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This international randomized controlled trial investigated whether adding weekly oral methotrexate to standard prednisolone therapy could reduce ENL flares in adults with severe erythema nodosum leprosum, a serious inflammatory complication of leprosy. Among 137 randomized participants across four countries, approximately 62% and 74.5% experienced ENL flares requiring additional prednisolone by 24 and 48 weeks respectively, with no statistically meaningful difference between the methotrexate and placebo groups (adjusted HR 0.98 and 0.95 respectively). Methotrexate also showed no benefit across secondary outcomes including flare severity, frequency, or health-related quality of life.
Why it matters
These findings are clinically significant because methotrexate had been considered a promising, affordable steroid-sparing option for ENL, a condition that affects populations in low-resource settings and often requires prolonged corticosteroid use with serious side effects. The results indicate that clinicians should not add methotrexate to prednisolone regimens for severe ENL, and that alternative steroid-sparing strategies remain an urgent unmet need for this patient population.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Background Erythema nodosum leprosum (ENL) is a severe inflammatory complication of leprosy that often requires prolonged corticosteroid therapy which is associated with adverse effects. Methotrexate is an affordable immunomodulatory agent with limited evidence for its use in ENL treatment. We evaluated whether weekly oral methotrexate in additional to prednisolone reduces the need for additional prednisolone in adults with severe ENL. Methods and Findings We performed an international, multicentre, double-blind, randomised, placebo-controlled trial conducted at five leprosy referral centres in Ethiopia, India, Indonesia, and Nepal. Adults aged 18-60 years with severe ENL were randomised to receive oral methotrexate and prednisolone, or matching placebo and prednisolone. All participants received an identical prednisolone regime over 20 weeks and were followed for 60 weeks. The primary outcome was time to first ENL flare requiring additional prednisolone, assessed over 24 and 48 weeks. Between January 2023 and June 2024, 231 individuals were screened and 137 were randomised (68 methotrexate and prednisolone; 69 placebo and prednisolone). By 24 weeks, 85/137 (62.0%) participants experienced an ENL flare requiring additional prednisolone; the adjusted hazard ratio (HR) for methotrexate versus placebo was 0.98 (95% CI 0.62-1.54). By 48 weeks, 102/137 (74.5%) experienced an ENL flare; adjusted HR 0.95 (95% CI 0.62-1.43). Secondary outcomes were similar: methotrexate did not reduce ENL severity at first flare, flare frequency, or severity of subsequent flares. Health-related quality of life improved substantially in both groups with no evidence of a differential treatment effect. Methotrexate was generally well tolerated. The trial was registered at ClinicalTrials.gov (NCT03775460). Conclusions Oral methotrexate added to prednisolone did not reduce the requirement for additional prednisolone or delay ENL flares compared to placebo and prednisolone, and our study does not support the use of methotrexate for severe ENL.