# Descriptions of the natural history of erythema nodosum leprosum to inform clinical classification – A semi-systematic review

## TL;DR

This paper reviews how ENL is classified over time and finds inconsistent use of terms like acute, recurrent, and chronic, suggesting the need for standardized definitions to improve research and treatment.

## Contribution

The study compares historical and modern ENL classifications to highlight inconsistencies and proposes consensus-based standardization.

## Key findings

- Historical and modern descriptions of ENL align in viewing it as a chronic condition.
- Current definitions of acute and chronic ENL are consistent, but recurrent and chronic definitions overlap.
- Standardized terminology is needed to improve data comparison and clinical guidelines.

## Abstract

Erythema nodosum leprosum (ENL) is a severe immunological complication of leprosy, characterised by painful nodules, fever, arthralgia, oedema, and systemic symptoms. Temporal classifications—acute, recurrent, and chronic—are inconsistently applied, complicating data comparisons. Standardised and agreed definitions are essential to ensure consistency in diagnosis, research, and clinical management.

To examine how temporal classifications of ENL are used in modern literature and compare them to descriptions from the pre-corticosteroid era.

We conducted a semi-systematic review of historical and contemporary literature. Historical texts published before 1940, prior to the introduction of sulfone antibiotics and corticosteroids, were purposively selected to capture descriptions of the natural history of ENL. For modern studies, we systematically searched PubMed, EMBASE, LILACS, SciELO, Scopus, African Index Medicus, Cochrane, and ClinicalTrials.gov from May 2024 to March 2025. The systematic review identified 572 articles after de-duplication, and 41 met inclusion criteria for providing definitions of ENL subtypes.

Five historical treatises were selected. Their clinical observations of nodular skin lesions with systemic symptoms—ranging in duration from weeks to months or even years—align with contemporary understandings of ENL. 41 studies included, at least one of the three temporal classifications (acute, recurrent, or chronic). The six-month criterion distinguishing acute and chronic ENL is used in all current definitions. However, definitions for recurrent and chronic ENL frequently overlapped, both referring to prolonged or multiple episodes after initial treatment, underscoring a lack of conceptual clarity.

The absence of standardised ENL terminology impedes data comparison, meta-analysis, and clinical guideline development. A Delphi consensus process and longitudinal observational studies are recommended to refine, standardise agreed ENL classifications.

Erythema nodosum leprosum (ENL) is a painful and often chronic immune-mediated complication of leprosy. It causes red nodules on the skin with fever and other organ inflammation. ENL may be severe and challenging to treat usually requiring immunomodulatory drugs. Doctors and researchers often use the terms “acute,” “recurrent,” and “chronic” to describe different patterns of ENL, but these terms are not used consistently. This makes it difficult to compare findings of studies, optimise treatment and develop guidelines.

We selected five historical medical texts published before antimicrobial and immunosuppressive treatments were available to identify descriptions of ENL and its natural history. We then compared them with modern published definitions of ENL identified following a systematic search of eight databases.

Historical descriptions of ENL were largely consistent with what we see today, describing it as a chronic disease. We found general agreement about the duration of ENL for acute and chronic disease but the definitions of recurrent ENL overlapped with those of chronic ENL.

Our findings highlight the need for an agreed evidence-based classification of ENL. We recommend using clinical data and a consensus-building process, such as the Delphi method to develop standardised definitions. This would help improve the design of research studies for this challenging complication of leprosy.