在系统性自身免疫性疾病患者中使用黄嘌呤氧化酶抑制剂优化硫嘌呤治疗：单中心经验
Optimizing Thiopurine Therapy with a Xanthine Oxidase Inhibitor in Patients with Systemic Autoimmune Diseases: A Single-Centre Experience.
作者信息
Belhocine Mériem, Mourad Alissar, Chapdelaine Aurélie, Mansour Anne-Marie, Troyanov Yves, Doré Maxime
机构信息
, MD, FRCPC, is an internal medicine specialist with Hôpital du Sacré-Coeur de Montréal, and a Clinical Professor of Medicine in the Faculty of Medicine, Université de Montréal, Montréal, Quebec.
, PharmD, MSc, was, at the time of this study, a PharmD student in the Faculty of Pharmacy, Université de Montréal, Montréal, Quebec. She has now graduated and is a pharmacist with the Centre intégré universitaire de santé et services sociaux du Centre-sud-de-l'Ile-de-Montréal, Montréal, Quebec.
出版信息
Can J Hosp Pharm. 2021 Fall;74(4):361-369. doi: 10.4212/cjhp.v74i4.3199.
BACKGROUND
Thiopurines are a mainstay of therapy for autoimmune diseases. However, up to 20% to 30% of patients experience overproduction of the methylated metabolites, known as 6-MMP, to the detriment of the active metabolite, 6-thioguanine nucleotide (6-TGN). These patients, commonly referred to as "shunters", are predisposed to thiopurine resistance and hepatotoxicity. In patients with inflammatory bowel diseases, the combination of thiopurine with a xanthine oxidase inhibitor (XOI) is used to reverse this skewed metabolism and to prevent treatment failure or hepatotoxicity. Data on the use of this strategy for patients with other diseases are limited.
OBJECTIVES
To investigate and describe the use of thiopurine-XOI combination therapy in shunters with systemic autoimmune diseases.
METHODS
Shunters treated in the study hospital between January 1, 2005, and December 31, 2015, were identified using the hospital's laboratory database, and clinical data were collected retrospectively. For each patient with optimization of thiopurine therapy, clinical and laboratory data were assessed over a 6-month period.
RESULTS
Thirty-four patients were identified as shunters; for 14 of these patients, thiopurine therapy was optimized with an XOI. In these 14 patients, the median dose of azathioprine was reduced from 1.95 to 0.78 mg/kg with combination therapy. In addition, median 6-TGN level increased from 135 to 385 pmol/8 × 10 erythrocytes ( = 0.001); furthermore, 6-TGN levels rose to above 235 pmol/8 ×10 erythrocytes for 11 of the 14 patients. Conversely, the median 6-MMP level decreased from 6267 to 271 pmol/8 × 10 erythrocytes ( = 0.001). Except for a 12% increase in mean corpuscular volume, no clinically significant changes in blood count were recorded. Notable infections were reported in 3 patients, and 1 patient had to discontinue treatment because of cytopenia. After 6 months, median prednisone daily dose was reduced by 74%, from 16.7 mg to 4.4 mg ( = 0.005), and 4 patients had been weaned off corticosteroids. Of the 14 patients, 11 (79%) were in full remission, and 2 (14%) were in partial remission.
CONCLUSION
Optimizing thiopurine therapy with an XOI may be a safe and effective strategy for patients with systemic autoimmune diseases.
背景
硫唑嘌呤是自身免疫性疾病治疗的主要药物。然而，高达20%至30%的患者会产生过量的甲基化代谢产物，即6 - 甲基巯基嘌呤（6 - MMP），这对活性代谢产物6 - 硫鸟嘌呤核苷酸（6 - TGN）不利。这些患者通常被称为“分流者”，易出现硫唑嘌呤耐药和肝毒性。在炎症性肠病患者中，硫唑嘌呤与黄嘌呤氧化酶抑制剂（XOI）联合使用可逆转这种代谢偏差，预防治疗失败或肝毒性。关于该策略在其他疾病患者中的应用数据有限。
目的
研究并描述硫唑嘌呤 - XOI联合疗法在患有系统性自身免疫性疾病的“分流者”中的应用情况。
方法
利用医院实验室数据库确定2005年1月1日至2015年12月31日在研究医院接受治疗的“分流者”患者，并回顾性收集临床数据。对于每位硫唑嘌呤治疗得到优化的患者，在6个月期间评估其临床和实验室数据。
结果
确定34例患者为“分流者”；其中14例患者采用XOI优化硫唑嘌呤治疗。在这14例患者中，联合治疗使硫唑嘌呤的中位剂量从1.95 mg/kg降至0.78 mg/kg。此外，6 - TGN的中位水平从135 pmol/8×10⁸红细胞升至385 pmol/8×10⁸红细胞（P = 0.001）；而且，14例患者中有11例的6 - TGN水平升至235 pmol/8×10⁸红细胞以上。相反，6 - MMP的中位水平从6267 pmol/8×10⁸红细胞降至271 pmol/8×10⁸红细胞（P = 0.001）。除平均红细胞体积增加12%外，血细胞计数未出现具有临床意义的变化。3例患者报告有明显感染，1例患者因血细胞减少不得不停止治疗。6个月后，泼尼松的中位日剂量降低了74%，从16.7 mg降至4.4 mg（P = 0.005），4例患者已停用糖皮质激素。14例患者中，11例（79%）完全缓解，2例（14%）部分缓解。
结论
对于患有系统性自身免疫性疾病的患者，用XOI优化硫唑嘌呤治疗可能是一种安全有效的策略。
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