Background: In the SELECT-COMPARE study, the Janus kinase inhibitor, upadacitinib (UPA), demonstrated significant improvements in the signs and symptoms of rheumatoid arthritis (RA) when administered at 15 mg once daily (QD) on background methotrexate (MTX) compared with adalimumab (ADA) plus MTX at Week 12 that were maintained through 72 weeks in patients with prior inadequate response to MTX.1 Objectives: To assess the long-term safety and efficacy of UPA vs ADA over 3 years in the ongoing long-term extension (LTE). Methods: Patients receiving background MTX were randomized 2:2:1 to UPA 15 mg QD, placebo (PBO), or ADA 40 mg every other week. Between Weeks 14-26, rescue was mandated for either lack of response ( Results: In total, 651, 651, and 327 patients were randomized at baseline to receive UPA, PBO, and ADA, respectively. Between Weeks 14-26, 252 (39%) patients were rescued from UPA to ADA, 159 (49%) were rescued from ADA to UPA, and all PBO patients were switched to UPA by Week 26.1 A higher proportion of patients randomized to UPA completed 3 years without rescue compared to those randomized to ADA (47% vs 36%, respectively). UPA was generally well-tolerated as assessed by the rates of TEAEs, including serious AEs, AEs leading to discontinuation of study drug, and AESIs, including serious and opportunistic infections, malignancies, adjudicated major adverse cardiac events or venous thromboembolism; Figure 1). Consistent with previous analyses, the event rates of AESIs were generally comparable between the UPA and ADA groups, while herpes zoster, lymphopenia, hepatic disorder, and CPK elevation were reported at higher rates with UPA. Consistent with earlier time points, greater proportions of patients randomized to UPA achieved low disease activity and remission at 3 years based on CDAI, as well as DAS28(CRP) ≤3.2 or Conclusion: The safety profile of UPA was consistent with the results reported previously and with the integrated Phase 3 safety analysis.1,2 Higher levels of clinical response continued to be observed with UPA vs ADA through 3 years of treatment. References: [1]Fleischmann R, et al. Ann Rheum Dis 2020;79:323. [2]Cohen SB, et al. Ann Rheum Dis 2020; doi: 10.1136/annrheumdis-2020-218510. Acknowledgements: AbbVie and the authors thank the patients, trial sites, and investigators who participated in this clinical trial. AbbVie, Inc was the trial sponsor, contributed to trial design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. No honoraria or payments were made for authorship. The authors thank Dr. Tim Shaw of AbbVie Inc. for his support with the interpretation of the data. Medical writing support was provided by Ramona Vladea, PhD, of AbbVie, Inc. Disclosure of Interests: Roy Fleischmann Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, and UCB, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, Janssen, Novartis, Pfizer Inc, Regeneron, Roche, Sanofi-Aventis and UCB, Eduardo Mysler Consultant of: AbbVie, AstraZeneca, Lilly, Pfizer, Roche, BMS, Sandoz, GSK, Janssen, Grant/research support from: AbbVie, AstraZeneca, Lilly, Pfizer, Roche, BMS, Sandoz, GSK, Janssen, Louis Bessette Consultant of: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly, Novartis, Gilead, Grant/research support from: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly, Novartis, Gilead, Charles Peterfy Shareholder of: Spire Sciences, Inc, Speakers bureau: Amgen, Bristol-Myers Squibb, Consultant of: Aclaris, Centrexion, Daiichi Sankyo, EMD, Serono, Five Prime, Flexion Therapeutics, Genentech, Gilead, GlaxoSmithKline, Istresso, Eli Lilly, Myriad Genetics, Novartis, Roche, SetPoint, Sorrento, UCB, Employee of: Spire Sciences, Inc, Patrick Durez Speakers bureau: BMS, Sanofi, Eli Lilly, Celltrion, Yoshiya Tanaka Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Teijin, Consultant of: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Teijin, Grant/research support from: Asahi-kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Ono, Jerzy Swierkot Speakers bureau: AbbVie, Sandoz, Pfizer, Roche, BMS, UCB, MSD, Accord, Janssen, Consultant of: AbbVie, Sandoz, Pfizer, Roche, BMS, UCB, MSD, Accord, Janssen, Grant/research support from: AbbVie, Sandoz, Pfizer, Roche, BMS, UCB, MSD, Accord, Janssen, Nasser Khan Shareholder of: AbbVie, Employee of: AbbVie, Xianwei Bu Shareholder of: AbbVie, Employee of: AbbVie, Yihan Li Shareholder of: AbbVie, Employee of: AbbVie, In-Ho Song Shareholder of: AbbVie, Employee of: AbbVie.