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. 2026 Jan 20:S2665-9913(25)00371-6.
doi: 10.1016/S2665-9913(25)00371-6. Online ahead of print.

Long-term outcomes of abatacept in individuals at risk of developing rheumatoid arthritis (ALTO): a randomised, double-blind, placebo-controlled trial

Andrew P Cope  1 , Marianna Jasenecova  2 , Joana C Vasconcelos  3 , Sumera Qureshi  2 , Karin A van Schie  4 , Andrew Filer  5 , Karim Raza  5 , Maria Antonietta D'Agostino  6 , Iain B McInnes  7 , Stefan Siebert  7 , John D Isaacs  8 , Arthur G Pratt  8 , Benjamin A Fisher  5 , Christopher D Buckley  9 , Paul Emery  10 , Kulveer Mankia  10 , Pauline Ho  11 , Maya H Buch  11 , Coziana Ciurtin  12 , Dirkjan van Schaardenburg  13 , Tom W J Huizinga  4 , René E M Toes  4 , Evangelos Georgiou  14 , Joanna Kelly  14 , Caroline Murphy  14 , A Toby Prevost  3 ; ALTO Study Investigators
Collaborators, Affiliations
Free article

Long-term outcomes of abatacept in individuals at risk of developing rheumatoid arthritis (ALTO): a randomised, double-blind, placebo-controlled trial

Andrew P Cope et al. Lancet Rheumatol. .
Free article

Abstract

Background: Clinical trials aimed at preventing rheumatoid arthritis in individuals at risk have had variable results. The long-term outcomes of disease interception, however, are not known. We aimed to examine the long-term effect of therapeutic intervention, with emphasis on efficacy and safety.

Methods: The Arthritis Prevention In the Preclinical Phase of Rheumatoid arthritis with Abatacept (APIPPRA) phase 2b, randomised controlled trial recruited 213 anti-citrullinated protein antibody (ACPA) positive individuals with arthralgia in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands, randomly assigning participants to 52 weekly subcutaneous injections of 125 mg abatacept (n=110) or placebo (n=103), with another 52 weeks of follow-up. The APIPPRA Long-Term Outcome (ALTO) study extended follow-up for between 4 and 8 years and study participants and clinical assessors remained masked to treatment group. The primary outcome was the time from randomisation to development of clinical synovitis in at least three joints, rheumatoid arthritis according to American College of Rheumatology-European Alliance of Associations for Rheumatology 2010 criteria, or first treatment with disease modifying anti-rheumatic drugs, whichever was met first. The primary outcome was also stratified by autoantibody profiles defined at the time of randomisation. People with lived experience of rheumatoid arthritis had input into the APIPPRA study design. The study was registered at ISRCTN (ISRCTN-12680338), and is completed.

Findings: Between April 26, 2021, and Jan 31, 2023, 143 APIPPRA study participants enrolled in ALTO: 71 in the abatacept group and 72 in the placebo group (mean age 48·2 years [SD 11·2], 112 [78%] females, 31 [22%] males, 116 [81%] White). Median follow-up time from randomisation was 55 months (IQR 23-74). Primary events increased by 54 to 119. The initial between-group difference in restricted mean arthritis-free survival time observed at 2 years in APIPPRA remained significant at 4 years (4·9 months 95% CI 0·1-9·6; p=0·044), although the magnitude of this difference diminished over time. Assessments of disease activity and patient reported outcomes revealed no significant differences between groups beyond the treatment period. However, although participants with a broad autoantibody profile at baseline were at highest risk of progressing, this subgroup responded better to abatacept. There were 18 serious adverse events in the abatacept group and 13 in the placebo group; none deemed related to study drug.

Interpretation: In this at-risk population, 1-year treatment with abatacept delayed progression to rheumatoid arthritis for up to 4 years. Those at highest risk of progression have a broad autoantibody profile but are more responsive to abatacept treatment.

Funding: Bristol Myers Squibb.

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Conflict of interest statement

Declaration of interests APC was the recipient of an Investigator Sponsored Research grant from Bristol Myers Squibb to fund the APIPPRA study, administered through King's College London. APC, MJ, SQ, MAD’A, BAF, PE, IBM, REMT, KR, and TWJH have received grant funding, consulting or speaker bureau fees, or have been beneficiaries of APIPPRA study funding from Bristol-Myers Squibb in the last 5 years. APC reports consultancy fees from AnaptysBio, BMS, CueBiosciences, Janssen, Medicxi, Lilly, Nucleome Therapeutics, Quell; honoraria from Lilly, Janssen; and participation on an advisory board for Galvani–GSK. AF reports grant funding from Johnson & Johnson, and Synact; and consultancy fees from Johnson & Johnson and Quell Therapeutics. IBM reports grant funding and consultancy fees from AbbVie, Amgen, BMS, Causeway Therapeutics, Cabaletta, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma, Compugen, AstraZeneca, Moonlake, Dextera, and Pioneering Medicines. SS reports grant funding from Eli Lilly, GSK, Johnson & Johnson (Janssen), Pfizer, and UCB; consultancy fees from AbbVie, AstraZeneca, Johnson & Johnson (Janssen), Syncona, Teijin Pharma, and UCB; honoraria from AbbVie, Amgen, Johnson & Johnson (Janssen), Novartis, Pfizer, and UCB; and support for attending meetings or travel from Johnson & Johnson (Janssen), Pfizer, and UCB. JDI reports grant funding from Pfizer, Janssen, and GSK; consultancy fees from AbbVie, BMS, AstraZeneca Eli Lilly, Roche, AnaptsyBio, Ono Pharma, Quell Therapeutics, and Sonoma; honoraria from AbbVie; and support for attending meetings or travel from Eli Lilly and Gilead. AGP reports research support from GSK, Pfizer, and Gilead; and royalties or licenses from Inflection Biosciences. BAF reports grant funding from Johnson & Johnson, Servier, Galapagos, Celgene, and Novartis; consultancy fees from Novartis, Roche, BMS, Johnson & Johnson, Servier, UCB, Sanofi, Galapagos, AstraZeneca, Kiniksa, Amgen, Otsuka, Cullinan, Quell, and OneFour Bio; and honoraria from Servier, Novartis, and Otsuka. CDB reports consultancy fees from Roche, AbbVie, GSK, Quell, and Takeda; honoraria from Pfizer and Genentech; and founding shares in Mestag Therapeutics. PE reports consultancy fees from Anatptysbio, Boehringer Ingelheim, Galapagos, Gilead, Immunovant, and Eli Lilly; honoraria from Eli Lilly and Boehringer Ingelheim; and support from attending meetings or travel from Eli Lilly. KM reports grants from AstraZeneca, Serac Healthcare, Deepcure, and Alfa Sigma; consultancy fees from AbbVie, ALLIn Bio, AstraZeneca, Galapagos, Engitix, Deepcure, Eli Lilly, Ventus Therapeutics, UCB, Zura Bio, and Alfa Sigma; honoraria from UCB, Alfa Sigma, and AbbVie; and support for attending meetings or travel from UCB and Alfa Sigma. PH reports honoraria from Novartis and UCB and support for attending meetings or travel from Novartis and UCB. MHB reports grants from Galapagos; consultancy fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Calluna Therapeutics, Elvara, Galapagos, Gilead, and Pfizer; honoraria from AbbVie, Boehringer Ingelheim, CESAS Medical, Medistream, Novo Nordisk, and Pfizer; and support for attending meetings or travel from Boehringer Ingelheim and UCB. REMT is named as inventor on a patent on the use of variable domain glycans on autoantibodies. All other authors declare that they have no other competing interests relating to this study.

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