Baseline demographics and disease characteristics
A total of 56 patients were randomised and treated, and baseline demographics and clinical characteristics were similar between the groups (). Overall, patients had a mean symptom duration of 7.9 months, with a mean C-reactive protein level of 1.1 mg/dl. At baseline, 55.4% of patients had at least one erosion; all patients were anti-CCP positive and 78.6% were RF seropositive. Overall, 12.5, 26.8 and 58.9% patients met one, two or three of the ACR criteria for RA at study entry, respectively.
Baseline demographics and clinical characteristics
shows the patient disposition. Over 6 months of treatment, 6/28 (21.4%) patients in the abatacept group and 11/28 (39.3%) patients in the placebo group discontinued; of these, three (10.7%) and eight (28.6%) were owing to lack of efficacy, respectively. After treatment cessation, from month 6 to year 2, 15 (53.6%) and 13 (46.4%) patients randomised to the original abatacept and placebo groups discontinued, respectively; 11 (39.3%) and 12 (42.9%) of these were owing to lack of efficacy. Seven (25.0%) and four (14.3%) patients randomised to abatacept and placebo completed 2 years, respectively.
Patient disposition over 2 years. AE, adverse event.
Development of rheumatoid arthritis by the ACR 1987 criteria
Over 1 year, six patients discontinued without developing RA for reasons other than lack of efficacy, and were not included in the primary efficacy analysis (prespecified). Therefore, 50/56 patients were evaluable; 26 and 24 were treated with abatacept and placebo, respectively. At year 1 (6 months after treatment discontinuation), 12/26 (46.2%) abatacept-treated and 16/24 (66.7%) placebo-treated patients had been diagnosed with RA as defined by the ACR criteria.4
The CIs for the difference between the two groups included zero (difference (95% CI) −20.5% (−47.4% to 7.8%)); therefore, the primary end point for this trial was not met.
Adjusted mean (standard error (SE)) changes from baseline to month 6 in abatacept- versus placebo-treated patients were 0.15 (0.17) versus 0.46 (0.18) for TS, 0.14 (0.17) versus 0.45 (0.18) for ES and 0 (0) versus 0.01 (0) for JSN scores, respectively (, respectively). Adjusted mean (SE) changes from baseline to year 1 (6 months after treatment cessation) in abatacept- versus placebo-treated patients were 0.01 (0.29) versus 1.11 (0.36) for TS, 0.01 (0.20) versus 0.86 (0.25) for ES and 0 (0.11) versus 0.26 (0.14) for JSN scores, respectively. Estimates of difference (95% CI) for abatacept versus placebo at year 1 were −1.10 (−2.05 to −0.15) for TS, −0.84 (−1.51 to −0.18) for ES and −0.26 (−0.63 to 0.11) for JSN scores. Confidence intervals did not include zero for either TS or ES. While radiographic assessments continued up to year 2, small patient numbers at this time point meant analysis of mean changes from baseline were not meaningful after year 1.
Figure 2 Radiographic progression. Adjusted mean change from baseline to month 6 and year 1 in (A) total score, (B) erosion score and (C) joint-space narrowing score. Data are based on the intention-to-treat population, using data available at the visit of interest (more ...)
Magnetic resonance imaging
Eleven abatacept- and 10 placebo-treated patients were eligible for MRI assessments. Osteitis scores improved from baseline to month 6 with abatacept (mean (SE) change −1.64 (1.48)), but deterioration was observed with placebo (1.40 (1.59)). For patients who remained in the trial at year 1, there was little progression in osteitis score in the abatacept group (n=9; change of 0.22 (0.49) from baseline). In the placebo group (n=6), however, osteitis scores worsened by 6.67 (4.22) from baseline. MRI erosion and synovitis scores showed a similar trend; at month 6, mean changes from baseline were 0.45 (0.37) and 0.27 (0.56), respectively, in the abatacept group, and 1.20 (1.09) and 1.60 (1.23) in the placebo group. By year 1, mean change from baseline in erosion and synovitis scores were 0 (0.17) and 0.22 (0.22), respectively, in the abatacept group versus 5.00 (3.20) and 2.33 (1.61) in the placebo group.
All patients were positive for anti-CCP2 antibodies at baseline. The percentage of anti-CCP2-positive patients declined in the abatacept group to 90.9% (20/22) at month 6, and 86.7% (13/15) at year 1, while in the placebo group, all patients remained positive at month 6 (19/19) and year 1 (10/10). These data are consistent with results for changes in serum levels of anti-CCP2 antibodies ().
Mean changes in serum anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) levels
At baseline, 85.7 and 71.4% of patients in the abatacept and placebo groups were positive for RF. The proportion of RFpositive patients at month 6 and year 1 was 59.1% (13/22) and 73.3% (11/15), respectively, in the abatacept group, and 70.0% (14/20) and 80.0% (8/10) in the placebo group. shows the mean changes in RF levels.
shows a Kaplan–Meier curve of discontinuations due to lack of efficacy over 2 years; the median times to discontinuation were 507 and 344 days in the abatacept and placebo groups, respectively. After 6 months, 71.4% (15/21) versus 35.0% (7/20) of patients were in DAS28-defined remission for the abatacept versus placebo groups, respectively (); at year 1 (following cessation of treatment for 6 months), the proportion of patients in DAS28-defined remission was 47.4% (9/19) versus 38.5% (5/13). At 6 months, the proportion of patients with zero swollen and tender joints was 62.5% (15/24) versus 14.3% (3/21), for the abatacept versus placebo groups, respectively; the proportion was 30.0% (6/20) versus 14.3% (2/14) at year 1 ().
Figure 3 Clinical efficacy. (A) Kaplan–Meier plot showing the proportion of patients who discontinued owing to lack of efficacy over 2 years. One patient was diagnosed with RA at baseline and was excluded from the analyses; *Patients who discontinued for (more ...)
Concomitant steroid use
During the 6-month treatment period, 17.9% of patients in each group were receiving low-dose (,10 mg prednisone equivalent) oral corticosteroids; in these patients, the mean (SD) dose was 4.8 (1.8) mg/day in the abatacept group and 6.0 (1.4) mg/day in the placebo group. From month 6 to year 2, 17.9 and 25.0% of patients in the abatacept and placebo groups were receiving patients in the abatacept and placebo groups were receiving low-dose oral corticosteroids, at a mean (SD) dose of 4.3 (1.2) and 6.0 (1.3) mg/day, respectively.
summarises safety data over the 6-month treatment period plus 56-day follow-up after last dose of the study drug. Adverse events (AEs) were reported in 18 (64.3%) abatacepttreated versus 20 (71.4%) placebo-treated patients. The most frequently reported AEs (more than two patients in either group) were diarrhoea, nasopharyngitis, urinary tract infection, gastroenteritis, pharyngolaryngeal pain and headache. One abatacept-treated patient (3.6%) discontinued owing to dyspnoea, and one placebo-treated patient (3.6%) discontinued owing to thrombocytopenia. Serious AEs were reported in one patient (3.6%) in each group. One was a basal cell carcinoma reported in a 74-year-old abatacept-treated patient (the only malignancy reported). The other was a case of lumbar sciatica in the placebo group. There were no reports of treatment-related serious AEs or discontinuations due to serious AEs. Infections were reported in 10 (35.7%) abatacept-treated and 11 (39.3%) placebo-treated patients. The most frequently reported infections (>10% overall) were nasopharyngitis (three abatacept vs two placebo patients), urinary tract infection (two abatacept vs three placebo patients) and gastroenteritis (no abatacept vs three placebo patients). Acute (within 1 h) infusional reaction was reported in one patient (3.6%) in each group, and peri- (within 24 h) infusional reactions were reported in two (7.1%) and three (10.7%) patients in the abatacept and placebo groups, respectively. No deaths occurred in either group.
Summary of safety over the 6-month treatment period*