Sustained disease remission and inhibition of radiographic progression in methotrexate-naive patients with rheumatoid arthritis and poor prognostic factors treated with abatacept: 2-year outcomes.

OBJECTIVE: To assess the efficacy and safety of abatacept plus methotrexate versus methotrexate alone in early erosive rheumatoid arthritis (RA). METHODS: The AGREE was a 2-year phase IIIb multinational study in early (≤ 2 years) RA. During the double-blind period (year 1), patients were randomly assigned 1:1 to receive abatacept+methotrexate or methotrexate alone; all patients received open-label abatacept+methotrexate during year 2. Clinical outcomes assessed included 28-joint disease activity score (DAS28) defined remission, low disease activity score (LDAS), American College of Rheumatology (ACR) responses and physical function. Radiographic outcomes were assessed using the Genant-modified Sharp total score (TS). Safety was monitored throughout. RESULTS: Of the 459 patients completing year 1, 433 patients (94.3%) completed year 2. DAS28-defined remission, LDAS, ACR and physical function were sustained through year 2 in the original abatacept+methotrexate group, with 55.2% in remission at 2 years. Upon introduction of abatacept in the methotrexate-alone group, additional patients achieved DAS28-defined remission (44.5% vs 26.9%), LDAS (60.4% vs 43.2%) and improved ACR 70 (49.8% vs 31.7%) for year 2 versus year 1. Less radiographic progression was observed at 2 years in the original abatacept+methotrexate group than the methotrexate-alone group (change in TS 0.84 vs 1.75, p<0.001). No new safety issues were seen. Similar rates of serious adverse events, serious infections and autoimmune events were observed in years 1 and 2. CONCLUSIONS: The AGREE trial was the first to examine the impact of T-cell co-stimulation modulation with abatacept in patients with early erosive RA. Early treatment with abatacept+methotrexate resulted in greater sustainable clinical, functional and radiographic benefits than methotrexate alone, with acceptable safety and tolerability. TRIAL REGISTRATION: NCT00122382.

Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors.

OBJECTIVES: To assess the efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis (RA) and poor prognostic factors. METHODS: In this double-blind, phase IIIb study, patients with RA for 2 years or less were randomly assigned 1 : 1 to receive abatacept (approximately 10 mg/kg) plus methotrexate, or placebo plus methotrexate. Patients were methotrexate-naive and seropositive for rheumatoid factor (RF), anti-cyclic citrullinated protein (CCP) type 2 or both and had radiographic evidence of joint erosions. The co-primary endpoints were the proportion of patients achieving disease activity score in 28 joints (DAS28)-defined remission (C-reactive protein) and joint damage progression (Genant-modified Sharp total score; TS) at year 1. Safety was monitored throughout. RESULTS: At baseline, patients had a mean DAS28 of 6.3, a mean TS of 7.1 and mean disease duration of 6.5 months; 96.5% and 89.0% of patients were RF or anti-CCP2 seropositive, respectively. At year 1, a significantly greater proportion of abatacept plus methotrexate-treated patients achieved remission (41.4% vs 23.3%; p<0.001) and there was significantly less radiographic progression (mean change in TS 0.63 vs 1.06; p = 0.040) versus methotrexate alone. Over 1 year, the frequency of adverse events (84.8% vs 83.4%), serious adverse events (7.8% vs 7.9%), serious infections (2.0% vs 2.0%), autoimmune disorders (2.3% vs 2.0%) and malignancies (0.4% vs 0%) was comparable for abatacept plus methotrexate versus methotrexate alone. CONCLUSIONS: In a methotrexate-naive population with early RA and poor prognostic factors, the combination of abatacept and methotrexate provided significantly better clinical and radiographic efficacy compared with methotrexate alone and had a comparable, favourable safety profile.

Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate.

OBJECTIVES: This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo. The primary objective of this study was to evaluate the mean change from baseline in Disease Activity Score (based on erythrocyte sedimentation rates; DAS28 (ESR)) for the abatacept vs placebo groups at day 197. METHODS: Patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) were randomised 3:3:2 to abatacept ( approximately 10 mg/kg every 4 weeks, n = 156), infliximab (3 mg/kg every 8 weeks, n = 165), or placebo (every 4 weeks, n = 110) and background MTX. Safety and efficacy were assessed throughout the study. RESULTS: Similar patient demographics and clinical characteristics were present at baseline between groups, with mean scores of approximately 1.7 for HAQ-DI and 6.8 for DAS28 (ESR). At 6 months, mean changes in DAS28 (ESR) were significantly greater for abatacept vs placebo (-2.53 vs -1.48, p<0.001) and infliximab vs placebo (-2.25 vs -1.48, p<0.001). For abatacept vs infliximab treatment at day 365, reductions in the DAS28 (ESR) were -2.88 vs -2.25. At day 365, the following response rates were observed for abatacept and infliximab, respectively: American College of Rheumatology (ACR) 20, 72.4 and 55.8%; ACR 50, 45.5 and 36.4%; ACR 70, 26.3 and 20.6%; low disease activity score (LDAS), 35.3 and 22.4%; DAS28-defined remission, 18.7 and 12.2%; good European League Against Rheumatism (EULAR) responses, 32.0 and 18.5%; and Health Assessment Questionnaire Disability Index (HAQ-DI), 57.7 and 52.7%. Mean changes in physical component summary (PCS) were 9.5 and 7.6, and mental component summary (MCS) were 6.0 and 4.0, for abatacept and infliximab, respectively. Over 1 year, adverse events (AEs) (89.1 vs 93.3%), serious AEs (SAEs) (9.6 vs 18.2%), serious infections (1.9 vs 8.5%) and discontinuations due to AEs (3.2 vs 7.3%) and SAEs (2.6 vs 3.6%) were lower with abatacept than infliximab. CONCLUSIONS: In this study, abatacept and infliximab (3 mg/kg every 8 weeks) demonstrated similar efficacy. Overall, abatacept had a relatively more acceptable safety and tolerability profile, with fewer SAEs, serious infections, acute infusional events and discontinuations due to AEs than the infliximab group. TRIAL REGISTRATION NUMBER: NCT00095147.

Reduced incidence of gastroduodenal ulcers associated with lumiracoxib compared with ibuprofen in patients with rheumatoid arthritis.

BACKGROUND: Lumiracoxib (Prexige; Novartis Pharma AG, Basel, Switzerland) is a cyclooxygenase-2 selective inhibitor associated with improved gastrointestinal safety compared with nonsteroidal anti-inflammatory drugs, in patients with osteoarthritis. AIM: To compare the gastroduodenal safety of lumiracoxib with ibuprofen and celecoxib in patients with rheumatoid arthritis. METHODS: A total of 893 patients with rheumatoid arthritis were randomized to lumiracoxib 400 mg once daily, lumiracoxib 800 mg once daily, ibuprofen 800 mg three times daily or celecoxib 200 mg twice daily for 13 weeks, in a double-blind randomised controlled clinical trial. The primary endpoint was the cumulative incidence of gastroduodenal ulcers over 13 weeks. RESULTS: The incidence of gastroduodenal ulcers >/=3 mm with lumiracoxib 400 mg once daily (2.8%) or lumiracoxib 800 mg once daily (4.3%) was significantly lower than with ibuprofen (13.6%, all P < 0.01) and not different from celecoxib (1.9%). The incidence of adverse events was similar for lumiracoxib 400, 800 mg and celecoxib (78, 75 and 77%, respectively) and higher with ibuprofen (86%). Discontinuation for adverse events was highest for ibuprofen (12.5% vs. 7.9-8.8% for the other groups). CONCLUSIONS: Lumiracoxib demonstrated gastroduodenal safety superior to ibuprofen and similar to celecoxib in patients with rheumatoid arthritis.

Lack of association of Human T-cell lymphotrophic virus type 1(HTLV-1) infection and rheumatoid arthritis in an endemic area.

In South Africa the association of HTLV-1 infection with myelopathy is well described in Kwa Zulu Natal, which is an endemic area for HTLV-1 infection. Japan also has a high background prevalence of HTLV-1 infection, and a significant association of HTLV-1 infection with rheumatoid arthritis has been reported. This study was undertaken to determine whether there was an association with HTLV-1 infection among black Africans with rheumatoid arthritis (RA) in Kwa Zulu Natal, South Africa. A randomly selected group of 110 black people with RA were studied. The age, sex and duration of disease were recorded and a rheumatoid factor test was performed. The presence of antibodies to HTLV-1 was assessed using an enzyme-linked immunosorbent assay. The integration of proviral DNA in peripheral blood monocytes was also studied using the polymerase chain reaction (PCR). Control data were available from a previously reported community-based study of 1018 subjects from the same geographical area. None of the 110 patients studied were positive for HTLV-1 infection by serology or by PCR. Although HTLV-1 infection is reported as a possible triggering agent for RA in Japan, we failed to detect any excess of HTLV-1 infection in black Africans with RA. Our findings are in agreement with observations in the USA and Europe.

Autonomic nervous system dysfunction in severe tetanus: current perspectives.

The enigma of autonomic nervous system dysfunction in severe tetanus is discussed in the light of recent and older evidence concerning the nature and action of tetanus toxin, its clinical effects, and therapy. Some suggestions for the pathogenesis and management of the cardiovascular disturbances are made.