Common Arthritis Drug Fails to Ease Severe Leprosy Complication in Global Trial

A large international clinical trial has delivered a disappointing but important verdict on one of the most hoped-for treatment advances for leprosy patients: methotrexate, a cheap and widely available immunomodulatory drug, does not reduce the need for additional steroid therapy in people suffering from severe erythema nodosum leprosum, a painful inflammatory complication of leprosy. The findings, published in PLOS Neglected Tropical Diseases, come from the MaPs in ENL trial, a multicentre, double-blind, randomised controlled study conducted at five leprosy referral centres across Ethiopia, India, Indonesia, and Nepal.

Erythema nodosum leprosum, often abbreviated ENL, is one of the most feared complications of leprosy. It is an immune-complex mediated condition that produces fever, tender skin nodules, nerve pain, and systemic inflammation, and it can recur in waves over months or even years. Standard treatment relies on high-dose corticosteroids, typically prednisolone, but prolonged steroid exposure carries a heavy burden of adverse effects, including diabetes, hypertension, osteoporosis, weight gain, and increased susceptibility to infection. Clinicians have long searched for a steroid-sparing agent that could control the inflammation while limiting this collateral damage.

Methotrexate emerged as a promising candidate. The drug, which suppresses inflammation by interfering with folate metabolism and is a mainstay of rheumatoid arthritis and psoriasis treatment, is affordable, orally administered, and already familiar to health systems in many leprosy-endemic countries. Earlier studies suggested possible benefit, but the evidence base was thin, consisting largely of small, uncontrolled observations. The ENLIST group, an international consortium of leprosy researchers, designed the MaPs in ENL trial to settle the question with rigorous methodology.

The trial enrolled adults aged 18 to 60 years with severe ENL. Between January 2023 and June 2024, 231 individuals were screened and 137 were randomised. Sixty-eight participants received weekly oral methotrexate at 15 milligrams, increased to 20 milligrams for those weighing 60 kilograms or more, in addition to prednisolone. Sixty-nine received matching placebo plus prednisolone. Critically, all participants received an identical 20-week prednisolone regimen beginning at 40 milligrams daily, ensuring that any difference in outcomes could be attributed to the methotrexate rather than to variations in steroid dosing. Participants were followed for a total of 60 weeks.

The primary outcome was the time to the first ENL flare requiring additional prednisolone, assessed at 24 and 48 weeks. The results were unambiguous. By 24 weeks, 85 of the 137 participants, or 62.0 percent, had experienced a flare requiring extra steroid therapy. The adjusted hazard ratio comparing methotrexate with placebo was 0.98, with a 95 percent confidence interval of 0.62 to 1.54, a result statistically indistinguishable from no effect. By 48 weeks, 102 participants, or 74.5 percent, had flared, and the adjusted hazard ratio was 0.95 with a confidence interval of 0.62 to 1.43. In plain terms, adding methotrexate neither delayed flares nor reduced how often patients needed rescue steroids.

Secondary outcomes told the same story. Methotrexate did not reduce the severity of ENL at the first flare, the frequency of flares, or the severity of subsequent episodes. Health-related quality of life, measured throughout the trial, improved substantially in both groups, but there was no evidence of a differential treatment effect between the methotrexate and placebo arms. On a more positive note, methotrexate was generally well tolerated, with no signal of serious safety concerns emerging from the trial data. The study was registered at ClinicalTrials.gov as NCT03775460 on 29 November 2018, and the trial’s methodological transparency, including its double-blind design and pre-specified outcomes, strengthens confidence in the null result.

The implications for clinical practice are significant. For decades, the management of severe ENL has been one of the most challenging aspects of leprosy care, and the prospect of a steroid-sparing option generated genuine enthusiasm among specialists. Methotrexate’s low cost made it especially attractive for the low-resource settings where leprosy remains endemic. The trial’s findings now mean that clinicians and guideline developers should not expect methotrexate to reduce steroid dependence in these patients, and the study’s authors state plainly that their results do not support the use of methotrexate for severe ENL.

Yet the trial also delivers valuable knowledge beyond the negative headline. It demonstrates that large, high-quality randomised trials are feasible in leprosy-endemic settings, spanning four countries and multiple referral centres with rigorous blinding and follow-up. It provides some of the best available natural history data on ENL, showing that nearly three-quarters of patients with severe disease experience flares requiring additional steroids within a year even under a standardised treatment protocol. This underscores how aggressive and persistent the condition can be, and it establishes a benchmark against which future therapies can be measured. The finding that quality of life improved substantially in both groups also offers a measure of reassurance that the standard prednisolone regimen, whatever its side-effect burden, delivers meaningful symptomatic relief.

The search for better ENL treatments now turns elsewhere. Researchers have investigated other immunomodulatory agents, including thalidomide, which remains effective in some settings but is restricted or unavailable in many countries because of its teratogenic history, as well as newer biologic approaches that remain largely untested in this population. The MaPs in ENL trial, by rigorously excluding methotrexate, helps direct attention and funding toward candidates with a stronger mechanistic rationale. For the estimated hundreds of thousands of people affected by leprosy worldwide, and for the minority who develop severe ENL reactions, the trial is a sobering reminder that progress against neglected tropical diseases often advances one carefully conducted negative result at a time. The full dataset and the collaboration behind it, coordinated through the Erythema Nodosum Leprosum International STudy Group, now constitute a foundation on which the next generation of ENL trials can be built.

Subject of Research: A randomised controlled trial of methotrexate as a steroid-sparing treatment for severe erythema nodosum leprosum

Article Title: Methotrexate and Prednisolone compared to placebo and prednisolone in the treatment of severe Erythema Nodosum Leprosum: An international multicentre, double-blind randomised controlled clinical trial—MaPs in ENL

Article References: de Barros, B., Sultana, F., Maximus, N., Pai, V. V., Wakade, A., Bhame, B., Acharya, B., Hamza, A., Getachew, A., Alinda, M. D., Listiawan, M. Y., Doni, S. N., Hagge, D. A., Napit, I., Shah, M., Darlong, J., Nicholls, P., Genser, B., Lambert, S. M., … on behalf of the Erythema Nodosum Leprosum International STudy (ENLIST) Group (2026). Methotrexate and Prednisolone compared to placebo and prednisolone in the treatment of severe Erythema Nodosum Leprosum: An international multicentre, double-blind randomised controlled clinical trial—MaPs in ENL. PLOS Neglected Tropical Diseases, 20(9), e0014739. https://doi.org/10.1371/journal.pntd.0014739

Image Credits: AI Generated

DOI: 10.1371/journal.pntd.0014739

Keywords: leprosy, erythema nodosum leprosum, methotrexate, prednisolone, randomised controlled trial, neglected tropical diseases, clinical trial, immunomodulation, corticosteroids, ENLIST, PLOS Neglected Tropical Diseases, steroid-sparing therapy