Section Review Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis: Drug-induced lupus: Possible mechanisms and their implications for prediction of which new drugs may induce lupus

Abstract

Lupus is an autoimmune disease, usually of unknown aetiology; however, when it is associated with the use of specific drugs it is known as drug-induced lupus (DIL). The drugs associated with the highest incidence of the syndrome have a functional group, such as an arylamine, hydrazine or sulfhydryl group, that is easily oxidised to reactive metabolites by activated leukocytes. The mechanism by which these drugs induce lupus is unknown and it is likely that several factors are involved. There are three mechanisms that seem most plausible. One possible mechanism involves an alteration, possibly by a reactive metabolite, of how antigens are processed and presented to T-cells leading to the presentation of cryptic antigens. Another possibility is that a reactive metabolite binds to the class II major histocompatibility antigen and induces an autoimmune reaction analogous to a graft versus host reaction. A third possibility is that the drug inhibits DNA methylation and this leads to an increase in DNA transcription and a generalised activation of the immune system. Based on the what is known about DIL it may be possible to predict which new drugs are most likely to induce lupus. Characteristics of the drug that may be important are: 1) whether the drug is used for chronic therapy; 2) whether a high dose of the drug is required; 3) the presence of a functional group that is easily oxidised to a reactive metabolite; 4) whether the drug inhibits DNA methylation.

Key Words:

• reactive metabolites
• autoimmune disease
• cryptic antigens
• graft-versus-host disease
• aromatic amines
• hydrazines
• DNA methylation
• complement