Recent advances in the understanding of severe cutaneous adverse reactions

Abstract

Severe cutaneous adverse reactions (SCARs) encompass a heterogeneous group of delayed hypersensitivity reactions, which are most frequently caused by drugs. Our understanding of several aspects of SCAR syndromes has evolved considerably over the last decade. This review explores evolving knowledge of the immunopathogenic mechanisms, pharmacogenomic associations, in vivo and ex vivo diagnostics for causality assessment, and medication cross-reactivity data related to SCAR syndromes. Given the rarity and severity of these diseases, multidisciplinary collaboration through large international, national and/or multicentre networks to collect prospective data on patients with SCAR syndromes should be prioritized. This will further enhance a systematized framework for translating epidemiological, clinical and immunopathogenetic advances into preventive efforts and improved outcomes for patients.

Figure 1

Proposed models of T-cell receptor (TCR), major histocompatability complex (MHC), drug interactions: In the hapten/prohapten model (i) a drug (e.g., penicillin) binds covalently to an endogenous peptide (e.g., albumin), forming a new molecule. Antigen presenting cells process and present it as short peptide fragments within the MHC binding cleft, some of which (peptide A) include drug epitopes (purple pentagon). If recognized by a TCR, a drug-specific immune response can ensue. In the pharmacological-interaction (P-I) model (ii) the drug binds non-covalently to certain MHC molecules or TCRs, stimulating specific TCR and thus generating drug-reactive T-cells. In the altered peptide repertoire model (iii) a drug (e.g., abacavir) binds non-covalently to the binding pocket of a MHC molecule (e.g. HLA-B*57:01), altering its conformation and allowing a new array of self-peptides (peptide B) to stably occupy it and stimulate T-cells. This can lead to drug-induced activation of autoimmunity (e.g., abacavir hypersensitivity reaction.) Adapted from Pavlos et al.

Figure 2

Basic structures of beta-lactams (adapted from Trubiano et al.). R denotes side chains. Cephalosporins have two side chains, R1 and R2. However, R2 is lost during hydrolysis.