AUA - SEMESTER 3

Immune Arthritis

May, 2010

Nicholas R. Sinclair, MD PhD

 Rheumatologic Disease
• Prominent Arthritic Problems
– Rheumatoid Arthritis, Psoriatic Arthritis,
Arthritis with GI disease, Ankylosing
Spondylitis, Reactive Arthritis &
Undifferentiated Spondyloarthropathies,
Lyme Disease, Non-Immune arthritis with
Immunologic Influences
• Prominent Anti-Nuclear Immune
Responses, such as SLE
• Prominent Muscle & Vascular Problems
Prominent Arthritic Forms of
Rheumatologic Disease
• Rheumatoid Arthritis
• Psoriatic Arthritis
• Arthritis with GI disease (IBD, intestinal bypass,
intestinal lipodystrophy)
• Ankylosing Spondylitis
• Reactive Arthritis & Undifferentiated
Spondyloarthropathies
• Lyme Disease (untreated chronic stage)
• Non-Immune arthritis with Immunologic
Influences
 Rheumatoid Arthritis
• Unknown Cause – Many Possibilities
• Multisystemic Disease – Variable Course
• Persistent Inflammatory Synovitis
• Cartilage Destruction & Bone Erosion
• Incidence – 1% with Familial Trends
– 20% concordance in monozygotic twins
• Women & Increased Age (both Sexes)
• HLA DR4 (DRB*0401) & related genes
• Other HLA-DR genes – add or protect
• HLA-DQ also important
Figure 13.1. Four types of hypersensitivity reaction are mediated by
immunological mechanisms that cause tissue damage

Figure 13.1. Four types of

hypersensitivity reaction

Rheumatoid Arthritis is a mix of Types II/III & Type IV

Types of Autoimmune Disease
• Organ-specific autoimmune
diseases, antigenic target is
restricted to certain tissues.
Diseases are managed by
physicians that specialize
that particular organ.
• Systemic autoimmune
diseases, antigenic target is
widely spread (produced in
or distributed to).
Rheumatologists look after
these diseases.
Etiology of Rheumatoid Arthritis
• Unknown – Chronic Infection in Susceptibles
• Mycoplasma, Epstein-Barr virus (EBV),
cytomegalovirus, parvovirus, and rubella virus
• Agent antigen accumulated in joints
• Adjuvant microbes induce autoimmune
response
• Reactivity to collagen II & heat shock proteins
• Molecular mimicry (?) – similarity with DR4
• Superantigens – HLA-DR & TCR ligation
• Peptidylarginine deiminase & citrullination
• Only proven environmental risk factor –
smoking
• Coffee & tea – not risk factors in recent trial
 Rheumatoid
Arthritis Was
New to Europe
in the ~1600’s
but Not to the
Americas:
Suggests an
Environmental
Trigger
 Figure 78-1 Pathogenetic events in
Figure 78-1 rheumatoid arthritis
Pathogenetic
events in
rheumatoid
arthritis. The
proliferative
synovial
pannus
invades at
the bone-
cartilage Cecil
interface Essentials
of Medicine
2004
 Table 78-1. Pathogenesis of Rheumatoid Arthritis
Tissue Phase Fluid Phase
Immune cell localization to synovial Immune complexes in synovial fluid
tissue
Complement activation and release of
T- and B-cell and monocyte recruitment C3a, C5a
T-cell activation and proliferation and Neutrophil recruitment and activation
cytokine release
Release of prostaglandins,
B-cell elaboration of rheumatoid factor leukotrienes, and reactive oxygen
and other antibodies species
Monocyte elaboration of inflammatory Release of lysosomal enzymes
cytokines: IL-1, TNF-α, IL-6
Vasodilation, development of joint
Synovial cell proliferation and activation effusions, pain, and swelling
by IL-1 and TNF-α
Superficial cartilage erosions
Release of inflammatory eicosanoids
(PGE2) Cecil
Synthesis of collagenase and other Essentials
matrix metalloproteinases of Medicine
Erosions of bone and cartilage IL-1 = interleukin-1 2004
IL-6 = interleukin-6
Osteoclast and chondrocyte activation PGE2 = prostaglandin E2
Release of proteases TNF-α = tumor necrosis factor-α.

Resorption of bone and cartilage

Figure 14.28 The pathogenesis of rheumatoid arthritis
 Figure 314-2
The progression of rheumatoid synovitis.
Table 278-1. HLA ASSOCIATIONS WITH RHEUMATOID ARTHRITIS
THIRD
HLA TYPES (ALLELES) HYPERVARIABLE
AND METHODS OF REGION AMINO ACID
DETECTION SEQUENCES
AlloAb MLC DNA
(DR) (Dw) (DRB1) 70 71 72 73 74 ETHNIC GROUPS
Associ- DR4 Dw4 *0401 Q K R A A Whites (west Europe)
ated
with RA DR4 Dw14 *0404
• R
• • • Whites (west Europe)

DR4 Dw15 *0405

• R
• • • Japanese, Chinese

DR1 Dw1 *0101

• R
• • • Asian Indians, Israelis

DR6 (14) Dw16 *1402

• R
• • • Yakima Native
Americans
DR10 - *1001 R R
• • • Spanish, Greeks,
Israelis
Not
associ-
DR4 Dw10 *0402 D E
• • • Whites (East Europe)

ated DR4 Dw13 *0403

• R
• • E Polynesians
with RA Cecil’s
DR2 Dw2 *1501 D A
• • • Whites
Textbook
Medicine
DR3 Dw3 *0301
• • • G R Whites
2005
Figure 5.18. Allelic variation occurs at specific sites within MHC molecules
 Figure 278-1 Rheumatoid arthritis (RA): Initiation

Figure 278-1 Rheumatoid

arthritis (RA): Initiation.

Cecil’s
Textbook
Medicine
2005
 Figure 278-2 Events involved in the pathogenesis
of rheumatoid synovitis progress

Cecil’s
Figure 278-2 Events involved in the pathogenesis of rheumatoid Textbook
synovitis progress from left to right Medicine
2005
 Figure 278-3
Figure 278-3 The joint distribution of the
two most common forms of arthritis-
The joint
rheumatoid arthritis and osteoarthritis distribution of
the two most
common forms
of arthritis -
rheumatoid
arthritis and
osteoarthritis -
Cecil’s are compared
Textbook and contrasted
Medicine
2005
Table 314-1 The 1987 Revised Criteria for the Classification of RA
1. Guidelines for classification
a. 4/7 criteria are required to classify a patient as having rheumatoid arthritis (RA).
b. Patients with two or more clinical diagnoses are not excluded.
2. Criteriaa
a. Morning stiffness: Stiffness in/around the joints lasting 1 h before maximal
improvement.
b. Arthritis of three or more joint areas: At least three joint areas, observed by a
physician simultaneously, have soft tissue swelling or joint effusions, not just bony
overgrowth. The 14 possible joint areas involved are right or left proximal
interphalangeal, metacarpophalangeal, wrist, elbow, knee, ankle, and
metatarsophalangeal joints.
c. Arthritis of hand joints: Arthritis of wrist, metacarpophalangeal joint, or proximal
interphalangeal joint.
d. Symmetric arthritis: Simultaneous involvement of same joint areas on both sides of
body.
e. Rheumatoid nodules: Subcutaneous nodules over bony prominences, extensor
surfaces, or juxtaarticular regions observed by a physician.
f. Serum rheumatoid factor: Demonstration of abnormal amounts of serum rheumatoid
factor by any method for which is positive in less than 5% of normal control subjects.
g. Radiographic changes: Typical changes of RA on posteroanterior hand and wrist
radiographs that must include erosions or unequivocal bony decalcification localized in
or most marked adjacent to the involved joints.
aCriteria a–d must be present for at least 6 weeks. Criteria b–e must be observed by a physician.
Table 278-3. DIFFERENTIAL DIAGNOSIS OF RHEUMATOID ARTHRITIS
DISORDER SUBCUTANEOUS RHEUMATOID
NODULES FACTOR
Viral arthritis (hepatitis B and C, - +/-
parvovirus, rubella, others)
Bacterial endocarditis +/- +
Rheumatic fever + -
Sarcoidosis + +
Reactive arthritis - -
Psoriatic arthritis - -
Systemic lupus erythematosus +/- +
Primary Sjögren's syndrome - +
Chronic tophus gout + -
Calcium pyrophosphate disease - -
Cecil’s
Polymyalgia rheumatica Textbook - -
Osteoarthritis (erosive) Medicine - -
2005
 Figure 278-4 Early rheumatoid arthritis

Cecil’s
Textbook
Medicine
2005

Figure 278-4 Early rheumatoid arthritis manifested as soft tissue swelling of the proximal
interphalangeal and metacarpophalangeal joints of the hand
 Cecil’s
Textbook
Figure 278-5 Severe advanced rheumatoid arthritis of the hands
Medicine
2005
 Cecil’s
Textbook
Medicine
2005

Figure 278-7 Radiographs of the knees in the two most common forms of arthritis -
rheumatoid arthritis and osteoarthritis
 Cecil’s
Textbook
Medicine
2005

Figure 278-8 Arthrogram with

a radiocontrast agent injected
into the knee - a large
synovial cyst (Baker's [British
surgeon] cyst)
Figure 278-9 Lateral
radiograph of the
cervical spine in
patients with
rheumatoid arthritis

Cecil’s
Textbook
Medicine
2005
 Lateral pathologic
specimen of the
cervical spine in
rheumatoid arthritis

Cecil’s
Textbook
Medicine
2005
 Cecil’s
Textbook
Figure 278-10 Rheumatoid nodules Medicine
2005
 Cecil’s
Textbook
Medicine
Figure 278-11 Rheumatoid nodulosis 2005
Figure 278-12 Rheumatoid vasculitis with small brown infarcts of
palms and fingers in chronic rheumatoid arthritis
Cecil’s
Textbook
Medicine
2005
 Cecil’s
Textbook
Medicine
Figure 278-13 Chest radiograph demonstrates discrete rheumatoid nodules 2005
Table 278-4. EXTRA-ARTICULAR MANIFESTATIONS OF RA
SITE MANIFESTATIONS
Skin Nodules, fragility, vasculitis, pyoderma gangrenosum
Heart Pericarditis, premature atherosclerosis, vasculitis,
valvular, and valve ring nodules
Lung Pleural effusions, interstitial lung disease, bronchiolitis
obliterans, rheumatoid nodules, vasculitis
Eye Keratoconjunctivitis sicca, episcleritis, scleritis,
scleromalacia perforans, peripheral ulcerative
keratopathy
Neuro- Entrapment neuropathy, cervical myelopathy,
logic mononeuritis multiplex (vasculitis), peripheral
neuropathy
Hemato- Anemia, thrombocytosis, lymphadenopathy, Felty's
poietic syndrome Cecil’s
Kidney Amyloidosis, vasculitis Textbook
Medicine
Bone Osteopenia
2005
 Figure 1. Schematic view of a
normal joint and its changes in
rheumatoid arthritis

Damaging
Mechanisms
in
Rheumatoid
Arthritis
Rheumatoid Nodule
Rheumatoid Nodules
 Figure 278-s2
Rheumatoid arthritis.
Nodules over the small
joints of the hands.

Cecil’s
Textbook
Medicine
2005
 Rheumatoid Nodule

Fibrinoid Necrosis

Epitheloid Macrophages
Lymphocytes
Figure 20.9n Histologically, rheumatoid nodules consist of a central zone of necrotic
material including collagen fibrils, noncollagenous filaments, and cellular debris; a
midzone of palisading macrophages that express HLA-DR antigens; and an outer zone of
granulation tissue
 Cecil’s
Figure 278-s1 Rheumatoid nodule within the substance of the Textbook
synovial membrane Medicine
2005
Articular Table 78-2. Clinical
Morning stiffness, "gelling" Characteristics of
Symmetrical joint swelling Rheumatoid Arthritis
Predilection for wrists, proximal interphalangeal,
metacarpophalangeal, and metatarsophalangeal joints
Erosions of bone and cartilage
Joint subluxation and ulnar deviation
Inflammatory joint fluid
Carpal tunnel syndrome
Baker's cyst
Nonarticular
Rheumatoid nodules: subcutaneous, pulmonary, scleral Cecil
Essentials
Vasculitis, especially skin, peripheral nerves, and bowel of Medicine
Pleuropericarditis 2004
Scleritis and episcleritis
Leg ulcers
Felty's syndrome (splenomegaly, leukopenia, and recurrent pulmonary infections)
Rheumatoid Arthritis
Rheumatoid Arthritis

Pannus

Erosion
Rheumatoid Arthritis
Figure 1 Synovial histology in rheumatoid
arthritis.
 Rheumatoid Arthritis
Figure 20.9c These X-ray and histologic pictures show an erosion typical
of rheumatoid arthritis

Erosion

Erosion
 Rheumatoid Arthritis
Figure 20.9j This slide shows the production of IgM and of
rheumatoid factor (RF) in the synovium from a patient with
rheumatoid arthritis (RA).

IgM Producing Cells

RF Producing Cells
 Rheumatoid Arthritis Synovium
Figure 20.9 Rheumatoid synovium show a lot of CD4 T cells in the
presence of MHC-II bearing cells

MHC-II
CD4
 Other Complications of RA
• Rheumatoid vasculitis
• Pleuropulmonary manifestations
• Cardiac problems
• Neurologic manifestations
• Eye problems
• Felty's syndrome
• Osteoporosis
• Increased incidence of lymphoma,
especially large B cell lymphoma
• RA in the Elderly
Nonsteroidal Anti-inflammatory Drugs
Aspirin & Nonacetylated salicylates
Nonsalicylate nonselective prostaglandin inhibitors
Selective cyclooxygenase-2 inhibitors
Slow-Acting Antirheumatic Drugs
Methotrexate
Leflunomide
Hydroxychloroquine
Minocycline
Sulfasalazine Table 78-3. Treatment of
d-penicillamine
Injectable gold salts Rheumatoid Arthritis
Oral gold
Azathioprine
Cyclosporine
Biologic Agents
Etanercept (soluble TNF-α receptor) Cecil
Essentials
Infliximab (anti-TNF-α antibody)
of Medicine
Anakinra (IL-1 receptor antagonist) 2004
Therapy in Rheumatoid Arthritis
Therapy in Rheumatoid Arthritis
 Anti-TNFa Anti-TNFa Anti-TNFa

Figure 15-7 Anti-inflammatory effects of anti-TNF-α therapy in

rheumatoid arthritis
 Table 278-5. KEYS TO OPTIMIZE
OUTCOME OF RA TREATMENT
Early, accurate diagnosis
Early DMARD therapy
Strive for remission in all patients Cecil’s
Textbook
Monitor carefully for treatment toxicities Medicine
Consider and treat comorbid conditions* 2005

*Important comorbid conditions include cardiovascular disease,

increased susceptibility to infections, and osteoporosis.
 Table 278-6. GLUCOCORTICOID
GUIDELINES
Avoid use of glucocorticoids without DMARDs
Prednisone >10 mg/day rarely indicated for articular
disease
Taper to the lowest effective dose
Use as "bridge therapy" until DMARD therapy
effective
Remember prophylaxis against osteoporosis
Cecil’s
DMARD =disease-modifying antirheumatic drug Textbook
Medicine
2005
 Responses to rituximab treatment in
patients with rheumatoid arthritis

Responses to rituximab (αCD20) treatment in patients with

rheumatoid arthritis
 Figure 1 Interactions among BAFF, APRIL and their receptors APRIL-R,
BCMA, TACI and BAFF-R. The figure shows the possible interactions
among the TNF-superfamily members, BAFF and APRIL & their receptors

↑ activity
SLE, RA Interactions among BAFF,
Anti-BAFF Antibody
Sjogren’s APRIL and their receptors
APRIL-R, BCMA, TACI and LymphoStat-B
BAFF-R
Fusion Protein
BAFF-R/IgG-Fc
↓ activity
CVID
IgA def

APRIL, a proliferation-inducing ligand; APRIL-R, APRIL receptor;

BAFF, B-cell-activating factor; BAFF-R, BAFF receptor; BCMA, B-
cell maturation antigen; TACI, transmembrane activator and
calcium modulator and cyclophilin ligand (CAML) interactor
 Figure 314-3
Algorithm for
the medical
management
of rheumatoid
arthritis.
Prominent Arthritic Forms
of Rheumatologic Disease
• Rheumatoid Arthritis
• Psoriatic Arthritis
• Arthritis with GI disease (IBD, intestinal
bypass, intestinal lipodystrophy)
• Ankylosing Spondylitis
• Reactive Arthritis & Undifferentiated
Spondyloarthropathies
• Lyme Disease (untreated chronic stage)
• Non-Immune arthritis with Immunologic
Influences
 Figure 25-26 Clinical evolution
of psoriasis

FIGURE 25-26 Clinical evolution of psoriasis. A, Early and eruptive lesions

may be dominated by signs of inflammation, including small pustules and
erythema (left). Established, chronic lesions demonstrate erythema
surmounted by characteristic silver-white scale (right). B, Histologically,
established lesions demonstrate marked epidermal hyperplasia,
parakeratotic scale, and neutrophils within the superficial epidermal layers.
 Figure 318-3
Characteristic lesions of psoriatic arthritis. Inflammation is prominent in the DIP joints
(left 5th, 4th, 2nd; right 3rd and 5th) and PIP joints (left 2nd, right 2nd, 4th, and 5th).
There is dactylitis in the left 2nd finger and thumb, with pronounced telescoping of the
left 2nd finger. Nail dystrophy (hyperkeratosis and onycholysis) affects each of the
fingers except the left 3rd finger, the only finger without arthritis.
 Cecil’s
Textbook
Medicine
2005

Figure 279-s1 Psoriatic arthritis. Asymmetric involvement of the DIP and

PIP joints. A 'sausage' digit (third digit bilaterally) results from
involvement of both the DIP and PIP joints.
 Cecil’s
Textbook
Medicine
2005

Figure 279-7 Nail pitting, onycholysis, and transverse ridging in

psoriatic arthritis. Dactylitis of the second toe is present
 Prominent Arthritic Forms
of Rheumatologic Disease
• Rheumatoid Arthritis
• Reactive Arthritis & Undifferentiated
Spondyloarthropathies
• Ankylosing Spondylitis
• Psoriatic Arthritis
• Arthritis with GI disease (IBD, intestinal bypass,
intestinal lipodystrophy)
• Lyme Disease (untreated chronic stage)
• Non-Immune Arthritides with Immunologic
Influences
 Table 279-4. ENTEROPATHIC ARTHRITIS
SACROILIITIS,
FEATURE PERIPHERAL ARTHRITIS SPONDYLITIS
CROHN'S DISEASE AND ARTHRITIS
Frequency in CD 10-20% 2-7%
HLA-B27 associated No Yes
Pattern Transient, symmetrical Chronic
Course Related to activity of CD Unrelated to CD activity
Effect of surgery Remission of arthritis uncommon No effect
Effect of anti-TNF Effective Effective
therapy

ULCERATIVE COLITIS AND ARTHRITIS

Frequency in UC 5-10% 2-7%
HLA-B27 associated No Yes
Pattern Transient Chronic
Course (More common in pancolitis than Cecil’s
proctitis)
Textbook
Related to activity of UC Unrelated Medicine
Effect of surgery Remission of arthritis No effect 2005
 Prominent Arthritic Forms
of Rheumatologic Disease
• Rheumatoid Arthritis
• Reactive Arthritis & Undifferentiated
Spondyloarthropathies
• Ankylosing Spondylitis
• Psoriatic Arthritis
• Arthritis with GI disease (IBD, intestinal bypass,
intestinal lipodystrophy)
• Lyme Disease (untreated chronic stage)
• Non-Immune Arthritides with Immunologic
Influences
 Figure 318-1
Early sacroiliitis in a patient with AS, indicated by prominent sacral bone
marrow edema (asterisks) on a coronal oblique STIR (short tau inversion
recovery) magnetic resonance image.
Figure 318-2 Spinal inflammation (spondylodiscitis) in a patient with AS and its
dramatic response to treatment with infliximab. Gadolinium-enhanced T1-
weighted magnetic resonance images, with fat saturation, at baseline and after
24 weeks of infliximab therapy.
 Cecil
Essentials
of Medicine
2004

Figure 79-1 A, Bilaterally symmetrical sacroiliitis in ankylosing spondylitis

 Cecil
Essentials
of Medicine
2004

Figure 79-1 B, Lumbar spondylitis in ankylosing spondylitis with symmetrical, marginal

bridging syndesmophytes and calcification of the spinal ligament
 Figure 45.35 C,
Anteroposterior
radiograph of
lumbosacral
vertebral column in
a young adult male
aged 22 years
 Sacroiliitis on the left, with narrowing and
sclerosis of the sacroiliac joint

This radiograph of the pelvis demonstrates a sacroiliitis on the left,

with narrowing and sclerosis of the sacroiliac joint. The SI joint on
the right appears relatively normal by comparison.
Figure 279-4 A 34-year-old
male who had ankylosing
spondylitis for 9 years and
neck pain. Radiographs
demonstrate narrowing of
the C2-C3 apophyseal
joints posteriorly and
anterior bridging marginal
syndesmophytes
extending from C2 to C5

Cecil’s
Textbook
Medicine
2005
Prominent Arthritic Forms
of Rheumatologic Disease
• Rheumatoid Arthritis
• Psoriatic Arthritis
• Arthritis with GI disease (IBD, intestinal
bypass, intestinal lipodystrophy)
• Ankylosing Spondylitis
• Reactive Arthritis & Undifferentiated
Spondyloarthropathies
• Lyme Disease (untreated chronic stage)
• Non-Immune arthritis with Immunologic
Influences
 Reactive Arthritis (ReA) &
Undifferentiated
Spondyloarthropathies
• ReA is acute nonpurulent arthritis with
an infection elsewhere in the body
• Spondyloarthropathy with enteric
infections in genetically susceptible
people (B27)
• Triad of arthritis, urethritis &
conjunctivitis
• Without infection or triad –
undifferentiated spondyloarthopathy
Reiter Looks A Little Like Hitler
 Reactive Arthritis
• HLA-B27 60-85%; ReA in 20% of exposed
B27; AS and ReA occur in different
families
• Common age group 18-40 years
• Male:Female 1:1 (AS is 3:1);  in gay men
• Enthesitis similar to AS
• S. flexneri, Y. enterocolitica, C. jejuni, C.
trachomatis, and other bacteria (produce
LPS, attack mucosal surfaces, invade
host cells, & survive intracellularly)
• Ag in synovium and synovial fluid WBC
for long periods of time
 Reactive Arthritis
• Ag-specific T cells (in synovium not
PBLs)
• Many T cells are CD4+ Th2
• Some T cells are CD8+ B27-restricted
CTLs
• Bacterial antigens → peptides that
serve as dominant T cell epitopes
• Patients with bladder cancer treated
with intra-bladder BCG develop ReA
(60% B27)
• B27 promotes prolonged survival of
bacterial antigens in joints to which T
cells react
 Reactive Arthritis
• ESR  in acute phase of ReA
• Mild anemia with acute phase reactants
•  neutrophils in synovial fluid
• 50-75% of patients are HLA-B27
• No organisms isolated but serologic
evidence of recent infection
• Diagnosis of ReA is a clinical one
• Exclude gonococcal & psoriatic arthritis
• No antecedent infection & not AS then
undifferentiated spondyloarthropathy
 undifferentiated SpA

enteropathic arthritis

Figure 279-1 Different SpA subsets

ankylosing spondylitis

Figure 279-1
Schematic
relationships among
psoriatic arthritis
the different SpA
subsets
reactive arthritis
Cecil’s
Textbook
Medicine
The Spondyloarthropathies (SpAs) 2005
 Table 279-2. CONTRAST OF RHEUMATOID
ARTHRITIS AND SPONDYLOARTHROPATHY
RHEUMATOID ANKYLOSING ENTEROPAT PSORIATIC REACTIVE
FEATURE ARTHRITIS SPONDYLITIS H ARTHRITIS ARTHRITIS ARTHRITIS
M/F ratio 1:3 3:1 1:1 1:1 10:1
HLA DR4 B27 B27(axial) B27(axial) B27
Joint Symmetric, Axial Axial and Axial and Axial and
pattern Peripheral peripheral asymmetric asymmetric
peripheral peripheral
Sacroiliac 0 Symmetric Symmetric Asymmetric Asymmetric
Syndesm 0 Smooth, Smooth, Coarse, Coarse,
ophyte marginal marginal nonmarginal nonmarginal
Eye Scleritis Iritis +/- 0 Iritis and
conjunctivitis

Skin Vasculitis 0 0 Psoriasis Keratoderma

RF >80% 0 0 0 0
Cecil’s
Textbook
Medicine
2005
 Cecil’s
Textbook
Medicine
Figure 279-5 Keratoderma blennorrhagicum 2005
T79-1. Comparison of the Spondyloarthropathies
Posturethral Postdysenteric Enteropa
Ankylosing Reactive Reactive thic Psoriatic
Spondylitis Arthritis Arthritis Arthritis Arthritis
Sacroiliitis +++++ +++ ++ + ++
Spondylitis ++++ +++ ++ ++ ++
Peripheral + ++++ ++++ +++ ++++
arthritis
Articular Chronic Acute or chronic Acute Acute or Chro
course >chronic chronic nic
HLA-B27 95% 60% 30% 20% 20%
Entheso- ++ ++++ +++ ++ ++
pathy
Common Eye Eye GU GI Skin
extra- Heart GU, Oral/GI Eye Eye Eye
articular Heart
Other Bekhterev's Reiter's syndrome, Reiter's Crohn's
names arthritis, Marie- SARA, NGU, syndrome disease,
Strümpell chlamydial ulcerative Cecil
disease arthritis colitis Essentials
of Medicine
2004
 Figure 318-4
Algorithm for diagnosis of the spondyloarthritides
 INFECTIOUS ARTHRITIS
• Suppurative Arthritis - gonococcus,
Staphylococcus, Streptococcus,
Haemophilus influenzae, and gram-
negative bacilli (E. coli, Salmonella,
Pseudomonas, and others
• Tuberculous Arthritis
• Lyme Arthritis
• Viral Arthritis
 Infectious agents may reach the joint via penetrating trauma or
hematogenously. In adults, a major risk is sepsis with injection drug
use. Sexually active adults are at risk for gonococcal arthritis. The
organisms that may often produce a pyogenic arthritis are:

PEAK AGE
ORGANISM GRAM STAIN
INCIDENCE
Hemophilus Gram negative
Children
influenzae coccobacilli
Neisseria Gram negative
Young adults
gonorrheae Infectious agents may reach the diplococci
Children &joint
young adults with
Salmonella Gram negative rods
sickle cell anemia
Staphylococcus Gram positive cocci
Adults
aureus in clusters
Escherichia coli Adults Gram negative rods

Pseudomonas Adults Gram negative rods

Prominent Arthritic Forms
of Rheumatologic Disease
• Rheumatoid Arthritis
• Psoriatic Arthritis
• Arthritis with GI disease (IBD, intestinal
bypass, intestinal lipodystrophy)
• Ankylosing Spondylitis
• Reactive Arthritis & Undifferentiated
Spondyloarthropathies
• Lyme Disease (untreated chronic stage)
• Non-Immune arthritis with Immunologic
Influences
 Lyme Borreliosis
• Spirochete, Borrelia burgdorferi, sensu lato
• Ticks of the Ixodes ricinus complex (Ixodes
scapularis)
• Expanding skin lesion, erythema migrans (EM;
stage 1, localized infection)
• Hematogenous spread to many different sites
(stage 2, disseminated infection)
– secondary annular skin lesions, meningitis, cranial
or peripheral neuritis, carditis, atrioventricular
nodal block, or migratory musculoskeletal pain
• Intermittent or chronic arthritis, chronic
encephalopathy or polyneuropathy, or
acrodermatitis may develop (stage 3,
persistent infection)
Figure 27.10 Transmission of Lyme disease
 Figure 8-41 Tiny deer tick
(bottom), which transmits
Lyme disease and Babesia
and Ehrlichia organisms,
contrasted with a larger
dog tick (top), which is not
thought to transmit human
infections
 Figure 392-1
Deer ticks (Ixodes scapularis, black-legged ticks) on a U.S. penny: larva
(below ear), nymph (right), adult male (above), and adult female (left).
 Box 1 Lyme disease
The spectrum of
clinical
manifestations
resulting from
infection with
Borrelia burgdorferi
Figure 43-9 Epidemiology of Borrelia infections
 Ixodes larvae become infected when they feed
on the mouse reservoir

Ixodes larvae become infected when they feed on the mouse reservoir. The
larva molts to a nymph in late spring and takes a second blood meal; in
this case, humans can be accidental hosts
 Etiologic Agent
• B. burgdorferi, the causative agent of Lyme
disease
• Fastidious, microaerophilic bacterium
• Small genome (~1.5 Mb), unusual linear
chromosome of 950 kb as well as 9 linear
and 12 circular plasmids
• Many immunogenic proteins - a number of
differentially expressed lipoproteins, most
of which are encoded by plasmid DNA
• B. burgdorferi sensu lato
– B. burgdorferi sensu stricto - North America
– + B. garinii (group 2) B. afzelii (group 3) –
Europe
– B. garinii, B. afzelii only - Asia
 Structure and
morphology of
Borrelia burgdorferi
Structure and morphology of
Borrelia burgdorferi
 Pathogenesis
• B. burgdorferi adapts to two different
environments: the tick and the mammalian
host (OspA, B, & C [aids in dissemination])
• Attaches to integrins, matrix glycosamino-
glycans, ECM, decorin in collagen
• CD14/TLR-2 signals for innate immunity
• T cell responses & B cell hyperactivity, ↑IgM
antibody (weeks) IgG (months)
• Lymphocyte infiltration of tissues, vasculitis
• Antigenic variation - VlsE
 Figure 27.11 Rash of erythema
chronicum migrans

Figure 27.11 Rash of erythema chronicum migrans on the leg

in Lyme disease. (erythema migrans)
 Localized & Disseminated Infection
• Early Infection: Stage 1 (Localized
Infection)
– Erythema migrans (EM) at 3-32 days pi - red
macule/papul expands slowly to form a
large annular lesion
– center of the lesion may become intensely
erythematous and indurated, vesicular, or
necrotic
– warm but not often painful
• Early Infection: Stage 2 (Disseminated
Infection)
• Late Infection: Stage 3 (Persistent
Infection).
 Localized & Disseminated Infection
• Early Infection: Stage 1 (Localized Infection)
• Early Infection: Stage 2 (Disseminated Infection)
– Hematogenous spread to many sites; days or weeks
– secondary annular skin lesions
– severe headache, mild stiffness of the neck, fever, chills, migratory
musculoskeletal pain, arthralgias, and profound malaise and fatigue
– generalized lymphadenopathy or splenomegaly, hepatitis, sore throat,
nonproductive cough, conjunctivitis, iritis, or testicular swelling
– intermittent and changing
– ~15% of untreated patients develop frank neurologic abnormalities
(meningitis, subtle encephalitic signs, cranial neuritis (including
bilateral facial palsy), motor or sensory radiculoneuropathy,
mononeuritis multiplex, cerebellar ataxia, or myelitis)
– Lymphocytic pleocytosis (~100 cells per μL) is found in CSF, often
along with elevated protein levels and normal or slightly low glucose
concentrations
– optic nerve inflammation (↑ intracranial pressure) may lead to blindness
– ~8% of patients develop cardiac involvement - atrioventricular block,
acute myopericarditis, left ventricular dysfunction, cardiomegaly or
pancarditis - lasts for only a few weeks
– musculoskeletal pain is common; migratory pain in joints, tendons,
bursae, muscles, or bones
• Late Infection: Stage 3 (Persistent Infection).
 Figure 43-11
Erythema
migrans rash
on the arm of
a patient with
Figure 43-11 Erythema migrans rash Lyme
borreliosis.
 Figure 2. Erythema Migrans Lesion

Figure 2. Erythema Migrans Lesion. An erythema migrans lesion has enlarged

over several days and now has a red border with clearing in the center
 Figure 352-s1 Expanding erythematous plaque of
erythema migrans on the neck

Cecil’s
Textbook
Figure 352-s1 Expanding erythematous plaque of erythema migrans Medicine
on the neck 2005
 Figure 352-s3 Erythema (chronicum) migrans

Cecil’s
Textbook
Medicine
2005
Figure 352-s3 Erythema (chronicum) migrans. Annular erythema that spreads
centrifugally. The peripheral erythematous border may or may not be sharply
demarcated and is usually 1-2 cm in width
 Figure 352-1 Erythema
Figure 352-1 Erythema migrans (EM) migrans (EM) is the major
dermatologic manifestation of
Lyme disease. Four days after
onset of EM, this patient
developed secondary annular
lesions, and some of their
borders have merged

Cecil’s
Textbook
Medicine
2005
SIGNS NO.OF PATIENTS (%)
Erythema migrans 314 (100)*
Multiple annular lesions 150 (48)
Lymphadenopathy - Regional 128 (41)
- Generalized 63 (20)
Pain on neck flexion 52 (17)
Malar rash 41 (13)
Erythematous throat 38 (12)
Conjunctivitis 35 (11)
Right upper quadrant tenderness 24 (8)
Splenomegaly 18 (6)
Table 352-1. EARLY
Hepatomegaly 16 (5)
SIGNS OF LYME
Muscle tenderness 12 (4)
DISEASE IN 314
Periorbital edema 10 (3)
PATIENTS Cecil’s
Evanescent skin lesions 8 (3)
Textbook
Abdominal tenderness 6 (2) Medicine
Testicular swelling 2 (1) 2005
SYMPTOMS NO.OF PATIENTS (%)
Malaise, fatigue, and lethargy 251 (80)
Headache 200 (64)
Fever and chills 185 (59)
Stiff neck 151 (48)
Arthralgias 150 (48)
Myalgias 135 (43)
Backache Table 352-1. 81 (26)
Anorexia 73 (23)
EARLY SIGNS
Sore throat 53 (17)
Nausea OF LYME 53 (17)
Dysesthesia DISEASE IN 314 35 (11)
Vomiting
PATIENTS 32 (10)
Abdominal pain 24 (8)
Photophobia 19 (6)
Hand stiffness 16 (5)
Dizziness 15 (5)
Cough 15 (5)
Cecil’s
Chest pain 12 (4) Textbook
Ear pain 12 (4) Medicine
Diarrhea 6 (2) 2005
 Cecil’s
Textbook
Medicine
2005

Figure 352-s2 Lyme disease. Lyme disease can cause a choroiditis (A) or
an optic neuritis (B and C)
Lyme Disease – Late Infection
• Arthritis occurs in late infectious in 60% of
patients who do not receive antibiotic
treatment for Borrelia burgdorferi infection
• Oligoarticular, large joints (knees) lasting
weeks to months; also small joints
• May lead to erosions in HLA-DR4
• Similarity between Borrelia outer surface
protein A (OspA) and LFA-1
• Fibrin deposits, villous hypertrophy, vascular
proliferation, microangiopathic lesions, &
lymphocyte/plasma cell infiltrates
• No RF or ANA
 Figure 43-12 Acrodermatitis chronica atrophicans

Figure 43-12 Acrodermatitis chronica atrophicans. Bluish-red skin

lesions characteristic of late, disseminated manifestions of Lyme
borreliosis.
Figure 8-40 Clinical stages of Lyme disease
 Cecil’s
Textbook
Medicine
2005
Figure 352-2 Antibody titers against Borrelia burgdorferi
166-1 Algorithm for Testing for and Treating Lyme Disease
Pretest Example Recommendation
Probability
High Patients with erythema Empirical antibiotic
migrans treatment without
serologic testing
Intermediate Patients with Serologic testing
oligoarticular arthritis and antibiotic
treatment if test
results are positive
Low Patients with nonspecific Neither serologic
symptoms (myalgias, testing nor
arthralgias, fatigue) antibiotic treatment
BOX 43-6. Bacteria and Diseases Associated with
Cross-Reactions in Serologic Tests for Lyme
Borreliosis
 Treponema pallidum
 Oral spirochetes
 Other Borrelia species
BOX 43-6. Bacteria and Diseases
 Juvenile Associated
rheumatoid arthritis in
with Cross-Reactions
Serologic Tests for Lyme Borreliosis
 Rheumatoid arthritis
 Systemic lupus erythematosus
 Infectious mononucleosis
 Subacute bacterial endocarditis
 Table 352-3. RECOMMENDATIONS FOR ANTIBIOTIC
TREATMENT OF LYME DISEASE IN ADULTS
EARLY LYME DISEASE†
Doxycycline, 100 mg, PO twice daily for 14-21 days
Amoxicillin, 500 mg, PO three times daily for 14-21 days
Cefuroxime axetil, 500 mg, PO twice daily for 21 days
If intolerant to all of the above drugs: erythromycin, 250 mg, PO four
times daily for 14-28 days
NEUROLOGIC MANIFESTATIONS Cecil’s
Bell's-like palsy alone Textbook
Oral regimens of doxycycline or amoxicillin may suffice Medicine
2005
Other neurologic abnormalities
Ceftriaxone, 2 g, IV daily for 14-28 days
Cefotaxime, 2 g, IV every 8 hours for 14-28 days
Penicillin G, 20 million units, IV daily (six divided doses) for 14-28 days
If intolerant to all of the above drugs: doxycycline, 100-200 mg, PO twice
daily (oral or intravenous) for 30 days‡
Table 352-3. RECOMMENDATIONS FOR ANTIBIOTIC
TREATMENT OF LYME DISEASE IN ADULTS
ARTHRITIS§
Doxycycline, 100 mg, PO twice daily for 30-60 days
Amoxicillin, 500 mg, PO three times daily for 30-60 days
Ceftriaxone, 2 g, daily for 14-28 days
Penicillin G, 20 million units, daily for 14-28 days
Cecil’s
CARDITIS¶ Textbook
Ceftriaxone, 2 g, IV daily for 14 days Medicine
2005
Penicillin G, 20 million units, IV daily for 14 days
Amoxicillin, 500 mg, three times daily for 21 days
Doxycycline, 100 mg, PO twice daily for 21 days
PREGNANCY
Standard therapy for given stage of disease; avoid doxycycline
TICK BITES
Rarely employ a single dose of doxycycline, 200 mg
 Figure 166-2
Algorithm for the treatment
of the various acute or
chronic manifestations of
Lyme borreliosis. AV,
atrioventricular. *For Lyme
arthritis, IV ceftriaxone (2 g
given once a day for 14–28
days) is also effective and
is necessary for a small
percentage of patients;
however, compared with
oral treatment, this regimen
is less convenient to
administer, has more side
effects, and is more
expensive.
 Figure 27.7
Transmission
in relapsing
fever
Figure 27.8 Course of events in relapsing fever
 The tick-borne borrelioses

Louse-borne relapsing fever – Borrelia recurrentis

Table 165-1 Manifestations of Tick-Borne Relapsing Fever
Acquired in the Northwestern United States and
Southwestern British Columbia
Sign or Symptom % Sign or Symptom %
Headache 94 Photophobia 25
Myalgia 92 Neck pain 24
Chills 88 Rash 18
Nausea 76 Dysuria 13
Arthralgia 73 Jaundice 10
Vomiting 71 Hepatomegaly 10
Abdominal pain 44 Splenomegaly 6
Confusion 38 Conjunctival injection 5
Dry cough 27 Eschar 2
Eye pain 26 Meningitis 2
Diarrhea 25 Nuchal rigidity 2
Dizziness 25
 Figure 165-1
Photomicrograph of tick-borne relapsing fever spirochete (B. hermsii) in a
Wright-Giemsa-stained peripheral blood film.
Table 165-2 Antibiotic Treatment of Louse-Borne
and Tick-Borne Relapsing Fever in Adults
Medication Louse-Borne Tick-Borne
Relapsing Fever Relapsing Fever
(Single Dose) (7-Day Schedule)
Oral
Erythromycin 500 mg 500 mg q6h
Tetracycline 500 mg 500 mg q6h
Doxycycline 100 mg 100 mg q12h
Chloramphenicol 500 mg 500 mg q6h
Parenterala
Erythromycin 500 mg 500 mg q6h
Tetracycline 250 mg 250 mg q6h
Doxycycline 100 mg 100 mg q12h
Chloramphenicol 500 mg 500 mg q6h
Penicillin G (procaine) 600,000 IU 600,000 IU daily

aFor tick-borne relapsing fever, parenteral therapy is used only until oral treatment is tolerated.
Juvenile Rheumatoid Arthritis
• Juvenile rheumatoid arthritis (JRA) is one of the
more common connective tissue diseases
• Affects 30,000 to 50,000 children in USA
• Oligoarticular (<5 joints involved), polyarticular (5
or more joints involved), & systemic variants
• Begins before age 16
• Arthritis lasting >6 weeks
• JRA differs from RA:
– oligoarthritis more common, systemic onset is more
frequent, large joints are affected more often than
small joints, rheumatoid nodules and rheumatoid
factor are usually absent, ANA common
• Pathogenetic factors similar to those in RA
 Prominent Arthritic Forms
of Rheumatologic Disease
• Rheumatoid Arthritis
• Psoriatic Arthritis
• Arthritis with GI disease (IBD, intestinal bypass,
intestinal lipodystrophy)
• Ankylosing Spondylitis
• Reactive Arthritis & Undifferentiated
Spondyloarthropathies
• Lyme Disease (untreated chronic stage)
• Non-Immune arthritis with Immunologic
Influences
 Non-Immune arthritis with
Inflammatory Influences
• Monosodium urate (Classical Gout)
• Calcium pyrophosphate dihydrate (CPPD)
• Calcium hydroxyapatite (HA)
• Calcium oxalate (CaOx)
• Clinical disease for all can be termed gout
• Most have prominent inflammatory reactions
• Treated with NSAIDS
 EMAIL, PHONE & TEXT SOURCES
• Email – nsinclai@rogers.com (anytime)
• Phone (Antigua) – 784-0049 (>6am, <9pm)
• Immunology: Janeway’s Immunobiology, 7th edition,
Murphy, Travers, Walport, Garland Science, 2008. ISBN
0-8153-4123-7.
• Pathology: Robbins & Cotran Pathological Basis of
Disease, 8th edition, by Kumar, Abbas, Fausto & Aster,
Elsevier/Saunders, 2009. ISBN-10 1416031219 or
1437707920
• Medicine: Harrison’s Principles of Internal Medicine,
17th edition, Fauci, Braunwald, Kasper, Hauser, Longo,
Jamison & Loscalzo, McGraw Hill, 2008. ISBN 978-0-07-
146633-2
• Medicine: Cecil Textbook of Medicine 22nd edition –
Online edition, Goldman & Ausiello, Saunders, 2005