Clinical and epidemiological research 1Sarasota Arthritis Research Center, Sarasota, Florida, USA 2New England Research Associates, Trumbull, Connecticut, Massachusetts, USA 3Instituto Reumatológico Strusberg, Córdoba, Argentina 4Centro Médico Toluca, Metepec, México 5Panorama Medical Centre, Western Cape, South Africa 6Bristol-Myers Squibb, Princeton, New Jersey, USA 7East Penn Rheumatology Associates, Bethlehem, Pennsylvania, USA Correspondence to Dr Jeffrey Kaine, Sarasota Arthritis Research Center, 1945 Versailles Street #101, Sarasota, FL 34239, USA; jkainemd@gmail.com Accepted 11 August 2011 Published Online First 13 September 2011 EXTENDED REPORT Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthritis: impact of withdrawal and reintroduction on immunogenicity, efﬁcacy and safety (Phase IIIb ALLOW study) Jeffrey Kaine,1 Geoffrey Gladstein,2 Ingrid Strusberg,3 Manuel Robles,4 Ingrid Louw,5 Sheila Gujrathi,6 Ramesh Pappu,6 Ingrid Delaet,6 Miranda Pans,6 Charles Ludivico7 ABSTRACT Objectives To assess the effect of a temporary interruption in subcutaneous (SC) abatacept on immunogenicity, safety and efﬁcacy in patients with active rheumatoid arthritis despite methotrexate in a phase III trial. Methods Following a 12-week open-label introduction (period I; intravenous abatacept loading dose and weekly ﬁxed-dose SC abatacept 125 mg), patients were randomised 2:1 to double-blind SC placebo or SC abatacept for 12 weeks (period II). At the end of period II, patients receiving SC abatacept continued treatment and patients on placebo were reintroduced to SC abatacept (12-week open-label period III). The co-primary end points were ELISA-detected immunogenicity rate and safety at the end of period II. Efﬁcacy was also monitored. Results Of 167 patients entering period I, 72% qualiﬁed for period II; during periods II and III, three patients discontinued treatment. Mean (SD) disease duration was 6.6 (6.5) years and Disease Activity Score 28 was 4.8 (0.8). The primary end point was met, with a non- signiﬁcant increase in immunogenicity upon withdrawal (7/73 placebo vs 0/38 abatacept in period II; p=0.119) which was reversed upon reintroduction of SC abatacept (2/73 vs 1/38, end period III). Safety was comparable regardless of withdrawal, with no unexpected events upon reintroduction. Two patients experienced reactions at the SC injection site. On withdrawal, patients experienced slight worsening in efﬁcacy which improved following reintroduction. Conclusions Overall immunogenicity to SC abatacept is low, consistent with intravenous abatacept, and is not signiﬁcantly affected by a 3-month interruption and reintroduction. This stop–start schedule was well tolerated, with little impact on safety and efﬁcacy. These are important considerations for the clinical use of SC abatacept. ClinicalTrials gov Identiﬁer NCT00533897 INTRODUCTION Patients with rheumatoid arthritis (RA) receive long- term treatment and sometimes require interruption of therapy—for example, in the event of surgery or side effects. Such interruption in biological disease- modifying antirheumatic drugs (DMARDs) may lead to reduced drug concentration which may heighten the potential for drug-induced antibody responses.1 2 Immunogenicity can, in turn, reduce drug concentrations via antibody-mediated drug clearance, and reduce efﬁcacy by preventing drug binding to the target. In addition, general immune- mediated toxicities such as infusion and subcuta- neous (SC) injection site reactions may increase.1–3 This has been seen with the anti-tumour necrosis factor agent inﬂiximab, for which serum sickness- like reactions have been observed at initiation and at reintroduction following extended withdrawal; such reactions were associated with increased immunogenicity, reduced serum concentrations and potential loss of efﬁcacy.4–7 Experience with intravenous abatacept has dem- onstrated consistent safety and sustained efﬁcacy, and a low immunogenicity rate that has no signiﬁ- cant impact on pharmacokinetics, safety and efﬁca- cy.1 Theoretically, administration of abatacept via the SC route may have an increased risk for immu- nogenicity due to potential differences in antigen presentation.2 8 Fixed (125 mg/week) dosing of SC abatacept has so far demonstrated low immunoge- nicity rates and titres, and comparable drug expo- sure to intravenous abatacept.9 SC administration of abatacept is generally safe and well tolerated in patients with RA, with comparable efﬁcacy to that seen with intravenous administration.9–11 This study assessed the effect of temporary withdrawal and reintroduction of 125 mg/week SC abatacept on immunogenicity, safety and efﬁcacy in patients with RA. METHODS Patients Patients in the ALLOW (Evaluation of Abatacept Administered SubcutaneousLy in AduLts With Active RheumatOid Arthritis: Impact of Withdrawal and Reintroduction on Immunogenicity, Efﬁcacy and Safety) trial met the criteria of the American Rheumatism Association (1987) for RA diagnosis and the American College of Rheumatology (1991) functional classes I, II or III. Patients had to have a Disease Activity Score 28 (DAS28; C reactive pro- tein (CRP)) of 3.2–5.1 and received methotrexate (MTX) for ≥3 months prior to treatment. Patients were excluded if they had serious acute or severe chronic/recurrent bacterial infection, or evi- dence of latent bacterial or viral infection, or were pre- viously treated with rituximab, abatacept, live vaccine 38 Ann Rheum Dis 2012;71:38–44. doi:10.1136/annrheumdis-2011-200344