Supplementary Material for: Genotypic and phenotypic characteristics of co-trimoxazole-induced cutaneous adverse reactions

Background. Co-trimoxazole has been reported as a common culprit drug for various cutaneous adverse drug reactions (CADRs). However, information on genotypic and phenotypic characteristics is still limited. We aimed to study clinical characteristics, genetic suitability, laboratory findings, and treatment outcome in patients with co-trimoxazole-induced CADR and determine variables associated with severe cutaneous adverse reactions (SCARs). Methods. The medical records of all patients diagnosed with co-trimoxazole-induced CADR during October 2015 and October 2021 were reviewed. Clinical characteristics and laboratory investigation with an emphasis on HLA class I and HLA-DRB1 results linked to subtypes of cutaneous adverse reactions were evaluated. Results. Seventy-two patients diagnosed with co-trimoxazole-induced CADR were included in the study. Mean age at diagnosis was 38.0±14.6 years old, and 72% were female. Subtypes of reactions included maculopapular eruption (MPE; 56.9%), drug reaction with eosinophilia and systemic symptoms (DRESS; 23.6%), Stevens-Johnson syndrome (SJS; 12.5%), fixed drug eruption (4.2%), and urticaria (2.8%). Characteristics that were significantly associated with SCARs included male gender (OR=3.01, 95%CI 1.04-8.75), HIV infection (OR=3.48, 95%CI 1.13-10.75), prophylactic use of co-trimoxazole (OR=4.89, 95%CI 1.54-15.57), and co-trimoxazole administration longer than 10 days (OR=7.65, 95%CI 2.57-22.78). HLA-B*38:02 was associated with co-trimoxazole-induced SJS, while HLA-A*11:01, HLA-B*13:01, and HLA-DRB1*12:01 were associated with co-trimoxazole-induced DRESS. HLA-B*52:01 was associated with co-trimoxazole-induced MPE. Conclusions. Co-trimoxazole could induce various phenotypes of CADRs. Genotypic and phenotypic factors that may potentially predict co-trimoxazole-induced SCARs include male gender, HIV infection, prophylactic and prolonged drug use, as well as the presence of HLA-A*11:01, HLA-B*13:01, HLA-B*38:02, or HLA-DRB1*12:01 alleles.

【背景】已有研究证实，复方新诺明（co-trimoxazole）是引发各类皮肤药物不良反应（cutaneous adverse drug reactions, CADRs）的常见致敏药物。然而，目前针对该类不良反应的基因型与表型特征的相关研究数据仍较为匮乏。本研究旨在分析复方新诺明诱导的皮肤药物不良反应患者的临床特征、遗传特征、实验室检查结果及治疗转归，并明确与重症皮肤药物不良反应（severe cutaneous adverse reactions, SCARs）相关的危险因素。
【方法】回顾性分析2015年10月至2021年10月期间确诊为复方新诺明诱导的皮肤药物不良反应的所有患者的病历资料。本研究对患者的临床特征及实验室检查结果进行了评估，重点分析了与皮肤药物不良反应亚型相关的人类白细胞抗原（Human Leukocyte Antigen, HLA）I类及HLA-DRB1基因分型结果。
【结果】本研究共纳入72例确诊为复方新诺明诱导的皮肤药物不良反应的患者。患者确诊时的平均年龄为38.0±14.6岁，其中女性占比72%。不良反应亚型包括斑丘疹（maculopapular eruption, MPE；56.9%）、嗜酸性粒细胞增多伴全身症状药物反应（drug reaction with eosinophilia and systemic symptoms, DRESS；23.6%）、史蒂文斯-约翰逊综合征（Stevens-Johnson syndrome, SJS；12.5%）、固定性药疹（4.2%）及荨麻疹（2.8%）。与重症皮肤药物不良反应显著相关的特征包括：男性性别（比值比（Odds Ratio, OR）=3.01，95%置信区间（95% Confidence Interval, 95%CI）：1.04~8.75）、HIV感染（OR=3.48，95%CI：1.13~10.75）、复方新诺明预防性给药（OR=4.89，95%CI：1.54~15.57）以及复方新诺明给药时长超过10天（OR=7.65，95%CI：2.57~22.78）。HLA-B*38:02与复方新诺明诱导的SJS相关，而HLA-A*11:01、HLA-B*13:01及HLA-DRB1*12:01与复方新诺明诱导的DRESS相关；HLA-B*52:01则与复方新诺明诱导的MPE相关。
【结论】复方新诺明可诱发多种表型的皮肤药物不良反应。可能用于预测复方新诺明诱导的重症皮肤药物不良反应的基因型与表型因素包括：男性性别、HIV感染、预防性用药及长期用药，以及携带HLA-A*11:01、HLA-B*13:01、HLA-B*38:02或HLA-DRB1*12:01等位基因。