What is the most likely diagnosis in a 52-year-old male with recurrent joint pain, hand rash, elevated C‑reactive protein and erythrocyte sedimentation rate, and negative rheumatoid factor and antinuclear antibody?

Clinical Impression: Seronegative Inflammatory Arthritis (Likely Seronegative Rheumatoid Arthritis)

This 52-year-old male with recurrent joint pain, hand rash, and markedly elevated inflammatory markers (CRP 48 mg/L, ESR 52 mm/h) despite negative RF and ANA most likely has seronegative inflammatory arthritis, with seronegative rheumatoid arthritis being the leading diagnosis.

Diagnostic Reasoning

Seronegative RA accounts for 20–30% of all rheumatoid arthritis cases and does not exclude the diagnosis—clinical synovitis takes precedence over serologic findings. 1 The combination of recurrent joint pain affecting the hands, elevated acute-phase reactants (CRP 48 mg/L and ESR 52 mm/h), and negative autoantibodies fits the profile of undifferentiated peripheral inflammatory arthritis (UPIA) that may evolve into definite seronegative RA. 2

Key Clinical Features Supporting Inflammatory Arthritis

• Hand involvement with rash: The presence of hand pain combined with a rash raises the differential to include psoriatic arthritis (which can present with polyarticular involvement, elevated CRP, and negative RF) or seronegative RA with extra-articular manifestations. 1 A thorough skin examination for psoriatic plaques, nail pitting, or onycholysis is essential to distinguish psoriatic arthritis from RA. 1, 3

• Markedly elevated inflammatory markers: CRP of 48 mg/L represents severe systemic inflammation far beyond non-inflammatory conditions like osteoarthritis. 1 Elevated CRP, especially at high levels, has diagnostic value for predicting RA and indicates active inflammatory disease requiring aggressive treatment. 1 ESR of 52 mm/h also suggests significant inflammation, though ESR and CRP can be discordant and are poorly correlated with disease activity in some RA patients. 4

• Negative RF and ANA: Negative RF does not exclude RA, as seronegative RA is common and has a similar prognosis to seropositive disease when treated appropriately. 1, 5 The negative ANA effectively excludes systemic lupus erythematosus as a primary diagnosis. 1

Essential Next Steps in Evaluation

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. 3 Look specifically for soft tissue swelling (boggy synovitis) rather than bony enlargement. 1

• Assess morning stiffness duration: Stiffness exceeding 30–60 minutes (ideally ≥1 hour) strongly suggests inflammatory arthritis rather than mechanical causes. 1, 3 This is a critical distinguishing feature from osteoarthritis, where stiffness is typically <30 minutes. 1

• Perform a squeeze test of MCPs and metatarsophalangeal (MTP) joints to assess for clinical synovitis—pain on compression indicates active inflammation. 1, 3

• Examine for extra-articular features: Check skin thoroughly for psoriatic plaques or nail changes (pitting, onycholysis), assess for conjunctivitis or urethritis (suggesting reactive arthritis), and evaluate for axial/entheseal involvement including sacroiliitis. 3

Critical Laboratory Work-Up

• Anti-CCP antibodies (anti-citrullinated protein antibodies): This test has 90% specificity for RA and can be positive when RF is negative. 1, 3 Anti-CCP is superior to RF for predicting erosive disease and has better diagnostic performance than inflammatory markers alone. 6

• Complete blood count with differential: Essential to assess for cytopenias before starting any disease-modifying therapy and to calculate disease activity scores. 1, 3

• Comprehensive metabolic panel: Including liver function tests, renal function, glucose, and urate levels—required before initiating methotrexate to ensure organ safety. 1, 3

• HLA-B27 typing: If there is any axial involvement, back pain, entheseal involvement, or features suggesting spondyloarthropathy or reactive arthritis. 2, 3 This is particularly important given the hand rash, which could represent reactive arthritis or psoriatic arthritis. 1

• Urinalysis: Part of the standard initial work-up for inflammatory arthritis. 2, 3

Essential Imaging Studies

• Bilateral hand, wrist, and foot X-rays at baseline: The presence of erosions on baseline radiographs is highly predictive for RA diagnosis and disease persistence, even in seronegative patients. 1, 3 Look for periarticular osteopenia, uniform joint space narrowing, and marginal erosions. 1

• Advanced imaging if clinical examination is equivocal: If clinical examination shows no definite synovitis but suspicion remains high, order ultrasound with Power Doppler or MRI. 1, 3 Ultrasound is 75% more accurate than physical examination alone for detecting synovitis. 1 MRI with IV contrast is more sensitive in early disease and detects bone marrow edema (osteitis), which is the strongest predictor of future erosive progression. 1

Differential Diagnoses to Exclude

Psoriatic Arthritis

• Can present with polyarticular involvement, elevated CRP, and negative RF. 1 The hand rash in this patient makes psoriatic arthritis a strong consideration. Careful examination for psoriatic plaques, nail changes (pitting, onycholysis), or dactylitis is essential. 1, 3

Reactive Arthritis

• Should be considered if there is recent conjunctivitis, urethritis, or gastrointestinal/genitourinary infection. 1 HLA-B27 testing is recommended when axial or entheseal manifestations are present. 1

Adult-Onset Still's Disease

• High-spiking fevers, a salmon-pink evanescent rash, and markedly elevated serum ferritin (>1,000 ng/mL) favor this diagnosis over RA. 1 Check serum ferritin if this is suspected. 7

Polymyalgia Rheumatica (PMR)

• Less likely given the hand involvement and rash, but PMR typically presents with bilateral shoulder and hip girdle pain, morning stiffness >45 minutes, and ESR >40 mm/h in patients >50 years. 7 This patient's age (52) and hand involvement make PMR less likely. 7

Critical Pitfalls to Avoid

• Do not delay treatment waiting for positive serology: Seronegative inflammatory arthritis requires the same aggressive approach as seropositive disease. 1, 3 Early treatment prevents irreversible joint damage. 1

• Do not dismiss the diagnosis based on normal inflammatory markers in future assessments: ESR and CRP are poor predictors of persistent arthritis and can be normal even in active inflammatory disease—up to 30% of RA patients have normal acute-phase reactants. 1, 3, 4 Clinical synovitis on examination takes precedence over laboratory values. 3

• Do not rely solely on autoantibody testing: Clinical context and examination findings are paramount. 3 Seronegative RA has similar clinical features to seropositive RA but may differ in severity. 8

Urgent Rheumatology Referral

Refer to rheumatology within 6 weeks of symptom onset if any of the following are present: clinical synovitis, small joints of hands or feet affected, more than one joint affected, symptoms persist despite initial management, or diagnostic uncertainty with progressive symptoms. 3 Early referral is critical to prevent irreversible joint damage, as multiple studies show better outcomes when treatment starts earlier. 1, 3

Monitoring Strategy

• Repeat clinical assessment with inflammatory markers every 4–6 weeks if UPIA is diagnosed. 3 UPIA is an exclusion diagnosis that must be constantly rethought as patients may develop features of a specific diagnosis over time. 2, 3

• Repeat hand, wrist, and foot X-rays at 6 months to monitor for radiographic progression. 3

• Use composite disease activity measures such as the Simplified Disease Activity Index (SDAI) or Clinical Disease Activity Index (CDAI) to guide treatment decisions, with a target of remission (SDAI ≤3.3) or low disease activity (SDAI ≤11). 1