Methotrexate and prednisolone study in erythema nodosum leprosum (MaPs in ENL) protocol: a double-blind randomised clinical trial

Abstract

IntroductionErythema nodosum leprosum (ENL) is an immunological complication of leprosy. ENL results in morbidity and disability and if it is not treated can lead to death. The current treatment consists of thalidomide or high doses of oral corticosteroids for prolonged periods. Thalidomide is not available in many leprosy endemic countries. The use of corticosteroids is associated with morbidity and mortality. Identifying treatment regimens that reduce the use of corticosteroids in ENL is essential. Methotrexate (MTX) is used to treat many inflammatory diseases and has been used successfully to treat patients with ENL not controlled by other drugs, including prednisolone and thalidomide. We present the protocol of the ‘MTX and prednisolone study in ENL’ (MaPs in ENL) a randomised controlled trial (RCT) designed to test the efficacy of MTX in the management of ENL.Methods and analysisMaPs in ENL is an international multicentre RCT, which will be conducted in leprosy referral centres in Bangladesh, Brazil, Ethiopia, India, Indonesia and Nepal. Patients diagnosed with ENL who consent to participate will be randomly allocated to receive 48 weeks of weekly oral MTX plus 20 weeks of prednisolone or 48 weeks of placebo plus 20 weeks of prednisolone. Participants will be stratified by type of ENL into those with acute ENL and those with chronic and recurrent ENL. The primary objective is to determine whether MTX reduces the requirement for additional prednisolone. Patients’ reported outcome measures will be used to assess the efficacy of MTX. Participants will be closely monitored for adverse events.Ethics and disseminationResults will be submitted for publication in peer-reviewed journals. Ethical approval was obtained from the Observational/Interventions Research Ethics Committee of the London School of Hygiene & Tropical Medicine (15762); The Leprosy Mission International Bangladesh Institutional Research Board (in process); AHRI-ALERT Ethical Review Committee, Ethiopia; Ethics Committee of the Managing Committee of the Bombay Leprosy Project; and The Leprosy Mission Trust India Ethics Committee; the Nepal Health and Research Council and Health Research Ethics Committee Dr. Soetomo, Indonesia. This study is registered at www.clinicaltrials.gov. This is the first RCT of MTX for ENL and will contribute to the evidence for the management of ENL.Trial registration numberNCT 03775460.

Methotrexate in erythema nodosum leprosum: Pitfalls to avoid

“…Traditional clinical dictum is to combine tapering doses of a rapidly acting agent such as prednisolone for acute disease control, along with a slower acting steroid sparing agent for long-term maintenance. 4 Remission was maintained in this case with prednisolone 15 mg, hence the "steroid-dependent ENL" seems to have been managed with continued steroid use, claimed advantage with methotrexate in controlling the reaction and its steroid sparing effects notwithstanding. The prolonged period required to obtain full impact of drugs like clofazimine and methotrexate should be heeded in assessing treatment response.…”

“…The authors again chose methotrexate as the therapy for ENL, which may not be a sagacious alternative in a patient with hemoglobin of 71 g/l, 3 and further, methotrexate may take 8-12 weeks for noticeable therapeutic effect in acute ENL. 3,4 We are for the use of methotrexate in ENL, however we do oppose the inappropriate use of this agent and then crediting it for the action it did not produce in the first case. Methotrexate was tapered off as soon the onset of action was expected.…”

Novel approaches in the treatment of Hansen’s disease (Leprosy): a case series of multidrug therapy of monthly rifampin, moxifloxacin, and minocycline (RMM) in the United States

“…In the treatment course of all patients included in this series, we reduced the prednisone dose and added methotrexate as a steroid-sparing agent with great success in treating immunologic reactions. 25 , 26 Importantly, the cumulative dose of methotrexate used to treat patients with immunologic reactions does not reach the maximum dose correlating with end-organ damage (liver and lung toxicities) 25 ( Table 3 ). A lower dose of glucocorticoids reduces the risk of many potential long-term sequelae, including metabolic, osteoarticular, and ocular complications.…”

Treatment and Evaluation Advances in Leprosy Neuropathy

“…The long-term use of corticosteroids for the control of leprosy reactions with neuritis (see below) increases the risk of serious morbidity from the side effects of these drugs [110]. As a result, there is increased interest in the use of steroidsparing agents such as methotrexate [111].…”