Department of Rheumatology, Clinical Research Center for Rheumatic Disease, NHO Kumamoto Saishunsou National Hospital, 2659 Suya, Kohshi, Kumamoto, 861-1196, Japan.
Mod Rheumatol. 2012 Aug;22(4):515-23. doi: 10.1007/s10165-011-0537-1. Epub 2011 Oct 13.
This study was performed to explore the possibility of an association between polymorphisms within the uridine diphosphate glucuronosyltransferase 1A1 gene (UGT1A1) and hyperbilirubinemia arising during tocilizumab therapy. We examined the distributions of 3 variant alleles, UGT1A1*6, *28, and 27, in 46 Japanese patients with rheumatoid arthritis (RA) who had received tocilizumab therapy for at least 24 weeks, grouped the patients according to their carriage status of these UGT1A1 variants, and determined the frequency of hyperbilirubinemia in each of the groups. Of the 46 patients treated with tocilizumab, 34 maintained normal bilirubin levels after 24 weeks, whereas the remaining 12 developed mild or moderate hyperbilirubinemia. Patients carrying 2 copies of UGT1A128 (28/28) were more likely to develop hyperbilirubinemia than those without UGT1A128. In addition, patients carrying 2 copies of variant alleles, either as homozygotes (UGT1A16/6 or 28/28) or as compound heterozygotes (UGT1A16/28), were at higher risk of hyperbilirubinemia as compared with those without either UGT1A16 or UGT1A128 (odds ratio [OR] 28.33; 95% confidence interval [CI] 2.39-336.00; p = 0.005). Multivariate logistic regression analysis confirmed the strong association of tocilizumab-induced hyperbilirubinemia with the presence of 2 copies of variant alleles (OR 25.51; 95% CI 2.35-276.53; p = 0.008), yielding an area under the receiver operating characteristics curve of 0.78 (95% CI 0.60-0.95, p = 0.005). Tocilizumab can induce hyperbilirubinemia in RA patients, especially those carrying UGT1A16/*6, *6/*28, and *28/*28 genotypes. Considering this genetic association, it may be unnecessary to withdraw this drug from RA patients in the absence of other signs of hepatic injury. Given that tocilizumab has the potential to inhibit UGT1A1-mediated glucuronidation, however, it may inhibit not only bilirubin metabolism but also UGT1A1-dependent detoxification of drugs, thereby increasing the risk of unwanted adverse events during RA therapy.
本研究旨在探讨尿苷二磷酸葡萄糖醛酸基转移酶 1A1 基因（UGT1A1）内多态性与托珠单抗治疗过程中发生高胆红素血症之间可能存在的关联。我们检测了 46 例接受托珠单抗治疗至少 24 周的日本类风湿关节炎（RA）患者中 3 种变异等位基因 UGT1A16、28 和 27 的分布情况，根据这些 UGT1A1 变异体的携带状态对患者进行分组，并确定了每组高胆红素血症的发生频率。在接受托珠单抗治疗的 46 例患者中，34 例在 24 周后胆红素水平保持正常，而其余 12 例出现轻度或中度高胆红素血症。与不携带 UGT1A128 的患者相比，携带 2 份 UGT1A128（28/28）的患者更易发生高胆红素血症。此外，与不携带 UGT1A16 或 UGT1A128 的患者相比，携带 2 份变异等位基因（UGT1A16/*6 或 *28/28 纯合子或 UGT1A16/28 复合杂合子）的患者发生高胆红素血症的风险更高（比值比 [OR] 28.33；95%置信区间 [CI] 2.39-336.00；p=0.005）。多变量逻辑回归分析证实，托珠单抗诱导的高胆红素血症与携带 2 份变异等位基因之间存在很强的关联（OR 25.51；95%CI 2.35-276.53；p=0.008），ROC 曲线下面积为 0.78（95%CI 0.60-0.95，p=0.005）。托珠单抗可引起 RA 患者发生高胆红素血症，尤其是携带 UGT1A16/*6、*6/*28 和 *28/*28 基因型的患者。鉴于这种遗传关联，在没有其他肝损伤迹象的情况下，可能没有必要从 RA 患者中停用这种药物。然而，由于托珠单抗有可能抑制 UGT1A1 介导的葡萄糖醛酸化，因此它不仅可能抑制胆红素代谢，还可能抑制 UGT1A1 依赖性药物解毒，从而增加 RA 治疗过程中发生不良事件的风险。
