Diagnostic Approach to Progressive Polyarthralgia with Negative Serology
This patient has undifferentiated peripheral inflammatory arthritis (UPIA) requiring systematic evaluation to identify the underlying cause, with seronegative rheumatoid arthritis, reactive arthritis, and early spondyloarthropathy as the leading diagnostic considerations. 1, 2, 3
Immediate Clinical Assessment
Perform a detailed 28-joint examination assessing proximal interphalangeal joints (PIPs), metacarpophalangeal joints (MCPs), wrists, elbows, shoulders, and knees for tenderness, swelling, and range of motion to identify definite clinical synovitis—not just arthralgia. 1, 2 Document the specific pattern: is this migratory (moving from joint to joint over days), additive (accumulating joints), or symmetric? 1, 4 Migratory polyarthritis suggests acute rheumatic fever or reactive arthritis, while symmetric small joint involvement points toward seronegative RA. 1, 3
Assess morning stiffness duration. If exceeding 30-60 minutes with multiple joint involvement, this strongly suggests inflammatory arthritis rather than mechanical causes. 2, 4 Perform a squeeze test of MCPs and metatarsophalangeal joints (MTPs) to assess for clinical synovitis. 2
Examine for extra-articular features: skin for psoriatic plaques or nail changes (psoriatic arthritis), conjunctivitis or urethritis (reactive arthritis), axial/entheseal involvement including sacroiliitis (spondyloarthropathy), and any rash distribution. 1, 4
Essential Laboratory Workup
Despite negative initial serology, order the following tests immediately:
- Anti-CCP antibodies if not already done—these have 90% specificity for RA and can be positive when RF is negative. 1, 2
- Repeat ESR and CRP to establish baseline inflammatory burden and for serial monitoring. Normal inflammatory markers do NOT exclude inflammatory arthritis, as 20-30% of RA patients can have normal acute phase reactants even with active disease. 1, 2, 3
- Complete blood count with differential to assess for cytopenias before any treatment. 1, 2
- HLA-B27 typing if there is any axial involvement, back pain, entheseal involvement, or features suggesting spondyloarthropathy or reactive arthritis. 1, 4
- ASO titers and throat culture if migratory polyarthritis is present to exclude acute rheumatic fever. 1, 3
- Hepatitis B, C, and HIV serologies as viral arthritis can mimic early RA and these are required before any immunosuppressive therapy. 2, 3, 4
Imaging Studies
Obtain bilateral hand, wrist, and foot X-rays at baseline. The presence of erosions is highly predictive for RA diagnosis and disease persistence, even in seronegative patients. 1, 2 These serve as critical baseline for monitoring structural damage progression. 1, 2
If clinical examination shows no definite synovitis but suspicion remains high, order ultrasound with Power Doppler or MRI. These modalities detect subclinical synovitis that predicts disease progression and can be diagnostic when clinical findings are equivocal. 2 MRI is more sensitive in early stages and detects bone marrow edema (osteitis), which is the best single predictor of future disease progression. 2
Critical Diagnostic Considerations
Seronegative RA accounts for 20-30% of all RA cases and has similar prognosis to seropositive disease. 2, 3 Negative RF and anti-CCP do NOT exclude RA—the diagnosis is primarily clinical based on definite synovitis in at least one joint not better explained by another disease. 1, 2
Do not delay evaluation or dismiss the diagnosis based on normal inflammatory markers. ESR and CRP are poor predictors of persistent arthritis and can be normal even in active inflammatory disease. 1, 2 Clinical synovitis on examination trumps laboratory values. 2
Exclude reactive arthritis by taking careful history of preceding genitourinary or gastrointestinal infections within the past 1-6 weeks. 1, 3 Look for oligoarthritis of large joints (knees, ankles, wrists) with conjunctivitis, urethritis, or back pain suggesting sacroiliitis. 1
Consider polymyalgia rheumatica if the patient is elderly with proximal muscle pain and stiffness in shoulders/hips without true weakness, though this typically has markedly elevated inflammatory markers. 1, 5
Rheumatology Referral
Refer to rheumatology within 6 weeks of symptom onset if any of the following are present: clinical synovitis (joint swelling on examination), small joints of hands or feet affected, more than one joint affected, symptoms persist despite initial management, or diagnostic uncertainty with progressive symptoms. 2, 3 Early referral is critical as early treatment prevents irreversible joint damage. 2
Monitoring Strategy
If UPIA is diagnosed, repeat clinical assessment with inflammatory markers every 4-6 weeks. 1, 4 UPIA is an exclusion diagnosis that must be constantly rethought, as patients may develop features of a specific diagnosis over time. 2 Repeat hand, wrist, and foot X-rays at 6 months to monitor for radiographic progression. 2
Common Pitfalls to Avoid
- Do not rely solely on autoantibody testing—clinical context and examination findings are paramount. 3, 4
- Do not assume normal CRP/ESR excludes inflammatory arthritis—up to 30% of RA patients have normal acute phase reactants. 1, 2
- Do not delay treatment waiting for positive serology—seronegative inflammatory arthritis requires the same aggressive approach as seropositive disease. 2, 3
- Prior NSAID use can mask the migratory pattern of acute rheumatic fever or reactive arthritis—take careful medication history. 1, 3