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Objective: To assess the overall safety, including rare events, of intravenous (IV) abatacept treatment in rheumatoid arthritis (RA)., Methods: Data from 8 clinical trials of IV abatacept in RA were pooled. Safety events were assessed during the short-term (duration ≤ 12 months) and cumulative (short-term plus longterm extensions) abatacept treatment periods. Incidence rates per 100 patient-years were calculated. Standardized incidence ratios (SIR) for hospitalized infections and malignancies were compared with external RA cohorts and, for malignancies, with the US general population., Results: There were 3173 IV abatacept-treated patients with 2331 patient-years of exposure in the short-term periods, and 4149 IV abatacept-treated patients with 12,132 patient-years of exposure in the cumulative period. Incidence rates for serious infections were low and consistent over time (3.68 for abatacept vs 2.60 for placebo during the short-term, and 2.87 for abatacept during the cumulative period). Hospitalized infections were generally similar to external RA patient cohorts and were consistent over time. Incidence rates of malignancies were similar for abatacept- and placebo-treated patients during the short-term period (0.73 vs 0.59) and remained low during the abatacept cumulative period (0.73). SIR of some tissue-specific malignancies (e.g., colorectal and breast) in the cumulative period tended to be lower, while others (lymphoma and lung) tended to be higher, compared with the general population; however, incidence rates were comparable with RA cohorts. Autoimmune events were rare and infusion reactions uncommon., Conclusion: Longterm safety of IV abatacept was consistent with the short-term, with no unexpected events and low incidence rates of serious infections, malignancies, and autoimmune events.

Objective: To assess safety, immunogenicity and efficacy in rheumatoid arthritis (RA) patients switched from long-term intravenous to subcutaneous (SC) abatacept., Methods: In this phase IIIb, open-label, single-arm trial, patients who completed ≥4 years of intravenous abatacept (in long-term extensions of two phase III studies) were enrolled to receive SC abatacept (125 mg/week). The primary objective was safety during the first 3 months after switching from intravenous therapy., Results: 123 patients entered the study (mean Disease Activity Score 28 (based on C reactive protein) and HAQ-DI of 3.4 and 0.94, respectively). At month 3, 120 (97.6%) patients were continuing to receive SC abatacept; no patients discontinued due to lack of efficacy. Adverse events (AEs) were reported in 49 (39.8%) patients through month 3. One patient (0.8%) discontinued due to an AE and one patient (0.8%) experienced a serious AE. Two (1.6%) patients had SC injection site reactions (erythema, pain), both with mild intensity. Clinical efficacy was maintained throughout. Limited impact on immunogenicity was observed when switching routes of administration., Conclusion: These data demonstrate that patients can switch from long-term monthly intravenous abatacept to a weekly fixed dose of 125 mg SC abatacept with no increased safety concerns. This study further supports SC abatacept as an alternative treatment option for patients with RA.

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.

Objective: Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was studied in a first-in-human trial in rheumatoid arthritis (RA) patients receiving concomitant methotrexate (MTX)., Methods: The ACTION trial was a combined phase I/II study of placebo plus MTX versus ocrelizumab plus MTX in 237 RA patients (intent-to-treat population). During phase I, 45 patients were treated with 1 of 5 escalating doses of study drug (infusions on days 1 and 15, 10-1,000 mg per each infusion). An additional 192 patients were randomized during phase II. Eligible patients had active disease, an inadequate response to treatment with at least MTX, rheumatoid factor positivity, and elevated levels of acute-phase reactants. The total study duration was 72 weeks. B cell pharmacodynamics over time was investigated., Results: Baseline demographics were similar among the treatment groups. Based on the entire 72-week data set, the incidence of serious adverse events in the ocrelizumab-treated patients was 17.9%, as compared with 14.6% in placebo-treated patients. The incidence of serious infections was 2.0% in all ocrelizumab-treated patients and 4.9% in placebo-treated patients. Infusion-associated adverse events were mostly grade 1 or grade 2 and were more frequent around the time of the first infusion. No serious infusion-associated adverse events were reported in the ocrelizumab group. Evidence of clinical activity was observed at all doses evaluated. Peripheral B cell depletion after infusion was rapid at all doses, with earlier repletion of B cells at doses of 10 mg and 50 mg. Human anti-human antibodies were detected in 19% and 10%, respectively, of those receiving 10 mg and 50 mg of ocrelizumab, compared with 0-5% of those receiving 200, 500, and 1,000 mg., Conclusion: Ocrelizumab therapy in combination with MTX was well tolerated. Doses of 200 mg (2 infusions) and higher showed better clinical responses, better reduction of C-reactive protein levels, and very low immunogenicity.