Methotrexate and Prednisolone compared to placebo and prednisolone in the treatment of Erythema Nodosum Leprosum - an international multicentre, double-blind randomised controlled clinical trial - MaPs in ENL
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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.
Author’s Summary
Why was this study done?
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Erythema nodosum leprosum (ENL) is a painful, relapsing inflammatory complication of leprosy that often requires prolonged courses of oral corticosteroids.
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Long-term corticosteroids can cause serious adverse effects including mortality in some settings
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Thalidomide is effective but is not accessible in many endemic countries.
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Methotrexate treatment is inexpensive and widely available, but high-quality evidence for its use in ENL is lacking.
What did the researchers do and find?
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We conducted an international, multicentre, double-blind randomised trial in four countries, enrolling 137 adults with severe ENL.
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Participants received either weekly oral methotrexate or identical placebo tablets, and 20-week course of oral prednisolone
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Methotrexate did not reduce the likelihood of ENL flares needing additional prednisolone at 24 or 48 weeks, nor did it reduce flare severity or overall flare burden.
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Quality of life improved markedly but with no clear difference between treatment groups.
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Methotrexate was generally well tolerated
What do these findings mean?
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Adding methotrexate to prednisolone does not provide clinically meaningful corticosteroid-sparing benefit for severe ENL.
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New therapies for severe ENL are required because even with high quality care corticosteroids are required at high doses for prolonged periods in most people
