What is the diagnosis and management for an adult patient with a history of autoimmune diseases, presenting with bilateral leg pain and swelling, accompanied by unilateral migratory joint pains in the lower extremities?

Bilateral Leg Pain & Swelling with Unilateral Migratory Joint Pains: Diagnostic Approach

This presentation in an adult with autoimmune disease history most likely represents seronegative inflammatory arthritis (possibly rheumatoid arthritis or reactive arthritis) or an immune-related adverse event if the patient is on immunotherapy, and requires urgent rheumatology referral within 6 weeks alongside immediate diagnostic workup. 1, 2

Immediate Clinical Assessment

Perform a focused 28-joint examination assessing proximal interphalangeal joints (PIPs), metacarpophalangeal joints (MCPs), wrists, elbows, shoulders, knees, and ankles for tenderness, swelling, and range of motion 1. The migratory pattern affecting lower extremity joints suggests either reactive arthritis (especially if large joints like knees and ankles are involved) or early inflammatory polyarthritis 3.

Key Historical Features to Document

• Morning stiffness duration: >30-60 minutes suggests inflammatory arthritis 3, 1
• Pattern of joint involvement: Symmetric small joint involvement points toward rheumatoid arthritis, while oligoarthritis of large joints with migratory pattern suggests reactive arthritis 3
• Improvement with NSAIDs vs. opioids: Response to NSAIDs/corticosteroids but not opioids strongly suggests inflammatory arthritis 3
• Immunotherapy exposure: If patient is on checkpoint inhibitors, median onset of immune-related arthritis is 38 weeks but ranges from 1-127 weeks 3
• Associated symptoms: Conjunctivitis, urethritis, back pain, or cervical pain suggest reactive arthritis with possible sacroiliitis 3

Physical Examination Priorities

• Squeeze test of MCPs and metatarsophalangeal joints (MTPs) to assess for clinical synovitis 1
• Skin examination for psoriatic plaques, nail changes, or the characteristic salmon-pink evanescent rash of Adult-Onset Still's Disease 3, 4
• Assess for extra-articular features: lymphadenopathy, splenomegaly, sore throat 4
• Vascular examination: Check femoral, popliteal, posterior tibial, and dorsalis pedis pulses to exclude peripheral arterial disease as a cause of leg pain 3

Essential Laboratory Workup

First-Line Tests (Order Immediately)

• Inflammatory markers: ESR and CRP (CRP preferred for ongoing monitoring) 1, 5
• Autoimmune panel: Rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), antinuclear antibodies (ANA) 1, 5, 2
• Complete blood count with differential: Assess for cytopenias, leukocytosis (>15×10⁹/L suggests infection or Adult-Onset Still's Disease), or anemia of chronic disease 1, 5, 4
• Comprehensive metabolic panel: Including liver function tests, renal function, glucose, and urate levels 1, 5
• Urinalysis 1, 5

Conditional Testing Based on Clinical Presentation

• HLA-B27: If symptoms suggest reactive arthritis, affect the spine, or spondyloarthropathy is suspected (axial or entheseal involvement) 1, 5, 4
• Creatine kinase (CK): If muscle weakness or pain suggests myositis 3
• Blood cultures: If fever is present or acute onset to identify bacteremia source 4

Pre-Treatment Screening (Before Starting DMARDs)

Screen for hepatitis B, hepatitis C, and tuberculosis before initiating any biologic or DMARD therapy 1, 5, 4. This is mandatory and treatment should not be delayed pending these results if inflammatory arthritis is confirmed 1.

Imaging Studies

Baseline Imaging (Order at Initial Presentation)

• Bilateral hand, wrist, and foot X-rays: Presence of erosions on baseline radiographs is highly predictive for RA diagnosis and disease persistence 1, 2
• X-rays of affected lower extremity joints: To assess for joint damage, erosions, and exclude alternative diagnoses 4

Advanced Imaging (If Diagnosis Uncertain)

• Ultrasound with Power Doppler: Superior to clinical examination for detecting subclinical synovitis when diagnosis is uncertain; can detect inflammation that predicts disease progression even when clinical examination is normal 1, 2
• MRI with IV contrast: More sensitive than ultrasound in early stages; detects bone marrow edema (osteitis), which is the best single predictor of future disease progression and functional deterioration 1

Differential Diagnosis Framework

Most Likely Diagnoses

1. Seronegative Rheumatoid Arthritis: Bilateral leg swelling with joint involvement, especially if symmetric and involving small joints 1, 2
2. Reactive Arthritis: Migratory oligoarthritis of large joints (knees, ankles) with possible conjunctivitis, urethritis, or back pain 3
3. Immune-Related Inflammatory Arthritis: If patient is on checkpoint inhibitors (CTLA-4 or PD-1/PD-L1 antagonists) 3
4. Polymyalgia Rheumatica-like Syndrome: Bilateral shoulder and/or hip pain with morning stiffness, possible swelling of hands and knees 3

Critical Diagnoses to Exclude

• Peripheral Arterial Disease: Check ankle-brachial index (ABI) if pulses are diminished; claudication symptoms are relieved with rest within 10 minutes 3
• Deep Venous Thrombosis: Unilateral leg swelling below the knee commonly results from DVT 6
• Septic Arthritis: Requires joint aspiration if infection is suspected 5
• Adult-Onset Still's Disease: High-spiking fevers (>39°C), characteristic salmon-pink rash, and arthritis/arthralgias 4

Diagnostic Algorithm

1. If clinical synovitis is present in ≥1 joint: Apply 2010 ACR/EULAR criteria scoring system (score ≥6/10 confirms definite RA) 1
2. If no definite synovitis but high suspicion: Consider ultrasound with Power Doppler or MRI to detect subclinical synovitis 1
3. If migratory pattern with large joint oligoarthritis: Consider reactive arthritis; check HLA-B27 and assess for extra-articular features 3, 1
4. If on immunotherapy: Evaluate for immune-related adverse events; initiate NSAIDs for mild symptoms, hold immunotherapy and start prednisone 10-20 mg/day for moderate symptoms 3

Immediate Management Considerations

If Inflammatory Arthritis is Confirmed

• Refer to rheumatology within 6 weeks of symptom onset; early treatment prevents irreversible joint damage 1
• Initiate methotrexate 15 mg weekly as first-line DMARD without delaying for complete serologic workup 1
• Consider short-term low-dose prednisone (10-20 mg daily) as bridge therapy while awaiting DMARD effect 3, 1
• Target remission (SDAI ≤3.3) or low disease activity (SDAI ≤11) with reassessment every 4-6 weeks 1

If Immune-Related Adverse Event (on Checkpoint Inhibitors)

• Grade 1 (mild pain/inflammation): Continue immunotherapy; initiate acetaminophen and/or NSAIDs 3
• Grade 2 (moderate pain limiting instrumental activities): Hold immunotherapy temporarily; initiate prednisone 10-20 mg/day; refer to rheumatology early 3
• Grade 3-4 (severe pain limiting self-care): Hold immunotherapy; refer to rheumatology; initiate prednisone 20 mg/day or higher; consider corticosteroid-sparing agents (methotrexate or IL-6 inhibition with tocilizumab) 3

Critical Pitfalls to Avoid

• Do not delay treatment waiting for positive serology: Seronegative RA accounts for 20-30% of cases and has similar prognosis 1
• Do not dismiss diagnosis based on normal ESR/CRP: Acute phase reactants are poor predictors and can be normal even in active disease 1
• Do not attribute bilateral leg swelling solely to venous insufficiency without excluding inflammatory arthritis, especially with joint pain 6
• Do not miss peripheral arterial disease: Distinguish vascular claudication (relieved with rest within 10 minutes) from inflammatory arthritis (morning stiffness >30 minutes) 3

Monitoring Strategy

• Repeat inflammatory markers (CRP, ESR) every 4-6 weeks after treatment initiation 1, 5
• Repeat X-rays at 6 and 12 months to monitor radiographic progression 1
• Serial rheumatologic examinations with 28-joint count every 4-6 weeks 1