This is the first trial to examine the impact of the modulation of T-cell co-stimulation with abatacept in patients with early RA. Both primary endpoints were met. Abatacept plus methotrexate was significantly better at inducing DAS28 (CRP)-defined remission and reducing radiographic progression compared with methotrexate alone. Sensitivity analyses demonstrated that background medications did not impact the primary endpoints. Consistent with previous studies of abatacept in patients with established RA,22 23
clinical responses (ACR criteria) and clinically meaningful improvements in both physical function and HRQoL were significantly higher in the abatacept plus methotrexate group compared with the group receiving methotrexate alone. In addition, the safety and tolerability of abatacept plus methotrexate was generally comparable to methotrexate alone.
The clinical benefits observed with abatacept plus methotrexate were coupled with significantly lower rates of radiographic progression compared with the methotrexate-alone group. In a patient population with established RA and an inadequate response to methotrexate from the Abatacept in Inadequate Responders to Methotrexate (AIM) study, the rate of structural damage progression was significantly lower during the second year of treatment compared with the first year.19
The 2-year results from the current trial will determine whether this effect is also observed in patients with early RA. In contrast to the lower rates of progression in TS and ES in the abatacept plus methotrexate group, rates of JSN progression were minimal in both groups and were not significantly different. Consistent with other trials in patients with early RA,6 7 8 9
baseline values and the progression of JSN scores were low in both treatment arms, and it is possible that there was not enough power to detect small differences in rates of progression between the two groups.
On-drug remission is now an important and realistic therapeutic goal, which is increasingly reflected in the design of clinical trials for RA. This abatacept study and an early RA etanercept trial10
are the first studies of biological agents to use DAS28-defined remission as a primary endpoint. Remission was also the primary endpoint of an early RA trial comparing combination non-biological DMARD therapy with monotherapy,24
although in that trial remission was defined using the ACR criteria.25
The clinical and radiographic efficacy benefits reported here, including the proportion of patients achieving DAS28 (CRP)-defined remission, are comparable with those observed in other similar trials of early RA with biological therapies.6 7 8 10
This is particularly encouraging because of the poor prognostic status of the patients in this study, as all were required to have erosions and to be RF or anti-CCP2-seropositive at baseline. In fact, approximately 90% of the patients were anti-CCP2 positive. These prognostic factors all correlate with poor long-term outcomes and an aggressive disease course.2 3
As a result of the chronic long-term nature of RA, the safety and tolerability of a therapeutic agent is of critical importance. In this study, the overall frequency of adverse events and serious adverse events (including serious infections and autoimmune events) was similar between treatment groups, and in some cases was numerically lower in the abatacept plus methotrexate group. Infusional reactions occurred more frequently in the abatacept plus methotrexate group and were mostly mild in severity. Across both groups there were no cases of tuberculosis or opportunistic infections. One case of cancer was reported across treatment arms (pancreatic cancer in the abatacept plus methotrexate group). These data are consistent with the safety findings in previous studies of abatacept-treated patients with RA of a longer disease duration.22 23
The safety and tolerability of abatacept plus methotrexate in this study was further supported by a high retention rate (>90%) and a low rate of discontinuations for safety reasons.
These data should be interpreted within the context of the trial. As these short-term, double-blind data are restricted to 1 year, the capacity to assess longer-term structural changes or detect infrequent safety-related events may be limited. It will be interesting to examine this group of poor prognosis patients over the second year of this 2-year trial in order to monitor whether the clinical, functional and radiographic benefits observed here are maintained or improved, as has been observed with abatacept in patients with established RA.13 14
As this study focused on a poor prognosis patient population who were seropositive for RF and/or anti-CCP, seronegative patients were not included. However, it should be noted that abatacept has previously been demonstrated to have efficacy in patients with established RA in a number of trials that have included both seropositive and seronegative patients.13 14
In summary, the combination of abatacept plus methotrexate was significantly more effective in inducing DAS28 (CRP)-defined remission and inhibiting radiographic progression than methotrexate alone in patients with early RA and poor prognostic factors. Coupled with a safety and tolerability profile comparable to methotrexate alone, these data support the early use of abatacept in RA patients with moderate to severe disease.