What are the possible diagnoses for a patient with migrating joint pain who is rheumatoid factor (RF) negative?

Migrating Joint Pain with Negative Rheumatoid Factor: Key Diagnoses

The most critical diagnosis to consider first is acute rheumatic fever (ARF), particularly if the patient is from a moderate- or high-risk population, followed by seronegative rheumatoid arthritis, reactive arthritis, viral arthropathies, and other seronegative spondyloarthropathies. 1, 2

Primary Differential Diagnoses

Acute Rheumatic Fever

• Migratory polyarthritis is a hallmark major criterion of ARF, characterized by joint involvement that moves from one joint to another over days 1
• The arthritis is highly responsive to salicylates and NSAIDs, which may mask the classic migratory pattern if taken before evaluation 1
• Critical pitfall: Prior NSAID use can obscure the diagnosis—always obtain a careful medication history 1
• ARF arthritis typically affects large joints (knees, ankles, elbows, wrists) in a sequential pattern 1
• Evidence of recent group A streptococcal infection (elevated ASO titers, positive throat culture) supports this diagnosis 1

Seronegative Rheumatoid Arthritis

• RF-negative RA accounts for 20-30% of all RA cases and has a similar prognosis to seropositive disease 3
• The American College of Rheumatology emphasizes that negative RF does not exclude RA 3, 4
• Anti-CCP antibodies should be measured in RF-negative patients, as they provide additional diagnostic value 1, 5
• A recent case report documented RA presenting with migratory joint pain in a 74-year-old woman who was RF-negative but anti-CCP positive 5
• Seronegative RA typically still shows symmetric small joint involvement (MCPs, PIPs, wrists, MTPs) on careful examination 2, 3
• Morning stiffness lasting ≥1 hour is characteristic 3, 6

Reactive Arthritis and Seronegative Spondyloarthropathies

• These conditions are genetically distinct from RA and closely associated with HLA-B27 7
• The American College of Rheumatology recommends careful exclusion of autoimmune, viral, or reactive arthropathies before diagnosing ARF 1
• Reactive arthritis often follows genitourinary or gastrointestinal infections 2
• Look for asymmetric oligoarthritis, enthesitis, dactylitis, and axial involvement 2, 8

Viral Arthropathies

• Multiple viral infections can cause migratory polyarthralgia including parvovirus B19, hepatitis B/C, and HIV 1, 8
• Viral arthritis is typically self-limited but can mimic early RA 1
• Screen for hepatitis B and C in all patients with unexplained polyarthritis 3, 8

Other Critical Diagnoses to Exclude

Septic arthritis must be excluded urgently, particularly if monoarticular involvement is present 1, 8

Crystal arthropathies (gout, pseudogout) can present with migratory symptoms 8

Systemic lupus erythematosus should be considered, especially with rash or systemic symptoms 1, 8

Hereditary hemochromatosis can mimic RA with chronic arthritis but lacks synovial inflammation 9

Diagnostic Algorithm

Initial Clinical Assessment

1. Document the exact pattern: Is it truly migratory (resolves in one joint as another becomes involved) or additive (accumulates joints)? 8, 6
2. Perform a 28-joint examination assessing PIPs, MCPs, wrists, elbows, shoulders, knees for tenderness and swelling 3, 8
3. Assess for clinical synovitis (joint swelling on examination, not just pain) 1, 3
4. Measure morning stiffness duration—exceeding 30-60 minutes suggests inflammatory arthritis 3, 6
5. Examine for extra-articular features: rash (erythema marginatum in ARF), nodules, psoriatic plaques, enthesitis 1, 2, 8

Essential Laboratory Workup

• Anti-CCP antibodies (high specificity 90%, moderate sensitivity 60% for RA) 3, 5
• ESR and CRP to assess inflammatory burden 1, 3, 8
• Complete blood count with differential 3, 8
• Comprehensive metabolic panel including liver and renal function 3, 8
• ANA and extractable nuclear antigens to screen for other connective tissue diseases 3, 8
• ASO titers and throat culture if ARF is suspected 1
• HLA-B27 if spondyloarthropathy is being considered 3, 8
• Hepatitis B, C, and HIV serologies 3, 8

Imaging Studies

• Bilateral hand, wrist, and foot X-rays to detect erosions, which predict RA diagnosis and disease persistence 3, 8
• Ultrasound or MRI if persistent arthritis with diagnostic uncertainty—can detect subclinical synovitis 3, 8
• Arthrocentesis if septic or crystal arthritis suspected (cell count, Gram stain, culture, crystals) 8

Critical Clinical Pitfalls

Do not delay treatment waiting for positive serology—seronegative RA is common and has similar prognosis to seropositive disease 3

Do not dismiss inflammatory arthritis based on normal ESR/CRP—acute phase reactants can be normal even in active disease 3

Prior NSAID use can mask the migratory pattern of ARF—always obtain detailed medication history 1

Autoantibody positivity alone does not make a diagnosis—clinical context is paramount 8

When to Refer to Rheumatology

Urgent referral is indicated if: 1, 8

• Clinical synovitis (joint swelling) is present on examination
• Small joints of hands or feet are affected
• More than one joint is affected
• Symptoms persist despite initial management
• Diagnostic uncertainty with complex presentations

The European League Against Rheumatism recommends urgent referral even with normal acute-phase response or negative RF if the above features are present 1