Musculoskeletal · PANCE / PANRE

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

DMARD classes for rheumatoid arthritis — start with methotrexate; escalate to biologics or JAK inhibitors if inadequate response.

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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