What is the differential diagnosis for a patient with recurrent migratory episodic large and small joint arthralgias (joint pain) lasting 2-3 days, recurring every 3-4 days, without joint swelling, early morning stiffness, or low back ache, and with negative Rheumatoid Factor (RF) and Anti-Cyclic Citrullinated Peptide (Anti-CCP) antibodies, and a normal pelvic X-ray?

Differential Diagnosis for Recurrent Migratory Episodic Arthralgias

The most likely diagnosis is palindromic rheumatism, a condition characterized by recurrent, self-limited episodes of joint pain and swelling that resolve completely without residual damage, particularly in seronegative patients with this exact temporal pattern. 1, 2

Primary Differential Diagnoses

1. Palindromic Rheumatism (Most Likely)

• This presentation is classic for palindromic rheumatism: recurrent episodes of acute oligoarthritis lasting 2-3 days with complete resolution, no radiographic changes, and the characteristic episodic pattern with symptom-free intervals. 1, 2
• The absence of joint swelling, negative RF and anti-CCP, and normal pelvic X-ray strongly support this diagnosis over established rheumatoid arthritis. 2, 3
• Critical prognostic point: 30-50% of palindromic rheumatism patients eventually develop rheumatoid arthritis, especially those who are seropositive for RF or anti-CCP—your patient's seronegativity suggests lower risk of progression. 2
• In seronegative patients with palindromic rheumatism, there is a high frequency of MEFV mutations, suggesting overlap with autoinflammatory diseases. 2

2. Early/Evolving Rheumatoid Arthritis

• Seronegative RA accounts for 20-30% of all RA cases and cannot be excluded based on negative antibodies alone. 4, 5
• However, the absence of clinical synovitis (no joint swelling), absence of morning stiffness, and the complete resolution between episodes makes established RA less likely at this time. 4, 6
• The migratory pattern without persistent joint involvement is atypical for RA, which characteristically shows symmetric, additive joint involvement. 6
• Key distinguishing feature: RA typically presents with morning stiffness lasting >30-60 minutes and palpable synovitis, both absent in this case. 4, 5, 6

3. Acute Rheumatic Fever (ARF)

• Migratory polyarthritis is a hallmark of ARF, with arthritis highly responsive to NSAIDs and salicylates. 7
• The American Heart Association notes that prior NSAID use can mask the classic migratory nature of ARF polyarthritis, making careful medication history essential. 7
• Critical consideration: In moderate- to high-incidence populations, polyarthralgia alone can be a major manifestation of ARF after excluding other causes. 7
• Must evaluate for: evidence of recent group A streptococcal infection (ASO titers, anti-DNase B), cardiac involvement (echocardiography), and other Jones criteria. 7

4. Reactive Arthritis/Seronegative Spondyloarthropathy

• The absence of low back pain and normal pelvic X-ray makes axial spondyloarthropathy less likely, but peripheral reactive arthritis remains possible. 7, 5
• Key features to assess: history of preceding gastrointestinal or genitourinary infection, entheseal involvement, conjunctivitis, urethritis, or skin manifestations. 5, 8
• HLA-B27 testing should be considered if there is any axial involvement, back pain, or entheseal symptoms. 7, 4, 5

5. Systemic Autoinflammatory Disorders (Periodic Fever Syndromes)

• These conditions can present with recurrent episodes of arthritis/arthralgia with symptom-free intervals. 1, 2
• Evaluate for: fever during episodes, family history, ethnic background (Mediterranean ancestry for Familial Mediterranean Fever), and other systemic features like serositis or rash. 1, 2

6. Viral Arthritis

• Several viral infections cause migratory polyarthralgia, including parvovirus B19, hepatitis B/C, and arboviral infections. 7
• Typically self-limited but can have a relapsing-remitting course in some cases. 7

Essential Diagnostic Workup

Immediate Laboratory Testing

• Repeat inflammatory markers (ESR and CRP) during an acute episode, as normal values between episodes do not exclude inflammatory arthritis. 7, 4, 5
• Anti-CCP antibodies if not already done, as they have 90% specificity for RA and can be positive when RF is negative. 4, 5, 8
• Complete blood count with differential to assess for cytopenias and systemic inflammation. 7, 4, 5
• Comprehensive metabolic panel including liver function, renal function, and uric acid to exclude metabolic causes and establish baseline. 4, 5
• Streptococcal serology (ASO titers, anti-DNase B) to evaluate for recent streptococcal infection suggesting ARF. 7
• HLA-B27 testing if any features suggest spondyloarthropathy or reactive arthritis. 7, 4, 5
• Viral serology including parvovirus B19 IgM, hepatitis B and C if clinically indicated. 7

Advanced Imaging During Acute Episode

• Ultrasound with Power Doppler of affected joints during an acute episode can detect synovial effusion versus synovial proliferation—the latter suggests evolution toward RA. 9, 3
• Synovial effusion alone without proliferation supports palindromic rheumatism, while both effusion and proliferation suggest conversion to early RA. 3
• Baseline bilateral hand, wrist, and foot X-rays to document absence of erosions and serve as baseline for monitoring. 7, 4, 5
• MRI of hands and wrists can detect subclinical synovitis, bone marrow edema, or early erosions not visible on plain radiographs, which would suggest evolving RA. 7, 9

Clinical Assessment

• Detailed 28-joint examination during an acute episode assessing PIPs, MCPs, wrists, elbows, shoulders, and knees for tenderness, swelling, and warmth. 4, 5, 8
• Squeeze test of MCPs and MTPs to assess for clinical synovitis. 7, 5
• Document morning stiffness duration—exceeding 30-60 minutes suggests inflammatory arthritis. 4, 5, 8
• Thorough skin examination for psoriatic plaques, nail changes, or rash. 5, 8
• Assess for extra-articular features: conjunctivitis, urethritis, entheseal tenderness, or cardiac findings. 7, 5

Critical Management Considerations

Monitoring Strategy

• Repeat clinical assessment with inflammatory markers every 4-6 weeks to monitor for evolution toward persistent inflammatory arthritis. 7, 5
• Repeat hand, wrist, and foot X-rays at 6 months to monitor for radiographic progression. 7, 5
• Serial ultrasound examinations can identify the period of conversion from palindromic rheumatism to early RA by detecting synovial proliferation. 3

Rheumatology Referral

• Refer to rheumatology within 6 weeks if any of the following develop: clinical synovitis on examination, persistent symptoms beyond typical episode duration, development of morning stiffness >30 minutes, or diagnostic uncertainty with progressive symptoms. 4, 5

Treatment Considerations

• Antimalarial therapy (hydroxychloroquine) may delay progression to RA or other connective tissue diseases in palindromic rheumatism. 2
• NSAIDs during acute episodes for symptomatic relief, but document response as ARF arthritis is characteristically highly responsive to salicylates. 7

Common Pitfalls to Avoid

• Do not dismiss the diagnosis based on negative RF and anti-CCP—seronegative inflammatory arthritis is common and requires the same vigilant monitoring. 4, 5
• Do not assume normal inflammatory markers exclude inflammatory disease—ESR and CRP can be normal even in active inflammatory arthritis, particularly between episodes. 7, 4, 5
• Do not delay evaluation waiting for positive serology—clinical findings take precedence over laboratory values. 4, 5
• Carefully document any prior NSAID use, as this can mask the classic migratory pattern of ARF or reactive arthritis. 7, 5
• Do not overlook the possibility of ARF in endemic areas—the migratory pattern and episodic nature are characteristic, and cardiac involvement can be subclinical. 7