AB0129 IL-6R GENETIC VARIANTS AS PREDICTORS OF CLINICAL RESPONSE TO TOCILIZUMAB IN RHEUMATOID ARTHRITIS PATIENTS
Authors: L. Sainz Comas, P. Riera, P. Moya, S. Bernal, A. Lasa, S. Jeria Navarro, D. Lobo Prat, H. Codes, I. Castellví, C. Díaz-Torné, A. Laiz, B. Magallares, A. M. Millán Arciniegas, H. Park, H. Corominas
Journal: Annals of the Rheumatic Diseases (2021)

Background: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease of unknown etiology. Tocilizumab (TCZ) is a first-line biological disease-modifying anti-rheumatic drug (bDMARD) which inhibits Interleukin 6 (IL-6) pathway through blockade of its receptor. At present, there is a lack of evidence to recommend the treatment of one bDMARD over another.(1) Seeking for genetic biomarkers to predict response to treatment could be key towards a personalized treatment strategy in rheumatology.(2) Objectives: We aimed to evaluate whether functional single nucleotide polymorphisms (SNPs) in the IL6R gene could predict response and/or toxicity to TZC in Caucasian patients diagnosed with RA. Methods: Retrospective analytical preliminar study of a cohort of 31 patients diagnosed with RA (ACR/EULAR 2010 criteria) who received treatment with TCZ within the last 10 years. Epidemiological, clinical and laboratory data were collected. DNA was extracted from EDTA blood samples. Three SNPs in the IL-6 receptor gene (rs12083537, rs2228145, rs4329505) were genotyped by real-time PCR with TaqMan probes. The associations between polymorphisms and clinicopathological features were evaluated using parametric tests. Efficacy was assessed as the difference of DAS-28 CRP at 6 months. The toxicities recorded were hepatotoxicity, infections, hypersensibility, gastrointestinal, hematological and dyslipidemia. Results: The 31 DNA samples from patients included were mainly female (83.9%) and had a mean age at diagnosis of 46.8 years. The mean duration of treatment was 51.3 months and, previously to initiate TCZ, they received a mean of 2,6 csDMARD and 1,7 bDMARD. The more frequent adverse effects were hypertransaminasemia (22.6%) and neutropenia (32.3%). Most relevant epidemiologic and clinical data is shown in Table 1. Table 1. Clinical characteristics. RA=Rheumatoid Arthritis. CCP= anti-Cyclic Citrullinated Peptides. RF=Rheumatoid factor. csDMARDs= conventional synthetic Disease-modifying antirheumatic drug. bDMARD= biological Disease-modifying antirheumatic drug. BMI=Body Mass Index. Sc=subcutaneous. Ev=endovenous. DAS28= Disease Activity Score in 28 joints Sex (n=31 ), n (% women/men) 26/5 (83,9%/16,1%) Age at diagnosis (n=31 ), years +- SD 46,8+- 12,8 Erosive RA (n=31), n(%) 14 (45,2%) Anti-CCP positive (n=31), n(%) UI+- SD 23 (74,2%) 259,7 +- 137,3 RF positive (n=31), n (%) UI+-SD 21 (67,7%) 189,4+- 114 Previous csDMARD (n=31 ), n°+-SD 2,6 +-1,3 Previous bDMARD (n=31), n°+- SD 1,7 +- 1,4 BMI (n=29), mean +- SD 29,3+- 5,1 Duration of treatment (n=31), months +-SD 51,3 +- 36,3 -Active treatment (n=12) -80,9+- 18,3 -Finished treatment (n=19) -32,6+- 32,2 Route of administration (n=31 ), n (%) sc/ev 11/20 (35,5/64,5) Basal DAS28 (n=30 ), mean+- SD 5,3 +- 1,1 DAS28 reduction at 6 months (n=28), mean+-SD 2,9 +-1,1 The univariate analyses showed that the rs2228145 variant was statistically associated with differences in DAS28 reduction at 6 months (p=0.042). Regarding efficacy, we also found a trend with the SNP rs4329505 (p=0.173), which could achieve statistical significance with the projected inclusion of more patients. No associations were found regarding adverse effects. Conclusion: The rs2228145 polymorphisms in the IL6R gene may be considered as a pharmacogenetic biomarker of TCZ response in RA patients. More studies are required in order to investigate the clinical use of pharmacogenetic biomarkers in rheumatic diseases. References: [1]Smolen, Josef S., Robert B., et al. 2020. “EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-Modifying Antirheumatic Drugs: 2019 Update.” Annals of the Rheumatic Diseases 79 (6): 685–99. [2]Tarnowski, Maciej, Agnieszka Paradowska-Gorycka, et al. 2016. “The Effect of Gene Polymorphisms on Patient Responses to Rheumatoid Arthritis Therapy.” Expert Opinion on Drug Metabolism &amp; Toxicology 12 (1): 41–55. Disclosure of Interests: None declared