Rheumatoid Arthritis

Chronic systemic autoimmune inflammatory disease primarily targeting synovial joints, characterized by symmetric polyarthritis, synovial hyperplasia (pannus formation), and progressive joint destruction if untreated.

Extra-articular manifestations reflect its systemic nature. Peak onset 30-50 years, female predominance (~3:1).

Pathogenesis involves genetic susceptibility (HLA-DRB1 shared epitope) and environmental triggers (smoking strongly implicated, especially in ACPA-positive disease) driving autoantibody production (rheumatoid factor, anti-citrullinated protein antibodies) and synovial inflammation.

Classified by:

• Seropositive (RF and/or anti-CCP positive); more common, generally more erosive/aggressive disease course

• Seronegative; RF/anti-CCP negative, diagnosis relies more heavily on clinical/imaging findings

• Symmetric polyarthritis, small joints predominant: MCP, PIP, wrist joints classically affected; also MTP joints; DIP joints and axial spine (except C1-C2) typically SPARED (helps distinguish from OA/psoriatic arthritis)

• Morning stiffness: prolonged, >1 hour (classic distinguishing feature from OA): improves with activity through the day

• Joint examination: soft, boggy synovial swelling (warm, tender), symmetric distribution

• Progressive deformities (late/untreated disease): ulnar deviation of fingers, swan-neck and boutonnière deformities, Z-thumb deformity, subluxation

• Systemic symptoms: fatigue, malaise, low-grade fever, weight loss; reflect systemic inflammatory burden

• Extra-articular manifestations (indicate more severe/seropositive disease):

• Rheumatoid nodules (subcutaneous, extensor surfaces; elbows)

• Pulmonary: interstitial lung disease, pleural effusion, nodules

• Cardiovascular: pericarditis, accelerated atherosclerosis (major mortality contributor: RA is an independent CV risk factor)

• Ocular: scleritis, episcleritis, keratoconjunctivitis sicca (secondary Sjögren's)

• Hematological: anemia of chronic disease, Felty's syndrome (RA + splenomegaly + neutropenia)

• Vasculitis (rare, severe disease)

• Cervical spine instability (atlantoaxial subluxation; screen before intubation/neck manipulation in longstanding disease)

• Red flag: sudden severe neck pain/neurological symptoms in RA patient ; think atlantoaxial subluxation with cord compression risk

Clinical diagnosis supported by serology and imaging ; 2010 ACR/EULAR classification criteria (score ≥6/10 classifies as RA): joint involvement (number/size of joints), serology (RF/anti-CCP), acute phase reactants (ESR/CRP), duration of symptoms (≥6 weeks).

• Rheumatoid factor (RF): positive in ~70-80% but not specific (also positive in other autoimmune conditions, chronic infections, some healthy individuals)

• Anti-CCP/ACPA (anti-citrullinated protein antibody): more specific for RA (~95%), can predate clinical onset by years, associated with more erosive disease

• Inflammatory markers: ESR, CRP elevated, correlate with disease activity (though can be normal in some active RA)

• FBC: normocytic anemia (anemia of chronic disease) common; thrombocytosis (acute phase reactant) in active disease

• Imaging:

• X-ray (hands/feet, baseline and monitoring): periarticular osteopenia, joint space narrowing, marginal erosions (later findings; may be normal early in disease)

• Ultrasound/MRI: detect synovitis and early erosions before visible on plain radiography ; increasingly used for early diagnosis and monitoring

• Disease activity scoring: DAS28 (28 joint count, combines tender/swollen joints, ESR/CRP, patient global assessment); used to guide treat-to-target strategy

Differentials: osteoarthritis (asymmetric, DIP involvement, brief morning stiffness, mechanical pattern), psoriatic arthritis (DIP involvement, dactylitis, psoriasis, asymmetric/axial involvement possible), SLE and other connective tissue diseases, viral arthritis (parvovirus B19, hepatitis; usually self-limiting), crystal arthropathy, polymyalgia rheumatica (older patients, proximal symptoms, dramatic steroid response).

Treat-to-target strategy: aim for remission or low disease activity, with regular monitoring (DAS28 or equivalent) and treatment escalation if target not met — early aggressive treatment (within "window of opportunity") significantly improves long-term outcomes.

Conventional synthetic DMARDs (csDMARDs); first-line, start promptly on diagnosis:

• Methotrexate: anchor drug, first-line for most patients; 7.5-25mg once weekly (oral or subcutaneous), with folic acid supplementation (5mg, taken a different day, typically day after MTX) to reduce toxicity; monitor FBC, LFTs, renal function regularly; teratogenic; contraception essential, contraindicated in pregnancy

• Alternatives/combination: sulfasalazine (2-3g/day divided doses), leflunomide (10-20mg od), hydroxychloroquine (200-400mg/day, often combination therapy, requires baseline/annual ophthalmology screening for retinopathy with long-term use)

• Combination csDMARD therapy (e.g., methotrexate + sulfasalazine + hydroxychloroquine: "triple therapy") is an effective and cost-effective strategy, comparable to biologic combination in many patients

Bridging therapy: short-course corticosteroids (oral prednisolone or IM/intra-articular depot) for rapid symptom control while DMARDs take effect (weeks); taper and discontinue as soon as feasible given long-term toxicity (osteoporosis, diabetes, infection risk, cardiovascular)

Biologic DMARDs (bDMARDs); added if inadequate response to csDMARDs (usually after methotrexate trial ± combination, per treat-to-target reassessment at 3-6 months):

• TNF inhibitors (first-line biologic class typically): etanercept, adalimumab, infliximab, certolizumab, golimumab; usually combined with methotrexate (reduces immunogenicity/anti-drug antibody formation)

• Alternative mechanisms for TNF inadequate response/intolerance:

• IL-6 receptor inhibitors: tocilizumab, sarilumab

• T-cell costimulation blocker: abatacept

• B-cell depletion: rituximab (particularly favored in seropositive disease, or where lymphoma history/contraindication to other biologics)

• Targeted synthetic DMARDs: JAK inhibitors (tofacitinib, baricitinib, upadacitinib); oral, effective, but carry boxed warnings (VTE, malignancy, major cardiovascular events, infection) particularly relevant in patients with cardiovascular risk factors/age >65/smokers ; used per risk-stratified guidance

Pre-biologic screening: TB screening (latent TB; interferon-gamma release assay or Mantoux, CXR), hepatitis B/C screening; reactivation risk with immunosuppression.

Monitoring: regular FBC, LFTs, renal function per DMARD-specific schedule; disease activity assessment (DAS28) at each visit; annual cardiovascular risk assessment (RA confers independent CV risk; aggressive risk factor management indicated); bone health assessment (osteoporosis risk from disease + corticosteroid use).

Adjunct/supportive:

• Physiotherapy, occupational therapy (joint protection techniques, splinting)

• NSAIDs for symptomatic relief (not disease-modifying, use adjunctively with gastroprotection as needed)

• Vaccination: influenza, pneumococcal (avoid live vaccines if on significant immunosuppression)

• Smoking cessation (worsens disease activity/response to treatment, particularly ACPA-positive disease)

Surgical management: joint replacement/synovectomy for severe joint damage refractory to medical management, or cervical spine stabilization for symptomatic atlantoaxial instability.

Referral: all suspected RA requires prompt (ideally within 6 weeks of symptom onset) rheumatology referral given the window-of-opportunity for treatment response.