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Spectrum of cutaneous adverse reactions to aromatic antiepileptic drugs and human leukocyte antigen genotypes in Thai patients and meta-analysis.

ABSTRACT: Aromatic antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs) add up to the limited use of the AEDs in the treatment and prevention of seizures. Human leukocyte antigen-B (HLA-B) alleles have been linked to AEDs-induced cADRs. We investigated the association between cADRs (including Stevens-Johnson syndrome; SJS/toxic epidermal necrolysis; TEN, drug reaction with eosinophilia and systemic symptoms; DRESS, and Maculopapular eruption; MPE) caused by AEDs (phenytoin, carbamazepine, lamotrigine, phenobarbital and oxcarbazepine) and HLA-B alleles in Thai population. Through the case-control study, 166 patients with AEDs-induced cADRs, 426 AEDs-tolerant patients (AEDs-tolerant controls), and 470 healthy subjects (Thai population) were collected. The HLA genotypes were detected using the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. We also performed a meta-analysis with these data and other populations. The carrier rate of HLA-B*15:02 was significantly different between AEDs-induced cADRs group and AEDs-tolerant group (Odds ratio; OR 4.28, 95% Confidence interval; CI 2.64-6.95, p < 0.001), AEDs-induced cADRs group and Thai population (OR 2.15, 95%CI 1.41-3.29, p < 0.001). In meta-analysis showed the strong association HLA-B*15:02 with AEDs-induced cADRs (OR 4.77, 95%CI 1.79-12.73, p < 0.001). Furthermore, HLA-B*15:02 was associated with SJS/TEN induced by AEDs (OR 10.28, 95%CI 6.50-16.28, p < 0.001) Phenytoin (OR 4.12, 95%CI 1.77-9.59, p = 0.001) and carbamazepine (OR 137.69, 95%CI 50.97-371.98, p < 0.001). This study demonstrated that genetic association for AEDs-induced cADRs was phenotype-specific. A strong association between HLA-B*15:02 and AEDs-induced SJS/TEN was demonstrated with an OR of 10.79 (95%CI 5.50-21.16, p < 0.001) when compared with AEDs-tolerant group. On the other hand, the carrier rates of HLA-B*08:01, HLA-B*13:01, and HLA-B*56:02 were significantly higher in the DRESS group compared with the AEDs-tolerant group (p = 0.029, 0.007, and 0.017, respectively). The HLA-B*15:02 allele may represent a risk factor for AEDs-induced cADRs.

SUBMITTER: Sukasem C

PROVIDER: S-EPMC8602035 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeSevere cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) to antiepileptic drug (AED), are rare, but result in significant morbidity and mortality. We investigated the major culprit drugs, clinical characteristics, and clinical course and outcomes of AED-induced SCARs using a nationwide registry in Korea.MethodsA total of 161 patients with AED-induced SCARs from 28 referral hospitals were analyzed. The causative AEDs, clinical characteristics, organ involvements, details of treatment, and outcomes were evaluated. We compared the clinical and laboratory parameters between SJS/TEN and DRESS according to the leading causative drugs. We further determined risk factors for prolonged hospitalization in AED-induced SCARs.ResultsCarbamazepine and lamotrigine were the most common culprit drugs causing SCARs. Valproic acid and levetiracetam also emerged as the major causative agents. The disease duration and hospital stay in carbamazepine-induced SJS/TEN were shorter than those in other AEDs (P< 0.05, respectively). In younger patients, lamotrigine caused higher incidences of DRESS than other drugs (P= 0.045). Carbamazepine, the most common culprit drug for SCARs, was associated with a favorable outcome related with prolonged hospitalization in SJS (odds ratio, 0.12; 95% confidence interval, 0.02-0.63, P= 0.12), and thrombocytopenia was found to be a risk factor for prolonged hospitalization in DRESS.ConclusionThis was the first large-scale epidemiological study of AED-induced SCARs in Korea. Valproic acid and levetiracetam were the significant emerging AEDs causing SCARs in addition to the well-known offending AEDs such as carbamazepine and lamotrigine. Carbamazepine was associated with reduced hospitalization, but thrombocytopenia was a risk factor for prolonged hospitalization. Our results suggest that the clinical characteristics and clinical courses of AED-induced SCARs might vary according to the individual AEDs.

Project description:Antiepileptic drugs frequently cause cutaneous adverse reactions (cADRs). Numerous studies have reported associations between human leukocyte antigen (HLA) alleles and cADRs caused by single antiepileptic drug in Southern Han Chinese people. However, the relationship between the HLA allele and cADRs sequentially induced by two or more antiepileptic drugs (AEDs-induced cross-reactivity) is unclear. To explore the associations between HLA alleles and AEDs-induced cross-reactivity, we prospectively recruited patients with AEDs-induced cross-reactivity from 2009 to 2017 and performed high-resolution genotyping to detect the HLA-A, B, C, and DRB1 alleles in patients for comparison with normal controls. To verify the important genotype, we compared its presence in patients with cross-reactivity to enlarged normal controls, and its presence in patients with carbamazepine (CBZ)-induced maculopapular exanthema (MPE) to CBZ-tolerant controls. Further, the important allele was replicated by meta-analysis. Twenty-three patients with AED-induced cross-reactivity and 500 healthy individuals were enrolled from Southern China. All patients had a mild rash without mucosal or systemic involvement. The HLA-B*13:01 allele was present in 34.78% (8/23) of patients, 14.60% (73/500) of healthy individuals, and 14.5% (763/5,270) healthy individuals, revealing a significant association (8/23 vs. 73/500; P = 0.02; OR: 3.12; 95% CI: 1.28-7.62; 8/23 vs. 763/5,270; P = 0.014; OR: 3.15; 95% CI: 1.33-7.46). HLA-B*13:01 was presented numerically higher in CBZ-induced MPE than that in CBZ-tolerant individuals without statistical significance (33/145, 22.76%, vs. 28/179, 15.64%; P = 0.103). Meta-analysis revealed an association between HLA-B*13:01 and cADRs induced by single AEDs or/and non-AEDs in Chinese and Thai populations (P = 0.000). This study suggests that HLA-B*13:01 is potentially associated with AED-cADRs in general, possibly with stronger effect in cross-reactivity. Screening for HLA-B*13:01 prior to starting AEDs therapy may help to avoid cADRs. However, this association requires further analysis in a multi-center study with a larger sample size.

Project description:PURPOSE:Nonsteroidal anti-inflammatory drugs (NSAIDs) are common cause of severe cutaneous adverse reactions (SCARs). The present study aimed to investigate the characteristics of SCARs induced by NSAIDs in the Korean SCAR registry. METHODS:A retrospective survey of NSAID-induced SCARs recorded between 2010 and 2015 at 27 university hospitals in Korea was conducted. Clinical phenotypes of SCARs were classified into Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), SJS-TEN overlap syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS). Causative NSAIDs were classified into 7 groups according to their chemical properties: acetaminophen, and propionic, acetic, salicylic, fenamic and enolic acids. RESULTS:A total of 170 SCARs, consisting of 85 SJS, 32 TEN, 17 SJS-TEN overlap syndrome and 36 DRESS reactions, were induced by NSAIDs: propionic acids (n=68), acetaminophen (n=38), acetic acids (n=23), salicylic acids (n=16), coxibs (n=8), fenamic acids (n=7), enolic acids (n=5) and unclassified (n=5). Acetic acids (22%) and coxibs (14%) accounted for higher portions of DRESS than other SCARs. The phenotypes of SCARs induced by both propionic and salicylic acids were similar (SJS, TEN and DRESS, in order). Acetaminophen was primarily associated with SJS (27%) and was less involved in TEN (10%). DRESS occurred more readily among subjects experiencing coxib-induced SCARs than other NSAID-induced SCARs (62.5% vs. 19.7%, P = 0.013). The mean time to symptom onset was longer in DRESS than in SJS or TEN (19.1 ± 4.1 vs. 6.8 ±1.5 vs. 12.1 ± 3.8 days). SCARs caused by propionic salicylic acids showed longer latency, whereas acetaminophen- and acetic acid-induced SCARs appeared within shorter intervals. CONCLUSIONS:The present study indicates that the phenotypes of SCARs may differ according to the chemical classifications of NSAIDs. To establish the mechanisms and incidences of NSAID-induced SCARs, further prospective studies are needed.

Project description:BackgroundThis active, open observational study aimed to investigate adverse drug reactions (ADRs) associated with six commonly used antiepileptic drugs (AEDs) in southern Chinese outpatients with epilepsy from 2003 to 2015.MethodsThe Wenzhou Epilepsy Follow-Up Registry Database (WEFURD) was established by a single epilepsy center in China in January 2003 to record AED efficacy and the associated ADRs by registered outpatients diagnosed with epilepsy. We reviewed the data of outpatients who had only taken one or more of six commonly used AEDs, namely, carbamazepine (CBZ), valproate (VPA), lamotrigine (LTG), oxcarbazepine (OXC), topiramate (TPM) and levetiracetam (LEV), and were registered in the WEFURD between 2003 and 2015. We evaluated the ADRs caused by the single or combined use of the above six specific AEDs based on the WHO-UMC scale. The data of the ADRs were categorized by age, sex, number of AEDs related to ADRs, medications, seriousness of ADRs, causality levels of the WHO-UMC scale and system organ class (SOC). The unit of analysis was one ADR.ResultsA total of 3069 epilepsy outpatients (1807 outpatients with 5049 eligible ADRs and 1262 outpatients without ADRs) were included. The overall ADR rate was 58.88% (1807/3069). An average of 2.79 ADRs (5049/1807) occurred per patient with an ADR; 53.8% of the 5049 ADRs were recorded in females, and 50.4% were caused by monotherapy. Of the ADRs, 10.6% (537/5049) were severe adverse reactions (SARs), including 34 serious adverse effects (SAEs). The SAR rates caused by one, two and three or more AEDs were 9.9, 10.0 and 19.6%, respectively (p < 0.001). Eighteen SOC categories were identified, and the top three were psychiatric disorders (1633/5049, 32.3%), neurological disorders (1222/5049, 24.2%) and gastrointestinal disorders (564/5049, 11.2%). Of the 537 SARs, skin and appendage disorders accounted for 24.4% (131/537). Among the 34 SAEs, serious allergies, fetal malformations, renal calculus and pancreatitis accounted for the majority.ConclusionsOur findings suggest that clinicians should pay attention to psychiatric ADRs and be alert for SARs, especially when three or more AEDs are used together. Moreover, active surveillance might provide another method of pharmacovigilance in China.

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Spectrum of cutaneous adverse reactions to aromatic antiepileptic drugs and human leukocyte antigen genotypes in Thai patients and meta-analysis.

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