Longitudinal performance of the ENLIST ENL severity scale in individuals with severe erythema nodosum leprosum: Responsiveness, trajectories and clinical features – a secondary analysis of the Methotrexate and Prednisolone study - MaPs in ENL

BACKGROUND: Erythema nodosum leprosum (ENL) is a severe inflammatory complication of lepromatous leprosy characterised by recurrent inflammatory episodes often requiring prolonged immunosuppression. The severity of ENL can be quantified using the validated and reliable ENLIST ENL Severity Scale (EESS). The longitudinal course of ENL and how it is captured using standardised severity measures has not been well described. We prospectively evaluated the changes in ENL severity over time using the EESS in a randomised clinical trial. METHODS: Ethics statement. The trial was performed according to the Helsinki Declaration as revised in 2024 and ethical approval was obtained from the London School of Hygiene & Tropical Medicine Research Ethics Committee (15762). Approval was obtained from Dr. Soetomo Hospital Ethics Committee, Indonesian Food and Drug Authority, Ethiopian Ministry of Education Ethics Committee, Ethiopian Food and Drug Authority, AHRI/ALERT Ethics Review Committee, Bombay Leprosy Project Committee, the Leprosy Mission Trust India Ethics Committee, Nepal Health Research Council and Department of Drug Administration, Nepal Government. All participants provided written informed consent before enrolment. MaPs in ENL was registered at www.clinicaltrials.gov (NCT03775460) and the Clinical Trials Registry India (CTRI/2020/11/029074). We conducted a prespecified secondary analysis of participants enrolled in the Methotrexate and Prednisolone Study in ENL, an international multicentre randomised controlled trial conducted in Ethiopia, India, Indonesia, and Nepal. Adults with severe ENL (EESS score ≥9) were followed for 60 weeks with repeated EESS assessments. Longitudinal trajectories were analysed using mixed-effects regression models. Item-level analyses characterised the clinical phenotype captured by the scale. Associations between EESS score, prednisolone exposure, and dermatology-specific health-related quality of life measured using the Dermatology Life Quality Index (DLQI) were examined. FINDINGS: A total of 135 participants contributed 1,958 EESS assessments. Mean EESS declined rapidly during the first four weeks of treatment (-2.10 points/week; 95% CI -2.36 to -1.84; p < 0.001), increased modestly during reduction in corticosteroid dose (weeks 4-20), and gradually declined thereafter. Severe ENL (EESS score ≥9) occurred in 20.6% of visits and was characterised primarily by pain and cutaneous inflammatory manifestations. Participants who required additional prednisolone had persistently higher EESS scores and showed limited improvement compared with those who did not receive additional prednisolone. Longitudinal EESS scores were strongly correlated with the DLQI score (Spearman's ρ = 0.75; p < 0.001). CONCLUSION: The EESS captures clinically meaningful changes in ENL severity, aligns with treatment decisions, and reflects patient-reported severity over time. These findings support the use of the EESS as a robust tool for monitoring ENL severity in both clinical research and routine care.