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?
AIncrease methotrexate to 25 mg
BSwitch to hydroxychloroquine
CAdd low-dose prednisone
DAdd a TNF inhibitor
ESwitch to leflunomide
Reveal answer & full explanation
Correct answer: D — Add a TNF inhibitor
AIncrease methotrexate to 25 mg
BSwitch to hydroxychloroquine
CAdd low-dose prednisone
DAdd a TNF inhibitor✓
ESwitch to leflunomide
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.
Switch to leflunomide — leflunomide is a standard conventional synthetic DMARD, and EULAR does allow trying another csDMARD when poor prognostic factors are absent, but seropositivity and persistent moderate activity despite an adequate methotrexate trial are both poor prognostic factors, so guidance calls for adding a biologic or targeted synthetic DMARD to methotrexate rather than a lateral csDMARD swap that also gives up the methotrexate backbone (lateral-switch trap).
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
BSulfasalazine
CHydroxychloroquine
DMethotrexate
EAzathioprine
Reveal answer & full explanation
Correct answer: D — Methotrexate
ALeflunomide
BSulfasalazine
CHydroxychloroquine
DMethotrexate✓
EAzathioprine
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.
Hydroxychloroquine — the conditionally preferred initial conventional DMARD in DMARD-naive rheumatoid arthritis with low disease activity, but it is too weak for the high disease activity, markedly elevated ESR, and erosions here; right-drug-wrong-disease-activity.
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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
• Anti-CD20 — rituximab (especially for RF-positive, refractory disease)
• T-cell costimulation blocker — abatacept
Targeted synthetic DMARDs (JAK inhibitors) — tofacitinib, baricitinib, upadacitinib (US labeling limits use to inadequate response or intolerance to at least one TNF inhibitor; class boxed warning for death, MACE, malignancy, thrombosis, and serious infection, with greatest risk at age 50 or older with cardiovascular risk factors or smoking)
Intra-articular corticosteroid for monoarticular flare
If the first biologic (usually a TNF inhibitor) fails, switch to another biologic, generally one with a different mechanism (abatacept, IL-6 inhibitor, rituximab), or a JAK inhibitor; continue methotrexate and never combine two biologics
Complications
Joint deformity and disability
Cervical spine instability (C1-C2 subluxation)
Cardiovascular disease — accelerated atherosclerosis (leading cause of death)
EULAR 2025 — EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biologic Disease-Modifying Antirheumatic Drugs: 2025 Update (Smolen et al., Ann Rheum Dis 2026;85:991-1009)
ACR/AAHKS 2022 — 2022 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty (Goodman et al., Arthritis Care Res 2022;74:1399-1408)
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