Abstract
Drug hypersensitivity reactions (HSRs) are increasing in the 21st Century with the ever expanding availability of new therapeutic agents. Patients with cancer, chronic inflammatory diseases, cystic fibrosis, or diabetes can become allergic to their first line therapy after repeated exposures or through cross reactivity with environmental allergens. Avoidance of the offending allergenic drug may impact disease management, quality of life, and life expectancy. Precision medicine provides new tools for the understanding and management of hypersensitivity reactions (HSRs), as well as a personalized treatment approach for IgE (Immunoglobuline E) and non-IgE mediated HSRs with drug desensitization (DS). DS induces a temporary hyporesponsive state by incremental escalation of sub-optimal doses of the offending drug. In vitro models have shown evidence that IgE desensitization is an antigen-specific process which blocks calcium flux, impacts antigen/IgE/FcεRI complex internalization and prevents the acute and late phase reactions as well as mast cell mediator release. Through a “bench to bedside” approach, in vitro desensitization models help elucidate the molecular pathways involved in DS, providing new insights to improved desensitization protocols for all patients. The aim of this review is to summarize up to date information on the drug HSRs, the IgE mediated mechanisms of desensitization, and their clinical applications.
Highlights
Drug hypersensitivity reactions (HSRs) are adverse effects of drugs [1,2]
Severe Cutaneous Adverse Reactions (SCAR) which include Acute Generalized Exanthematous Pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS), and Toxic Epidermal Necrolysis (TEN) have a severe clinical presentation with different treatment and poor clinical outcomes [13,14]. These phenotypes and endotypes can be further assessed through biomarkers such as skin testing (ST), and specific IgE and basophil activation tests (BAT), which help identify mast cell involvement in the HSRs as well as cross reactivity between drugs [7,9,10,11,25,26,27,28,29]
Cytokine production occurs over 4–6 h after cross-linking due to the activation of several adaptor proteins required for the activation of nuclear factor-κB (NF-κB), nuclear factor of activated T-cells (NFAT), signal transducer and activator of transcription 6 (STAT-6), and activator protein 1 (AP-1) transcription factors which are crucial for the expression of many cytokine proteins, including IL-6, TNF-α, IL-1β and IL-13 [46,47]
Summary
Drug hypersensitivity reactions (HSRs) are adverse effects of drugs [1,2]. Among the four most common HSRs described by Gell and Coombs, the most studied reactions are IgE (Immunoglobuline E)/mast cell mediated reactions which can cause cardiovascular collapse and anaphylaxis, leading to drug discontinuation which decrease quality of life and/or life expectancy [3,4,5,6]. Severe Cutaneous Adverse Reactions (SCAR) which include Acute Generalized Exanthematous Pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS), and Toxic Epidermal Necrolysis (TEN) have a severe clinical presentation with different treatment and poor clinical outcomes [13,14] These phenotypes and endotypes can be further assessed through biomarkers such as skin testing (ST), and specific IgE and basophil activation tests (BAT), which help identify mast cell involvement in the HSRs as well as cross reactivity between drugs [7,9,10,11,25,26,27,28,29]. A major step in improving clinical desensitization protocols was insight from in vitro studies on how dosing and timing during the desensitization protocol inhibited cell degranulation and cytokine production
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