一例硫唑嘌呤导致的快速进展性脱发病例,以及日本自身免疫性大疱病患者中 NUDT15 变体的流行情况:一项单中心回顾性观察研究。

Sho Katayama, Kentaro Izumi, Inkin Ujiie, Hideyuki Ujiie
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引用次数: 0

摘要

自身免疫性水疱病(AIBDs)分为丘疹性荨麻疹(pemphigus)和丘疹性荨麻疹(pemphigoid),是一种相对罕见的皮肤疾病,由分别针对去鳞屑蛋白和半去鳞屑蛋白的自身抗体引起。虽然全身使用皮质类固醇激素是 AIBD 的一线治疗方法,但硫唑嘌呤作为一种类固醇替代药物也经常被联合使用。硫唑嘌呤会被代谢为硫鸟嘌呤核苷酸(TGNs),这是其主要的活性代谢产物。纽狄克水解酶 15(NUDT15)在调节硫鸟嘌呤核苷酸方面起着关键作用。众所周知,硫唑嘌呤的严重副作用,包括白细胞减少症和脱发,在 NUDT15 变体患者中尤其严重。单核苷酸多态性 c.415C >T(p.Arg139Cys)是与严重硫嘌呤毒性相关的最常见的 NUDT15 变异之一。最近,我们治疗了一例患有 NUDT15 变体的寻常天疱疮患者,患者在接受硫唑嘌呤治疗期间出现了快速进展的弥漫性脱发和骨髓抑制。以往有关 NUDT15 多态性的报道主要集中于炎症性肠病或血液恶性肿瘤患者,而 NUDT15 多态性在 AIBD 中的流行情况仍不清楚。这凸显了研究 AIBD 中 NUDT15 多态性的迫切性,以便更好地了解影响硫唑嘌呤不良反应的遗传因素。为了明确NUDT15变体在日本AIBD患者中的流行情况,我们回顾性地查阅了2018年至2023年期间来北海道大学医院就诊的78名AIBD患者(26名大疱性类天疱疮患者、26名寻常型天疱疮患者、17名叶状天疱疮患者和9名其他AIBD患者)的病历。在这些患者中,NUDT15变体Arg/Arg、Arg/Cys和Cys/Cys的频率分别约为72%、23%和5%。我们的研究结果表明,NUDT15变体在AIBD患者中的流行率与之前对其他疾病患者的研究结果相似。这些结果强调了在日本的 AIBD 患者开始硫唑嘌呤治疗前筛查 NUDT15 变体的重要性。
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A case of rapidly progressive hair loss due to azathioprine, and the prevalence of NUDT15 variants among Japanese patients with autoimmune blistering diseases: A single-center retrospective observational study.

Autoimmune blistering diseases (AIBDs), classified into pemphigus and pemphigoid, consist of relatively rare skin disorders caused by autoantibodies that target desmosomal and hemidesmosomal proteins, respectively. Although systemic corticosteroids are used as a first-line treatment for AIBDs, azathioprine is frequently co-administered as a steroid-sparing agent. Azathioprine is metabolized into thioguanine nucleotides (TGNs) which are its major active metabolites. The enzyme nudix hydrolase 15 (NUDT15) plays a key role in regulating TGNs. Serious side effects of azathioprine, including leukopenia and alopecia, are known to be particularly problematic in individuals with NUDT15 variants. The single-nucleotide polymorphism c.415C >T (p.Arg139Cys) is one of the most frequent NUDT15 variants associated with severe thiopurine toxicity. Recently, we treated a case of pemphigus vulgaris in a patient with NUDT15 variants in which the patient developed rapidly progressive diffuse hair loss and myelosuppression while receiving azathioprine. Previous reports on NUDT15 polymorphisms mainly focused on patients with inflammatory bowel disease or hematological malignancies, and the prevalence of NUDT15 polymorphisms remains unknown in AIBDs. This highlights the urgent need for research on NUDT15 polymorphisms in AIBDs to achieve a better understanding of the genetic factors influencing adverse reactions to azathioprine. To clarify the prevalence of NUDT15 variants in Japanese patients with AIBDs, we retrospectively reviewed the medical records of 78 patients with AIBDs (26 with bullous pemphigoid, 26 with pemphigus vulgaris, 17 with pemphigus foliaceus, and nine with other AIBDs) who had come to Hokkaido University Hospital between 2018 and 2023. The frequencies of NUDT15 variants of Arg/Arg, Arg/Cys, and Cys/Cys in these patients were approximately 72%, 23%, and 5%, respectively. Our findings indicate a prevalence of NUDT15 variants in AIBD patients that is similar to the prevalences of previous studies on patients with other diseases. These results emphasize the importance of screening for NUDT15 variants prior to initiating azathioprine treatment in Japanese patients with AIBDs.

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