FRI0228 Ugt1a1 genetic variants are associated with increases in bilirubin levels in rheumatoid arthritis patients treated with sarilumab
Authors: A Damask, A Boyapati, JD Hamilton, S Hamon, C Paccard, J Parrino, J van Adelsberg, NM Graham, J Penn, A Lopez, J Reid, J Overton, A Baras, AR Shuldiner, C Paulding
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Sarilumab is a human mAb that blocks IL-6 from binding to both membrane-bound and soluble IL-6Rα. Variants in the <i>UGT1A1</i> gene have been shown to be strongly associated with increased unconjugated bilirubin levels in patients treated with tocilizumab, another IL-6Rα inhibitor.<sup>1,2</sup><i>UGT1A1</i> encodes the enzyme responsible for the glucuronidation of bilirubin and variation in this gene is also responsible for Gilbert9s syndrome, a mild benign condition characterized by elevations in unconjugated bilirubin and jaundice. The underlying main genetic variation responsible for Gilbert9s syndrome has been identified as a TA repeat located in the promoter of <i>UGT1A1</i> (UGT1A1*28 allele), which is in linkage disequilibrium with a single nucleotide polymorphism, rs6742078, previously associated with higher bilirubin levels after tocilizumab treatment.<sup>1</sup> <h3>Objectives</h3> To test for an association between rs6742078 and bilirubin levels in RA patients treated with sarilumab. <h3>Methods</h3> DNA was collected from patients enrolled in MOBILITY (NCT01061736), which evaluated the efficacy and safety of sarilumab + methotrexate (MTX) in RA patients with inadequate response to MTX. The pharmacogenetic analysis was conducted in 599 Caucasian patients treated with MTX + sarilumab (150 or 200 mg q2w) or placebo. Log-transformed unconjugated and total bilirubin levels were analyzed at baseline and over the treatment period (using maximum bilirubin). <h3>Results</h3> There was a strong association between the rs6742078 TT genotype and higher unconjugated bilirubin levels. The least squares mean (SE) for patients at baseline with the TT genotype was 0.48 (0.02) mg/dL vs 0.25 (0.009) and 0.21 (0.009) mg/dL for those with GT and GG genotypes, respectively (<i>p</i>=1.02×10<sup>-21</sup>). After sarilumab treatment, the difference between genotype groups increased over the course of the study (<i>p</i>=4.3×10<sup>-10</sup>; Figure). In the binary analysis of maximum total bilirubin in sarilumab-treated patients, the TT genotype was significantly associated with mild bilirubin elevations (OR =34.7; <i>p</i>=1.2×10<sup>-8</sup>; Table). <h3>Conclusions</h3> The association observed between the rs6742078 TT genotype in <i>UGT1A1</i> and unconjugated bilirubin elevations in sarilumab-treated patients is consistent with previous observations in tocilizumab-treated patients. These findings suggest that sarilumab-related increases in bilirubin levels are likely benign and caused by common genetic variation in <i>UGT1A1</i> and are not due to underlying liver injury. <h3>References</h3> Mori et al. Mod Rheumatol. 2012;22:515–523. Lee et al. Pharmacogenet Genomics. 2011;21:365–374. <h3>Acknowledgements</h3> This study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Editorial support was provided by MedThink SciCom and funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. <h3>Disclosure of Interest</h3> A. Damask Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Boyapati Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Hamilton Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, S. Hamon Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, C. Paccard Shareholder of: Sanofi R&amp;D, Employee of: Sanofi R&amp;D, J. Parrino Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. van Adelsberg Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, N. Graham Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Penn Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Lopez Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Reid Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Overton Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Baras Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Shuldiner Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, C. Paulding Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc