Updates on the immunopathology and genomics of severe cutaneous adverse drug reactions.

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS) cause significant morbidity and mortality and impede new drug development. HLA class I associations with SJS/TEN and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome have aided preventive efforts and provided insights into immunopathogenesis. In SJS/TEN, HLA class I-restricted oligoclonal CD8+ T-cell responses occur at the tissue level. However, specific HLA risk allele(s) and antigens driving this response have not been identified for most drugs. HLA risk alleles also have incomplete positive and negative predictive values, making truly comprehensive screening currently challenging. Although, there have been key paradigm shifts in knowledge regarding drug hypersensitivity, there are still many open and unanswered questions about SCAR immunopathogenesis, as well as genetic and environmental risk. In addition to understanding the cellular and molecular basis of SCAR at the single-cell level, identification of the MHC-restricted drug-reactive self- or viral peptides driving the hypersensitivity reaction will also be critical to advancing premarketing strategies to predict risk at an individual and drug level. This will also enable identification of biologic markers for earlier diagnosis and accurate prognosis, as well as drug causality and targeted therapeutics.

Potential Biomarker Identification by RNA-Seq Analysis in Antibiotic-Related Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A Pilot Study.

One of the most severe forms of cutaneous adverse drug reactions is "drug reaction with eosinophilia and systemic symptoms" (DRESS), hence subsequent avoidance of the causal drug is imperative. However, attribution of drug culpability in DRESS is challenging and standard skin allergy tests are not recommended due to patient safety reasons. Whilst incidence of DRESS is relatively low, between 1:1000 and 1:10 000 drug exposures, antibiotics are a commoner cause of DRESS and absence of confirmatory diagnostic test can result in unnecessary avoidance of efficacious treatment. We therefore sought to identify potential biomarkers for development of a diagnostic test in antibiotic-associated DRESS. Peripheral blood mononuclear cells from a "discovery" cohort (n = 5) challenged to causative antibiotic or control were analyzed for transcriptomic profile. A panel of genes was then tested in a validation cohort (n = 6) and compared with tolerant controls and other inflammatory conditions which can clinically mimic DRESS. A scoring system to identify presence of drug hypersensitivity was developed based on gene expression alterations of this panel. The DRESS transcriptomic panel identified antibiotic-DRESS cases in a validation cohort but was not altered in other inflammatory conditions. Machine learning or differential expression selection of a biomarker panel consisting of 6 genes (STAC, GPR183, CD40, CISH, CD4, and CCL8) showed high sensitivity and specificity (100% and 85.7%-100%, respectively) for identification of the culprit drug in these cohorts of antibiotic-associated DRESS. Further work is required to determine whether the same panel can be repeated for larger cohorts, different medications, and other T-cell-mediated drug hypersensitivity reactions.

Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles.

OBJECTIVES: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Still's disease with atypical lung disease. We sought to characterise features of patients with Still's disease with DRESS compared with drug-tolerant Still's controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort. METHODS: In a case/control study, we collected a multicentre series of patients with Still's disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still's controls (n=65). We retrospectively analysed clinical data from all Still's subjects and typed 94/131 for HLA. European Still's-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still's cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still's-DRESS cases (n=64) compared with drug-tolerant Still's controls (n=30). KD subjects (n=19) were similarly studied. RESULTS: Still's-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still's-DRESS (64%) versus drug-tolerant Still's (3%; p=1.2×10-14). We found striking enrichment for HLA-DRB1*15 haplotypes in Still's-DRESS cases versus INCHARGE Still's controls (p=7.5×10-13) and versus self-identified, ancestry-matched Still's controls (p=6.3×10-10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions. CONCLUSIONS: DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.

Genotyping HLA alleles to predict the development of Severe cutaneous adverse drug reactions (SCARs): state-of-the-art.

Introduction: Pharmacogenomics has great potential in reducing drug-induced severe cutaneous adverse drug reactions (SCARs). Pharmacogenomic studies have revealed an association between HLA genes and SCARs including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).Areas covered: Pharmacogenomics-guided therapy could prevent severe drug hypersensitivity reactions. The US Food and Drug Administration (FDA), Clinical Pharmacogenetics Implementation Consortium (CPIC), and Dutch Pharmacogenetics Working Group (DPWG) provided guidelines in the translation of clinically relevant and evidence-based SCARs pharmacogenomics research into clinical practice. In this review, we intended to summarize the significant HLA alleles associated with SCARs induced by different drugs in different populations. We also summarize the SCARs associated with genetic and non-genetic factors and the cost-effectiveness of screening tests.Expert opinion: The effectiveness of HLA screening on a wider scale in clinical practice requires significant resources, including state-of-the-art laboratory; multidisciplinary team approach and health care provider education and engagement; clinical decision support alert system via electronic medical record (EMR); laboratory standards and quality assurance; evidence of cost-effectiveness; and cost of pharmacogenomics tests and reimbursement.

Raltegravir-associated Drug-Reaction With Eosinophilia and Systemic Symptoms Syndrome in a Pediatric Patient Without Characteristic Human Leukocyte Antigen B*57:01 or B*53:01 alleles.

We present the first published case of raltegravir-associated drug-reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a child without characteristic human leukocyte antigen haplotypes HLA-B*57:01 or HLA-B*53:01. A 4-year-old African American female with perinatally acquired human immunodeficiency virus infection was hospitalized for DRESS after starting a raltegravir-based antiretroviral regimen.

The HLA-B*13:01 and the dapsone hypersensitivity syndrome in Korean and Asian populations: genotype- and meta-analyses.

BACKGROUND: The human leukocyte antigen (HLA)-B*13:01 was reported as an important risk factor for dapsone hypersensitivity syndrome (DHS) in Chinese and Thai populations. RESEARCH DESIGN AND METHODS: From the Korean nationwide registry, seven subjects with previous DHS were included. Their HLA allele/phenotype frequencies were compared with 8 dapsone-tolerant subjects recruited from a single institution, and general population (n = 485) in Korea. The authors also performed a meta-analysis with these data using previous Chinese and Thai studies. RESULTS: Among the seven DHS subjects, 85.7% presented with the HLA-B*13:01 allele. The HLA-C*03:04, HLA-DRB1*12:02 (both in linkage disequilibrium with HLA-B*13:01), and HLA-A*02:01 alleles were also presented in 85.7%, 71.4%, and 71.4%, respectively. Subjects with HLA-B*13:01 were susceptible to developing DHS compared to dapsone-tolerant controls (odds ratio [OR]: 73.667) and the Korean general population (OR: 139.500). HLA-C*03:04 (OR: 40.935), HLA-DRB*12:02 (OR: 36.613), and HLA-A*02:01 (OR: 5.862) showed similar results. In meta-analysis, HLA-B*13:01 was associated with dapsone-induced hypersensitivity (overall OR: 42.692), and subgroup analyses according to the control types demonstrated similar results (OR:43.694 and 41.866, respectively). CONCLUSIONS: Similar to previous Asian population studies, HLA-B*13:01 is significantly associated with the risk of DHS in Korea. These associations may be useful for preventing DHS and improving drug safety.

Adverse reactions to vancomycin and cross-reactivity with other antibiotics.

PURPOSE OF REVIEW: Glycopeptide antibiotics such as vancomycin are frequently utilized to treat resistant Gram-positive infections such as methicillin-resistant Staphylococcus aureus. The current literature on glycopeptide and lipoglycopeptide structure, hypersensitivity and potential cross-reactivity was reviewed, highlighting implications for safe prescribing. RECENT FINDINGS: Structurally similar, glycopeptides could theoretically cross-react. Immediate reactions to vancomycin include non-IgE-mediated reactions (e.g. red man syndrome) and IgE-mediated hypersensitivity (e.g. anaphylaxis), sharing clinical features. Vancomycin can activate mast cells via MAS-related G-protein-coupled receptor X2, an IgE-independent receptor implicated in non-IgE reactions. In-vivo and in-vitro testing for suspected IgE-mediated reactions to glycopeptides remain ill-defined. Vancomycin is increasingly recognized to cause severe cutaneous adverse reactions (SCAR), with drug reaction with eosinophilia and systemic symptoms (DRESS) predominantly reported. Vancomycin DRESS has been associated with HLA-A32:-01, with a number needed to prevent of 1 in 74. Data demonstrating cross-reactivity amongst glycopeptides and lipoglycopeptides is limited to case reports/series. SUMMARY: Further studies and in-vivo/in-vitro diagnostics are required for better differentiation between IgE and non-IgE glycopeptide reactions. Despite its association with vanomycin DRESS, utility of pharmacogenomic screening for HLA-A32: 01 is ill-defined. Although HLA-A32:01 has been associated with vancomycin DRESS, its utility for pharmacogenomic screening is ill defined. Further clinical and immunological cross-reactivity data for glycopeptide/lipoglycopeptide antibiotics is required.

Genetic Association of Co-Trimoxazole-Induced Severe Cutaneous Adverse Reactions Is Phenotype-Specific: HLA Class I Genotypes and Haplotypes.

Co-trimoxazole (CTX) causes various forms of severe cutaneous adverse reactions (SCARs). This case-control study was conducted to investigate the involvement between genetic variants of human leukocyte antigen (HLA) and CYP2C9 in CTX-induced SCARs, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) in Thai patients. Thirty cases of CTX-induced SCARs were enrolled and compared with 91 CTX-tolerant controls and 150 people from the general Thai population. Cases comprised 18 SJS/TEN and 12 DRESS patients. This study demonstrated that genetic association of CTX-induced SCARs was phenotype-specific. HLA-B*15:02 and HLA-C*08:01 alleles were significantly associated with CTX-induced SJS/TEN, whereas the HLA-B*13:01 allele was significantly associated with CTX-induced DRESS. In addition, a significant higher frequency of HLA-A*11:01-B*15:02 and HLA-B*13:01-C*03:04 haplotypes were detected in the group of CTX-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and DRESS cases, respectively. Genetic association of CTX-induced SCARs is phenotype-specific. Interestingly, these association was observed only in HIV-infected patients but not in non-HIV-infected patients.

Association of HLA genotypes with phenytoin induced severe cutaneous adverse drug reactions in Thai children.

PURPOSE: Phenytoin (PHT) is a common causative drug for severe cutaneous adverse drug reactions (SCARs) in children. SCARs, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are associated with a variation in HLA genotypes. Blood screening for specific HLA allele before PHT prescription would help in the reduction of the incidence of PHT induced SCARs. This study was to investigate the association between variations of HLA genotypes and PHT induced SCARs in Thai children. METHODS: Cases were Thai children aged between 0-18 years diagnosed with SCARs from PHT. Control groups were Thai children of corresponding age who had taken PHT for a least 12 weeks without any hypersensitivity reaction and healthy population controls. Blood samples from both groups were collected for HLA genotyping using a reverse-sequence specific oligonucleotide (SSO) probes method. Carrier rates of HLA alleles were compared between 22 cases (17 DRESS and 5 SJS-TEN), 60 tolerant controls and 649 population controls. RESULTS: Two HLA alleles includingHLA-B*51:01 and HLA-C*14:02 were significantly associated with PHT induced DRESS (OR 5.83; 95 % CI 1.36-25.00, p = 0.022 and OR 5.85; 95 % CI 1.16-29.35, p = 0.039). HLA-B*38:02 was significantly associated with PHT induced SJS-TEN (OR12.67; 95 % CI 1.50-106.89, p = 0.044). Haplotype analysis demonstrated the association of HLA haplotype A*11:01-B*51:01-C*14:02 and PHT induced DRESS compared to tolerant controls and the healthy population control group (OR 8.92; 95 % CI 1.47-54.02, p = 0.019, and OR 10.2; 95 % CI 3.04-34.21, p = 0.002). HLA haplotype B*38:02-C*07:01 in PHT induced SJS-TEN was significantly higher than those in tolerant controls and the healthy population control group (40 % vs 3.3 % vs 0.3 %; OR 19.33; 95 % CI 1.98-188.59, p = 0.027 and OR 215.67; 95 % CI 22.40-2076.04, p = 0.0003. HLA-B*15:02 was not associated with PHT induced SCARs. SIGNIFICANCE: An association betweenHLA-B*51:01 and HLA-C*14:02 and PHT induced DRESS and HLA-B*38:02 and PHT induced SJS-TEN has been demonstrated in Thai children.

New genetic predictors for abacavir tolerance in HLA-B*57:01 positive individuals.

Abacavir hypersensitivity syndrome (ABC HSS) is strongly associated with carriage of human leukocyte antigen (HLA)-B*57:01, which has a 100% negative predictive value for the development of ABC HSS. However, 45% of individuals who carry HLA-B*57:01 can tolerate ABC. We investigated immune and non-immune related genes in ABC HSS (n = 95) and ABC tolerant (n = 43) HLA-B*57:01 + patients to determine other factors required for the development of ABC HSS. Assignment of phenotype showed that ABC HSS subjects were significantly less likely than tolerants to carry only ERAP1 hypoactive trimming allotypes (p = 0.02). An altered self-peptide repertoire model by which abacavir activates T cells is in keeping with observation that endoplasmic reticulum aminopeptidase 1 (ERAP1) allotypes that favour efficient peptide trimming are more common in ABC HSS patients compared to patients who tolerate ABC. Independently, non-specific immune activation via soluble cluster of differentiation antigen 14 (sCD14) may also influence susceptibility to ABC HSS.

HLA-B*58:01 Genotyping to Prevent Cases of DRESS and SJS/TEN in East Asians Treated with Allopurinol-A Canadian Missed Opportunity [Formula: see text].

BACKGROUND AND OBJECTIVE: East Asians exposed to the urate-lowering drug allopurinol have a predilection for severe cutaneous drug reactions such as drug-induced hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Screening is recommended in patients of East Asian descent for the presence of HLA-B*58:01 prior to allopurinol initiation to avoid these complications. Utilization rates of the HLA-B*58:01 predictive screening test within the Greater Vancouver area, which has a population composed of 40.1% people of East Asian descent, are unknown. MEASURES: We identified cases of DRESS or SJS/TEN due to allopurinol using the Vancouver General Hospital dermatology consult service database. We next compared the frequency in which the HLA-B*58:01 screening test was ordered since 2012 to the estimated frequency of new prescriptions for allopurinol prescribed for the management of gout among the East Asians. RESULTS: We report 5 cases of East Asian patients exposed to allopurinol for management of gout between 2012 and 2016, who developed DRESS (4 patients) or SJS/TEN (1 patient). All were of HLA-B*58:01 genotype, representing preventable cases. The HLA-B*58:01 test was ordered 6 times in 2012, whereas the estimated number of new cases of allopurinol-prescribed gout among patients of East Asian descent during that time period was 13. For 2012, testing was ordered for only 46% of at-risk patients. CONCLUSION: We continue to observe cases of severe cutaneous drug reactions among high-risk individuals due to allopurinol exposure. The HLA-B*58:01 screening test for allopurinol hypersensitivity is underutilized in our geographic area.

High and variable population prevalence of HLA-B*56:02 in indigenous Australians and relation to phenytoin-associated drug reaction with eosinophilia and systemic symptoms.

Phenytoin drug reaction with eosinophilia and systemic symptoms (DRESS) in 3 Aboriginal Australians positive for HLA-B*56:02 has been previously reported. We report the allele frequency of HLA-B*56:02 in 2 South Australian populations, 1 Aboriginal (4.8%, 95% confidence interval 2.4-7.8%) and the other European (0%). We compared the frequency with publicly available information on HLA-B*56:02 status in other Indigenous Australian (n = 4) and European Australian cohorts (n = 1). In the Indigenous Australian cohorts, HLA-B*56:02 allele frequency ranged from 1.3 to 19%. We also describe an additional case of phenytoin DRESS (RegiSCAR DRESS score 7) in an Aboriginal Australian that was associated with HLA-B*56:02 and with CYP2C9*1/*3 genotype. In Aboriginal Australians, phenytoin DRESS appears distinctly linked to HLA-B*56:02 with an allele carriage rate substantially higher than in Europeans, but also with considerable regional variation. Investigations of human leucocyte antigen and other contributing genes and severe adverse drug reactions in understudied non-European populations are required to optimize safe medication use and inform risk mitigation strategies.

A Rapid Allele-Specific Assay for HLA-A*32:01 to Identify Patients at Risk for Vancomycin-Induced Drug Reaction with Eosinophilia and Systemic Symptoms.

Human leukocyte antigen (HLA) alleles have been implicated as risk factors for immune-mediated adverse drug reactions. The authors recently reported a strong association between HLA-A*32:01 and vancomycin-induced drug reaction with eosinophilia and systemic symptoms. Identification of individuals with the risk allele before or shortly after the initiation of vancomycin therapy is of great clinical importance to prevent morbidity and mortality, and improve drug safety and antibiotic treatment options. A prerequisite to the success of pharmacogenetic screening tests is the development of simple, robust, cost-effective single HLA allele test that can be implemented in routine diagnostic laboratories. In this study, the authors developed a simple, real-time allele-specific PCR for typing the HLA-A*32:01 allele. Four-hundred and fifty-eight DNA samples including 30 HLA-A*32:01-positive samples were typed by allele-specific PCR. Compared with American Society for Histocompatibility and Immunogenetics-accredited, sequence-based, high-resolution, full-allelic HLA typing, this assay demonstrates 100% accuracy, 100% sensitivity (95% CI, 88.43% to 100%), and 100% specificity (95% CI, 99.14% to 100%). The lowest limit of detection of this assay using PowerUp SYBR Green is 10 ng of template DNA. The assay demonstrates a sensitivity and specificity to differentiate the HLA-A*32:01 allele from closely related non-HLA-A*32 alleles and may be used in clinical settings to identify individuals with the risk allele before or during the course of vancomycin therapy.

Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions.

Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10-9 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10-9 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.