What is the best course of treatment for a patient with mononeuritis multiplex, subcutaneous swelling, and inflammation in the bilateral lower limbs with bullae, swelling of the right upper limb with weakness, elevated Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP), leukocytosis, and a history of thrombocytopenia?

Systemic Vasculitis with Mononeuritis Multiplex: Urgent Immunosuppression Required

This patient requires immediate high-dose corticosteroids combined with a steroid-sparing immunosuppressive agent (cyclophosphamide or rituximab) to prevent irreversible nerve damage and address the underlying systemic vasculitis.

Clinical Presentation Analysis

This presentation is highly concerning for systemic vasculitis with the following key features:

• Mononeuritis multiplex (asymmetric peripheral nerve involvement) 1
• Severe systemic inflammation (ESR 80, CRP 400, WBC 26,000) 2, 3
• Subcutaneous inflammation with bullae (suggesting cutaneous vasculitis) 2
• Thrombocytopenia with elevated immature platelet fraction (IPF) (indicating peripheral consumption/inflammation) 1
• ANA negative (making lupus less likely, pointing toward ANCA-associated vasculitis or polyarteritis nodosa) 2, 1

Immediate Diagnostic Workup Required

Before initiating treatment, obtain:

• ANCA panel (c-ANCA/PR3 and p-ANCA/MPO) - essential for diagnosing ANCA-associated vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis, or eosinophilic granulomatosis with polyangiitis) 2, 1
• Hepatitis B and C serologies - polyarteritis nodosa can be HBV-associated 1
• Nerve conduction studies and EMG - to document the extent of mononeuritis multiplex 2, 3, 4
• Nerve and/or skin biopsy - to confirm vasculitis histologically, though treatment should not be delayed if clinical suspicion is high 2, 4
• Complete blood count with differential - to assess eosinophilia (EGPA consideration) 1

Treatment Algorithm

Phase 1: Induction Therapy (Immediate)

Start high-dose corticosteroids immediately - do not wait for biopsy results given the risk of irreversible nerve damage 2, 3, 4:

• Methylprednisolone 1 gram IV daily for 3 days, then transition to oral prednisone 1 mg/kg/day (maximum 60-80 mg daily) 2, 3
• Mononeuritis multiplex is the single strongest predictor of treatment failure with corticosteroids alone and necessitates combination immunosuppression 1

Add steroid-sparing immunosuppressive agent within 48-72 hours 3, 1:

• Cyclophosphamide (preferred for severe vasculitis with organ-threatening disease) OR
• Rituximab (alternative with similar efficacy and potentially better safety profile) OR
• Azathioprine 150 mg/day (if cyclophosphamide/rituximab unavailable or contraindicated) 2, 3

The evidence strongly supports that mononeuritis multiplex at presentation predicts the need for immunosuppressive therapy beyond corticosteroids alone (hazard ratio 1.81, P=0.02) 1. Patients treated with corticosteroids alone have significantly higher rates of treatment failure (37%), relapse (52%), and permanent sequelae 1.

Phase 2: Monitoring Response (First 4 Weeks)

• Serial neurological examinations every 3-7 days to assess for progression or stabilization of weakness 3, 4
• Repeat inflammatory markers (ESR, CRP) weekly initially - clinical improvement is more important than complete normalization 5, 3
• Monitor for steroid and immunosuppressant toxicity (infection screening, glucose monitoring, bone protection) 6

Phase 3: Maintenance and Taper

• Continue combination therapy for minimum 6-12 months after achieving remission 3, 1
• Gradual corticosteroid taper over 6-12 months to lowest effective dose (<10 mg/day prednisone) 6, 3
• Maintain immunosuppressive agent for 18-24 months total to prevent relapse 1

Critical Prognostic Factors

Mononeuritis multiplex is a poor prognostic indicator requiring aggressive treatment 1:

• 45% of patients with mononeuritis multiplex require additional immunosuppressive therapies beyond initial treatment 1
• Mean Vasculitis Damage Index is significantly higher (2.93 vs 1.96, P<0.001) in patients requiring add-on therapies, reflecting more frequent permanent sequelae 1
• Irreversible nerve damage can occur within weeks if treatment is delayed 7, 3

Common Pitfalls to Avoid

1. Delaying immunosuppression while awaiting biopsy results - the window for preventing permanent nerve damage is narrow 3, 1

2. Using corticosteroids alone - this is inadequate for mononeuritis multiplex and leads to high rates of treatment failure and relapse 1

3. Attributing elevated inflammatory markers to infection alone - while infection must be excluded, the constellation of findings here strongly suggests vasculitis 2, 3

4. Premature steroid taper - relapses are common (52% in one series) and lead to cumulative damage 1

5. Ignoring the thrombocytopenia - while it resolved, this indicates active systemic inflammation and potential for other organ involvement 1

Rheumatology Referral

Urgent rheumatology consultation within 24-48 hours is mandatory 6, 7:

• All patients with suspected systemic vasculitis and mononeuritis multiplex require specialist input 6
• Rheumatology will guide long-term immunosuppression strategy and monitor for disease-specific complications 7, 8

The combination of mononeuritis multiplex with severe systemic inflammation represents a medical emergency requiring immediate aggressive immunosuppression to prevent irreversible neurological damage 3, 1, 4.