Exploring recent advances in drugs severe cutaneous adverse reactions immunopathology

Abstract

Severe cutaneous adverse reactions to drugs (SCARs) are rare but life-threatening delayed allergies. While they primarily affect the skin, they can also affect internal organs. Accordingly, they present with diverse clinical symptoms that vary not only between SCARs subtypes but also among patients. Despite the availability of topical and systemic treatments, these only address the symptoms and not the cause. To develop more effective therapies, it is necessary to elucidate the complexity of the pathophysiology of SCARs in relation to their severity. In line with the new type IV hypersensitivity reactions nomenclature proposed by the European Academy of Allergy and Clinical Immunology (EAACI), this review highlights the current insights into the intricate immune mechanisms engaged, the interplay between the culprit drug and genetic predisposition in drug presentation mechanisms, but also how external factors, such as viruses, are implicated in SCARs. Their relevance to the development of targeted medicine is also discussed.

Keywords: T‐cell‐mediated diseases; delayed hypersensitivity classification; drug allergy; immunopathology; severe cutaneous adverse reactions.

FIGURE 1

Clinical phenotype of SCARs. Clinical presentations are various among SCARs, from exanthema covered by amicrobial pustules for AGEP (A), extensive purplish exanthema with acral oedema for DRESS (B), and extensive skin detachment for TEN (C). Image credit: Dr Marie Tauber. AGEP, Acute Generalized Exanthematous Pustulosis; DRESS, Drug Reaction with Eosinophilia and Systemic Symptoms; SCARs, severe cutaneous adverse reactions; SJS/TEN, Stevens‐Johnson Syndrome/Toxic Epidermal Necrolysis.

FIGURE 2

Immune mechanisms associated with SCARs and potential therapeutic targets. All SCARs are type IV reactions. SJS/TEN is characterized by a T1 (type 1) signature (A) in which cytotoxic cells including CD8⁺ T cells and NK but also innate cells such as neutrophils secrete granulysin, LL37, annexin‐a1, MMP9, and others leading to the apoptosis or necroptosis of the keratinocytes, implicated in the epidermal detachment. DRESS is characterized by a T2 (type 2) signature (B) in which CD4⁺ and CD8⁺ T cells promote the recruitment of eosinophils by producing IL‐5 and CCL11. Type 2 cells, Treg and monocytes are also amplifying the pathological processes. AGEP is characterized by a T3 (type 3) signature (C) in which CD4⁺ and CD8⁺ T cells, type 3/17 (T_H17) cells promote the neutrophils infiltration by the production of CXCL8, CCL5, IFNγ, IL‐4, IL‐5 leading to the formation of pustule and epithelial damage. Off‐labeled drugs suggested for each SCAR are highlighted in red. (>>>) represents the differentiation from one cell to another. AGEP, Acute Generalized Exanthematous Pustulosis; CCL, chemokine ligand; CD, cluster of differentiation; cMO, classical monocytes; CXCL, chemokine (C‐X‐C motif) ligand; DC, dendritic cell; DRESS, Drug Reaction with Eosinophilia and Systemic Symptoms; FPR1, formyl peptide receptor 1; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; IFNγ, interferon gamma; IL, interleukin; iNOS, inducible nitric oxide synthase; JAK, janus kinases; LEF‐1, lymphoid enhancer binding factor 1; MMP9, epidermal matrix metalloproteinase 9; NET, neutrophil extracellular traps; NK, natural killer cell; NO, nitric oxide; pMO, non‐classical monocytes; SJS/TEN, Stevens‐Johnson Syndrome/Toxic Epidermal Necrolysis; STAT, signal transducer and activator of transcription proteins; TCF‐1, T cell factor 1; T_H, T helper; TNFα, tumor necrosis factor alpha; TRAIL, TNF‐related apoptosis‐inducing ligand; Treg, regulatory T cell; T_RM, resident memory T cell; TWEAK, TNF‐like weak inducer of apoptosis.

FIGURE 3

Three major drug binding/presentation theories and additional suggested mechanisms in SCARs. An antigen‐presenting cell (APC) presents a peptide A on its MHC‐I, which can bind specifically to the TCR of a T‐cell, unlike the peptide B (top panel). When a drug is added, three models are possible based on this interaction depending on the type of drug: The hapten/pro‐hapten model in which the drug binds to the endogenous peptide (A), the p‐i model in which the drug binds directly to the TCR or MHC‐I (B), and the altered peptide repertoire model in which the drug binds to the binding pocket of the HLA modifying the affinity to the peptide A into the peptide B (C). Additional mechanisms, including the form of the drug (metabolized or not) which can be sometimes influenced by genetic factors (D), the peptide loading process depending or not on the tapasin changing the affinity of the peptide (E), the HLA predisposition (F) and the TCR clonotype (G). ER, endoplasmic reticulum; HLA, human leukocyte antigen; MHC‐I, major histocompatibility complex 1; P‐i, pharmacological interaction of drugs; TCR, T cell receptor.

FIGURE 4

Relationship between virus reactivation and immune response in SCARs. SCARs may be the cause of virus reactivation (A) either by the up‐regulation of immune receptors for virus entry and replication (left panel) or by promoting the activation of Treg leading to a immunosuppressive virus‐friendly environment (right panel). Alternatively, virus infection (with or without associated drug prescription) might promote SCARs (B) by influencing the production/proliferation of SCARs immune cells and mediators (left panel) or by a cross‐reaction of memory T cells to a HLA: Drug similar to a HLA: Virus (right panel). (?) Represents theoretical mechanisms not demonstrated. APC, antigen‐presenting cell; HLA, human leukocyte antigen; SCARs, severe cutaneous adverse reactions; TCR, T cell receptor; Treg, regulatory T cells.