Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial.

Autor:	Cope AP; Centre for Rheumatic Diseases, King's College London, London, UK. Electronic address: andrew.cope@kcl.ac.uk., Jasenecova M; Centre for Rheumatic Diseases, King's College London, London, UK., Vasconcelos JC; Nightingale-Saunders Clinical Trials & Epidemiology Unit, King's College London, London, UK., Filer A; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK., Raza K; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK., Qureshi S; Centre for Rheumatic Diseases, King's College London, London, UK., D'Agostino MA; Division of Rheumatology, Fondazione Policlinico Universitario A Gemelli, IRCCS, Catholic University of the Sacred Heart, Rome, Italy., McInnes IB; School of Infection and Immunity, University of Glasgow, Glasgow, UK., Isaacs JD; Translational & Clinical Research Institute, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK., Pratt AG; Translational & Clinical Research Institute, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK., Fisher BA; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK., Buckley CD; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Emery P; Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK., Ho P; Centre for Musculoskeletal Research, University of Manchester, Manchester, UK., Buch MH; Centre for Musculoskeletal Research, University of Manchester, Manchester, UK., Ciurtin C; Centre for Adolescent Rheumatology Versus Arthritis, Division of Medicine, University College London, London, UK., van Schaardenburg D; Amsterdam University Medical Centres, Reade, Amsterdam Rheumatology and Immunology Centre, Amsterdam, Netherlands., Huizinga T; Department of Rheumatology, Leiden University Medical Centre, Leiden, Netherlands., Toes R; Department of Rheumatology, Leiden University Medical Centre, Leiden, Netherlands., Georgiou E; King's Clinical Trials Unit, King's College London, London, UK., Kelly J; King's Clinical Trials Unit, King's College London, London, UK., Murphy C; King's Clinical Trials Unit, King's College London, London, UK., Prevost AT; Nightingale-Saunders Clinical Trials & Epidemiology Unit, King's College London, London, UK.
Jazyk:	angličtina
Zdroj:	Lancet (London, England) [Lancet] 2024 Mar 02; Vol. 403 (10429), pp. 838-849. Date of Electronic Publication: 2024 Feb 13.
DOI:	10.1016/S0140-6736(23)02649-1
Abstrakt:	Background: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. Methods: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). Findings: Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. Interpretation: Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. Funding: Bristol Myers Squibb. Competing Interests: Declaration of interests APC, PE, IBM, RT, KR, and TH received grant funding from Bristol Myers Squibb. APC, PE, and BAF received consulting fees from Bristol Myers Squibb. APC, PE, and MAD'A received speakers' bureau fees from Bristol Myers Squibb. MJ and SQ were beneficiaries of the APIPPRA study grant awarded by Bristol Myers Squibb. All other authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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