Do patients with eosinophilic granulomatosis with polyangiitis require trimethoprim‑sulfamethoxazole (cotrimoxazole) prophylaxis, and what does current evidence indicate?

Cotrimoxazole Prophylaxis in EGPA: Not Routinely Indicated

Patients with EGPA do NOT routinely require cotrimoxazole prophylaxis unless they are receiving cyclophosphamide or rituximab for severe disease. The current evidence clearly distinguishes EGPA from other ANCA-associated vasculitides (particularly GPA) in this regard.

When Cotrimoxazole IS Indicated in EGPA

For patients with EGPA receiving cyclophosphamide or rituximab, cotrimoxazole prophylaxis is conditionally recommended to prevent Pneumocystis jirovecii pneumonia 1. This recommendation is based on low-quality evidence but follows standard practice for patients on intensive immunosuppression.

• Dosing for PJP prophylaxis: One double-strength tablet (800 mg sulfamethoxazole/160 mg trimethoprim) daily 2
• Duration: Continue throughout treatment with cyclophosphamide or rituximab and for a period after discontinuation

When Cotrimoxazole Is NOT Indicated in EGPA

The evidence for cotrimoxazole in EGPA differs fundamentally from GPA:

Key Distinction from GPA

In granulomatosis with polyangiitis (GPA), cotrimoxazole has a dual role:

1. PJP prophylaxis during intensive immunosuppression
2. Relapse prevention - reduces relapses by 40% (relative risk 0.40) in GPA patients in remission 3

However, this relapse-prevention benefit has NOT been demonstrated in EGPA. The 2021 ACR/Vasculitis Foundation guideline 1 and the 2023 Nature Reviews Rheumatology guideline 4 make no mention of cotrimoxazole for relapse prevention in EGPA, only for PJP prophylaxis during cyclophosphamide/rituximab therapy.

Why the Difference?

The mechanism by which cotrimoxazole prevents relapses in GPA is thought to involve:

• Suppression of Staphylococcus aureus nasal carriage 5
• Anti-inflammatory effects 5

These mechanisms are relevant to GPA's upper respiratory tract pathophysiology but do not apply to EGPA's distinct pathogenesis, which centers on eosinophilic inflammation and IL-5-mediated mechanisms rather than granulomatous upper airway disease.

Treatment Algorithm for EGPA

For severe EGPA (FFS ≥1, peripheral neuropathy, alveolar hemorrhage, or organ-threatening disease):

• Induction: High-dose glucocorticoids + cyclophosphamide OR rituximab 4, 1
• Add cotrimoxazole prophylaxis (one DS tablet daily) 1
• Maintenance: Glucocorticoids + rituximab and/or mepolizumab and/or DMARDs 4

For non-severe EGPA (FFS = 0, no severe organ involvement):

• Induction: Glucocorticoids + mepolizumab (preferred) OR methotrexate/azathioprine/mycophenolate 1
• No cotrimoxazole needed unless other risk factors for PJP exist
• Maintenance: Glucocorticoids alone or with mepolizumab 4

Common Pitfalls to Avoid

1. Do not extrapolate GPA data to EGPA: The evidence supporting cotrimoxazole for relapse prevention in GPA 3, 5, 6 does not apply to EGPA's different pathophysiology

2. Monitor for drug interactions: If cotrimoxazole is used with methotrexate, be aware of potential interactions when dosed at 800/160 mg twice daily (though prophylactic dosing is generally safe) 1

3. Consider side effects: In the GPA trial, 20% of patients discontinued cotrimoxazole due to adverse effects 3

4. EGPA-specific considerations: Focus on optimizing asthma control with inhaled therapies and consider mepolizumab (IL-5 antagonist) for glucocorticoid-sparing and relapse prevention rather than cotrimoxazole 4, 1

Bottom Line

Cotrimoxazole in EGPA is reserved for PJP prophylaxis during cyclophosphamide or rituximab therapy only. Unlike GPA, there is no evidence supporting its use for relapse prevention in EGPA. The focus in EGPA management should be on appropriate immunosuppression, glucocorticoid tapering, and increasingly, targeted biologics like mepolizumab.