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Objective: To report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled data from three randomised clinical trials (RCT) followed by open-label extension (OLE) study., Methods: Cumulative data from three phase 3 core trials and their OLE were analysed. Safety variables assessed included treatment-emergent adverse events (AEs), serious AEs (SAEs), AEs of special interest and laboratory results. Efficacy assessments included ACR20/50/70 responses, Disease Activity Score 28 (C-reactive protein) <3.2, CDAI remission and low disease activity (LDA), SDAI remission and LDA, HAQ-DI decrease of 0.22 unit and Boolean 2.0 remission., Results: A total of 2304 patients received OKZ in combination with MTX either once every 2 weeks or once every 4 weeks. Event rates per 100 patient-years in OKZ every 2 weeks and OKZ every 4 weeks, respectively, were 9.57 and 9.13 for SAEs; 2.95 and 2.34 for serious infections; 0.09 and 0.05 for gastrointestinal perforations; 0.58 and 0.83 for major adverse cardiovascular events; and 0.45 and 0.50 for malignancies. No increase in the rate of any AE was observed over 106 weeks of treatment. The evaluation of laboratory variables demonstrated the expected changes, like neutropenia, elevation of liver enzymes and blood lipids. Clinical response rates remained stable during the OLE., Conclusion: The long-term safety and tolerability of OKZ in combination with MTX remained stable. The efficacy of OKZ was maintained through week 106. These findings support OKZ as a treatment option for patients with active RA., Competing Interests: Competing interests: The analysis was funded by JSC R-Pharm. EF: research grants from BMS, Eli Lilly, Novartis, Roche; consulting fees from Abbvie, BMS, Eli Lilly, Gilead Sciences, Galapagos, Novartis, Roche, Sanofi, Sobi; speakers’ bureau for Abbvie, BMS, Eli Lilly, Gilead Sciences, Galapagos, Medac, Novartis, Roche, Sanofi, Sobi; RF: Consultant for AbbVie, Arthrosi, BMS, Galvani, Genentech, Gilead, GSK, InventisBio, Janssen, Eli Lilly, Novartis, Pfizer, Proviant, Recor, UCB, Vyne; Clinical Study grants: AbbVie, Acceleron, Arthrosi, Biosplice, BMS, Cugene, Flexion, Galvani, Gilead, GSK, Horizon, Idorsia, Janssen, LG Chem, Eli Lilly, Novartis, Pfizer, Proviant, Sankyo, UCB, Viela. SF: consulting fees from ICON and PPD contract research organisations, shareholder of Pfizer, INC stocks, consulting fees from R-Pharm; EK: employee of R-Pharm, with no R-Pharm stock; ML: research grants from Amgen, Biogen, UCB, Sun Pharmaceuticals, Abbvie, Pfizer, Novartis, Lilly, GSK, R-Pharm; EN: speakers’ bureau for AbbVie, Eli Lilly, Janssen, Novartis, Pfizer; DB, SG, SK and MS: employee of R-Pharm, with no R-Pharm stock; JS: Editor-in-Chief of ARD, research grants from Abbvie, Astra-Zeneca, Lilly; consulting fees from Abbvie, Galapagos/Gilead, Novartis-Sandoz, BMS, Samsung, Sanofi, Chugai, R-Pharma, Lilly; speakers’ bureau for Samsung, Lilly, R-Pharm, Chugai, MSD, Janssen, Novartis-Sandoz; RF: consulting fees from AbbVie, BMS, Gilead, Galvani, GSK, Janssen, Eli Lilly, Novartis, Pfizer, R-Pharm, UCB; speakers bureaus for AbbVie; Pfizer; R-Pharm. Disclosure forms provided by the authors are available in the full text of this article., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Background: Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway., Methods: A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document., Results: The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring., Conclusions: The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers., Competing Interests: Competing interests: DA: Grants or contracts from any entity: AbbVie, Amgen, Eli Lilly, Novartis, Roche, SoBi and Sanofi; Consulting fees: AbbVie, Amgen, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche and Sandoz; Support for attending meetings and/or travel: AbbVie, Gilead, Sandoz, Pfizer, BMSAK: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Bristol-Myers Squibb, Celgene, Eli-Lilly, Gilead, Janssen, Merck Sharp and Dohme, Novartis and PfizerKK: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Boehringer Ingelheim, UCB Pharma and AbbVie; Support for attending meetings and/or travel: AbbVie, Gilead, Sandoz, Pfizer and BMSJI: Grants or contracts from any entity: Pfizer, GSK and Janssen; Consulting fees: AbbVie, Gilead and BMS; Payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events: AbbVie, Gilead and Roche; Support for attending meetings and/or travel: Eli Lilly and Gilead; Participation on a Data Safety Monitoring Board or Advisory Board: Eli Lilly; Leadership or fiduciary role in other board, society, committee or advocacy group: Versus Arthritis Board member (unpaid) NS: Grants or contracts from any entity: AstraZeneca, Boehringer Ingelheim, Novartis and Roche Diagnostics; Consulting fees: Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, MSD, Novartis, Novo Nordisk, Pfizer and SanofiMV: Grants or contracts from any entity: PfizerBC: Grants or contracts from any entity: Pfizer, Roche, Chugai and Novartis; Consulting fees: AbbVie, Celltrion, Janssen, Gilead-Galapagos, Eli Lilly, Novartis, Roche-Chugai; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, BMS, Celltrion, Gilead-Galapagos, Janssen, Eli Lilly, Merck, Pfizer and Roche-ChugaiNB: All support for the present manuscript: Vienna Medical Academy; Consulting fees: Amgen, EULAR, Galapagos, Global Alliance for Patient Access, Grunenthal, Eli Lilly, Pfizer and Sanofi; Support for attending meetings and/or travel: EULAR and Global Alliance for Patient Access; Receipt of equipment, materials, drugs, medical writing, gifts or other services: GalapagosJB: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Eli Lilly and Galapagos; Participation on a Data Safety Monitoring Board or Advisory Board: SyneosGRB: All support for the present manuscript: Sanofi; Consulting fees: AbbVie, Galapagos, Lilly, Pfizer, Roche and Sanofi; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Galapagos, Lilly, Pfizer, Roche and SanofiVPB: Grants or contracts from any entity: NIH (NIAID/NIAMS), The Cedar Hill Foundation, Amgen and BMS; Consulting fees: Amgen, BMS, Genzyme, Gilead, Janssen, Pfizer and Sanofi-Aventis; Participation on a Data Safety Monitoring Board or Advisory Board: KAI for NIHRC: noneEC: Grants or contracts from any entity: Bio-Cancer, Biogen, Novartis, Pfizer and Sanofi; Consulting fees: AbbVie, Amgen, BMS, Biocon, Eli Lilly, Galapagos, Chugai Pharma, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi and RPharm; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Amgen, BMS, Chugai Pharma, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, RPharm and Sanofi; Support for attending meetings and/or travel: Gilead, Galapagos, AbbVie and Eli LillyMT: Grants or contracts from any entity: Albireo, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, Alnylam and Ultragenyx; Consulting fees: Albireo, BioMX, Boehringer Ingelheim, Falk, Genfit, Intercept, Janssen, MSD, Gilead, Novartis, Shire, Phenex and Regulus; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Falk Foundation, Gilead, Intercept and MSD; Support for attending meetings and/or travel: AbbVie, Falk, Gilead and Intercept; Patents planned, issued or pending: Co-Inventor patent on medical use of nor-UDCATS: Grants or contracts from any entity: AbbVie and Roche; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Roche, Sanofi, Takeda and NovartisCC: Grants or contracts from any entity: AbbVie, Boehringer Ingelheim, Ewopharma, Lilly, Novartis and Pfizer; Consulting fees: AbbVie, Amgen, Boehringer Ingelheim, Ewopharma, Lilly, Novartis and Pfizer; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Amgen, Boehringer Ingelheim, Ewopharma, Lilly, Novartis and Pfizer; Participation on a Data Safety Monitoring Board or Advisory Board: AbbVie, Amgen, Boehringer Ingelheim, Ewopharma and Pfizer; Leadership or fiduciary role in other board, society, committee or advocacy group: Romanian Society of Rheumatology, Romanian Registry of Rheumatic Diseases and Romanian League against RheumatismMKC: Grants or contracts from any entity: Gilead; Consulting fees: AstraZeneca, BMS, GSK and Shannon Pharmaceuticals; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca and Gilead; Leadership or fiduciary role in other board, society, committee or advocacy group: Arthritis Foundation, New York Chapter; Stock or stock options: Johnson and Johnson, Regeneron and AmgenMD: All support for the present manuscript: Medical academy of Vienna; Grants or contracts from any entity: Roche, Sanofi, Pfizer, AbbVie, Eli Lilly, BMS, Merck, Galapagos and UCB; Consulting fees: Roche, Sanofi, Pfizer, AbbVie, Eli Lilly, BMS, Merck, Galapagos and UCB; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, Sanofi, Pfizer, AbbVie, Eli Lilly, BMS, Merck, Galapagos and UCBGP: none. DvdH: Consulting fees: AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Novartis, Pfizer and UCB Pharma; Other financial or non-financial interests: Director of Imaging Rheumatology bv.PE: Grants or contracts from any entity: Abbvie, BMS, Lilly, Novartis, Pfizer, Roche and Samsung; Consulting fees: Abbvie, Astra-Zeneca, Boehringer Ingelheim, Galapagos, Gilead, Eli Lilly and Novartis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Abbvie, BMS, GSK, Eli Lilly and NovartisEM: All support for the present manuscript: University of Vienna funding; Grants or contracts from any entity: Roche, Jansen, Pfizer, AbbVie and Novartis; Consulting fees: GSK, Roche, Novartis, AbbVie, Pfizer, Janssen, Eli Lilly and AstraZeneca; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: GSK, Pfizer, AbbVie, Lilly, Amgen, Janssen and AstraZeneca; Participation on a Data Safety Monitoring Board or Advisory Board: GSKRF: Consulting fees: AbbVie, Amgen, BMS, GSK, Gilead, Pfizer, Novartis and Eli Lilly; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie and Pfizer; Participation on a Data Safety Monitoring Board or Advisory Board: AbbVie, Pfizer, Eli Lilly and GSKCG: noneKH: Grants or contracts from any entity: Pfizer and BMS; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbViePAM: Grants or contracts from any entity: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Eicos, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi and Takeda; Royalties or licenses: UpToDate; Consulting fees: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Immagene, InflaRx, Jannsen, Kiniksa, Kyverna, Magenta, MiroBio, Mitsubishi, Neutrolis, Novartis, Pfizer, Regeneron, Sparrow, Takeda and TalarisTT: Grants or contracts from any entity: Chugai Pharmaceutical; Consulting fees: Chugai, Janssen and Rpharma; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Chugai, BMS, Janssen and SanofiXM: Consulting fees: BMS, Novartis, Galapagos, Sanofi, GSK, Pfizer, Janssen and UCBKW: Grants or contracts from any entity: BMS and Pfizer; Consulting fees: AbbVie, BMS, Eli Lily, Galapagos, Gilead, Pfizer, Roche, UCB, GSK, Novartis, AstraZeneca, Regeneron and SanofiMdW: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Pfizer, Celgene, Eli Lilly and UCBKP: Payments for lectures: Roche, AbbVie, Pfizer, Eli Lilly, Amgen, SOBI, UCB and MSD; Advisory Board: Roche, AbbVie, Pfizer, Eli Lilly, Amgen, SOBI, UCB and MSDPN: Grants or contracts from any entity: Roche, Abbvie, Pfizer, Janssen, Gilead/Galapagos, BMS, Novartis and Eli Lilly; Consulting fees: Abbvie, Pfizer, janssen, BMS, Novartis, Lilly, Roche and Gilead/Galapagos; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Abbvie, Pfizer, janssen, BMS, Novartis, Lilly, Roche and Gilead/GalapagosYT: Grants or contracts from any entity: Asahi-Kasei, Abbvie, Chugai, Mitsubishi-Tanabe, Eisai, Takeda, Corrona, Daiichi-Sankyo, Kowa and Behringer-Ingelheim; Consulting fees: Eli Lilly, Daiichi-Sankyo, Taisho, Ayumi, Sanofi, GSK and Abbvie; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Gilead, AbbVie, Boehringer-Ingelheim, Eli Lilly, Mitsubishi-Tanabe, Chugai, Amgen, YL Biologics, Eisai, Astellas, Bristol-Myers and AstraZenecaCD: Grants or contracts from any entity: FWF Austria and Celgene; Consulting fees: AbbVie, MSD, Pfizer, Roche, Sanofi, Janssen, Novartis, Eli Lilly and Galapagos; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, MSD, Pfizer, Roche, Sanofi, Janssen, Novartis, Eli Lilly and Galapagos; Support for attending meetings and/or travel: AbbVie, MSD, Pfizer, Roche, Sanofi, Janssen, Novartis, Eli Lilly and Galapagos; Receipt of equipment, materials, drugs, medical writing, gifts or other services: MSDMLH: Grants or contracts from any entity: Novartis, Roche and Sandoz; Consulting fees: BMS and Samsung Bioepis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: MSD, AbbVie, Novartis, Merck, Eli Lilly, Medac and Sandoz; Support for attending meetings and/or travel: The DANBIO registry; Participation on a Data Safety Monitoring Board or Advisory Board: CellTrion and Eli Lilly; Leadership or fiduciary role in other board, society, committee or advocacy group: Chair of the DANBIO steering committee, Member of the Danish Rheumatism Association’s Board, Member of the Danish Rheumatism Association’s research council, Member of EULAR Quality of Care Committee, Co-chair of the EuroSpA collaboration; Receipt of equipment, materials, drugs, medical writing, gifts or other services: Study drug for the NORD-STAR study/ Abatacept and Certolizumab pegolHSK: Consulting fees: Roche, Chugai and Sanofi-Aventis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, Chugai and Sanofi-Aventis; Participation on a Data Safety Monitoring Board or Advisory Board: Roche, Chugai and Sanofi-AventisMN: Grants or contracts from any entity: Pfizer, Amgen, Galapagos and AbbVie; Consulting fees: AbbVie; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Celgene and AbbVie; Participation on a Data Safety Monitoring Board or Advisory Board: AbbVieAS: Grants or contracts from any entity: oint, unconditional grant from AbbVie, Amgen, BMS, Celltrion, Fresenius Kabi, Hexal, Lilly, MSD, Viatris, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis and UCB; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, Pfizer, Roche, Sanofi and UCBAL: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, MSD, Alfasigma, Celltrion, BMS, Celgene, Eli-Lilly, Sanofi Genzyme, Pfizer, Galapagos, Gilead, Novartis and SOBIAR: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Angelini, Pfizer, Novartis, Reckitt Benckiser and SOBI; Leadership or fiduciary role in other board, society, committee or advocacy group: President, Pediatric Rheumatology European Society (PReS)ARR: Consulting fees: Sanofi, Roche, AbbVie, Eli Lilly, Gilead, BMS and Novartis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Pfizer, Sanofi, UCB, BMS, Gilead, Roche, Novartis and Janssen; Payment for expert testimony: AbbVie, Novartis and Gilead; Support for attending meetings and/or travel: AbbVie and Sanofi; Participation on a Data Safety Monitoring Board or Advisory Board: RPharmIM: Grants or contracts from any entity: AbbVie, BMS, Eli Lilly, Janssen, Pfizer, UCB, Amgen and Novartis; Consulting fees: AbbVie, BMS, Eli Lilly, Janssen, Pfizer, Sanofi, Novartis, Gilead, Amgen, UCB, GSK and Moonlake; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie; Leadership or fiduciary role in other board, society, committee or advocacy group: Vice Principal & Head of MVLS College/University of Glasgow, Board Member/ NHS Greater Glasgow & Clyde and Evelo; Stock or stock options: Causeway Therapeutics, Compugen, Cabaletta and EveloBio; JS: grants to his institution from Abbvie, Astro, AstraZeneca, Janssen, Lilly, Merck Sharpe & Dohme, Pfizer, and Roche; Expert advice for, or had symposia speaking engagements with, AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO Pharma, Janssen, Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, R-Pharm, Roche, Samsung, Sanofi and UCB., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)