Carbamazepine Hypersensitivity Research Articles

Large-Scale Deletions of Mitochondrial DNA in Epilepsy Patients Treated with Carbamazepine

Mitochondrial dysfunction, caused by large-scale deletion mutations, can lead to impaired function of the mitochondrial respiratory chain, reduced ATP production, and serious effects on most energy-consuming organs, such as neurons, and can induce seizures in epilepsy. Carbamazepine (CBZ), the first-line drug used in the treatment of epilepsy, can be harmful to mitochondria and its side effects may be related to mitochondrial dysfunction. In this study, mitochondrial DNA (mtDNA) large-scale deletions were identified in 65 CBZ-treated patients with epilepsy, including 32 patients with CBZ-induced hypersensitivity and 33 with CBZ tolerance. Using the PCR method, mtDNA large-scale deletions were identified in 21/65 epilepsy patients (32.31%), including 9/32 CBZ-hypersensitivity patients (28.13%) and 12/33 CBZ-tolerance patients (36.36%). However, this difference was not statistically significant. The “common deletion” of 4977 bp was the most prevalent deletion. Remarkably, the new deletion of 4876 bp in a CBZ-tolerance patient was reported for the first time. Quantitative PCR analysis showed that the level of mtDNA large-scale deletion was significantly lower in the hypersensitivity group than in the tolerance group (p < 0.05). Besides, analysis of the association between the level of mtDNA large-scale deletion and mtDNA copy number with the clinical features of CBZ hypersensitivity patients showed no relationship with age and severity of skin lesions (p > 0.05). However, there was a statistically significant association between the level of mtDNA large-scale deletions and sex (p < 0.01). Further studies are needed to evaluate the role of mtDNA large-scale deletions in epilepsy and their association with antiepileptic drugs.

Characterization of Drug-Specific CD4+ T-Cells Reveals Possible Roles of HLA Class II in the Pathogenesis of Carbamazepine Hypersensitivity Reactions

Carbamazepine (CBZ) is an aromatic anticonvulsant known to cause drug hypersensitivity reactions, which range in severity from relatively mild maculopapular exanthema to potentially fatal Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN). These reactions are known to be associated with human leukocyte antigen (HLA) class I alleles, and CBZ interacts preferentially with the related HLA proteins to activate CD8+ T-cells. This study aimed to evaluate the contribution of HLA class II in the effector mechanism(s) of CBZ hypersensitivity. CBZ-specific T-cells clones were generated from two healthy donors and two hypersensitive patients with high-risk HLA class I markers. Phenotype, function, HLA allele restriction, response pathways, and cross-reactivity of CBZ-specific T-cells were assessed using flow cytometry, proliferation analysis, enzyme-linked immunosorbent spot, and enzyme-linked immunosorbent assay. The association between HLA class II allele restriction and CBZ hypersensitivity was reviewed using Allele Frequency Net Database. Forty-four polyclonal CD4+ CBZ-specific T-cell clones were generated and found to be restricted to HLA-DR, particularly HLA-DRB1*07:01. This CD4+-mediated response proceeded through a direct pharmacological interaction between CBZ and HLA-DR molecules. Similar to the CD8+ response, CBZ-stimulated CD4+ clones secreted granulysin, a key mediator of SJS-TEN. Our database review revealed an association between HLA-DRB1*07:01 and CBZ-induced SJS-TEN. These findings implicate HLA class II antigen presentation as an additional pathogenic factor for CBZ hypersensitivity reactions. Both HLA class II molecules and drug-responsive CD4+ T-cells should be evaluated further to gain better insights into the pathogenesis of drug hypersensitivity reactions.

HLA-B*57:01/Carbamazepine-10,11-Epoxide Association Triggers Upregulation of the NFκB and JAK/STAT Pathways

Measure of drug-mediated immune reactions that are dependent on the patient's genotype determine individual medication protocols. Despite extensive clinical trials prior to the license of a specific drug, certain patient-specific immune reactions cannot be reliably predicted. The need for acknowledgement of the actual proteomic state for selected individuals under drug administration becomes obvious. The well-established association between certain HLA molecules and drugs or their metabolites has been analyzed in recent years, yet the polymorphic nature of HLA makes a broad prediction unfeasible. Dependent on the patient's genotype, carbamazepine (CBZ) hypersensitivities can cause diverse disease symptoms as maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms or the more severe diseases Stevens-Johnson-Syndrome or toxic epidermal necrolysis. Not only the association between HLA-B*15:02 or HLA-A*31:01 but also between HLA-B*57:01 and CBZ administration could be demonstrated. This study aimed to illuminate the mechanism of HLA-B*57:01-mediated CBZ hypersensitivity by full proteome analysis. The main CBZ metabolite EPX introduced drastic proteomic alterations as the induction of inflammatory processes through the upstream kinase ERBB2 and the upregulation of NFκB and JAK/STAT pathway implying a pro-apoptotic, pro-necrotic shift in the cellular response. Anti-inflammatory pathways and associated effector proteins were downregulated. This disequilibrium of pro- and anti-inflammatory processes clearly explain fatal immune reactions following CBZ administration.

Next-generation sequencing-based HLA typing reveals the association of HLA-B*46:01:01 and HLA-DRB1*09:01:02 alleles with carbamazepine-induced hypersensitivity reactions in Vietnamese patients with epilepsy

Several studies have reported an association between certain human leukocyte antigen (HLA) alleles and carbamazepine (CBZ)-induced hypersensitivity reactions in patients with epilepsy. Here, the relationship between the clinical spectrum and the HLA allele profiles in patients with CBZ-induced hypersensitivity reactions was investigated using next-generation sequence (NGS) data obtained from 65 Vietnamese patients with epilepsy, including 33 with CBZ-tolerance and 32 patients with CBZ-hypersensitivity, in which only 8 with severe cutaneous adverse drug reactions and 24 were mild-hypersensitive patients. Three loci of HLA class I (HLA-A, -B, and -C) and two loci of HLA class II (HLA-DQA1 and -DRB1) were included in our analysis. We observed a higher prevalence of three alleles, HLA-B*46:01:01, HLA-DQA1*03:02:01, and HLA-DRB1*09:01:02, in the CBZ hypersensitivity group compared to that in the CBZ tolerant group. Notably, all hypersensitive patients with HLA-DQA1*03:02:01 also harbored HLA-DRB1*09:01:02. We also used molecular modeling to gain mechanistic insight into the interactions of HLA-B*46:01 and HLA-DRB1*09:01 with CBZ. Our findings proposed the direct interaction of CBZ with peptide-binding pockets of these HLA proteins. The sensitivity and specificity of HLA-B*46:01:01 in considering with the appearance of HLA-DRB1*09:01:02 were 46.88% and 84.85%, respectively. Our data suggest that the presence of HLA-B*46:01:01/HLA-DRB1*09:01:02 is a potential marker of CBZ-induced hypersensitivity reactions in Vietnamese patients.

Evaluation of clinical and genetic factors in the population pharmacokinetics of carbamazepine.

AimsCarbamazepine can cause hypersensitivity reactions in ~10% of patients. An immunogenic effect can be produced by the electrophilic 10,11‐epoxide metabolite but not by carbamazepine. Hypothetically, certain single nucleotide polymorphisms might increase the formation of immunogenic metabolites, leading ultimately to hypersensitivity reactions. This study explores the role of clinical and genetic factors in the pharmacokinetics (PK) of carbamazepine and 3 metabolites known to be chemically reactive or formed through reactive intermediates.MethodsA combination of rich and sparse PK samples were collected from healthy volunteers and epilepsy patients. All subjects were genotyped for 20 single nucleotide polymorphisms in 11 genes known to be involved in the metabolism or transport of carbamazepine and carbamazepine 10,11‐epoxide. Nonlinear mixed effects modelling was used to build a population‐PK model.ResultsIn total, 248 observations were collected from 80 subjects. A 1‐compartment PK model with first‐order absorption and elimination best described the parent carbamazepine data, with a total clearance of 1.96 L/h, central distribution volume of 164 L and absorption rate constant of 0.45 h−1. Total daily dose and coadministration of phenytoin were significant covariates for total clearance of carbamazepine. EPHX1‐416G/G genotype was a significant covariate for the clearance of carbamazepine 10,11‐epoxide.ConclusionOur data indicate that carbamazepine clearance was affected by total dose and phenytoin coadministration, but not by genetic factors, while carbamazepine 10,11‐epoxide clearance was affected by a variant in the microsomal epoxide hydrolase gene. A much larger sample size would be required to fully evaluate the role of genetic variation in carbamazepine pharmacokinetics, and thereby predisposition to carbamazepine hypersensitivity.

The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity.

Drug hypersensitivity reactions that resemble acute immune reactions are linked to certain human leucocyte antigen (HLA) alleles. Severe and life-threatening Stevens Johnson Syndrome and Toxic Epidermal Necrolysis following treatment with the antiepileptic and psychotropic drug Carbamazepine are associated with HLA-B*15:02; whereas carriers of HLA-A*31:01 develop milder symptoms. It is not understood how these immunogenic differences emerge genotype-specific. For HLA-B*15:02 an altered peptide presentation has been described following exposure to the main metabolite of carbamazepine that is binding to certain amino acids in the F pocket of the HLA molecule. The difference in the molecular mechanism of these diseases has not been comprehensively analyzed, yet; and is addressed in this study. Soluble HLA-technology was utilized to examine peptide presentation of HLA-A*31:01 in presence and absence of carbamazepine and its main metabolite and to examine the mode of peptide loading. Proteome analysis of drug-treated and untreated cells was performed. Alterations in sA*31:01-presented peptides after treatment with carbamazepine revealed different half-life times of peptide-HLA- or peptide-drug-HLA complexes. Together with observed changes in the proteome elicited through carbamazepine or its metabolite these results illustrate the mechanistic differences in carbamazepine hypersensitivity for HLA-A*31:01 or B*15:02 patients and constitute the bridge between pharmacology and pharmacogenetics for personalized therapeutics.

Diagnostic Utility of Human Leukocyte Antigen B*15:02 Screening in Severe Carbamazepine Hypersensitivity Syndrome.

Background:Despite many studies suggesting an association between human leukocyte antigen (HLA)-B*15:02 and carbamazepine (CBZ)-induced severe cutaneous adverse drug reactions essentially toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS), the evidence of association in different populations and the degree of association remain uncertain.Materials and Methods:The primary analysis was based on population control studies. Data were pooled by means of a random-effects model, and sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR−), diagnostic odds ratios (DOR), and areas under the summary receiver operating characteristic curve (AUC) were calculated.Results:In 23 population control studies, HLA-B*15:02 was measured in 373 patients with CBZ-induced TEN/SJS and 3452 patients without CBZ-induced TEN/SJS. The pooled sensitivity, specificity, LR+, LR−, DOR, and AUC were 0.67 (95% confidence interval [CI] = 0.63–0.72), 0.98 (95% CI = 0.98–0.99), 19.73 (95% CI = 10.54–36.92), 0.34 (95% CI = 0.23–0.49), 71.38 (95% CI = 34.89–146.05), and 0.96 (95% CI = 0.92–0.98), respectively. Subgroup analyses for Han Chinese, Thai, and Malaysian populations yielded similar findings. Specifically, racial/ethnic subgroup analyses revealed similar findings with respect to DOR for Han Chinese (99.28; 95% CI = 22.20–443.88), Thai (61.01; 95% CI = 23.05–161.44), and Malaysian (30; 95% CI = 7.08–126.68) populations, which are similar to the pooled DOR for the relationship between the HLA-B*15:02 allele and CBZ-induced TEN/SJS across all populations (71.38; 95% CI = 34.89–146.05).Conclusions:The present study reveals that CBZ is the leading cause of TEN/SJS in many countries. Screening of HLA-B*15:02 may help patients to prevent the occurrence of CBZ-induced TEN/SJS, especially in populations with a higher (≥5%) risk allele frequency.

Fever and Transaminitis: A Case of Carbamazepine Hypersensitivity Reaction Associated With Human Herpes Virus 6 Reactivation

Introduction: Carbamazepine is an aromatic anticonvulsant commonly used for the treatment of epilepsy and trigeminal neuralgia. Carbamazepine has been associated with hepatotoxicity ranging from mild transaminitis to fatal liver failure. Here, we highlight a rare case of carbamazepine hypersensitivity reaction associated with human herpesvirus 6 (HHV-6) reactivation. Case Description: A 60-year-old woman presented with a 2-week history of fevers, chills, fatigue, and myalgias. Approximately 3 weeks prior, she had been initiated on carbamazepine for left glossopharyngeal neuralgia. In the ED, she was febrile to 39.5 C. Laboratory workup revealed hemoglobin 14.1, leukocytes 5.5, creatinine 0.74, ALT 474, AST 562, alkaline phosphatase 148, total bilirubin 0.8, albumin 3.9, and INR 1.1. Acetaminophen and ethanol levels were unremarkable. An infectious work-up including urinalysis, chest x-ray, and blood cultures was negative. Abdominal ultrasound demonstrated normal hepatic echotexture, no focal masses, and normal gallbladder and biliary tree. After admission, she continued to have high-grade fevers to 39.4 C. Additional laboratory testing including hepatitis virus panel, EBV, CMV, HSV, HIV, tick-borne panel, thyroid function, antinuclear antibody, anti-smooth muscle and antimitochondrial antibodies was unremarkable. HHV-6 PCR was positive. CT chest, abdomen, and pelvis were negative for an infectious, inflammatory, or neoplastic process. Carbamazepine was discontinued and she was initiated on a slow prednisone taper with improvement in her symptoms and liver tests. Discussion: This clinical vignette highlights a case of drug-induced hypersensitivity reaction secondary to carbamazepine. Asymptomatic transaminitis with initiation of carbamazepine is not uncommon and typically resolves with drug discontinuation. Clinically apparent hepatotoxicity is uncommon but can present as drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, which can sometimes progress to acute liver failure and even death. Several case reports have described an association between reactivation of HHV-6 and carbamazepine hypersensitivity syndrome with unclear underlying mechanism. While eosinophilia, lymphadenopathy, and rash are typical features of carbamazepine hypersensitivity reaction that were absent in this case, the time course of symptoms, positive HHV-6, and lack of an alternative diagnosis were consistent with this clinical entity.

Carbamazepine induced Stevens Johnson Syndrome: a case report from a tertiary care hospital

Stevens Johnson Syndrome is a rare but life-threatening skin disease and Carbamazepine is considered as one of the most common cause. The reported frequency of serious Carbamazepine hypersensitivity reaction is between 1/1000 and 1/10000 new exposures to the drug. Here, we report a case of a 40 year old female patient, who developed multiple ulcerative lesions all over the body three days after starting treatment with Carbamazepine for Trigeminal Neuralgia. (Worldwide Unique Number- 2017-58502 and AMC Report Number- BJGMC-Pune/Nov-2017/BBG-1860) Stevens Johnson Syndrome was diagnosed. Carbamazepine was withdrawn, and the patient was treated with topical and intravenous antibiotics. A biopsy was done which confirmed the diagnosis of Stevens Johnson Syndrome.

Allergy to chlorpromazine and valproic acid following carbamazepine hypersensitivity in a patient with an HLA-B*4601 allele

A 73-year-old man, exhibiting psychomotor excitement after traumatic brain injury, developed allergic cutaneous eruptions and hepatic inflammation that did not resolve after the cessation of carbamazepine (CBZ). Fusing maculopapular erythema was observed in the face, neck, presternal region, and bilaterally in the forearms and feet. A drug-induced lymphocyte stimulation test revealed hypersensitivity to chlorpromazine (CPZ) and valproic acid (VPA), as well as to CBZ. The allergic reaction with eosinophilia to CPZ and VPA was suspected to have emerged following CBZ hypersensitivity, since previous treatment with CPZ and VPA prior to the introduction of CBZ had not been associated with adverse reactions earlier in the course of treatment. Recent studies have indicated linkages between severe CBZ hypersensitivity – but not mild CBZ hypersensitivity – and specific leukocyte antigens, HLA-B*1502 and HLA-A*3101, in Asian and European populations. The present case exhibited the HLA-B*4601 allele, which is associated with a high relative risk for the development of CBZ-induced maculopapular eruptions in Japanese and Han Chinese populations. Although cross-hypersensitivity among aromatic compounds, including CBZ and CPZ, is well-established, data regarding CBZ allergy-associated hypersensitivity to VPA are limited. In the present case, a cutaneous allergy to mianserin (a tetracyclic antidepressant) was also observed later in the course of treatment, suggesting additional cross-reactivity exists among aromatic psychotropic drugs. Thus, the association between the HLA-B*4601 allele and allergic reactions to VPA, aromatic psychotropic drugs, and CBZ should be further examined in future studies.

Randomized trial of betahistine mesilate tablets as augmentation for oxcarbazepine and carbamazepine in treating vestibular paroxysmia.

BackgroundVestibular paroxysmia (VP) is a rare episodic peripheral vestibular disorder. This study was conducted to compare the efficacy and acceptability of carbamazepine (CBZ) plus betahistine mesilate tablets (BMT) (CBZ+BMT) and oxcarbazepine (OXC) plus BMT (OXC+BMT) in treating VP, and investigated whether the synergistic effect could be increased along with the increased dose of BMT.MethodsVP patients were recruited and randomly assigned to receive CBZ+BMT or OXC+BMT. The doses of CBZ and OXC were set to 200 and 300 mg/time, twice daily, respectively. The doses of BMT were set to 12 and 18 mg/time, twice daily. Half of the patients in each group received BMT 12 mg/time and the other half received BMT 18 mg/time. The treatment was continued for 12 weeks. The vertigo frequency, vertigo score, vertigo duration, response rate, and drug-related side effects were analyzed.ResultsIn total, 92 patients in the CBZ+BMT group and 93 patients in the OXC+BMT group completed this trial. After 12 weeks of treatment, the two groups had similar average vertigo frequency, average vertigo score, average vertigo duration, and response rate. But the incidence of side effects was significantly higher in the CBZ+BMT group than in the OXC+BMT group (p=0.04). Subgroup analysis found that patients receiving BMT (18 mg) had greater reductions in average vertigo frequency, average vertigo duration, and average vertigo score, and higher response rates than patients receiving BMT (12 mg).ConclusionThese results demonstrated that OXC+BMT may be suitable as an alternative method in VP patients with CBZ hypersensitivity, and the synergistic effect could be increased along with the increased dose of BMT.

Role of Pharmacogenomics in Antiepileptic Drug Therapy: Current Status and Future Perspectives.

Growing evidence indicates that pharmacogenomics will positively impact treatment for patients with epilepsy in the near future, leading to the implementation of a precision-based use of antiepileptic drug (AED) therapy, thereby providing a cornerstone for precision medicine. In this review, we briefly summarize the studies of pharmacogenomics in epilepsy, recent advances, and how it may progress in the future. We subdivided the review into two main sections: genetic variants that may modulate response to AEDs through pharmacokinetics or pharmacodynamics mechanisms; and gene variants that may affect tolerability and safety of AEDs. Results from most studies have been contradictory, due to several flaws, including small sample sizes, inaccurate phenotyping, and genotyping strategies. However, even with these limitations, very recent developments indicate that the goal of incorporating genetic data into clinical practice may be attainable in the near future. In addition, recent pharmacogenomic studies of hypersensitivity reactions to AEDs have also made important strides, as its prevention appears attainable with the identification of HLA-A genotypes for patients at high risk of carbamazepine hypersensitivity. To better clarify the relationship between genetic factors and AEDs, future studies will require more precise epilepsy phenotypes, larger sample sizes, and astute use of new genotyping strategies. Reasonably, this will lead to novel therapeutic approaches in drug targeting and antiepileptogenesis.

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients.

ObjectiveTo characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs.MethodsWe conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed.ResultsWe report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients.ConclusionsThe identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.

Mass Spectrometric Characterization of Circulating Covalent Protein Adducts Derived from Epoxide Metabolites of Carbamazepine in Patients.

Carbamazepine (CBZ) is an effective antiepileptic drug that has been associated with hypersensitivity reactions. The pathogenesis of those reactions is incompletely understood but is postulated to involve a complex interplay between the drug's metabolism, genetic variation in human leukocyte antigens, and adverse activation of the immune system. Multiple T-cell activation mechanisms have been hypothesized including activation by drug-peptide conjugates derived from proteins haptenated by reactive metabolites. However, definitive evidence of the drug-protein adducts in patients has been lacking. In this study, mass spectrometry was used to characterize protein modifications by microsomally-generated metabolites of CBZ and in patients taking CBZ therapy. CBZ 10,11-epoxide (CBZE), a major electrophilic plasma metabolite of CBZ, formed adducts with glutathione-S-transferase pi (GSTP; Cys47) and human serum albumin (HSA; His146 and His338, but not Cys34) in vitro via notably divergent side-chain selectivity. Both proteins were adducted at the same residues by undefined monoxygenated metabolites ([O]CBZ) when they were incubated with human liver microsomes, NADPH and CBZ. There was also evidence for formation of a CBZ adduct at His146 and His338 of HSA derived via dehydration from an intermediate arene oxide adduct. Glutathione trapping of reactive metabolites confirmed microsomal production of CBZE and indicated simultaneous production of arene oxides. In 15 patients prescribed CBZ therapy, [O]CBZ-modified HSA (His146) was detected in all subjects. The relative amount of adduct was moderately positively correlated with plasma concentrations of CBZ (r2 = 0.44, p = 0.002) and CBZE (r2 = 0.35, p = 0.006). Our results have provided the first chemical evidence for microsomal production of [O]CBZ species that are able to escape the microsomal domain to react covalently with soluble proteins. This study has also demonstrated the presence of circulating [O]CBZ-modified HSA in patients without hypersensitivity reactions who were receiving standard CBZ therapy. The implications of those circulating adducts for susceptibility to CBZ hypersensitivity merit further immunological investigation in hypersensitive patients.

Assessment of gene expression profiles of peripheral blood mononuclear cells from patients with a history of carbamazepine hypersensitivity

BackgroundCarbamazepine (CBZ) therapy is associated with hypersensitivity reactions, which can be multisystemic and sometimes fatal. The pathogenesis of these reactions is incompletely understood but heterologous immunity generated to viral antigens has been proposed as a potential mechanism. Our aim was to investigate changes in gene expression profiles of peripheral blood mononuclear cells (PBMCs) from patients with CBZ hypersensitivity to characterise the pathways involved in immune activation. MethodsPBMCs were isolated from five individuals with a history of hypersensitivity to CBZ. The PBMCs were incubated for 24 h with CBZ, carbamazepine 10,11-epoxide (CBZE), cell culture medium, or tetanus toxoid. Expression profiles for mRNA and microRNA were generated with microarrays (Affymetrix, Santa Clara, CA, USA). Differential gene expression was undertaken by limma analysis in the R statistical software. Ingenuity pathway analysis (IPA) was used to define the molecular mechanisms in development of CBZ hypersensitivity. FindingsIncubation of PBMCs with CBZ, CBZE, and tetanus toxoid led to significant differential expression (log2-fold change >1 or <–1, p<0·05) of multiple mRNA (n=204) and microRNA (n=148) transcripts with little overlap between the different incubation conditions. The top differentially expressed genes for CBZ-treated and CBZE-treated cells identified in IPA analysis were COX8A, IFI35, IFIT3, PARP9, PARP12, PTGES, RSAD2, USP18, USP41, miR433, miR455, miR3194, miR4723, and miR345. These genes were highly interconnected in functional networks and defined five top functional categories—namely, viral infection, psoriasis, inflammation of body region or organ, and antiviral response. InterpretationIncubation of PBMCs from CBZ hypersensitive individuals with CBZ or CBZE led to treatment-specific changes in gene expression associated with activation of antiviral and inflammatory pathways. These CBZ-specific and CBZE-specific mRNA and microRNA changes could potentially act as novel diagnostic biomarkers and treatment targets for CBZ hypersensitivity reactions, but further validation and confirmation of specificity in larger numbers of patients are needed. FundingVY was supported by the North West England Medical Research Council Fellowship Scheme (clinical pharmacology and therapeutics), which is funded by the Medical Research Council (grant number G1000417/94909), ICON, GlaxoSmithKline, AstraZeneca, and the Medical Evaluation Unit.

The HLA-A*31:01 allele: influence on carbamazepine treatment.

Carbamazepine (CBZ) is an effective anticonvulsant that can sometimes cause hypersensitivity reactions that vary in frequency and severity. Strong associations have been reported between specific human leukocyte antigen (HLA) alleles and susceptibility to CBZ hypersensitivity reactions. Screening for HLA-B*15:02 is mandated in patients from South East Asia because of a strong association with Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). HLA-A*31:01 predisposes to multiple phenotypes of CBZ hypersensitivity including maculopapular exanthema, hypersensitivity syndrome, and SJS/TEN in a range of populations including Europeans, Japanese, South Koreans and Han Chinese, although the effect size varies between the different phenotypes and populations. Between 47 Caucasians and 67 Japanese patients would need to be tested for HLA-A*31:01 in order to avoid a single case of CBZ hypersensitivity. A cost-effectiveness study has demonstrated that HLA-A*31:01 screening would be cost-effective. Patient preference assessment has also revealed that patients prefer pharmacogenetic screening and prescription of alternative anticonvulsants compared to current standard of practice without pharmacogenetic testing. For patients who test positive for HLA-A*31:01, alternative treatments are available. When alternatives have failed or are unavailable, HLA-A*31:01 testing can alert clinicians to 1) patients who are at increased risk of CBZ hypersensitivity who can then be targeted for more intensive monitoring and 2) increase diagnostic certainty in cases where hypersensitivity has already occurred, so patients can be advised to avoid structurally related drugs in the future. On the basis of the current evidence, we would favor screening all patients for HLA-A*31:01 and HLA-B*15:02 prior to starting CBZ therapy.

Polymorfism Of CYP2C9 And 3A5 and carbamazepine hypersensitivity reactions in Brazilian subjects

Polymorfism Of CYP2C9 And 3A5 and carbamazepine hypersensitivity reactions in Brazilian subjects

Polymorfism Of CYP2C9 And 3A5 and carbamazepine hypersensitivity reactions in Brazilian subjects

Background The cytochrome P450 2C9 and 3A5 enzymes are predominantly found in the human liver, and have important functions in the metabolism of antiepileptics. Genetic polymorphisms in these genes are associated with altered enzymatic activities and may give rise to the risk of drug hypersensitivity. Therefore, we analyze the association between CBZ hypersensitivity reactions (CHR) and polymorphisms of CYP2C9 and 3A5 in a population of Sao Paulo, Brazil. Methods Case-control study in which we genotyped the SNP of CYP2C9 (rs1057910, rs1799853) and 3A5 (rs776746) of samples obtained from 52 subjects with varying severities CHR, 82 tolerants, and 366 control subjects, all from Sao Paulo, Brazil. According to the alleles presente, each subject was classified as normal, decrease or increased funcion for the enzyme. The phenotype was evaluated based on standardized scoring systems using an adapted ENDA (European Network of Drug Allergy) questionnaire, medical records and on the clinical follow-up. The patch test with the culprit drug was performed according the ENDA recommendations.

Genetics of immune-mediated adverse drug reactions: a comprehensive and clinical review.

Adverse drug reactions (ADRs) are common and are a major problem in drug therapy. Patients experience unnecessary morbidity and mortality whilst many effective drugs are withdrawn because of ADRs in a minority of patients. Recent studies have demonstrated significant associations between human leukocyte antigens (HLA) and predisposition to ADRs such as drug-induced skin injury (DISI) and drug-induced liver injury (DILI). HLA-B*58:01 has been significantly associated with allopurinol-induced hypersensitivity. Associations between HLA and carbamazepine hypersensitivity reactions demonstrate both ethnicity and phenotype specificity; with HLA-B*15:02 associated with Stevens-Johnson syndrome and toxic epidermal necrolysis in South East Asian patients only whilst HLA-A*31:01 is associated with all phenotypes of hypersensitivity in multiple ethnicities. Studies of ximelagatran, an oral direct thrombin inhibitor withdrawn because of hepatotoxicity, found associations between HLA-DRB1*07:01 and HLA-DQA1*02:01 and ximelagatran DILI. Interestingly, HLA-B*57:01 is associated with both abacavir DISI and flucloxacillin DILI but the reasons for the different phenotype of ADR remains unknown. Pharmacogenetic screening for HLA-B*57:01 prior to abacavir therapy has significantly reduced the incidence of abacavir hypersensitivity syndrome in clinical practice. No other HLA associations have been translated into clinical practice because of multiple reasons including failure to replicate, inadequate sample sizes, and our lack of understanding of pathophysiology of ADRs. Here, we review genetic associations that have been reported with ADRs and discuss the challenges that scientists, clinicians, pharmaceutical industry and regulatory agencies face when attempting to translate these associations into clinically valid and cost-effective tests to reduce the burden of ADRs in future.

HLA Restriction of Carbamazepine-Specific T-Cell Clones from an HLA-A*31:01-Positive Hypersensitive Patient

HLA-A*31:01 is associated with carbamazepine (CBZ) hypersensitivity in Caucasian and Japanese populations. Herein, we show that HLA-A*31:01+ restricted the activation of carbamazepine-specific CD8(+) T-cells, which provides an immunological basis for the genetic association. Furthermore, CD4(+) T-cells were activated with carbamazepine in a HLA-DRB1*04:04-restricted manner, indicating that a common HLA haplotype may contribute to the multiclonal T-cell response seen in European patients with CBZ hypersensitivity.