What is the most likely diagnosis in a 52‑year‑old man with recurrent joint pain, recurrent rash, elevated C‑reactive protein and erythrocyte sedimentation rate, and normal antinuclear antibody, rheumatoid factor, and uric acid levels?

Most Likely Diagnosis: Seronegative Rheumatoid Arthritis or Undifferentiated Peripheral Inflammatory Arthritis

The most likely diagnosis in this 52-year-old man with recurrent joint pain, recurrent rash, markedly elevated inflammatory markers (CRP 48 mg/L, ESR 52 mm/hr), and negative RF, ANA, and uric acid is seronegative rheumatoid arthritis (RA) or undifferentiated peripheral inflammatory arthritis (UPIA) requiring systematic evaluation. 1

Key Diagnostic Considerations

Seronegative Rheumatoid Arthritis (Primary Consideration)

• Seronegative RA accounts for 20–30% of all RA cases and does not exclude the diagnosis when RF and anti-CCP are negative. 1 Clinical synovitis with elevated inflammatory markers takes precedence over serologic findings. 1

• The combination of recurrent joint pain with markedly elevated CRP (48 mg/L) and ESR (52 mm/hr) strongly indicates active inflammatory arthritis rather than non-inflammatory conditions like osteoarthritis. 1 CRP levels this high represent severe systemic inflammation far beyond what would be expected in degenerative disease. 1

• Symmetric involvement of small joints (hands/feet), morning stiffness ≥30 minutes (ideally ≥1 hour), and polyarticular involvement are characteristic features that should be specifically assessed on examination. 1, 2

Critical Differential Diagnoses to Exclude

• Psoriatic arthritis can present identically with polyarticular involvement, elevated CRP, and negative RF/anti-CCP. 1 Perform meticulous skin examination for psoriatic plaques, nail pitting, onycholysis, or dactylitis to distinguish this from RA. 1

• Adult-onset Still's disease must be considered given the recurrent rash. Look specifically for high-spiking fevers, salmon-pink evanescent rash, and markedly elevated serum ferritin (>1,000 ng/mL) as hallmarks. 1 ESR elevation occurs in 95–98% of Still's disease cases. 3

• Reactive arthritis should be evaluated if there is history of recent conjunctivitis, urethritis, or gastrointestinal/genitourinary infection. 1 HLA-B27 testing is indicated if axial or entheseal involvement is present. 1

• Polymyalgia rheumatica is possible in this age group but typically presents with bilateral shoulder and hip girdle pain without true synovitis, which differs from the joint pain described. 1

Essential Immediate Workup

Mandatory Laboratory Tests

• Anti-CCP antibodies (anti-citrullinated protein antibodies) must be ordered immediately alongside RF, as anti-CCP has 90% specificity and 60% sensitivity for RA. 1 Both should be tested simultaneously at initial presentation. 1

• Complete blood count with differential to assess for cytopenias and calculate disease activity scores. 1

• Comprehensive metabolic panel including liver enzymes, renal function, glucose, and urate to establish baseline before DMARD therapy. 1

• Serum ferritin to evaluate for Still's disease, as ferritin is markedly elevated (>1,000 ng/mL) in this condition. 1, 4

• Urinalysis as part of standard initial workup. 1

Imaging Studies

• Bilateral hand, wrist, and foot radiographs immediately. 1 The presence of erosions on baseline films is highly predictive of RA diagnosis and persistent disease. 1 Look for periarticular osteopenia, uniform joint space narrowing, and marginal erosions. 1

• If clinical examination shows no definite synovitis but suspicion remains high, order ultrasound with Power Doppler or MRI. 1 Ultrasound is 75% more accurate than physical examination for detecting subclinical synovitis. 1 MRI with IV contrast detects bone marrow edema (osteitis), the strongest predictor of future erosive progression. 1

Detailed Clinical Assessment Required

Focused Joint Examination

• Perform 28-joint count assessment examining proximal interphalangeal joints (PIPs), metacarpophalangeal joints (MCPs), wrists, elbows, shoulders, and knees for tenderness and swelling. 1 Look specifically for soft tissue swelling (boggy, synovial) rather than hard bony enlargement. 1

• Squeeze test of MCPs and MTPs—pain on compression indicates synovitis and supports inflammatory arthritis. 1

• Document duration of morning stiffness (>30 minutes strongly suggests inflammatory arthritis; ≥1 hour is characteristic of RA). 1, 2

Rash Characterization

• Describe the rash in detail: location, morphology, timing relative to joint symptoms, and whether it is evanescent (appears and disappears rapidly, suggesting Still's disease). 1

• Examine for psoriatic features including scalp involvement, extensor surfaces, intergluteal cleft, and nail changes. 1

Application of 2010 ACR/EULAR Classification Criteria

Calculate the classification score (≥6/10 points confirms RA): 1

• Joint involvement: Score based on number and size of involved joints (up to 5 points). 1
• Serology: Negative RF and ACPA = 0 points (but does not exclude RA). 1
• Acute phase reactants: Abnormal CRP (48 mg/L) or ESR (52 mm/hr) = 1 point. 1
• Symptom duration: ≥6 weeks = 1 point. 1

Critical Clinical Pearls

• Do not delay treatment waiting for positive serology. Seronegative RA is common (20–30% of cases) and has similar prognosis to seropositive disease. 1 Clinical synovitis with elevated inflammatory markers is sufficient to initiate therapy. 1

• Do not dismiss the diagnosis based on normal RF/ANA. 1 Approximately 50% of patients with active RA can have normal acute phase reactants, though this patient's markedly elevated CRP and ESR make active inflammation certain. 5, 6

• CRP of 48 mg/L predicts aggressive disease with high risk of radiographic progression if untreated. 1 This level of elevation indicates the need for urgent rheumatology referral and early DMARD therapy. 1

• Refer to rheumatology within 6 weeks of symptom onset if inflammatory arthritis is suspected, as early treatment prevents irreversible joint damage. 1 Given the recurrent nature and elevated markers, referral should be expedited. 1

Prognostic Implications

• Persistently elevated CRP at diagnosis predicts severe disease with high risk of progressive joint erosions and functional deterioration. 1 This patient's CRP of 48 mg/L places him in a high-risk category requiring aggressive treatment. 1

• The presence of erosions on baseline radiographs (if found) is highly predictive of aggressive disease and disease persistence. 1