Rheumatoid Arthritis: Covucci A

Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Pérez N, Silva CA, Abud-Mendoza C, Burgos-Vargas R, Gerloni V, Melo-Gomes JA, Saad-Magalhães C, Sztajnbok F, Goldenstein-Schainberg C, Scheinberg M, Penades IC, Fischbach M, Orozco J, Hashkes PJ, Hom C, Jung L, Lepore L, Oliveira S, Wallace CA, Sigal LH, Block AJ, Covucci A, Martini A, Giannini EH, Anonymous00184, Anonymous00185. · IRCCS G Gaslini, PRINTO, Genoa, Italy. · Lancet. · Pubmed #18632147 No free full text.

Abstract: BACKGROUND: Some children with juvenile idiopathic arthritis either do not respond, or are intolerant to, treatment with disease-modifying antirheumatic drugs, including anti-tumour necrosis factor (TNF) drugs. We aimed to assess the safety and efficacy of abatacept, a selective T-cell costimulation modulator, in children with juvenile idiopathic arthritis who had failed previous treatments. METHODS: We did a double-blind, randomised controlled withdrawal trial between February, 2004, and June, 2006. We enrolled 190 patients aged 6-17 years, from 45 centres, who had a history of active juvenile idiopathic arthritis; at least five active joints; and an inadequate response to, or intolerance to, at least one disease-modifying antirheumatic drug. All 190 patients were given 10 mg/kg of abatacept intravenously in the open-label period of 4 months. Of the 170 patients who completed this lead-in course, 47 did not respond to the treatment according to predefined American College of Rheumatology (ACR) paediatric criteria and were excluded. Of the patients who did respond to abatacept, 60 were randomly assigned to receive 10 mg/kg of abatacept at 28-day intervals for 6 months, or until a flare of the arthritis, and 62 were randomly assigned to receive placebo at the same dose and timing. The primary endpoint was time to flare of arthritis. Flare was defined as worsening of 30% or more in at least three of six core variables, with at least 30% improvement in no more than one variable. We analysed all patients who were treated as per protocol. This trial is registered, number NCT00095173. FINDINGS: Flares of arthritis occurred in 33 of 62 (53%) patients who were given placebo and 12 of 60 (20%) abatacept patients during the double-blind treatment (p=0.0003). Median time to flare of arthritis was 6 months for patients given placebo (insufficient events to calculate IQR); insufficient events had occurred in the abatacept group for median time to flare to be assessed (p=0.0002). The risk of flare in patients who continued abatacept was less than a third of that for controls during that double-blind period (hazard ratio 0.31, 95% CI 0.16-0.95). During the double-blind period, the frequency of adverse events did not differ in the two treatment groups. Adverse events were recorded in 37 abatacept recipients (62%) and 34 (55%) placebo recipients (p=0.47); only two serious adverse events were reported, both in controls (p=0.50). INTERPRETATION: Selective modulation of T-cell costimulation with abatacept is a rational alternative treatment for children with juvenile idiopathic arthritis. FUNDING: Bristol-Myers Squibb.

Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E. · Rheumatology and Immunology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Arthritis Rheum. · Pubmed #16947384 links to  free full text

Abstract: OBJECTIVE: To assess the safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis (RA) who had been receiving > or =1 traditional nonbiologic and/or biologic disease-modifying antirheumatic drugs (DMARDs) approved for the treatment of RA for at least 3 months prior to entry into the study. METHODS: This was a 1-year, multicenter, randomized, double-blind, placebo-controlled trial. Patients were randomized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range, or placebo. RESULTS: The abatacept and placebo groups exhibited similar frequencies of adverse events (90% and 87%, respectively), serious adverse events (13% and 12%, respectively), and discontinuations due to adverse events (5% and 4%, respectively). Five patients (0.5%) in the abatacept group and 4 patients (0.8%) in the placebo group died during the study. Serious infections were more frequent in the abatacept group than in the placebo group (2.9% versus 1.9%). Fewer than 4% of patients in either group experienced a severe or very severe infection. The incidence of neoplasms was 3.5% in both groups. When evaluated according to background therapy, serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent (22.3%) than in the other subgroups (11.7-12.5%). CONCLUSION: Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician- and patient-reported disease outcomes. However, abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events. Therefore, abatacept is not recommended for use in combination with biologic therapy.