Rheumatoid Arthritis (RA)

Definition

• Robbins & Kumar Basic Pathology, p. 792

Epidemiology

• Textbook of Family Medicine 9e, p. 877

Pathogenesis

• TNF, IL-1, IL-6 (from macrophages) - recruit and activate leukocytes; stimulate proteases that destroy hyaline cartilage. TNF is considered the key mediator - hence the therapeutic efficacy of TNF antagonists.
• IL-17 (from Th17 cells) - recruits neutrophils and monocytes.
• RANKL (on activated T cells) - stimulates osteoclasts → bone resorption.

• Anti-Citrullinated Peptide Antibody (ACPA): Targets proteins where arginine is posttranslationally converted to citrulline (fibrinogen, type II collagen, α-enolase, vinculin). Present in up to 70% of RA patients. Highly specific diagnostic marker.
• Rheumatoid Factor (RF): IgM or IgA autoantibodies binding the Fc portion of IgG. Present in ~80% of patients. Less specific - can appear in healthy individuals.

• HLA-DR4 allele linked to ACPA-positive RA.
• Molecular mimicry: a citrullinated vinculin epitope resembles a microbial epitope, presented by HLA-DR4.
• Environmental triggers include smoking, infections, and gut microbiome alterations.
• Robbins & Kumar Basic Pathology, pp. 791-793

Morphology / Pathology

• Synovium becomes edematous, thickened, and hyperplastic with villi
• Synoviocyte hyperplasia and proliferation
• Dense infiltrates of CD4+ T cells, B cells, plasma cells, and macrophages
• Increased vascularity (angiogenesis)
• Neutrophils and fibrin on synovial surfaces
• Osteoclastic activity → periarticular erosions and subchondral cysts

Clinical Features

Onset

• ~70% insidious (over weeks to months)
• ~10% acute onset (best prognosis)
• ~20% intermediate
• "Palindromic RA": brief episodes of swelling in large joints (knee, wrist) that resolve completely between attacks

Articular features

• Symmetric synovitis of small joints first - PIP, MCP joints of hands and feet
• Larger joints (wrists, ankles, elbows, knees) involved later
• Joints: swollen, warm, painful, stiff (especially in the morning)
• Morning stiffness >1 hour - hallmark
• Constitutional symptoms: fatigue, malaise, weight loss, low-grade fever, anemia

Characteristic deformities

• Ulnar deviation of fingers
• Swan-neck deformity (PIP hyperextension, DIP flexion)
• Boutonniere deformity (PIP flexion, DIP hyperextension)

Extra-articular manifestations

• Rheumatoid nodules (skin)
• Pulmonary: interstitial lung disease, rheumatoid nodules
• Cardiovascular: accelerated atherosclerosis, pericarditis
• Ocular: keratoconjunctivitis sicca (secondary Sjogren's), scleritis
• Neurological: cervical myelopathy (atlantoaxial subluxation), peripheral neuropathy
• Vasculitis
• Secondary amyloidosis (with longstanding disease)

Diagnosis

1987 ACR Revised Criteria (Traditional Format)

Note: The 2010 ACR/EULAR criteria are now preferred for early diagnosis and emphasize joint involvement pattern, serology (RF/ACPA), acute phase reactants (CRP/ESR), and symptom duration (score ≥6/10 confirms RA).

Key laboratory tests

• RF - positive in ~80%; also positive in other conditions
• ACPA (anti-CCP) - more specific than RF; positive in ~70%; may precede symptoms by years
• ESR, CRP - elevated in active disease
• CBC - normocytic normochromic anemia is common
• Synovial fluid: >2000 WBC/mm³, predominantly neutrophils; no crystals

Imaging

• X-ray: joint space narrowing, periarticular osteopenia, marginal erosions (appear months-years after onset)
• MRI/Ultrasound: earlier detection of synovitis and erosions

Treatment

DMARDs (Disease-Modifying Antirheumatic Drugs)

Biologic DMARDs

• Etanercept - subcutaneous, p75 TNF-α receptor-Fc fusion protein; alone or with MTX
• Infliximab - IV anti-TNF monoclonal antibody (75% human/25% mouse); FDA-approved only with MTX; screen for latent TB (PPD) before starting
• Adalimumab (Humira) - fully human anti-TNF; 40 mg SC every other week; greatest effect when combined with MTX

• Abatacept (CTLA-4-Ig) - blocks T-cell co-stimulation
• Rituximab - anti-CD20, depletes B cells; used in RF/ACPA-positive disease
• Tocilizumab - anti-IL-6 receptor
• JAK inhibitors (tofacitinib, baricitinib) - targeted synthetic DMARDs

Important: Anti-TNF agents are not curative - patients must remain on them to avoid flares. Long-term use increases risk of opportunistic infections, particularly M. tuberculosis. Screen for latent TB before initiation.

Symptomatic therapy

• NSAIDs: Reduce pain and inflammation but do not alter disease progression. Used to bridge while awaiting DMARD effect. Risk of GI bleeding is significant (one in three RA patients hospitalized or die from GI bleed at some point).
• Glucocorticoids: Intra-articular injections (triamcinolone, methylprednisolone) for localized flares - not >3 times/joint/year. Low-dose oral prednisone as bridge therapy.

Surgery

• Carpal tunnel release
• Synovectomy
• Joint fusion (arthrodesis)
• Arthroplasty (joint replacement) - ~90% of older patients with severe disease achieve significant functional improvement

Prognosis

• RF-positive, polyarticular disease: >70% chance of joint damage/erosion within 2 years without treatment
• Seronegative patients may stabilize or regress
• Early, aggressive DMARD therapy substantially improves long-term outcomes
• Increased cardiovascular mortality is a major concern

• Robbins & Kumar Basic Pathology, pp. 791-793
• Textbook of Family Medicine 9e, pp. 877-884
• Recent review: Management strategies in rheumatoid arthritis - Konzett V, Aletaha D, Nat Rev Rheumatol, Dec 2024 [PMID: 39448800]