| Objective:Stevens-Johnson syndrome(SJS)and toxic epidermal necrolysis(TEN)are severe cutaneous adverse reactions that develop in response to specific triggers such as medications and certain infections.Although the incidence of SCARs is low,the mortality and disability rate caused by them were very high.Phenytoin(PHT)is one of the most commonly used drugs in the treatment of epilepsy,adverse reactions of it mainly occur in skin,and with the SJS and TEN to be the most.The occurrence of SCARs greatly limits the clinical use of PHT,and is also the main reason for clinical drug withdrawal.A large number of recent studies have indicated that human leukocyte antigen(HLA)gene are closely related to a variety of drug induced SCARs,such as HLA-B * 57:01 and abacavir,and HLA-B * 15:02 and carbamazepine.The aim of this paper was to evaluate the relationship between HLA-B * 15:02 and PHT induced SJS / TEN using systematic and meta-analysis.Method: Two researchers performed independent and extensive searches in the Cochrane Library,EMBASE,MEDLINE and OVID from inception to December 2017.Researches explored the relationship between HLA-B * 15:02 and SJS / TEN were included by the inclusion criteria(1)all participants were epileptic patients;(2)the studies were case-control studies;(3)the SJS / TEN were induced by PHT;(4)HLA-B * 15:02 allele could be detected in the included participants;(5)sufficient data could be got to calculate the frequency of HLA-B * 15:02 carriers among controls and cases;(6)the diagnosis is defined according to the percentage of damaged skin surface area,The skin of the damaged area of <10% is defined as SJS,the skin damaged area between 10%-30% is defined as SJS / TEN overlap,skin damaged area > 30% is defined as TEN;and excluded by exclusion criteria:(1)research type is a review or case report;(2)without a full text;(3)the multiple medications of epilepsy patients,SJS / TEN may be induced by other antiepileptic drugs,such as carbamazepine or lamotrigine;(4)for the patients less than 3 years of age.At the same time,the following data were extracted according to the pre-designed scheme: 1.basic information: first author and published year;2.Characteristics of the subjects: race of the participants,characteristics of cases and controls as well as PHT exposure dose.The relationship between HLA-B*15: 02 and PHT-induced SJS/TEN was identified by using overall odds ratios(ORs)with the corresponding 95% confidence intervals(CIs).Heterogeneity among the studies were analyzed by I2 and χ2 test,stability of the study was assessed by sensitivity analysis(changing the effect model from random effect model to fixed effect model,and comparing the two results of them).The funnel plot was constructing to evaluate publication bias.Review Manager(version 5.3)software was used for meta-analysis.Results: 6 articles with 74 cases and 378 controls(PHT tolerance control group)were included in this study.Articles included in this study were assessed by Newcastle-Ottawa Scale(NOS),and all 6 articles were considered as highquality literature.Meta-analysis showed that the incidence of PTH-induced SJS/TEN in HLA-B * 15:02 allele carriers is 4.61 times as high as that in noncarriers(OR=4.61,95%CI: 2.65-8.01,P<0.00001),no significant heterogeneity was observed in this study(I2 = 0%,P χ2 = 0.54).Sensitivity analysis were performed by changing the model and showed that the results were stable and reliable.Conclusion: This study showed a strong association between the HLA-B * 15:02 allele and the SJS/TEN induced by PHT.Therefore,it is suggested that the allele should be detected before the clinical use of PHT,which can predict the patients who carry this allele and guide the administration and / or use of PHT.The current research sample is small,and further multicenter study and large prospective observation study is needed to enhance the evidence that HLA-B * 15:02 is closely related to SJS / TEN.objective: The occur as severe cutaneous adverse drug reactions(SCARs)induced by phenytoin(PHT),one of the most cost-effective antiepileptic drugs(AEDs),a certain extent limit clinical use of PHT.Stevens-Johnson syndrome(SJS)and toxic epidermal necrolysis(TEN)are severe cutaneous adverse reactions that can be induced by PHT.Genetic polymorphisms of the cytochromes P450(CYP)have been proposed as key elements for the susceptibility to PHT-related SCARs in certain ethnicities.CYP2C9* 3,which is encoded by CYP2C9* 3 mutant allele,is the key enzyme in PHT metabolism.The aim of this meta-analysis was to evaluate the association between CYP2C9 * 3 mutant allele and PHT-induced SJS/TEN.Methods: Two reviewers respectively conducted extensive searches in multiple databases,including the Cochrane Library,EMBASE,Pub Med,OVID,and EBSCO.The electronic databases were searched from inception until 5 June 2017.Researches explored the relationship between CYP2C9* 3 and SJS/TEN were enrolled by the inclusion criteria and exclusion criteria((1)were casecontrol studies;(2)explored relationships between CYP2C9* 3 and PHT-induced SJS or TEN;(3)compared patients with PHT-induced SJS or TEN with PHTtolerant patients or the general population;(4)reported sufficient data to calculate frequency of CYP2C9 * 3 carriers among cases and controls;and(5)defined the diagnosis of SJS and TEN by the percentage of skin surface area damaged,where <10% involvement was defined as SJS,10%-30% involvement was defined as SJS/TEN overlap,and >30% involvement was defined as TEN.Studies were excluded if they were(1)review articles or case reports;or(2)articles without full text available;or(3)repeated publication;or(4)the patients less than 3 years of age).And the following data which were extracted from the study according to the prepare designed method.The data included:(1)first author and year of publication;(2)characteristics of subjects: participants ethnicity,case and control characteristics,matching criteria and PHT exposure dose.Overall odds ratios(ORs)with corresponding 95% confidence intervals(CIs)were used to identify the relationship between the presence of CYP2C9*3 and PHT-induced SJS/TEN.The heterogeneity among the studies were analyzed by using I2 and χ2 test,the research results stability evaluated were analyzed by the sensitivity analysis(pooling data in a random effects model and comparing the result with that of a fixed effects model).The funnel plot was constructing to evaluate publication bias.Data analysis was performed using Review Manager(version 5.3).Results: Four studies,with 117 PHT-induced SJS/TEN cases and 338 matched controls(PHT-tolerant patients)or 4231 population controls(general population),were identified.The 4 articles included in the study were evaluated according to the Newcastle-Ottawa(NOS)scale,and all of them were high-quality literatures.SJS and TEN were found to be significantly associated with the CYP2C9 * 3 allele,comparing both matched controls(OR,8.93;95% CI,2.63-30.36;P = 0.0005)with substantial heterogeneity(I2 = 46%)and population controls(OR=8.86,95%CI: 5.23-15.00;P <0.00001).Substantial heterogeneity(I2 = 46%)was observed in the former.A subgroup analysis found that differences in ethnicity probably be the main source of heterogeneity in this study.Sensitivity analysis,which was performed by exchanging the two effects models,demonstrated that our results were robust.Conclusion: A significant association between CYP2C9 * 3 and PHT induced SJS/TEN was identified,especially in a Thai population.CYP2C9 * 3 is thus a credible predictive genetic marker of PHT-induced SJS/TEN.However,these findings were only based on a small number of case-control studies.Further multicenter studies and large prospective observational studies are,however,still required to determinethe influence of CYP2C*3 on blood levels of PHT and its metabolites,and their association with SJS/TEN. |
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