scholarly journals A Comprehensive Review of HLA and Severe Cutaneous Adverse Drug Reactions: Implication for Clinical Pharmacogenomics and Precision Medicine

2021 ◽  
Vol 14 (11) ◽  
pp. 1077
Author(s):  
Chiraphat Kloypan ◽  
Napatrupron Koomdee ◽  
Patompong Satapornpong ◽  
Therdpong Tempark ◽  
Mohitosh Biswas ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Precision Medicine ◽  
Adverse Drug Reactions ◽  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Population Level ◽  
Stevens Johnson Syndrome ◽  
Drug Reactions ◽  
Drug Induced ◽  
Systemic Symptoms

Human leukocyte antigen (HLA) encoded by the HLA gene is an important modulator for immune responses and drug hypersensitivity reactions as well. Genetic polymorphisms of HLA vary widely at population level and are responsible for developing severe cutaneous adverse drug reactions (SCARs) such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), maculopapular exanthema (MPE). The associations of different HLA alleles with the risk of drug induced SJS/TEN, DRESS and MPE are strongly supportive for clinical considerations. Prescribing guidelines generated by different national and international working groups for translation of HLA pharmacogenetics into clinical practice are underway and functional in many countries, including Thailand. Cutting edge genomic technologies may accelerate wider adoption of HLA screening in routine clinical settings. There are great opportunities and several challenges as well for effective implementation of HLA genotyping globally in routine clinical practice for the prevention of drug induced SCARs substantially, enforcing precision medicine initiatives.

Cutaneous reactions to drugs

2020 ◽  
pp. 5752-5760
Author(s):  
Sarah Walsh ◽  
Daniel Creamer ◽  
Haur Yueh Lee
Keyword(s):  
Adverse Drug Reactions ◽  
Adverse Reactions ◽  
Normal Function ◽  
Stevens Johnson Syndrome ◽  
Drug Reactions ◽  
Drug Induced ◽  
Drug Eruptions ◽  
Fixed Drug ◽  
Iatrogenic Illness ◽  
Systemic Symptoms

Adverse reactions to medications are common and important cause of iatrogenic illness. Severe cutaneous adverse drug reactions include toxic epidermal necrolysis, Stevens–Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis, which together constitute 2% of all adverse drug reactions and may be life-threatening. Less severe drug-induced skin reactions such as exanthems, urticaria, lichenoid drug rashes, and fixed drug eruptions are more common, sometimes termed benign cutaneous adverse reactions, and generally resolve without sequelae. Drugs may also cause adverse events due to alteration of the normal function of the skin or its appendages. This may take the form of photosensitivity, abnormal pigmentation, or disrupted growth of hair or nails.

scholarly journals HLA Association with Drug-Induced Adverse Reactions

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Wen-Lang Fan ◽  
Meng-Shin Shiao ◽  
Rosaline Chung-Yee Hui ◽  
Shih-Chi Su ◽  
Chuang-Wei Wang ◽  
...  
Keyword(s):  
Adverse Drug Reactions ◽  
Antithyroid Drug ◽  
Human Leukocyte ◽  
Stevens Johnson Syndrome ◽  
Drug Reactions ◽  
Drug Induced ◽  
Hla Association ◽  
Hla Genes ◽  
Johnson Syndrome ◽  
Life Threatening

Adverse drug reactions (ADRs) remain a common and major problem in healthcare. Severe cutaneous adverse drug reactions (SCARs), such as Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) with mortality rate ranges from 10% to more than 30%, can be life threatening. A number of recent studies demonstrated that ADRs possess strong genetic predisposition. ADRs induced by several drugs have been shown to have significant associations with specific alleles of human leukocyte antigen (HLA) genes. For example, hypersensitivity to abacavir, a drug used for treating of human immunodeficiency virus (HIV) infection, has been proposed to be associated with allele 57:01 of HLA-B gene (terms HLA-B∗57:01). The incidences of abacavir hypersensitivity are much higher in Caucasians compared to other populations due to various allele frequencies in different ethnic populations. The antithyroid drug- (ATDs- ) induced agranulocytosis are strongly associated with two alleles: HLA-B∗38:02 and HLA-DRB1∗08:03. In addition, HLA-B∗15:02 allele was reported to be related to carbamazepine-induced SJS/TEN, and HLA-B∗57:01 in abacavir hypersensitivity and flucloxacillin induced drug-induced liver injury (DILI). In this review, we summarized the alleles of HLA genes which have been proposed to have association with ADRs caused by different drugs.

scholarly journals Immunohistopathological Findings of Severe Cutaneous Adverse Drug Reactions

2017 ◽  
Vol 2017 ◽  
pp. 1-5 ◽  
Author(s):  
Mari Orime
Keyword(s):  
Adverse Drug Reactions ◽  
Clinical Manifestations ◽  
Hypersensitivity Syndrome ◽  
Conclusive Evidence ◽  
Stevens Johnson Syndrome ◽  
Drug Reactions ◽  
Drug Induced ◽  
Cutaneous Manifestations ◽  
Johnson Syndrome ◽  
Systemic Symptoms

Diagnosis of severe cutaneous adverse drug reactions should involve immunohistopathological examination, which gives insight into the pathomechanisms of these disorders. The characteristic histological findings of erythema multiforme (EM), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) provide conclusive evidence demonstrating that SJS/TEN can be distinguished from EM. Established SJS/TEN shows full-thickness, extensive keratinocyte necrosis that develops into subepidermal bullae. Drug-induced hypersensitivity syndrome (DIHS) and exanthema in drug reaction with eosinophilia and systemic symptoms (DRESS) each display a variety of histopathological findings, which may partly correlate with the clinical manifestations. Although the histopathology of DRESS is nonspecific, the association of two or more of the four patterns—eczematous changes, interface dermatitis, acute generalized exanthematous pustulosis- (AGEP-) like patterns, and EM-like patterns—might appear in a single biopsy specimen, suggesting the diagnosis and severe cutaneous manifestations of DRESS. Cutaneous dendritic cells may be involved in the clinical course. AGEP typically shows spongiform superficial epidermal pustules accompanied with edema of the papillary dermis and abundant mixed perivascular infiltrates. Mutations in IL36RN may have a definite effect on pathological similarities between AGEP and generalized pustular psoriasis.

scholarly journals Pharmacogenomics of Allopurinol and Sulfamethoxazole/Trimethoprim: Case Series and Review of the Literature

2021 ◽  
Vol 11 (2) ◽  
pp. 71
Author(s):  
Ogechi Ikediobi ◽  
Jeremy A. Schneider
Keyword(s):  
Adverse Drug Reactions ◽  
Drug Targets ◽  
Case Series ◽  
Human Leukocyte ◽  
Hypersensitivity Syndrome ◽  
Outpatient Setting ◽  
Stevens Johnson Syndrome ◽  
Review Of The Literature ◽  
Drug Reactions ◽  
Drug Induced

Severe cutaneous adverse drug reactions (SCAR) such as the Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DIHS) can be induced by a plethora of medications. The field of pharmacogenomics aims to prevent severe adverse drug reactions by using our knowledge of the inherited or acquired genetic risk of drug metabolizing enzymes, drug targets, or the human leukocyte antigen (HLA) genotype. Dermatologists are experts in the diagnosis and management of severe cutaneous adverse drug reactions (SCAR) in both the inpatient and outpatient setting. However, most dermatologists in the US have not focused on the prevention of SCAR. Therefore, this paper presents a case series and review of the literature highlighting salient examples of how dermatologists can apply pharmacogenomics in the diagnosis and especially in the prevention of SCAR induced by allopurinol and sulfamethoxazole/trimethoprim, two commonly prescribed medications.

scholarly journals The Roles of Immunoregulatory Networks in Severe Drug Hypersensitivity

2021 ◽  
Vol 12 ◽  
Author(s):  
Yun-Shiuan Olivia Hsu ◽  
Kun-Lin Lu ◽  
Yun Fu ◽  
Chuang-Wei Wang ◽  
Chun-Wei Lu ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Hypersensitivity Syndrome ◽  
Stevens Johnson Syndrome ◽  
Hypersensitivity Reactions ◽  
Drug Induced ◽  
Johnson Syndrome ◽  
Signaling Receptors ◽  
Systemic Symptoms

The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit drug hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce hypersensitivity reactions including SJS/TEN and DRESS/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of drug hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type drug hypersensitivity in the hope of identifying potential pharmacologic targets.

Clinical Phenotypes of Severe Cutaneous Drug Hypersensitivity Reactions

2019 ◽  
Vol 25 (36) ◽  
pp. 3840-3854 ◽  
Author(s):  
Hakan Guvenir ◽  
Tugba Arikoglu ◽  
Emine Vezir ◽  
Emine Dibek Misirlioglu
Keyword(s):  
Adverse Drug Reactions ◽  
Drug Hypersensitivity ◽  
Stevens Johnson Syndrome ◽  
Facial Oedema ◽  
Hypersensitivity Reactions ◽  
Drug Reactions ◽  
Cutaneous Manifestations ◽  
Clinical Phenotypes ◽  
Drug Eruptions ◽  
Drug Hypersensitivity Reactions

Drug hypersensitivity reactions are clinically heterogenous ranging from mild to severe. Most drug hypersensitivity reactions are accompanied by cutaneous manifestations. Fever, mucous membrane involvement, large blisters, facial oedema, pustulosis and visceral involvement are clinical features that lead to suspicion of severe adverse drug reactions. Severe cutaneous adverse drug reactions (SCARs) include Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis. Serum sickness like reactions, drug induced vasculitis and generalized bullous fixed drug eruptions are less severe clinical entities. SCARs are uncommon but associated with significant morbidity and mortality. Physician should be aware of specific red flags and danger signs to immediately identify these reactions. Immediate drug withdrawal is mandatory. Early diagnosis and appropriate treatment significantly affect the prognosis of the disease. The purpose of our review is to discuss clinical phenotypes of severe cutaneous drug hypersensitivity reactions.

scholarly journals Severe Cutaneous Adverse Drug Reactions in Bangladesh: A Review in a Tertiary Level Hospital

2016 ◽  
Vol 12 (2) ◽  
pp. 71-75
Author(s):  
Md Niamul Gani Chowdhury ◽  
Mohammad Enamul Hoque ◽  
Md Abdul Latif Khan ◽  
Md Shirajul Islam Khan
Keyword(s):  
Adverse Drug Reactions ◽  
Armed Forces ◽  
Stevens Johnson Syndrome ◽  
Military Hospital ◽  
Case Report Form ◽  
Drug Reactions ◽  
Female Ratio ◽  
Medical College ◽  
Johnson Syndrome ◽  
Systemic Symptoms

Introduction: The Severe Cutaneous Adverse Drug Reactions (SCADRs) are rare but life-threatening as these encompass drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalized exanthematous pustulosis (AGEP). Objective: To estimate the incidence of SCADRs and to find out the cause in Bangladesh. Materials and Methods: 50 patients with SCADRs were studied over a period of 1 year from January 2015 to December 2015 in the Department of Dermatology, Combined Military Hospital, Dhaka. Data were collected from the informant and recorded in structured Case Report Form. Quantitative data were expressed as mean and standard deviation and qualitative data as frequency and percentage. Results: Clinical diagnosis of the study subjects recognized 46.0% cases as SJS, 28(19.0%) as TEN, 16.0% as DRESS and 10.0% as AGEP. The maximum incidence (46%) was seen in the age group of 31-50 years; mean age of the patient was 37.42+5.3 years. Male and female ratio was 2.84:1. Anticonvulsant group of drugs could give rise to maximum incidence of SCADRs. Carbamazepine was responsible in 22.0% cases of SCADRs, followed by Phenytoin in 16.0% patients and Phenobarbital in 14.0% cases. Conclusion: SCADRs were seen mostly with the anticonvulsant drugs belonging to Carbamazepine and Phenytoin group. SCADRs deserve continuous monitoring to plan preventive strategies. Journal of Armed Forces Medical College Bangladesh Vol.12(2) 2016: 71-75

scholarly journals Dermoscopic Aspects of Cutaneous Adverse Drug Reactions

2021 ◽  
pp. e2021136
Author(s):  
Gabriela Rossi ◽  
André Da Silva Cartell ◽  
Renato Marchiori Bakos
Keyword(s):  
Adverse Drug Reactions ◽  
Adverse Reactions ◽  
Stevens Johnson Syndrome ◽  
Drug Reactions ◽  
Acute Generalized Exanthematous Pustulosis ◽  
Johnson Syndrome ◽  
Vascular Structures ◽  
Systemic Symptoms ◽  
Exanthematous Pustulosis ◽  
Cutaneous Adverse Reactions

Background: Little is known about the dermoscopic evaluation of cutaneous adverse drug reactions (CADRs). Objectives: To evaluate the dermoscopic patterns of CADRs and identify those associated with severe cutaneous adverse reactions to drugs (SCARDs). Patients and Methods: Patients included in this study from May 2015 to April 2016 had presented with CADRs. CADR presentation and classification were based on standard criteria. SCARDs included Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), overlap SJS/TEN, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). The dermoscopic features of CADRs were described and compared according to the severity of the reactions. Results: Sixty-nine patients were included. Sixteen patients (23.2%) presented SCARDs. The main dermoscopic findings in SJS, overlap SJS/TEN and TEN were black dots or necrotic areas (100%). Erosion [respectively, 4/6 (66.7%), 3/3 (100%) and 1/1 (100%)], necrotic borders [respectively, 4/6 (66.7%), 3/3 (100%) and 1/1, (100%)] and epidermal detachment [respectively, 5/6 (83.3%); 2/3 (66.7%) and 1/1 (100%)] were also common among these reactions. Erythema and purpuric dots were the main dermoscopic findings [respectively, 5/6 (83.3%) and 4/6 (66.7%)] in DRESS. In non-severe reactions, the most prevalent structures were erythema and purpura in exanthema [respectively, 31/33 (93.9%) and 24/33 (72.7%)] and erythema and vascular structures in urticarial reactions [respectively, 6/6 (100%) and 3/6 (50%)]. Black dots or necrotic areas, epidermal detachment, necrotic borders and erosion were highly associated with SCARDs (P < 0.001). Conclusions: Dermoscopy improves clinical recognition of SCARDs.

scholarly journals Profile of cutaneous adverse drug reactions of carbamazepine

2017 ◽  
Vol 6 (12) ◽  
pp. 2876
Author(s):  
Meenakshi B. ◽  
Nirmala Devi P. ◽  
Radha M. ◽  
Abdul Rahuman M. B. ◽  
Shantaraman K.
Keyword(s):  
Adverse Drug Reactions ◽  
Drug Hypersensitivity ◽  
Hypersensitivity Syndrome ◽  
Stevens Johnson Syndrome ◽  
Future Research ◽  
Drug Reactions ◽  
Duration Of Treatment ◽  
College Hospital ◽  
Skin Reactions ◽  
Maculopapular Eruption

Background: Carbamazepine, a commonly used antiepileptic drug is known to produce adverse effects including dangerous reactions like cutaneous hypersensitivity reactions such as drug induced hypersensitivity syndrome (DHS), Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The FDA released a warning that serious and potentially fatal skin reactions may occur after carbamazepine in patients positive for the HLA-B*1502 allele which occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. This study profiles the cutaneous adverse drug reactions reported in this institute over a period of 3 years.Methods: This retrospective study was conducted at Tirunelveli Medical College Hospital by analysing patient case records based on adverse drug reactions reported between August 2014 and July 2017 in the adverse drug reaction monitoring centre. The age, gender, diagnosis, type of cutaneous ADR, duration of treatment, seriousness of reaction and outcome were recorded and analysed.Results: Among the total 25 reactions 36% were benign and 64% were severe reactions. According to Pharmaco vigilance Program of India 80% of the reactions were serious and 20% non serious. The commonest benign skin reaction was maculopapular eruption. SJS and TEN were the two very serious reactions which affected 8 patients totally. Exfoliative dermatitis was reported in 7 patients and Drug Hypersensitivity Syndrome (DHS) in one patient.Conclusions: Severe cutaneous reactions occur after carbamazepine and prevention of ADR requires prediction of predisposition which requires special studies of HLA or genomic assessment. These are the issues of interest for future research.

scholarly journals An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity

2018 ◽  
Vol 2018 ◽  
pp. 1-22 ◽  
Author(s):  
Chun-Bing Chen ◽  
Riichiro Abe ◽  
Ren-You Pan ◽  
Chuang-Wei Wang ◽  
Shuen-Iu Hung ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Drug Hypersensitivity ◽  
Clinical Manifestations ◽  
Human Leukocyte ◽  
Hypersensitivity Syndrome ◽  
Cell Receptor ◽  
Stevens Johnson Syndrome ◽  
Diagnostic Tools ◽  
Drug Induced ◽  
Skin Reactions

Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.

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