What is the appropriate initial evaluation and management for a rheumatoid arthritis patient on low‑dose methylprednisolone 4 mg daily and methotrexate 20 mg weekly who has had a fever for seven days without other symptoms?

Urgent Evaluation for Infection in an Immunosuppressed RA Patient

This patient requires immediate and comprehensive infectious workup, as prolonged fever in someone on methotrexate and corticosteroids represents a potentially life-threatening infection until proven otherwise.

Immediate Diagnostic Approach

Priority: Rule Out Serious Infection

The combination of methotrexate 20 mg weekly and methylprednisolone 4 mg daily creates significant immunosuppression, making this patient highly vulnerable to opportunistic and typical infections 1.

Essential initial investigations:

• Complete blood count with differential – assess for leukopenia, neutropenia, or pancytopenia that could indicate bone marrow suppression from methotrexate or evolving sepsis 2, 1
• Comprehensive metabolic panel – evaluate liver transaminases (methotrexate hepatotoxicity), renal function (affects methotrexate clearance), and albumin 3, 1
• Inflammatory markers – CRP and ESR to quantify inflammatory burden
• Blood cultures (at least 2 sets) – obtain before any antibiotic administration
• Urinalysis and urine culture – common source in immunosuppressed patients
• Chest radiograph – screen for pneumonia, including atypical presentations and methotrexate-induced pneumonitis 4, 5

Critical Differential Diagnoses Beyond Infection

While infection is the primary concern, three methotrexate-related complications must be considered:

1. Methotrexate-induced pneumonitis – presents with fever, dry cough, and dyspnea; can occur even 4 weeks after drug discontinuation 4, 5. If respiratory symptoms are present or chest X-ray shows infiltrates, this diagnosis becomes urgent.

2. Methotrexate-related lymphoproliferative disorder (MTX-LPD) – rare but serious; presents with fever, night sweats, weight loss, lymphadenopathy, and can trigger macrophage activation syndrome 2. Check for lymphadenopathy, hepatosplenomegaly, and consider LDH, ferritin levels.

3. Drug-induced fever – methotrexate itself can cause fever as an adverse effect 1, but this is a diagnosis of exclusion only after thorough infectious workup.

Immediate Management Decisions

Do NOT Empirically Stop Methotrexate Initially

Continue methotrexate while completing the infectious workup unless there is evidence of:

• Severe cytopenias (absolute neutrophil count <1000/μL, platelets <50,000/μL) 3, 1
• Transaminases >3 times upper limit of normal 3
• Clinical suspicion of methotrexate pneumonitis (respiratory symptoms + infiltrates) 4, 5
• Confirmed serious infection requiring immediate immunosuppression reduction

Empiric Antibiotic Therapy

Initiate broad-spectrum antibiotics immediately if:

• Patient appears septic (hypotension, tachycardia, altered mental status)
• Neutropenia is present (ANC <1500/μL)
• Clear infectious source is identified (pneumonia, urinary tract infection, cellulitis)

The choice should cover typical and atypical organisms, considering the immunosuppressed state 2.

Corticosteroid Management

Do NOT abruptly stop methylprednisolone 4 mg daily – this patient is at risk for adrenal insufficiency after chronic corticosteroid use 6. Continue the current dose during acute evaluation. The 4 mg daily dose is relatively low and does not require immediate adjustment unless specific complications arise 3, 6.

Additional Targeted Investigations Based on Initial Findings

If chest X-ray shows infiltrates:

• High-resolution CT chest to differentiate infection vs. methotrexate pneumonitis 4, 5
• Consider bronchoscopy with bronchoalveolar lavage if diagnosis remains unclear 4

If cytopenias are present:

• Peripheral blood smear
• Reticulocyte count
• Consider bone marrow aspiration if pancytopenia with concern for MTX-LPD or macrophage activation syndrome 2

If no clear source identified after initial workup:

• Tuberculosis screening (QuantiFERON or PPD, sputum if indicated)
• HIV testing
• Viral serologies (EBV, CMV) – particularly relevant given MTX-LPD association with EBV 2
• Echocardiography if endocarditis suspected
• CT chest/abdomen/pelvis to evaluate for occult abscess, lymphadenopathy, or malignancy 2

Common Pitfalls to Avoid

Do not assume fever is simply an RA flare – immunosuppressed patients with prolonged fever require exhaustive infectious evaluation first 2, 1.

Do not delay blood cultures – obtain before antibiotics whenever possible; even a single dose can render cultures negative.

Do not overlook methotrexate pneumonitis – it can present weeks after drug discontinuation and requires high clinical suspicion 5. The absence of respiratory symptoms does not exclude it entirely.

Do not abruptly stop corticosteroids – taper slowly if discontinuation is needed; abrupt cessation risks adrenal crisis 6.

Disposition and Monitoring

This patient likely requires hospital admission for:

• Expedited diagnostic workup
• Close monitoring for clinical deterioration
• Potential empiric antibiotic therapy
• Observation for evolving signs of serious infection or methotrexate toxicity 2, 1

Outpatient management may be considered only if:

• Patient is hemodynamically stable
• No evidence of severe infection or cytopenias
• Reliable follow-up within 24-48 hours is ensured
• Initial workup (labs, cultures, imaging) can be completed urgently