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• Methotrexate in erythema nodosum leprosum (MaPs in ENL)
  Tarun Narang, Hitaishi Mehta, Sunil Dogra and Bhushan Kumar
  Published on: 2 February 2021

• Published on: 2 February 2021

  Methotrexate in erythema nodosum leprosum (MaPs in ENL)

  • Tarun Narang, Dermatologist Department of Dermatology, Venereology and Leprology; Postgraduate Institute of Medical Education & Research; Chandigarh, India
  • Other Contributors:
    • Hitaishi Mehta, Dermatologist
    • Sunil Dogra, Dermatologist
    • Bhushan Kumar, Dermatologist

  We read with interest the MaPs in ENL study protocol (de Barros et al, BMJ open 2020).[1] The availability of an alternative drug for cases of chronic or recurrent type 2 lepra reaction with steroid toxicity or unresponsiveness is the need of the hour and although drugs like thalidomide, cyclosporine etc. are prescribed in such patients but cost, adverse effect or non-availability are the major deterrents in their use. The researchers must be complimented for their bold decision to choose methotrexate based only on case reports or a short series of patients (15 patients in total were given methotrexate for type 2 reactions).[2] This is a well-designed protocol aimed at possibly adding another drug to our therapeutic armamentarium for the crippling erythema nodosum leprosum (ENL) reactions. If found useful, methotrexate has the advantage of being a cheap, easy to administer and readily available drug.

  The study proposes to randomize patients with acute, chronic or recurrent ENL into two groups, receiving 20 weeks of prednisolone with either 48 weeks of methotrexate or placebo. While use of methotrexate is justified in patients with chronic and recurrent ENL, , same might not be applicable to cases of acute ENL. Acute ENL, by definition, is an episode that lasts lesser than 24 weeks,[3] as has been defined in the study protocol as well. Most of these cases with acute episode respond well to corticosteroids, clinical response has been observed as early as in 2 week...

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  We read with interest the MaPs in ENL study protocol (de Barros et al, BMJ open 2020).[1] The availability of an alternative drug for cases of chronic or recurrent type 2 lepra reaction with steroid toxicity or unresponsiveness is the need of the hour and although drugs like thalidomide, cyclosporine etc. are prescribed in such patients but cost, adverse effect or non-availability are the major deterrents in their use. The researchers must be complimented for their bold decision to choose methotrexate based only on case reports or a short series of patients (15 patients in total were given methotrexate for type 2 reactions).[2] This is a well-designed protocol aimed at possibly adding another drug to our therapeutic armamentarium for the crippling erythema nodosum leprosum (ENL) reactions. If found useful, methotrexate has the advantage of being a cheap, easy to administer and readily available drug.

  The study proposes to randomize patients with acute, chronic or recurrent ENL into two groups, receiving 20 weeks of prednisolone with either 48 weeks of methotrexate or placebo. While use of methotrexate is justified in patients with chronic and recurrent ENL, , same might not be applicable to cases of acute ENL. Acute ENL, by definition, is an episode that lasts lesser than 24 weeks,[3] as has been defined in the study protocol as well. Most of these cases with acute episode respond well to corticosteroids, clinical response has been observed as early as in 2 weeks.[4] It has been reported in a large epidemiological study that about one third of all ENL reactions are single episode.[5] Moreover, methotrexate may take up to 3 weeks for noticeable therapeutic effect as cited by the authors, so its required benefit will not be available in acute ENL.[6] Current World Health Organization (WHO) guidelines also recommend corticosteroids for a duration of 12 weeks in severe ENL.[7]

  Administering methotrexate to such patients for a prolonged duration of 48 weeks (51 weeks to be precise–as per protocol) does not seem to be scientifically or ethically justifiable. Such prolonged administration of methotrexate (up to 25 mg/ week) in acute ENL cases will add to potential hematological and biochemical toxicities of multidrug therapy (MDT).[8] The researchers are definitely not looking at the data for preventing the occurrence of another episode of acute reaction. The continued administration of methotrexate is bound to create a bias- because of the possibility of delay in the occurrence or reduced severity of the next ENL episode. Few unfortunate patients with long standing ENL of more than 4 years could also have been included.

  The protocol recommends, daily supplementation of 5 mg of folic acid to reduce the adverse effects of methotrexate. The dosage seems to be in excess of the usual recommendations by various dermatology and rheumatology guidelines, which range from 0.5-2 mg per day.[9-11] Although there is no consensus on dosage of folic acid supplements, there is some evidence suggesting that higher doses may possibly reduce the therapeutic efficacy of methotrexate.[12-14]

  Under the ‘indications for additional steroids’- there is mention of Type 1 reaction – it is not clear if these patients will also be included in the analysis.

  A recommendatory comment is in order on the continuation and regularity of the MDT for those on MDT. Also if a patient develops ENL after the completion of MDT- how the fear of activity of disease is to be assuaged- whether an additional anti-leprosy drug (clofazimine was recommended earlier)– would be added to the regimen.

  REFERENCES

  1. de Barros B, Lambert SM, Shah M, et al. Methotrexate and prednisolone study in erythema nodosum leprosum (MaPs in ENL) protocol: a double-blind randomised clinical trial. BMJ Open 2020;10:e037700.
  2. Perez-Molina JA, Arce-Garcia O, Chamorro-Tojeiro S, et al. Use of methotrexate for leprosy reactions. Experience of a referral center and systematic review of the literature. Travel Med Infect Dis 2020;37:101670.
  3. Walker SL, Balagon M, Darlong J, et al. ENLIST 1: An International Multi-centre Cross-sectional Study of the Clinical Features of Erythema Nodosum Leprosum. PLoS Negl Trop Dis 2015;9:e0004065-e.
  4. Kaur I, Dogra S, Narang T, et al. Comparative efficacy of thalidomide and prednisolone in the treatment of moderate to severe erythema nodosum leprosum: a randomized study. Australas J Dermatol 2009;50:181-5.
  5. Kumar B, Dogra S, Kaur I. Epidemiological characteristics of leprosy reactions: 15 years experience from north India. Int J Lepr Other Mycobact Dis 2004;72:125-33.
  6. Warren RB, Weatherhead SC, Smith CH, et al. British Association of Dermatologists’ guidelines for the safe and effective prescribing of methotrexate for skin disease 2016. Br J Dermatol 2016;175:23-44.
  7. World Health Organization. WHO Guidelines for the management of severe erythema nodosum leprosum (ENL) reactions. Geneva, Switzerland: World Health Organization 2015. Available from: https://www.who.int/lep/research/WHOenlguide.pdf
  8. Cruz R, Bührer-Sékula S, Penna GO, et al. Clinical trial for uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): adverse effects approach. An Bras Dermatol. 2018;93:377-84
  9. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012;64:625-39.
  10. Chakravarty K, McDonald H, Pullar T, et al. BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Rheumatology (Oxford) 2008;47:924-5.
  11. Kalb RE, Strober B, Weinstein G, et al. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. J Am Acad Dermatol 2009;60:824-37.
  12. Khanna D, Park GS, Paulus HE, et al. Reduction of the efficacy of methotrexate by the use of folic acid: post hoc analysis from two randomized controlled studies. Arthritis Rheum 2005;52:3030-8.
  13. Salim A, Tan E, Ilchyshyn A, et al. Folic acid supplementation during treatment of psoriasis with methotrexate: a randomized, double-blind, placebo-controlled trial. Br J Dermatol 2006;154:1169-74.
  14. Chládek J, Simková M, Vanecková J, et al. The effect of folic acid supplementation on the pharmacokinetics and pharmacodynamics of oral methotrexate during the remission-induction period of treatment for moderate-to-severe plaque psoriasis. Eur J Clin Pharmacol 2008;64:347-55.

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  Conflict of Interest:
  None declared.

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