Musculoskeletal · PANCE / PANRE

Rheumatoid Arthritis (RA)

Written & clinically reviewed by Ryan Busch, PA-C · Updated August 2026 · Report an error

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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Question 1MusculoskeletalMedium
A 40-year-old man with seropositive rheumatoid arthritis has persistent morning stiffness and swollen, tender wrists and metacarpophalangeal joints despite an adequate 6-month trial of subcutaneous methotrexate 20 mg weekly with folic acid. His Disease Activity Score 28 (DAS28) is 4.2, indicating moderate disease activity. He has no active infection, and tuberculosis and hepatitis B screening are negative. Which of the following is the most appropriate next step in management?
  • AAdd a TNF inhibitor
  • BIncrease methotrexate to 25 mg
  • CSwitch to hydroxychloroquine
  • DAdd low-dose prednisone
Reveal answer & full explanation
Correct answer: A — Add a TNF inhibitor
  • AAdd a TNF inhibitor✓
  • BIncrease methotrexate to 25 mg
  • CSwitch to hydroxychloroquine
  • DAdd low-dose prednisone

Why Add a TNF inhibitor is correct

  • Moderate rheumatoid arthritis activity (DAS28 4.2) persisting after an adequate 6-month trial of methotrexate meets the definition of an inadequate response to conventional synthetic DMARD therapy.
  • Per current ACR rheumatoid arthritis guidance, the next step after inadequate response to maximally tolerated methotrexate is to add a biologic or targeted synthetic DMARD; a TNF inhibitor (etanercept, adalimumab, infliximab) is a standard first choice.
  • Tuberculosis and hepatitis B have already been screened, which is required before initiating biologic therapy.

Why the others are wrong

  • Increase methotrexate to 25 mg — after an adequate-dose, 6-month trial with persistent moderate activity, marginal uptitration is not the guideline-directed step; this is a dose-optimization anchoring trap.
  • Switch to hydroxychloroquine — hydroxychloroquine is a weaker conventional DMARD used for mild disease or in combination; switching to it as monotherapy steps therapy down rather than escalating it (premature closure).
  • Add low-dose prednisone — glucocorticoids are a short-term bridge for symptom control, not a disease-modifying escalation; relying on prednisone here is the right-idea-wrong-step error.
Question 2MusculoskeletalMedium
A 68-year-old man has 3 months of symmetric synovitis of the metacarpophalangeal and proximal interphalangeal joints, sparing the distal interphalangeal joints, with morning stiffness lasting more than 1 hour. Rheumatoid factor is positive at a titer of 1:640 and anti-cyclic citrullinated peptide (anti-CCP) antibody is strongly positive. The ESR is 88 mm/h, and hand radiographs show marginal erosions. Which of the following is the most appropriate first-line treatment?
  • ALeflunomide
  • BAzathioprine
  • CMethotrexate
  • DSulfasalazine
Reveal answer & full explanation
Correct answer: C — Methotrexate
  • ALeflunomide
  • BAzathioprine
  • CMethotrexate✓
  • DSulfasalazine

Why Methotrexate is correct

  • Symmetric MCP/PIP synovitis sparing the DIP joints, prolonged morning stiffness, high-titer rheumatoid factor and anti-CCP, an elevated ESR, and marginal erosions establish rheumatoid arthritis.
  • Per ACR guidance, methotrexate is the preferred initial DMARD for DMARD-naive rheumatoid arthritis, especially with the moderate-to-high disease activity seen here, often bridged with low-dose glucocorticoids.
  • Early DMARD therapy in a treat-to-target strategy limits erosive joint damage.

Why the others are wrong

  • Leflunomide — an effective conventional DMARD, but it is reserved for patients who cannot tolerate or take methotrexate rather than used as the initial anchor drug.
  • Azathioprine — rarely used in rheumatoid arthritis and less effective at preventing erosions than methotrexate, so it is not appropriate initial therapy.
  • Sulfasalazine — an effective DMARD but a second choice to methotrexate for initial therapy in high-activity disease; right-class-wrong-first-line.
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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 classExamplesKey monitoring / cautions
Conventional (csDMARD)Methotrexate, hydroxychloroquine, sulfasalazine, leflunomideCBC/LFT/Cr q8-12 wk; HCQ — annual eye exam; teratogenic except HCQ/SSZ
TNF inhibitor (bDMARD)Etanercept, adalimumab, infliximabTB and hepatitis B screening; infection risk; demyelinating disease caution
IL-6 inhibitor (bDMARD)Tocilizumab, sarilumabGI perforation risk in diverticulitis; LFTs, lipids, neutrophil count
Anti-CD20 (bDMARD)RituximabHepatitis B reactivation; infusion reactions; useful in RF/CCP+ disease
T-cell costim (bDMARD)AbataceptLower infection risk profile; caution in COPD
JAK inhibitor (tsDMARD)Tofacitinib, baricitinib, upadacitinibBoxed 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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Commonly confused with

vs Osteoarthritisvs Psoriatic Arthritisvs Systemic Lupus Erythematosusvs Polymyalgia Rheumatica

Related Musculoskeletal diagnoses

Osteoarthritis (OA)GoutPseudogout (CPPD Disease)Systemic Lupus Erythematosus (SLE)Polymyalgia Rheumatica (PMR)Giant Cell Arteritis (GCA)FibromyalgiaAnkylosing Spondylitis (Axial Spondyloarthritis)Psoriatic Arthritis (PsA)Septic ArthritisOsteomyelitisOsteoporosisAcute Low Back Pain and Lumbar RadiculopathyLumbar Spinal Stenosis

Differentials & related conditions

Reactive Arthritis

Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA or PAEA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants; End of Rotation™ is a program of the Physician Assistant Education Association.