What is the role of Folitrax (methotrexate) in the management of leucocytoclastic vasculitis?

Methotrexate in Leucocytoclastic Vasculitis

Methotrexate (Folitrax) should be reserved as a second-line or alternative agent for severe cutaneous leucocytoclastic vasculitis that has failed first-line therapies including dapsone and systemic corticosteroids, with azathioprine being the preferred steroid-sparing immunosuppressant in this setting.

Treatment Algorithm for Leucocytoclastic Vasculitis

First-Line Therapy

• Dapsone is the initial steroid-sparing agent for cutaneous leucocytoclastic vasculitis unresponsive to supportive measures 1
• Systemic corticosteroids should be initiated for severe disease 1

Second-Line Immunosuppression

• Azathioprine combined with systemic corticosteroids is the guideline-recommended approach for severe cutaneous leucocytoclastic vasculitis unresponsive to first-line therapy, though evidence is limited to case series 1
• Methotrexate can be considered as an alternative maintenance agent in vasculitis, with evidence showing it is as effective as azathioprine for maintenance therapy in certain vasculitides 1

Methotrexate Dosing and Administration

When methotrexate is used for vasculitis:

• Dose: 20-25 mg/week (oral or parenteral), starting at 15 mg/week and escalating over 1-2 months if tolerated 1
• Route: Oral administration is standard, though parenteral (subcutaneous or intramuscular) may be more effective in patients with malabsorption 1
• Supplementation: Folic acid or folinic acid should be co-prescribed to reduce gastrointestinal toxicity 1

Evidence Quality and Positioning

The evidence for methotrexate in leucocytoclastic vasculitis specifically is limited:

• For ANCA-associated vasculitis (a different entity), methotrexate has Level 1B evidence as a less toxic alternative to cyclophosphamide for non-organ-threatening disease 1
• For cutaneous leucocytoclastic vasculitis, the evidence is restricted to case reports and small case series 1, 2, 3, 4
• Azathioprine has more established evidence in cutaneous vasculitis compared to methotrexate 1

Critical Safety Considerations

Monitoring Requirements

• Baseline: Full blood count and liver function tests before starting 1
• Ongoing: Monthly monitoring of complete blood count and liver enzymes 1
• Renal function: Methotrexate should not be used in patients with GFR <60 ml/min per 1.73 m² 5

Common Toxicities

• Gastrointestinal: Nausea, vomiting, diarrhea, and stomatitis (10-18% discontinuation rate) 1
• Hepatotoxicity: Monitor AST; withhold if AST doubles, then rechallenge after normalization 1
• Pneumonitis: Rare but serious (2-3 cases per 100 patient-years in some populations) 1

Important Paradox: Methotrexate as a Cause

Critical caveat: Methotrexate itself can paradoxically induce leucocytoclastic vasculitis, even at low doses (5-7.5 mg/week) 6, 7. This hypersensitivity reaction has been documented in rheumatoid arthritis patients and presents with:

• Hemorrhagic and necrotic cutaneous lesions 7
• Temporal relationship between methotrexate intake and vasculitis onset 6
• Resolution with drug withdrawal and recurrence with rechallenge 6, 4

This creates a clinical dilemma: methotrexate can both treat and cause leucocytoclastic vasculitis. Careful assessment of temporal relationships between drug initiation and symptom onset is essential 6, 7.

When to Choose Methotrexate Over Azathioprine

Consider methotrexate when:

• Azathioprine intolerance or contraindication exists 5
• TPMT deficiency precludes azathioprine use 1
• Concurrent rheumatoid arthritis requires treatment, as methotrexate addresses both conditions 4

Duration of Therapy

• Maintenance duration: Typically 18-24 months after achieving remission 5
• 3-year remission rate: 51% for methotrexate (compared to 69% for azathioprine in one series) 1
• Methotrexate may take longer to achieve remission compared to cyclophosphamide in patients with pulmonary involvement 1

Practical Implementation

For severe cutaneous leucocytoclastic vasculitis refractory to dapsone:

1. Initiate systemic corticosteroids (prednisolone 1 mg/kg/day) 1
2. Add azathioprine as first-choice steroid-sparing agent (evidence-based guideline recommendation) 1
3. Reserve methotrexate for azathioprine failure, intolerance, or TPMT deficiency 5
4. Start methotrexate at 15 mg/week, escalate to 20-25 mg/week over 1-2 months 1
5. Co-prescribe folic acid 5 mg two or three days apart from methotrexate 1
6. Taper corticosteroids to maintenance dose of 5-10 mg/day by 4-5 months 1