Hypersensitivity reactions to small molecule drugs

Abstract

Drug hypersensitivity reactions induced by small molecule drugs encompass a broad spectrum of adverse drug reactions with heterogeneous clinical presentations and mechanisms. These reactions are classified into allergic drug hypersensitivity reactions and non-allergic drug hypersensitivity reactions. At present, the hapten theory, pharmacological interaction with immune receptors (p-i) concept, altered peptide repertoire model, and altered T-cell receptor (TCR) repertoire model have been proposed to explain how small molecule drugs or their metabolites induce allergic drug hypersensitivity reactions. Meanwhile, direct activation of mast cells, provoking the complement system, stimulating or inhibiting inflammatory reaction-related enzymes, accumulating bradykinin, and/or triggering vascular hyperpermeability are considered as the main factors causing non-allergic drug hypersensitivity reactions. To date, many investigations have been performed to explore the underlying mechanisms involved in drug hypersensitivity reactions and to search for predictive and preventive methods in both clinical and non-clinical trials. However, validated methods for predicting and diagnosing hypersensitivity reactions to small molecule drugs and deeper insight into the relevant underlying mechanisms are still limited.

Immunological Mechanisms in Cutaneous Adverse Drug Reactions

“…This latter explanation, which departs from the classical hapten theory, is referred to as the pharmacological interactions with immune receptor (p-i) concept ( Fig. 1 ) ( Roujeau, 2006 ; Brockow and Romano, 2008 ; Pavlos et al ., 2015 ; Pirmohamed et al ., 2015 ; Chen et al ., 2018 ; Pichler, 2019 ; Han et al ., 2022 ; Wilkerson, 2022 ; Wuillemin et al ., 2022 ).…”

“…Immune-mediated ADRs can be classified based on the primary immune cell involved ( Redwood et al ., 2018 ) and the Gell and Coombs classification ( Wilkerson, 2022 ). B-cell-mediated reactions correspond to Gell-Coombs types I-III, while T-cell-mediated reactions correspond to Gell-Coombs type IV ( Roujeau, 2006 ; Brockow and Romano, 2008 ; Pichler, 2019 ; Han et al ., 2022 ; Wilkerson, 2022 ). Type I reactions are characterized by immunoglobulin E (IgE)-mediated immediate responses ( Fig.…”

JAK-STAT pathway inhibitors in dermatology

“…As with other medications, except in immunologically-mediated reactions, adverse effects (AEs) and risks associated with medications that interfere with cytokine signaling and transcription pathways, cell growth factors, and induction of cell apoptosis, are directly proportional to the following conditions: (i) Occurrence of concomitant diseases (latent tuberculosis, HIV infection, HTLV-1, Chagas disease, autoimmune diseases, inflammatory bowel disease (IBD), thrombophilia, liver, kidney and hematological diseases); (ii) Medication dosage; (iii) Treatment duration, and (iv) Metabolic pathways altered by gene polymorphism (glucose-6-phosphate dehydrogenase deficiency, slow acetylation, HLA predisposition to severe adverse reactions, as in the case of abacavir, HLA-B*5701). 21 …”

Noninfectious causes of fever in hematologic malignancies. Are antibiotics still indicated?

“…Fever commonly occurs in type III HSRs involving the formation of antigen-antibody complexes, typified by serum sickness sometimes seen after ATG administration [31]. Fever also commonly occurs with type IV HSRs involving activation and expansion of T-lymphocytes [32,33 ▪ ,34,35]. Type IV HSRs are commonly associated with allopurinol, antiepileptic drugs, dapsone, penicillin, other beta-lactam antibiotics, sulfonamide drugs, and minocycline [33 ▪ ,35].…”

“…Fever can also occur via nonimmunologic mechanisms. For example, by direct activation of mast cells and basophils, vancomycin, and other drugs can also result in HSRs [32,35]. Amphotericin products and bleomycin also act as pyrogens and can induce fever through nonimmunologic mechanisms [33 ▪ ,38,39].…”