3.

RHEUMATOID ARTHRITIS

DEFINITION

Rheumatoid Arthritis (RA) is a chronic, inflammatory, systemic, autoimmune

disorder affecting primarily cartilage and bone of small and middle-sized joints.

The course of disease is highly variable, ranging from mild cases with non-
erosive, even sometimes spontaneously remitting disease, to severe, rapidly
progressive and destructive RA. Recent analysis of genetic risk factors,
autoantibody responses and therapeutic studies suggests, however, that clinical
RA might consist of pathogenetically distinct subgroups, and that different
treatment strategies should be applied to patients within these groups.

RA is considered an autoimmune disease, implying breakdown of immunological

tolerance towards self at a given point in a patient’s life. The trigger initiating
this breakdown is so far unknown.

CLASSIFICATION OF RA

1. Auto antibodies:
 ACPA positive RA
 ACPA negative RA

 RF positive RA
 RF negative RA (better prognosis, better survival, less extra-articular
manifestations)

2. The onset
 Very early RA
 Early RA
 Chronic RA
EPIDEMIOLOGY

RA affects approximately 0.5-1% of European and North-American adults.

Prevalence is estimated as 3.3 to 10.7 per 103 cases (South Europe - USA).
Annual incidence rates are estimated to be 16.5 to 38 cases (per 105) in
Southern Europe and USA.
Women are more frequently affected than men (a ratio of 0.3).

PATHOGENESIS

Witebsky postulated that a disease must fulfill three criteria to be considered

autoimmune in nature:
1) the presence of autoantibodies or a cell-mediated immune response against
an autoantigen

The presence of rheumatoid factor (RF), an autoantibody, targeting the Fc-part

of human IgG in the blood of the RA patients, is a prove for the first postulate.
They form immune complexes activating complement in the joint leading to
release of chemotactic factors (recruiters of effectors cell in the joint) and
increased vascular permeability.

The autoantibody most likely directly related to RA-pathogenesis, targets

proteins containing the atypical amino-acid citrullin. Citrullination is a process
by which arginine residues in a given protein are posttranslationally modified in
the presence of relatively high calcium-concentrations by an enzyme called PAD
(peptidyl arginine deiminase). Citrullination means degradation of intracellular
proteins during apoptosis. New anti-citrullinated protein antibodies (ACPA, anti-
CCP) are directed against the citrullinated fillagrin. The ACPA are present in
about 50% of the patients with RA.

2) the autoantigen is known (is usually known, demonstrating pathogenetic

relevance of the respective autoantibody has proven far more difficult)
3) a similar disease can be initiated in animals based on an analogous immune
response (4). (hard to be proven)

Factors involved in the pathogenesis of RA

1. Genetic factors

Fifty percent of the variation in prevalence of RA is caused by genetic factors.

(proven by the concordance rates in monozygotic twins).

The most relevant genetic factor is the shared epitope. Is found in HLA class II
molecules on chromosomal location 6p21.3. Several HLA-DRB1 molecules
(*0101, *0102,*0401, *0404, *0405, *0408, *1001 and *1402) share a common
amino acid sequence at position 70-74 in the third hypervariable region of the
DRβ1-chain. This sequence consists of glutamineleucine-arginine-alanine-
alanine (QKRAA), QRRAA or RRRAA. The shared epitope is implicated in the
binding of a putative arthritogenic peptide. The amino acids at position 70 and
71 flanking positions 72-74 (RAA) seem to modulate the T cell response, thus
influencing the risk conferred by the shared epitope to the development of RA.

2.The Environmental Factors

 factors promoting citrullination of proteins
 triggers of innate immunity

Infections:
 Mycobacteria,
 Epstein-Barr Virus,
 Parvovirus B19 etc.

Smoking confers an increased risk for the development of RA (ACPA positive RA,
and a more severe evolution of RA). Smoking induces an anti-citrullin specific
immune response by inducing apoptosis and subsequently citrullination in
alveolar cells.
Coffee consumption is associated with ACPA positive RA.

Alcohol seemed to have a protective effect on the development of ACPA-positive

RA.

High body-mass index is related with ACPA-negative RA.

Other (presumed) risk factors:

 mineral oils (e.g. motor oils, hydraulic oils etc.) was found to be a risk
factor for ACPA-positive RA in males in a Swedish cohort.
 sex hormones and reproductive factors (female predominance)
 pregnancy

The immune system in RA

The trigger of the immunological tolerance breakdown in RA, is still unknown.

Known facts:
 the synovium in RA is infiltrated by T cells, B cells, mast cells, neutrophils,
monocytes
 the T and B lymphocytes, the mast cells, the neutrophils and monocytes
proliferate and produce proinflammatory cytokines/chemokines (eg. Il1,
Il6, TNFα, IFN-Υ etc.) in the synovium
 additional effector cells are recruited alongside with vascular growth
factors
 the vascular growth factors promote neovascularisation and vascular
leakage
 the synovial fibroblasts and osteoclasts are activated, thus promoting the
degradation of the bone and cartilage
 the T cells – MHS class II (the effectors that recognize the autoantigen as
foreign) are activated via antigen presenting cells (eg. dendritic cells, B
cells)
 in RA the regulatory T cells (Treg) are incapable of controlling the
 activation and reactivation of the effectors cells (also T cells)
 the myth: RA was considered a Th1-mediated autoimmune disease- was
due to the lack of Th2
 Th1 cell – correlates with proinflammatory cytokines: Il1, Il6, Il12, IFNΥ
and TNF α – the main activator of monocytes
 Th2 cell – correlates with noninflammatory cytokines: Il2, Il4, Il10
 the newcomers: Il 23, Il 17, Th 17
 Il 12 shares a common subunit with Il 23
 Il 23 is found in sera, synovial fluid and synovial biopsy
 Il 23 is one of the drivers of Il 17 production
 Il 17 is an activator of macrophages, thus leading to production of
proinflammatory cytokines such as TNFα
 Th 17 – Il 17, TNFα, Il 6, Il 22, GM-CSF
 B – cells roles:
 cytokine production (Il6, TNF, IL10)
 antigen presenting cells
 modulation of T cell responses
 autoantibody production
 Mast cells – involved in driving local synovial inflammation
 Monocytes/macrophages roles:
 strong phagocytic activity,
 antigen presentation,
 secretion of proinflammatory cytokines,
 expression of Fc-receptors responsive to (auto-) antibodies
 expression of immune complexes,
 complement activation and regulation,
 fibroblast activation
 tissue degradation
 remodeling
 toll like receptor (TLR) expression
 The fibroblast and osteoclasts roles:
 the destruction of cartilage and bone
 the degradation of cartilage is due to the synovial fibroblast
  the bone degradation is due to the osteoclasts
 the degradation of cartilage is due to the secretion of matrix
metalloproteinases (MMPs) - MMP-1, -3, -13, -14 and - 15 and cathepsins
B, K, L.
 Osteoclastogenesis, is the differentiation of osteoclasts from precursor
cells.
 Osteoclastogenesis requires M-CSF and the presence of an osteoclast
differentiation factor (ODF).
 the ODF is similar /identical with RANKL (receptor activator of NKkB
ligand), osteoprotegrin ligend (OPG-L) and TRANCE (TNF related
activation induce cytokine).
 RANKL is present in RA patients.
 RANKL is expressed by T cells, synovial fibroblast and neutrophils.
 Osteoclastogenesis is down regulated by the Th1 cells (IFNΥ), the Th2
cells (IL4, Il10), Il12 and Il18.

CLINICAL MANIFESTATIONS

The onset of the disease:

 acute
 subacute
 insidious and gradual (the most common)

B symptoms:
 low grade fever
 fatigue (loss of energy)
 weight loss

Common symptoms:
 pain (typical - small joints involvement)
 small joints swelling
 stiffness (morning and after resting stiffness that lasts more than 30
 minutes)

Other symptoms:
 extra-articular manifestations (pleuritis, pericarditis etc.)

Joints involvement:
 symmetrical
 mono, oligoarthritis – less common
 poliarthritis – more common
 joints first involved - swelling of the proximal interphalangeal
(PIP) joints, the metacarpophalangeal (MCP) joints, the wrists and the
metatarsophalangeal (MTP) joints
 the DIP joints are not usually part of the clinical tableau (differential
diagnose with psoriatic arthritis)
Common deformities of the joints:
 Fusiform swelling (spindle shape fingers) – synovitis of PIP joints
 Swan-neck deformity – contraction of the flexors of the MCPs, the flexor
contraction of the MCP joint, hyperextension of PIP, flexion of DIP joint
 Boutonniere deformity – flexion of the PIP, hyperextension of the DIP
joints
 Ulnar deviation of fingers
 subluxations of MCPs
 “Piano key” ulnar head secondary to destruction of the ulnar collateral
ligament
 Claw/hammer toe – inflammation of the MTP joints with subluxation of
the metatarsal heads.

The dorsal and the lumbar spine are not usually involved in RA.
Thirty to fifty patients with RA are complaining of the cervical spine. The C1-C2
is the most commonly involved level. The pattern of the cervical spine
involvement is:
C1-C2 subluxation - (atlantoaxial) subluxation
  anterior subluxation is caused by synovial proliferation around the
odontoid process and the C1 arch, thus leading to the rupture of the alar
and transverse ligaments. It is more than 3 mm between the arch of C1
and the odontoid of C2. The risk of spinal cord compression is when the
anterior atlanto-odontoid interval is more than 9mm or the posterior
atlanto-odontoid interval is less than 14 mm.
 vertical subluxation - is the result of collapse of the lateral articulations
between C1-C2. The odontoid impinge the brainstem.
 lateral
 posterior
C1-2 impactions – destructions between the occipitoatlantal and atlantoaxial
joints.
Subaxial involvement – the C2-C3, C3-C4 facets and intervertebral disks are
involved.
Tenosynovitis, bursitis and carpal tunnel syndrome may be the first
manifestations of RA.

Extraarticular manifestations in RA

Pulmonary manifestations
a. Pleural disease – pleural effusion, pleurisy
Pleural effusion is characterized by:
 cellular exudates
 high protein levels
 high lactate dehydrogenase levels
 low glucose levels
 low ph (infections)
b. Nodules
Its can be solitary or multiple. Its can resolve spontaneously or cavitate.
Caplan’s syndrome equals coil miners with RA and pulmonary rheumathoid
nodules.
c. Interstitial pulmonary fibrosis (IPF) – fibrosing alveolitis
Is characterized by dyspnea, Velcro rales and primary fibrosis (lower lobes). A
rapid progression of IPF is called Hamman-Rich syndrome.
d. Bronchiolitis obliterans (BO) – Attention to the side effects of
Penicilamine!!! Patients are complaining of dyspnea. It can be visualized
hyperinflated chest x-rays and small airways obstruction on pulmonary
function test.
e. Bronchiolitis obliterans with organizing pneumonia (BOOP)
f. Nonspecific interstitial pneumonitis (NSIP)

Cardiac manifestations
a. Pericarditis – can lead to pain, tamponade (rare), constriction
(uncommon)
b. Nodules – valvular problems, conduction abnormalities
c. Coronary arteritis – myocardial infarction
d. Myocarditis – congestive heart failure

Ocular manifestations
a. episcleritis
b. scleritis
c. retinal nodules
d. choroid nodules

Dermatologic manifestations
a. vasculitis
Types of vasculitis in RA:
 Leukocytoclastic vasculitis (inflammation of postcapillary venules)–
palpable purpura
 Small arteriolar vasculitis – infarcts of digit pulp + distal sensorial
neuropathy (vasculitis of vasa nervorum)
 Medium vessel vasculitis – livedo reticularis, visceral arteritis +
mononeuritis multiplex
 Pioderma gangrenosum
b. subcutaneous nodules
c. palmar erythema
Neuromuscular manifestations
a. mononeuritis multiplex
b. peripheral neuropathy
c. entrapment neuropathy – median nerve (carpal tunnel), posterior tibial
nerve (tarsal tunnel), ulnar nerve (cubital tunnel), radial nerve –
interosseous branch

Hematologic manifestations
a. Felty’s syndrome – splenomegaly, leukopenia
b. Lymphomas
c. Large granular lymphocyte syndrome

Others
Sjögren’s syndrome
Amyloidosis – AA associated amyloidosis – poor controlled RA – nephrotic
syndrome

Miscellaneous manifestations:

Palindromic rheumatism – affects the large joints, lasts a few hours, days and
remits spontaneously.
RS3PE syndrome – acute severe onset of symmetrical synovitis of the small
joints of the hands, wrists and flexors sheats plus pitting edema of the dorsum of
the hand (“boxing glove” hand). Ussually affects 70 years old Caucasian males. All
patients are RF negative.

LABORATORY FINDINGS

1. Inflammatory markers
 ESR (erythrocyte sedimentation rate) elevated
 CRP (C-reactive protein) elevated
 2. Antibodies
 RF (rheumatoid factor) – is a series of antibodies that recognize
the Fc portion of an IgG molecule as it’s antigen. Isotypes of RF:
IgG, IgA, IgM, IgE.
 anti - CCP antibodies
 ANA (antinuclear antibodies)
3. thrombocytosis – active disease
4. leucocytosis – active disease
5. low levels of hemoglobin - anemia
6. serum iron – low levels – acute phase reaction
7. ferritin – high levels – acute phase reaction
8. serum albumin – low levels – negative acute phase reactant
9. Synovial fluid is characterized by:
 inflammatory pattern
 WBC (white blood cells) 5000-50.000/mm3
 > 50% of PMN’s
 elevated protein level
 low glucose level
 negative cultures
 no crystals

IMAGISTIC FINDINGS

Radiographic features of RA – ABCDE’S

Conventional radiography is still the golden standard in RA.
A – Alignment, abnormal, no ankylosis
B – Bones – periarticular (juxta-articular) osteoporosis, no osteophytes or
periostitis
C – Cartilage – uniform joint space loss in weight bearing joints, no cartilage or
soft tissue cacification
D – Deformities – boutonniere, swan neck, ulnar deviation – symmetrical
distribution
E - Erosions, marginal
S – Soft tissue swelling, nodules without calcifications

Ultrasound in RA
It is an extension of the clinical exam. It can show the synovitis of the involved
joints, erosions (at an early stage of the disease) and tendinitis/tenosynovitis.

MRI can depict the erosions of the wrist and fingers earlier than ultrasound. The
marrow edema shown in MRI is not a patognomonic sign in RA. It reveals only a
site of inflammation.

CLASSIFICATION CRITERIA

The 2010 American College of Rheumatology/European League Against

Rheumatism classification criteria for rheumatoid arthritis

Target population (Who should be tested?):

Patients who
1) have at least 1 joint with definite clinical synovitis (swelling)
2) with the synovitis not better explained by another disease

Classification criteria for RA (score-based algorithm: add score of categories A–

D; a score of ≥ 6/10 is needed for classification of a patient as having definite RA)

A. Joint involvement
1 large joint 0
2 to 10 large joints 1
1 to 3 small joints (with or without involvement of large joints) 2
4 to10 small joints (with or without involvement of large joints) 3
>10 joints (at least 1 small joint) 5

B. Serology (at least 1 test result is needed for classification)

Negative RF and negative ACPA 0
Low-positive RF or low-positive ACPA 2
High-positive RF or high-positive ACPA 3

C. Acute-phase reactants (at least 1 test result is needed for classification)

Normal CRP and normal ESR 0
Abnormal CRP or abnormal ESR 1

D. Duration of symptoms
< 6 weeks 0
≥ 6 weeks 1

DIFFERENTIAL DIAGNOSES

1. Osteoarthritis/ hand osteoarthritis

2. Psoriatic arthritis
3. Spondylarthopathies
4. Polymyalgia rheumatica with peripheral arthritis
5. Reactive arthritis
6. Acute sarcoid athropathy (Löfgren’s syndrome)
7. Systemic Lupus Erythematosus
8. Other connective tissue diseases
9. Gout (tophi)
10. Amyloidosis
11. Sarcoidosis
12. Xanthoma
13. Rheumatic Fever

DISEASE ASSESSMENT

The activity of the disease can be quantified by different indexes. The most
common used are:

Disease Activity Score - DAS 28 consists of: 28-swollen joint counts (28-SJC)
and 28-tender joint counts (28-TJC) in addition to patient global assessments of
disease activity on a visual analogue scale (VAS) and erythrocyte sedimentation
rate (ESR) or CRP (C reactive protein).

Simplified Disease Activity Index (SDAI) includes 28-SJC and 28-TJC, patient
and investigator global assessments of disease activity on a VAS and C-reactive
protein (CRP).

Clinical Disease Activity Index (CDAI) is the SDAI without the lab assessment.

PROGNOSTIC MARKERS
The known predictors of structural damage are: RF, anti-CCP antibodies, acute
phase reactants, the erosive disease.
The mortality predictors are: extraarticular manifestations, comorbidities, age,
physical status, education, RF.
The major cause of death among RA patients is cardiovascular and
cerebrovascular diseases. Male sex and age at disease onset have been found to
predict both the occurrence of cardiovascular events and death. Alongside with
the cardiovascular events an increased moratlity is due to disease activity, age,
level of education, comorbidities and corticotherapy.

TREATMENT

DMARD – “disease modifying” drug that has a positive impact on radiological

outcome of joint damage (erosions and joint space narrowing).

The front line DMARDs are:

 Methotrexate – MTX
 Sulfasalazine – SSZ
 Hydroxycloroquine – HCQ
 Leflunomide

The less used DMARDs are:

 Azathioprine – AZA
  Gold
 Minocycline
 Ciclosporin
 D- Penicillamine – D-Pen

The benefits of DMARDs are:

 Control of sign and symptoms – joint involvement
 Improvement of functional status
 Improvement of quality of life
 Retardation of radiographic evidence of erosions

TREATMENT OBJECTIVES – EARLY REMISSION

 number of swollen and tender joints

 morning stiffness
 synovitis
 fatigue
 acute phase reaction

A. NON BIOLOGIC DMARDS – first line of treatment

1. Methotrexate (MTX) is the golden standard of the therapy in RA.

Methotrexate proved to be efficient on radiographic progression. It inhibits the:
 pyrimidinie synthesis – (DNA)
 de novo purine synthesis – (DNA, RNA)
 the depletion of tetrahydrofolate (protein synthesis, RNA, DNA)
MTX is:
 absorbed rapidly, completely after dosage not exceeding 30mg/m2
 postabsortion 50-70% bounds to plasma protein (albumin)
 transported via an active carrier-mediated system into the hepatic cells
beeing converted to MTX polyglutamate
 80-90% renal excrete
   % biliary excreation

Dose: 20-25 mg/ w orally, parentally (EVP, sc, im)

Predisposing factors for toxicity:

 Increased dose
 Prolonged exposure
 Advanced age
 Renal insufficiency
 Concomitant use of other antifolates
 Liver fibrosis – rare (monitoring- AST, ALT; no liver biopsy)

Hypersensitivity do not correlate with:

 Cumulative dose
 Age
 Way of administration

Risk is due to:

 Age
 Diabetes
 Previously lung disease
 ≠ Pneumocystis jerovici pneumonia
SMOKING – is not a risk factor for MTX treatment.
Side effects:
 3% - leucopenie, trombocytopenia, megaloblastic anaemia, pancytopenia
 Subcutaneous rheumatoid nodules
 MTX is teratogenic – no - pregnancy (appropiate contraceptive measures)

2. Leflunomide is an izoxazole derivate. It’s active metabolite is malonitrilamide

A77 1726.
It inhibits the de novo pirimidine synthesis, thus inhibiting the proliferative and
anti-inflammatory effects.
It suppresses the TNF α induced cellular responses.
It inhibits the MMP (matrix metalloproteinases) and the osteoclasts.
T1/2 is 15 days.

Dose: 20mg/day po; in remission the dose is 10mg/day po.

Wash out – cholestiramine 3x8g/d 11 days.
No wash out – 2 years.

Contraindication:
 Obstructive biliary disease
 Liver disease
 Viral hepatitis
 Severe immunodeficiency
 Rifampicin treatment

Side effects:
 Diarrhoea
 Alopecia
 Rash
 Leucopenia
 Hepatotoxicity
 Hypertention
 teratogenic/fetal death

3. Sulfasalazine ia a 5 aminosalicylic acid derivate.It is metabolised via colonic

intestinal flora. It’s active metabolites are: sulfapyridine, 5-amino-salicylic acid
(5-ASA).

Dose: 2-3 g/day.

Side effects
 Gastrointestinal
  Central nervous system toxicity – headache; dizziness
 4-5% rash
 myelosuppresion !!!
 fever + rash+ abnormal liver function – viral illness

4. The antimalarial agents - Hydroxicloroquine (HCQ), Cloroquine (CQ) are 4

– aminoquinoline derivatives. Its absorbed from the gastrointestinal tract.

Dose: the onset 1200mg/d then 400mg/d.

Retinal toxicity :
 HCQ > 6.5 mg/kg/w
 CQ > 3mg/kg/w
 More than 10 years of treatment
 Impaired renal or liver function
 Age > 60 years old
 Obesity
 Macular degeneration
 History – previously antimalarial drugs
 Rarely – myopathy (HCQ)

5. Cyclosporin is a fungal peptide with immunosuppressive properties. Inhibits

the proliferation and activation of T cells and the secretion of the
proinflammatory cytokines. The efficiency of Cyclosporin was proven in
association with MTX.

Side effects
 Hypertrichosis
 Tremor
 Gum hyperplasia
 Hypertension
 Dose related with the loss of renal function
Dose: 2.5 mg/kgc –increased with 0.5-0.75 mg/kgc

6. Other DMARDS
Azathioprine (Imuran)
 Immunossupresor
 Mielossupresion
 Risk of lymphoma, non-melanoma skin cancer
 Hepatotoxicity
D-Penicillamin
 Tetracycline derivates – inhibits metalloproteinase activity involved in
joint destruction
 Adjunctive therapy in early RA

B. BIOLOGIC DMARDS – second line of treatment

a. Anti TNFα
 Infliximab
 Etanercept
 Adalimumab
 Golimumab
 Certolizumab
b. LyB - anti CD 20
 Rituximab
c.Co-stimulation
 Abatacept
d. Il-1
 Anakinra
e.Il6
 Tocilizumab

a. Anti TNFα
1. INFLIXIMABUM (REMICADE)
It is a human murine chimeric antibody.
Dose: 3 mg/kgc PEV 0-2-6-8 weeks afterwards increasing the dose (if not LDA
or remmission) till 10mg/kgc.
2. ETANERCEP (ENBREL)
It is a recombinant TNFα receptor fused to a human Fc molecule creating a TNFα
binding agent.
Dose: 50mg sc weekly.
3. ADALIMUMABUM (HUMIRA)
It is a human antiTNFα antibody.
Dose: 40mg sc bimonthly.
4. GOLIMUMABUM (SIMPONI) similar with Infliximab but it is given once
monthly sc.
5. CERTOLIZUMABUM (CYMZIA) is a humanised pegylate antiTNFα antibody.
Dose:
 2, 4 week 400mg (2x200mg)
 400mg monthly .
B. RITUXIMAB (MABTHERA) is a monoclonal chimeric (huminised and murine
sequences) anti CD20 antibody.
C. TOCILIZUMAB (RoActemra) is an inhibitor of IL 6 receptor.
Dose: 4mg/kgc lunar PEV
D. ANAKINRA is a recombinant Il 1 antagonist.
E. ABATACEPT (ORENCIA) is a soluble recombinant fully human protein that
comprises the extracellular domain of CTLA4 and the Fc portion of the IgG1
molecule that has been modified to prevent complement activation.

C. NON DMARD therapies

Glucocorticosteroids
 Prednisolone – the most used
 Dexamethasone

Pleiotropic effects:
 Immunosupressive effects
  Anti-inflammatory effects
 Rapid and effective mode of action
 Adm.: per os, PEV (pulse therapy), ia – thumb rule (no > 4 adm. at the
same joint/year; metilprednisolone, triamcinolone + derivates)

Dose: low - 10 mg/d, high 10-30mg/d

NSAIDS + COXIBS
 Pathophysiological mechanisms
Nociceptive pain:
 Inflammation
 OA
Non-nociceptive pain due to sensitization:
 Secondary fibromyalgia
Neuropathic pain:
 Carpian tunnel syndrome

EULAR evaluation:
 Gastrointestinal
 Cardiovascular
 Renal

TAKE HOME MESSAGES

RA is an independent risk factor for cardiovascular disease.

In patients with early RA, anti-CCP antibody positivity is an excellent predictor
for the outcome of the disease.
Not all destructive polyarthritis is rheumatoid or psoriatic arthritis.
Remission or low disease activity are the target in RA.

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