Beyond corticosteroids: A scoping review of alternative therapies for type 1 and type 2 leprosy reactions

Leprosy (Hansen's disease), caused by Mycobacterium leprae and Mycobacterium lepromatosis, remains a significant public health concern in endemic regions including Brazil, India, Indonesia, Ethiopia, and the Democratic Republic of Congo [1]. Despite the availability of multidrug therapy (MDT), leprosy reactions continue to represent a major source of morbidity, contributing to irreversible nerve function impairment and disability if inadequately managed. Leprosy reactions are acute inflammatory episodes that may occur before, during, or after MDT. Two principal reaction types are recognised, classified according to the Ridley-Jopling scale - a histopathological and immunological spectrum classifying leprosy from tuberculoid (TT) through borderline tuberculoid (BT), mid-borderline (BB), and borderline lepromatous (BL) to lepromatous (LL) [2]: • Type 1 reactions (T1R), also known as reversal reactions, are cell-mediated delayed hypersensitivity responses occurring predominantly in BT, BB and BL leprosy. They manifest with acute neuritis, oedema of existing skin lesions, and risk of rapid, potentially irreversible, nerve damage. • Type 2 reactions (T2R), or erythema nodosum leprosum (ENL), are immune complex-mediated reactions occurring in LL and BL patients. ENL can be recurrent, chronic, and systemic, involving skin, nerves, eyes, joints, and viscera. The Lucio phenomenon - a severe necrotising variant of T2R occurring in diffuse lepromatous leprosy - represents an important differential that will be considered within the scope of this review. As T1R and T2R differ broadly with respect to immunopathology, treatment paradigms, and outcome assessment, evidence will be synthesised separately for Type 1 and Type 2 reactions, wherever feasible [3]. Systemic corticosteroids (predominantly prednisolone and prednisone) constitute the current standard of care for both reaction types. However, significant limitations exist: prolonged use leads to well-documented adverse effects (hypertension, hyperglycaemia, osteoporosis, adrenal suppression), and ENL in particular is prone to corticosteroid dependency and recurrence upon tapering [4]. Thalidomide, effective for ENL through tumour necrosis factor (TNF) inhibition, carries severe teratogenicity risks and is unavailable in many endemic, low-resource settings [5]. A growing body of literature has explored alternative and adjunct therapies - including steroid-sparing immunomodulators (methotrexate [MTX], azathioprine [AZA]), TNF- inhibitors (infliximab, etanercept), procedural therapies (nerve decompression surgery), anti-inflammatory agents (pentoxifylline), and non-pharmacological interventions (rehabilitation, occupational therapy, physiotherapy) - yet no comprehensive synthesis of this evidence exists. This scoping review aims to systematically map the available evidence on alternative therapies for leprosy reactions, identify research gaps, and inform future research and clinical guidelines.