PMID- 37942277 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231110 IS - 1759-720X (Print) IS - 1759-7218 (Electronic) IS - 1759-720X (Linking) VI - 15 DP - 2023 TI - Rheumatoid arthritis disease activity and adverse events in patients receiving tofacitinib or tumor necrosis factor inhibitors: a post hoc analysis of ORAL Surveillance. PG - 1759720X231201047 LID - 10.1177/1759720X231201047 [doi] LID - 1759720X231201047 AB - BACKGROUND: In patients with rheumatoid arthritis (RA), persistent inflammation and increasing disease activity are associated with increased risk of adverse events (AEs). OBJECTIVES: To assess relationships between RA disease activity and AEs of interest in patients treated with tofacitinib or tumor necrosis factor inhibitors (TNFi). DESIGN: This was a post hoc analysis of a long-term, postauthorization safety endpoint trial of tofacitinib versus TNFi. METHODS: In ORAL Surveillance, 4362 patients aged ⩾50 years with active RA despite methotrexate, and ⩾1 additional cardiovascular (CV) risk factor, were randomized 1:1:1 to tofacitinib 5 or 10 mg twice daily or TNFi for up to 72 months. Post hoc time-dependent multivariable Cox analysis evaluated the relationships between disease activity [Clinical Disease Activity Index (CDAI)], inflammation [C-reactive protein (CRP)], and AEs of interest. The AEs included major adverse CV events (MACE), malignancies excluding nonmelanoma skin cancer (NMSC), venous thromboembolism (VTE), serious infections, herpes zoster (HZ), nonserious infections excluding HZ (NSI), and death. RESULTS: Across treatments, risk for NSI was higher when patients had CDAI-defined active disease versus remission; MACE and VTE risks trended higher, but did not reach significance. Hazard ratios for MACE, malignancies excluding NMSC, VTE, infections, and death rose by 2-9% for each 5-mg/L increment in serum CRP. The interaction terms evaluating the impact of treatment assignment on the relationship between disease activity and AEs were all p > 0.05. CONCLUSION: In ORAL Surveillance, higher NSI risk was observed in the presence of active RA versus remission. The risk of MACE and VTE directionally increased in active disease versus remission, although statistical power was limited due to small event numbers in these categories. The relationship between active disease and AEs was not impacted by treatment with tofacitinib versus TNFi. REGISTRATION: NCT02092467. CI - (c) The Author(s), 2023. FAU - Karpouzas, George A AU - Karpouzas GA AD - Division of Rheumatology, Harbor-UCLA Medical Center, and the Lundquist Institute, Torrance, CA, USA. FAU - Szekanecz, Zoltan AU - Szekanecz Z AD - Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. FAU - Baecklund, Eva AU - Baecklund E AD - Department of Medical Sciences, Uppsala University, Uppsala, Sweden. FAU - Mikuls, Ted R AU - Mikuls TR AD - Division of Rheumatology, University of Nebraska Medical Center and VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA. FAU - Bhatt, Deepak L AU - Bhatt DL AD - Mount Sinai Heart, Icahn School of Medicine at Mount Sinai Health System, New York, NY, USA. FAU - Wang, Cunshan AU - Wang C AD - Inflammation and Immunology, Pfizer Inc, Groton, CT, USA. FAU - Sawyerr, Gosford A AU - Sawyerr GA AD - Inflammation and Immunology, Pfizer Inc, New York, NY, USA. FAU - Chen, Yan AU - Chen Y AD - Inflammation and Immunology, Pfizer Inc, Collegeville, PA, USA. FAU - Menon, Sujatha AU - Menon S AD - Inflammation and Immunology, Pfizer Inc, Groton, CT, USA. FAU - Connell, Carol A AU - Connell CA AD - Inflammation and Immunology, Pfizer Inc, Groton, CT, USA. FAU - Ytterberg, Steven R AU - Ytterberg SR AD - Division of Rheumatology, Mayo Clinic, Rochester, MN, USA. FAU - Mortezavi, Mahta AU - Mortezavi M AUID- ORCID: 0000-0003-4666-071X AD - Inflammation and Immunology, Pfizer Inc, 66 Hudson Boulevard, New York, NY 10001, USA. LA - eng SI - ClinicalTrials.gov/NCT02092467 PT - Journal Article DEP - 20231106 PL - England TA - Ther Adv Musculoskelet Dis JT - Therapeutic advances in musculoskeletal disease JID - 101517322 PMC - PMC10629315 OAB - The link between disease activity and adverse medical events in people with rheumatoid arthritis taking tofacitinib or tumor necrosis factor inhibitors. Why was the study done? * People with rheumatoid arthritis (RA) who have uncontrolled symptoms (high disease activity) have a higher chance of having adverse medical events (medical problems that occur during treatment with a medication) than people who have mild symptoms (low disease activity). * We looked at the link between levels of disease activity and the risk of having adverse medical events in people with RA who took tofacitinib or a tumor necrosis factor inhibitor (TNFi) medication. What did the researchers do? * We used the results of ORAL Surveillance, a long-term safety trial in people with RA. o In this study, people with RA were 50 years or older and at high risk of a major cardiovascular event such as heart attack or stroke. * For up to 6 years, people took tofacitinib 5 or 10mg tablets two times a day or TNFi injections. * We used statistical tests to examine the link between different levels of RA disease activity or inflammation and different adverse medical events, such as: o major cardiovascular events (such as heart attack, stroke, or death due to heart failure) o cancers o blood clots o infections o deaths. What did the researchers find? * In people who took tofacitinib or TNFi: o People with active disease (those with RA symptoms) had a higher risk of infections that did not lead to hospitalization (nonserious infections) than people in remission (those with very mild symptoms or no symptoms at all). o People with active disease also had a slightly higher risk of major cardiovascular events and blood clots than those in remission. o Higher levels of inflammation led to increased risk of major cardiovascular events, cancers, blood clots, infections, and deaths. What do the findings mean? * Active RA disease leads to higher risk of adverse medical events. * The medication used (tofacitinib or TNFi) did not affect the link between levels of RA disease activity and adverse medical events. * This study was limited by the low number of adverse medical events recorded. OABL- eng OTO - NOTNLM OT - DMARDs OT - autoinflammatory conditions OT - inflammation OT - outcome measures OT - rheumatoid arthritis COIS- GAK has received research grants from Pfizer Inc, has acted as a consultant for Janssen and Sanofi-Genzyme-Regeneron, and has participated in speakers' bureau activities for Sanofi-Genzyme-Regeneron. ZS has acted as a consultant for AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche, and Sanofi, has acted as a paid instructor for AbbVie, Eli Lilly, Gedeon Richter, Novartis, Pfizer Inc, and Roche, and has participated in speakers' bureau activities for AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche, and Sanofi. EB declares no competing interests. TRM has received research grants from Bristol Myers Squibb and Horizon, has acted as a consultant for Gilead Sciences, Horizon, Sanofi and UCB, and served on the Steering Committee for ORAL Surveillance for Pfizer Inc. DLB served as a member of the Steering Committee for ORAL Surveillance, with funding from Pfizer Inc paid to Brigham and Women's Hospital. DLB has also served as an advisory board member for ANGIOWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has served on the Board of Directors for AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TOBESOFT; has acted as the Inaugural Chair of the American Heart Association Quality Oversight Committee; has acted as a consultant for Broadview Ventures; has been a member of the Data Monitoring Committees for Acesion Pharma, Assistance Publique-Hopitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the NIH-funded MINT Trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI Clinical Trial Steering Committee funded by Boehringer Ingelheim; AEGIS-II Executive Committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (Clinical Trial Steering Committees), Cowen and Company, Duke Clinical Research Institute (Clinical Trial Steering Committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME Steering Committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS Operations Committee, Publications Committee, Steering Committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME Steering Committees), and Wiley (Steering Committee); has acted as Deputy Editor for Clinical Cardiology, Chaired the NCDR-ACTION Registry Steering Committee, and Chaired the VA CART Research and Publications Committee; has been named on a patent for sotagliflozin assigned to Brigham and Women's Hospital, who assigned to Lexicon (neither DLB nor Brigham and Women's Hospital receive any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker BioMarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Eli Lilly, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald's Heart Disease), has been a site co-investigator for Abbott, BIOTRONIK, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; has been a trustee for the American College of Cardiology; and has worked on unfunded research for FlowCo and Takeda. GAS has acted as a consultant for Pfizer Inc, and was an employee of Syneos Health Inc at the time of the analysis, who were paid contractors to Pfizer Inc in the development of this manuscript and in providing statistical support. SRY has acted as a consultant for Corbus Pharmaceuticals, Kezar Life Sciences, and Pfizer Inc. SRY also acted as a member of the Steering Committee for ORAL Surveillance. CW, YC, SM, and MM are employees and shareholders of Pfizer Inc. CAC was an employee and shareholder of Pfizer Inc at the time of the analysis. EDAT- 2023/11/09 06:42 MHDA- 2023/11/09 06:43 PMCR- 2023/11/06 CRDT- 2023/11/09 04:25 PHST- 2023/05/12 00:00 [received] PHST- 2023/08/25 00:00 [accepted] PHST- 2023/11/09 06:43 [medline] PHST- 2023/11/09 06:42 [pubmed] PHST- 2023/11/09 04:25 [entrez] PHST- 2023/11/06 00:00 [pmc-release] AID - 10.1177_1759720X231201047 [pii] AID - 10.1177/1759720X231201047 [doi] PST - epublish SO - Ther Adv Musculoskelet Dis. 2023 Nov 6;15:1759720X231201047. doi: 10.1177/1759720X231201047. eCollection 2023.