Rheumatoid Arthritis

John Imboden MD

Rheumatoid arthritis: typical presentation

• Prevalence 1%• Female > male (3:1)• Peak onset: age 30s to

40s• Insidious onset of joint

pain & AM stiffness lasting hours

• Swelling of wrists and small joints of the hands

The natural history of rheumatoid arthritis

at presentation after 5 years after 15 years

- Chronic disease- Progressive damage leading to joint deformity & disability- Extra-articular disease: nodules, lung, eye, vasculitis, etc - Diminished life expectancy

Rheumatoid Arthritis• Polyarthritis of synovial lined joints

– Characteristic pattern of joint involvement• Inflammatory arthritis

– autoimmune• Destructive arthritis

– Cartilage degradation– Erosion of bone adjacent to joints– Joint deformities

• Systemic disease

Rheumatoid Arthritis: pathogenesis

• Etiology uncertain• Autoimmune disease

– Characteristic autoantibodies• Genetic predisposition• Mechanisms of joint damage

Rheumatoid Arthritis: autoantibodies

• Rheumatoid factor– Autoantibody to Fc region of IgG– Occur in c. 70% of RA patients– Despite the name, not specific for RA

• Antibodies to citrullinated protein epitopes– Occur in c. 70% of RA patients– Highly specific for RA– May be pathogenic

Posttranslational modification of proteins: PAD converts arginine to citrulline

Peptidylargininedeiminase (PAD)

RA-associated autoantibodies recognize protein epitopes containing

citrulline

Peptide sequence Antibody recognition

ESSRDGSRHPRSHD No

PAD

ESSRDGScitHPRSHD Yes

Protein Citrullination• Constitutive citrullination of proteins in skin

and elsewhere– Physiological roles of citrullination are diverse

and incompletely understood• Citrullination of proteins occurs in inflamed

joints in many forms of arthritis– NOT specific for RA

• Loss of tolerance to citrullinated proteins is specific for RA

Antibodies to Citrullinated Protein Epitopes

• Detected using synthetic cyclic citrullinated peptides – “anti-CCP antibodies”

• Anti-CCP positive RA:– Genetically distinct form of RA– More aggressive arthritis

RA: genetic susceptibility

• Heritability 60% • Multiple genes involved• Most important: HLA-DRB1

– Encodes b chain of a MHC class II antigen– Linked to “CCP-positive” RA

Environmental event(s) Genetic predisposition

Loss of tolerance to self antigens

Preclinical autoimmunity

Clinically apparent joint inflammation (synovitis)

Synovial inflammation in RA

Synovial inflammation in RA

Synovitis: - proliferation of synovial lining cells - influx of mononuclear cells - angiogenesis Pannus: - the component of the inflamed synovium that invades cartilage and bone

Joint effusion: - influx of neutrophils into synovial fluid

normal rheumatoid joint joint

Joint inflammation in RA Rheumatoid wrist Normal wrist

Inflammation within bone synovial inflammation

3 Tesla MRI provided by Xiaojuan Li PhD

Cytokine production in rheumatoid synovium

• Large number of cytokines produced• Macrophage-derived cytokines:

– Proinflammatory cytokines: TNF-a, IL-1, IL-6– Dominant cytokines in quantitative terms

• T cell cytokines: – Interleukin-17 > interferon-g (Th17 cells may

be more important than Th1)

Mechanisms of joint inflammation and destruction in RA:

conclusions from trials with selective inhibitors Response

Target Clinical Joint damage

T cell co-stimulation ++ ++B cell ++ ++

Proinflammatory cytokinestumor necrosis factor ++ ++interleukin-1 + +interleukin-6 ++ ++

Roles of TNF and IL-1 in cartilage degradation and erosion of bone

cartilagebone

Induce chondrocytes andfibroblasts to produce matrix metalloproteinases and otherproteases that degrade cartilage

Together with RANK-RANKL interactions, promote differentiation of precursorsinto osteoclasts, which are the destructive element where the pannus invades bone

RA: clinical presentation

• Onset: usually insidious– Patients typically present after weeks to

months of symptoms• Articular symptoms dominate• Constitutional symptoms

– Common: fatigue, low grade fever (<38°C) – Uncommon: extensive weight loss, fever > 38°C

RA: articular symptoms

RA is an inflammatory arthritis:– Morning stiffness

• Often lasts hours• Can be the dominant symptom

– Joint pain and stiffness improve with activity– “gel phenomenon”

• Stiffness recurs after prolonged inactivity

RA: joint involvement

• Symmetric– e.g., both wrists, both knees

• Additive• Polyarthritis (>5 joints involved)• Arthritis, not just arthralgias

– Involved joints: tender and swollen– Larger joints: warm, effusions

• Not erythematous

RA: pattern of joint involvement• Hands (involved in >90%)

– Wrists, metacarpophalangeal (MCP) & proximal interphalangeal (PIP) joints

– Spares distal interphalangeal (DIP) joints • Axial skeleton

– Cervical spine can be involved– Spares thoracic, lumbosacral spine, SI joints

• Large joints• Feet

Early RA with fusiform swelling of the 3rd and 4th PIP joints

1 year prior to 6 months after 3 years after onset onset of RA onset of symptoms of symptoms

Rheumatoid arthritis: irreversible damage can occur early in disease course

Radiographic changes in the same joint over time

Radiographic changes occur early and precede joint deformities by years

(adapted from Wolfe & Sharp, Arth Rheum 41: 1571, 1998)

0

5

10

15

20

0 10 20

years

coun

t joint narrowing

joint erosions

jointdeformities

Arb

itrar

y sc

ale

Characteristic joint deformities in RA

“Swan neck”deformities:hyperextensionof PIPs and flexion of DIPs

“Boutonniere” deformity:flexion of PIP and hyperextension of DIP

Characteristic joint deformities in RA

Ulnar deviationof the fingers

Volar subluxationof MCPs

Rheumatoid nodules

Note the symmetry of the joint involvement

Characteristic joint deformities in RA

Subluxation of the metatarsals as a consequence of MTP arthritis

RA: extraarticular manifestations

• Common:– Rheumatoid nodules– Sicca (Sjögren) syndrome– Interstitial lung disease– Ocular inflammation: Scleritis and episcleritis

• Uncommon:– Vasculitis– Clinically apparent pleuritis or pericarditis– Felty syndrome (RA, splenomegaly, neutropenia)

Rheumatoid nodule

RA: Laboratory findings• Routine laboratory:

– Mild to moderate anemia– Mild to moderate thrombocytosis

• High erythrocyte sedimentation rate or elevated C-reactive protein

• Synovial fluid analysis– Inflammatory – WBC counts usually in 5,000 – 50,000 range– Neutrophil predominance

RA: Autoantibodies

• Anti-CCP Antibodies– High specificity – Identifies patients with more aggressive joint

disease• Rheumatoid factor

– Limited specificity– Patients who develop extra-articular disease

are almost always “sero-positive” for RF

Diagnosis of RA

• Clinical diagnosis• Key feature: inflammatory polyarthritis

affecting proximal joints of the hands • Compatible laboratory data, serologies,

and radiographs• Exclusion of other causes of inflammatory

polyarthritis

Diagnosis: some mimics of RA• Acute viral infections: self-limited polyarthritis

– Acute parvovirus B19 infection in adults• Chronic hepatitis C infection

– RF-positive non-erosive chronic polyarthrtis• Systemic lupus and other systemic rheumatic

diseases • Spondyloarthropathies • Primary osteoarthritis of the hands• Systemic vasculitis

Goals of therapy for RA

• Reduce signs and symptoms of inflammation

• Prevent joint deformities

Treatments for RA• Nonsteroidal anti-inflammatory drugs

– Aspirin 1890s• Low dose glucocorticoids

– Early 1950s• Disease-modifying antirheumatic drugs

(DMARDs)– Methotrexate mid-1980s

• Biological agents– Anti-TNF agents late 1990s

Raoul Dufy “La Cortisone” 1951

Methotrexate: most commonly used DMARD

• Mainstay of treatment for RA– reduces signs and symptoms in majority– slows radiographic progression

• Works slowly (weeks)• Uncertain mechanism of action in RA

Biological agents for RA• Monoclonal antibodies, receptor/antibody

chimeras • Targets:

– Tumor necrosis factor (TNF)– T cell-costimulation– B-cells– IL-6 receptor

• Parenteral administration (SQ or IV)• Toxicity (infection, ?malignancy)• $$$

Anti-TNF therapy of RA• Reduces signs and symptoms for patients with

active disease despite methotrexate• Combination of anti-TNF and methotrexate:

– superior to either agent alone for reducing disease activity

– prevents radiographic progression for most patients, at least for 1-2 years

• Not all patients respond, and many responses are incomplete

Treatment of RA: general principles

• Patients should be started on effective therapy (eg, a DMARD) within 3 months of diagnosis

• Combination therapy appears more effective than monotherapy

• Goal is remission or “mild” activity by standardized assessments

• There are few head-to-head comparisons to guide therapeutic decisions

A therapeutic approach to new onset RA

• Start prednisone 5 mg/day– Acts quickly, joint-protective

• Start methotrexate– Initiate long term therapy with an agent shown to

retard radiographic progression• If disease still active despite optimal

methotrexate, add an anti-TNF agent– Alternative: start with methotrexate plus anti-TNF

• If disease refractory to anti-TNF, switch to another biological agent

Rheumatoid arthritis: 2010

• Treatable, but not curable– Therapies can slow or even prevent joint

damage• Early RA is a therapeutic opportunity

– Clinical remission achieved in 50%• Most treated RA patients have residual

mild to moderate activity• 10-20% have refractory disease

Rheumatoid arthritis: key points• Pathogenesis

– Genetic predisposition– Anti-CCP antibodies– Connection between proinflammatory cytokines and

joint destruction• Clinical course of RA: descriptors of common

joint deformities, extraarticular manifestations• Distinguish RA from osteoarthritis,

spondyloarthropathies, and lupus• Major classes of therapies