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Diagnostic Tools and Biomarkers for Severe Drug Eruptions International Journal of Molecular Sciences Review Diagnostic Tools and Biomarkers for Severe Drug Eruptions Manabu Yoshioka, Yu Sawada * and Motonobu Nakamura Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan; [email protected] (M.Y.); [email protected] (M.N.) * Correspondence: [email protected] Abstract: In accordance with the development of human technology, various medications have been speedily developed in the current decade. While they have beneficial impact on various diseases, these medications accidentally cause adverse reactions, especially drug eruption. This delayed hypersensitivity reaction in the skin sometimes causes a life-threatening adverse reaction, namely Stevens-Johnson syndrome and toxic epidermal necrolysis. Therefore, how to identify these clinical courses in early time points is a critical issue. To improve this problem, various biomarkers have been found for these severe cutaneous adverse reactions through recent research. Granulysin, Fas ligands, perforin, and granzyme B are recognized as useful biomarkers to evaluate the early onset of Stevens-Johnson syndrome and toxic epidermal necrolysis, and other biomarkers, such as miRNAs, high mobility group box 1 protein (HMGB1), and S100A2, which are also helpful to identify the severe cutaneous adverse reactions. Because these tools have been currently well developed, updates of the knowledge in this field are necessary for clinicians. In this review, we focused on the detailed biomarkers and diagnostic tools for drug eruption and we also discussed the actual usefulness of these biomarkers in the clinical aspects based on the pathogenesis of drug eruption. Keywords: drug eruption; Stevens-Johnson syndrome; toxic epidermal necrolysis; biomarker; Citation: Yoshioka, M.; Sawada, Y.; diagnosis Nakamura, M. Diagnostic Tools and Biomarkers for Severe Drug Eruptions. Int. J. Mol. Sci. 2021, 22, 7527. https://doi.org/10.3390/ijms 1. Introduction 22147527 The current advancement of various technologies gives us many beneficial advantages for living in this world, as an abundance of chemicals, molecules, and medications have Academic Editor: Naoko Kanda been developed [1,2]. These materials can accidentally influence the human body, creating disadvantages for human health, with the representative adverse reaction being allergies Received: 7 June 2021 against these materials, sometimes causing a critical life-threatening reaction in the human Accepted: 11 July 2021 body [3–5]. Immunity in peripheral organs regulates host defense function against external Published: 14 July 2021 environmental stimuli. Skin is a representative peripheral lymphoid organ, which is located on the most outside in the human body and is well exposed to external stimuli Publisher’s Note: MDPI stays neutral and antigens [6–8]. Some harmful external antigens provoke cutaneous immune response with regard to jurisdictional claims in mediated by Type IV delayed hypersensitivity reaction [9]. This is one of the major published maps and institutional affil- pathogenesis of drug eruption, which sometimes develops into severe cutaneous drug iations. adverse reactions, such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which increases the risk of medication-induced-death [10]. In the current treatment, there is a limited number of impact treatments against these severe cutaneous adverse reactions. Therefore, it is important for clinicians to identify the detection at an early stage Copyright: © 2021 by the authors. in severe cutaneous drug adverse events and the useful biomarkers for severe cutaneous Licensee MDPI, Basel, Switzerland. adverse events [11]. It is also important to run a pharmacovigilance program in order to This article is an open access article detect new associations among drugs and new cutaneous reactions early on [12]. This distributed under the terms and review focused on the biomarker and diagnostic tools for the detection of severe cutaneous conditions of the Creative Commons adverse events and other minority types of drug eruption by searching keywords, “drug Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ eruption”, “biomarker”, and “symptom” using Pubmed. These findings will be helpful for 4.0/). the further direction of these fields in the future. Int. J. Mol. Sci. 2021, 22, 7527. https://doi.org/10.3390/ijms22147527 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 17 other minority types of drug eruption by searching keywords, “drug eruption”, Int. J. Mol. Sci. 2021, 22, 7527 “biomarker”, and “symptom” using Pubmed. These findings will be helpful for2 ofthe 17 further direction of these fields in the future. 2.2. Pathogenesis Pathogenesis of of Drug Drug Eruption Eruption TheThe pathogenesis pathogenesis of of drug drug eruption eruption is classified is classified into into allergic allergic and andnon-allergic non-allergic reactions reac- [13].tions In [ 13an]. allergic In an allergic reaction, reaction, the majority the majority of drug oferuption drug eruption is mediated is mediated by type IV by delayed type IV hypersensitivitydelayed hypersensitivity reaction, and reaction, the importance and the importance of this mechanism of thismechanism is proven by is commonly proven by usedcommonly patch testing used patch and lymphocyte testing and stimulation lymphocyte test stimulation for the diagnosis test for the[14–17]. diagnosis On the [14 basis–17]. ofOn the the pathogenesis, basis of the pathogenesis,type IV delayed type hypersen IV delayedsitivity hypersensitivity reaction consists reaction of two consists phases, of namely,two phases, sensitization namely, sensitizationand elicitation and (Figure elicitation 1) [9,18]. (Figure In1 )[the9 ,sensitization18]. In the sensitization phase, the exposurephase, the to exposure external to externalantigens antigens promotes promotes cutaneous cutaneous dendritic dendritic cell cell maturation maturation and and migrationmigration to to draining draining lymph lymph nodes nodes for for the the in inductionduction of of antigen-specific antigen-specific memory memory T T cells cells fromfrom naïve naïve T T cells. cells. After After the the establishment establishment of of sensitization sensitization against against the the causative causative drug, drug, the the nextnext administration administration of of the the drug drug initiates initiates the the elicitation elicitation of of the the immune immune response response and and causes causes cytotoxiccytotoxic cell-mediated cell-mediated immune immune responses responses in in peripheral peripheral lymphoid lymphoid organs. organs. FigureFigure 1. 1. TheThe mechanism mechanism of of delayed delayed hypersensitivi hypersensitivityty reaction reaction in in the the skin skin.. In In the the mechanisms mechanisms of of delayed delayed hypersensitivity hypersensitivity reaction,reaction, there there are are two two phases, phases, namely, namely, the the sensitization sensitization phase phase and and the the elicitation elicitation ph phase.ase. In In the the sensitization sensitization phase, phase, after after externalexternal antigen antigen exposure, exposure, antigen antigen presenta presentationtion cells cells pick pick up up antigens antigens and and migrat migratee into into draining draining lymph lymph nodes nodes to to present present antigens to naïve T cells for the induction of effector cells. In the elicitation phase, the next exposure of antigen drives antigens to naïve T cells for the induction of effector cells. In the elicitation phase, the next exposure of antigen drives antigen presentation cells to initiate effector cell activation and cause inflamed tissue reaction. antigen presentation cells to initiate effector cell activation and cause inflamed tissue reaction. + InIn the the severe severe types types of of drug drug eruption, eruption, cytotoxic cytotoxic immune immune cells, cells, such such as as CD8 CD8+ TT cells, cells, NKNK cells, cells, and and NKT NKT cells cells identify identify the the specific specific epitopes epitopes HLA-drug HLA-drug interaction interaction and and produce produce cytotoxiccytotoxic proteins proteins such such as as Fas Fas ligand, ligand, perforin, perforin, granzyme granzyme B, B, and and granulysin granulysin and and provoke provoke epidermalepidermal keratinocytekeratinocyte cell cell death, death, which which is associated is associated with the severewith clinicalthe severe manifestation clinical manifestationof SJS/TEN. of SJS/TEN. 3.3. Clinical Clinical Sign Sign and and Biomarker Biomarker for for Drug Drug Eruption Eruption 3.1.3.1. Intertriginous Intertriginous Eruption Eruption as as a aClinical Clinical Sign Sign for for Acute Acute Generalized Generalized Exanthematous Exanthematous PustulosisPustulosis (AGEP) (AGEP) IntertriginousIntertriginous drug drug eruption eruption is is an an exanth exanthemem characterized characterized by by the the rapid rapid onset onset after after thethe causative causative drug drug administration administration and and occurs occurs in in the the predilection predilection sites sites including including inguinal inguinal foldsfolds and and axillae axillae [19,20], [19,20], and and is is recognized recognized in in some some cases, cases, but but not not all, all, as as the the mild mild form form of of AGEP. As the mechanism of intertriginous drug eruption, type IV delayed hypersensitivity reaction has
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