Ab0407 impact of seropositivity on drug retention of biologics and jak inhibitors -the answer cohort study

Background 2022 EULAR recommendation announced that biological disease-modifying antirheumatic drugs (bDMARDs) and janus kinase inhibitors (JAKi) are considered in the phase Ⅱtreatment of rheumatoid arthritis (RA). On the other hand, serum rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) titer are reported to affect bDMARDs and JAKi efficacy. However, we still lack reliable evidence of the impact of RF and ACPA titer on these agents’ retention, which may reflect both effectiveness and safety. Objectives The aim of this multicenter (7 university-related hospitals) [1,2] , retrospective study was to clarify the impact of RF or ACPA titer on treatment retention of bDMARDs and JAKi in patients with RA, which may be useful for adequate treatment selection in a real-world setting. Methods This study assessed 5,343 treatment courses of bDMARDs and JAKi introduced from 2001 to 2022 (TNF inhibitors [TNFi]=2,724, anti-IL-6 receptor antibody [aIL-6R]=1,227, cytotoxic T lymphocyte-associated antigen-4-Ig [CTLA4-Ig]=906, JAKi=486; bDMARDs/JAKi naive cases 50.6%, baseline age 60.0 years, female 83.5%, disease duration 10.3 years, DAS28-ESR 4.3, RF positivity 78.3%, ACAP positivity 82.8%, combined methotrexate [MTX] dose 8.4mg/week [47.8%], and prednisolone [PSL] dose 5.9mg/day [28.2%]). Patients were classified into three groups according to their serum RF (IU/mL) and ACPA (U/mL) titer: negative (RF<15 or ACPA<4.5), low positive (15≦RF<100 or 4.5≦ACPA<100), or high positive (100≦RF or 100≦ACPA), respectively. Reasons for discontinuation were classified into four categories by each attending physician: 1) lack of effectiveness (primary and secondary), 2) toxic adverse events (infection, malignancies, and cardiovascular events, et al.), 3) non-toxic reasons (patient preference and pregnancy, et al.), and 4) remission. Retention rates of each discontinuation reason were estimated at 24 months using the Kaplan-Meier method and adjusted for potential clinical confounders (age, sex, concomitant PSL and MTX, switched number of bDMARDs or JAKi, and prior use of TNFi, aIL-6R, CTLA4-Ig, or JAKi) using Cox proportional hazards modeling. Results Adjusted discontinuation rates for each reason were as follows: due to lack of effectiveness was aIL-6R=21.4%, JAKi=27.1%, CTLA4-Ig=30.4%, and TNFi=36.2% (Cox P<0.001 between 4 groups), due to toxic adverse events was CTLA4-Ig=12.1%, aIL-6R=12.5%, TNFi=13.3%, and JAKi=14.6% (Cox P=0.369 between 4 groups). When categorized by RF (Figure 1a), adjusted discontinuation rates due to lack of effectiveness were listed in ascending order as follows, respectively; RF negative (aIL-6R, 16.2%; TNFi, 30.5%; CTLA4-Ig, 33.8%; JAKi, 39.9%; Cox P<0.001), low positive (aIL-6R, 19.6%; JAKi, 21.7%; CTLA4-Ig, 26.6%; TNFi, 29.9%; Cox P<0.001) and high positive (aIL-6R, 25.4%; JAKi, 28.1%; CTLA4-Ig, 31.2%; TNFi, 38.6%; Cox P<0.001). When categorized by ACPA (Figure 1b), discontinuation rates due to lack of effectiveness were listed in ascending order as follows, respectively; ACPA negative (aIL-6R, 20.9%; TNFi, 28.8%; JAKi, 30.7%; CTLA4-Ig, 43.4%; Cox P<0.001), low positive (aIL-6R, 19.2%; JAKi, 26.4%; CTLA4-Ig, 27.3%; TNFi, 33.6%; Cox P<0.001) and high positive (aIL-6R, 23.1%; JAKi, 25.6%; CTLA4-Ig, 29.7%; TNFi, 35.2%; Cox P<0.001). Conclusion Considering lack of effectiveness, aIL-6R showed highest continuation rates compared to other agents regardless of RF/ACPA positivity or titer levels. On the other hand, CTLA4-Ig and JAKi showed higher continuation rates, although TNFi showed lower continuation rates in RF/ACPA-positive (low or high titer) cases compared with RF/ACPA-negative cases. References [1]Ebina K, et al. Drug tolerability and reasons for discontinuation of seven biologics in 4466 treatment courses of rheumatoid arthritis-the ANSWER cohort study. Arthritis Res Ther. Apr 11 2019;21(1):91. [2]Ebina K, Etani Y, et al. Factors affecting drug retention of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study. Sci Rep. Jan 7 2022;12(1):134. Figure 1. Acknowledgements: NIL. Disclosure of Interests Yuki Etani Speakers bureau: Asahi-Kasei, Eisai, Eli Lilly, Mitsubishi-Tanabe and Nippon Zoki., Grant/research support from: Eli Lilly., Kosuke Ebina Speakers bureau: AbbVie, Amgen, Asahi-Kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Pfizer, Sanofi, Taisho, and UCB Japan., Consultant of: Asahi-Kasei and Taisho, Grant/research support from: AbbVie, Asahi-Kasei, Eisai, Mitsubishi-Tanabe, and Teijin Pharma., Employee of: KE is affiliated with the Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, which is supported by Taisho., Yasutaka Okita Speakers bureau: Chugai Pharmaceutical, Pfizer, and Ono Pharmaceutical., Yuichi Maeda Speakers bureau: Eli Lilly Japan K.K., Chugai Pharmaceutical Co. Ltd., Pfizer Inc., Bristol Myers Squibb, and Mitsubishi Tanabe Pharma Corporation., Grant/research support from: Eli Lilly Japan K.K., Kohei Tsujimoto: None declared, Akira Onishi Speakers bureau: Pfizer Inc., Bristol-Myers Squibb., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K, Ono Pharmaceutical Co., UCB Japan Co., Mitsubishi Tanabe Pharma Co., Eisai Co. Ltd., Abbvie Inc., Takeda Pharmaceutical Co. Ltd., and Daiichi Sankyo Co. Ltd., Grant/research support from: Pfizer Inc., Bristol-Myers Squibb., Advantest, Ayumi, and the Health Care Science Institute., Employee of: Department of Advanced Medicine for Rheumatic Diseases is supported by Nagahama City, Shiga, Japan, Toyooka City, Hyogo, Japan, and five pharmaceutical companies (Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co. Ltd, UCB Japan Co. Ltd, AYUMI Pharmaceutical Co., and Asahi Kasei Pharma Corp.). It is also supported by grants from Daiichi Sankyo Co. Ltd. Above-mentioned pharmaceutical companies were not involved in the study design, data collection and analysis, manuscript writing, and manuscript submission., Hideo Onizawa: None declared, Takaichi Okano: None declared, Keisuke Nishimura: None declared, Ayaka Yoshikawa: None declared, Hideyuki Shiba Speakers bureau: Pfizer, Mitsubishi-Tanabe, Asahi-Kasei, Abbvie, Eisai, Chugai, Janssen, Sanofi, UCB Japan, GlaxoSmithKline K.K., Astellas Pharma Inc, Hideki Amuro: None declared, Yonsu Son: None declared, Motomu Hashimoto Grant/research support from: Abbvie, Asahi Kasei, Astellas, Ayumi, Brystol Meyers, Chugai, EA Pharma, Eisai, Daiichi Sankyo, Eli Lilly, Nihon Shinyaku, Novartis Pharma, Tanabe Mitsubishi., Tadashi Okano Speakers bureau: Abbvie, Chugai, Eli Lilly, Janssen and Novartis Pharma., Grant/research support from: Abbvie, Asahi Kasei, Chugai, Eisai, Eli Lilly and Tanabe Mitsubishi.“, Ryota Hara Speakers bureau: AbbVie, Eisai, Wataru Yamamoto: None declared, Atsushi Kumanogoh Speakers bureau: Chugai, Eisai, Tanabe, Mitsubishi, Abbvie, and Ono, Grant/research support from: Chugai, Seiji Okada: None declare.d.