What is the most likely diagnosis and initial treatment for a 30‑year‑old woman with intermittent symmetric swelling of the hands and wrists, elevated erythrocyte sedimentation rate, elevated C‑reactive protein, increased total protein, and positive antinuclear antibody?

Most Likely Diagnosis: Rheumatoid Arthritis

The most likely diagnosis is rheumatoid arthritis (RA), and initial treatment should be methotrexate 15 mg weekly combined with short-term low-dose prednisone as bridge therapy, initiated immediately without waiting for complete serologic workup. 1

Diagnostic Reasoning

This 30-year-old woman presents with the classic triad for RA:

• Symmetric small joint involvement (hands and wrists) with intermittent swelling 1, 2
• Elevated inflammatory markers (ESR and CRP), which indicate active systemic inflammation 3, 1
• Positive ANA with elevated total protein, suggesting autoimmune activity 3

The symmetric involvement of small joints, particularly hands and wrists, is the hallmark presentation of RA in young women. 2, 4 Morning stiffness lasting >30 minutes would further support this diagnosis if present. 1, 5

Critical Diagnostic Features to Confirm

Clinical examination must document:

• Soft tissue swelling (boggy, not bony) at metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints 1, 5
• Positive "squeeze test" across MCPs and metatarsophalangeal (MTP) joints 1
• Duration of morning stiffness (>30 minutes suggests inflammatory arthritis) 1, 2
• Number of tender and swollen joints using 28-joint count 1

Essential Immediate Laboratory Workup

Order these tests now before starting treatment:

• Rheumatoid factor (RF) and anti-CCP antibodies - both should be ordered simultaneously, as anti-CCP has 90% specificity versus RF's 70% specificity for RA 1, 4
• Complete blood count with differential - to assess for cytopenias before starting methotrexate 1
• Comprehensive metabolic panel - including liver function tests, renal function, glucose, and urate 3, 1
• Hepatitis B, Hepatitis C, and tuberculosis screening - required before any biologic therapy 1, 4
• Baseline bilateral hand, wrist, and foot X-rays - erosions predict aggressive disease and are highly predictive for RA diagnosis 1

Do not delay treatment waiting for serology results. Seronegative RA accounts for 20-30% of cases and has similar prognosis to seropositive disease. 1

Applying the 2010 ACR/EULAR Classification Criteria

Calculate the diagnostic score (≥6/10 points = definite RA): 1

• Joint involvement: Multiple small joints (hands/wrists) = likely 3-5 points depending on exact count
• Serology: Pending RF and anti-CCP results = 0-3 points
• Acute phase reactants: Elevated ESR and CRP = 1 point
• Duration: If symptoms ≥6 weeks = 1 point

Even without serology, this patient likely meets criteria based on clinical presentation alone.

Critical Differential Diagnoses to Exclude

Psoriatic arthritis - Examine skin carefully for psoriatic plaques, nail pitting, or onycholysis. 1 This can present identically to RA but with negative RF/anti-CCP. 1

Systemic lupus erythematosus (SLE) - The positive ANA warrants checking anti-dsDNA and extractable nuclear antigens (ENA panel) to exclude lupus, though symmetric polyarthritis with elevated CRP is more consistent with RA. 3, 1

Adult-onset Still's disease - Consider if there are high spiking fevers, salmon-pink rash, or markedly elevated ferritin (>1000 ng/mL). 3 However, the symmetric small joint pattern favors RA.

Viral arthritis - Recent viral infection (parvovirus B19, hepatitis B/C, EBV) can mimic early RA but typically resolves within 6 weeks. 3 Persistent symptoms beyond 6 weeks favor RA.

Immediate Treatment Plan

Start methotrexate 15 mg weekly immediately as first-line disease-modifying antirheumatic drug (DMARD), with plan to escalate to 20-25 mg weekly if needed. 1, 4

Add short-term low-dose prednisone 10-20 mg daily as bridge therapy while awaiting DMARD effect (typically 6-12 weeks). 1 Plan to taper glucocorticoids once disease control achieved.

Prescribe folic acid 1 mg daily to reduce methotrexate toxicity. 4

Refer to rheumatology within 6 weeks of symptom onset, as early treatment prevents irreversible joint damage. 1 Do not delay referral waiting for complete workup.

Disease Activity Monitoring

Reassess every 4-6 weeks using:

• Simplified Disease Activity Index (SDAI) incorporating tender joint count, swollen joint count, patient global assessment, evaluator global assessment, and CRP 1
• Target: Remission (SDAI ≤3.3) or low disease activity (SDAI ≤11) 1
• Repeat CRP at each visit to monitor inflammatory activity 1, 6

If inadequate response after 3 months of methotrexate: Consider triple DMARD therapy (methotrexate + hydroxychloroquine + sulfasalazine) or adding a biologic agent such as a TNF inhibitor. 1

Common Pitfalls to Avoid

Do not dismiss RA diagnosis based on normal inflammatory markers in future visits - approximately 50% of patients with active RA can have normal ESR/CRP. 1 Clinical synovitis takes precedence over laboratory values.

Do not wait for positive RF/anti-CCP to start treatment - seronegative RA is common and requires the same aggressive early treatment. 1

Do not use ESR alone for monitoring - CRP is preferred as it is more reliable, not age-dependent, and changes more rapidly with disease activity. 1, 6 ESR has frequent confounding factors (anemia, renal disease, age) that make it misleading. 6

Do not delay imaging - baseline X-rays are essential to document absence of erosions and monitor for radiographic progression at 6 and 12 months. 1 If X-rays are normal but clinical suspicion remains high, consider ultrasound with Power Doppler or MRI to detect subclinical synovitis. 1