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Rheumatoid Arthritis (RA) - Complete USMLE Guide

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1. Epidemiology

• Prevalence: ~1% of adults worldwide; women:men ratio is 2-3:1
• Peak onset: 4th-6th decade, but can occur at any age
• HLA association: HLA-DR4 (and HLA-DR1) - the "shared epitope" on HLA-DRB1 is the strongest genetic risk factor
• Smoking is the major environmental risk factor (triggers citrullination of proteins, generating autoantigens)
• Associated with increased cardiovascular mortality (leading cause of excess death in RA)

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2. Pathophysiology

1. Trigger: Environmental exposures (especially cigarette smoke) induce citrullination of proteins in susceptible individuals (HLA-DR4 shared epitope)
2. Autoantibodies generated: Anti-citrullinated protein antibodies (ACPA/anti-CCP) and Rheumatoid Factor (RF = IgM against IgG Fc)
3. Immune cascade:
   • APCs activate CD4+ T helper cells (Th1, Th17) in the synovium
   • T cells activate B cells → plasma cells → RF and ACPA production
   • Macrophages release TNF-α, IL-1, IL-6 → drive synovial inflammation
   • IL-17 from Th17 cells upregulates VEGF and MMPs → cartilage degradation
   • RANKL (produced by T cells) → osteoclast activation → bone erosion
4. Pannus: Proliferating synovial tissue (fibroblast-like synoviocytes) invades cartilage and bone → irreversible joint destruction
5. Synovial fluid: Inflammatory - WBC 2,000-100,000 cells/μL (mostly PMNs), low glucose, low complement, elevated LDH

"In rheumatoid arthritis the chronically inflamed synovium is densely crowded with activated T-cells... High levels of IL-15 within the synovial membrane can recruit and activate T-cells whose secretion of cytokines and ability to induce macrophage synthesis of TNF contributes significantly to the disease." - Roitt's Essential Immunology

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3. Clinical Features

Articular Manifestations

Classic Hand Deformities

• Ulnar deviation at MCPs (most common)
• Swan-neck deformity: PIP hyperextension + DIP flexion
• Boutonniere deformity: PIP flexion + DIP hyperextension
• Z-thumb: IP flexion + MCP hyperextension of thumb
• Hammer toe / Cock-up toes at MTPs

Baker Cyst

• Popliteal synovial cyst behind the knee
• Can rupture → calf pain mimicking DVT

Extra-Articular Manifestations (much more common in RF/ACPA-positive patients)

• Rheumatoid nodules (20% of patients) - subcutaneous, firm, non-tender, on extensor surfaces (olecranon), pressure points; histology shows palisading granuloma with central fibrinoid necrosis
• Small vessel vasculitis (brown infarcts of fingers/palms)

• Pleuritis/pleural effusion (exudate, low glucose, low complement)
• Caplan syndrome: RA + pneumoconiosis → large pulmonary nodules
• Interstitial lung disease (ILD) - particularly UIP pattern
• Bronchiolitis obliterans, pulmonary hypertension

• Pericarditis (most common cardiac manifestation)
• Myocarditis, coronary vasculitis

• Keratoconjunctivitis sicca (secondary Sjogren - most common eye finding)
• Scleritis (painful, red - indicates severe disease)
• Episcleritis (milder, self-limited)
• Scleromalacia perforans (painless scleral thinning → severe)

• Carpal tunnel syndrome (median nerve compression - most common peripheral nerve involvement)
• Tarsal tunnel syndrome (tibial nerve at ankle)
• Mononeuritis multiplex (from vasculitis)
• C1-C2 subluxation → cervical myelopathy

• Anemia of chronic disease (most common)
• Felty Syndrome: RA + splenomegaly + neutropenia (triad) - seen in severe, RF-positive, longstanding disease; risk of recurrent bacterial infections

• Fatigue, weight loss, low-grade fever, muscle wasting
• Increased risk of lymphoma (especially diffuse large B-cell lymphoma)
• Amyloidosis (AA type) in chronic untreated disease

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4. Diagnosis

2010 ACR/EULAR Classification Criteria (Score ≥6 = RA)

Laboratory Findings

Imaging

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5. Treatment

Goals

• Remission (or lowest possible disease activity) - "treat-to-target" strategy
• Prevent joint damage and disability
• Treat comorbidities (CV risk, osteoporosis, infections)

Step-by-Step Treatment

Step 1: Conventional (Synthetic) DMARDs (csDMARDs)

Step 2: Biologic DMARDs (bDMARDs) - if csDMARD fails

• Etanercept (soluble TNF receptor-Fc fusion)
• Infliximab, Adalimumab, Certolizumab, Golimumab (anti-TNF antibodies)
• Side effects: Increased risk of TB reactivation (screen with TST/IGRA before use), serious bacterial infections, demyelinating disease, drug-induced lupus (infliximab), CHF exacerbation

Step 3: Targeted Synthetic DMARDs (tsDMARDs) - JAK Inhibitors

Glucocorticoids

• Prednisone ≤10 mg/day as bridge therapy while DMARDs take effect (slow onset)
• Rapidly effective but chronic toxicity is extensive (infection risk increases 25-100% at 5-10 mg/day)
• Intra-articular injections useful for flares
• Never use steroids alone without a DMARD

NSAIDs

• Symptomatic relief only - do NOT alter disease course
• Always combine with a DMARD
• COX-2 inhibitors: less GI toxicity but CV risk (especially relevant in RA patients already at high CV risk)

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6. Monitoring Disease Activity

• DAS28 (Disease Activity Score with 28 joints) - includes tender/swollen joint counts, ESR or CRP, patient global assessment
• CDAI, SDAI, ACR20/50/70 response criteria (used in clinical trials)

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7. Complications & Comorbidities

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8. Special Scenarios

Seronegative RA

• ~25% of RA patients are RF and ACPA negative
• Tend to have milder articular disease
• Less extra-articular manifestations
• Nodules in a seronegative patient → consider tophaceous gout or other diagnosis

Drug-Induced Lupus from RA Treatment

• Infliximab (anti-TNF) can cause drug-induced lupus (anti-histone antibodies positive)

Pregnancy

• RA often improves during pregnancy (due to immune tolerance shift)
• Usually flares postpartum
• Methotrexate and leflunomide are teratogenic - must stop before conception
• Hydroxychloroquine and sulfasalazine are relatively safe in pregnancy

Juvenile Idiopathic Arthritis (JIA)

• RF-positive polyarticular JIA = essentially juvenile RA
• ANA-positive girls with oligoarthritis → highest risk of uveitis (anterior; silent)

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9. Differential Diagnosis

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10. USMLE High-Yield Pearls

1. RF is NOT specific - positive in SBE, Sjogren, SLE, chronic infections, normal elderly (5-10% of healthy adults)
2. Anti-CCP is most specific test for RA (>95% specific); also predicts erosive disease and positive years before clinical onset
3. Morning stiffness >1 hour = inflammatory arthritis (RA); <30 min = OA
4. DIP joints SPARED in RA (involved in OA and psoriatic arthritis)
5. Methotrexate = anchor drug for RA; must add folic acid to prevent toxicity
6. Screen for latent TB before starting any biologic (especially TNF inhibitors)
7. Cervical spine is the only axial spine involved in RA (C1-C2 atlantoaxial); rest of axial spine spared
8. Felty syndrome = RA + splenomegaly + neutropenia (severe, seropositive, longstanding disease)
9. Caplan syndrome = RA + occupational dust exposure + pulmonary nodules (coal workers' pneumoconiosis)
10. Baker cyst rupture mimics DVT; synovial cyst in popliteal fossa
11. Cardiac: pericarditis is most common cardiac manifestation
12. Eye: keratoconjunctivitis sicca (secondary Sjogren) is most common; scleritis = severe disease
13. Pleural effusion in RA = exudate with LOW glucose (characteristic), low complement
14. Hydroxychloroquine causes bull's eye retinopathy → annual eye exam required
15. Tocilizumab (IL-6R blocker) raises serum cholesterol and can mask fever
16. JAK inhibitors (tofacitinib, baricitinib) increase risk of herpes zoster reactivation
17. RA improves in pregnancy, flares postpartum
18. Rheumatoid nodule histology = central fibrinoid necrosis surrounded by palisading histiocytes
19. Amyloidosis (AA type) can complicate longstanding untreated RA (secondary amyloidosis)
20. X-ray sequence: periarticular osteopenia → joint space narrowing → marginal erosions → deformity

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11. USMLE Buzzword List

• Pannus formation
• Synovial hypertrophy
• Anti-CCP / ACPA (anti-citrullinated protein antibody)
• Rheumatoid factor (IgM anti-IgG Fc)
• HLA-DR4 / shared epitope
• TNF-α, IL-1, IL-6, IL-17, RANKL
• CD4+ T cells, Th1, Th17

• Symmetric polyarthritis
• PIP + MCP involvement (DIP spared)
• Morning stiffness >1 hour
• Ulnar deviation (MCPs)
• Swan-neck deformity (PIP hyperextension + DIP flexion)
• Boutonniere deformity (PIP flexion + DIP hyperextension)
• Z-thumb
• Baker cyst (popliteal)
• C1-C2 atlantoaxial subluxation
• Cricoarytenoid joint involvement → hoarseness/stridor

• Rheumatoid nodule (extensor surface, olecranon, palisading granuloma)
• Felty syndrome (RA + splenomegaly + neutropenia)
• Caplan syndrome (RA + pneumoconiosis + large lung nodules)
• Scleritis / scleromalacia perforans
• Keratoconjunctivitis sicca (secondary Sjogren)
• Carpal tunnel syndrome
• Mononeuritis multiplex
• Pericarditis
• Low glucose pleural effusion
• AA amyloidosis

• RF positive (not specific)
• Anti-CCP positive (highly specific; predicts erosive disease)
• Elevated ESR, CRP
• Anemia of chronic disease
• Synovial WBC 2,000-100,000 (PMN predominant)
• Low complement in synovial/pleural fluid

• Juxta-articular osteopenia (first X-ray sign)
• Marginal erosions (later X-ray sign)
• Joint space narrowing

• Methotrexate (anchor drug) + folic acid
• Hydroxychloroquine (bull's eye retinopathy)
• Sulfasalazine
• Leflunomide (teratogenic; cholestyramine washout)
• TNF inhibitors (TB screening mandatory)
• Abatacept (CTLA4-Ig; blocks T cell costimulation)
• Rituximab (anti-CD20)
• Tocilizumab (anti-IL-6R; raises cholesterol; masks fever)
• Tofacitinib / Baricitinib / Upadacitinib (JAK inhibitors)
• Drug-induced lupus → infliximab
• Herpes zoster reactivation → JAK inhibitors
• Treat-to-target (goal = remission)

• RA vs OA: DIP spared in RA, involved in OA
• RA vs Psoriatic: RA symmetric, no DIP; Psoriatic asymmetric, DIP + dactylitis
• RA vs SLE: RA erosive; SLE non-erosive (Jaccoud)
• RA vs Septic: synovial WBC >50,000 + fever → septic
• RA vs Gout: negatively birefringent crystals in gout; tophi vs nodules

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1. RF can be positive in viral arthritis (transiently) - don't jump to RA if the illness is acute and <6 weeks
2. DIP involvement rules out RA - if DIP is the dominant joint, think OA or psoriatic
3. Psoriatic is seronegative (RF negative) despite being inflammatory and erosive - the "pencil-in-cup" X-ray and dactylitis are the distinguishing clues