Rheumatoid Arthritis (RA)
Chronic symmetric inflammatory polyarthritis with autoantibodies and erosive joint damage.
Also known as: RA, rheumatoid, seropositive arthritis
Overview
Chronic systemic autoimmune disease causing symmetric inflammatory polyarthritis with synovial proliferation (pannus), articular cartilage destruction, and bony erosions. Extra-articular manifestations are common.
Epidemiology
Affects ~1% of adults worldwide. Peak onset 30-50 years; women outnumber men 2-3:1. Strong association with HLA-DRB1 'shared epitope' alleles.
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Risk factors
- Female sex
- Family history of RA or other autoimmune disease
- Cigarette smoking (strongest modifiable risk factor; interacts with HLA-DRB1)
- Periodontal disease (Porphyromonas gingivalis citrullination hypothesis)
- Obesity
- Postpartum period (relative immune rebound)
Pathophysiology
Loss of immune tolerance to citrullinated self-peptides drives B-cell production of rheumatoid factor (RF) and anti-citrullinated protein antibodies (anti-CCP). Synovial T-cell and macrophage activation produces TNF, IL-1, IL-6, and IL-17, sustaining synovitis. Hyperplastic synovium (pannus) invades cartilage and subchondral bone, with osteoclast activation (RANKL-mediated) producing characteristic marginal erosions.
Clinical presentation
Symptoms
- Insidious symmetric polyarthritis of small joints (MCP, PIP, wrists, MTPs)
- Morning stiffness lasting >1 hour, improving with activity
- Fatigue, low-grade fever, weight loss
- Hand weakness and difficulty with grip
Signs / physical exam
- Boggy, warm, tender MCP/PIP/wrist synovitis
- Sparing of DIPs (key distinction from OA and PsA)
- Late deformities: ulnar deviation, swan-neck and boutonnière deformities, Z-thumb
- Rheumatoid nodules (extensor surfaces, olecranon)
- C1-C2 instability with neck pain → anesthesia caution
Classic findings
Symmetric MCP/PIP/wrist swelling with positive MCP/MTP squeeze test, plus rheumatoid nodules in seropositive disease.
Differential diagnosis
- Osteoarthritis — DIP/CMC involvement, brief AM stiffness, normal inflammatory markers, no erosions
- Psoriatic arthritis — DIP involvement, dactylitis, nail pitting, psoriasis; RF/CCP usually negative
- Systemic lupus erythematosus — Non-erosive Jaccoud arthropathy; multisystem features; positive ANA, dsDNA
- Polymyalgia rheumatica — Age >50, proximal shoulder/hip girdle stiffness without small-joint synovitis; markedly elevated ESR
- Viral arthritis (parvovirus B19, hepatitis C, chikungunya) — Acute symmetric polyarthritis with recent viral illness; usually self-limited <6 weeks
- Crystal arthropathy (polyarticular gout, CPPD) — Crystals on arthrocentesis; tophi or chondrocalcinosis
- Reactive arthritis — Oligoarticular, asymmetric, lower-extremity predominant; preceded by GU/GI infection
Diagnostic workup
Diagnostic criteria
2010 ACR/EULAR classification: score ≥6 of 10 across (a) joint involvement, (b) serology (RF/anti-CCP), (c) acute-phase reactants, and (d) symptom duration ≥6 weeks classifies as RA.
Labs
- RF and anti-CCP (anti-CCP higher specificity; both predict erosive disease)
- ESR and CRP (elevated, used to track activity)
- CBC (normocytic anemia of chronic disease), CMP, LFTs
- ANA (often positive but nonspecific)
- Hepatitis B/C and TB screening before biologic therapy
- Arthrocentesis if monoarticular flare or to exclude septic arthritis: inflammatory fluid WBC 2,000-50,000
Imaging
- Plain radiographs of hands and feet — periarticular osteopenia, symmetric joint-space narrowing, marginal erosions (MTPs often earliest)
- Ultrasound or MRI — more sensitive for early synovitis and erosions before plain-film changes
- Cervical spine flexion/extension films in established disease to assess atlantoaxial subluxation prior to surgery or intubation
Diagnostic algorithm
| DMARD class | Examples | Key monitoring / cautions |
|---|---|---|
| Conventional (csDMARD) | Methotrexate, hydroxychloroquine, sulfasalazine, leflunomide | CBC/LFT/Cr q8-12 wk; HCQ — annual eye exam; teratogenic except HCQ/SSZ |
| TNF inhibitor (bDMARD) | Etanercept, adalimumab, infliximab | TB and hepatitis B screening; infection risk; demyelinating disease caution |
| IL-6 inhibitor (bDMARD) | Tocilizumab, sarilumab | GI perforation risk in diverticulitis; LFTs, lipids, neutrophil count |
| Anti-CD20 (bDMARD) | Rituximab | Hepatitis B reactivation; infusion reactions; useful in RF/CCP+ disease |
| T-cell costim (bDMARD) | Abatacept | Lower infection risk profile; caution in COPD |
| JAK inhibitor (tsDMARD) | Tofacitinib, baricitinib, upadacitinib | Boxed warning: MACE, malignancy, VTE, mortality in CV-risk patients >50 |
Treatment
First-line
- Early DMARD therapy within 3 months of diagnosis — methotrexate is anchor drug; start 10-15 mg PO/SC weekly with folic acid 1 mg daily
- Conventional DMARDs — methotrexate, hydroxychloroquine, sulfasalazine, leflunomide (often combined as 'triple therapy')
- Bridging low-dose prednisone (≤10 mg/day) until DMARD takes effect; taper as tolerated
- NSAIDs — ibuprofen, naproxen, meloxicam for symptomatic relief (do not modify disease)
Second-line / adjunct
- Biologic DMARDs if inadequate response to methotrexate after 3-6 months:
- • TNF inhibitors — etanercept, adalimumab, infliximab, golimumab, certolizumab
- • IL-6 inhibitor — tocilizumab, sarilumab
- • Anti-CD20 — rituximab (especially for RF-positive, refractory disease)
- • T-cell costimulation blocker — abatacept
- Targeted synthetic DMARDs (JAK inhibitors) — tofacitinib, baricitinib, upadacitinib (boxed warning for MACE, malignancy, VTE in patients >50 with cardiovascular risk)
- Intra-articular corticosteroid for monoarticular flare
Complications
- Joint deformity and disability
- Cervical spine instability (C1-C2 subluxation)
- Cardiovascular disease — accelerated atherosclerosis (leading cause of death)
- Felty syndrome — RA + splenomegaly + neutropenia
- Secondary Sjögren syndrome
- Interstitial lung disease, pleural effusion (exudative, low glucose)
- Rheumatoid vasculitis (skin ulcers, mononeuritis multiplex)
- Increased risk of lymphoma (especially with poorly controlled disease)
- Infection risk from immunosuppression
PANCE pearls
- DIP sparing is a hallmark of RA — DIP involvement should prompt consideration of OA or psoriatic arthritis.
- Anti-CCP is more specific than RF and may precede clinical disease by years.
- Methotrexate is contraindicated in pregnancy and significant hepatic or renal disease; alcohol must be limited.
- Always rule out septic arthritis in a single hot, swollen joint in an RA patient — they are at higher infection risk.
References
- ACR 2021 — 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis (Fraenkel et al., Arthritis Care Res 2021)
- ACR/EULAR 2010 — 2010 Rheumatoid Arthritis Classification Criteria (Aletaha et al., Arthritis Rheum 2010)
- EULAR 2022 — EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological DMARDs: 2022 Update (Smolen et al., Ann Rheum Dis 2023)
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