accomplished
by applying heat or laser energy to the openings (punctual cautery); this
causes a scar to form. These measures work well for most patients with
dry eye. Care, however, should be exercised to make sure tear production
is low enough that blocking of tear outflow will not cause epiphoria (an
overflow of tears onto the face). This can be very disconcerting.
Many patients with dry eye have blepharitis, which is also known as
Meibomian gland dysfunction. The dysfunction of these glands located
at the edges of the eyelids causes excessive tear evaporation and dryness.
Treatments directed to improving the function of these important glands
include the application of hot compresses to the lids and cleansing of
the lid margins with a moist cloth and/or a cotton-tipped applicator. In
addition, the use of broad-spectrum antibiotic such as tetracycline or
minocycline, taken by mouth, can provide considerable relief from
symptoms.
 TREATMENT OF DRY EYE
119

Another area that excited a great deal of interest recently is the use
of nutritional supplements to treat dry eye. Specifically, there is reason
to believe that the ingestion of foods or nutritional supplements con-
taining omega-3 and omega-6 essential fatty acids can aid in the syn-
thesis of the oils produced by the Meibomian glands of the lid. These
essential fatty acids are found in flaxseed oil, fish oils, and in supple-
ments found in pharmacies, natural food stores, and supermarkets.
While no large, controlled studies have yet been published, there is con-
siderable anecdotal evidence from patients and physicians to support
their value.
Recently the Food and Drug Administration approved the first pre-
scription drop therapeutic treatment for dry eye directed to improving
cell function rather than treating a symptom. This medication, cyclo-
sporin A (Restasis, Allergan), suppresses inflammation in the eye tissue
and allows the glands to recover their function. It must be taken for at
least three to six months before significant improvement can be seen,
and not all patients respond. How long treatment must be maintained
has not yet been determined.
Currently, no FDA-approved drugs are available for tear stimulation.
However, data from clinical studies also suggest that medication used to
treat dry mouth (e.g., pilocarpine) may also provide symptomatic relief
of dry eye.
A number of other approaches to the treatment of dry eye are cur-
rently in clinical testing. These include medications that stimulate pro-
duction of mucin by the surface cells of the eye; medications that supply
hormones to the glands of the eye, restoring the balance important for
glandular function; agents that stabilize the tear film; and others that
suppress inflammation. In the not too distant future it is likely that your
doctor will have an increasing variety of new treatments to relieve pain
and restore the eye tissue to a more normal state.

Special Considerations
Patients with dry eye who also have other eye problems necessitating
surgery, such as cataracts, should know that there is a slightly increased
risk for delayed healing after surgery. This is usually not a serious prob-
lem, and patients can anticipate equally good results. They should, how-
ever, discuss their dry eye with their surgeon, since it might necessitate
_
THE NEW SJOGREN'S SYNDROME HANDBOOK
120

a slight change in surgical technique or medication schedule. Patients

who wish to undergo Lasik surgery should discuss the pros and cons of
the procedure with their rheumatologist and ophthalmologist.

Patients and Their Environment

Patients with dry eye are highly sensitive to the environment. Dry
and/or windy conditions—such as on an airplane or when biking—pro-
mote loss of tears through evaporation. The frequent instillation of ar-
tificial tears when in these situations can prove remarkably successful in
alleviating irritative symptoms. In addition, prolonged use of video ter-
minals decreases the frequency of blinking, thus causing excessive tear
loss. Studies have shown that lowering the computer monitor below eye
level results in a decrease in the width of the eyelid opening and signif-
icantly conserves tears.
The use of wraparound glasses or side panels with spectacles (mois-
ture chamber glasses) can limit the effects of air currents on tear evap-
oration. The use of cool compresses during periods of ocular irritation
can provide relief. The secret is to experiment with these techniques, use
tear substitutes and other treatments prescribed by the doctor, and adjust
activities to minimize environmental challenges. Most patients can ex-
perience considerable improvement and enhance their sense of well-
being. The future is promising for continued development of even better
treatments.

Summing Up
Dry eye in Sjogren's is managed with artificial tears, punctal occlu-
sion, ocular lubricants, cyclosporine drops, or possibly dietary or envi-
ronmental measures. In clinical development are exciting new agents that
will change the way we approach dry eye in the next few years.
 Philip C. Fox, DOS

15 Treatment of
Dry Mouth

DRY MOUTH is A hallmark symptom of Sjogren's syndrome. The term

xerostomia is used in the medical literature to describe this subjective
sensation of dryness of the oral cavity. The cause of dry mouth in Sjo-
gren's syndrome is a reduction in the amount of saliva produced by the
major and minor salivary glands and changes in the composition of
the secretions. This is a result of autoimmune-mediated alterations in the
salivary glands that lead to a loss of fluid-secreting cells and disruption
of normal secretion mechanisms.

A Brief Review of Dry Mouth

There are three pairs of major salivary glands—the parotid, subman-
dibular, and sublingual glands—and hundreds of minor salivary glands
scattered throughout the oral cavity. These glands produce and secrete
into the mouth a complex fluid containing critical protective factors.
Saliva helps preserve the dentition, protect the oral soft tissues, and fa-
cilitate important oral functions such as chewing, swallowing, and
speaking. In the absence of adequate salivation, there are many negative
effects in the mouth. Due to the loss of the antimicrobial, remineralizing,
and cleansing properties of saliva, there is a marked increase in dental
caries. Caries may appear and progress rapidly. Microbial populations
are altered in the mouth, resulting in an increased incidence of bacterial
and fungal infections. In particular, Candida infections are frequent and
may be resistant to treatment. The oral mucosa may become thinner,
reddened, and painful, with sensitivity to spicy foods. Chewing and

111
THE NEW SJOGREN S SYNDROME HANDBOOK
_
122

swallowing become more difficult with less fluid present in the mouth.
It may be hard to form a compact food bolus and move it through the
oral cavity to the pharynx. Speaking may be compromised due to lack
of lubrication of the soft tissues. Even taste may be affected, as tastants
must be in solution in order to be fully appreciated. Accompanying these
changes is a persistent feeling of dryness, not just of the mouth, but also
of the throat, nose, and pharynx. The salivary gland dysfunction of Sjo-
gren's syndrome has profound effects on the oral cavity and oral
functions.

Treatment of Dry Mouth

Simple relief of symptoms of oral dryness is desirable but incomplete.
There are several goals to treatment of salivary gland dysfunction and
xerostomia in Sjogren's syndrome: (1) to relieve dryness symptoms, (2)
to prevent anticipated oral complications, (3) to stimulate salivary gland
function, and (4) to promote repair of salivary gland damage. The ideal
therapy would accomplish all these. At present, however, there is no
single treatment that will satisfy all these goals. However, with careful
attention, close cooperation between patients and professionals, and a
systematic approach to treatment, most aspects of dry mouth in Sjogren's
syndrome can be managed and improved.
The mainstay of symptomatic treatment is water. The importance of
adequate hydration of the oral cavity for the Sjogren's syndrome patient
cannot be overemphasized. Water should always be available, with small
sips taken frequently. Water does more than relieve the immediate sense
of dryness. It helps hydrate the oral mucosa and cleanse the mouth,
partially replacing these functions of saliva. Dehydration causes oral dry-
ness and reduced salivary output, so adequate water intake is important
to maintain maximum salivary function. If small amounts of water are
used each time, this will limit the total volume consumed and reduce
frequent urination, a complaint of many patients. Small sips of water
also help chewing and swallowing.
Increasing the humidity may be helpful as well. During the winter
months, humidity can be very low, and this will contribute to feelings
of oral dryness. This is a particular problem at night, when salivary
function normally is reduced and breathing is often through the mouth.
The use of a humidifier placed at the bedside can help relieve nighttime
 TREATMENT OF DRY MOUTH
123

dryness, thereby improving sleep. Humidifiers should be cleaned often

and the water in the reservoir replaced daily.
There are many saliva replacement products (see Appendix 3). Pa-
tients should try different products to see if any are beneficial. The effects
are temporary but may be helpful for those with very dry mouth. In
Europe, there are saliva replacement products that contain mucins (a
prominent component of human saliva) from animal sources. These are
reported to have greater patient acceptance, but the studies are limited.
Some patients use artificial saliva at bedtime and during the night in
order to limit their nighttime water intake and the subsequent need for
frequent urination during the night.
There are also numerous moisturizers, lubricants, rinses, gels, and
emollients (see Appendix 3) that are promoted for relief of dry mouth
symptoms. These can be applied to the lips and inside of the mouth.
Personal preference should guide the selection of a product. Most will
provide temporary relief of dryness and mucosal discomfort. Alcohol,
tobacco and caffeine can have drying effects on the oral cavity and
should be avoided or limited. Many carbonated beverages contain caf-
feine and are quite acidic. They should not be used regularly for relief
of dryness symptoms.
Symptoms often can be relieved effectively by stimulating salivary
output. Means of doing this are discussed below in the section on stim-
ulation of salivary gland function.

Prevention of Oral Complications

Generation of dental caries requires the presence of bacteria and a
carbohydrate source for them to metabolize. Therefore, much of the
destruction of the teeth found in Sjogren's syndrome patients can be
controlled with vigorous oral hygiene measures and dietary modifica-
tions. Meticulous oral hygiene should include flossing at least daily and
tooth brushing after each meal. The goal is to remove the bacteria that
attach to the teeth, as well as their food sources. In the absence of car-
iogenic bacteria, decay will not occur. Similarly, if the bacteria are de-
prived of fermentable carbohydrates, they will not produce acids that
can demineralize the tooth surface. Sugar in the diet should be mini-
mized, and sticky sweets, such as cookies and candies that adhere to the
teeth, should be avoided. When sugary foods are consumed, the teeth
THE NEW SJOGREN'S SYNDROME HANDBOOK
124

should be brushed—or at least rinsed—immediately. Regular use of

acidic beverages, like many soft drinks, should be avoided as well. In
addition to oral hygiene and diet, the use of fluoride is an important
preventive measure. Fluoride helps to repair early demineralization of
the tooth (the first step in dental caries) and strengthens the tooth sur-
face. A fluoride-containing toothpaste should be used, and topical flu-
oride applications may be indicated. The frequency, type, and mode of
application of topical fluoride (daily, weekly; rinse, high-concentration
gel; self- or professionally applied; brushed on, applied in a custom tray,
etc.) should be discussed with the dentist. The determination should be
made based on the caries rate and severity of the salivary gland dys-
function. In some cases, a fluoride varnish may be applied to the teeth
by the dentist. Experimental studies have shown that early caries can be
repaired with solutions containing high concentrations of calcium and
phosphate. This is one of the prominent functions of natural saliva. The
use of a remineralizing solution may be indicated in Sjogren's syndrome
patients and should be discussed with the dentist.
Fungal infections, usually caused by Candida albicans spp., are com-
mon in dry mouth patients. A confusing aspect of diagnosis is that these
often do not present in the common white mucocutaneous form (known
by most people as "thrush"). Instead, the mucosa may appear red or
irritated, the so-called chronic erythematous form of candidiasis. Patients
may complain of a burning sensation. The area should be cultured and
treatment instituted with a topical therapeutic. Due to a lack of natural
antifungal components usually provided in saliva, the infection may re-
cur. Many infections are difficult to manage and resistant to therapy, and
treatment may be prolonged. This is a problem, as most topical antifun-
gal preparations (rinses and lozenges) have a very high sugar content. A
rinse without sugar should be used or formulated. If a sugar-containing
preparation is used, particularly a slowly dissolving lozenge, patients
must brush well afterward. Although use of a systemic antifungal agent
seems ideal in Sjogren's syndrome, if salivary function is low this ap-
proach may also fail, as much of the drug is delivered through salivary
secretion and may fail to reach the affected mucosa. Aggressive topical
treatment will be successful given sufficient time and may be repeated as
often as necessary.
 _
TREATMENT OF DRY MOUTH
125

TABLE 15.1 MEANS OF STIMULATING

SALIVARY FUNCTION

Topical/Local Approaches
Gustatory stimulation
Masticatory stimulation
Anhydrous crystalline maltose
Acupuncture

Systemic Secretogogues
Pilocarpine
Cevimeline
Bromhexine
Anetholetrithione
TNF-alpha blockers

Stimulation of Salivary Function

There are many ways to stimulate salivary output. They may be di-
vided into topical or local approaches and systemic therapies (Table
15.1). By stimulating the remaining salivary gland tissue, a patient will
get all the benefits of natural saliva in the oral cavity and relief of dryness
symptoms. The success of this is dependent on the amount of secretory
function that remains and the efficacy of the stimulation. Even modest
increases in salivary output may translate into significant symptomatic
improvement. A deficiency in all current therapies is the transient nature
of the stimulation. Even systemic parasympathomimetic drugs have a
duration of action of only a few hours. However, symptomatic relief of
dryness may persist beyond the immediate period of increased salivary
output with chronic use of these agents. This is likely due to beneficial
effects on the mucosa from the increased amounts of saliva.

Topical and Local Therapies

Saliva can be stimulated effectively by almost any oral activity. Chew-
ing or sucking on an object will result in a robust increase in saliva
output. Salivation is also responsive to taste, particularly sour and bitter.
The use of flavored gums and lozenges remains a mainstay of palliative
therapy of dry mouth. The combination of gustatory and masticatory
stimulation can transiently increase salivation and relieve symptoms of
dry mouth. Patients with diminished salivation should use sugar-free
_
THE NEW SJOGREN'S SYNDROME HANDBOOK
126

gums, lozenges, candies, or mints for symptomatic relief of xerostomia.

The use of sugar-free products must be stressed, as otherwise the addi-
tion of sugar bathing the dentition will only increase the caries risk and
negate the benefits of increased salivary output. Xylitol is an acceptable
sweetener that has been shown to reduce dental caries. Recent clinical
trials have reported on the use of a lozenge composed of anhydrous
crystalline maltose as a treatment for dry mouth in Sjogren's syndrome.
Maltose has a very low cariogenic potential and may improve symptoms
and salivary function. Some patients benefit from sucking on a cherry
pit, smooth stone, or other non-nutritive object. This may increase sal-
ivation without any sugar or calories.
Although not strictly a local therapy, acupuncture relies on applica-
tion of the needles to specific locations, often in close proximity to the
oral cavity. There have been a number of clinical studies of acupuncture
to treat xerostomia, and the authors reported some benefit for relief of
symptoms and improvement in salivary output. One problem with these
studies is the difficulty in providing for appropriate placebo controls in
clinical trials of acupuncture. One trial that used superficial, non-site-
specific acupuncture as a control found that the control group had im-
provements similar to those of the active acupuncture group. At present,
acupuncture remains a possible approach to enhancing salivary function
that requires further study. Acupuncture may serve as a useful adjunct
to management of dry mouth.

Systemic Therapies
There are many systemic agents that are capable of stimulating sali-
vary output (Table 15.1). The most extensive clinical evidence has been
with pilocarpine (Salagen). Pilocarpine is a parasympathomimetic agent
with mild beta-adrenergic-stimulating properties. It has been proposed
as a treatment for dry mouth for over a hundred years. A number of
well-designed and well-controlled studies of substantial size have ex-
amined the effects of pilocarpine on dry mouth and salivary function in
patients with Sjogren's syndrome. These clinical trials have consistently
demonstrated that at doses of 5 to 10 mg three or four times daily
(maximum 30 mg a day), pilocarpine can significantly improve symp-
toms of dry mouth and increase salivary output. Salivary secretion is
maximally stimulated approximately one hour after dosing with pilo-
carpine, and increases over baseline salivary output are found for three
 TREATMENT OF DRY MOUTH
127

to four hours. No tolerance to the secretogogue effects of pilocarpine

has been reported, nor has long-term improvement in baseline salivary
function been found. Increased salivary output is transient, dose-related,
and consistent.
Serious adverse events are rare with pilocarpine. While side effects
such as sweating, flushing, and urinary frequency are common, they are
typically of mild or moderate intensity and of relatively short duration.
Side effects may also be alleviated by taking the medication after meals.
Use of pilocarpine is contraindicated in individuals with uncontrolled
asthma, narrow-angle glaucoma, or acute iritis. Caution is advised with
use in patients with cardiovascular disease.
Another parasympathomimetic agent, cevimeline (Evoxac), has also
been studied in large, well-controlled trials. At doses of 30 mg three
times daily, cevimeline was shown to significantly improve symptoms of
dry mouth and increase salivary output in patients with Sjogren's syn-
drome. Cevimeline is similar pharmacologically to pilocarpine, although
the onset of increased salivation may be somewhat later and the duration
of action longer. The safety and adverse event profiles are very similar
to pilocarpine as well, with sweating, light-headedness, and nausea com-
mon complaints among patients. Cevimeline has been reported to have
a high selective affinity for M3 subtype muscarinic receptors, the pre-
dominant receptor subtype in the salivary glands.
Bromhexine, although not FDA-approved, has been proposed as a
salivary stimulant and treatment for dry mouth in Sjogren's syndrome.
However, there are no well-controlled studies demonstrating that this
agent will increase salivary output or improve dry mouth symptoms.
There may be some benefit for dry eye symptoms in Sjogren's syndrome,
but this has not been shown for the oral cavity.
Anetholetrithione, although not FDA-approved, is an agent that has
been demonstrated to increase salivation in individuals with mild sali-
vary gland dysfunction. The dose studied was 25 mg three times daily.
In more severe cases of secretory hypofunction in Sjogren's syndrome
patients, however, anetholetrithione was ineffective. Though there has
been an interesting report suggesting a synergistic effect between aneth-
oletrithione and pilocarpine, there are inadequate clinical trials of this
drug.
Several large clinical trials have been conducted using interferon-
alpha (IFN-alpha) (not FDA-approved), as a high-dose injectable or a
THE NEW SJOGREN'S SYNDROME HANDBOOK
128

low-dose lozenge, for treatment of dry mouth and decreased salivation

in Sjogren's syndrome. The low-dose lozenge formulation, at 150 IU
three times a day, was found to reduce xerostomia and increase salivary
output in some studies. In one study, after six months of treatment minor
salivary gland inflammation also improved. Side effects and adverse
events were minimal. Further clinical trials will be necessary to define
appropriate doses and to demonstrate fully the efficacy of this experi-
mental agent.
Infliximab, etanercept, and adalimumab are TNF-alpha blockers used
in treatment of rheumatoid arthritis. (TNF-alpha is a cytokine that is
felt to be a central component of inflammatory reactions.) In preliminary
uncontrolled studies in Sjogren's syndrome, infliximab has shown sig-
nificant benefit in a number of clinical and functional parameters, in-
cluding increased salivary flow rate and improvement in symptoms of
oral dryness. Some of these benefits remained after one year. A recent
European multicenter placebo-controlled trial of infliximab failed to
demonstrate improvement in dry mouth symptoms or salivary function
compared to placebo. These disparate results need to be resolved with
larger placebo-controlled studies.
Many other agents have been proposed as potential salivary stimu-
lants and dry mouth treatments in Sjogren's syndrome. While some may
be effective, there are inadequate well-controlled clinical trials available
at present to recommend their use. In deciding whether to try one of
these agents, it is important to look closely at the potential adverse ef-
fects and carefully consider the risk-to-benefit ratio.

Repair of Salivary Gland Alterations

There are no agents that have been shown definitively to promote
repair of salivary gland damage in Sjogren's syndrome. As noted above,
IFN-alpha did show improvements in minor salivary gland histopathol-
ogy, although this study was in a small number of subjects and should
be repeated. This is a significant finding, however, as other agents, in-
cluding prednisone and a nonsteroidal anti-inflammatory drug, failed to
have any effect on salivary pathology in earlier trials. Additional clinical
trials that look microscopically at the salivary glands to determine the
effects of the newer biologies that are being studied at present in Sjo-
gren's syndrome, such as infliximab and etanercept, are needed.
 TREATMENT OF DRY MOUTH
1Z9

Future Directions for Management of Dry Mouth In

Sfogren's Syndrome
There is a need for improved secretogogues that will have fewer side
effects, an increased duration of stimulatory activity, and greater po-
tency. Current therapies are restricted to agents that act primarily via
the muscarinic receptor. Future drugs may be directed to other receptors
known to stimulate salivary cells. It is also possible that small-molecule
drugs may be developed that target salivary receptors with greater spec-
ificity and consequently have fewer adverse effects.
Novel approaches will have to be found for individuals with too little
remaining salivary function to be helped by approaches directed at in-
creasing salivary output. In these individuals, directed cell growth and
repair may be possible, perhaps using gene therapy techniques. This will
be feasible with improved knowledge of salivary cell growth control.
The goal would be natural repair of the salivary gland. There is also the
possibility of salivary transplantation or creation of a biocompatible ar-
tificial salivary gland. It is likely that a combination of these approaches
will result in many more therapeutic options in the near future.

Summing Up
The current management of the dry mouth is mostly symptomatic
and transiently ameliorative. Medications are modestly effective but do
little about the underlying process. Exciting investigations are ongoing
which might lead to more definitive relief of this uncomfortable feature
of the syndrome.
 Aikaterinl D. Chrysochou, MD
Fotini C Soliotis, MD
Stuart S. Kassan, MD
Haralampos M. Moutsopoulos, MD

16 Systemic Therapies
in Sjogren's

A MAJOR GOAL OF therapy in Sjogren's syndrome is to treat the main

symptoms of dry eye and dry mouth. Replacement of decreased secre-
tions and administration of stimulators of tear and saliva secretion are
the most important therapeutic measures for those patients. In addition,
a variety of drugs for specific symptoms or complications of Sjogren's
are available for extraglandular involvement. Immunosuppressive ther-
apies are reserved only for serious and life-threatening major organ
involvement.

The Respiratory Tract

Sjogren's patients may also develop inflammation of the upper air-
ways (laryngotracheobronchitis) due to dryness and difficulty handling
thickened secretions. Thus mucolytic agents (e.g., guaifenesin), which
reduce the viscosity of the mucus, are useful for thinning secretions of
the air tubes. These agents also improve the difficulty in clearing foreign
material that has been inhaled into the respiratory tract. For example,
bromhexine (not available in the United States) at a dose of 48 mg/day
may be of benefit. Its side effects are nausea, an unpleasant sensation
that is vaguely referred to the stomach and abdomen and which often
leads to vomiting, diarrhea, gastrointestinal bleeding, and rash. It is con-
traindicated in pregnancy, in patients with a history of peptic ulcer, and
in those with active tuberculosis. Ambroxol (also not available in the
United States) at a dose of 120 mg/day may also be useful in mouth and

130
 SYSTEMIC THERAPIES IN SJOGREN S
131

lung dryness. It should not be administered in pregnancy or during lac-

tation, or in people suffering from peptic ulcer. Drinking a lot of water
while taking these drugs should be always encouraged. Home humidi-
fiers to moisten the air can also be of help in relieving the symptoms of
mild inflammation of the air tubes (tracheobronchitis). Prescribed neb-
ulizers that deliver water droplets into the small airways may be of some
benefit. If pulmonary function tests confirm blockage of airflow in the
bronchi or if wheezing is present due to very thick mucus, bronchodi-
lators can be prescribed in combination with mucolytic drugs. Salbuta-
mol (albuterol) relaxes smooth muscle of the small air tubes (bronchi)
by action on beta-2 receptors with little effect on the heart rate. When
inhaled, the usual dose is 200-400 meg every four to six hours. The
patient may experience nervousness, dizziness, fatigue, dry mouth, un-
pleasant taste, stomach upset, difficulty urinating, vision changes, chest
pain or palpitations, muscle cramping, or tremor. Caution must be taken
in patients with coronary heart disease and palpitations because beta-2
agonists can affect the heart rate. Concurrent use of beta-adrenergic
blockers, such as propanolol, should be avoided because they antagonize
albuterol's effects.
Inflammation of the substance of the lung (interstitial lung disease,
ILD) may also occur in Sjogren's patients. The standard treatment for
ILD is oral prednisone at a dose of 1 mg/kg daily with subsequent dose
decrease. Prednisone is administered for at least six months, and the
response is monitored with comprehensive clinical evaluation, repeated
pulmonary function tests, and high-resolution lung computed tomogra-
phy scans. The long-term use of corticosteroids may cause skin thinning,
acne, hirsutism, cataracts, premature atherosclerosis, gastritis, peptic ul-
cer, menstrual disturbances, osteoporosis, muscle weakness, diabetes
mellitus, hypertension, and heightened risk of infections. Patients should
be careful with salt and sugar intake, may need to take medicine to
minimize the risk of gastrointestinal disturbances, and should be en-
couraged to drink milk and to take calcium supplements and other spe-
cial drugs to prevent osteoporosis. Blood tests should be done regularly
in order to measure the levels of glucose and electrolytes. Steroids be-
come less effective when co-administered with phenytoin and phenobar-
bital, both drugs used for epilepsy, and rifampicin, an antibiotic. They
should not be given with alcohol and nonsteroidal anti-inflammatory
THE NEW SJOGREN'S SYNDROME HANDBOOK
132

drugs (NSAIDs), because they may induce peptic ulcer disease more eas-
ily. They also interact with digitalis (e.g., digoxin, digitoxin), some di-
uretics, and anticoagulants.
Azathioprine is an immunosuppressive drug that can be used as an
alternative when high doses of corticosteroids are needed to control the
disease. It is administered orally, at a dose of 1-2 mg/kg, usually in
association with prednisone, to every symptomatic patient with ILD or
those patients with functional, radiologic, or histologic evidence of on-
going interstitial lung disease. Its major side effect is myelosuppression,
or toxicity in the bone marrow, which may result in decreased produc-
tion of blood cells, thus making the patient susceptible to infection and
bleeding. Gastrointestinal side effects occur frequently with azathioprine
and are mostly loss of appetite, nausea, vomiting, and elevation of liver
enzymes; monitoring of blood cells and liver function tests are necessary
for these patients. Caution must also be taken that azathioprine is not
administered with allopurinol, a drug used for decreasing the levels of
uric acid in the blood in patients with a history of gout, because then
bone marrow toxicity increases dramatically.
Other immunosuppressive drugs such as cyclophosphamide (Cy-
toxan) and cyclosporine (Neoral) are sometimes employed in cases re-
sistant to the drug treatment mentioned above.
Inflammation of the pleura, the lining around the lung, is treated with
nonsteroidal anti-inflammatory drugs or corticosteroids. Increased pres-
sure in the main vessel that takes blood from the heart to the lungs
(pulmonary hypertension, PHT) is a very rare complication in Sjogren's
patients. PHT may occur as a result of long-standing inflammation of
the lungs (ILD). Thus treatment of the underlying disease may improve
pulmonary hypertension. These patients usually need oxygen therapy.
Almitrine bismesylate improves oxygenation of the lungs, probably by
reducing blood supply to areas of the lungs that are not well ventilated.
Vasodilators such as nifedipine, hydralazirie, and verapamil alleviate
symptoms but do not prolong life expectancy in patients with pulmonary
hypertension; they may also cause low blood pressure and faintness (hy-
potension), especially in association with other drugs such as beta-
blockers, and increase heart rate, and so should be prescribed with cau-
tion in patients suffering from coronary heart disease.
Long-term therapy with intravenous infusion of epoprostenol (pros-
tacycline) at an initial dose of 2 ng/kg/min is of benefit and improves
 SYSTEMIC THERAPIES IN SJOGREN'S
133

life expectancy in patients with PHT. It is capable of dilating blood ves-

sels and potentially prevents platelets from sticking together. It causes
lowering of the blood pressure, and this may be worsened by other va-
sodilator drugs and diuretics. Risk of bleeding may be increased when
co-administered with aspirin, warfarin, or heparin, which inhibit blood
clotting. During therapy, patients may experience mild or severe head-
ache, nausea, vomiting, muscle pain, back pain, difficulty in breathing,
flushing, fever or chills, unusual bleeding or bruising, or diarrhea.
Thinning of the blood with warfarin to prevent blood clotting in the
vessels is also effective therapy in PTH. An endothelin receptor antag-
onist, bosentan, is a promising new drug for the treatment of pulmonary
hypertension and is administered orally. High concentrations of a sub-
stance called endothelin-1 have been found in the lungs of both primary
and secondary pulmonary hypertension patients. Endothelin-1 causes
vessels to become narrow and increases the thickness of the blood vessel
wall. Bosentan has be shown to be of benefit in patients with pulmonary
hypertension.

Kidneys
When kidneys are involved in Sjogren's patients and cannot get rid
of acids (distal renal tubular acidosis, RTA), there is increased risk of
kidney stone formation. Oral alkaline preparations containing sodium
and potassium citrate are used to decrease this risk. Furthermore, low
blood potassium level (hypokalemia) is another complication of RTA. It
is usually asymptomatic but in some instances may lead to muscle weak-
ness or even paralysis and palpitations. Increasing the intake of
potassium-rich foods (such as oranges and bananas) is usually not
enough on its own to raise potassium levels adequately. Intravenous ad-
ministration of potassium is necessary when the potassium level is very
low, while in other instances oral potassium supplements are used. The
use of potassium-sparing diuretics such as amiloride, triamterene, and
spironolactone is preferable in these patients. Amiloride is preferred to
spironolactone because the latter can sometimes cause disturbances in
the menstrual cycle in women and gynecomastia in men.
Polydipsia and polyuria due to nephrogenic diabetes insipidus (DI) is
another manifestation of impaired tubular function in Sjogren's. This
results from partial or complete resistance to the effects of antidiuretic
hormone (ADH) in the kidney tubules. ADH is a substance produced
THE NEW SJOGREN'S SYNDROME HANDBOOK
134

by the brain that acts on the kidneys and normally prevents water loss.
A number of therapies are available that can prevent water loss in these
patients, including diuretics, NSAIDs, and a low-salt, low-protein diet.
Thiazide diuretics in combination with a low-salt diet can decrease
polyuria; hydrochlorothiazide at a dose of 25 mg once or twice daily
causes mild water loss from the body, diminishing water delivery to the
areas of the kidney that are sensitive to ADH and thus reducing urine
output. The potassium-sparing diuretic amiloride may also be helpful
when administered together with thiazide diuretics because it partially
blocks the potassium wasting induced by those diuretics.
NSAIDs can also be used as treatment because they enhance the ac-
tion of ADH. Thus they are capable of increasing the concentrating abil-
ity of kidneys. However, not all NSAIDs have the same effect.
A low-salt, low-protein diet may also result in decreasing the urine
output.
Because most patients with nephrogenic DI have partial rather than
complete resistance to ADH, it is possible that bringing hormone levels
above normal may increase the renal effect of ADH and reduce water
loss. Therefore, desmopressin (brand name DDAVP), a drug that en-
hances reabsorption of water in the kidneys by increasing permeability
of the collecting tubules, may be tried in patients who have polyuria
refractory to the treatments mentioned above.
Glomerulonephritis, or inflammation of the kidney glomeruli, can be
treated with corticosteroids and other immunosuppressive drugs. It is
rare in patients with primary Sjogren's but occurs more frequently in
those with other overlapping conditions and especially in systemic lupus
erythematosus. The treatment of moderate to severe glomerulonephritis
is high doses of corticosteroids together with another drug called cyclo-
phosphamide given intravenously (1 g/m2 every month for at least six
months). Cyclophosphamide is an agent that prevents cell division by
inhibiting DNA synthesis; it also suppresses ihe immune system. Because
it is broken down in the liver and can affect liver function, monitoring
of liver function is necessary. Another serious side effect is inflammation
of the bladder, known as hemorrhagic cystitis, which may be prevented
if cyclophosphamide is used in combination with a drug called mesna.
A small percentage of patients may develop bladder cancer after many
years of cyclophosphamide therapy. Examination of the bladder with
the help of a tube (cystoscopy) may by useful for early diagnosis. Side
 SYSTEMIC THERAPIES IN SJOGREN'S
135

effects of cyclophosphamide closely related to the time of infusion are

headache, skin rash, facial flushing, nasal congestion, nausea and vom-
iting. About ten days after the infusion low counts of white cells in the
blood (leucopenia) may be observed. Therefore, monitoring parameters
for all patients should include a complete blood count, as well as blood
urea nitrogen, uric acid, serum electrolytes, and serum creatinine before
each infusion. Cyclophosphamide may decrease digoxin serum levels
when co-administered, while other drugs such as allopurinol and chlo-
ramphenicol can increase its toxicity. It also interacts with anesthetic
agents as well as cimetidine, doxorubicin, and thiazide diuretics. Patients
must not become pregnant or breast-feed during therapy. Cyclophos-
phamide may induce disturbances in the menstrual cycle and even men-
opause, especially when administered in women over 32 years of age.
An alternative therapy is mycophenolate mofetil (2 g/day). It also
suppresses the immune system, and its main side effects are nausea, vom-
iting, diarrhea or constipation and cramps. It may also cause blood dis-
turbances such as low counts of white and red blood cells.
When patients with glomerulonephritis have a condition called mixed
cryoglobulinemia (due to the presence of cryoglobulins, special antibod-
ies in blood that become active in low temperature), plasmapheresis to
remove the cryoglobulins may be a useful therapy.

The Gastrointestinal Tract

In addition to salivary glands, Sjogren's can affect the esophagus, the
stomach, and the pancreas.
Pilocarpine is a drug commonly used for the treatment of dry mouth
(xerostomia) and dry eye. It is given at a dose of 5 mg three or four
times a day, and the total daily dose should not exceed 30 mg. First used
for the treatment of simple chronic glaucoma, it stimulates cholinergic
receptors present in the eye, the blood vessels, the heart, the lungs and
the salivary glands, and as a result increases tear and saliva secretion.
Side effects include sweats, flushing, feeling hot, exacerbation of asthma,
and blurred vision, especially at night. Also, because it increases bowel
and bladder motility, many patients need to go to the toilet frequently.
In case patients do not tolerate the drug, smaller doses may be ad-
ministered; for example, one to three 5 mg doses per day can be given
after meals. Pilocarpine should not be administered to patients with
closed-angle glaucoma or uncontrolled asthma, or in pregnancy. Its
THE NEW SJOGREN'S SYNDROME HANDBOOK
136

administration could potentially cause excessive slowing of the heart rate

(heart block) in patients also taking beta-blockers and should be ap-
proached with caution.
Cevimeline is a new drug that also increases the production of saliva,
and possibly of tears and other secretions. Like pilocarpine, cevimeline
binds to cholinergic receptors, causing increased saliva secretion. The
usual dosage is 30 mg orally three times a day. Its interactions and con-
traindications are similar to those of pilocarpine. Moreover, certain
drugs that are also metabolized by the liver may increase cevimeline's
activity: amiodarone, fluoxetine, paroxetine, quinidine, ritonavir, dilti-
azem, erythromycin, itraconazole, ketoconazole, and verapamil.
Abnormal contraction of the esophagus, known as esophageal dys-
motility, can be treated with drugs that relax the smooth muscle of this
part of the gastrointestinal tract. Nitroglycerine (0.3 to 0.6 mg, placed
under the tongue) or longer-acting agents such as isosorbide dinitrate
(10 to 30 mg orally before meals) and nifedipine (10 to 20 mg orally
before meals) may be of benefit. Common side effects of nitrates are
headache, light-headedness, and hypotension. Concurrent use of silden-
afil is contraindicated because it lowers the blood pressure with nitrates.
Calcium channel blockers such as nifedipine may also be used as treat-
ment for esophageal dysmotility. They may cause flushing, leg swelling,
dizziness, light-headedness, transient drop of the blood pressure, palpi-
tations, nausea, and heartburn.
Gastroesophageal reflux may be treated initially with lifestyle modi-
fications such as loss of weight, elevation of the head of the bed, eating
smaller meals, avoidance of lying down within three hours of eating,
and cessation of smoking and drinking if excessive. Mild acid reflux can
be alleviated with administration of antacids. These act by forming a
coat that protects the lining of the stomach and esophagus from the acids
produced by the stomach; however, excessive use may result in diarrhea
and increased levels of sodium, calcium, and magnesium in the blood.
Moreover, drugs that reduce acid production by the stomach are used
for the treatment of acid reflux and esophagitis (inflammation of the
esophagus caused by long-standing acid reflux). These drugs can be di-
vided into two groups: H2 receptor antagonists, such as cimetidine, ran-
itidine, famotidine, and nizatidine, and proton pump inhibitors, such as
omeprazole, lansoprazole, and pantoprazole. These drugs are generally
preferred to antacids because they are more effective and have few side
 SYSTEMIC THERAPIES IN SJOGREN'S
137

effects. However, some patients with Sjogren's already have reduced acid
secretion in the stomach, due to the fact that the cells that produce acid
have been destroyed by long-standing inflammation. This is known as
chronic atrophic gastritis. In some patients it can result in pernicious
anemia due to lack of a substance that is necessary for the absorption
of vitamin B12, which is important for the production of blood cells.
Pernicious anemia is typically treated with intramuscular cyanocobala-
min in a dose of 1,000 meg (1 mg) every day for one week, followed
by 1 mg every week for four weeks and then 1 mg every month for the
remainder of the patient's life. Oral and nasal formulations are also
available, but they require strict patient compliance. Monitoring of
blood potassium level is necessary within the first few days of the initi-
ation of treatment because a drop may occur due to increased utilization
of potassium in the production of new blood cells.
Acute inflammation of the pancreas (acute pancreatitis) is a very rare
complication of Sjogren's. Rarely, involvement of the pancreas may re-
sult in pancreatic enzyme deficiency, which is treated by oral adminis-
tration of pancreatic enzymes, one to two capsules with each meal.

The Liver
Liver disease in primary Sjogren's syndrome is rare and mild, and
most patients do not have any symptoms. Liver involvement can be sus-
pected when there is elevation of the liver enzymes upon routine testing
which is not attributed to medication. Primary biliary cirrhosis (PBC) is
the most common liver disease associated with Sjogren's. It is character-
ized by an ongoing immunologic attack on the small bile ducts of the
liver, which destroys their architecture and prevents the normal flow of
bile acid from the liver into the intestine. This process eventually leads
to scarring of the liver (cirrhosis) and liver failure. The presence of an-
timitochondrial antibodies (AMAs) in the blood is the most sensitive
indicator of underlying liver pathology in primary Sjogren's syndrome
patients. The management of PBC has two goals: treatment of the symp-
toms and complications that result from chronic cholestasis (obstruction
of bile flow), and suppression of the underlying pathogenic process.
Itching of the skin (pruritus) is a common symptom in patients with
PBC. It can often be controlled by nonspecific measures such as warm
baths and emollients. If these measures fail, cholestyramine (4-16 g per
day) and colestipol are usually effective in the treatment of moderate to
THE NEW SJOGREN'S SYNDROME HANDBOOK
138

severe pruritus. These drugs are nonabsorbable resins, which bind many
substances in the gut lumen, including bile acids. However, they are rel-
atively unpalatable, can induce constipation, and can interfere with the
absorption of many drugs, including digoxin, warfarin, propanolol, and
thiazide diuretics. Ursodeoxycholic acid (UDCA) is a naturally occurring
bile acid that lowers bile acid levels and can help alleviate pruritus. Other
modalities used for the same purpose are colchicine, methotrexate, and
phototherapy.
Two forms of metabolic bone disease can occur in patients with pri-
mary biliary cirrhosis: osteoporosis and osteomalacia. The latter is now
uncommon due to better dietary management and vitamin D supple-
mentation. The diagnosis of osteoporosis is established by the demon-
stration of decreased bone mineral density. The administration of vita-
min D is controversial, while calcium supplementation (to increase
intake to at least 1,500 mg/day) is generally recommended because it is
safe and avoids occult calcium deficiency in some patients. Administra-
tion of biphosphonates (e.g., alendronate) may also be effective in the
treatment of osteoporosis. A high level of cholesterol in the blood (hy-
percholesterolemia) is a common feature of PBC and other forms of
cholestatic liver disease. The available data suggest that patients with
PBC are not at high risk for developing atherosclerosis. Thus adminis-
tration of drugs to lower cholesterol levels remains controversial, and in
some cases a low-fat diet may be adequate.
Patients with PBC may develop diarrhea and weight loss due to poor
absorption of dietary fat (steatorrhea). This can be partially treated with
restriction of fat intake. Medium-chain triglycerides (MCTs) may be
added if caloric supplementation is required to maintain body weight.
Each milliliter of MCT oil contains 7.5 calories, and most patients can
tolerate a daily intake of 60 ml. This oil can be taken directly by the
teaspoon or can be used as salad oil or in cooking.
Patients with PBC may malabsorb the fat-soluble vitamins A, D, E,
and K. Deficiency of vitamin E is uncommon unless the disease is ad-
vanced. Many PBC patients do have a deficiency of vitamin A, but they
are usually asymptomatic. They respond well with oral administration
of 15,000 units per day, while parenteral supplementation may be nec-
essary for those complaining of night blindness. If untreated, vitamin D
deficiency may lead to osteomalacia. Vitamin K is important for blood
 SYSTEMIC THERAPIES IN SJOGREN'S
139

clotting, but clinically important deficiency of vitamin K rarely occurs

in PBC. Only patients with end-stage liver disease require vitamin K
supplementation.
Approximately 20 percent of PBC patients have an underactive thy-
roid gland (hypothyroidism). The treatment of thyroid disorders is the
same as in patients without Sjogren's syndrome. The most reliable test
for diagnosis and follow-up of this disorder is the thyroid-stimulating
hormone (TSH) blood level. Hypothyroidism is treated with thyroid hor-
mone replacement at a dose that keeps TSH levels in the normal range.
Some PBC patients develop xanthomas, which are deposits of cho-
lesterol in skin. Xanthelasmas, which are deposits of cholesterol in the
skin folds around the eyes, are more common. These lesions develop in
patients whose serum cholesterol exceeds 600 mg/dl (15.6 mmol) for
more than three months. Planar xanthomas develop in the palms of the
hands and in the soles of the feet and are painful. Because they can affect
the patient's quality of life, planar xanthomas are usually treated. Treat-
ment consists of large-volume plasmapheresis performed at one- to two-
week intervals. Once the serum cholesterol level approaches normal,
xanthomas will gradually resolve. This treatment is inconvenient, ex-
pensive, and indicated in only a small minority of patients with PBC.
Most such patients undergo liver transplantation because of severe liver
disease.
Portal hypertension (increased pressure in the portal vein, PHT) is a
complication of cirrhosis and is treated with propanolol taken orally and
sometimes by a surgical procedure in order to lower pressure in the
portal vein.
There has been less success in treating the immune system's attack
on the bile ducts in patients with PBC. A number of drugs have been
shown to have little effect in slowing the disease. These include corti-
costeroids, penicillamine, cyclosporine, and azathioprine.
The drug ursodeoxycholic acid (13 to 15 mg per day) has been shown
to delay the progression of PBC to end-stage liver disease. It improves
patient survival and is well tolerated. Colchicine, a drug used for the
treatment and prevention of gout, can also slow the rate of progression
of PBC but does not stop it. It is contraindicated in serious kidney failure
and in liver, heart, or blood disorders. Its main side effects are nausea,
vomiting, diarrhea, and abdominal pain. When co-administered with
THE NEW SJOGREN'S SYNDROME HANDBOOK
140

vitamin B12 supplements, it reduces the absorption of the vitamin. Meth-

otrexate, a drug that suppresses the immune system, may be helpful in
PBC, but more trials are needed to establish its effectiveness.
In conclusion, suppression of the underlying disease in PBC remains
still an unresolved problem, and some patients may eventually require
liver transplantation. However, one must always keep in mind that PBC
is most of the time mild or asymptomatic in Sjogren's patients; thus liver
failure is really a very rare occurrence.

Other Systemic Manifestations and Therapies

NSAIDs can be taken by patients who suffer from mild to moderate
joint pain (arthralgias). Their main side effects are indigestion, stomach
pains, and water retention. Also, they can cause bleeding from stomach
ulcers and therefore must not be given to people with a history of peptic
ulcer. NSAIDs can affect the function of the liver and kidneys, and pro-
longed administration of these drugs should be avoided particularly in
the elderly and those suffering from heart failure.
Antimalarial drugs (such as hydroxychloroquine at a dose of 200 to
400 mg daily) are used for mild systemic manifestations of Sjogren's such
as inflammation of the joints, skin rashes, swollen glands, and fever;
moreover, some investigators feel that they are disease-modifying agents.
Hydroxychloroquine can take one to two years to have maximal effect,
and there are controlled studies showing its efficacy. The most common
side effects are nausea, vomiting, and (less usually) diarrhea. To lessen
these problems one can slowly increase the daily dose of the drug or
take it at bedtime. The advantage of using these drugs compared to
NSAIDs is that they do not cause ulcer formation, bleeding from the
stomach, or kidney failure. However, skin rashes as well as itching of
the skin and mild allergic reactions may sometimes occur. Antimalarials,
especially chloroquine, may rarely cause eye problems. Inability to focus,
which resolves a few days after starting treatment, does not usually re-
quire discontinuation of the drug. Damage to the cells of the eye that
perceive light (retinopathy) is a rare complication that occurs with high
doses of the drug given for long periods of time; it can cause color
blindness and blurred vision. If detected early, it is reversible with dis-
continuation of the drug. That is why a semiannual ophthalmologic ex-
amination is necessary for those patients taking antimalarials. Rarely,
 SYSTEMIC THERAPIES IN SJOGREN S
141

these drugs can affect the production of blood cells in the bone marrow.
They should not be given in patients with deficiency of the enzyme
G6PD, present in blood cells, because they can cause breaking of blood
cells, known as hemolytic anemia. However, these drugs have been
shown to be safe in pregnancy. No defects have been noted in newborns
whose mothers were taking antimalarials while pregnant.
Propionic acid gels are sometimes given for the treatment of vaginal
dryness. Dyspareunia (discomfort during sexual intercourse) is a com-
mon symptom among patients with Sjogren's syndrome. Use of vaginal
moisturizing agents on a regular basis and lubricants before intercourse
is recommended. A more effective therapy for postmenopausal women
is vaginal estrogen therapy. This can help with vaginal dryness and stress
incontinence (loss of urine) and can reduce the frequency of urinary tract
infections.
Dryness of mouth, eyes, and vagina can lead to infections. Antibiotics
may be necessary for bacterial parotitis and urinary tract infections.
Candidiasis of the mouth and vagina is treated with antifungal agents
(nystatin, clotrimazole) in the form of pills, oral gels, or vaginal sup-
positories.
Apart from drugs used for the alleviation of the symptoms of Sjo-
gren's, other drugs, the so-called immunomodulators, may affect the pro-
gression of the disease and are usually used in patients with secondary
Sjogren's syndrome. Azathioprine, cyclophosphamide, or mycophenolate
are used together with steroids when severe but rare complications of
Sjogren's occur, such as vasculitis, peripheral neuropathy, pericarditis,
kidney involvement, and hemolytic anemia. As mentioned above, some
investigators feel that antimalarials are immunomodulatory drugs as
well.
Plasmapheresis may also be applied when a patient with Sjogren's
syndrome suffers from peripheral neuropathy due to cryoglobulinemia.
These patients suffer from numbness or burning sensations in their hands
and feet or have muscle weakness. Immunosuppressive agents such as
cyclophosphamide in combination with high-dose corticosteroids can
also be used; dosage and method of administration are similar to those
employed in glomerulonephritis.
In case of inflammation of the lining of the heart (pericarditis), the
amount of fluid around the heart is usually mild to moderate and most
TABLE 16.1 DRUGS IN SJOGREN'S SYNDROME: SYMPTOMATIC TREATMENT

Generic name Trade name Indication

Bromhexine * Thinning secretions of the air tubes

Ambroxol *

Salbutamol (albuterol) Ventolin Bronchial dilation

Almitrine bismesylate * Interstitial lung disease

Nifedipine Adalat Pulmonary hypertension

Epoprostenol Flolan
Bosentan Tracleer

Amiloride Midamor Renal tubular acidosis

Triamterene Dyrenium
Spironolactone Aldactone

Pilocarpine Salagen Dry mouth and eyes

Cevimeline Evoxac

Nonsteroidal anti- Brufen Arthralgias

inflammatory drugs,
e.g., ibuprofen

Nitroglycerine Esophageal dysmotility

Isosorbide dinitrate Imdur

Antacids, e.g., aluminium Maalox Acid reflux and esophagitis

hydroxide gel Aludrox
Cimetidine Tagamet
Ranitidine Zantac
Nizatidine Axid
Omeprazole Prilosec
Lansoprazole Prevacid

Pancreatic enzymes Cotazym Pancreatic enzyme deficiency

Cyanocobalamin Dicopac Pernicious anemia

Cholestyramine Questran Pruritus in primary biliary cirrhosis (PBC)

Colestipol Colestid

Alendronate Fosamax Osteoporosis in PBC

Vitamin D

Medium-chain triglycerides Tazorac Maintaining body weight in PBC

continued
Generic name Trade name Indication

Vitamin A Vitamin malabsorption in PBC

Vitamin K Aqua-Mephyton Rarely in end-stage liver disease

Ursodeoxycholic acid Ursofalk Inhibition of progression of PBC

Levothyroxine Hypothyroidism

Vaginal estrogen therapy Vaginal dryness

Antibiotics, e.g., tetracy- Bacterial infection of the parotid glands

cline, amoxycillin and urinary tract infections

Antifungal agents, e.g., Mycostatin, Fungal infection of the mouth and vagina
nystatin, clotrimazole Mycelex

*Not available in the United States

TABLE 16.2 DRUGS IN SJOGREN'S SYNDROME: IMMUNOMODULATORY

EFFECT

Generic name Trade name Indication

Corticosteroids, e.g., Deltasone Interstitial lung disease (ILD),

prednisone, Medrol glomerulonephritis, PBC, pleuri-
methylprednisolone tis, pericarditis

Azathioprine Imuran ILD, PBC, pericarditis

Cyclophosphamide Cytoxan ILD, glomerulonephritis, peripheral

neuropathy, vasculitis, hemolytic
anemia, cryoglobulinemia

Cyclosporine Sandimmune ILD, PBC

Neoral

Mycophenolate mofetil Cellcept Glomerulonephritis

Methotrexate Folex, PBC

Nexate

Antimalarials, e.g., Plaquenil Rash, arthralgias

hydroxychloroquine
THE NEW SJOGREN'S SYNDROME HANDBOOK
144

of the time subsides with the use of drugs. Oral steroids at a dose of 1
mg/kg are used together with a steroid-sparing drug such as azathio-
prine. In this way tapering of corticosteroids becomes easier thereafter.
Tables 16.1 and 16.2 summarize some of the agents reviewed in this
chapter.
 (eanne L. MeMn, MS, OTR/L, FAOTA

17 Taming Sjogren's:
Fighting Fatigue,
Lifestyle Factors, and
Nondrug Management

ONCE A PERSON DEVELOPS a serious illness or condition that cannot be

cured with medication or surgery, it is extremely helpful to approach
healing from a very broad, holistic perspective that will strengthen over-
all health and the immune system in addition to treating or reducing the
specific symptoms. This process is called self-management.
The four cornerstones of optimal health are restorative sleep, healthy
nutrition, exercise that promotes cardiovascular fitness, and positive
mood. Improving health in these areas constitutes a wellness approach
to treating autoimmune disorders such as Sjogren's syndrome, rheuma-
toid arthritis, lupus, and noninflammatory conditions including fibro-
myalgia. This chapter focuses on how patients can use these behaviors
to improve overall health.

Fatigue
Fatigue is one of the most common symptoms for which people with
Sjogren's syndrome and other rheumatic diseases request help. My pa-
tients tell me, "I could cope with the pain and other symptoms if I just
weren't so tired. It is fatigue that gets me down." Fatigue can be affected
by sleep, level of inflammation, level of physical fitness, stress, depres-
sion, and nutrition. Table 17.1 illustrates some common fatigue patterns.

145
THE NEW SJOGREN'S SYNDROME HANDBOOK
146

TABLE 17.1 CAUSES OF FATIGUE AND COMMON PATTERNS OF FATIGUE

• Deconditioning—fatigue following minimal level of any physical activity

• Depression—fatigue all the time, no matter how much sleep; often worst in
the morning; person may sleep excessively (10 or more hours)
• Fibromyalgia syndrome (FMS)—wake up feeling tired, exhausted, or
unrefreshed; best energy in the afternoon
• Osteoarthritis (OA)—fatigue at end of day, early evening, or after physical
activity
• Rheumatoid arthritis (RA)—fatigue in early afternoon, refreshed by nap;
systemic fatigue resulting from disease flare, usually lasts all day and is not
resolved with a nap
• Systemic lupus erythematosus (SLE)—fatigue, exhaustion, not resolved
with sleep; lessens with control of disease

Fatigue Management Training

Prior to the mid-1980s, the primary rehabilitation approach to treat-
ing fatigue associated with rheumatic diseases was energy conservation
training. It simply taught people how to conserve their limited energy
resources. Then research on exercise and arthritis demonstrated that peo-
ple with rheumatoid arthritis, osteoarthritis, lupus, and fibromyalgia
could improve their fitness level and functional ability through proper
exercise. Now fatigue management training for people with rheumatic
diseases includes fitness exercise training in addition to education of ef-
fective use of time and energy. Time management, planning, pacing, and
prioritizing are actually more helpful than just energy conservation for
people with Sjogren's syndrome. Also, many over-the-counter and pre-
scription medications can cause fatigue or disturb sleep. Check with your
physician or pharmacist, for there are sometimes alternatives. In addition
to exercise, healthy sleep and good nutrition are critical to managing
fatigue.
To start a fatigue management program, patients should start on a
healthy diet, get involved with an aerobic fitness exercise program (see
Table 17.2), and do everything possible to eliminate factors that impair
sleep. The program should be undertaken for at least 12 weeks; if no
improvement is evident after that time, the doctor should be consulted
about a referral to a sleep specialist or rehabilitation program that does
fatigue management training.
 TAMING SJOGREN'S
147

TABLE 17.2 TECHNIQUES FOR THE MANAGEMENT

OF FATIGUE

Exercise
Sleep
Time management, pacing, prioritizing
Energy conservation
Healthy nutrition
Evaluation of medications that can cause fatigue

Sleep and Fatigue

Most people with autoimmune disorders have been told that fatigue
is part of the disorder, so they just assume that the illness is the source
of their fatigue and they try to accept it. If they have obvious insomnia,
they may see it as a cause of their fatigue. But if they sleep through the
night and wake tired, they think the illness is causing the fatigue. But
often the real problem is that these people have poor-quality sleep that
is not deep enough and therefore is nonrestorative. Sleep starts with
light, stage 1 sleep and progresses to deep, stage 4 sleep followed by a
phase called rapid eye movement (REM) sleep. This cycle takes about
90 minutes and then repeats. There are about six cycles in an eight-hour
period. Stage 4 sleep is called restorative sleep because although the body
is very quiet, the brain turns into a chemical factory, producing essential
neurochemicals such as serotonin, growth hormone, and cortisol, among
many others. People can sleep soundly in stage 3 sleep, but if they don't
get enough of stage 4 sleep, they can wake up tired, irritable, and achy.
When a person's mood is irritable, the entire body is hypersensitive or
irritable.
People can tell that they have had enough stage 4 sleep if they wake
up feeling mentally rested and restored. How rested someone feels is
more important than how many hours are slept or how many awaken-
ings occur during the night. So here are some options to consider.
Possibility #1: The patient sleeps an ideal number of hours most
nights and wakes feeling mentally rested five out of seven mornings with-
out sleeping pills, antihistamines, or alcohol but has fatigue during the
day. In this case, the patient probably has good-quality sleep; poor sleep
is not the source of the fatigue. Other factors such as pain, decondition-
THE NEW SJOGREN'S SYNDROME HANDBOOK
148

ing, stress, depression, nutritional factors, or simply overdoing and not

pacing could be contributing to the fatigue, in addition to systemic in-
flammation from the autoimmune disorder itself.
Possibility #2: The patient sleeps an ideal number of hours without
using sleeping pills but wakes feeling tired or exhausted. In this case, the
patient may have nonrestorative sleep. Improving the quality of sleep
would likely reduce fatigue.
The most common factors that reduce quality of sleep and are easy
to fix are (1) caffeine (which can stay in the system for 20 hours), (2)
sleeping with the TV or a light on, (3) having windows that let light in
at night or in the early morning, as seeing white light (even when using
the bathroom) stops the secretion of sleep hormone (melatonin), (4) do-
ing exercise too close to bedtime, (5) doing work activities in the hour
before bed (not allowing enough time to wind down), (6) eating late,
heavy meals, (7) drinking alcohol after dinner (alcohol causes frag-
mented sleep at night), (8) and mattresses that are too firm or sagging.
Factors that are more difficult to fix are (1) smoking (nicotine dis-
turbs sleep), (2) pets on the bed, (3) use of antidepressant medications
such as selective serotonin reuptake inhibitors, (4) children that need
attending, (5) partners who snore, (6) noise from neighbors, (7) arguing
or having stressful phone calls right before bed, (8) bladder disorders,
and (9) use of corticosteroid medications for asthma or autoimmune
disorders. For some people, not getting regular exercise reduces sleep
quality. Taking a warm bath in the evening can be helpful, but a hot
bath too close to sleep time can increase core temperature and make it
difficult to cool down sufficiently to fall asleep easily. The same results
can occur with exercise, so vigorous exercise should be done at least
three hours before bedtime. A relaxing walk in the evening often helps
people relax and sleep better, and gentle stretching before bed can help
reduce morning stiffness in patients with arthritis. Medications that
cause insomnia should be taken as early in the day as possible. If there
is any suspicion that medications or pain are disturbing sleep, talk to
the doctor, and see the section on pain below.
Having healthy sleep means being able to go to sleep when desired,
returning to sleep easily after awakening, sleeping as long as desired,
and waking up feeling mentally rested. This is possible without taking
medication or alcohol for sleep. Patients may not want to face the chal-
 TAMING SJOGREN S
149

lenges of the day and may not be energetic, but they feel rested, as if
they have had enough sleep. And this feeling lasts longer than a few
minutes. Ideally, it lasts through the whole morning.
If a patient has daytime fatigue and snores or has a sense of stopping
breathing or having difficulty breathing at night, the doctor should be
consulted. Sleep apnea (a type of abnormal breathing during sleep) is a
disorder that can cause these symptoms, and it is treatable with an oxy-
gen device, surgery, or a dental appliance.
White light from a TV, night-light, or the moon can disturb sleep. It
is darkness that triggers the secretion of melatonin, the sleep hormone.
An inexpensive way to test whether moonlight is a problem is to use a
nighttime eye shade (a soft satin one with an extra piece to block light
from the sides of your nose is better than a stiff eyeshade). The ones
distributed on airlines work well. Red light does not disturb sleep in the
way white light does.

Sleep Medications
The key to using sleep for maintaining or restoring health is to be
able to sleep deeply and wake feeling rested without drugs. When this
occurs, the body and the brain are in balance, and the biochemical
"switch" in the brain that allows a person to go from wakefulness to
sleep is working. Taking drugs at night may help somewhat to increase
sleep, but they do not fix a switch that is not working. They bypass the
natural sleep process and induce sleep through an artificial or alternative
pathway, so the body continues out of balance, and any health problems
to which this contributes remain. Medications can sometimes serve as a
stepping-stone to correcting a problem, but they should not be the des-
tination. (There are some exceptions to this rule, such as medications
for severe anxiety disorders and other mental illness.) The way to "fix
the switch" is by changing the physiology of the brain. This can be done
through exercise, relaxation training, nutrition, sleep, and even changing
one's attitude toward something. For example, say on a particular Sat-
urday a patient gets a lot of enjoyable exercise and that night sleeps
great, far better than usual. This is because the exercise changed the
physiology of the brain and improved the working of the biochemical
switches necessary for deep sleep. Pills cannot do this because they create
sleep through an artificial pathway. Drug-induced sleep is not the same
THE NEW SJOGREN'S SYNDROME HANDBOOK
150

as or as good as natural sleep; all sleep specialists are in agreement on

this issue. Some sleeping pills may also make dry eye and dry mouth
worse.
It has only been during the last 20 years that science has begun to
uncover new and surprising facts about the purposes of sleep. A few
years ago it was thought that the main purpose of sleep was simply to
give the body a rest. But now we know that although the body seems
quiet during deep sleep, the chemistry lab of the brain is in high gear,
replenishing the neurochemicals that control all the body's functions,
including mood, heartbeat, and digestion. And the greatest amount of
cellular repair in the body occurs during deep sleep. This makes deep
sleep one of the most essential elements in maintaining general health,
both mental and physical.

Nutrition
Daily fatigue, chronic pain, poor sleep, or fibromyalgia are signs that
the body's chemistry is out of balance. The good news is that the body
is always trying to bring its chemistry back into balance. Good nutrition
and vitamins can help the body win this battle. Good nutrition can in-
fluence mood, energy level, thinking ability, and sleep. It is not simply a
matter of eating a certain food or taking a certain vitamin and having
the Sjogren's syndrome go away or the fibromyalgia and lupus disappear.
It is a matter of eating to increase health and stamina and to improve
the chemistry in the body, including the brain. Any pattern of foods or
supplementation that reduces symptoms is probably improving body
chemistry.
People with fatigue problems or fibromyalgia often report that they
have developed increased sensitivity to everything, especially medications
and drugs such as caffeine and alcohol. Many patients stop drinking
alcoholic beverages because alcohol makes them feel awful. Some people
report a new sensitivity to certain foods, such as sugar, other sweeteners,
chocolate, and red meat. They feel worse after eating these foods. It can
be very helpful to pay attention to responses to foods and eliminate any
that increase symptoms. If it seems that several foods may be problem-
atic but it is not clear which ones, it is helpful to work with a nutri-
tionist, who can design an elimination or cleansing diet that lasts for
two weeks, followed by a process of reintroducing foods to the diet one
at a time so that the response to each can be evaluated. Look at how
 TAMING SJOGREN'S
151

foods affect pain, fatigue, sleep, alertness, energy, and mood. A word of
caution: if a certain food makes one or more symptoms worse, it does
not mean that the patient is allergic to that food. He or she may just be
sensitive to or intolerant of it. Stress, poor sleep, depression, and fibro-
myalgia can make the system hypersensitive to the substance, similar to
the way it may be hypersensitive to touch, sound, or other irritants. As
health improves, tolerance to these foods is likely to improve.
Here are some of the basic nutritional guidelines to reduce the symp-
toms of fatigue, irritability, and hypersensitivity and help the body
achieve optimal health:

Nutrition and Fatigue

Tiredness can exacerbate depression, anxiety, or irritableness and
lower motivation for participating in activities or exercise. Most nutri-
tionists agree that eating a healthy diet (one low in fats, sugar, and ad-
ditives but with adequate protein and high in complex carbohydrates
from vegetables, whole grains, and fruits) helps improve energy, mood,
and motivation, allowing a person to participate in more physical activ-
ities, which in turn reduces stress and improves sleep. If a person is
feeling energetic, he or she is more likely to exercise during the day.
Eating a high-protein, low-fat breakfast and lunch can improve energy
and stamina for the day. It can also help in weight loss by increasing
energy and metabolism so that calories burn off faster. (See Table 17.3
defining food categories.)
The type of meal that maximizes alertness and ability to respond
quickly is a high-protein (12 or more grams), low-fat (20 percent of
calories from fat) meal. Studies have shown that eating this type of meal
at breakfast and lunch can improve mental alertness by increasing levels
of the neurochemicals dopamine and noradrenaline, which are made
from the amino acid tyrosine.
Food can influence sleep in several ways. In the evening and before
bed certain foods can interfere with sleep, and others can facilitate sleep.

Foods That Interfere with Sleep

When taken too close to bedtime, highly acidic foods, such as to-
matoes, oranges, grapefruit, and citrus juices, can disrupt sleep. Acidic
foods are stimulants, which is why they are associated with breakfast
and make a great natural pick-me-up in the late afternoon. Herbal teas
THE NEW SJOGREN'S SYNDROME HANDBOOK
152

TABLE 17.3 FOOD CATEGORIES

Complex Carbohydrates
Whole grains: rice, corn, oatmeal, wheat
Vegetables
Beans (legumes), fresh and dried
Fruits, including avocado
Starches: potatoes, rice, breads, pasta

Simple Carbohydrates
Sweets: candy, sodas, cookies, cake, pie, pastry
Sugar, syrup, honey

Good Sources of Protein

Animal products: meat, chicken, fish
Eggs
Dairy: milk, yogurt, cottage cheese
Soy beans, tofu, and vegetarian "meats" (tofu dogs, bacon, etc.)
Fruit juice smoothies made with protein powder, milk, or yogurt

High-Fat Foods
Oils, butter, margarine, mayonnaise, salad dressing
Fried foods: potato chips, corn chips, doughnuts, french fries
Fatty meats: bacon, sausage, salami, bologna, hot dogs
Olives
Nuts
Ice cream

that contain citrus can also interfere with sleep. Multivitamins and B-
complex vitamins, both of which increase energy, and vitamin C sup-
plements, which are acidic, can all interfere with sleep. They should be
taken with breakfast or lunch to enhance energy. Cayenne pepper,
horseradish, and other hot spices are also "uppers" that can interfere
with sleep. People with Sjogren's syndrome generally avoid these sub-
stances because they are irritating and drying.
Optimal hydration is critical to good health and hardiness. Dehydra-
tion can interfere with sleep. (On the other hand, too much liquid before
bed can interrupt sleep by necessitating trips to the bathroom.) Seven to
eight glasses of water or noncaffeinated drinks are recommended a day
(caffeine is a diuretic). One of the first signs of dehydration is fa-
 TAMING SJOGREN S
153

tigue. Patients who are tired should take account of how much water
they have had and should drink a glass of water to see if it increases
energy and alertness.
Eating foods that are hard to digest, such as raw apples, nuts, pop-
corn, raw vegetables, or spicy foods, right before bed can interfere with
sleep. Dieting and going to bed hungry can also interfere with sleep.
Alcohol is a commonly used sleep aid, but it is not a good one. It
has a calming, sleep-inducing effect, but it results in fragmented sleep
and can cause rebound insomnia after just a few hours of sleep. Also,
alcohol is a diuretic and encourages dehydration, and it increases the
symptoms of restless-leg syndrome and can simply make people more
restless in bed. It is better to have wine or another alcoholic drink with
an early dinner and have nonalcoholic, decaffeinated drinks between
dinner and sleep. Also, optimal hydration helps reduce the negative ef-
fects of alcohol on your body.
Caffeine requires special consideration. It is a long-acting drug that
can profoundly interfere with sound sleep. Some people are very aware
that caffeine makes them feel jittery or irritates their stomach, aggravates
irritable bowel syndrome, or interferes with their sleep. They gladly give
it up to feel better. For others, especially people addicted to caffeine or
those who used to drink it before going to bed at night, the connection
between caffeine and poor sleep seems remote and not applicable to
them. But once a sleep disorder has developed, the system becomes hy-
persensitive, and the body's response to caffeine (or nicotine or alcohol)
can change. When a patient has difficulty sleeping or wakes up tired in
the morning, the best thing to do is to avoid all caffeine, including that
contained in coffee, tea, sodas, chocolate, cocoa, and over-the-counter
medications such as Excedrin. Patients who continue to have problems
sleeping should wean themselves from all caffeine. People who are ad-
dicted to caffeine need to reduce consumption gradually to avoid with-
drawal headaches. Decaffeinated coffee contains between 3 and 10 per-
cent of the caffeine of regular coffee, depending on the brand and brew
method (Sanka has the lowest amount at 1 percent). Both regular and
decaffeinated coffees are very acidic drinks. Acid is an irritant to the
digestive tract and a stimulant to muscles, increasing tightness. (Also,
caffeine contributes to calcium loss in the bones, which is of concern to
women at risk for osteoporosis.)
THE NEW SJOGREN'S SYNDROME HANDBOOK
154

Foods That Can Help Sleep

Foods that increase serotonin and muscle relaxation may promote
sleep. A carbohydrate snack such as cookies low in sugar, graham crack-
ers, saltines, bread, or rice cakes with a little jam can increase serotonin
in the brain. Eating a protein snack tends to increase energy and interfere
with the production of serotonin. Milk, however, even though it supplies
protein, is effective as a bedtime snack. Milk may help people relax
because it is high in calcium, which reduces acidity in the body and is
thought to be calming. It is also high in magnesium, which can reduce
muscle tension and blood pressure.
Chocoholics with desperate cravings in the evening should try white
chocolate, which contains no caffeine.

Smoking
Although nicotine is not a nutritional substance, it can alter nutrition
and body chemistry. Nicotine constricts blood flow in the small capil-
laries, reducing circulation in the hands, feet, face, and muscles. It is a
poison to the body and creates an unhealthy chemical imbalance. And
it is a stimulant that interferes with sleep.
Very tense patients who smoke to relax, or who smoke more when
depressed or worried, should talk to a physician about the possibility of
nondrying antidepressant medications to encourage relaxation while
withdrawing from nicotine.

Stress Management
I have met many people with illness who refuse to participate in
stress-management classes because they know what is causing their
stress—for example, their marriage, children, job, or boss—and know
they cannot get rid of these problems. But the goal of stress management
is not to get rid of all stress, which is impossible, but instead to learn
how to handle stress so that it does not affect the body physically in the
form of headaches, insomnia, tight muscles, rashes, high blood pressure,
nervousness (anxiety), depression, and so on. In other words, if stress is
having a physical effect, it is not being handled well. Stress can magnify
or compound the symptoms of Sjogren's syndrome, fibromyalgia, rheu-
matoid arthritis, or lupus.
 TAMING SJOGREN'S
155

Stress management training can take many forms, but classes and
individual therapy generally include the following:

1 Guidance in how to identify big and small stresses

2 Education on how stress affects the body and health
3 Identifying how stress is handled, the types of stress that are handled
well, and the types that result in physical symptoms
4 Techniques to manage anger or communicate effectively (assertive-
ness training)
5 New ways to think about stressful events so that they cause less re-
action (cognitive-behavioral therapy, which includes techniques to
help stop the mind from worrying and obsessing about problems or
stopping the mind from racing)
6 Time management skills, including prioritizing activities
7 Relaxation methods to regain control over your body and relax the
muscles at will

Hydration Management
This topic covers the full array of self-management strategies to im-
prove systemic hydration, increase humidity in the environment, and
maximize moisture for eyes, mouth, and skin. The most obvious way to
improve systemic hydration is to drink enough liquids. Most people with
Sjogren's or dry skin in general find it helpful to use a humidifier in the
home and especially in the bedroom at night. These need regular clean-
ing, so the best model is one that is easy to clean.
The brain is very reactive to the environmental atmosphere. That is
why we can become irritable in rooms that are too warm or during
periods of dry, hot winds. Air rich in negatively charged ions may have
a refreshing and calming effect on us and increase brain serotonin. The
greatest amount of negative ions are at the base of a waterfall, which is
one reason they have such a calming effect on people. At night, the best
environment for sleeping is with the air cool and the blankets warm. Of
course, people with Raynaud's phenomenon need a temperature that
works best for their circulation. The early morning, when there is dew
THE NEW SJOGREN'S SYNDROME HANDBOOK
156

on the ground, and the early evening, after it cools down, are also at-
mospheres with greater negative ions, so these are ideal times to take a
relaxing or invigorating walk.
Specific techniques for enhancing moisture for the eyes, skin, and
mouth are covered in Appendix 3.

Pain Management
Poor sleep or nonrestorative sleep, depression, anxiety, lack of exer-
cise, and unhealthy nutrition can all magnify the pain signals. This pro-
cess is called pain amplification.
In health care, pain management refers to a program that teaches
patients how to gain control over pain by reducing factors that magnify
or aggravate pain. Pain management programs include:

1 Techniques for reducing anxiety, stress, and depression

2 Learning to let go of the fear of a flare of pain or progression of pain
by learning self-management of symptoms
3 Learning to reduce pain and suffering by understanding the response
to symptoms, setting goals, and having methods for determining pro-
gress so that the focus can be on progress instead of problems
4 Counseling or psychotherapy to help cope with losses related to ill-
ness and developing plans to maximize the possibility of a productive
and satisfying life even though not all the pain may be gone

Rehabilitation Professionals and Services

Physical Therapy
Ideally, people should participate in a community fitness program on
a regular basis. If this is difficult, a physical therapist can help patients
design a fitness program and show them how to gradually increase ex-
ercise with the goal of participating in a community program.
Physical therapy can alleviate a localized physical problem contrib-
uting to pain, such as trigger points or a specific tight muscle. When the
main problem is generalized stiffness and discomfort, as in fibromyalgia,
a total-body stretching and toning exercise program is the most effective.
 TAMING SJOGREN S
157

For neck and back stiffness, physical therapists can apply specific
manual techniques to release tight muscles. Physical therapists can teach
deep breathing, relaxation, and self-massage techniques. They can ex-
plain how to use devices that allow the application of focal pressure to
release trigger points at home.

Occupational Therapy
Occupational therapists are concerned with patients' ability to do
activities that occupy their time, mind, and hands—that is, the functional
activities that occupy the day. This may include a vocation, but it is not
limited to work activities. Occupational therapists are trained in the
fields of both physical rehabilitation and psychiatry. They can offer a
wide range of services that can help both physically and emotionally.
Occupational therapists can help patients evaluate their daily routine,
to see whether their method for carrying out activities is helping or hin-
dering healing. In many pain programs, occupational therapists teach
stress management, fatigue management, sleep hygiene, assertiveness
training, values clarification, joint protection techniques, time manage-
ment, and planning and pacing skills, all techniques that can help reduce
pain, stress, anxiety, and fatigue. If job or home activities are contrib-
uting to an increase in neck, back, or arm pain, an occupational therapist
can evaluate workstation, methods, and postural stress and make specific
recommendations for reducing the strain on the body. The majority of
hand therapists are occupational therapists, and they can provide specific
therapy, custom splints, and exercises for hand, elbow, and shoulder
pain. The overall goal of occupational therapy is to improve the ability
to carry out daily activities and to reduce disability.

Psychotherapy
A psychotherapist is a health professional who uses a variety of psy-
chological therapy techniques to help patients understand the issues that
may be contributing to depression, anxiety, and poor sleep. They can
help patients understand and manage stress and pain better. A psycho-
therapist may be a psychiatrist, psychologist, social worker, or counselor.
Seeing a psychotherapist does not mean the symptoms are all in the
patient's head; rather, it helps the patient understand that emotions and
stress can affect level of pain or symptoms, and helps the patient take
THE NEW SJOGREN'S SYNDROME HANDBOOK
158

advantage of the latest techniques and research in psychology to help

reduce symptoms. See Chapter 18 for further discussion.

Biofeedback
Biofeedback is a treatment that allows patients to see on a computer
screen or machine how tense the muscles are. This feedback allows pa-
tients to learn effective techniques for reducing muscle tension or emo-
tional distress. With this method, it is also possible to teach patients how
to raise their body temperature, which can be helpful for managing Ray-
naud's phenomenon. Biofeedback can also be beneficial for management
of headaches, jaw pain (temporomandibular joint syndrome), teeth
grinding, and high blood pressure. It is administered by health profes-
sionals who are certified biofeedback technicians, or by other profes-
sionals such as occupational or physical therapists and psychologists
who are certified to do so.
 |oan E. Broderick, PhD
Evelyn J. Bromet, PhD

18 Conquering Sjogren's

IN THIS CHAPTER, we discuss anger, depression, fatigue, and chronic

pain, four critical issues that Sjogren's patients often face on a daily
basis. We then consider strategies for managing these challenges.

Jane's Story
Jane was a family court attorney who was enjoying the last few years
of her law practice. The youngest of her three children was a sophomore
in high school, enabling Jane to devote herself more fully to her work.
For the past 20 years, she had successfully juggled raising young children
and working part time representing abused and neglected children in
family court proceedings. She was passionate about her work and was
delighted with the new opportunities to sit on committees and conduct
professional workshops to promote improved care for these vulnerable
children. Despite working more hours professionally, Jane remembers
commenting to her husband that she was feeling less stressed in her life
than she had been 10 years earlier, when she was juggling more respon-
sibilities at home and with the children. The increased freedom to throw
herself fully into her work was exhilarating. At the same time, meno-
pause was around the corner, and Jane was beginning to notice the small
physical changes that accompany it: dry and sagging skin, less vaginal
lubrication, less energy, some mood swings, and of course changes in
her cycle. But, as Jane tells the story, she was taking this in stride, as she
had most of the minor physical ailments that had come and gone
through her life. These little annoyances were trivial compared with the
suffering she had observed in her sister, who had been struggling for the
past eight years with lupus, and in her aunt, who had been crippled by

159
THE NEW SJOGREN'S SYNDROME HANDBOOK
160

rheumatoid arthritis. However, as time progressed, even though she was

through menopause, the symptoms were not lessening. Rather, they were
getting worse. Now her eyes were gritty and dry, she was awakening
repeatedly during the night with a parched mouth, and for the first time
she was experiencing chronic heartburn and frequent constipation.
Worst of all was the overwhelming fatigue that made getting through
her day feel like she was trying to scale Mt. Everest. Jane was bewildered
and self-critical. Everyone says that getting old is hard, but why was she
handling it so poorly? She loved her job, her children were becoming
competent young adults, and she and her husband still enjoyed each
other's company. It was a visit to her dentist for a toothache that began
the journey to a diagnosis. Dr. Jacobs, her dentist, remarked that she
was developing decay at the gum line and on the incisal edges of her
front teeth. He recommended that Jane see her primary care doctor for
a full checkup. Blood tests revealed that Jane's rheumatoid factor and
ANA were elevated. The journey continued with a consultation with a
rheumatologist, who eventually made the diagnosis of Sjogren's syn-
drome. At first Jane was relieved to finally have a medical explanation
for why she had been feeling so awful. Then the deeper implications
began to sink in. Sjogren's is a chronic illness with few treatment options
available. There was going to be little her doctor could do to reduce her
symptoms of dryness or fatigue. This was a life sentence! She couldn't
fathom what she had done to deserve this. It was so unfair. Finally at
the point in her life when she had the opportunity to focus on her own
interests and enjoy life with fewer responsibilities, it was being stolen
away from her. Jane began to struggle with anger and depression.

Anger
Anger is an inevitable reaction to having a chronic illness. Our par-
ents and teachers told us that life isn't fair, but developing a chronic
disease such as Sjogren's syndrome was not what anyone bargained for.
Most of us believe that if we work hard and conduct ourselves with
reasonable moral integrity, then we will enjoy the fruits and blessings
that come with that. The plaintive "Why me?" reverberates over and
over in the mind of the newly diagnosed patient. "What did I do to
deserve this?" is the question that prompts the answer "Nothing" and
generates the anger. We can all think of people who abused their bodies
 CONQUERING SJOGREN'S
_
161

for years through poor nutrition, smoking, substance abuse, or no ex-

ercise but whose health seems unaffected by these behaviors.
Human nature drives us to search for causal explanations for im-
portant events in our lives. We need to make sense of how personal
choices and external events determine our subsequent experience. We
draw lessons from these explanations such that we feel that we can exert
a reasonable amount of control over what happens in our life. Most of
us share the general view that when bad things happen to people, they
probably contributed to it one way or the other. They lived in the wrong
neighborhood, didn't work hard enough, lacked self-control, were self-
indulgent, or didn't have sufficient moral character. We are constantly
bombarded by news reports about how our choices and our environment
determine our health. Headlines scream at us that being overweight leads
to diabetes, heart disease, and certain types of cancer. Smoking leads to
cancer, heart disease, stroke, and emphysema. Lack of exercise contrib-
utes to high cholesterol, fatigue, and diminished conditioning that makes
daily tasks more difficult to complete as we age. Insufficient calcium
results in accelerated bone loss with the consequence of increased risk
of bone fractures, most importantly hip fractures, and osteoporosis. Es-
pecially in the United States, we are avid consumers of health news in
our effort to try to take control of our destiny.
Given this context, it is not surprising that individuals diagnosed with
Sjogren's syndrome, like many patients with chronic illness, inflict in-
tense examination on themselves to uncover the root causes of their
illness: "What did I do wrong? How did I bring this on myself? What
should I have done differently to prevent this illness? How are women
who didn't get this illness different from me?" When the answers are
not satisfying, anger follows. "I've lived my life as well as anyone else.
There is no good reason for me to have gotten Sjogren's. I have been
betrayed!" This sense of betrayal can profoundly challenge our spiritual
beliefs as well as our view of our bodies.
For most of us as children, our bodies worked like an exquisite Swiss
watch. It ran almost perfectly, with just an occasional cold or childhood
illness. A scraped knee, a broken arm, or a pulled muscle were the only
times we paid any attention to our body. During puberty our body began
to behave in surprising ways, but we easily assimilated these changes
into our emerging self-identity. For the healthy individual, body and self
THE NEW SJOGREN'S SYNDROME HANDBOOK
162

are one and the same; there is no dichotomy or divergence. This is not
so for the patient struggling with an illness. What emerges is an internal
splitting: there is "me," and separate from that is "my body," which is
behaving poorly. The "me" feels profoundly betrayed by "my body."
Anger, disappointment, and frustration with "my body" are all anger
directed at the self. We experience ourselves as defective. We demand
that our body get its act together, because we will not tolerate this poor
performance. When this does not happen, we are outraged.
The most virulent anger is that directed toward the self, but it is not
limited to that. Many patients with Sjogren's syndrome and other
chronic illness gradually develop pervasive anger at the health care es-
tablishment and particularly past and present health care providers.
"Why did it take so long for me to be diagnosed?" "I knew it wasn't
all in my head; how dare they keep telling me that I was just depressed
or stressed with my teenage children." "I waited three months for this
visit with the specialist (not to mention the hour and a half in his
crowded waiting room) and then spent no more than 10 minutes with
the doctor, who wouldn't take the time to answer all of my questions
and didn't have any useful recommendations other than to do my best
to live with it. I got more answers from a Web site!" "I am tired of
being made to feel like a psychologically dysfunctional malcontent when
I go to doctors trying to figure out what my symptoms are about and
what I can do about them. 'It's just your Sjogren's, stop worrying about
it' makes me feel that I am wasting the doctor's time and that I am
coping poorly." The ride home from the office is dominated by tearful
anger at the doctor, resurgence of anger at "my body," and now the
added anger at "the self" for coping so poorly.

Sadness and Depression

It is not surprising that many patients with a chronic medical illness
also experience depression. For many Sjogren's patients, the pain, fa-
tigue, and other symptoms that come with the disease exhaust their emo-
tional resources, and depression sets in. Moreover, diminished perfor-
mance in meaningful life tasks, be it care of one's home, child care,
employment, or hobbies, creates a sense of deep loss and disappoint-
ment. Chronic illnesses such as Sjogren's almost always require that the
patient engage in a process of redefining the self from the pre-illness state
to the current illness state. From the patient's point of view, this new
 CONQUERING SJOGREN S
163

self is inadequate because in so many areas it is less capable than the

former, healthy self. A sense of loss is pervasive. Not only is the patient
suffering from the physical symptoms of the disease, but she is also suf-
fering from the loss of important positive experiences at home, on the
job, with friends, and with hobbies that used to provide much enjoyment
and personal fulfillment. In some cases the losses can be severe, through
partial or full disability for employment and through separation, divorce,
or other ended relationships.
When depression becomes persistent and impairing, it is a medical
illness, not a moral failing, as many people imply. Research has discov-
ered that when a person develops clinical depression, many changes oc-
cur throughout the body. Sleep is affected through disrupted patterns in
brain wave activity, frequent nighttime awakenings associated with dif-
ficulty returning to sleep, and a feeling of exhaustion even after a full
night of rest. Digestion becomes sluggish, appetite can increase or de-
crease substantially, and weight gain or weight loss is common. Speech
and movement can become noticeably slower. The neurochemical and
hormonal balances are altered, along with the functioning of the immune
system. These physiological changes are accompanied by the well-known
psychological symptoms of depression. Patients experience sadness,
guilt, hopelessness, a sense of personal failure, and pessimism about the
future. Pleasure from enjoyable activities, including sex, is markedly less.
Toxic thoughts predominate, with a sense of worthlessness and shame
that can progress to the belief that one would be better off dead, if for
no better reason than to end the suffering. Family and coworkers will
take note of many of these symptoms but will probably be most dis-
turbed by the chronic irritability. When a patient has five or more such
symptoms lasting at least two weeks, we determine that the person is
suffering from a clinical depression rather than the garden-variety fluc-
tuations in mood that we all experience in times of stress. Whereas most
of us will rapidly get over these transient mood disturbances and are
usually able to distract ourselves or otherwise help make ourselves feel
better, a patient with clinical depression can do neither. Just as we can't
will ourselves to lower our cholesterol, increase our insulin, or mend our
damaged heart valve, neither can depressed patients will themselves to
snap out of their depression, no matter how hard they may try. For a
doctor, a family member, or the patient herself to suggest that is to add
insult to injury.
THE NEW SJOGREN'S SYNDROME HANDBOOK
164

Studies report that at any given time approximately 6-8 percent of

people in the United States suffer from depression. In primary care pa-
tients, however, the rate is closer to 30-50 percent. Sjogren's patients are
not immune from this. Indeed, a recent survey of the membership of the
Sjogren's Syndrome Foundation (SSF) found that 29 percent reported
depression as one of their most troubling problems.
Sjogren's presents a unique challenge to the treatment of depression
by virtue of its primary symptom, dryness. Antidepressant medication is
the most common tool for treating depression. Although medication can
take several weeks to achieve its therapeutic effect, and patient and
physician may need to tinker with more than one medication, research
finds that 80 percent of depressed patients will experience a significant
improvement in their depression with antidepressant therapy. How-
ever, many antidepressant medications have anticholinergic effects that
result in dry mouth and constipation. These side effects are mild and
generally well tolerated by many patients, but for the Sjogren's patient,
they are often intolerable, making such patients poor candidates for this
form of drug treatment. Many complementary medicines also have side
effects. For example, St. John's wort (Hypericum perforatum) can in-
crease photosensitivity and cause dry mouth as well. Depending on the
situation, individual or group counseling may be a more desirable form
of treatment.

Fatigue
Fatigue is another very distressing symptom associated with Sjogren's.
Fatigue was the third most common symptom, after dry eye and dry
mouth, reported in the SSF 1998 survey, with 77 percent of members
listing it as one of their most troubling symptoms. The fatigue that pa-
tients with chronic illness describe is not the same as the tiredness that
people without such an illness feel after staying up too late or putting
in a long day of yard work. It goes much deeper, as though most of our
life force has been drained away. It can feel like we have a three-ton
gorilla on our back, so just moving about and doing the simplest tasks
require all the energy we can muster. Waking up in the morning and
already feeling totally exhausted can be very discouraging.
A couple of points are worth noting. First, we need to become good
observers of the patterns that are associated with fluctuations in our
levels of fatigue, either increasing or decreasing. A very typical pattern
 CONQUERING SJOGREN's
165

is seen in the patient who has been having a stretch of fatigue and then
has a couple of days of more energy. Like a kid at a carnival, the patient
jumps for joy and runs around doing all kinds of things. This overdoing
can often result in a big crash with severe fatigue. Pacing is a strategy
that is very helpful at avoiding this seesaw effect. It involves maintaining
a level of activity that is punctuated with quieter, restful times regardless
of how much energy we seem to have at the moment. It functions to
keep us from drifting into either extreme end of the activity spectrum—
either too little activity or too much. Neither is healthy for the patient
with fatigue.
A second and perhaps even more important issue is how we reconcile
ourselves to having less energy to do things in life. Many SSF members
reported in the survey that they cut down on family or social activities
(58 percent), limited physical activities (64 percent), and did less work
around the house (64 percent). We live in a society where being pro-
ductive is equated with success; it is very closely linked with our self-
esteem. Unless we feel that we have something to contribute, we may
begin to question our worth as human beings. We find ourselves being
battered every day by our judgments about our productivity. Buying a
birthday cake rather than making it at home can feel like a major trans-
gression if we've been raised to believe that only homemade cakes are
valued. Likewise, vacuuming every other week rather than weekly can
prompt self-ridicule and accusations of being dirty, lazy, and inadequate.
In the workplace, it can be just as bad. Reducing work hours or sales
territory can create feelings of inadequacy and failure in an environment
that is aggressively focused on bigger and more.
Dealing with this issue takes guts. It really means questioning our
assumptions about what makes a person worthwhile and valuable. It
involves scrutinizing our priorities and investing our limited energy in
those activities that are most important to us. Yes, we could manage to
bake and ice the birthday cake, but then we'd be too exhausted to enjoy
the birthday party. Which is more important? Most of us would answer
that it is spending enjoyable time with people we care about. So we'll
need to do a lot of self-talk to assuage our guilt about the bakery cake
in order to make the healthiest decision. When it comes to dealing with
fatigue, all of the "shoulds" that we've acquired are the enemy. They
are what drive us to try to do too much, because behind the "should"
is the belief that if we don't, then either something awful will happen or
THE NEW SJOGREN'S SYNDROME HANDBOOK
166

(worse) we will be a worthless human being. These are incredibly pow-

erful taskmasters. We need to muster the courage to question all of our
"shoulds" and those that are imposed by our family, friends, and work-
place. What we find when we do this is that many can be put aside or
modified without dire consequences. Maintaining our self-esteem is the
most important goal.

Pain
Many patients with Sjogren's experience chronic pain. Joint pain may
be an effect of Sjogren's, or it may be due to the fact that many Sjogren's
patients have an additional rheumatologic disorder such as rheumatoid
arthritis, osteoarthritis, scleroderma, or fibromyalgia. Pain is one of the
most distressing symptoms to experience. By definition it is very unpleas-
ant and keeps intruding like a loud dog that won't stop barking. Patients
with chronic pain describe how exhausting it can be to constantly strug-
gle to cope with the pain. Dealing with pain for short bursts of time is
difficult enough, but when it goes on for days, weeks, and longer, it can
wear a person out. It is not surprising that patients with chronic pain
consistently have higher rates of depression than patients with less or no
pain. Earlier we noted that overall, 29 percent of SSF members reported
depression as one of their most troubling symptoms. In fact, depression
is significantly higher in SSF members with pain syndromes such as fi-
bromyalgia (45 percent) and migraine headache (41 percent).
How we respond to pain can powerfully influence our total pain
experience. Very early in our development, the occurrence of pain signals
that some harm is being inflicted on our body and that we need to take
immediate action to stop it. The young child who reaches out and
touches something hot quickly withdraws her hand and learns that the
pain signaled that her fingers were getting burned. When we burn our
finger, scrape our knee falling off our bike, or stub our toe, each instance
of pain is appropriately interpreted as harm coming to our body. Human
beings have strong emotional reactions to pain and a strong instinct to
avoid harm. The child who has fallen off her bike is crying as much
from the surprise, fear, and embarrassment of the event as she is crying
from the pain. To take the example a step farther, the more frightened
and distressed she feels, the more pain she will feel.
The difficulty with chronic pain is that it doesn't always follow the
simple rules learned as a child. Often chronic pain is not associated with
 CONQUERING SJOGREN'S
167

an acute harm being directed toward the body that must be stopped
immediately. For the vast majority of conditions associated with chronic
pain, pulling away or stopping an activity will do little to stop the pain.
Take fibromyalgia, for example, where it feels like awful things are hap-
pening in the muscles. The pain is not signaling harm to the muscles;
rather, it appears that the pain is being generated by chemical imbalances
in the nervous system. Dealing effectively with chronic pain starts with
relearning the meaning of pain such that it no longer sets off the disaster
alarm system in our mind. The sirens have to be turned off, the fear has
to be quieted, and the catastrophizing has to be minimized. Instead of
going with our first impulse—"Oh, no! This is terrible; I can't stand it.
Please make it stop!"—we have to learn new ways of talking to our-
selves. Recognizing the pain, registering disappointment, and then re-
assuring ourselves that we don't need to be alarmed set the stage for
subsequent coping strategies that can considerably reduce the perception
of pain and its impact on our life.

Managing Depression, Anger, Fatigue, and Pain

Approaches to Coping
Given the choice, no one would opt for coping with a chronic illness.
Everyone would sign up for the cure. Modern medicine has dazzled us
with cutting-edge breakthroughs in treating disease. Even something as
deadly as AIDS has begun to submit to the clever strategies and healing
tools of doctors. The National Institutes of Health spend billions of dol-
lars every year researching cures for asthma, diabetes, heart disease, can-
cer, and many other diseases. The cure for Sjogren's syndrome, unfor-
tunately, does not appear to be around the corner. Thus, when we are
told that we need to learn to cope with an illness, it suggests that it's
okay to settle for coping instead of pulling out all of the stops to elim-
inate the symptoms or the disease entirely. "Is my doctor really putting
all of his energy into figuring out what is wrong with me and trying
different things to help? Or once he realizes that it's a nonmalignant,
chronic illness, does he lose interest and any motivation to keep explor-
ing ways to help? Does anyone realize how incredibly hard it is to cope
with all of these symptoms and the way it interferes with my life?"
In fact, we face all kinds of challenges throughout our lives that re-
quire us to cope with situations that we can't fix or "cure." Consider
THE NEW SJOGREN S SYNDROME HANDBOOK
168

the challenge of financial problems, a stressful marriage, the death of a

spouse or child, a gang-infested neighborhood, a difficult boss, ethnic or
racial discrimination, or even difficult in-laws. Coping with situations
that are far from optimal is an inescapable part of the human condition.
Illness is just one of the greatest challenges for people who are otherwise
blessed. However, there is no rule that says that an individual can't have
many difficult challenges in life. It is not uncommon to see patients strug-
gling with Sjogren's syndrome on top of a series of already very difficult
life circumstances. For patients living in dangerous communities, or who
have stressful, low-paying jobs, or whose family life is chaotic, there is
a mountain of challenges to cope with. Life's unfairness conies in many
shapes and sizes.
Researchers have been studying coping with daily hassles and large
adversity for the last 30 years. Much has been learned during that time
about what makes coping effective and what styles of coping are asso-
ciated with poor outcome. There is also work that has been done that
looks at patients' readiness to begin the process of coping. This research
shows that patients are at different stages of readiness for coping. Some
are well on their way, while others are still at the first stage where they
only want to consider a cure and do not want to consider steps that
they could take to manage their illness better. Where patients stand in
terms of their readiness for adaptive coping is in part tied to their state
of mind: how much of their energy is still going into anger and how
depressed they are. Both anger and depression are states of mind that
interfere with the view that we can be calm, accepting, and empowered
to achieve a good quality of life in spite of life's challenges. When we
feel like a wronged party, a victim, we seek to blame and to demand
justice and restitution. When we are depressed, our sadness, pessimism,
lack of energy, and helplessness undercut our ability to think positively
and creatively about ways to adapt. Effective coping with Sjogren's re-
quires first a self-assessment of the state of our anger and mood. Both
need to be brought within healthy limits, or the impact of our illness on
our well-being is going to continue to be negative.
In the section on depression, we noted that many Sjogren's patients
are depressed and that the side effects of antidepressant medications may
be intolerable because they increase dryness. Fortunately, medication is
not the only way to successfully treat depression. One option that we
mentioned is psychological therapy. Indeed, research has shown that
 _CONQUERING SJOGREN
_S
169

some types of psychological therapy can be just as effective as medica-

tion for treating depression: cognitive-behavioral therapy and interper-
sonal therapy. Each of these treatments helps the patient to break the
negative spiral of social withdrawal and losing interest in pleasurable
activities. Cognitive-behavioral therapy helps patients to think about
themselves and their situations in ways that are more positive. A shift
to thinking about the cup as half full rather than half empty is a simple
example of this. Reducing the maladaptive coping pattern called "catas-
trophizing" is an especially important cognitive change for Sjogren's pa-
tients and those with other chronic diseases. Research clearly shows that
patients who come to dire conclusions about their situation have a much
poorer outcome than those who do less catastrophizing. Interpersonal
therapy addresses the functioning of our interpersonal relationships,
which are so important to our feeling positively about ourselves and our
lives. Therapy that focuses on improving and enriching our interpersonal
experiences can have a dramatic effect on depression.
Physical exercise has also been shown to have positive effects on
mood and well-being. Although it is not recommended as a primary
treatment for clinical depression, it can be a very important component
of an overall approach to reducing depression. Moreover, physical ex-
ercise has so many other positive benefits. There is another negative
spiral very common in medical patients, called deconditioning. Pain,
stiffness, and fatigue are all compelling reasons that cause patients to
shy away from physical activity. However, as patients do less activity,
stiffness, pain, fatigue, and sleep problems actually increase. The body
becomes deconditioned—that is, weak and out of shape. The more de-
conditioning sets in, the worse patients feel and the less likely they are
to be active. It is not uncommon for patients to explain that they know
they should be more active, but every time they are, they feel that they
pay a heavy price for the next few days with aches and exhaustion. For
them, exercise seems to only make things worse. Patients who report this
are not lazy or whiners; rather, they are describing a common problem
that requires some expert guidance to solve. Unless patients know what
types of activity or exercise are appropriate for their particular condition
and how much to do, many will fail. Patients with joint disease, such as
rheumatoid arthritis, osteoarthritis, or fibromyalgia, can aggravate their
illness with the wrong forms of exercise. Many patients have to start out
very slowly and very gradually build up their stamina and endurance.
THE NEW SJOGREN'S SYNDROME HANDBOOK
170

Likewise, knowing which exercises are best and which to avoid makes
all the difference in starting and maintaining a successful reconditioning
program. Physical therapists are trained to design individualized pro-
grams for patients, to continuously reassess progress, and to work out
difficulties that emerge along the way. This type of professional guidance
can be the difference between demoralizing failure and success for many
patients.
A less individualized approach, but much better than trying to figure
it out on your own, is the Arthritis Foundation's People with Arthritis
Can Exercise (PACE) classes. PACE is a group exercise program led by
trained instructors that uses gentle activities to help increase joint flexi-
bility and range of motion and to help maintain muscle strength and
increase overall stamina. A second program available through the local
chapters is the Arthritis Foundation's Aquatic Program. Since water pro-
vides buoyancy and protects the joints from impact, it is especially com-
fortable for patients with arthritis pain and stiffness. Like the PACE
program, it takes patients through a series of gentle exercises to increase
flexibility, strength, and stamina. Reversing the deconditioning spiral can
be one of the most important steps a patient can take to improve the
quality of their life. More information about these programs is available
at www.arthritis.org.

Communicating Needs
Human beings have a deep need to share their experiences and to
feel understood. Communication weaves our life journey with those
around us. It is a fundamental way of helping us to make sense of our
experiences and to have others recognize and validate those experiences.
When we listen to ourselves speak out loud, we sometimes gain a dif-
ferent perspective about events compared with listening to the private,
internal dialogue in our head. Plus, the reactions and comments of those
we are speaking to provide further input into our evolving view of the
experience and its meaning for us.
Communication is fundamental to the day-to-day human experience.
But not all communication is effective or successful. It can break down
at lots of points along the way. It can start with ineffective delivery of
the information, and it can continue with woefully inept listening. In all
cases, ineffective communication is a source of distress and a frequent
precipitant of disappointment and interpersonal conflict. How is it that
 CONQUERING SJOGREN S
171

such a vital aspect of successful living is often done so poorly? Probably

because we've never been explicitly taught good communication and
listening skills. It is not an accident that many corporations spend
thousands of dollars sending their executives and managers to commu-
nication training programs. They can have a great product or service,
but if they don't know how to convey that to their potential customers
in a convincing way, they won't get sales. Furthermore, if they don't
know how to listen to what their customers are describing about their
particular needs, they can't address these issues and sell more product.
Good communication is no less important for Sjogren's patients. We
need to be able to tell people what is happening to us, how we are
feeling, and what we need. The more important an experience is to us,
the greater our need to share it. Like other patients with a chronic illness,
Sjogren's can become a central focus of our lives. We are trying to un-
derstand it and to master it. When we talk about it with others, we are
no longer alone with it. Our emotions such as pain, fear, and anger are
recognized, and our struggle is validated. Joining the Sjogren's Syndrome
Foundation and participating in the activities of local chapters and sup-
port groups can help. It opens up opportunities to hear that others will
help us or at least that they sympathize with us. When we communicate
effectively, we inform others of what we are or are not able to do and
why. And not least of all, good communication equips us with the ability
to specifically ask for what we need. We need to be direct—it's a mistake
to assume that other people can read our mind.
Sjogren's syndrome presents special issues for communication. Some-
times we sense that our comments and complaints are becoming old and
tiresome for our friends and family. Basically, we worry that they don't
want to hear about it anymore. There is nothing new to be said and
nothing new to be done. But if we struggle along quietly in order not
to create discomfort in the people around us, we may create a sense of
isolation for ourselves. However, recognizing that our illness creates dis-
tress in those who care about us can help us to solve this communication
dilemma.
Most of us tend to respond to difficulties by problem solving; this is
particularly true for men. But none of us likes to feel helpless and inept
at solving the problem. At this point in time, Sjogren's syndrome is a
chronic problem that can't be totally solved. It is going to persist and
perhaps even worsen over time. Not a happy affair for the problem
_
THE NEW SJOGREN'S SYNDROME HANDBOOK
172

solver! What we need to realize and then communicate is that often we

are not expecting anyone to solve the problem. We may be feeling par-
ticularly bad today and just want to whine and complain a little, so that
we are not alone with the experience. Sometimes we are just looking for
some sympathy—a little extra love and concern as a salve for the hurt.
All of this serves to keep us from feeling alone and to be reassured that
we are important and loved by others and that they will continue to
stick by us. So if these are the things that we are really looking for when
we talk about our illness, we need to let people off the hook of trying
to make it better for us; instead, we should let them just listen and give
us support. Many of the people in our life will be willing to do this.
Communication with our health care professionals is a special case.
We have a limited amount of time with them, we have several of them
(rheumatologist, dentist, ophthalmologist, etc.), we may feel intimidated,
and often we have hefty expectations about their ability to solve our
problems. It is no wonder that Sjogren's patients often leave their doc-
tor's office upset by what did not happen.
The intersection between patient and doctor that is problematic is
when the patient has expectations for the doctor that are not reasonable.
Doctors are limited by the boundaries of current medical science, and
medical science has limitless frontiers of yet undiscovered knowledge.
What this means for Sjogren's patients is that our doctors are not going
to know precisely what is causing our dryness and other associated
symptoms. Although it is frustrating to us, they may have to watch a
symptom over weeks, months, or years to generate confidence in their
interpretation of its meaning for our health. And they may never figure
out what to do about it. Patients' responses to many treatments still
resemble a game of chance: some patients will improve, others will show
no response, while others will suffer serious side effects. If we want a
healthy, productive relationship with our doctor, we need to have rea-
sonable expectations. We have to be willing to accept that our doctor
may not know and may have little or nothing in his tool kit to help. At
the same time, we need to be educated and informed consumers and be
on top of possible new treatments.
The next time you have an appointment with your doctor, try the
following. Before you go, imagine leaving the doctor's office having had
a very successful visit. What about the visit was pleasing? Did he or she
spend some extra time with you so you could get through many of your
 CONQUERING SJOGREN's
173

questions? Did he express empathy for the rough time you've been
having? Did he give you some suggestions about ways of managing your
symptoms so you can get more done and feel more comfortable? Did he
reassure you? Was he willing to talk with you without getting irritated
about the magnet therapy you were thinking of trying or a new herb
that you heard about? Did he agree to talk with your other doctors to
keep your medical care better coordinated? Remember that your agenda
and that of your doctor are not necessarily in sync when you enter the
exam room, and doctors are no better at mind reading than anyone else.
Once you've identified what made the imagined visit a success for you,
then consider what steps you can take to make it happen. Clear, direct
communication with your doctor about what you need from the visit
will increase the likelihood of success. If you don't ask, it's going to be
hard to get what you want. On the other hand, if after a few visits with
your doctor, you are still leaving the office dissatisfied, then you have to
do some soul-searching about your style and expectations or you need
to consider whether another doctor would form a more satisfying part-
nership with you.

Take Control
In 1977, Dr. Albert Bandura, a psychologist at Stanford University,
introduced what has become a very important concept in the manage-
ment of chronic illness. The concept, self-efficacy, refers to a person's
belief in his or her ability to exert control over important aspects of life,
as opposed to having to passively accept things as they are. Like most
personal characteristics, individuals vary in how much of the character-
istic they have. Over the past 25 years, research has focused on the
impact of self-efficacy in patients with chronic illness, especially rheu-
matologic diseases. The studies have repeatedly come up with the same
result: the greater the sense of self-efficacy, that is, the ability to reduce
symptoms and disability, the lower the ratings of pain, fatigue, depres-
sion, disability, and so on. What is fascinating is that the research sug-
gests that patients higher on self-efficacy are not necessarily doing any-
thing different, such as exercising or pacing, compared with patients
with lower self-efficacy. Rather, it appears that having a mind-set of
empowerment over adversity rather than a mind-set of victimization can
contribute to greater well-being in these patients.
Let's take a very salient example. Dryness is a noxious experience,
THE NEW SJOGREN'S SYNDROME HANDBOOK
174

one that readily creates feelings of being trapped and victimized by those
suffering with it morning, noon, and night. For the patient with little
self-efficacy, the belief is that only medication or a cure can lessen the
extreme discomfort, and they have little choice but to endure it. Such
patients believe that nothing they do will make any difference. Compare
this with the Sjogren's patient who has a take-charge attitude, who keeps
trying different strategies to see what helps, and who knows that once
the doctors or nurses have done their job, then the patient's job of ef-
fectively managing their illness is just beginning. In the field of pain,
research has discovered that many factors come into play to determine
how much pain a patient experiences. The mind-body connection is re-
ally at work with pain as well as many other symptoms. How we talk
to ourselves about our pain, how we emotionally react to our pain, and
how we alter our behavior in response to pain ultimately play a large
part in how much pain we experience. Similarly, how we react to dryness
plays a large part in how much it interferes with our functioning. The
key issue is the extent to which we feel that we can have some control
over our symptoms and disability. The more we accept responsibility,
then the less passive and victimized we will be, and the more likely we
are to make important and effective contributions to our health and
well-being.

Summing Up
The mind-body relationship is extremely important in patients with
Sjogren's syndrome and can affect patient perception of fatigue, pain,
and other symptoms. Development of more effective psychosocial coping
strategies can greatly alleviate symptoms and improves patient quality
of life.
 Swamy Venuturupalll, MD

19 Complementary and
Alternative Therapies
for Sjogren's Syndrome

SJOGREN'S SYNDROME is a chronic autoimmune condition characterized

by the sicca syndrome complex. Oftentimes Sjogren's is associated with
other autoimmune disorders such as rheumatoid arthritis (RA) and sys-
temic lupus erythematosus (SLE). An estimated 35-50 percent of pa-
tients with Sjogren's have an inflammatory arthritis similar to rheuma-
toid arthritis, and approximately 50 percent of patients have symptoms
suggestive of fibromyalgia (a chronic pain syndrome with significant mus-
cle soreness).
In this chapter, a review of the available evidence to support the use
of complementary and alternative medicine (CAM) for Sjogren's syn-
drome is presented. An extensive search of the scientific literature yielded
very few clinical studies dealing with Sjogren's syndrome specifically.
Hence, a significant part of this chapter will focus on the use of CAM
for arthritis and fibromyalgia, both very common associations in Sjo-
gren's syndrome.
Complementary and alternative medicine refers to a wide array of
therapies that are not generally learned in conventional medical training
or used in conventional medical practice. In the last decade these ther-
apies have become extremely popular, with about 40 percent of Amer-
icans using CAM for chronic conditions, at an estimated annual expen-
diture of $27 billion per year. Patients with rheumatic diseases perhaps
use CAM at a rate greater than for all other diseases.

175
THE NEW SJOGREN'S SYNDROME HANDBOOK
176

Several important issues and concerns arise with the use of CAM by
patients:

1 A lot of these therapies, even though considered natural, are not free
of side effects and toxicity.
2 Since a lot of these medications are manufactured without proper
regulation, there may be undeclared additions and adulterations to
the medicines.
3 The authenticity of the claimed ingredients is a huge question mark.

4 There is a possibility of severe interactions between prescribed med-

icine and CAM.
5 There are several behavioral patterns associated with CAM, such as
medication discontinuation, use of CAM with no professional super-
vision, and a low willingness to report CAM side effects on the part
of patients and practitioners that may adversely affect patient health.

With this background, the following therapies will be discussed for

their relevance to rheumatic diseases:

Dietary therapies

Herbal therapies and nutriceuticals

Manual and manipulative therapies

Acupuncture
Ayurveda and yoga
CAM therapies specific for Sjogren's syndrome

Diet and Dietary Therapies

Panush and colleagues reviewed the scientific literature on diet and
dietary therapies for rheumatic conditions in an issue of Rheumatic Dis-
ease Clinics of North America. The following is a summary of the major
studies reviewed and presented in that publication.
 COMPLEMENTARY AND ALTERNATIVE THERAPIES
177

Fasting
Fasting has been proposed as a therapy for rheumatic conditions.
Several clinical trials have shown that fasting improved symptoms of
rheumatic disease in some patients. For example, 5 of 15 patients with
rheumatoid arthritis who fasted for 7 to 10 days showed improvement,
compared with only 1 of 10 controls in one study. Another prospective
study investigated the effects of complete fasting on patients with RA.
Forty-three patients underwent a fast, consisting only of water, that
lasted seven days. Both objective and subjective symptoms showed sig-
nificant improvement. Thus, fasting may improve rheumatic conditions.
This improvement might be a result of weight loss and malnutrition,
which can suppress immunity. Fasting in a Sjogren's patient, however,
can exacerbate dryness due to dehydration.

Elimination or Exclusion Diets

Exclusion or elimination diets are used to detect foods that are sus-
pected of causing food allergies and thus triggering attacks of illness.
Suspected foods are avoided for a specified period of time to clear the
system and are then reintroduced in a carefully controlled sequence.
Symptoms that reappear are thought to be a reaction to particular foods.
These foods are then eliminated from the diet for a considerable time.
Several studies have been conducted to determine whether sensitivity
to certain foods can exacerbate RA symptoms. For example, Darlington
and colleagues reported that some patients with rheumatoid arthritis
benefited from the elimination of certain foods, including corn, wheat,
pork, bacon, orange juice, milk, oats, rye, eggs, beef, coffee, malt, cheese,
grapefruit, tomato, butter, sugar, and soy, in descending order of fre-
quency. These patients experienced symptomatic deterioration with the
reintroduction of these foods. None of these studies has been rigorously
controlled, and therefore none can be interpreted as being definitive.
More recent studies by Panush and colleagues gave patients blinded
food challenges of food in capsule form. Only 3 of 16 patients convinc-
ingly demonstrated an increase in subjective and objective rheumatologic
symptoms when they were challenged in this blinded manner with foods
that they claimed to be allergic to.
Based on a review of all the available evidence, it appears that only
a small number of rheumatoid arthritis patients clearly demonstrate
THE NEW SJOGREN'S SYNDROME HANDBOOK
178

food-related allergies. These patients will benefit from the elimination of

these foods from their diet.

Elemental or Hypoallergenic Diets

Elemental diets contain no complex protein or peptides, but do con-
tain free amino acids, which are components of the proteins and the
peptides. In some experiences in the published literature, elemental diets
appear to be beneficial. For example, in the study by Panush and col-
leagues in which patients were challenged with allergens in a double-
blind fashion, most patients showed improvement on an elemental diet,
suggesting that there may be a role for this diet in treating rheumatic
conditions.

Dietary Supplements
Ginger has been used for many years in Ayurveda (the traditional
Indian medical system) and other healing traditions. In an open trial of
28 patients, ginger was shown to be effective in reducing inflammatory
symptoms.
Bromelain is an enzyme derived from the pineapple plant. There is
no clinical evidence to support the use of bromelain for rheumatic
conditions.
Collagen type II was studied in a multicenter, double-blind, placebo-
controlled trial. There was no efficacy associated with the use of collagen
type II for rheumatoid arthritis patients in this trial.
Shark cartilage has been suggested as a treatment for osteoarthritis,
rheumatoid arthritis, and lupus, but there are no adequate clinical trials
to substantiate the use of shark cartilage.
The higher susceptibility of women to autoimmune conditions has
suggested a role for sex steroids in these diseases. Low serum levels of
dehydroepiandrosterone (DHEA) have been measured in postmenopau-
sal women with RA, men with RA, and patients with SLE. DHEA has
been preliminarily studied in RA and Sjogren's, but did not show any
efficacy. Research is currently being conducted on the use of DHEA in
SLE, and these studies show a lot of promise in controlling the symptoms
of SLE. DHEA is not without side effects, which include prostate en-
largement in men and masculinization or liver damage in women, in-
creased risk for heart disease, insulin resistance, and uterine and other
hormone influenced cancers. Hence, if DHEA is being used for rheumatic
 COMPLEMENTARY AND ALTERNATIVE THERAPIES
179

diseases, it needs to be done in proper dosing under the guidance of a

physician.

Vitamin and Nutritional Therapies

Antioxidants such as vitamin A, C, and E have been studied for their
role in preventing oxidative tissue damage and in preventing rheumatic
diseases. Low levels of beta-carotene (the precursor to vitamin A) were
found in the blood of rheumatoid arthritis patients compared with con-
trols. However, no study of the administration of vitamin A to RA pa-
tients has been done. Vitamin A deficiency can cause dry eye but is
seldom detected among people with Sjogren's.
In randomized control trials, vitamin E was found to be as effective
as diclofenac, which is a nonsteroidal anti-inflammatory drug, and more
effective than placebo in reducing symptoms of rheumatoid arthritis.
Ascorbic acid or vitamin C has been found at low levels in the blood
of RA patients, but there is no convincing clinical data for its use in
rheumatoid arthritis, or other rheumatic disorders.

Dietary Fatty Acids

Omega-3 and omega-6 fatty acids have been found to have several
anti-inflammatory properties. Eicosapentaenoic acid is an omega-3 fatty
acid found in cold-water fish. Gamma-linolenic acid is an omega-3 fatty
acid found in large quantities in plant seed oils such as flaxseed oil,
borage seed oil, and evening primrose oil.
The clinical usefulness of fish oils and plant-derived fatty acids has
been studied in multiple clinical trials. A review of all these clinical trials
suggest that fish oil is superior to placebo for improving joint tenderness
and morning stiffness in rheumatoid arthritis patients. Flaxseed oil
showed initial benefit in RA patients, but after three months of follow-
up, no beneficial improvements were demonstrated.
Polyunsaturated fatty acids have not been consistently beneficial in
the treatment of SLE. Fish oil has been shown to be useful in patients
with Raynaud's phenomenon and in some patients of rheumatoid
arthritis.
Thus, fish oil and plant seed oils may have modest benefits at best in
rheumatic conditions. Fish oil supplements, unlike whole fish, typically
do not contain any mercury, and can be taken in anti-inflammatory dos-
ages without problems.
THE NEW SJOGREN'S SYNDROME HANDBOOK
180

Herbal Anti-inflammatory Medications

Herbal medications are exceedingly popular for a variety of condi-
tions. Between 1990 and 1997 use of herbal medicines increased by 400
percent in the United States. A large proportion of these are used for
rheumatologic conditions. While a lot of patients believe that herbal
medicines are safer than pharmaceuticals, this is not always the case.
The use of herbal therapies may give rise to significant side effects
and interactions with prescribed medications. Moreover, since the man-
ufacture of herbal supplements is not well regulated, the potency of
herbs may vary from batch to batch, and this could give rise to many
additional problems. Having said this, it appears that the incidence of
adverse effects from herbal therapies is fairly low.
Most of the herbs used as anti-inflammatories seem to affect the cy-
clooxygenase and lipooxygenase pathways, which are pathways that
cause inflammation in the body. These are the same pathways that are
targeted by nonsteroidal anti-inflammatory drugs such as aspirin, ibu-
profen, celecoxib, and so on. Other pathways that reduce inflammatory
mediators have also been shown to be affected favorably. Herbal med-
ications may have weaker inhibition of inflammatory pathways com-
pared with synthetic drugs. Thus, herbal anti-inflammatory medications,
while not as potent as synthetic drugs, may have fewer adverse effects
than pharmaceuticals. In acute and severe pain, herbs are probably less
helpful than pharmaceuticals, but may have a role to play in milder and
more chronic pain.
Recently, a systematic review of the scientific literature described 19
randomized controlled trials. Encouraging data was found for evening
primrose oil, borage seed oil, devil's claw, Phytodolor (a commercially
available mixture of herbs), and willow bark extract.

Evening Primrose Oil

Evening primrose oil contains GLA (gamma-linoleic acid) and eico-
sapentaenoic acid, which are anti-inflammatory fatty acids. In a well-
conducted clinical trial evening primrose oil was found to be superior
to placebo for osteoarthritis. Side effects reported were nausea and rash.
Patients who are on antipsychotic medications should avoid this because
of increased risk of seizures. The recommended dose is 500-1,500 mg
of GLA.
 COMPLEMENTARY AND ALTERNATIVE THERAPIES
181

Borage Seed Oil

Borage seed oil contains GLA. Two randomized, placebo-controlled
trials showed significant improvement in arthritis with its use. Negligible
side effects were reported in the trials. A dose of 1-2 grams has a po-
tentially toxic amount of pyrazolidine alkaloids, and patients on antie-
pileptic drugs should avoid it because of increased seizure risk.

Devil's Claw
This is a very popular herb used for inflammatory conditions. The
active principle is harpagoside. Two randomized, controlled trials
showed positive results in acute low back pain patients. Two other ran-
domized, controlled trials showed positive results in osteoarthritis pa-
tients. The recommended dose is up to 9 grams per day for three to four
months. Significant gastrointestinal toxicity may occur, and it is contra-
indicated in patients with ulcer disease. Also, it is contraindicated in
patients who are on the anticoagulant warfarin, because devil's claw
increases in the level of warfarin in the blood.

Phytodolor
Phytodolor is a commercially available product from Germany. A
dose of 100 ml contains the following herbs: Populus tremula 60 ml,
Fraxmus excelsior 20 ml, and Solidago vergaurea 20 ml. There are four
randomized controlled trials on rheumatic pain of all sorts, with a total
of 225 patients. All four studies showed a significant decrease in pain
compared with placebo. The therapeutic dosage is 30-40 drops three
times a day. No significant adverse reactions have been reported.

Willow Bark Extract

The active ingredient in willow bark is salicin (an aspirin-like com-
pound). Two randomized, controlled trials showed benefit in osteoar-
thritis patients compared with placebo. However, there are many pos-
sible side effects, including exacerbation of asthma, allergic rhinitis,
contact dermatitis, salicylate toxicity, and liver and kidney damage. This
drug also interacts with many other medications; for example, it in-
creases levels of phenytoin (an anti-epileptic) and warfarin (a blood
thinner).
THE NEW SJOGREN'S SYNDROME HANDBOOK
18Z

Acupuncture
Acupuncture is a component of traditional Chinese health care and
can be traced back 2,000 years. The general theory of acupuncture is
based on the premise that there are patterns of energy that flow through
the body that are essential for health. Acupuncture is believed to correct
imbalances of energy or qi as it flows through 12 primary meridians
(channels) and 8 extraordinary meridians. Practitioners may use heat,
pressure, friction, suction, electric stimulation, and lasers in addition to
the traditional needles that are placed on specific points in the affected
meridians.
Acupuncture has been studied in clinical trials for the treatment of
osteoarthritis (degenerative arthritis), rheumatoid arthritis, fibromyalgia,
and back pain. One of the significant problems in studying acupuncture
in randomized clinical trials is the designing of a placebo arm, where
controlled acupuncture needs to be given to patients without them
knowing that they are in a placebo group. This significant design issue
makes the study of acupuncture very difficult, and hence very few good
clinical trials have been conducted. Having said that, there appears to
be fairly good evidence that acupuncture is better for back pain than
sham or placebo acupuncture. There is only one good trial that has
studied acupuncture for fibromyalgia in a scientifically sound way, and
this trial shows that acupuncture may help. There is only one good ran-
domized trial using acupuncture for rheumatoid arthritis, and again, this
shows that acupuncture may be helpful. For the pain of osteoarthritis
of the knee, there is strong evidence that acupuncture is better than sham
acupuncture.
There is no clear-cut evidence that the use of acupuncture improves
a patient's ability to function (as opposed to improving the symptom of
pain). Thus acupuncture may be used as an adjunct when dealing with
pain from any of the above conditions.

Ayurvedic Medicine
The term Ayurveda is a Sanskrit word that translates as "knowledge
of life or longevity" and refers to the ancient Indian system of medicine.
This is a comprehensive system that incorporates its own theory of ill-
ness, pathogenesis of different conditions, and a therapeutic pharmaco-
poeia that includes several hundred herbs and thousands of combina-
 COMPLEMENTARY AND ALTERNATIVE THERAPIES
183

tions of these herbs. Therapeutics in Ayurveda are multifaceted and

include diet, yoga and other exercise therapies, mental relaxation tech-
niques, and herbal therapies along with purification therapies.
Ayurveda is still practiced in India and is now becoming increasingly
popular in the West. Ayurvedic theory of disease is based on the tridosha
theory, which holds that the body contains three humors or doshas called
vata, pitta, and kapha. Vata is involved with psychomotor activities,
pitta with metabolism, and kapha with structural integrity of the body.
Each person is believed to have a unique combination of vata, pitta,
and kapha in the body at the time of birth. This combination changes
as the person progresses through life. When there is an abnormal ac-
cumulation or deficiency of one or more doshas in one's body, disease
is thought to result. Ayurvedic therapies are usually aimed at restoring
the balance of these three doshas to the original unique combination of
each person.
Numerous herbs have been described in Ayurvedic literature to pos-
sess antirheumatic activity. Unfortunately, clinical trials of these are far
and few between. In one randomized clinical trial, Kulkarni and col-
leagues studied a combination of four Ayurvedic herbs in osteoarthritis
patients. These included Withania somnifera, Boswellia serrata, Cur-
cuma longa, and zinc ash. The patients on the Ayurvedic herbal com-
bination did significantly better than the placebo group. In another trial,
Chopra and colleagues studied two Ayurvedic formulas, RA-1 and RA-
11, in rheumatoid arthritis patients. Again, these herbs resulted in sig-
nificant improvement in symptoms compared with placebo.
Ayurvedic medicine holds a lot of promise for treating a number of
conditions. Intriguingly, Ayurvedic medicine strongly believes in a con-
nection between the gut and rheumatic conditions, something that has
been validated more recently by Western science in conditions such as
ankylosing spondylitis and other disorders. A lot of the herbs that are
thought to be active against arthritis have not been validated in random-
ized clinical trials. This is clearly something that needs to be done. More-
over, Ayurvedic herbs suffer from the same problem as other herbal med-
ications, namely, lack of standardization and lack of quality regulation.
The use, development, and scientific validation of Ayurvedic herbs is
certainly a very important potential source of future treatments for rheu-
matic conditions.
THE NEW SJOGREN'S SYNDROME HANDBOOK
184

Yoga
Yoga is a complete system of spiritual and physical pursuit that aims
to unite the body with the mind. This system developed many thousands
of years ago in India and is still practiced today. The popular form of
yoga in the West is hatha yoga, which emphasizes certain postures. Ha-
tha yoga, "the yoga of activity," addresses the body and mind and re-
quires discipline and effort. In addition to the postures, yoga includes
an entire philosophy of life. Thus, yoga is meant to be practiced in the
larger context of a spiritual discipline. Large numbers of Americans are
practicing yoga for its proposed health benefits.
As a therapy, yoga is a system designed to refine human physiology.
Postures or asanas, if done properly, are believed to affect every gland
and organ in the body. Postures have to be adjusted to position various
organs, joints, and bones properly so that the desired physiologic
changes may occur. Distribution of the body weight has to be even on
the joints and muscles so that there is no injury. Therapeutic yoga is a
performance of postures for treating medical disorders.
A review of the evidence that is published about yoga shows a few
positive clinical trials. References to clinical trials in asthma, hyperten-
sion, pain management, diabetes, and mood have been found. However,
the quality of most of these studies is not very good.
In the rheumatic diseases, two small, controlled, but non-double-
blind studies performed by Garfinkel and colleagues show promise for
the use of yoga in osteoarthritis of the fingers and carpal tunnel
syndrome.
There are certain risks to yoga treatment, which may include flaring
of rheumatic conditions if proper precautions are not taken. For ex-
ample, for persons with arthritis, a posture should be developed slowly,
with as little strain on the inflamed joints and muscles as possible.
Choosing an appropriate yoga instructor is certainly a challenge, and
this itself limits its use as a therapeutic modality for arthritis.

Alternative Therapies Specifically for

Sjogren's Syndrome
A search of the scientific literature on CAM therapies for Sjogren's
syndrome resulted in only five published articles. In a study by Johansson
and colleagues, mouth rinses with the linseed extract salinum were stud-
ied in a controlled, double-blind manner. The use of salinum with or
 COMPLEMENTARY AND ALTERNATIVE THERAPIES
185

without chlorhexidine (an antimicrobial substance) was shown to reduce

oral bacterial counts, oral dryness, and symptoms of speaking problems
and oral burning. Thus the salinum may be useful in reducing oral symp-
toms in patients with Sjogren's syndrome.
In another study, Longo Vital, an herb-based tablet enriched with
vitamins, was studied in patients with Sjogren's syndrome and compared
with placebo. The authors showed that Longo Vital may have a modest
effect on clinical and immunoinflammatory markers in Sjogren's
syndrome.
Lastly, List and colleagues studied acupuncture in treating patients
with primary Sjogren's syndrome. The authors were not able to show
any statistically significant differences between the acupuncture group
and the control group in unstimulated salivary secretion and most sub-
jective variables. Based on this study, acupuncture cannot be recom-
mended to patients for symptoms of oral or eye dryness.

Summing Up
In this broad overview of common CAM therapies for Sjogren's syn-
drome I have not reviewed several common therapies, such as manual
and manipulative therapies, since they are mainly useful for symptomatic
relief from pain syndromes and may have limited relevance to Sjogren's
syndrome patients. Traditional Chinese medicine and other traditional
healing systems have not been dealt with in significant detail; this would
be beyond the scope of this chapter. Cited and additional references are
available by contacting swamy_ucla@yahoo.com.
Based on a review of CAM for Sjogren's and related disorders, it is
clear that CAM may play a positive role in managing Sjogren's symp-
toms, arthritis, and fibromyalgia. Finding a qualified CAM professional
is not always easy, and neither is finding high-quality CAM products.
Most patients find it hard to communicate about CAM with their health
care professionals, but they must attempt to do so, because the potential
for adverse interactions between conventional medicines and CAM is a
risk that should be minimized.
 Stanley R. Pillemer, MD

20 How Are Drugs Tested

for Sjogren's?

RELATIVELY FEW DRUGS HAVE been thoroughly tested for the treatment
of Sjogren's syndrome. Current treatment for Sjogren's is aimed at the
symptoms, inflammation and complications of the disease. While a num-
ber of preparations are available for treating the complications of Sjo-
gren's, such as those for yeast infections, which can exacerbate problems
with mouth or vaginal dryness, and compounds for treatment of dry
itchy skin, these medications and products were not expressively tested
and approved for Sjogren's. Thus far, the only drugs approved for Sjo-
gren's are for the dry mouth and dry eye symptoms of the disease. These
drugs mark a major step forward in treating Sjogren's patients. However,
few drugs to treat Sjogren's systemically have been tested, and no defin-
itive evidence is available at this time showing that drugs that target the
immune system are beneficial in Sjogren's.

Why Have So Few Drugs Been Tested for the Treatment

of Sjogren's?
Aspects of the disease have hampered drug development. First, the
lack of unanimity on diagnostic criteria for Sjogren's discouraged inves-
tigators in academia and the pharmaceutical industry from testing new
treatments for the disease. However, published criteria for classifying
cases as Sjogren's are very similar and vary mainly in their stringency.
Closer agreement has emerged in recent years on diagnostic criteria
and has resulted in the publication of revised classification criteria by
the American-European Consensus Group. In addition, the disease has

186
 HOW ARE DRUGS TESTED FOR SJOGREN'S?
187

been perceived as being mild and not life-threatening. Thus, there

has been a reluctance to use, test, or develop more powerful drugs in
individuals with Sjogren's, because of concerns that the hazards of treat-
ment would outweigh the potential benefits. Also, the best measures to
assess the response of the disease to treatment have not been well char-
acterized yet.
Over the past few years, meetings have been held to develop consen-
sus on the optimal outcome measures for Sjogren's. This has resulted in
a candidate set of outcome measures and a framework for their vali-
dation. Typically, clinical trials of Sjogren's have used measures that in-
cluded symptoms of dryness and fatigue, objective measures of dry eye,
such as the Schirmer test, van Bijsterveld score (a test for ocular dryness
using a dye), or tear breakup time; objective measures of oral dryness
such as stimulated or unstimulated salivary flow rates; and blood tests
such as the erythrocyte sedimentation rate (ESR or sed rate) and the
level of immunoglobulin G. In addition, the Short Form 36 (SF-36), a
36-item questionnaire that measures health-related quality of life, has
been considered. Considerable work lies ahead in the validation of out-
come measures in Sjogren's.

What Does Participation in a Clinical Trial Entail?

In part, what participation involves is related to the nature of the
drug, biologic, or device that is being tested. It is also related to the
phase of testing, which will be discussed below. A trial will usually in-
volve a screening process that may begin with a telephone conversation.
A screening visit is usually scheduled to determine whether or not a
potential participant meets the criteria for inclusion in the study. For
example, the investigators who designed the trial may require that a
patient with Sjogren's also has a positive test for anti-Ro/SSA, even
though a negative test does not preclude a diagnosis of Sjogren's. Also,
it is important to be sure that a subject does not have any of the exclu-
sion criteria, such as pregnancy. Usually the screening visit will involve
completing questionnaires, a physical examination, blood tests, and
sometimes X-rays or other radiological tests. In some cases, biopsies may
be required. Before entering into a clinical trial, it is key to understand
what the study is about, what treatment subjects will actually receive,
and a clear and realistic assessment of the risks involved in the study.
These issues should be presented in a clear manner in the informed-
THE NEW SJOGREN'S SYNDROME HANDBOOK
188

consent document that all prospective subjects are asked to read and
sign if they agree to participate in the study.

How Are the Interests of Human Subjects Participating

in Clinical Trials Protected?
Clinical research protocols must be reviewed by institutional review
boards (IRBs) to determine the level of risk of the investigation or clinical
trial, and to ensure that the participants have been adequately informed
of the likely and possible risks of the study through informed-consent
documents. IRBs ensure that the investigators comply with the regula-
tions regarding clinical research. Typically, after the initial review, the
study must undergo continuing review at intervals (at least annually)
determined by the IRBs. An IRB is generally composed of individuals
with experience in the disease under investigation, such as physicians,
dentists, and psychologists. In addition, a biostatistician may be helpful
in assessing that the information obtained from the study will be useful
and will justify the participation of human subjects. However, there are
often scientific review committees in research organizations to ensure
that the design of the clinical trial is sound. In addition, one or more
lay persons serve on the IRB to advocate for participants. They provide
very useful input on the questions that participants might have and in
ensuring that the informed-consent document will be well understood
by the target population for the trial.

What Is the General Process for the Development and

Testing of New Drugs?
The development of new treatments for various diseases is extremely
complex and usually involves an understanding of the mechanisms of
the disease. Basic science laboratory and animal studies often test hy-
potheses about the mechanisms of diseases. Then particular molecules
may be targeted to block a deleterious process or augment a favorable
process. The dominant paradigm is that of bringing a new treatment
from the basic science laboratory bench to patients ("bench to bedside").
However, it is clear that the reverse also occurs, in that problems con-
fronting clinicians may lead to basic science investigations of the mech-
anisms. Also, drugs that are approved for the treatment of one disease
may serendipitously be found to be useful in an unrelated disease. This
may prompt the formal investigation of the treatment in clinical trials.
 HOW ARE DRUGS TESTED FOR SJOGREN'S?
189

New drugs may be developed from preclinical laboratory investiga-

tions and animal studies. Existing drugs may already have been devel-
oped, tested, and approved for the treatment of other diseases before
being considered for Sjogren's. In some cases special large-scale industrial
robotic systems are used to synthesize thousands of new compounds.
Compounds may also be extracted from plants, fungi, bacteria, or other
sources. In some settings a very large number of compounds may be
screened by placing them into contact with cell line suspensions to de-
velop a profile of their biological effects, which would suggest potential
applications for the drugs.
Once these drugs have been identified, a much slower process is un-
dertaken. Usually, the Food and Drug Administration (FDA) is consulted
very early in the drug development process, since the FDA may require
preclinical studies that have not been considered by the drug developers.
Preclinical studies in animals allow for the determination of the drug's
safety and biological mechanisms of action. Dosing studies can be per-
formed in animals to determine the likely dose for humans. Prior to any
clinical studies in humans, the FDA is consulted again before researchers
file an investigational new drug application. The purpose of this meeting
with the FDA is to resolve any preclinical issues and to ensure that the
details of the drug development process for subsequent phases of drug
development will be acceptable to the agency. After this, the drug de-
velopment process will follow several phases. The general process is
specified in the Code of Federal Regulations. By and large, drug devel-
opment within industry tends to be on a "go/no-go" basis. At each step,
safety, feasibility, and cost have to be considered, and many drugs do
not progress beyond the early investigations. When failed drugs are in-
cluded, the cost of bringing a single new drug to market may be in the
hundreds of millions of dollars.
In the early stages, feasibility assessments take into account the prev-
alence of the disease (the number of existing cases in the population)
and its incidence (the number of new cases per population per unit of
time, e.g., cases per 100,000 population per year), since rare diseases
may not allow a pharmaceutical company sufficient return to cover the
costs of development. In addition, careful attention is given to the design
of the human clinical trials to ensure that valid answers to important
questions, appropriate to each phase of development, are obtained. A
protocol is written outlining the background data motivating testing of
THE NEW SJOGREN'S SYNDROME HANDBOOK
190

the drug, the study design, the rationale for the number of subjects to
be enrolled in the study, what measures will be used to determine the
success or failure of the treatment, how potential adverse events will be
monitored, how the data will be managed and analyzed, what will be
done during subjects' visits, a copy of the informed consent document,
and other considerations pertinent to the trial. This protocol undergoes
scientific, IRB, and other reviews. For each phase of development, pro-
tocols must be written, and various reviews are required. The develop-
mental phases are outlined below.

Phase I: Dose and Safety Testing

Phase I testing usually involves 20 to 100 subjects. An idea of the
safety and appropriate dosing levels has already been obtained in ani-
mals. Here subjects are treated with low doses that are increased care-
fully. If adverse events are observed at a particular dose, higher doses
are usually not tried. Studies of how the drug is absorbed, metabolized,
and cleared in humans give a more comprehensive picture of the drug.
Although animal studies may have suggested the drug may be useful in
treating particular disease processes, no attempt is made in Phase I stud-
ies to determine whether the treatment works.

Phase II: Further Assessment of Safety in a Larger

Number of Patients and Evidence of Efficacy
Phase II studies usually involve 100 to 300 subjects. Efficacy refers
to whether a drug is able to successfully treat a condition and is usually
determined under controlled conditions. It should be distinguished from
effectiveness, which is evaluated among patients in the real world and
is usually determined after a drug is already on the market. Phase II
investigations allow drugs that have emerged from Phase I studies with
an acceptable safety profile to be further tested for safety. The data from
the Phase II study are used to calculate the number of patients required
to establish safety and efficacy in the pivotal Phase III study.

Phase III: Proof of Efficacy and Further Safety Testing

Phase III usually involves 300 to 1,000 subjects. During this phase
determination of efficacy is of major importance. Many disorders are
not sufficiently common to allow a Phase III study to be performed at
one center. Typically, then, these studies are conducted with several par-
 HOW ARE DRUGS TESTED FOR SJOGREN'S?
191

ticipating centers and a coordinating center. Usually laboratory samples,

images, and data are sent to the coordinating center, which carries out
the data analysis and monitors the progress of the study to ensure that
it follows the protocol and standard operating procedures. The larger
number of patients included in this phase also provides a further op-
portunity for closely monitoring the safety of the drug. An independent
data safety monitoring committee carefully follows the safety of the drug
and may call for the termination of a trial if safety is inadequate or if
the new treatment displays such great efficacy that it would be unethical
for the patients on the control treatment to continue in the trial. Phase
III trials are generally randomized, double-blind, controlled trials. Pa-
tients entering the trial are randomly assigned to either the new drug
that is being tested (active treatment) or a control treatment. The control
treatment may be a standard drug used in the treatment of a disease or
a placebo, a fake treatment that appears convincingly like the active
treatment under investigation. Double-blinding, also called double-
masking, means that both the investigators performing assessments on
the study subjects and the subjects being assessed in the trial do not
know whether they are receiving the new treatment or the control treat-
ment. In this way bias (factors that interfere with analyzing a trial) is
minimized.

Phase IV: Postmarketing Surveillance

In Phase IV studies, the emphasis is on safety. When Phase III has
been completed, the sponsor must file a new drug application with the
FDA. The application involves voluminous documentation of the data
on safety and efficacy that have been acquired across all phases of the
study. FDA advisory committees, which are constituted to address spe-
cialized disease areas, recommend approval or disapproval of the drug.
In addition to experts in the field, the committees include lay and patient
representatives. Guidance documents are updated from time to time and
are available at the FDA's Web site, www.fda.gov.
Here is a hypothetical example of the development of a new drug. It
is known that cells called lymphocytes gather in salivary glands of Sjo-
gren's patients as part of the immune and inflammatory process that
fuels the disease. Dr. Sharp, a researcher at Clinical University, has dis-
covered that biopsies of the salivary glands of her patients contain a
unique type of lymphocyte that has not previously been described. It
THE NEW SJOGREN S SYNDROME HANDBOOK
_
192

carries a distinctive molecule on its surface. She conducts studies in mice

that have the same kind of inflammation in their glands, and finds that
the animals also have lymphocytes with the distinctive surface molecule.
She makes antibodies against the molecule to target these lymphocytes
so that they can be destroyed, and finds that this dramatically diminishes
the inflammation in the animals' salivary glands. Investigators at ABC
Pharmaceuticals read her published report and are able to replicate her
findings in the original mouse strain as well as another type of mouse
with Sjogren's-like features. The company produces a humanized version
of the antibody. The company investigates the immunological effects,
toxicology, and dosing in several strains of animals with the mouse an-
tibody as well as the new humanized antibody. In consultation with the
FDA they perform further studies to establish the safety profile and then
scale up production of pharmaceutical-grade antibodies for testing in
humans. A protocol is written. The protocol is subject to scientific review
to establish that the rationale and design of the study are sound. The
documentation is sent to the IRBs of the institutions or groups that will
participate in the trial. The major task of the IRBs is to ensure that the
trial is ethical and safe and that the subjects will be adequately informed
about what the study involves and its potential risks. New rules adopted
in 2003 under the Health Insurance Portability and Accountability Act
also apply to clinical trials which protect patients' confidentiality. The
ABC pharmaceutical company then performs dosing and safety studies
in healthy human subjects. If the drug successfully passes through Phases
I through III, a new drug application can be filed with the FDA. If ap-
proved, production and marketing is undertaken and drug safety is fur-
ther monitored in Phase IV postmarketing surveillance studies. After a
decade of work and staggering costs, a new agent is available for the
treatment of Sjogren's. (For existing drugs that have a well-known safety
profile and are used for the treatment of related problems, testing for
use in the treatment of Sjogren's is much less arduous.)
 Marilyn Solsky, MD
Michael H. Welsman, MD

21 Adjunctive Measures,
Comorbidities, and
Reproductive Issues
in Sjogren's

PATIENTS WITH SJOGREN'S SYNDROME are well aware of their symptoms

of dry eye and dry mouth; however, Sjogren's is a systemic illness, and
patients need to be aware of certain risk factors and comorbidities that
exist with this disease. Patients with Sjogren's secondary to another rheu-
matic condition such as systemic lupus erythematosus (SLE) or rheu-
matoid arthritis (RA) need to be cognizant of the potential additional
complications of these conditions.

Infections
Medications used to treat the chronic signs and symptoms of Sjo-
gren's generally include at least one anti-inflammatory and often more.
Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and
immunosuppressants such as methotrexate or azathioprine all have the
capability to suppress fevers. Any temperature a patient develops on
these medications is extremely significant and should be immediately
brought to the attention of a physician. The fever may represent an acute
infection or a disease flare. Patients on immunosuppressants are suscep-
tible to infections from organisms that usually do not affect those with
intact immune systems; patients need to be aware that any acute change
in symptoms, such as fatigue or malaise, may herald an infection, even
if no temperature is present.

193
THE NEW SJOGREN S SYNDROME HANDBOOK
194

If a patient with Sjogren's is found to have an infection and is treated

with an antibiotic, then there needs to be monitoring for the develop-
ment of yeast infections. Sjogren's patients are especially prone to oral
candidiasis because of decreased oral secretions. Many patients with au-
toimmune diseases are sulfa-sensitive, and if possible an alternative an-
tibiotic should be used.

Allergies
Patients with allergies such as allergic rhinitis or hay fever often have
elevated levels of an immunoglobulin called IgE. Levels of IgE are gen-
erally the same in patients with autoimmune diseases as in the general
population. Patients with Sjogren's syndrome are no more prone to de-
veloping allergies than people without Sjogren's. However, the treatment
for allergy symptoms often involves the use of a decongestant or anti-
histamine that can further exacerbate mouth and eye dryness. Fortu-
nately, with some of the newer agents, such as cetirizine, fexofenadine,
and loratadine, these sicca side effects have been minimized.
For allergy patients for whom symptomatic treatment is not helpful,
allergy shots (called desensitization) are often recommended. However,
patients with autoimmune diseases may react poorly to allergy shots,
and the shots may cause disease flares. If allergy shots are indicated,
then patients should proceed slowly, possibly with lower doses of the
sensitizing allergen, and stop if there is a flare of the disease.
The best treatment for allergies, although it may not always be prac-
tical, is to avoid exposure to the allergen.

Osteoporosis
Patients with Sjogren's syndrome, and particularly patients with sec-
ondary Sjogren's, are at an increased risk for developing osteoporosis,
especially if they are taking an anti-inflammatory medication such as
methotrexate or corticosteroids. Corticosteroids affect bone mineraliza-
tion almost immediately, and any patient on chronic steroids should be
on an agent that treats osteoporosis. The American College of Rheu-
matology recommends obtaining a baseline bone density measurement
for any patient receiving corticosteroids. All patients with chronic in-
flammatory diseases should be involved in a weight-bearing exercise pro-
gram and should be taking 1,200-1,500 mg of calcium and 400 IU of
 ISSUES IN SJOGREN'S
195

vitamin D daily, unless they have a risk factor for developing kidney
stones or have other kidney impairment.
Medications that are currently available for treating osteoporosis are
calcitonin (by injection or nasal inhalation), the bisphosphonates, teri-
paratide, and selective estrogen receptor modulators. Teriparatide mim-
ics the action of parathyroid hormone and stimulates the formation of
new bone. The other agents inhibit further bone resorption. There are
currently two oral bisphosphonates available, alendronate and risedron-
ate; these are taken weekly on an empty stomach. Some patients may
find that these medications cause severe esophagitis; for patients unable
to take the oral bisphosphonates, the intravenous forms of the bisphos-
phonates, pamidronate or zolendronate, may be better tolerated. Teri-
paratide is an analogue of parathyroid hormone and is taken as a daily
injection. Raloxifene is the most widely used estrogen receptor modu-
lator; however, while it does help prevent osteoporosis and does not
adversely affect breast tissue, it also does not prevent the problem of hot
flashes.
Male patients with Sjogren's should have testosterone levels checked,
since low testosterone levels are an additional risk factor for osteopo-
rosis, and may be decreased in men with autoimmune diseases.

Autoantibodies, Neonatal Disease, and Pregnancy

Anti-Ro/SSA and Anti-La/SSB Antibodies

Antibodies are part of the body's normal defense mechanism; they
usually are directed against foreign antigens such as bacteria, and will
inactivate and destroy them. In autoimmune diseases, it is believed, there
is a "misreading" of antigens and the antibodies become directed against
the self's normal proteins, sometimes causing disease, rather than pro-
tecting against it. One of the criteria used for the diagnosis of Sjogren's
syndrome is the presence of antibody to Ro/SSA and/or La/SSB. Different
clinical associations have been identified with Ro/SSA or La/SSB, or both
antigens together. Sometimes antibodies are merely markers of the pres-
ence of a disease and have little or no involvement in the pathogenesis
or mechanisms that produce the disease. Anti-Ro/SSA has been associ-
ated with several clinical manifestations, including a low platelet count
and a low white count in Sjogren's; it has also been associated with
THE NEW SJOGREN'S SYNDROME HANDBOOK
196

pulmonary disease in lupus. Both the anti-Ro/SSA and anti-La/SSB an-

tibodies have been associated with development of congenital heart
block in neonates and a syndrome referred to as neonatal lupus.

Pregnancy
During a healthy pregnancy the mother's antibodies are transported
across the placenta into the bloodstream of the developing fetus. This
movement of maternal antibodies across the placenta begins at or
around the end of the first trimester. Because the fetus is incapable of
making its own antibodies until after birth, these maternal antibodies
are critical for helping the developing fetus fight infection. Unfortunately,
the placenta cannot distinguish between antibodies that are beneficial
for the fetus and those that may be harmful.

Mothers with Anti-Ro/SSA and Anti-La/SSB Antibodies

One of the most interesting associations of an antibody with clinical
disease was the realization that anti-Ro/SSA and anti-La/SSB antibodies
are associated with congenital heart block and a characteristic skin rash
in neonates (see pages 76-77). This disease complex was termed neo-
natal lupus because the first babies who were noted to have heart block
were born to women who had systemic lupus erythematosus. However,
it is now understood that the pathology for these illnesses is not related
to lupus but is conferred by the presence of the anti-Ro/SSA or anti-La/
SSB antibody. At the time of the pregnancy the mother may not even be
known to have SLE or Sjogren's. Whether or not a woman who has
anti-Ro/SSA or anti-La/SSB antibody but is asymptomatic at the time of
her pregnancy eventually develops a connective tissue disease is contro-
versial. One long-term study has suggested that only about 2 percent of
mothers who are asymptomatic during their pregnancy develop SLE.
Other investigators feel that eventually all mothers with anti-Ro/SSA and
anti-La/SSB antibodies will develop an autoimmune disease, although in
one author's experience the disease occurred 26 years after the patient
had delivered her baby. It appears that anti-Ro/SSA binds cardiac con-
duction tissue more strongly than other cardiac tissue. However, this
does not completely explain the pathogenesis of the disease, because
maternal cardiac conduction tissue is not adversely affected by the pres-
ence of this antibody. The conduction defect that the infants develop is
quite serious and can lead to permanent heart block.
 ISSUES IN SJOGREN'S
197

The rash the infants develop has a slightly raised texture but is gen-
erally flat and may be somewhat circular in appearance. The rash lasts
as long as maternal immunoglobulin lasts in the newborn circulation,
approximately six months.
Clinical testing for the presence of anti-Ro/SSA and anti-La/SSB an-
tibodies can be done by one of two different testing methodologies, im-
munodiffusion or enzyme-linked immunosorbent assay (ELISA). Testing
by immunodiffusion is less sensitive and may miss some lower levels of
the antibody. The better test, and the one more widely used, is the
ELISA, which tests a patient's blood against highly purified forms of the
Ro/SSA and La/SSB antigens. The Ro/SSA antigen is composed of two
separate proteins. The unit used for measuring the size of a protein is a
kilodalton (kD). One of the Ro/SSA proteins is 52 kD, and the other is
60 kD. La/SSB is composed of one protein that is 48 kD in size. There
is a test that can distinguish between the two sizes of Ro/SSA proteins,
the immunoblot or Western blot. This distinction becomes relevant
for women who have the anti-Ro/SSA antibody and wish to become
pregnant.
Women who have the anti-Ro/SSA antibody who may be at lower
risk for having infants with heart block have been demonstrated to have
three characteristics: (1) they have low titers of anti-Ro/SSA antibodies,
(2) they do not have anti-La/SSB antibodies, and (3) immunoblot shows
antibodies only to the 60 kD anti-Ro/SSA antibody and not to the 52kD
protein.
The overall occurrence of complete congenital heart block is 1 in
every 20,000 births. Anti-Ro/SSA and/or anti-La/SSB was found in 83
percent of neonates with complete congenital heart block. If a mother
has anti-Ro/SSA or anti-La/SSB antibodies, then the chances of her
having an infant affected with neonatal lupus are between 1 and 5 per-
cent. If she has already had a child with heart block, then the risk of
having a second affected child may be as high as one in six. It is possible
that if the first child had heart block, the second child will have a skin
rash, or vice versa.
The rash that can occur with neonatal lupus is self-limiting and usu-
ally disappears by age eight months to one year. Of more concern is the
risk of complete congenital heart block. A mother with the anti-Ro/SSA
or anti-La/SSB antibody may not necessarily have any problems with her
pregnancy. However, hers is considered a high-risk pregnancy and should
THE NEW SJOGREN'S SYNDROME HANDBOOK
198

be closely monitored. If this is her first pregnancy, then an echocardi-

ogram should be obtained at about the 18th week of pregnancy and
repeated at 6-week intervals until the 30th week. At about 30 weeks the
infant's heart rate should be audible on routine obstetrical examination.
If a heart block is detected, it is unlikely to be reversible. Under these
circumstances treatment is watchful waiting and following the infant
with weekly echocardiograms. If the echocardiogram detects inflamma-
tion around the heart or if the heart block is not complete (referred to
as second-degree heart block), then treatment with dexamethasone may
be indicated.
If complete heart block is detected, then the infant may still be able
to live a normal life even without a pacemaker, or the infant may require
pacemaker placement within the first three months of life, or death may
occur in utero. Based on the experience of Dr. Jill Buyon, who heads the
National Institute of Arthritis and Musculoskeletal and Skin Diseases—
funded research registry for neonatal lupus, of 113 infants with neonatal
lupus, 19 percent died within the first three months and 58 percent re-
quired pacemakers.
Infants born with neonatal lupus do not appear to be at any increased
risk for developing lupus in later life unless the mother has SLE. Any
child born to a mother with SLE, especially if the child is a girl, has an
approximately 10 percent increased risk for developing lupus.

Mothers Without Anti-Ro/SSA or Anti-La/SSB Antibodies

Women with primary Sjogren's syndrome who do not have antibodies
to Ro/SSA or La/SSB do not have any additional risk factors for preg-
nancy. Women with Sjogren's syndrome secondary to another connective
tissue disease, especially SLE, do have extra considerations for a high-
risk pregnancy, but it is beyond the scope of this chapter to discuss these
issues. Women with connective tissue diseases who are contemplating
pregnancy are referred to their physicians for further information re-
garding special factors that may affect their pregnancy

Antiphospholipid Antibodies
Another antibody that may be present in patients with Sjogren's syn-
drome is the anticardiolipin antibody. This antibody is associated with
certain hypercoaguable phenomenon that lead to clotting in the arteries
and/or veins, and clinically may be present as phlebitis, blood clots to
 ISSUES IN SJOGREN'S
199

the lungs, occlusion of the blood vessels that provide circulation to the
eye, heart attacks, small strokes, or recurrent spontaneous miscarriages.
Anticardiolipin antibodies are part of a broader class of substances
found in the blood, antiphospholipid antibodies. Sometimes these terms
are used interchangeably, although they refer to slightly different com-
pounds. Phospholipids are involved in blood clotting and constitute part
of several different proteins that are associated with an increased risk
for adverse clotting events. The first coagulation disorder described was
identified in two patients with SLE. In laboratory testing the patients'
blood appeared to be too thin because of the presence of a protein that
interfered with blood clotting. But, in fact, this protein predisposed the
patients to more clotting events, creating what is referred to as a hyper-
coaguable condition. It is now known that this protein is found in pa-
tients without lupus, but the initial name has remained, and the protein
became known as the lupus anticoagulant. Subsequently several other
phospholipid compounds that are associated with hypercoaguable states
have been identified, most notably anti-beta-2-glycoprotein I. The clin-
ical events associated with these antibodies have been referred to as the
antiphospholipid antibody syndrome.

Mothers with Antiphospholipid Syndrome

Women who have the antiphospholipid antibodies, particularly an-
tibodies to cardiolipin, are at greater risk for experiencing recurrent
spontaneous abortions. Placental thrombosis results in frequent abor-
tions in the first trimester and recurrent fetal loss in the second and third
trimesters. Mothers with antiphospholipid antibodies may also experi-
ence significant lowering of their platelet counts (thrombocytopenia)
during their pregnancy.
Besides having a role in spontaneous abortions, antiphospholipid an-
tibodies have also been associated with preeclampsia, intrauterine
growth retardation, and infertility.
The mere presence of the antiphospholipid antibody, however, does
not automatically imply that any adverse event will occur. Different au-
thors have reported varying experiences with patients who have anti-
phospholipid antibodies. In one author's experience, fewer than 31 per-
cent of all patients with antiphospholipid antibodies ever experienced
thrombosis. Other reports suggest that women with anticardiolipin an-
tibodies will have a 50 to 75 percent chance of having fetal loss. The
THE NEW SJOGREN S SYNDROME HANDBOOK
200

management of pregnant women with antiphospholipid antibody syn-

drome needs to be individually determined, based on whether this is a
patient's first pregnancy, whether she has had other episodes of fetal
wastage, or whether she has an active underlying connective tissue dis-
ease. Treatment usually includes low-dose aspirin therapy; in some cases
heparin is used. Prednisone use is reserved for special circumstances.
With anticoagulant therapy and careful monitoring, the chances of a
normal term delivery is reported to be approximately 97 percent.

Immunizations
Patients with autoimmune diseases are more susceptible to infections,
due either to the nature of the underlying illness or to the side effects of
immunosuppressant medications. Although immunization against spe-
cific infections may provide additional protection, the use of some vac-
cinations must be avoided or approached with caution.
Immunization against influenza, pneumonia, and tetanus is generally
safe but not always effective in patients on high doses of steroids or
other immune suppressants. Unless there arise emergent reasons for ad-
ministering these immunizations—for example, giving a tetanus vaccine
after an acute puncture wound—these vaccines should probably be given
only when patients are on a steroid dose of 20 mg a day or less, or when
immune suppressants can be at least temporarily discontinued.
The smallpox vaccine should not be given to patients with Sjogren's
syndrome or other connective tissue diseases because it is an attenuated
live vaccine, and in patients who are immunosuppressed the vaccine can
actually induce the disease. The safety of other live vaccines, such as
polio, mumps, BCG, yellow fever, measles, or rubella, has not been es-
tablished in patients who are on high doses of immunosuppressants.
Patients who have children receiving these vaccines should avoid contact
with their children's oral and fecal secretions for approximately two
weeks.
For patients traveling to third world countries, the benefit of receiving
immunization to hepatitis A or typhoid probably outweighs the risks,
but it should be discussed with the patient's physician.
Meningococcal vaccines are directed against certain components of
the bacterial capsule; most older children and young adults who receive
the vaccine develop immunity. However, in a population of patients with
no spleen who had been treated with chemotherapy and radiation ther-
 ISSUES IN SJOGREN'S
201

apy for a lymphoma, a poor antibody response was seen. The menin-
gococcal vaccine appears to be safe for patients with connective tissue
diseases but theoretically may not confer immunity to patients on high
doses of immunosuppressants.
Lyme vaccine at present remains somewhat controversial, as there is
theoretical concern that the vaccine could induce Lyme disease in genet-
ically susceptible individuals. A decision to receive Lyme vaccine should
be determined individually between patient and physician.
Since exacerbations of disease have been reported among SLE pa-
tients receiving hepatitis B vaccine, and the vaccine has also been thought
to induce lupus, immunization against hepatitis B should be decided on
an individual basis based on risk factors and in conjunction with the
patient's physician.

The Comorbldlties of Aging

Sjogren's syndrome tends to affect an older population; the mean age
of patients who have Sjogren's syndrome is 55 years. In this age group,
even persons not affected by Sjogren's may experience symptoms of
mouth and eye dryness. The eye dryness may be aggravated by the use
of contact lenses. In patients with Sjogren's syndrome these symptoms
may be intensified by the use of medications used to treat conditions
associated with aging, such as hypertension, muscle spasms, and urinary
incontinence. Beta-blockers (alone or in combination with other drugs),
propanolol, labetolol, alpha-blockers, and clonidine are antihyperten-
sion drugs that can cause increased dryness. Two medications used for
treating muscle spasms, cyclobenzaprine and methocarbamol, are also
associated with mouth dryness. This is also true for bethanechol and
oxybutynin, used for treating incontinence. Over-the-counter prepara-
tions for relieving symptoms of congestion, including chlorpheniramine
maleate, pseudoephedrine, and other medications combined with them,
have the same side effect of dry mouth. Patient's with Sjogren's who take
any of these drugs need to be aware that these medications can exac-
erbate their symptoms; if necessary, they should request that their phy-
sician place them on a different medication.
It has now been well established that patients with autoimmune dis-
eases are at increased risk for cardiovascular complications, and this risk
is greatly increased by the use of corticosteroids. One indicator for this
risk factor is the level of homocysteine, a circulating protein in patients'
THE NEW SJOGREN'S SYNDROME HANDBOOK
202

blood that can be quantified by a simple laboratory test. Patients can

find out from their physicians if their level of homocysteine is being
monitored. Elevated levels, if found, can be lowered by taking folic acid.
Elevated blood pressure also occurs with an aging population. New
data confirm that lower blood pressure readings (a systolic blood pres-
sure of 120 or less and a diastolic blood pressure of 80 or less) are
associated with a decreased incidence of heart disease and stroke. Pa-
tients need to be aware that NSAIDs and corticosteroids can elevate
blood pressure, and they may need to take additional medications to
keep their blood pressure within a normal range. Corticosteroids can
also affect blood glucose levels and induce diabetes, which can cause
further problems with hypertension and arteriosclerosis. A similar effect
of steroids is seen on lipid levels. Elevations in cholesterol and triglyc-
erides, seen in general in an older population, can be aggravated by the
use of steroids.

Thyroid Disease
The most frequent organ-specific autoimmune disease in patients
with Sjogren's syndrome is autoimmune thyroiditis. About half of pa-
tients with Sjogren's syndrome have thyroid disease. In a study of 77
patients with lupus, 8 patients who had thyroid disease also had Sjo-
gren's syndrome. Sjogren's syndrome and autoimmune thyroid disease
may be related to each other pathogenetically.

Gynecologic Considerations
Women with Sjogren's syndrome are often significantly bothered by
vaginal dryness, painful intercourse, and vaginal yeast infections. If
women do not discuss this problem with their physician, they may use
petroleum jelly to help relieve their symptoms, and this actually results
in more tissue injury, interferes with the vagina's natural cleansing mech-
anism, and can impair sperm mobility in couples trying to conceive.
Cortisone creams are equally unhelpful, as they can further thin tissue
and may promote yeast infections.
There are several preparations available (and some being developed)
to help with this underreported but important symptom. Various sterile
lubricants, including K-Y jelly, which is water soluble and not subject to
the difficulties posed by petroleum jelly, and Surgilube are useful vaginal
lubricants. Maxilube, Vagisil, Sylk, and Astroglide are also water-soluble
 ISSUES IN SJOGREN S
Z03

and nonirritating but have different physical characteristics than K-Y

and Surgilube. Two nonhormonal vaginal moisturizers that may be used
to help with general vaginal dryness are Replens and Lubrin, which is a
vaginal insert. A once-a-week vaginal lubricant, Vagikote, is undergoing
clinical trials. Vagifem is an estrogen-based topical intravaginal prepa-
ration that when used twice weekly can help with atrophic vaginitis and
vaginal dryness in postmenopausal women. Although the absorption of
estrogen is much lower than with the use of an oral or transdermal
estrogen preparation, there is still a risk associated with all estrogen
preparations, and the use of estrogen replacement needs to be deter-
mined on an individual basis after discussion with a health professional.
Women with Sjogren's are at increased risk for yeast infections be-
cause of vaginal dryness. This risk is further increased by a compromised
immune system and the use of corticosteroids, the use of antibiotics, and
the loss of estrogen's protective effects on normal vaginal bacteria in
postmenopausal women. Any diabetes or blood sugar abnormality also
predisposes patients to vaginal yeast infections. The irritation of vaginal
dryness may mimic symptoms of a vaginal yeast infection, and treatment
should be given only after an accurate diagnosis has been established.
Once a diagnosis is determined, effective treatment is available with over
the counter preparations such as Gyne-Lotrimin. Vaginal creams may be
more effective than vaginal suppositories because they provide more cov-
erage. Fluconazole, a one-dose oral treatment, is more costly but more
convenient for the treatment of vaginal yeast infections.

Summing Up
Beyond dry eye and dry mouth, patients with Sjogren's syndrome
have several unique challenges, but by being aware of several treatable
risk factors, such as osteoporosis, hypertension, and cardiovascular dis-
ease, and discussing therapeutic options regarding immunizations and
symptomatic treatment with their physicians, patients with Sjogren's syn-
drome can decrease some of the comorbidities associated with this
disease.
This page intentionally left blank
 PART V

Outcomes and
Future Directions

What happens to Sjogren's patients? What can they look forward to?
Fortunately, most individuals with the syndrome have a normal life ex-
pectancy. However, their quality of life often leaves a lot to be desired.
Are there any new investigational approaches or promising leads? Where
does our research stand? In this final section, potential breakthroughs
are discussed within the context of discussing the natural course of the
syndrome.
This page intentionally left blank
 David S. Hallegua, MD

22 Can I Work?

SJOGREN'S SYNDROME is known to cause eye and mouth dryness, fatigue,

fever, joint pain, and muscle pain, but it also involves organs such as the
lung, kidney, brain, and lymph glands. The severity of the illness varies
widely; it can even be life-threatening and result in disability and in-
ability to work. The mean age of a patient with Sjogren's syndrome is
around 55, which suggests that many of these patients may qualify for
Medicare benefits and Social Security payments at age 65.

What Is Disability?
Disability can be defined in general terms as being unable to perform
a task in the workplace because of signs or symptoms of an illness. The
word disability has specific meaning in insurance policies, where it refers
to a change in the patient's capacity to carry out specific personal, social,
and job-related tasks due to the presence of impairment. An impairment
is a physical or mental constraint resulting from an illness. Your physi-
cian determines this, though the presence of an impairment does not
always mean that a patient is disabled. For example, the presence of
swollen and tender joints on examination is an impairment and needs
to be documented in the medical record. A handicap refers to the social
consequences that result from having an impairment or disability. Ex-
amples of this is documentation of limitation of one or more life's ac-
tivities that were previously normal for the patient, the use of an assistive
device such as a wheelchair or prosthesis, or needing more time than
necessary to complete a certain task.

207
THE NEW SJOGREN'S SYNDROME HANDBOOK
208

Factors Contributing to Disease Severity in

Determining Disability
There are various demographic and psychosocial factors that can
combine with an ailment's signs and symptoms to determine whether the
person becomes disabled or not, such as age, gender, personality, level
of education, social support, and pressure from colleagues and family.
Other factors that impact a person's ability to work include the type of
work, whether the person is self-employed, and how experienced the
person is in a specific line of work. All of these factors are important to
consider in determining disability.

What State and Federal Programs Are Available to the

Disabled Person?
The two major government programs that compensate a person for
being unable to work include Social Security disability and workers'
compensation. The Social Security Administration provides two pro-
grams, Social Security disability insurance (Title II) (SSDI, also called
disability insurance benefits), and Supplemental Security Income (Title
XVI) (SSI). Eligibility for federal and state medical insurance programs
such as Medicare and Medicaid is contingent on qualifying for either
SSDI or SSI.
Numerous private insurance companies also provide disability in-
come provided the employer or patient pays a certain premium.

Social Security Disability Insurance (SSDI)

SSDI is a federally regulated program that was established in the
1950s under Title II of the Social Security Act. Employers and workers
contribute to a trust fund in the form of deductions from their payroll
taxes. Workers receive benefits based on lifetime contributions if they
meet certain published criteria. SSDI is one of the largest disability in-
surance programs in the world.
In order to qualify for SSDI, the Social Security Administration re-
quires the individual to be unable "to engage in any substantial gainful
activity by reason of any medically determinable physical or mental im-
pairment which can be expected to result in death or which has lasted
or can be expected to last for a continuous period of not less than 12
months." Unlike some private insurance companies, SSDI does not pro-
 CAN I WORK?
209

vide partial disability compensation if the person is not able to work at

his or her job but is able to work or be trained for another vocation
even at the minimum wage. The program attempts to show some flexi-
bility with the wide ranges of individual's impairments, education, and
vocational achievements. An individual who has received SSDI for 24
months may qualify for Medicare.

Supplemental Security Income (SSI)

People who do not qualify for SSDI due to the lack of contributions
to the Social Security program may qualify for SSI under Title XVI of
the Social Security Act. This requires the estimation of the patient's fi-
nancial assets by a means test. This program pays a monthly amount to
financially strapped people who qualify for disability. Patients who qual-
ify for SSI may also qualify for Medicaid, a state-sponsored medical
insurance for people who are indigent and unable to work.

Workers' Compensation
Workers' compensation is a nationwide state-run mandatory pro-
gram that has to be provided to all employees to cover them for on-the-
job accidents or occupation-related illnesses. Most programs are pri-
vately owned or state-sponsored; there is also a federal program for
federal employees through the Department of Labor. Any injury that
occurs during work or an illness that can be proven to have resulted
from or been exacerbated by their occupation is covered under this pro-
gram regardless of any culpability on the part of the employee in its
causation. Workers' compensation can pay claims for partial disability.
As a result of the Americans with Disabilities Act, employers who have
fifteen or more employees are mandated to modify the workplace to
accommodate someone with a disability.

What Eligibility Criteria Are Necessary to Qualify for

Social Security Disability?
A worker who is between 31 and 65 years of age who has contrib-
uted to Social Security for at least 20 out of the preceding 40 quarters
may apply for SSDI. Unmarried minor children and spouses caring for
minor or disabled children are also eligible. The Social Security Admin-
istration examines the medical and work history provided by the claim-
THE NEW SJOGREN'S SYNDROME HANDBOOK
210

ant for evidence that supports the inability of the employee to earn more
than $700 per month and for objective assessment of the magnitude and
degree of the impairment documented in the medical history.

How Does Social Security Determine If a Person

Is Disabled?
First, the SSA determines if the individual can earn at least $700 per
month. Next, objective signs confirming the validity of symptoms caus-
ing the impairment are looked at. These symptoms have to prevent the
worker from carrying out his or her usual tasks. Finally, the impairment
in question must meet the requirements set under the SSA list of defined
impairments and levels of disease activity.

Social Security Administration List of Defined

Impairments That Apply to Sjogren's Syndrome
Currently Sjogren's syndrome is not on the SSA's list of defined im-
pairments. Disability for Sjogren's syndrome is currently applied under
"Impairments of the Immune System" (section 14.00) using either the
category "Systemic Lupus Erythematosus" or "Undifferentiated Con-
nective Tissue Disease." The Sjogren's Syndrome Foundation has re-
cently petitioned the commissioner for the SSA to include Sjogren's syn-
drome separately under the list of impairments in the immune system
category. Further, they have suggested changes in the listing of impair-
ments in the various organ systems that are affected by Sjogren's syn-
drome. For example, under "Special Senses" (section 2.00), the dryness
and inflammation of the eyes specific to Sjogren's, and the disability it
creates, would be listed if they were approved by the Social Security
Administration. The various impairments that may apply to Sjogren's
syndrome for disability are listed in Table 22.1.

What Happens if the Applicant's Impairment Does Not

Meet the Listed Criteria?
A physician or a specially trained vocational specialist employed by
the Social Security Disability Determination Service performs a physical
abilities test if the person does not meet the listed criteria. The testing
for specific abilities such as standing, sitting, lifting, carrying, pushing,
pulling, and so on is called determination of the person's residual func-
tional capacity. These abilities are measured against set Department of
TABLE 22.1 SOCIAL SECURITY DISABILITY IMPAIRMENTS POTENTIALLY
APPLICABLE TO SJOGREN'S SYNDROME

1.00 Impairment of the Musculoskeletal System

Five types of impairments can be listed under this category:
A. Loss of function in a limb or part of the body
B. Disorders of the spine
C. Postsurgical residual disability for at least 6 months
D. Major joint damage, such as to the hip, knee, ankle, shoulder, elbow,
wrist, or hand
E. Decreased joint range of motion
Under this category, the following are included:
1.02 Active inflammatory arthritis present on exam for at least 3 months in
spite of active treatment and expected to continue for at least 12
months (must be corroborated by specific immunologic tests or test
supporting the presence of inflammation)
1.03 Arthritis of a major weight-bearing joint from any cause
1.04 Arthritis of one major joint in each of the upper extremities
1.05 Disorders of the spine such as a compression fracture

2.00 Impairment of the Special Senses

Two types of impairments may be applied to Sjogren's in special circumstances
due to severe dry eye or inflammation of components of the eyeball.
Hearing loss may be due to damage to the nerve that conducts sound to
the brain or due to middle ear disease.
A. Change in visual acuity, field of vision, muscle function, or a loss of
visual efficiency
B. A hearing impairment, vertigo (sensation of spinning), or loss of speech
Under this category, the following are included:
2.03 Visual efficiency of the eye of 20 percent or less after correction (visual
efficiency is the product of the percent of remaining visual acuity and
the percent of remaining visual field efficiency)
2.07 Severe disturbance of balance function

3.00 Impairment of the Respiratory System

Severe dryness of the airways can result in a chronic, debilitating cough. The
following category of impairments may apply to Sjogren's syndrome:
3.01 Chronic pulmonary insufficiency, defined as a decrease in the amount
of air that can be ventilated out with maximal force and the lung
capacity to enable oxygen to diffuse through the lung membranes
(values obtained should be equal to or less than the minimum value
on tables set up by the Social Security Administration)

continued
TABLE 22.1 continued

8.00 Impairment of the Skin

Extensive involvement of the skin that is not responsive to treatment and is
expected to last at least 12 months may qualify for disability.

11.00 Impairment of the brain and spinal cord

Categories of impairments that may occur due to brain and spinal cord in-
volvement due to Sjogren's include:
11.02 Epilepsy—seizures that occur more than once a month despite ad-
herence to treatment for at least 3 months
11.04 Central nervous system accident—with persistent speech difficulty or
comprehension or weakness in two limbs that impairs gait or
function
11.14 Peripheral neuropathy—numbness or weakness of the hands or feet
that impairs gait or function

12.00 Impairment of mental function

12.02 Organic mental disorders (psychological or behavioral abnormalities
can result from brain or spinal cord involvement due to Sjogren's
syndrome; testing must document loss of specific cognitive abilities
and difficulty with activities of daily living or work)

13.00 Neoplastic diseases (cancers)

13.06 Lymph nodes—lymphoma with progressive disease that is not con-
trolled with treatment (lymphoma may affect 5 to 7 percent of Sjo-
gren's patients during the course of the illness; the risk for lym-
phoma is estimated to be 44 times greater than in the general
population)

14.00 Impairment of the immune system

14.02 Systemic lupus erythematosus—this illness is characterized by fever,
constitutional symptoms and multisystem involvement, usually fulfill-
ing the 1982 Revised Criteria for the Classification of Systemic Lupus
Erythematosus (Sjogren's syndrome is often listed under this category
since a separate category does not exist)
14.03 Vasculitis—inflammation of the blood vessels due to infectious, aller-
gic, or autoimmune causes (may occur due to connective-tissue dis-
orders such as Sjogren's syndrome)
14.06 Undifferentiated connective tissue disorder—with major joint involve-
ment or severe impairment of eye, lung, skin, or brain as defined un-
der 1.00, 2.00, 3.00, 8.00, 11.00, 12.00 or 13.00
 CAN I WORK?
213

Labor standards and are used to determine whether the individual is

capable of performing sedentary, light, medium, heavy, or very heavy
work. The physical requirements for these various categories include:

TABLE 22.2
Type of work Sitting Standing Lifting Physical demands

Sedentary Most of Occasional Occasional ss 10 Ibs Very little

time
Light work Half the Frequent 20 Ibs max., frequent Push or pull arm/
time =s 10 Ibs leg controls
Medium work Part of time Very often 50 Ibs More strenuous
max., frequent =s 25 than light work
Ibs
Heavy work Part of time Very often 100 Ibs More strenuous
max., frequent «s 50 than medium work
Ibs
Very heavy Part of time ^ 100 Ibs, frequent More strenuous
work ^ 50 Ibs than heavy work

Other factors determining the residual functional capacity includes

the ability for the person to hear and speak, and his or her mental fac-
ulties. The degree of fatigue suffered helps to determine this capacity as
well. The examiner also determines how well the applicant carries out
activities of daily living: grooming and hygiene, and social and loco-
motor functions. If the examiner determines that the person is not able
to perform the activities of his or her job adequately based the appli-
cant's age, training, education, and previous work experience, then the
individual may be granted disability even if he or she does not meet the
listed criteria.

Can Someone Petition to Have the Application

Reexamlned If It Has Been Rejected?
Most of the initial applications that are reviewed by the initial phy-
sician panel are rejected. A person may request to have another physician
panel examine the case, at which point approximately a third of the
applications are approved. Rejected applications may be filed in front of
an administrative law judge; approximately 50 percent of these are ap-
proved. Petitions denied after this stage may be appealed to the Social
THE NEW SJOGREN S SYNDROME HANDBOOK
214

Security Council and ultimately to a U.S. district court. About 50 percent

of all applications to the SSA are ultimately approved.

Are All Applicants Eligible for Vocational

Rehabilitation?
All applicants are eligible for vocational rehabilitation if the SSA ex-
aminer feels that the person is capable of retraining in a different field.
The disability payments are continued, and tuition and transportation
fees for rehab are usually paid by the participating agencies. Vocational
rehabilitation is a benefit offered by the Federal Rehabilitation Act of
1973. All states are required to have a vocational rehabilitation pro-
gram, which is funded by both the federal and state governments. The
program provides counselors who can evaluate the disabled person's
ability and interest in different areas of work. They also provide living
and schooling expenses, costs of job training, and special equipment
purchasing, and assist in job placement. Usually the program covers
most of the expenses of tuition and retraining, particularly for individ-
uals who are indigent.

Can an Individual Work While Receiving Benefits?

The disability benefits continue for nine months while a person works
and earns at least $200 a month. If the person has worked for a cu-
mulative period of nine months, then the disability payments continue
for a period of three months and then stop. The payments get reinstated
for any month in the next three years if the applicant is not able to earn
at least $700 a month during this period. Medicare benefits continue for
at least 39 months even though the person has come off disability.

Summing Up
Most patients with Sjogren's syndrome are able to work and lead
productive lives. However, a subset with more severe systemic disease or
a malignancy have severe impairments that make them eligible for dis-
ability payments. Most Sjogren's patients can benefit from modifications
in their work environment so that extremes of temperature and exposure
to fumes and solvents are avoided and their workstations are modified
to be ergonomic to help prevent and diminish disabling symptoms
due to joint pain and fatigue or dry and painful eyes.
 Clio P. Mavragani, MD
Stuart S. Kassan, MD
Haralampos M. Moutsopoulos, MD

23 What Will Happen

To Me?

SJOGREN'S SYNDROME is a chronic disease without a cure. It's a tough

disease to live with day in and day out. However, many tools are avail-
able to Sjogren's patients to help them live a long and productive life,
as we have seen in previous chapters. No one can tell a patient what
will happen to her or him over time, but we can talk about some of the
potential complications. Sjogren's is said to be a "lifestyle-threatening"
but not life-threatening disease. In fact, although the symptoms of Sjo-
gren's syndrome, such as dry mouth and eyes, can negatively impact
quality of life and are long-lasting, this disorder rarely completely in-
capacitates or shortens life span. In cases of secondary Sjogren's syn-
drome, outcome is related to the underlying disorder. Complications
from primary Sjogren's syndrome can occur at various levels, depending
on the organs involved.
Most of the patients with Sjogren's syndrome will have a mild, al-
though sometimes debilitating, clinical course with no significant impact
on their general health. Evidence from recent studies supports this view,
showing that these patients live as long as their peers.

Late Sequelae: Extraglandular Complications and

Lymphoma Development
One should not forget that a few patients suffer from severe Sjogren's
syndrome, which can lead to the development of vasculitis and lym-
phoma in later life. The severe form of the disease usually presents with
red spots on the lower legs (purpura), low complement (C4) levels, and

Z15
THE NEW SJOGREN'S SYNDROME HANDBOOK
216

cryoglobulins in the blood. Purpuric lesions can be itchy, do not blanch

with pressure, and usually come and go. Complement is a protein that
participates in our defense against microbes, while cryoglobulins are a
special group of immunoglobulins that precipitate under cold tempera-
tures.
Years after the diagnosis of the disease is established, these patients
develop vasculitis, which is eventually associated with destruction of the
blood vessel wall due to deposition of immune complexes (clusters of
antibodies with their antigens). As a result, complement is activated. This
is the reason why low levels of it are found in the blood. Two types of
vessels are involved in vasculitis in patients with Sjogren's syndrome:
small and medium-sized arteries. Involvement of small vessels leads to
the development of purpura. When the small arteries of the peripheral
nerves are affected, weakness or a sensation of numbness and/or pins
and needles can occur in the hands and legs in a stocking/glove distri-
bution. When the small vessels of the kidney are involved, glomerulo-
nephritis can develop, manifested by the presence of blood in the urine
(microscopic hematuria). On the other hand, when medium-sized vessels
are affected, infarction and necrosis of the small bowel can occur. Ane-
mia and a reduced number of lymphocytes (lymphopenia) are also noted
in this group of patients.
Low complement levels have been found to be the strongest predictor
for subsequent death in this patient group. At any given age the risk of
death in this group of patients is twice as high as in the general popu-
lation. In contrast, in the absence of purpura, low complement (C4)
levels, and cryoglobulins in the blood, the disease course is benign and
mortality rates are similar to those observed in the general population.
It is important to note that in most of the cases, the severe features of
the disease are found at the onset, when the diagnosis is made.
Therefore, the doctor knows from the beginning that certain high-risk
patients should be carefully evaluated at regular intervals.
Lymphomas are tumors of the lymphatic system. This system is a
network of organs, ducts, and nodes that interact with the blood's cir-
culatory system to transport a watery clear fluid called lymph through-
out the body. The lymphatic system is also involved in the production
and transport of lymphocytes, which are white blood cells that partici-
pate in the body's defense against foreign invaders.
 WHAT WILL HAPPEN TO ME?
217

The first, most common sign of lymphomas may be painless enlarge-

ment of one or more lymph nodes, usually in the neck, armpits, or groin.
They can also cause systemic symptoms, referred to as B symptoms, that
include drenching night sweats and weight loss. Fever is often present,
which may occur only at night in episodes that last several days followed
by periods of no fever. Patients with B symptoms usually have more
extensive and severe disease.
Diagnosis of lymphoma is based on lymph node biopsy. A small piece
of lymph node is removed and examined under the microscope. This is
done generally under local anesthesia; however, sometimes, general an-
esthesia is required.
Two major types of lymphoma are recognized, depending on the his-
tological findings on lymph node biopsy. These are referred to as Hodg-
kin's and non-Hodgkin's lymphomas. According to histological appear-
ance and the type of cells that are present, these are also distinguished
by grade, low or high.
It is of note that the prevalence of lymphoma in patients with Sjo-
gren's syndrome is estimated to be approximately 4 percent. Lymphomas
in Sjogren's syndrome are mainly low-grade non-Hodgkin's lymphomas,
which arise frequently in the lymphoid tissues found in various mucosal
sites of the body; they are called mucosa-associated lymphoid tissue
(MALT) lymphomas. They tend to be localized mainly in the salivary
glands, but they commonly involve other sites of the body such as lymph
nodes, the nasopharynx, the lung, and the stomach. Bone marrow is
rarely affected. B symptoms are not frequently reported. Median survival
for these patients is approximately six years. However, a smaller per-
centage of patients develop more aggressive, high-grade lymphomas. Un-
fortunately, for these patients the median survival is approximately two
years from the time of diagnosis.
Treatment of lymphomas in patients with Sjogren's syndrome is based
on their histological grade. In low-grade localized lymphomas affecting
the exocrine glands, a wait-and-watch policy is recommended, because
in these patients the survival rate did not differ between treated and
untreated patients. In low-grade disseminated lymphomas, a single che-
motherapeutic agent is suggested. However, in patients with high-grade
lymphomas or low-grade lymphomas transforming to high-grade, com-
bination chemotherapy is required. Unfortunately, despite therapy, the
THE NEW SJOGREN S SYNDROME HANDBOOK
218

TABLE 23.1 PROGNOSTIC CONSIDERATIONS IN SJOGREN'S

• Two major types of complications of Sjogren's syndrome are recognized:

glandular (exocrine glands) and extraglandular (systemic).
• Glandular complications include dental caries and mouth infections,
opacification of the cornea with blurring of the vision, dry and brittle skin,
painful sexual intercourse, difficulty in swallowing, and megaloblastic anemia.
• Extraglandular complications include kidney, lung, and liver involvement
without severe sequelae in the majority of cases.
• Patients without systemic manifestations at the time of diagnosis (arthritis,
Raynaud's phenomenon, dry cough, kidney and liver problems) are unlikely to
develop such symptoms in the future.
• The presence of purpura, low complement levels, and cryoglobulins are
adverse predictors for lymphoma development.
• Life expectancy in the majority of patients with Sjogren's syndrome is normal.

outcome in these patients is poor. Currently, we are not aware of pre-

dictive factors for development of high-grade lymphoma or for the trans-
formation from low-grade to high-grade lymphoma.
In a recent study, the main causes of death for 11 out of 261 patients
with Sjogren's syndrome who were followed for many years were re-
ported. These included lymphoma, cardiac failure due to damage of the
muscle of the heart, tumor of the parotid gland, inflammation of the
blood vessels, emphysema (chronic lung disease characterized by ob-
struction of the bronchi), stroke, old age, and pulmonary embolism. The
last of these is due to increased levels of gamma globulins, which lead
to an increased tendency for clotting and plugging of the pulmonary
vessels, manifested as shortness of breath and pain in the chest.

Summing Up
In conclusion, the overwhelming majority of Sjogren's syndrome pa-
tients have a generally mild course with a normal life expectancy. How-
ever, in the presence of negative predictors, the development of lympho-
proliferative disorder is a possibility. In these cases, careful monitoring
should be performed with regular follow-ups, in order to early detect
and manage such a complication (see Table 23.1).
 Arthur Grayzel, MD

24 Is There Hope for

a Cure?

WHAT CAN PATIENTS WITH sjOGREN's look forward to in the next decade
or two? Advances in basic medical science, especially immunology, ge-
netics, and pharmacology, certainly offer hope that Sjogren's can be con-
quered, if not cured. This chapter will review some of the most prom-
ising current areas of investigation, but the cure may come from research
as yet unknown.
Basic research that could lead to a cure for Sjogren's syndrome falls
into two main categories. One category relates to the underlying im-
munologic mechanisms that lead to autoimmune diseases in general and
to Sjogren's in particular. The other relates to the mechanisms of water
transport across cell membranes and the hormones and other mediators
that control the process.
As described in Chapter 5, autoimmunity reflects an immune system
that is out of control. A simple, general scheme for this process might
include environmental factors and a breakdown in a normal barrier such
that a self-protein or antigen is strongly presented to an immune system
with a genetic predisposition to respond in a way that perpetuates the
response, leading to chronic inflammation and tissue damage. Inflam-
matory bowel disease (IBD) might illustrate this process. It is thought
that the combination of a breakdown in the integrity of the lining of the
small intestine and a change in the bacteria that inhabit the intestines
leads to the presentation of a new antigen or antigens to the lymphocytes
that are always abundant beneath the intestinal lining. This initiates a

219
THE NEW SJOGREN S SYNDROME HANDBOOK
220

local immune and inflammatory response that in some predisposed in-

dividuals continues as a chronic process. The antigen in IBD is unknown,
and there are likely to be many possible antigens. The antigens in some
other autoimmune diseases, such as type 1 diabetes, are known; in Sjo-
gren's, several candidates—such as the muscarinic M3 receptors and the
recently described protein ICA69 (Chapter 4), which are present in sal-
ivary glands—may play a role.
Even if the process leading to autoimmunity in Sjogren's and other
diseases is completely understood, it may be quite a while before this
knowledge is translated into effective treatment or a cure. In the mean-
time, two more immediate, if less disease-specific, approaches are being
actively explored. The first is to transplant organs or glands. Advances
in chemotherapy to prevent rejection and more exciting methods to in-
duce tolerance of transplanted tissue hold promise in the transplantation
of the pancreatic islets, which produce insulin in patients with type 1
diabetes. Similar experiments are under way to transplant salivary glands
in mice as a first step to develop this approach to the treatment of Sjo-
gren's. A related approach is to use the same methods to induce tolerance
to the offending antigens, as described above.
A second exciting area of basic research related to Sjogren's deals
with aquaporins, the molecules that actually move water across the cell
membranes of glands and into the ducts, which eventually leads to saliva
in the mouth and tears in the eye. The movement of water is an active
process that appears to be under positive and negative control by me-
diators such as the autonomic nervous system, acetylcholine, and nitric
oxide. Detailed knowledge of the mechanisms of water transport and its
control can lead to the development of pharmacologic agents to increase
the flow of saliva and tears, but these agents would act only upon glands
that were not yet destroyed and maintained some residual glandular
function. This approach would not technically represent a cure, since
such pharmacologic agents would do nothing to stop the underlying
immune process and the continuing inflammation and destruction of the
glands (see Table 24.1).
Under a mandate from Congress, the National Institutes of Health
has established an Autoimmune Diseases Coordinating Committee,
which in turn has produced an Autoimmune Diseases Research Plan. As
this plan gets implemented by the various components of NIH and there
 IS THERE HOPE FOR A CURE?
221

TABLE 24.1 CURRENT RESEARCH STRATEGIES FOR NEW TREATMENTS IN

SJOGREN'S SYNDROME

Improved drugs to control inflammation

Nonsteroidal anti-inflammatory agents (e.g., COX-3 inhibitors)
Improved antimalarials (e.g., pure isomers)
Improved corticosteroids (e.g., budesonide derivatives)
Improved immunosuppressives
Newer anticytokine agents
Improved drugs to treat dryness
Autonomic-system-mediated therapies
Neurotransmitter-mediated therapies
New delivery systems (e.g., aquaporins)
Biologic agents for Sjogren's
Targeting M3 receptors
Tolerizing agents (e.g., peptides, vaccines)
Gene therapies
Transplantation of salivary glands
Measures to prevent lymphoma

is increased support for research on the individual autoimmune diseases,

including Sjogren's (which has a prominent place in the research plan),
patients with Sjogren's can look forward to ever more targeted research
on Sjogren's and with it the hope for a cure.
This page intentionally left blank
 PART VI

Appendices
This page intentionally left blank
APPENDIX 1
FOR FURTHER READING

Chapter 1—The History of Sjogren's Syndrome

Wollheim FA, A humble gentleman at 100, Clin Exp Rheumatol 1999; 17:
648-652.
Morgan WS, Castleman B, A clinicopathologic study of "Mikulicz's dis-
ease," Amer J Pathol 1953; 29: 471-503.
Bloch KJ, Buchanan WW, Wohl MJ, Bunim JJ, Sjogren's syndrome: a clinical,
pathological and serological study of 62 cases, Medicine 1965; 44: 187-
231.

Chapter 2—What Is Sjogren's Syndrome?

Bloch KJ, Buchanan WW, Wohl MJ, Bunim JJ, Sjogren's syndrome, a clinical,
pathological and serological study of 62 cases, Medicine 1965; 44:187-
231.
Vitali C, Bombardiere S, Jonsson R, Moutsopoulos HM, Alexander EL,
Carson SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal
N, Weissman MH, Classification criteria for Sjogren's syndrome: a re-
vised version of the European Criteria proposed by the American Euro-
pean group. Ann Rheum Dis 2002; 61: 554-558.

Chapter 3—Who Develops Sjogren's Syndrome?

Garcia-Carrasco M, Ramos-Casals M, Rosas J, Pallares L, Calvi-Alen J,
Cervera R, Font J, Ingelmo M, Primary Sjogren's syndrome: clinical and
immunologic disease patterns in a cohort of 400 patients, Medicine (Bal-
timore) 2002; 81: 270-280.
Pillemer SR, Matteson EL, Jacobsson LT, Martens PB, Melton LJ, O'Fallon
WM, Fox PC, Incidence of physician-diagnosed primary Sjogren's syn-
drome in residents of Olmstead County, Minnesota, Mayo Clin Proc
2001; 76: 593-599.

225
APPENDIX 1
226

Thomas E, Hay EM, Hajeer A, Silman AJ, Sjogren's syndrome: a

community-based study of prevalence and impact, Br J Rheumatol 1998;
37: 685-686.

Chapter 4—What Leads to Dryness?

Pflugfelder, SC, Solomon A, Stern ME, The diagnosis and management of
dry eye: a twenty-five-year review. Cornea 2000; 19(5): 644-649.
Fox RI, Sjogren's syndrome: current therapies remain inadequate for a com-
mon disease. Exp Opin Invest Drugs 2000; 9(9): 2007-2016.
Atkinson JC, Fox PC, Sjogren's syndrome: oral and dental considerations.
J Am Dent Assoc 1993 Mar; 124(3): 74-76, 78-82, 84-86.

Chapter 5—Sjogren's Syndrome: A Genetic and

Immunologlc Perspective
James JA, Harley JB, Scofield RH, Role of viruses in systemic lupus erythe-
matosus and Sjogren's syndrome, Curr Opin Rheumatol 2000; 13: 370-
376.
Vitali C, Bombardiere S, Jonsson R, Classification criteria for Sjogren's syn-
drome: a revised version of the European criteria proposed by the
American-European Consensus Group, Ann Rheum Dis 2002; 61: 554-
558.
Daniels TE, Sjogren's syndrome: clinical spectrum and current diagnostic
controversies. Adv Dent Res 1996; 10: 3-8.
Manoussakis MN, Moutsopoulos HM, Sjogren's syndrome: current con-
cepts, Adv Intern Med 2001; 47: 191-217.

Chapter 6—Generalized Symptoms and Signs

of Sjogren's Syndrome
Tziofas AG, Moutsopoulos H, Sjogren's syndrome, in Rheumatology, 3rd
edition, MC Hochberg et al., eds., Mosby, 2003, pp. 1431-1443.
Pavlidis NA, Karsh J, Moutsopoulos HM, The clinical picture of primary
Sjogren's syndrome: a retrospective study, J Rheumatol 1982; 9: 685-
690.
Klippel J, Dieppe P, eds., Rheumatology, 2nd edition, Mosby, 1998.
Kelley W, Harris E, Ruddy S, Sledge C, Textbook of rheumatology, 4th
edition, Saunders, 1993.
Carsons S, Daniels T, Dana R, Talal N, Sjogren's syndrome: new insights
and new treatment, Winthrop University Hospital, 2001.
Carsons S ed., The new Sjogren's syndrome handbook, Oxford University
Press, 1998.

Chapter 7—The Dry Eye

Lemp MA, Report of the National Eye Institute/Industry workshop on clin-
ical trials in dry eyes, CLAO J 1995; 21: 221-232.
 FOR FURTHER READING
227

Dana, MR, Hamrah P, Role of immunity and inflammation in corneal and

ocular surface disease associated with dry eye, Adv Exp Med Biol 2002;
506: 729-738.
Argueso P, Balaram M, Spurr-Michaud S, Keutmann HT, Dana MR, Gipson
IK, Decreased levels of the goblet cell mucin MUC5AC in tears of pa-
tients with Sjogren syndrome, Invest Ophthalmol Vis Sci 2002; 43:1004-
1011.

Chapter 8—The Salivary Glands, Ears, Nose, and Larynx

Sharp K, Sjogren's syndrome, Gale Encyclopedia of Alternative Medicine,
K Krapp and JL Longe eds., Gale, 2001.
Martin D, Sjogren's syndrome, Johns Hopkins Arthritis Center.
National Oral Health Information Clearinghouse, Dry mouth brochure,
1 NOHIC Way, Bethesda, MD.

Chapter 9—The Dry Mouth: A Dental Perspective on Sjogren's

Navazesh M, How can oral health care providers determine if patients have
dry mouth? JADA 2003; 134: 613-620.
Daniels TE, Wu AJ, Xerostomia—clinical evaluation and treatment in gen-
eral practice, CDA Journal 2000; 28: 933-941, available at http://www
.cda.org/member/pubs/j ournal/j our 1200/xero.html.
Mandel I, Surattanont F, Bilateral parotid swelling: a review, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 2002; 93: 221-237.

Chapter 10—The Internal Organs In Sjogren's

Tzioufas AG, Moutsopoulos HM, Sjogren's syndrome, in Rheumatology,
2nd edition, J Klippel and P Dieppe eds., Gower, 1998, 32.1-12.
Manoussakis MN, Moutsopoulos HM, Sjogren's syndrome: current con-
cepts, Advances in Internal Medicine 2001; 47: 191-217.
Soliotis FC, Mavragani CP, Moutsopoulos HM, Central nervous system in-
volvement in Sjogren's syndrome, Annals Rheum Dis 2004; 63: 616-
620.
Kassan, SS, Moutsopoulos, HM, Clinical manifestations and early diagnosis
of Sjogren's Syndrome, Arch Intern Med, 164: 1275-1284, 2004.

Chapter 11—Manifestations of Connective Tissue Diseases Seen

In Secondary Sjogren's
Klippel J, Crofford L, Stone J, Weyand C eds., Primer on the Rheumatic
Diseases, Arthritis Foundation, 2001.
Kelley W, Harris E, Ruddy S, Sledge C eds., Textbook of Rheumatology,
Saunders, 1997.
Wallace D, Hahn B eds., Dubois' Lupus Erythematosus, Lippincott Williams
and Wilkins, 2002.
APPENDIX 1
228

Chapter 12—Useful Studies: Blood Tests, Imaging,

Biopsies, and Beyond
Garcia-Carrasco M, Ramos-Casals M, Rosas J, Pallares L, Calvo-Alen J,
Cervera R, Primary Sjogren's syndrome: clinical and immunologic disease
patterns in a cohort of 400 patients, Medicine 2002; 81: 270-280.
Vitali C, Bombardiere S, Jonsson R, Moutsopoulos HM, Alexander EL,
Carson SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemar SR, Talal
N, Weissman MH, Classification criteria for Sjogren's syndrome: a re-
vised version of the European Criteria proposed by the American Euro-
pean group, Ann Rheum Dis 2002; 61: 554-558.
Markusse HM, Pillay M, Breedveld FC, The diagnostic value of salivary
gland scintigraphy in patients suspected of primary Sjogren's syndrome,
Br J Rheum 1993; 32: 231-235.

Chapter 13—How Can I Be Sure It's Really Sjogren's?

Schein, OD, Hochberg, MC, Munoz B, et al., Dry eye and dry mouth in the
elderly: a population-based assessment. Arch Int Med. 1999; 159: 1359.
Itescu S, Winchester R, Diffuse infiltrative lymphocytosis syndrome: a dis-
order occurring in human immunodeficiency virus-1 infection that may
present as a sicca syndrome, Rheumatic Diseases Clinics of North Amer-
ica 1992; 18(3): 683-697.
Loustajud-Ratti V, Riche A, Liozon E, Labrousse F, Soria P, Rogez S, Babany
G, Delaire L, Denis F, Vidal E, Prevalence and characteristics of Sjogren's
syndrome or sicca syndrome in chronic hepatitis C virus infection: a
prospective study, Journal of Rheumatology 2001; 10: 2245-2251.

Chapter 14—Treatment of Dry Eye

Bron AD, Diagnosis of dry eye, Surv Ophthalmol 2001; 45 supp. 2: S221-
226.
Pflugfelder SC, Solomon A, Stein ME, The diagnosis and management of
dry eye, Cornea 2000; 19: 644-649.
Schaumberg DA, Buring JE, Sullivan DA, Dana MR, Hormone replacement
therapy and dry eye syndrome, JAMA 2001; 286: 2114-2119.

Chapter 15—Treatment of Dry Mouth

Al-Hashimi I, The management of Sjogren's syndrome in dental practice,
J Am Dent Assoc 2001; 132: 1409-1417.
Brennan MT, Shariff G, Lockhart PB, Fox PC, Treatment of xerostomia: a
systematic review of therapeutic trials, Dent Clin N Am. 2002; 46: 847-
856.
Grisius MM, Salivary gland dysfunction: a review of systemic therapies, Oral
Surg Oral Med Oral Pathol 2001; 92: 156-162.

Chapter 16—Systemic Therapies in Sjogren's

Linardaki G, Moutsopoulos HM, The uncertain role of immunosuppressive
agents in Sjogren's syndrome, Cleve Clin J Med 1997; 64: 523-526.
 FOR FURTHER READING
Z29

Moutsopoulos NM, Moutsopoulos HM, Therapy of Sjogren's syndrome,

Springer Semin Immunopathol 2001; 23: 131-145.
Tzioufas AG, Moutsopoulos HM, Sjogren's syndrome, in Rheumatology,
3rd edition, J Smolen et al. eds., Gower, 2003.

Chapter 17—Taming Sjogren's: Fighting fatigue, Lifestyle Factors,

and Nondrug Management
Melvin J, Fibromyalgia—Getting Healthy, American Occupational Therapy
Association, Rockville, MD, 1996.

Chapter 18—Conquering Sjogren's

Barendregt PJ, Visser MR, Smets EM, Tulen JH, van den Meiracker A,
Boomsma F, Markusse HM, Fatigue in primary Sjogren's syndrome, Ann
Rheum Dis 1998; 57: 291-295.
Broderick JE, Mind-body medicine in rheumatologic disease, Rheumatic Dis-
ease Clinics of North America 2000; 26: 161-176.
Rumpf TP, Hammitt KM, The Sjogren's Syndrome Survival Guide, New
Harbinger, 2003.
Valtysdottir ST, Gudbjornsson B, Lindqvist U, Hallgren R, Hetta J, Anxiety
and depression in patients with primary Sjogren's syndrome, J Rheumatol
2000; 27: 165-169.

Chapter 19—Complementary and Alternative Therapies

for Sjogren's
Complementary and Alternative Therapies for Rheumatic Conditions, Rheu-
matic Disease Clinics of North America 1999; 25(4), and 2000; 26(1)
2000.
Lad VD, Ayurveda: the science of self-healing, 2nd edition, Lotus, 1985.
Rotblatt M, Ziment I, Evidence-based herbal medicine, Hanley and Belfus,
2001.
Additional references cited can be obtained by contacting Dr. Venuturupalli
directly.

Chapter 20—How Are Drugs Tested for Sjogren's?

1. Anaya JM, Talal N, Sjogren's syndrome comes of age. Semin Arthritis
Rheum 1999; 28:355-9.
2. Vivino FB, Al-Hashimi I, Khan Z, et al., Pilocarpine tablets for the treat-
ment of dry mouth and dry eye symptoms in patients with Sjogren syn-
drome: a randomized, placebo-controlled, fixed-dose, multicenter trial.
P92-01 Study Group. Arch Intern Med 1999; 159:174-81.
3. Petrone D, Condemi JJ, Fife R, Gluck O, Cohen S, Dalgin P, A double-
blind, randomized, placebo-controlled study of cevimeline in Sjogren's
syndrome patients with xerostomia and keratoconjunctivitis sicca. Ar-
thritis Rheum 2002; 46:748-54.
4. Vitali C, Bombardieri S, Jonsson R, et al., Classification criteria for Sjo-
APPENDIX 1
230

gren's syndrome: a revised version of the European criteria proposed by

the American-European Consensus Group. Ann Rheum Dis 2002; 61:
554-8.
5. Bowman SJ, Pillemer S, Jonsson R, et al., Revisiting Sjogren's syndrome
in the new millennium: perspectives on assessment and outcome mea-
sures. Report of a workshop held on 23 March 2000 at Oxford, UK.
Rheumatology (Oxford) 2001; 40:1180-8.
6. Kaitin KI, Bryant NR, Lasagna L, The role of the research-based phar-
maceutical industry in medical progress in the United States. J Clin Phar-
macol 1993; 33:412-7.
7. Anello C, Emerging and recurrent issues in drug development. Stat Med
1999; 18:2301-9.
8. Lipsky MS, Sharp LK, From idea to market: the drug approval process.
J Am Board Fam Pract 2001; 14:362-7.
9. Kaitin KI, Melville A, Morris B, FDA advisory committees and the new
drug approval process. J Clin Pharmacol 1989; 29:886-90.
lO.Ellenberg SS, Independent data monitoring committees: rationale, oper-
ations and controversies. Stat Med 2001; 20:2573-83.

Chapter 21—Adjunctive Measures, Comorbldlties, and

Reproductive Issues in Sjogren's
Bick RL, Antiphospholipid thrombosis syndromes, Hematol Oncol North
America 2003; 17(1): 115-147.
Buyon, JP, Pregnancy in women with Sjogren's syndrome: neonatal prob-
lems, in The new Sjogren's syndrome handbook, S Carsons, EK Harris
eds., Oxford University Press, 1998, 134-139.
Fox RI, Michelson P, Tornwall J, Approaches to the treatment of Sjogren's
syndrome, in Textbook of Rheumatology, S Ruddy, ED Harris Jr., CB
Sledge eds., Saunders, 2001, 1027-1038.

Chapter 22—Can I Work?

Disability evaluation under social security, Social Security Administration,
Office of Disability, 1999.

Chapter 23—What Will Happen to Me?

loannidis JP, Vassiliou VA, Moutsopoulos HM, Long-term risk of mortality
and lymphoproliferative disease and predictive classification of primary
Sjogren's syndrome, Arthritis Rheum. 2002; 46: 741-747.
Skopouli FN, Dafni U, loannidis JP, Moutsopoulos HM, Clinical evolution
and morbidity and mortality of primary Sjogren's syndrome, Semin Ar-
thritis Rheum 2000; 29: 296-304.
Voulgarelis M, Moutsopoulos HM, Lymphoproliferation in autoimmunity
and Sjogren's syndrome, Curr Rheumatol Rep 2003; 5: 317-323.
 FOR FURTHER READING
-—-
231

Chapter 24—Is There Hope for a Cure?

Winer S et al., Primary Sjogren's syndrome and deficiency of ICA69, Lancet
2002; 360: 1063-1069.
Hakala M, Niemela R, Does autonomic impairment have a role in patho-
physiology of Sjogren's syndrome? Lancet 2000; 355: 1032-1033.
 Katherine Morland Hammitt
Sjogren's Syndrome Foundation

APPENDIX 2
RESOURCE MATERIALS

Organizations
The Sjogren's Syndrome Foundation
Web site: www.sjogrens.org
Phone: 800-475-6473, 301-718-0300
The primary source of information and support for Sjogren's syndrome, spe-
cifically serving Sjogren's patients and health care providers. Offers a wealth
of materials and information on Sjogren's syndrome, related symptoms, and
overlapping disorders. Watch the SSF Web site for information on Sjogren's,
resource materials, educational seminars, support group meetings, contacts,
and research and advocacy initiatives in Sjogren's. You may also call 800-
475-6473 or 301-718-0300 to speak with a foundation staff member. Join
the foundation and receive the Moisture Seekers newsletter to stay informed
about the newest treatments and research and learn about practical tips and
strategies for coping with Sjogren's. Made up of top clinicians and research-
ers in Sjogren's from around the world, the SSF Medical and Scientific Ad-
visory Board authors, reviews, and recommends materials, and serves as a
clearinghouse for medical information on Sjogren's.
Your membership not only provides you with access to up-to-date infor-
mation, but your membership and donations also support the work of the
foundation as cited in its mission to:

• Educate patients and their families about Sjogren's syndrome

• Increase public and health care provider awareness of Sjogren's syndrome
• Encourage research for new treatments and a cure

Many resource materials are available from the Sjogren's Syndrome Foun-
dation, including books, pamphlets, brochures, audiotapes, and educational

232
 RESOURCE MATERIALS
233

as well as exercise videos. In addition, SSF maintains lists of treatment centers

and products. Try the SSF and the SSF Store (found at www.sjogrens.org) first!

While the Sjogren's Syndrome Foundation provides information on related

and overlapping diseases, you might also wish to contact other not-for-profit
organizations that focus solely on these diseases or include Sjogren's syn-
drome in their education. These organizations include:
American Autoimmune Related Diseases Association
Web site:www.aarda.org
Phone: 586-776-3900
Arthritis Foundation
Web site:www.arthritis.org
Phone: 800-283-7800
Lupus Foundation of America, Inc.
Web site:www.lupus.org
Phone: 202-349-1155
Lupus Research Institute
Web site:www.lupusresearchinstitute.org
Phone: 212-685-4118
Scleroderma Foundation
Web site: www.scleroderma.org
Phone: 800-722-4673
Scleroderma Research Foundation
Web site: www.srfcure.org
Phone: 800-441-2873

Federal Government Resource and Treatment Center

Sjogren's Syndrome Clinic
National Institute of Dental and Craniofacial Research
Building 10, Room 1N113
10 Center Drive MSC 1190
Bethesda, MD 20892-1190
Phone: 301-435-8528
http://wwwdir.nidcr.nih.gov/dirweb/grtb/sjogrens/SjogrenIndex.asp

Books Specifically on Sjogren's Syndrome

The Sjogren's Syndrome Survival Guide, by Teri P. Rumpf, PhD, and Kath-
erine Morland Hammitt, New Harbinger Publications, 2003
This invaluable resource on Sjogren's syndrome provides the latest med-
ical information, research results, and treatment methods available as well
as effective self-help strategies. Patients learn how to improve their quality
APPENDIX 2
234

of life by taking an active role in their care and developing true partnerships
with their doctors. Hammitt compiles clear answers to questions she and
many other Sjogren's patients long found inaccessible, while Rumpf, a clin-
ical psychologist, covers aspects of relationships, work, and finding informed
and supportive medical care.
A Body Out of Balance: Understanding and Treating Sjogren's Syndrome,
by Ruth Fremes and Nancy Carteron, Avery/Penguin Putnam, 2003
Fremes, a Sjogren's patient, discusses Sjogren's symptoms, while her doc-
tor, Carteron, explains the biological process, diagnosis, and treatment. This
book provides readers with a comprehensive guide to the wide array of
symptoms of Sjogren's, traditional and complementary treatments, and cop-
ing mechanisms for patients to devise their own holistic personal treatment
plan.
Understanding Sjogren's Syndrome, by Sue Dauphin, Pixel Press, 1993
Dauphin's book is filled with practical advice and an easy-to-understand
explanation of Sjogren's syndrome. She covers the seriousness of this disease
with a wonderful sense of humor and examples from her own and other
patients' experiences.
The Official Patient's Sourcebook on Sjogren's Syndrome: A Revised and
Updated Director for the Internet Age, edited by James N. Parker and
Philip M. Parker, ICON Group International, 2002
In addition to providing basic information on Sjogren's syndrome, the
authors explain how to search for and find practical information. Directions
focus on Internet use and include instruction on finding information about
clinical trials, research studies on Sjogren's, medications, alternative medi-
cine, nutrition, medical libraries, and insurance rights.

Pamphlets Specifically on Sjogren's Syndrome

Products Used by People with Sjogren's Syndrome, published by the Sjo-
gren's Syndrome Foundation and updated regularly
This pamphlet lists prescription and over-the-counter drugs and products
for common symptoms of Sjogren's, the company that produces each item,
and how to contact those manufacturers. Copies are available from the
Sjogren's Syndrome Foundation by calling 301-718-0300 or e-mailing
ssf@sjogrens.org. SSF members can also download a copy from the Web site
at www.sjogrens.org.
Sjogren's Syndrome Self-Help: Tips for More Comfortable Living, by Dona
Frosio, introduction by Steven Taylor, published by the Sjogren's Syn-
drome Foundation, first published in 1996, and revised in 2001 and in
2003
 RESOURCE MATERIALS
235

This pamphlet was authored by a Sjogren's syndrome patient, foundation

support group president, and frequent speaker at foundation meetings. Fro-
sio offers helpful ideas for living with Sjogren's based on her own experiences
and those contributed by others with Sjogren's. Copies are available from
the Sjogren's Syndrome Foundation by calling 301-718-0300 or e-mailing
ssf@sjogrens.org. SSF members can also download a copy from the Web site
at www.sjogrens.org.

Questions and Answers about Sjogren's Syndrome, a publication of the U.S.

Department of Health and Human Services, National Institutes of
Health, National Institute of Arthritis and Musculoskeletal and Skin Dis-
eases, 2001, NIH Publication No. 01-4861
The Sjogren's Syndrome Foundation assisted NIAMS in the compilation
of this Q&A booklet, which includes answers to common questions about
Sjogren's syndrome, including symptoms, causes, diagnosis, and treatment.
Copies are available from NIAMS, NIH, 1 AMS Circle, Bethesda, MD
20892-3675, or on the NIAMS Web site at www.nih.gov/niams/healthinfo.
It may be viewed online at www.niams.nih.gov/hi/topics/sjogrens/index.htm.

Dry Mouth (Xerostomia), a publication of the National Institutes of Health

(NIH), National Institute of Dental and Craniofacial Research, 2002,
NIH Publication No. 02-3174
This brochure discusses the causes of dry mouth, the importance of saliva
to oral health, provides steps to follow to relieve dryness, and includes in-
formation on the Dry Mouth/Sjogren's Syndrome Clinic at the National In-
stitute of Dental and Craniofacial Research. Copies are available by writing
the National Oral Health Information Clearinghouse, 1 NOHIC Way, Be-
thesda, Maryland 20892-3500, or calling them at 301-402-7364. You can
also order or download a copy from the NIH Web site at http://www
.nohic.nidcr.nih.gov/cgi-bin/ohpubgen_new.

Highly Recommended Books on Coping with Chronic Illness

A Delicate Balance: Living Successfully with Chronic Illness, by Susan Mil-
strey Wells, Perseus Publishing, 1998
Finding the Way Home: A Compassionate Approach to Illness, by Gayle
Heiss, QED Press, 1997
Beyond Chaos: One Man's Journey Alongside His Chronically III Wife, by
Gregg Piburn, Arthritis Foundation, 1999
The Chronic Illness Workbook: Strategies and Solutions for Taking Back
Your Life, by Patricia A. Fennell, New Harbinger Publications, 2001
Sick and Tired of Feeling Sick and Tired: Living with Invisible Chronic Ill-
ness, by Paul J. Donoghue and Mary E. Siegel, W. W. Norton, 2000
APPENDIX 2
Z36

Practical Guides
Disability Workbook for Social Security Applicants, by Douglas M. Smith,
Physicians' Disability Services, Inc., 5th edition, 2001
Arthritis Today Drug Guide, Arthritis Foundation, updated annually

Books on Related and Overlapping Diseases and Symptoms

The Autoimmune Connection: Essential Information for Women on Diag-
nosis, Treatment, and Getting On with Your Life, by Rita Baron-Faust
and Jill P. Buyon, McGraw-Hill/Contemporary Books, 2003
Living Well with Autoimmune Disease: What Your Doctor Doesn't Tell You
That You Need to Know, by Mary J. Shomon, HarperCollins, 2002
Thriving with Your Autoimmune Disorder: A Woman's Mind-Body Guide,
by Simone Ravicz, New Harbinger, 2000
Numb Toes and Aching Soles: Coping with Peripheral Neuropathy, by John
A. Senneff, MedPress, 1999
Numb Toes and Other Woes: More on Peripheral Neuropathy, by John A.
Senneff, MedPress, 2001
The Lupus Book: A Guide for Patients and Their Families, by Daniel J.
Wallace, Oxford University Press, 1995
Coping with Lupus, by Robert Phillips, Avery, 2001
Lupus: Everything You Need to Know, by Robert G. Lahita and Robert H.
Phillips, Avery, 1998
All About Fibromyalgia: A Guide for Patients and Their Families, by Daniel
J. Wallace and Janice Brock Wallace, Oxford University Press, 2002
The Interstitial Cystitis Survival Guide: Your Guide to the Latest Treatment
Options and Coping Strategies, by Robert M. Moldwin, New Harbinger,
2000
Coping with Chronic Fatigue Syndrome: Nine Things You Can Do, by Fred
Friedberg, New Harbinger, 1995
The Scleroderma Book: A Guide for Patients and Families, by Maureen D.
Ma yes, Oxford University Press, 1999
All About Osteoarthritis: The Definitive Resource for Arthritis Patients and
Their Families, by Nancy E. Lane and Daniel J. Wallace, Oxford Uni-
versity Press, 2002

Resources Available in Spanish

The Sjogren's Syndrome Foundation publishes a brochure on Sjogren's in
Spanish. Contact the foundation for information at www.sjogrens.org, or
call 800-475-6473. In addition, an information sheet on Sjogren's syndrome
is available from the U.S. Department of Health and Human Services, Na-
tional Institutes of Health, National Institute of Arthritis and Musculoskel-
etal and Skin Diseases.
See also Sindrome de Sjogren, by Juan-Manuel Anaya C., Manuel Ramos
C., Mario Garcia C., Corporation Para Investigaciones Biologicas, Medellin,
 RESOURCE MATERIALS
—

Colombia, 2001, and (for professionals) Sindrome de Sjogren, edited by Ma-

nuel Ramos-Casals, Mario Barcia-Carrasco, Juan Manuel Anaya, Joaquim
Coll, Ricard Cervera, Josep Font, Miguel Ingelmo, Masson, Barcelona, 2003

Textbooks In Rheumatology
Kelley's Textbook of Rheumatology, 6th edition, Shaun Ruddy et al. editors,
Saunders, 2000
Arthritis and Allied Conditions: A Textbook of Rheumatology, 14th edition,
William Koopman et al., Lippincott Williams and Wilkins, 2001
Clinical Primer of Rheumatology, William Koopman et al., editors, Lippin-
cott Williams and Wilkins, 2003
Rheumatology, 3rd edition, Marc Hochberg et al., Mosby, 2003
Primer on the Rheumatic Diseases, John H. Klippel et al., editors, Arthritis
Foundation, 2001
Treatment of the Rheumatic Diseases: A Companion to Kelley's Textbook
of Rheumatology, Michael H. Weisman et al., Saunders, 2000
Oxford Textbook of Rheumatology, 2nd edition, P. J. Maddison et al., ed-
itors, Oxford University Press, 1998

Textbooks In Related Specialties

Burket's Oral Medicine: Diagnosis and Treatment, 10th edition, M. S.
Greenberg and M Click, editors, Decker, 2003
"Neurologic disease in Sjogren's syndrome," by Elaine Alexander, chapter 4
in Systemic Diseases, Part III, Handbook of Clinical Neurology vol. 27,
no. 71, M. J. Aminoff and C. G. Goetz, editors, Elsevier Science, 1998
"Sjogren's Syndrome," by Ann L. Parke, chapter 57 in Women and Health,
Marlene B. Goldman and Maureen C. Hatch, editors, Academic Press,
2000

Professional Societies
American College of Rheumatology (ACR): www.rheumatology.org
American Academy of Ophthalmology (AAO): www.aao.org
The Association for Research in Vision and Ophthalmology (ARVO): www
.arvo.org
American Optometric Association 4AO A): www.aoanet.org
American Dental Association (ADA): www.ada.org
International and American Associations of Dental Research (IADR/AADR):
www.iadr.org
American Dental Education Association (ADEA): www.adea.org
American Dental Hygienists' Association (ADHA): www.adha.org
 Bonnie T. Litton
Joan Manny
{Catherine Morland Hammitt
Sjogren's Syndrome Foundation

APPENDIX 3
PRODUCTS FOR SJOGREN'S PATIENTS

Updates have been provided to the Sjogren's Syndrome Foundation for many
years by many different people. The latest updates were compiled by Bonnie
T. Litton, Joan Manny, and Katherine Morland Hammitt, who give special
thanks to the many Sjogren's Syndrome Foundation members who contrib-
uted their suggestions that helped make this list possible. Sjogren's syndrome
patients depend largely upon over-the-counter drugs and products to help
ameliorate their symptoms, although some prescription drugs are now avail-
able for dry mouth and dry eye. Patients often need to try different products
to see which ones work best for them and, especially in the case of prescrip-
tion medications, have the least number of side effects. We do not attempt
to list or discuss prescription medications for the systemic aspects of Sjo-
gren's syndrome; these are covered in the relevant chapters, especially in
Chapter 16, "Systemic Therapies in Sjogren's." Many patients want to know
what products are available and which products have been tried and rec-
ommended by other patients. We must emphasize, however, that the list
provided by the Sjogren's Syndrome Foundation can in no way be compre-
hensive. New products frequently come onto the market, and others are
discontinued. Check with the foundation to obtain the latest list in booklet
form or on the members-only section of the foundation Web site at www
.sjogrens.org. We are also not acquainted with every product, so please con-
tact the foundation if you, as a Sjogren's syndrome patient or health care
professional who treats Sjogren's patients, find additional products that are
especially helpful. The Sjogren's Syndrome Foundation in no way endorses
any of the products mentioned in this listing. The products listed are those
most frequently used by our members. We strongly advise that you check
any medications, treatments, or products mentioned with your own physi-
cian, dentist, and/or pharmacist. Manufacturer phone numbers and Web site

Z38
 PRODUCTS FOR SJOGREN'S PATIENTS
239

addresses are provided where available. Preservative-free products are indi-

cated with an asterisk.

PRODUCTS FOR DRY EYE

Artificial Tears
The Sjogren's Syndrome Foundation's Medical and Scientific Advisory Board
recommends that people who use artificial tears more than four times
daily avoid products with preservatives. Consult your physician to see
if you should use preservative-free products. If so, read labels carefully.
Preservative-free products and those with preservatives often have similar
sounding names. Preservatives often used in artificial tears include chloro-
butanol, benzalkonium, and thimerosal.

Akwa Tears 800-535-7155 Akorn Inc.

www.akorn.com
*Bion Tears 800-451-3937 Alcon Laboratories, Inc.
www.alconlabs.com
Dakrina, Dwell (both by 800-969-6601 Apothecure Inc.
prescription) www.apothecure.com
Healthy Relief Eye Drops 800-240-9780 Similasan Corporation
#1 www.healthyrelief.com
GenTeal Mild, GenTeal 888-669-6682 Novartis Ophthalmics
Moderate www.novartisophthalmics
.com
* GenTeal Lubricant Eye 888-669-6682 Novartis Ophthalmics
Drops—Single Dose www.novartisophthalmics
.com
* Moisture Eyes Lubricant 800-553-5340 Bausch & Lomb Pharma-
Eye Drops/Artificial Tears ceuticals, Inc.
www.bausch.com
* Moisture Eyes Liquid Gel 800-553-5340 Bausch &c Lomb Pharma-
Lubricant Eye Drops ceuticals, Inc.
www.bausch.com
Murine Tears 877-854-0853 Prestige International
Brands
www.murine.com
Nature's Tears 800-272-5525 Watson Pharmaceuticals
www.watsonpharm.com
* Nature's Tears EyeMist 800-367-6478 Rogue Springs Biologic
Aqua Technologies
www.naturestears.com
APPENDIX 3
Z40

NutraTear 800-969-6601 Apothecure, Inc.

www.apothecure.com
* Refresh Celluvisc 800-347-4500 Allergan, Inc.
www.allergan.com
* Refresh Endura Lubricant 800-347-4500 Allergan, Inc.
Eye Drops www.allergan.com
Refresh Liquigel Lubricant 800-347-4500 Allergan, Inc.
Eye Drops www.allergan.com
* Refresh Tears and Refresh 800-347-4500 Allergan, Inc.
Plus www.allergan.com
Rohto Zi for Eyes 800-688-7660 The Mentholatum Co.
www.mentholatum.com
Sodium chloride solution 800-535-7155 Akorn Inc.
5% www.akorn.com
Systane 800-451-3937 Alcon Laboratories, Inc.
www.alconlabs.com
Teargen, Teargen II 800-327-4114 IVAX Pharmaceuticals,
Inc.
www.ivaxpharmaceutical
.com
* Tears Again Sterile Lubri- 800-233-5469 Cynacon/OCuSOFT, Inc.
cant Liquid Gel www.ocusoft.com
* Tears Naturale Free 800-451-3937 Alcon Laboratories, Inc.
www.alconlabs.com
Tears Renewed 800-535-7155 Akorn Inc.
www.akorn.com
TheraTears Liquid Gel Lu- 800-579-8327 Advanced Vision Research
bricant Eye Gel www.theratears.com
* TheraTears Lubricant Eye 800-579-8327 Advanced Vision Research
Drops www.theratears.com
*Viva Drops 800-325-6789 Vision Pharmaceuticals
Inc.
www.visionpharm.com

Artificial Tear Insert

*Lacrisert (prescription) 800-396-6250 Merck & Co.
www.merck.com

Ocular Lubricants and Gels

Ocular lubricants are made with and without lanolin. You should consult
with your physician to see if one or the other is better for you.
 PRODUCTS FOR SJOGREN'S PATIENTS
Z41

*AkwaTears Ointment 800-535-7155 Akorn Inc.

www.akorn.com
GenTeal Lubricant Eye Gel— 888-669-6682 Novartis Ophthalmics
Severe www.novartisophthalmics
.com
Lacrilube Ointment 800-347-4500 Allergan, Inc.
www.allergan.com
*Moisture Eyes PM 800-553-5340 Bausch & Lomb Pharma-
Ointment ceuticals, Inc.
www.bausch.com
*Puralube Ointment 800-645-9833 E. Fougera & Co.
www.fougera.com
*Refresh PM Ointment 800-347-4500 Allergan, Inc.
www.allergan.com
Sodium chloride 5% oph- 800-535-7155 Akorn Inc.
thalmic ointment www.akorn.com
"Tears Again Night and 800-233-5469 Cynacon/OCuSOFT, Inc.
Day Gel www.ocusoft.com
*Tears Naturale P.M. 800-451-3937 Alcon Laboratories, Inc.
Lubricant Eye Ointment www.alconlabs.com
*Tears Renewed Ointment 800-535-7155 Akorn Inc.
www.akorn.com
Additional Options for Dry Eye Relief
Tranquileyes Eye Hydrating 866-393-3267 Eyeeco
Therapy www.eyeeco.com
Drugs That Decrease Inflammation and Increase Tear How
*Restasis (prescription) 800-347-4500 Allergan, Inc.
www.allergan.com
Tablets/Capsules to Stimulate Lacrlmal Gland Function
BioTears 888-303-2111 Biosyntrix, Inc.
www.biosyntrix.com
Hydroeye 888-433-4726 Science Based Health
www.sciencebasedhealth
.com
Nutrition for the Eyes
Ocuvite Lutein 800-553-5340 Bausch & Lomb Pharma-
ceuticals, Inc.
www.bausch.com
TheraTears Nutrition for 800-579-8327 Advanced Vision Research
Dry Eyes www.theratears.com
APPENDIX 3
242

Tear Duct (Punctal) Plugs

Collagen Plugs (prescrip- 800-376-8327 Lacrimedics
tion) (collagen; dissolvable) www.lacrimedics.com
Herrick Lacrimal Plug (pre- 800-376-8327 Lacrimedics
scription) (silicone; www. lacrimedics.com
canalicular)
Parasol Punctal Occluder 888-905-7770 Odyssey Medical Inc.
System (temporary/ www.odysseymed.com
removable)
Punctum Plugs (prescrip- 800-222-7584 Eagle Vision, Inc.
tion) (silicone; temporary/ www. eagle vis .com
removable)
Sharpoint (silicone; tempo- 800-523-3332 Surgical Specialties
rary/ removable) www.sharpoint.com
Smartplug (canalicular) 888-727-6100 Medennium Inc.
www.medennium.com

Eye Wash Solutions

Bausch & Lomb Soothing 800-553-5340 Bausch & Lomb Pharma-
Eye Wash ceuticals, Inc.
www.bausch.com
Collyrium for Fresh Eyes 800-553-5340 Bausch & Lomb Pharma-
Eye Wash ceuticals, Inc.
www. bausch.com

Seasonal Allergy Conjunctivitis

Acular (prescription) 800-347-4500 Allergan, Inc.
www.allergan.com

Vernal Conjunctivitis, Keratitls, and Keratoconjuncttvftls

Alomide (prescription) 800-451-3937 Alcon Laboratories, Inc.
www.alconlabs.com

Moisture Shields for the Eyes

Moist-Eye Moisture Panels 800-222-7584 Eagle Vision, Inc.
www.eaglevis.com
Panoptx Windless Eyewear 877-726-6789 Panoptx
www.panoptx.com
Wrap-Around Glasses 800-556-7170 Leonard Safety Equipment
www.leonardsafety.com
 PRODUCTS FOR SJOGREN'S PATIENTS
243

Sterile Eyelid Cleansers

EyeScrub 866-451-5949 Novartis Ophthalmics
www.novartisophthalmics
.com
OCuSOFT Lid Scrub 800-233-5469 OCuSOFT, Inc.
www.ocusoft.com

PRODUCTS FOR DRY MOUTH

Products That Stimulate Salivary How
Biotene Dry Mouth Gum 800-922-5856 Laclede, Inc.
www.laclede.com
Evoxac (cevimeline HC1) 877-324-4244 Daiichi Pharmaceutical
(prescription) Corp.
www.daiichius.com
Salagen (pilocarpine) 800-644-4811 MGI Pharma, Inc.
(prescription) www.mgipharma .com
Salix Saliva Stimulating 800-288-2844 Scandinavian Natural
Lozenges Products
www.scandinavian
formulas.com
TheraGum with xylitol and 800-643-3639 OMNII Oral
calcium Pharmaceuticals
www. omniipharma .com
Xylichew Sugar Free Chew- Tundra Trading, Inc.
ing Gum www.tundratrading.com

Oral Moisturizers
Biotene Oral Balance Mois- 800-922-5856 Laclede, Inc.
turizing Gel www.laclede.com
Caphosol (prescription) 781-864-2559 InPharma Inc.
(dispensed at compouding www.caphosol.com
pharmacies)
Entertainer's Secret 800-308-7452 KLI Corp.
www.entertainers-secret
.com
Moi-Stir Solution and Moi- 800-968-7772 Kingswood Labs, Inc.
Stir Swabs www.moi-stir.com
MouthKote with Yerba 800-457-4276 Parnell Pharmaceuticals,
Santa Inc.
www.parnellpharm.com
APPENDIX 3
244

Orajel Dry Mouth Moistur- 800-952-5080 Del Laboratories

izing Gel www.orajel.com
Saliva Substitute 800-848-0120 Roxanne Laboratories,
Inc.
www.roxane.com
Salivart 800-321-9348 Gebauer Co.
www.gebauerco.com
TheraSpray with xylitol 800-643-3639 OMNII Oral
Pharmaceuticals
www.omniipharma.com

Special Toothpastes, Mouthwashes, and Products and Devices for

Cleaning Teeth
Aquafresh Toothpaste 888-825-5249 GlaxoSmithKline
www.gsk.com
Biotene Antibacterial Dry 800-922-5856 Laclede, Inc.
Mouth Toothpaste Gentle www.laclede.com
Mint Gel Dry Mouth
Toothpaste
Biotene Alcohol-Free 800-922-5856 Laclede, Inc.
Mouthwash www.laclede.com
Colgate Total Floss 800-225-3756 Colgate Oral
Pharmaceuticals
www.colgateprofessional
.com
ControlRx Toothpaste 800-643-3639 OMNII Oral
(prescription) Pharmaceuticals
www.omniipharma.com
FlossRx 800-643-3639 OMNII Oral
Pharmaceuticals
www.omniipharma.com
Glide Floss 800-645-4337 Procter & Gamble
www.glidefloss.com
Orajel Dry Mouth Moistur- 800-952-5080 Del Laboratories
izing Toothpaste www.orajel.com
PerioMed 800-643-3639 OMNII Oral
Pharmaceuticals
www.omniipharma.com
Sensodyne Toothpaste 888-825-5249 GlaxoSmithKline
www.gsk.com
 PRODUCTS FOR SJOGREN*S PATIENTS
245

Sonicare—The Sonic 800-682-7664 Philips Oral Healthcare,

Toothbrush Inc.
www.somcare.com
Squigle Enamel Saver 877-718-0718 Squigle, Inc.
Toothpaste www.squigle.com

Preparations to Protect and/or Remlnerallze Teeth

Caphosol (prescription) 781-864-2559 Impharma Inc.
(dispensed at compounding www.caphosol.com
pharmacies)
ControlRx Toothpaste (pre- 800-643-3639 OMNII Oral
scription) Neutral Sodium Pharmaceuticals
Fluoride www.omniipharma.com
Gel-Kam Gel (prescription) 800-225-3756 Colgate Oral
Stannous Fluoride Pharmaceuticals
www.colgateprofesional
.com
Gel-Tin Liquid (prescrip- 800-325-1881 Young Dental Mfg.
tion) Stannous Fluoride www.youngdental.com
OMNIIGel (prescription) 800-643-3639 OMNII Oral
Stannous Fluoride Pharmaceuticals
www.omniipharma.com
PreviDent Brush-on Sodium 800-225-3756 Colgate Oral
Fluoride Gel (prescription) Pharmaceuticals
www.colgateprofessional
.com
PreviDent 5000 Plus (pre- 800-225-3756 Colgate Oral
scription) Sodium Fluoride Pharmaceuticals
www.colgateprofessional
.com
Revive Gel 800-328-1276 Dental Resources Inc.
www.dentalresourcesinc
.com

Products to Soothe Dry Lips

Blistex Medicated Lip 888-784-2472 Blistex, Inc.
Ointment www.blistex.com
Carmex Lip Moisturizer 414-421-7707 Carma Laboratories, Inc.
www.carma-labs.com
Lip-Fix Cream 800-227-2445 Elizabeth Arden
www.elizabetharden.com
APPENDIX 3
246

Lip Medex 888-784-2472 Blistex, Inc.

www. blistex.com
Neutrogena Lip Moisturizer 800-582-4048 Neutrogena Corp.
www.neutrogena.com
Neutrogena Instant Lip 800-582-4048 Neutrogena Corp.
Remedy, Neutrogena Over- www.neutrogena.com
night Lip Treatment
Vaseline Lip Therapy 800-243-5804 Cheseborough-Ponds, Inc.
www. unileverus.com

PRODUCTS FOR DRY NOSE

Moisturizers for Nasal Mucosal Tissue
Afrin Nasal Spray 908-298-4000 Schering-Plough Health-
Care Products, Inc.
www.schering-plough.com
www.afrin.com
Ayr Saline Nasal Gel 800-324-1880 B.E Ascher & Co., Inc.
www.bfascher.com
Little Noses 800-754-8853 Little Remedies Products/
Vetco, Inc.
www.littleremedies.com
Na-Zone 800-250-4258 Snuva, Inc.
www.snuva.com
Ocean Nasal Spray 800-343-0164 Fleming $£ Co.
www.flemingcompany.com
Pretz Spray with Yerba 800-457-4276 Parnell Pharmaceuticals,
Santa Inc.
www.parnellpharm.com
Sinus Rinse 877-477-8633 NeilMed Products, Inc.
www.nasalrinse.com

PRODUCTS FOR DRY SKIN

Moisturizers, Creams, and Cleansing Products
AmLactin Cream and 800-654-2299 Upsher-Smith
Lotion www.upsher-smith.com
Aveeno moisturizing lotions 877-298-2525 Johnson & Johnson Con-
and cream sumer Products
www.aveeno.com
 PRODUCTS FOR SJOGREN'S PATIENTS
Z47

Bag Balm 800-232-3610 Dairy Association Co, Inc.

www.bagbalm.com
Borage Therapy Body 800-448-0298 ShiKai Products
Lotion and Hand Cream www.shikai.com
Carmol 20 800-929-9300 Bradley Pharmaceuticals,
Inc.
www.bradpharm.com
Cetaphil moisturizing Galderma Laboratories,
lotions L.P.
www.cetaphil.com
Curel Ultra Healing Ther- 800-572-2931 The Andrew Jergens
apy Lotion Company
www.curel.com
Derm-Apply Moisturizing 800-250-4258 Snuva, Inc.
Lotion www.snuva.com
Eucerin Moisturizing Lo- 800-227-4703 Beiersdof Inc.
tion and Eucerin Dry Skin www.eucerinus.com
Therapy
Glycerin Hand Therapy 800-541-8647 Camille Beckman
www.camillebeckman
online.com
Lac-Hydrin (prescription) Bristol Meyers Squibb
www.bms.com
Lubriderm for Sensitive 800-223-0182 Pfizer Consumer
Skin and Lubriderm Skin Healthcare
Therapy www.prodhelp.com
Neutrogena Norwegian 800-582-4048 Neutrogena Corp.
Formula Body Cream, and www.neutrogena.com
Hand Cream
Nivea Extra Enriched 800-227-4703 Beiersdorf Inc.
Lotions www.niveausa.com
St. Ives with Vitamin E and St. Ives Laboratories, Inc.
Advanced Therapy Lotion, www.stives.com/products
St. Ives Intensive Healing
Vanicream Skin Cream and 800-325-8232 Pharmaceutical Specialties,
Vanicream Lite Lotion Inc.
www.vanicream.com
Vitec Vitamin E Lotion 800-325-8232 Pharmaceutical Specialties,
Inc.
www.paico.com
APPENDIX 3
248

Zim's Crack Creme 800-319-2225 Perfecta Products

www.crackcreme.com

Other commonly used products that patients listed and that should be
easy to find at your local drug store include Basis Soap, Keri Lotion, John-
son's Baby Oil with aloe vera and Vitamin E, Moisturel, and Vaseline Wa-
ter Resistant Lotion.

PRODUCTS FOR VAGINAL DRYNESS

Astroglide, Silken Secret 800-848-5900 BioFilm, Inc.
www.astroglide.com
Estrace Vaginal Cream 800-521-8813 Warner Chilcottt
(prescription) www.warnerchilcott.com
Feminease 800-457-4276 Parnell Pharmaceuticals,
Inc.
www.parnellpharm .com
K-Y Long Lasting Vaginal 877-592-7263 Personal Products Co.
Moisturizer
Lubrin Vaginal Inserts 973-882-1505 Bradley Pharmaceuticals,
Inc.
www.bradpharm.com
Maxilube Personal 800-531-3333 Mission Pharmacal Co.
Lubricant www.missionpharmacal
.com
Premarin Vaginal Cream 800-934-5556 Wyeth Pharmaceuticals
(prescription) www.wyeth.com
Replens Long-Lasting Vagi- 877-507-6516 LDS Consumer Products
nal Moisturizer www.replens.com

HUMIDIFIERS
Kaz Personal Humidifier 800-827-6712 KAZ Home Environment
www.kaz.com
Venta Airwasher 888-333-8218 Venta-Airwasher LLC
www.venta-airwasher.com

FOOTWEAR FOR NEUROPATHY PAIN

Thor-Lo Walking Crew 888-846-7567 THOR-LO, Inc.
WX-11 S www.thorlo.com
 PRODUCTS FOR SJOGREN'S PATIENTS
249

PRODUCTS AND MEDICATIONS FOR REFLUX

Antacids are often the first line of defense against reflux and include those
that contain aluminum and magnesium salts (for example, Alka-Seltzer,
Maalox, Mylanta, Pepto-Bismol, Rolaids, and Riopan) and those that con-
tain calcium carbonate (for example, Turns, Titralac, and Alka-2). Foaming
agents such as Gaviscon, to help combat reflux, can also be found over the
counter.

HZ Blockers
H2 blockers are available over the counter or in greater strengths by
prescription.

Axid AR (nizatidine) 800-545-5979 Eli Lilly and Company

Limited
www.lilly.com
Pepcid AC (famotidine) 800-755-4008 Merck Consumer Pharma-
ceuticals Co.
www.pepcidac.com
Tagamet HB (cimetidine) 800-482-4394 GlaxoSmithKline
www.tagamethb.com
Zantac 75 (ranitidine) 888-825-5249 GlaxoSmithKline
www.gsk.com

Proton Pump Inhibitors

Aciphex (rabeprazole) Janssen Pharmaceutica Inc.
(prescription) www.aciphex.com
Nexium (esomeprazole) 800-236-9933 AstraZeneca LP
(prescription) www.purplepill.com
Prevacid (iansoprazole) 800-621-1020 TAP Pharmaceutical Prod-
(prescription) ucts Inc.
www.prevacid.com
Prilosec (omeprazole) 800-236-9933 AstraZeneca LP
www.priloseconline.com
Protonix (pantoprazole) 800-934-5556 Wyeth Pharmaceuticals
(prescription) www.protonixrx.com
APPENDIX 4
GLOSSARY

achlorhydria: Gastric acid deficiency.

ACR (American College of Rheumatology): A professional association of
United States rheumatologists. Criteria (definitions) of many rheumatic
diseases are called the ACR Criteria.
adenopathy: A swelling of the lymph nodes. In Sjogren's syndrome, this
usually occurs in the neck and jaw region.
alopecia: Hair loss.
albumin: A protein that circulates in the blood and carries materials to cells.
alveoli: Air sacs of the lungs.
amylase: An enzyme present in saliva; another form of amylase is produced
by the pancreas.
Analgesic: A drug that alleviates pain.
angular cheilitis: Sores at the corners of the mouth (angles of the lips).
antibody: Substance in the blood that is normally made in response to in-
fection. Also referred to as immunoglobulins such as IgG, IgM, etc.
anticentromere antibody: Antibodies to a cell nucleus associated with
scleroderma.
anticardiolipin antibody: An antiphospholipid antibody.
anti-DNA (anti-double-stranded DNA): Antibodies to DNA; seen in half of
patients with lupus.
anti-ENA (extractable nuclear antibodies): A group of antibodies that in-
cludes anti-Sm and anti-RNP.
antigen(s): A chemical substance that provokes the production of antibody.
In tetanus vaccination, for example, tetanus is the antigen injected to
produce antibodies and hence protective immunity to tetanus.
antimalarial drugs: Quinine-derived drugs, which were first developed to
treat malaria and can manage Sjogren's, such as hydroxychloroquine
(Plaquenil).

250
 GLOSSARY
251

antinuclear antibodies (ANA): Autoantibodies directed against components

in the nucleus of the cell. Screening test for lupus and other connective
tissue diseases including Sjogren's syndrome.
antispasmodic drugs: Medications that quiet spasms. Usually used in refer-
ence to the gastrointestinal tract.
antiphospholipid antibody: Antibodies to a constituent of cell membranes
seen in one-third of those with SLE. In the presence of a cofactor, these
antibodies can alter clotting and lead to strokes, blood clots, miscar-
riages, and low platelet counts. Also detected as the lupus anticoagulant.
anti-RNP: Antibody to ribonucleoprotein. Seen in lupus and mixed connec-
tive tissue disease.
anti-Sm: Anti-Smith antibody; found only in lupus.
anti-SSA (Ro antibody): Associated with Sjogren's syndrome, sun sensitivity,
neonatal lupus, and congenital heart block.
anti-SSB (La antibody): Almost always seen with anti-SSA.
apoptosis: Programmed cell death.
arteriole: A very small artery.
arthralgia: Pain in a joint.
arthritis: Inflammation of a joint.
ascites: An abnormal fluid that collects in the abdomen due to certain liver
and other disorders.
atrophy: A thinning of the surface; a form of wasting.
autoantibody: Antibody that attacks the body's own tissues and organs as
if they were foreign.
autoimmunity: A state in which the body inappropriately produces antibody
against its own tissues. The antigens are components of the body.
B cell or B lymphocyte: A white blood cell that makes antibodies.
basal (resting) rate: Unstimulated (used in reference to both tears and sali-
vary flow).
bolus: A morsel of food, already chewed, ready to be swallowed.
bronchi: Branches of the trachea.
buffer: A mixture of acid or base that, when added to a solution, enables
the solution to resist changes in the pH that would otherwise occur when
acid or alkali is added to it.
cartilage: Tissue material covering bone. The nose, outer ears, and trachea
consist primarily of cartilage.
chronic active hepatitis: A disorder that occurs when viral hepatitis proceeds
in an active state beyond its usual cause.
calcification: A process in which tissue or noncellular material in the body
becomes hardened as the result of deposits of insoluble calcium salts.
candidiasis: Moniliasis. A condition due to an overgrowth of the yeast (fun-
gus) Candida.
cariostatic: Having the ability to help prevent dental caries.
celiac disease: Gluten intolerance.
APPENDIX 4
252

complete blood count (CBC): A blood test measuring the amount of red
cells, white blood cells, and platelets in the body.
congenital heart block: A dysfunction of the rate/rhythm conduction system
in the fetal or infant heart.
central nervous system: The brain and spinal cord.
collagen vascular disease: See connective tissue disease.
connective tissue disease: A disorder marked by inflammation of the con-
nective tissue (joints, skin, muscles) in multiple areas. In most instances,
connective tissue diseases are associated with autoimmunity.
cornea: The clear "watch crystal" structure covering the pupil and iris (col-
ored portion of the eye). It is composed of several vital layers, all of
which are functionally important. The surface layer, or epithelium, is
covered by the tears, which lubricate and protect the surface.
corticosteroid: A hormone produced by the adrenal cortex gland. Natural
adrenal gland hormones have powerful anti-inflammatory activity and
are often used in the treatment of severe inflammation affecting vital
organs. The many side effects of corticosteroids should markedly curtail
their use in mild disorders.
crossover syndrome: An autoimmune process that has features of more than
one rheumatic disease.
cryoglobulins: Protein complexes circulating in the blood that are precipi-
tated during cold.
cryptogenic cirrhosis: Liver disease of unknown etiology (origin) in patients
with no history of alcoholism or previous acute hepatitis.
dermatomyositis: An autoimmune process directed against muscles associ-
ated with skin rashes.
diuretics: Medications that increase the body's ability to rid itself of fluids.
double-blind study: One in which neither the physician nor the patients be-
ing treated know whether patients are receiving the active ingredient be-
ing tested or a placebo (an inactive substance).
dysorexia: Impaired or deranged appetite.
dysphagia: Difficulty in swallowing. In Sjogren's syndrome this may be at-
tributable to several causes, among them a decrease in saliva, infiltration
of the glands at the esophageal mucosa, or esophageal webbing.
dyspnea: Air hunger resulting in labored or difficult breathing, sometimes
accompanied by pain.
ecchymosis: A purplish patch caused by oozing of blood into the skin; ec-
chymoses differ from petechiae in size.
edema: Swelling caused by retention of fluid.
ELISA (enzyme-linked immunosorbent assay): A very sensitive blood test for
detecting the presence of autoantibodies.
epistaxis: Nosebleed or hemorrhaging from the nose, which may be caused
by dryness of the nasal mucous membrane in Sjogren's syndrome.
 GLOSSARY
253

erythema: A medical term for a red color, usually associated with increased
blood flow to an inflamed area, often the skin.
erythrocyte: Red blood cell.
esophagus: A canal (narrow tube) with muscular walls allowing passage of
food from the pharynx, or end of the mouth, to the stomach.
erythrocyte sedimentation rate (ESR): Measures the speed at which a column
of blood settles. Most common and simple test for inflammation.
etiology: The cause(s) of a disease.
eustachian tube: The tube running from the back of the nose to the middle
ear.
exocrine glands: Glands that secrete mucus.
exocrinopathy: Disease related to the exocrine glands.
exocrine glands: A gland that secretes outwardly through ducts.
fibromyalgia: A form of non-neuropathic chronic neuromuscular pain as-
sociated with fatigue, disordered sleeping, and tender points in the soft
tissues.
fibrosis: Abnormal formation of fibrous tissue.
fissure: A crack in the tissue surface (skin, tongue, etc.).
fluorescein stain: A dye that stains areas of the eye surface in which cells
have been lost.
gastritis: Stomach inflammation.
gene: Consisting of DNA, it is the basic unit of inherited information in our
cells.
genetic factors: Traits inherited from parents, grandparents, and so on.
gingiva: The gums.
gingivitis: Inflammation of the gums.
granuloma: A nodular, inflammatory lesion.
human leukocyte antigens (HLA): A group of genes that governs the ability
of lymphocytes, such as T cells and B cells, to respond to foreign and
self substances.
idiopathic: Of unknown cause.
immunogenetics: The study of genetic factors that control the immune
response.
immunoglobulin E (IgE): Antibody associated with allergies.
immunoglobulins (gamma globulins): The protein fraction of serum respon-
sible for antibody activity. Measurement of serum immunoglobulin levels
can serve as a guide to disease activity in some patients with Sjogren's
syndrome.
immunomodulators: Medications that affect the body's immune system.
immunosuppressive agents: A class of drugs that interferes with the function
of cells composing the immune system. See lymphocyte.
immunosuppressive agents. Drugs used in the chemotherapy of malignant
disease and in the prevention of transplant rejection are generally im-
APPENDIX 4
254

munosuppressive and occasionally are used to treat severe autoimmune

disease.
incisal: Cutting edge (of a tooth).
interstitial: Supporting structure of the substance of an organ or tissues.
interstitial nephritis: Inflammation of the connective tissue of the kidney,
usually resulting in mild kidney disease characterized by frequent uri-
nation. Interstitial nephritis may be associated with Sjogren's syndrome.
intraoral: Inside the mouth.
keratoconjunctivitis sicca: Condition, also called dry eye, that most fre-
quently occurs in women in their forties and fifties. If it is associated with
a dry mouth and/or rheumatoid arthritis, the condition is referred to as
Sjogren's syndrome.
lacrimal: Relating to the tears.
lacrimal glands: Two types of glands that produce tears. Smaller accessory
glands in the eyelid tissue produce the tears needed from minute to min-
ute. The main lacrimal glands, located just inside the bony tissue sur-
rounding the eye, produce large amounts of tears.
larynx: Voice box.
latent: Not manifest but potentially discernible.
lip biopsy: Incision of approximately 2 cm on the inside surface of the lower
lip and excision of some of the minor salivary glands for microscopic
examination and analysis.
lymph: A fluid collected from the tissues throughout the body, flowing
through the lymph nodes and eventually added to the circulating blood.
lymphocyte: A type of white blood cell concerned with antibody production
and regulation. Collections of lymphocytes are seen in the salivary glands
of Sjogren's syndrome patients.
lymphoma: A severe proliferation (increase) of abnormal (malignant) lym-
phocytes, manifested as cancer of the lymph glands. Although exceed-
ingly rare, lymphoma occurring as a complication of severe Sjogren's
syndrome has been identified by immunologists.
matrix: The section of the tooth enamel that holds calcium and phosphate
minerals.
mixed connective tissue disease: A connective tissue disease that manifests
as an overlap of other connective-tissue disorders.
Meibomian glands: Fat-producing glands in the eyelids that produce an es-
sential component of tears.
mucin: Thinnest layer of the tear film; layer closest to the cornea.
mucolytic agents: Medications that tend to dissolve mucus. Most patients
with dry eye complain of excess mucous discharge. Some patients may
benefit from these medications if other tear-film-enhancing drops are not
very effective.
necrosis: Tissue death.
nephritis: An inflammation of the kidneys.
 GLOSSARY
255

neutrophil: A granulated white blood cell involved in bacterial killing and

acute inflammation.
nonspecific: Caused by other diseases or multiple factors.
nonsteroidal anti-inflammatory drugs (NSAIDS): Anti-inflammatory agents
blocking the action of prostaglandins used to treat pain that occur in
rheumatoid arthritis and other connective-tissue disorders. Examples in-
clude ibuprofen (Motrin, Advil) and naproxen (Aleve).
olfactory: Relating to the sense of smell.
ophthalmologist: A physician who specializes in diseases and surgery of the
eye.
oral mucosa: The lining (mucous membrane) of the mouth.
oral soft tissue: Tongue, mucous lining of the cheeks, and lips.
otitis: Inflammation of the ear, which may be marked by pain, fever, abnor-
malities of hearing, deafness, tinnitus (a ringing sensation), and vertigo.
In Sjogren's syndrome, blockage at eustachian tubes due to infection can
lead to conduction deafness and chronic otitis.
otolaryngologist: Physician specializing in ear, nose, and throat disorders.
palate biopsy: A punch biopsy near the junction of the hard and soft palates
to sample the minor salivary glands in that region.
palpable: Perceptible to touch.
parasympathetic nervous system: The part of the autonomic nervous system
whose functions include constriction of the pupils of the eyes, slowing of
the heartbeat, and stimulation of certain digestive glands. These nerves
originate in the midbrain, the hindbrain, and the sacral region of the
spinal cord; impulses are mediated by acetylcholine.
parotid gland flow: An empirical quantitative measure of the amount of
saliva produced over a certain period of time. Normal parotid gland flow
rate is 1.5 ml/min. In Sjogren's syndrome, the flow rate is approximately
0.5 ml/min, with diminution of the flow rate correlating inversely with
the severity of disease.
parotid glands: One of the three pairs of major salivary glands. They are
located in front of the ear.
pericardium: The lining of the heart.
photosensitivity: Sensitivity to ultraviolet light.
pleura: A sac lining the lung.
primary biliary cirrhosis (PBC): Impairment of bile excretion secondary to
liver inflammation and scarring.
perforation: A hole.
pericarditis: Inflammation of the lining of the heart.
periodontitis: Inflammation of the tissues surrounding and supporting the
teeth.
peripheral nerves: Nerves outside the central nervous system.
petechia: A small, pinpoint, nonraised, perfectly round, purplish red spot
caused by intradermal or submucosal hemorrhaging.
APPENDIX 4
256

pharynx: Throat.
placebo: An inactive substance used as a "dummy" medication.
plaque: A thin, sticky film that builds up on the teeth, trapping harmful
bacteria.
plasma: The fluid portion of the circulating blood.
pleurisy: Inflammation of the pleura (membrane surrounding the lungs and
lining the walls of the rib cavity).
polymyositis: A connective tissue disorder characterized by muscle pain and
severe weakness secondary to inflammation in the major voluntary
muscles.
psoralen: A drug administered orally or topically for the treatment of vitiligo
(white patches caused by loss of pigment).
puncta: Small holes in the eyelids that normally drain tears. Patients with
severe dry eye benefit from punctal closure, which allows maximal tear
preservation.
purpura: A condition characterized by hemorrhage into the skin, appearing
as crops of petechiae (very small red spots).
radioactive isotope: Radioactive material used in diagnostic tests.
radionuclide studies: A technique in which radioactive isotopes, such as ra-
diolabeled human serum albumin, are injected into an organ. A gamma
scintillation camera, coupled with a digital computer system and a cath-
ode ray display, reads the radioactive emissions. Areas of perfusion will
show marked radiographic emissions; areas of obstruction will show no
activity.
Raynaud's phenomenon: Painful blanching of the fingertips on exposure to
cold. This may be seen alone or in association with a connective tissue
disease.
reflux: A regurgitation due to the return of gas, fluid, or small amount of
food from the stomach.
renal: Relating to the kidneys.
rheumatoid arthritis: A form of arthritis characterized by inflammation of
the joints, stiffness, swelling, synovial hypertrophy, and pain.
rheumatoid factor: An autoantibody whose presence in the blood usually
indicates autoimmune activity.
rheumatologist: A physician skilled in the diagnosis and treatment of rheu-
matic conditions.
rose bengal: A dye that stains abnormal or sick cells on the surface of the
eye. This diagnostic dye allows the ophthalmologist to follow the treat-
ment of dry eye.
salicylates: Aspirin-like drugs.
salivary scintigraphy: Measurement of salivary gland function through in-
jection of radioactive material.
sarcoidosis: A systemic disease with granulomatous (nodular, inflammatory)
 GLOSSARY
257

lesions involving the lungs and, on occasion, the salivary glands, with
resulting fibrosis.
Schirmer test: The standard objective test to diagnose dry eye. Small pieces
of filter paper are placed between the lower eyelid and eyeball and soak
up the tears for five minutes. The value obtained is a rough estimation
of tear production in relative terms. Lower values are consistent with dry
eye. It is important to emphasize that no single test can be considered
diagnostic unless the condition is severe.
scleroderma: A connective tissue disorder characterized by thickening and
hardening of the skin. Sometimes internal organs (intestines, kidneys) are
affected, causing bowel irregularity and high blood pressure.
secretogogue: A medication that can stimulate salivary flow.
serum: The fluid portion of the blood (obtained after removal of the fibrin
clot and blood cells), distinguished from the plasma in the circulation
blood.
sialochemistry: Measurement of the constituents in saliva.
sialography: X-ray examination of the salivary duct system by use of liquid
contrast medium. Radiologically sensitive dye is placed into the duct sys-
tem, outlining the system clearly.
signs: Changes that can be seen or measured.
Sjogren's antibodies: Abnormal antibodies found in the sera of Sjogren's syn-
drome patients. These antibodies react with the extracts of certain cells,
and a test based on this principle can be helpful in the diagnosis of
Sjogren's syndrome. See also SSA and SSB.
Sjogren's syndrome: A symptom complex of dry eye, dry mouth, and dryness
of other mucous membranes associated with inflammation of the lacrimal
and/or salivary glands. It can occur alone (50 percent) or in association
with a connective tissue disease.
SLE (systemic lupus erythematosus): An inflammatory connective tissue
disease.
SSA: Sjogren's syndrome-associated antigen A (anti-Ro).
SSB: Sjogren's syndrome-associated antigen B (anti-La).
steatorrhea: Passage of large amounts of fat in the feces, as occurs in pan-
creatic disease and the malabsorption syndromes.
steroids: Cortisone-derived medications.
sublingual glands: One of the three pairs of major salivary glands. They are
located in the floor of the mouth under the tongue.
submandibular glands: One of the three pairs of major salivary glands. They
are located below the lower jaw.
symptoms: Changes patients feel.
systemic: Any process that involves multiple organ systems throughout the
body.
synovitis: Inflammation of the tissues lining a joint.
APPENDIX 4
258

synovium: Tissue that lines a joint.

T cell: A lymphocyte (white blood cell) responsible for immunologic
memory.
thymus: A gland in the neck responsible for immunologic memory.
thrush: A form of candidiasis. Infection of the oral tissues with Candida
albicans.
thyroiditis: A disease in which autoantibodies cause immune system cells
(lymphocytes) to destroy the thyroid gland.
titer: Test showing the strength or concentration of a particular volume of
a solution. Usually refers to amounts of antibody present.
TMJ (temperomandibular joint): The joint of the lower jaw where the ball-
and-socket arrangement is formed by the condyle of the lower jaw (the
ball) and the fossa of the temporal bone (the socket). The joint space is
filled with synovial or lubricating fluid. This joint and the surrounding
synovial tissues may become inflamed if rheumatoid arthritis accompa-
nies Sjogren's syndrome and involves the joint.
trachea: Windpipe.
tracheobronchial tree: The windpipe and the bronchi into which it
subdivides.
UCTD (undifferentiated connective tissue disease): Features of autoimmun-
ity such as inflammatory arthritis or Raynaud's in a patient who does
not meet the ACR criteria for lupus, rheumatoid arthritis or other
disorders.
ultraviolet light (UV light): A spectrum of light including UVA (320-400
nanometers), UVB (290-320 nanometers), and UVC (200-290
wavelengths).
urticaria: Hives.
vasculitis: Inflammation of a blood vessel.
venule: A very small vein.
viscera: The organs of the digestive, respiratory, urogenital, and endocrine
systems, as well as the spleen, heart, and great vessels (blood and lymph
ducts).
vitiligo: White patches on the skin due to loss of pigment.
xerophthalmia: Dry eyes.
xerostomia: Dryness of the mouth caused by the arresting of normal salivary
secretions. It occurs in diabetes, drug therapy, radiation therapy, and
Sjogren's syndrome.
xylitol: A sweetening agent with cariostatic properties.
INDEX

ACE (angiotensin-converting enzyme) in- anti-inflammatory medications, 180, 181.

hibitors, 88 See also NSAIDs
acid reflux (gastro-esophageal reflux), 38, anti-La/SSB antibody, 4, 7, 27, 29, 93,
73, 79, 88, 136, 142, 249 195-98; and congenital heart block,
acinar cells, 18, 58 76-77, 196-98; tests for, 85, 94, 97,
acupuncture, 126, 182, 185 101-2
acute phase reactants, 98-99 antimalarial drugs, 86, 140-41, 143
adenopathy (lymph node swelling), 12, 21, antimitochondrial antibodies (AMAs), 75,
92, 111 137
age of onset, 11, 12, 82, 108 anti-muscarinic receptor, 28
aging, comorbidity of, 201-2 antineurophil cytoplasmic antibodies
AIDS. See HIV (ANCA), 91
alcohol, 148, 150, 153 antinuclear antibodies (ANA), 12, 27-28,
allergic conjunctivitis, 50 84, 85, 90; test for, 94, 97, 100
allergies, 107, 194 antiphospholipid antibody syndrome
allopurinol, 132 (APS), 86-87, 198-200
alternative medicine. See complementary anti-Ro/SSA antibody, 4, 7, 11, 27, 29,
and alternative medicine (CAM) 195-98; and congenital heart block,
ambroxol, 130-31 76-77, 196-98; testing for, 12, 85,
American College of Rheumatology 94, 97, 101-2, 187
(ACR), 84, 95, 194 apoptosis (cell death), 20
American-European Consensus Group, 186 arthritis, 37-38; osteoarthritis, 146, 178,
amiloride (diuretic), 133, 134, 142 180, 181, 182, 184. See also rheuma-
amylase (enzyme), 74 toid arthritis
androgens, 19 Arthritis Foundation, 170
anemia, 74, 79, 137, 141, 142 artificial saliva, 123
anetholetrithione, 127 artificial tear preparations, 116, 117-18,
anger, coping with, 160-62, 168 239-40
angular cheilitis, 63 atrophic gastritis, 73-74, 137
anti-acetylcholine muscarinic receptors, atrophic rhinitis, 54
102 autoantibodies, 25-29, 31, 35, 90,195-96;
antiallergy medications, 44, 50 sicca symptoms, 81; testing for, 102-3
anti-alpha-fodrin (autoantibody), 102-3 autoimmune disease, xv, 7, 11, 12, 95;
antibodies, 46, 58, 61; anticardiolipin, causes of, 220; testing for, 97, 110-
198-99; antimitochondrial, 75, 137; 12; theories of, 18, 20-23; women
antineurophil cytoplasmic (ANCA), and, 19. See also specific condition
91; antiphospholipid, 85, 86-87,198- Autoimmune Diseases Research Plan, 220
99; and congenital heart block, 76- autonomic nervous system, 38
77. See also antinuclear antibodies Ayurvedic medicine, 182-83
(ANAs); autoantibodies azathioprine, 70, 75, 90, 132, 144
antidepressants, 45, 107, 164
antidiuretic hormone (ADH), 133-34
anti-DNA (anti-double-stranded DNA), 85 bacteria: and saliva, 17, 61; and tooth de-
antihistamines, 32, 107 cay, 61, 62, 123

259
INDEX
260

bacterial infections, 21-22, 28, 46, 69, lergies, 194; immunizations, 200-201;
108 osteoporosis, 131, 138, 161, 194-95.
Bandura, Albert, 173 See also infections; thyroid disease
basal tears, 15-16 complementary and alternative medicine
biofeedback, 158 (CAM), 175-85; accupuncture, 126,
bisphosphonates, 138, 195 182, 185; Ayurvedic medicine, 182-
bladder inflammation. See interstitial 83; diet and diet therapies, 176-81;
cystitis herbal medications, 180-81, 182-83,
blepharitis (eyelid inflammation), 46, 50, 185; yoga, 184
118 congenital heart block, 76-77, 196-98
blinking, 16, 120 conjunctiva, 41, 42
Bloch, Kurt, 4 conjunctiva! impression cytology, 50
blood clotting, 87, 133, 138-39, 198-99 conjunctivitis, 50
blood tests, 98-103, 110, 187; abnormali- connective tissue diseases, 81-96, 100; an-
ties (serologies), 112; acute phase re- tiphospholipid antibody syndrome
actants, 98-99; antinuclear antibod- (APS), 86-87, 198-200; and autoim-
ies, 101-2; autoantibodies, 101-3; mune disorders, 95; mixed, 90-91,
cryoglobulins, 99; hematologic tests, 102; scleroderma, xv, 87-88, 93, 94,
98-99; immunodiffusion tests, 197; 95, 100; and secondary Sjogren's, 92-
for kidney disease, 135; rheumatoid 93; symptoms, 81; undifferentiated,
factor, 100-101 91-92, 212. See also rheumatoid ar-
B lymphocytes, 7, 25, 26, 53 thritis; vasculitis
body-mind connection, 174, 184 coping approaches, 167-70; exercise, 146,
borage seed oil, 181 148, 149, 169-70; psychotherapy, 78,
bosentan, 71, 133, 142 156, 157-58, 168-69
brain disease, 78, 212 cornea, 16, 17, 19, 41, 42-43, 46. See
bromelain, 178 also dry eye
bromhexine, 127, 130 corticosteroids, 71, 134, 144, 193; and
bronchoscopy, 70 aging, 201, 202; and interstitial lung
Bunim, Joseph, 4 disease, 70, 131-32, 143; and osteo-
Buyon, Jill, 198 porosis, 131, 194
coughing, 37, 56
cranial nerves, 39, 77
caffeine, 148, 150, 153 CREST (scleroderma) syndrome, 87, 94,
calcium channel blockers, 89, 136 95
Caiman and colleagues, 104 cryoglobulinemia, 72, 91, 99, 101, 135,
candidiasis, 63-64, 121, 124, 141, 194. 141
See also yeast infections cryoglobulins, 99, 101, 135, 216
carcinoma, 27. See also lymphoma cure, research for, 219-21
cardiac catherization, 71 cyanocobalamin, 137
cardiolipin, antibodies to, 198-99 cyclophosphamide, 70, 132, 141; and
cariogenic bacteria. See dental caries glomerulonephritis, 72, 134-35
carpal tunnel syndrome, 78, 79-80, 184 cyclosporine, 119, 132, 143
Castleman, Benjamin, 3 cytokines, 18, 19, 25, 53
central nervous system, 12, 86, 212
cevimeline (Evoxac), 127, 136, 142
chemotherapy, 60 Darlington and colleagues, 177
cholesterol, 139 deconditioning, 146, 169, 170. See also
cholestyramine, 75 exercise
Chopra and colleagues, 183 dehydroepiandrosterone (DHEA), 178-
chronic active hepatitis (CAH), 75 79
cirrhosis. See primary biliary cirrhosis dental caries (tooth decay), 61, 62-63,
(PBC) 121, 123-24, 126
clinical trials, 127-28, 183, 187-90, 192; dental disease, xvi, 45
double-blinding in, 191; informed depression, 6, 40, 51, 60, 78, 107; coping
consent in, 187-88, 190 with, 168-69; and fatigue, 146; and
cognitive-behavioral therapy, 169 fibromyalgia, 110; and loss, 163;
colchicine, 139 management of, 162-64
collagen type II, 178 dermatomyositis, 89-90
collagen vascular diseases. See connective devil's claw, 181
tissue diseases diabetes, 109; mellitus, 7, 60; nephro-
communication, 170-73 genic, 72, 133, 134
comorbidities, 193-203; aging, 202-2; al- diagnosis, xvi, 11; differential, 106-12; of
 INDEX
261

dry eye, 115-16; of dry mouth, 65- endothelin-1, 133

67 environmental agents, 32, 106-8, 120
diagnostic criteria, 97, 186 enzymes, 46, 48, 52, 74
diet and dietary therapies, 176-80; dietary epoprostenol (prostacycline), 71, 132
fatty acids, 119, 179; elemental or Epstein-Barr virus (EBV), 21, 29
hypoallergenic, 178; elimination or erythrematosus candidiasis, 124. See also
exclusion, 177-78; fasting, 177; sug- candidiasis; yeast infections
ary foods, 123-24; supplements, 178; erythrocyte sedimentation rate (ESR), 98,
vitamins and nutrition, 179. See also 187
nutrition esophageal dysmotility, 73, 79, 136, 142
differential diagnosis, 106-12; and envi- esophagitis, 73, 136, 142
ronmental factors, 106-8 estrogen, 19, 28, 141, 195, 203
diffuse infiltrative lymphocytosis syndrome etanercept, 128
(OILS), 108, 109 evening primrose oil, 180-81
digestion aid, 61. See also reflux exercise, 146, 148, 149, 161, 169-70
disability and work, 207-14; definitions, exocrine glands, 15, 22, 23, 73; lympho-
207; labor standards, 213; Social Se- cytes in, 18, 20. See also lacrimal
curity guidelines, 208-12; vocational glands; salivary glands
rehabilitation, 214 eyelid inflammation (blepharitis), 46, 50 ,
discomfort, 43, 51. See also pain 118
diuretics, in kidney disease, 72, 133-34 eye symptoms, 5, 140. See also dry eye
drug development and testing, 186-92; (keratoconjunctivitis sicca)
clinical trials, 127-28, 183, 187-90;
efficacy of, 190; FDA approval, 119,
189, 191, 192; phases of, 190-92 fatigue, 6, 145-50, 160, 164-66; and de-
drug side effects. See side effects, drug hydration, 152-53; and fibromyalgia,
dry eye (keratoconjunctivitis sicca, KCS), 110-11; management training, 146;
3, 8, 27, 41-52, 93; clinical exam, 45- and nutrition, 150, 151-52; patterns
46; conditions that mimic, 50-51; eye and causes of, 109-10, 146; sleep
surface changes in, 41-43; functional and, 147-49; and viral infections, 21;
circuit in, 30-32; as impairment, 211; and work, 213. See also chronic fa-
laboratory tests for, 49-50, 102; pre- tigue syndrome (CFS)
sentation in, 43-45; product listing fetal injury, 77, 196-200
for, 239-43; tear film, 16-17, 41, 42, fibromyalgia, 31, 110-11,156, 167, 182;
43; tear secretion tests, 46-49; treat- and fatigue, 146, 150
ment for, 115-20. See also lacrimal filamentary keratitis, 46
glands; tears fish oil, 119, 179
dry mouth (xerostoma), 28, 30-32, 58-67; flaxseed oil, 119, 179
causes of, 58-60; clinical trials for, fluorescein staining, 48, 116
127-28; diagnostic testing of, 65-67; fluoride, 124
functions of saliva, 60-61; oral prob- Food and Drug Administration (FDA),
lems caused by, 61-65, 121-22; pre- 119, 189, 191, 192
vention of complications in, 123-24; functional circuit, 30-32
product listing for, 243-46; salivary fungal infection, 63-64, 121, 124; treat-
function therapies for, 125-28; symp- ment of, 141, 143
toms, 8, 30-31, 62; systemic thera-
pies for, 126-28; treatment of, 121-
29. See also salivary glands Garfinkel and colleagues, 184
dryness (sicca symptoms), 5-6, 7, 92, 175; gastritis, atrophic, 73-74, 137
autoimmune theories, 20-23; causes gastroesophageal reflux disease (GERD),
of, 15-23; environmental, 106-8; the- 88, 136. See also acid reflux
ory of development, 18-23 gastrointestinal tract, 38, 73-74, 94; ther-
dysphagia. See swallowing difficulties apies for, 135-37
genetics, 12, 22-23, 24-25, 32
ginger, 178
ears, 55-56, 211 gingivitis (gum disease), 45, 64
echocardiogram, 198 GLA (gamma-linoleic acid), 180-81
electrolyte imbalance, 38-39. See also po- glomerulonephritis, 68, 86, 216; treatment
tassium levels of, 72, 134, 135, 143
ELISA (enzyme-linked immunosorbent as- "glove and stocking" pattern, 77
say), 49, 197 Gourgerot, Henri, 3
endocrine disorders, 109 Grave's disease, 39-40, 103. See also
endoscopy, 73 hypothyroidism
INDEX
262

guanifenisen, 56, 57 fungal, 63-64, 121, 124, 141, 143;

gynecologic considerations: products for, nasal, 54, 55; viral, 20-21, 22, 27-
248; vaginal secretions, 45, 141; vagi- 29. See also bacterial infections
nal symptoms, 40, 143, 202-3. See inflammation, 6, 18; ear, 56; kidney, 72;
also women of lacrimal glands, 7, 45; systemic re-
action, 98; and viral infections, 21.
See also specific disorders
Hadden, W. B., 3 inflammatory bowel disease, 219-20
halitosis (bad breath), 64 infliximab, 128
handicap, 207. See also disability and informed-consent documents, 187-88, 190
work institutional review boards (IRBs), 188,
Hashimoto's thyroiditis, 82, 103 190, 192
health care professionals, 172 interferon-alpha (IFN-alpha), 127-28
Health Insurance Portability and Account- internal organs, 68-80; gastrointestinal
ability Act (2003), 192 tract, 38, 73-74, 94, 135-37; nervous
hearing loss, 55-56, 211 system, 23, 38, 77-78; respiratory
heart problems, 75-77, 144; congenital, tract, 69-71, 94, 130-33, 211. See
196-98; pericarditis, 76, 85, 88, 141 also heart problems; kidney problems;
Heliobacter pylori, 21-22 liver disease; lung disease
hematologic alterations, 99-100 international classification criteria, 7-9,
hepatitis C virus, 20, 29, 60, 109; and 186
cryoglobulinemia, 99, 101 interpersonal therapy, 169
hepatitis virus, 4, 38, 74, 75 interstitial cystitis, 39, 72, 134
herbal medications, 180-83 interstitial lung disease (ILD), 69-71, 131-
hives (uriticaria), 37 32, 142, 143
HIV (human immunodeficiency virus), 4, interstitial nephritis, 68, 71, 79, 86
20, 29, 60, 108, 109 interstitial pneumonitis, 37
homocystine, 201-2 itching (pruritis), 38, 50, 75, 137-38, 142
hormones, 11, 19, 28, 103^; ADH, 133-
34; estrogen, 19, 28, 141, 195, 203;
replacement therapy, 19, 107; thyroid- jaundice, 38, 74
stimulating, 139 Johansson and colleagues, 184
HRCT (high-resolution computed tomog- joint inflammation, 82-83. See also fibro-
raphy) scans, 70 myalgia; osteoarthritis; rheumatoid
human histocompatible antigen (HHA), arthritis
24-25
human leukocyte antigen (HLA), 12, 22
human lymphotrophic leukemia virus keratoconjunctivitis sicca (KCS). See dry
(HTLV-1), 20, 29 eye
humidification, 55, 122-23, 131, 248 kidney problems, 88, 133-35; glomerulo-
hydration, 122, 131, 152-53, 155-56 nephritis, 68, 72, 86, 134, 135, 143,
hypersensitivity, 151, 153 216; interstitial nephritis, 68, 71, 79,
hypokalemia, 38-39. See also potassium 86; lupus nephritis, 85-86; and
levels potassium levels, 38-39, 71-72, 133;
hypopharynx, 54 renal tubular acidosis, 71-72, 142
hypothyroidism, 39-40, 103, 139, 143 Kulkami and colleagues, 183

ICA-69 (self-antigen), 22-23 labial salivary gland biopsy (LSG), 104-5.

immune system, 32, 210, 212 See also lip biopsy
immunizations, 200-201 laboratory tests, 49-50, 97-103. See also
immunodiffusion tests, 197 blood tests
immunoglobulins, 27, 36, 52, 77, 101, labor standards. See work and disability
216; and allegies, 194. See also lacrimal glands, 19, 28, 30, 46; inflamma-
antibodies tion of, 7, 45; tear production in, 15-
immunomodulators, 141, 143 17, 44-45. See also dry eye; tears
immunosuppressants, 79, 193. See also lanryngotracheobronchitis, 69, 130
azathioprine; corticosteroids larynx (voice box), 56
impairment, 207, 210. See also disability late sequelae, 215-18
and work Leber, Theodor, 3
incidence of Sjogren's, 10, 189 lip biopsy, 31, 67, 81, 104-5, 112
incontinence, 201 lipid layer, 17
infections, 20-22, 61, 108-9, 193-94; List and colleagues, 185
 INDEX
263

liver disease, 27, 74-75; primary biliary nausea, 38, 130, 132
cirrhosis (PBC), 38, 74, 75, 79, 94, neonatal lupus syndrome, 102, 196, 197,
111-12, 137-40, 143; therapies for, 198
137-40 nephritis. See kidney problems
Longo Vital, 185 nephrogenic diabetes insipidus, 72, 133,
lung disease, 37, 68, 69-71, 79, 85, 131- 134
33; pulmonary hypertension (PHT), nerve destruction, 18-19
70-71, 132-33, 142 nerve problems, 39
lupus. See systemic lupus erythematosus nervous system, 23, 38, 77-78
(ELS) neuropathy: peripheral, 39, 77, 79-80, 92,
lupus nephritis, 85-86 141, 212; sensory, 77; trigeminal, 39,
lyme vaccine, 201 78
lymph node swelling (adenopathy), 12, 21, neurotransmitters, 30, 102
92, 111 nicotine, 148, 154
lymphocytes, 18, 30, 37, 58, 68, 70; and nitroglycerine, 73, 136, 142
apoptosis, 20; B and T, 7, 25-26, 53; nose. See under nasal
testing for, 103, 104 NSAIDs (nonsteroidal anti-inflammatory
lymphoma, 12, 39, 65, 216-18; and hepa- drugs), 131-32,134, 140, 180, 193
titis, 4, 109 nutrition, 119, 151-53, 179; and fatigue,
lysozyme (enzyme), 49, 52 146, 150, 151-52. See also diet and
dietary therapies
magnetic resonance imaging (MRI), 66
management of Sjogren's, 159-74; and an- occupational therapy, 157
ger, 160-62; coping strategies for, 167- ocular exam, 45-46
70; and depression, 162-64; and fa- ocular lubricants, 118
tigue, 164-66; and pain, 166-67,174; ocular symptoms. See dry eye (keratocon-
patient history of, 159-60; self- junctivitis sicca)
efficacy, 173-74; and sleep needs, ocular tests, 8
161, 163 omega fatty acids, 119, 179
medications: for dry eye, 44-45; and in- oral examination, 65
somnia, 148; sleep, 149-50. See also oral functional problems, 64
drugs; side effects, drug oral hygiene, 63, 64, 123-24
medium chain triglycerides (MCTs), 138 oral moisturizers, 243. See also hydration
Meibomian glands, 45, 46, 118 oral mucosa, 61, 65, 121, 122, 124
melatonin, 149 oral symptoms, 8, 28, 30, 187. See also
meningococcal vaccine, 200-201 dry mouth (xerostoma)
metabolic disorders, 109-10. See also dia- oral tests, 8
betes; thyroid osteoarthritis, 146, 178, 180, 181, 184;
Mikulicz's syndrome, 3 and acupuncture, 182
milk, 131, 154 osteoporosis, 131, 138, 161, 194-95
mind-body connection, 174, 184
mixed connective tissue disease, 90-91,
102 pain: in dry eyes, 44; management of,
mononeuritis, 77, 80, 92 156, 166-67, 174, 180; musculoskele-
mononucleosis, 21 tal, 110
Morgan, William, 3 pancreatitis, 38, 74, 137
mouth dryness. See dry mouth; oral Panush and colleagues, 176, 177
symptoms parotitis, 108, 111, 141, 143
mucolytic agents, 69, 130 pathogenesis, 25-27, 29
mucosa-associated lymphoid tissue patient-doctor communication, 172-73
(MALT) lyrnphoma, 217 patients, informed consent of, 187-88,
mucous layer, 17 190
mucus gland dysfunction, 37 patient story, 159-60
multiple sclerosis, 39 PBC. See primary biliary cirrhosis
musculoskeletal impairments, xvi, 211 People with Arthritis Can Exercise
musculoskeletal pain, 110 (PACE), 170
myosotis, 89-90 pericarditis, 76, 85, 88,141
periodontal disease, 45, 64. See also den-
tal caries; gingivitis
nasal problems, 52-55, 69, 246 peripheral neuropathy, 39, 77, 79-80, 92,
National Institutes of Health, xv, 167, 141, 212
220 pernicious anemia, 74, 79, 137, 142
INDEX
264

phospholipids, 85, 86-87, 199 St. John's wort (Hypericum perforatum),

physical therapy, 156-57, 170 164
phytodolor, 180, 181 salbutamol (albuterol), 131, 142
pilocarpine, 3, 126-27, 135-36, 142 saline replacement, 55
placebos, 126, 128, 183, 191 salinum, 184-85
plant seed oils, 119, 179, 180-81 saliva, 5, 60-61, 63, 123; drugs to stimu-
plasmapheresis, 77, 135, 139, 141 late secretion of, 135-36, 243
pleurisy, 70 salivary glands, 17-18, 28, 45, 52-57,
pneumonia, 37 62; biopsy of, 32, 67, 81, 104-5,
polymyositis, 89-90 112; dysfunction of, 58-59, 122, 124;
portal hypertension (PHT), 139 EBV dormancy in, 21; enlargement
potassium levels, 38-39, 71-72, 133, 137 of, 7, 12, 65, 92, 108; function of, 30;
prednisone, 131, 132 repair of alterations in, 128, 129;
pregnancy, 77, 196-200 scintigraphy, 66, 105; stimulation
prevalence of Sjogren's, 10, 189 therapies for, 125-28. See also dry
primary biliary cirrhosis (PBC), 38, 74, mouth
75, 94, 111-12; treatment for, 79, sarcodosis, 60, 111
137-40, 143 Schirmer test, 46-47, 106, 116, 187
primary Sjogren's, 6, 11-12 scientific review, 192. See also clinical
prolactin (hormone), 103 trials
protein RNA complexes, 7 scintigraphy, 66, 105
pruritis (itching), 38, 50, 75, 137-38, 142 scleroderma, xv, 87-88, 93, 100; CREST
psychotherapy, 78, 156, 157-58, 168-69 variant, 87, 94, 95
pulmonary hypertension (PHT), 70-71, secondary Sjogren's, 6, 82, 92-93, 100,
132-133, 142 112. See also connective tissue diseases
purpura, 36, 92, 215-16 secretogogue, 93, 129
self-antigen, 22-23
self-management, 145
radiation therapy, 60 sensory neuropathy, 77
Ramos-Casals and colleagues, 99 serotonin, 154, 155
Random House Dictionary, 5 sex hormones, 19, 103. See also estrogen
Raynaud's phenomenon, 11, 37, 82, 88, sexual dysfunction, 45
89, 155, 179 shark cartilage, 178
reflex tears, 15-16 sialochemistry, 67. See also saliva
reflux, gastro-esophageal, 38, 73, 79, 88, sialography, 66
136, 142, 249 sialometry, 65-66, 105
rehabilitation professionals and services, sicca symptoms. See dry eye; dry mouth;
156-58 dryness (sicca symptoms)
Reifman and colleagues, 104 side effects, drug, 32, 58, 59, 136, 164;
renal colic, 39. See also kidney disease antimalarials, 140—41; in dry mouth
renal tubular acidosis (RTA), 71-72, 142 therapy, 127, 129; dryness as, 19, 59,
reproductive issues, 196-200 107-8; herbal, 180-81; in respiratory
research and cure, 219-21. See also clini- therapy, 131-33
cal trials signs and symptoms, xvi, 5-6, 35-40; air-
respiratory tract, 69-71, 94, 130-33, 211 way problems, 37; arthritis, 37-38;
retroviruses, 29; HIV, 8, 20, 29, 60, 108, drugs in treatment of, 142; dry
109 mouth, 62, 65; gastrointestinal, 38;
Rheumatic Disease Clinics of North kidney problems, 38-39; Raynaud's
America, 176 phenomenon, 11, 37, 82, 88, 89, 155,
rheumatoid arthritis (RA), xv, 7, 82-83, 179; skin problems, 35-37. See also
175, 183; and acupuncture, 182; di- dry eye; dry mouth; dryness
etary supplements for, 178, 179; dry sinuses, 52, 54
eye in, 43; and fasting, 177; and fa- Sjogren, Henrik, 3- 4, 5, 6, 38
tigue, 146; and lupus, 86; and peri- Sjogren's Syndrome Foundation (SSF), xv,
carditis, 76; and secondary Sjogren's, 8, 10, 93, 171; addresses for, 232;
6, 37-38, 70, 83, 94, 100, 193; test- and Social Security, 210; survey by,
ing for, 101; TNF-alpha blockers to 164, 165, 166
treat, 128 skin problems, 35-37, 87-90, 212, 246-
rheumatoid factor (RF), 100-101 48; dermatomyositis, 89-90; itching
rheumatologic disorders: See osteoarthritis; (pruritis), 38, 50, 75, 137-38, 140,
rheumatoid arthritis; scleroderma; 142; and lupus, 84-85; in neonates,
fibromyalgia 196-97; scleroderma, xv, 87-88, 93,
rose bengal staining, 3, 31, 47, 105 94, 95, 100. See also vasculitis
 INDEX
265

SLE. See systemic lupus erythematosus Hashimoto's, 82, 103; hypothyroid-

sleep, 44, 146, 147-53, 163; and fatigue, ism, 39-40, 103, 139, 143
147-49; and food, 150, 151-53, 154; T lymphocytes, 7, 25-26, 53
medications, 149-50; restorative vs. TNF-alpha blockers, 128
nonrestorative, 110, 147-48 tongue, 63. See also dry mouth
sleep apnea, 149 tooth decay (dental caries), 61, 62-63,
smoke/smoking, 44, 148, 154 121, 123-24, 126
Social Security disability, 208-12 tracheobronchitis, 69, 131
SSDI. See Social Security disability treatment, 115-29; for dry eye, 115-20;
Stedman's Medical Dictionary, 5 for dry mouth, 121-29. See also sys-
steroids, 55, 79-80, 90, 131-32, 200; in temic therapies; specific treatments
treating vasculitis, 77, 80. See also trigeminal neuropathy, 39, 78
corticosteroids
stomatopyrosis, 63
stress management, 154-55 ultrasound, 66
sugary foods, 62, 123-24, 150 undifferentiated connective tissue disease,
Supplemental Security Income (SSI), 209 212
swallowing difficulties, 38, 64, 65, 88, 89, ursodeoxycholicacid (UDCA), 75,138,139
122; and esophageal dysmotility, 73,
79
symptoms. See dry eye; dry mouth; signs vaccines, 200-201
and symptoms vaginal dryness, products for, 248
syndrome, defined, 5 vaginal secretions, 45,141
systemic lupus erythematosus (SLE), xv, 6, vaginal symptoms, 40, 143, 202-3
70, 84-86, 95, 175; antibodies in, 7, vasculitis, 68, 72, 91-92, 94; cutaneous,
94; and anti-nuclear antibodies, 26, 99; as impairment, 212; and mono-
84, 85, 102; and APS syndrome, 87, neuritis, 77, 80, 92; and purpura, 36,
199; and DHEA, 178; and fatigue, 215-16
146; as impairment, 212; and kidney vasodilators, 132
disease, 72, 85-86, 134; neonatal, viral infections, 20-21, 22, 27-29. See
102, 196, 197, 198; and pericarditis, also hepatitis; HIV
76, 85; and secondary Sjongren's, 193; visual impairment, 44, 211. See also dry
testing for, 100 eye
systemic therapies, 130-44; dry mouth, vitamins, 75, 138-39,143, 152, 179; B12,
126-28; gastrointestinal tract, 135- 74, 79, 140
37; heart, 141, 144; kidneys, 133- vocational rehabilitation, 214
35; liver, 137-40; overview of drugs
in, 142-43; respiratory tract, 130- warfarin, 181
33 wellness approach, 145
willow bark extact, 181
women, 12, 19; and gynecologic con-
Talal, Norman, 4 siderations, 40, 45, 141, 143, 202-3,
taste buds, 61 248; hormonal influences on, 11, 19,
tear breakup time (TBUT) tests, 48-49, 28
116, 187 work and disability, 207-14; definitions,
tear film, 16-17, 43, 44; layers in, 17, 41, 207; labor standards, 213; Social Se-
42 curity guidelines, 208-12; vocational
tears: artificial, 116,117-18, 239-40; lac- rehabilitation, 214
toferrin in, 49; lysozyme in, 49, 52; workers' compensation, 209
osmolarity test, 49; production of, 15-
17, 44—45; protein analysis in, 49-50;
secretion tests for, 46-49. See also dry xanthelasmas/xanthomas, 139
eye; lacrimal glands xerostoma. See dry mouth
teriparatide, 195 x-ray images, 66
testing. See blood tests; clinical trials; di-
agnostic tests; drug tests; laboratory
tests yeast infections, 194, 202-3. See also
theory of development, 18-23 candidiasis
thyroid disorders, 12, 45, 110, 139, 202; yoga, 184