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 Highly specific for RA May be pathogenic

Posttranslational modification of proteins: PAD converts arginine to citrulline Peptidylarginine deiminase (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 normal rheumatoid joint joint 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

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 cytokines tumor necrosis factor ++ ++ interleukin-1 + + interleukin-6 ++ ++

Roles of TNF and IL-1 in cartilage degradation and erosion of bone Induce chondrocytes and fibroblasts to produce matrix metalloproteinases and other proteases that degrade cartilage Together with RANK-RANKL interactions, promote differentiation of precursors into osteoclasts, which are the destructive element where the pannus invades bone cartilage 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 Additive 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

Rheumatoid arthritis: irreversible damage can occur early in disease course 1 year prior to 6 months after 3 years after onset onset of RA onset of symptoms of symptoms 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) Arbitrary scale

Characteristic joint deformities in RA “Swan neck” deformities: hyperextension of PIPs and flexion of DIPs “Boutonniere” deformity: flexion of PIP and hyperextension of DIP

Characteristic joint deformities in RA Ulnar deviation of the fingers Volar subluxation of 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 Rheumatoid factor 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