Metabolism of Drugs by Activated Leukocytes: Implications for Drug-Induced Lupus and Other Drug Hypersensitivity Reactions

: Severe delayed drug hypersensitivity reactions comprise different clinical entities and can involve different immune medSevere delayed drug hypersensitivity reactions comprise different clinical entities and can involve different immune-mediated mechanisms. Common examples are severe cutaneous adverse reactions and druginduced internal organ injuries.iated mechanisms. Common examples are severe cutaneous adverse reactions and drug induced internal organ injuries. The incidence of such reactions is overall low but seems to be on the rise reaching numbers as high as 9 per million individuals-years in the case of SJS/TEN and in DRESS. Such conditions carry an important associated morbidity, and mortality can attain 40% in SJS/TEN patients, making these hypersensitivity reactions important targets when implementing preventive measures. Several risk factors have been identified, some being transverse, for reactions severity as older age and underlying chronic diseases. The recent advances in pharmacogenetics allowed the identification of specific populations with higher risk and permitted strategic avoidance of certain drugs being HLA-B*57:01 screening in patients initiating abacavir the best successful example. In this work we reviewed the epidemiology of SCARs and liver/kidney/lung drug induced immune-mediated reactions. We focus in particular aspects such as prevalence and incidence, drugs involved, mortality and risk factors. : The incidence of such reactions is overall low but seems to be on the rise reaching numbers as high as 9 per million individuals-years in the case of SJS/TEN and DRESS. Such conditions carry an important associated morbidity, and mortality can attain 40% in SJS/TEN patients, making these hypersensitivity reactions important targets when implementing preventive measures. : Several risk factors have been identified for reaction severity; some are transverse, such as older age and underlying chronic diseases. The recent advances in pharmacogenetics allowed the identification of specific populations with higher risk and permitted strategic avoidance of certain drugs being HLA-B*57:01 screening in patients initiating abacavir the best successful example. In this work, we reviewed the epidemiology of SCARs and liver/kidney/lung drug-induced immune-mediated reactions. We focus on particular aspects such as prevalence and incidence, drugs involved, mortality and risk factors.

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HLA Associations and Clinical Implications in T-Cell Mediated Drug Hypersensitivity Reactions: An Updated Review

Journal of Immunology Research ◽

10.1155/2014/565320 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 37

Author(s):

Chi-Yuan Cheng ◽

Shih-Chi Su ◽

Chi-Hua Chen ◽

Wei-Li Chen ◽

Shin-Tarng Deng ◽

...

Keyword(s):

T Cell ◽

Drug Hypersensitivity ◽

Human Leukocyte ◽

Hypersensitivity Syndrome ◽

Stevens Johnson Syndrome ◽

Hypersensitivity Reactions ◽

Genetic Associations ◽

Drug Induced ◽

Hla Alleles ◽

Drug Hypersensitivity Reactions

T-cell mediated drug hypersensitivity reactions may range from mild rash to severe fatal reactions. Among them, drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS), Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN), are some of the most life-threatening severe cutaneous adverse reactions (SCARs). Recent advances in pharmacogenetic studies show strong genetic associations between human leukocyte antigen (HLA) alleles and susceptibility to drug hypersensitivity. This review summarizes the literature on recent progresses in pharmacogenetic studies and clinical application of pharmacogenetic screening based on associations between SCARs and specific HLA alleles to avoid serious conditions associated with drug hypersensitivity.

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Novel Concepts for Drug Hypersensitivity Based on the Use of Long-Time Scale Molecular Dynamic Simulation

Journal of Pharmaceutics ◽

10.1155/2016/9520361 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Takahiro Murai ◽

Norihito Kawashita ◽

Yu-Shi Tian ◽

Tatsuya Takagi

Keyword(s):

Drug Hypersensitivity ◽

Human Leukocyte ◽

Md Simulations ◽

Hypersensitivity Reactions ◽

Drug Induced ◽

Leukocyte Antigen ◽

Cell Clones ◽

Drug Hypersensitivity Reactions ◽

Long Time ◽

Underlying Mechanisms

The discovery that several drug hypersensitivity reactions (DHRs) are associated with specific human leukocyte antigen (HLA) alleles has attracted increasing research interest. However, the underlying mechanisms of these HLA-induced DHRs remain unclear, especially for drug-induced immediate activation of T-cell clones (TCCs). Recently, a novel hypothesis involving partial detachment between self-peptide(s) and the HLA molecule (altered peptide-HLA (pHLA) model) has been proposed to explain these phenomena. In order to clarify this hypothesis, we performed long-timescale molecular dynamics (MD) simulations. We focused on HLA-B⁎57:01-restricted abacavir hypersensitivity reactions (AHRs), one of the most famous DHRs. One of the simulation results showed that this altered-pHLA model might be driven by an increase in the distance not only between HLA and self-peptides but also between the α1 and α2 helices of HLA. Our findings provide novel insights into abacavir-induced immediate activation of TCCs and these findings might also be applied to other DHRs, such as HLA-B⁎58:01-restricted allopurinol hypersensitivity reactions.

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Skin testing and drug challenge in the evaluation of drug hypersensitivity reactions

Allergy and Asthma Proceedings ◽

10.2500/aap.2021.42.200091 ◽

2021 ◽

Vol 42 (1) ◽

pp. 16-21 ◽

Cited By ~ 1

Author(s):

Anna R. Wolfson ◽

Aleena Banerji

Keyword(s):

Negative Impact ◽

Skin Testing ◽

Drug Hypersensitivity ◽

Clinical History ◽

Hypersensitivity Reactions ◽

Causative Drug ◽

Care Assessment ◽

Drug Hypersensitivity Reactions ◽

Drug Challenge ◽

Drug Challenges

Immediate hypersensitivity to drugs is characterized by symptoms such as hives, swelling, and wheezing. To prevent a negative impact on care, assessment by an allergist is important. Evaluation requires a clear clinical history, but it is often lacking or vague, which makes a diagnosis difficult. Allergists instead can use skin testing and drug challenge to evaluate drug hypersensitivity reactions, which help the patient and provider understand the causative drug(s) and, more importantly, enables the use of the exonerated drug(s). Although penicillin skin testing is standardized, well described, and widely used, skin testing for most other drugs requires the use of a nonirritating skin testing concentration that can have a low negative predictive value. Drug challenges are the criterion standard for confirming tolerance. The allergist must obtain an in-depth clinical history and then follow with skin testing and/or drug challenges when indicated to determine which drugs can be de-labelled and which should be avoided. In this review, we focused on the evaluation of drug hypersensitivity reactions to antibiotics, perioperative agents, biologics, and chemotherapeutics.

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Severe Drug Hypersensitivity Reactions: Clinical Pattern, Diagnosis, Etiology and Therapeutic Options

Current Pharmaceutical Design ◽

10.2174/1381612822666160928125152 ◽

2017 ◽

Vol 22 (45) ◽

pp. 6852-6861 ◽

Cited By ~ 16

Author(s):

Maren Paulmann ◽

Maja Mockenhaupt

Keyword(s):

Drug Hypersensitivity ◽

Therapeutic Options ◽

Hypersensitivity Reactions ◽

Clinical Pattern ◽

Drug Hypersensitivity Reactions ◽

Pattern Diagnosis

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Clinical Phenotypes of Severe Cutaneous Drug Hypersensitivity Reactions

Current Pharmaceutical Design ◽

10.2174/1381612825666191107162921 ◽

2019 ◽

Vol 25 (36) ◽

pp. 3840-3854 ◽

Cited By ~ 2

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.

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Early Biomarkers for Severe Drug Hypersensitivity Reactions

Current Pharmaceutical Design ◽

10.2174/1381612825666191107105440 ◽

2019 ◽

Vol 25 (36) ◽

pp. 3829-3839 ◽

Cited By ~ 1

Author(s):

Adriana Ariza ◽

Maria J. Torres ◽

Carmen Moreno-Aguilar ◽

Rubén Fernández-Santamaría ◽

Tahia D. Fernández

Keyword(s):

Drug Exposure ◽

Drug Hypersensitivity ◽

Clinical Manifestations ◽

Skin Tests ◽

Time Interval ◽

Hypersensitivity Reactions ◽

Early Biomarkers ◽

Immunological Mechanisms ◽

Drug Hypersensitivity Reactions ◽

Delayed Reactions

Drug hypersensitivity reactions (DHRs) are typically classified into immediate and delayed reactions based on the time interval between drug exposure and onset of symptoms. Clinical manifestations range from mild to severe and life-threatening reactions. The most severe clinical entities are anaphylaxis and anaphylactic shock for immediate reactions, and severe cutaneous adverse reactions such as Steven Johnson Syndrome and Toxic Epidermal Necrolysis for delayed reactions. The diagnosis is complex and challenging, as drug provocation tests and even skin tests can be very risky procedures, which makes them not recommended. Therefore, it is necessary to search for useful early biomarkers to manage the diagnosis of these reactions. These biomarkers could be useful to determine the clinical entity, but not to identify the culprit drug. Some of the currently available biomarkers are few genetic associations of drug allergy with polymorphisms of human leukocyte antigen (HLA), the detection of inflammatory and lipid mediators in serum, or the detection of cytokines, chemokines, and cytotoxic markers in skin biopsies. In this literature review, it has been summarize the immunological mechanisms involved in severe reactions, both immediate and delayed, and different early biomarkers: those currently used for the diagnosis of these reactions as well as possible early biomarkers that could be useful with further studies to standardize their clinical use.

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