title: Tocilizumab-induced hyperbilirubinemia in Japanese patients with rheumatoid arthritis: its association with UDP glucuronosyltransferase 1A1 gene polymorphisms.
abstract: 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 UGT1A1*28 (*28/*28) were more likely to develop hyperbilirubinemia than those without UGT1A1*28. In addition, patients carrying 2 copies of variant alleles, either as homozygotes (UGT1A1*6/*6 or *28/*28) or as compound heterozygotes (UGT1A1*6/*28), were at higher risk of hyperbilirubinemia as compared with those without either UGT1A1*6 or UGT1A1*28 (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 UGT1A1*6/*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.
authors: Department of Rheumatology, Clinical Research Center for Rheumatic Disease, NHO Kumamoto Saishunsou National Hospital, 2659 Suya, Kohshi, Kumamoto, 861-1196, Japan. moris@saisyunsou1.hosp.go.jp
authors: Shunsuke
authors: S
authors: Mori
authors: Kaoru
authors: K
authors: Terada
authors: Yukitaka
authors: Y
authors: Ueki
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D001663:Bilirubin / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D007564:Japan; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000099148:UGT1A1 Enzyme
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme; C502936:tocilizumab