T cells play a fundamental role in the upstream initiation and perpetuation of the pathologic immune response in rheumatoid arthritis (RA), resulting in downstream inflammation and destruction (1). Following antigen recognition, T cells require a costimulatory signal for full activation, with one of the best characterized pathways being the engagement of CD80/86 on antigen-presenting cells with CD28 on T cells (2). Following the normal immune response, endogenous CTLA-4 down-regulates CD28-mediated T cell activation by binding to CD80/86 with higher avidity than CD28 (3). The important role of T cells in the immune response in RA makes T cell activation a rational therapeutic target for treatment of this disease.
Abatacept is a fully human soluble fusion protein that consists of the extracellular domain of human CTLA-4 linked to the modified Fc portion of human IgG1. Abatacept is the first in a new class of agents for the treatment of RA that selectively modulates the CD80/86:CD28 costimulatory signal required for full T cell activation. Abatacept, a selective costimulation modulator, has previously demonstrated efficacy, safety, and tolerability in combination with methotrexate (MTX) in clinical trials of patients in whom the response to MTX was inadequate (4, 5). Furthermore, a trial of abatacept on a background of disease-modifying antirheumatic drugs (DMARDs) in patients with an inadequate response to anti–tumor necrosis factor (anti-TNF) therapy recently demonstrated a significant efficacy benefit of abatacept in this unique RA patient population (6).
The Abatacept Study of Safety in Use with Other RA Therapies (ASSURE trial) was designed to assess the safety of abatacept compared with placebo in patients with active RA during 1 year of abatacept treatment added to a background of treatment with ≥1 of the traditional nonbiologic and/or biologic DMARDs currently approved for the treatment of RA. This trial was designed to assess the safety of abatacept in patients with RA who would be encountered in clinical practice.
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- PATIENTS AND METHODS
Several randomized studies have demonstrated the efficacy of abatacept in patients with active RA. In a phase IIb trial (5), therapy with abatacept plus MTX in patients with an inadequate response to MTX provided significant improvements in terms of the ACR 20% (ACR20), ACR50, and ACR70 criteria (9) compared with placebo at 1 year (for ACR20, 63% versus 36%; for ACR50, 42% versus 20%; for ACR70, 21% versus 8%). A phase III trial in a similar patient population demonstrated similar benefit with abatacept versus placebo (for ACR20, 73% versus 40%; for ACR50, 48% versus 18%; for ACR70, 29% versus 6%) (12), while a further phase III trial of 6 months duration in patients with a current or previous inadequate response to anti-TNF therapy also demonstrated significant benefit with abatacept in this unique patient population (for ACR20, 50% versus 19.5%; for ACR50, 20% versus 4%; for ACR70, 10% versus 2%) (6). In all trials, abatacept provided significant improvement in patients' physical function and quality of life (5, 6, 12).
The primary end point of the ASSURE trial was to evaluate the safety of abatacept compared with placebo when added to a background of approved synthetic DMARDs and/or biologic DMARDs over the course of 1 year, in a blinded, randomized study. This study revealed overall similarity between the abatacept and placebo groups in their respective frequency of AEs, SAEs, and severe or very severe AEs; furthermore, discontinuations due to AEs were infrequent in both treatment groups. The overall frequency of neoplasms was similar in the abatacept and placebo groups. Lung cancer was the most frequently reported solid malignancy in this study (n = 3). A causal relationship to abatacept therapy is considered less likely in this group, considering that 2 of these patients had a very short duration of treatment, and 1 patient had an abnormal radiograph at baseline. However, the data are too limited to permit a definitive conclusion, and longer-term observation will be required. There were no reports of lymphoma, tuberculosis (for which patients were screened prior to treatment), or demyelinating disorders.
When assessed according to background therapy, the rates of AEs and SAEs were similar in the subgroup receiving abatacept plus nonbiologic background therapy and the subgroup receiving placebo plus nonbiologic background therapy. However, AEs, SAEs, and discontinuations were all most frequent when abatacept was combined with background biologic therapy. It should be noted that the proportion of patients who experienced an SAE was greater among those receiving leflunomide plus abatacept than in those receiving leflunomide plus placebo; however, there was no trend for any specific organ system class or type of SAE, and the sample size of this group was relatively small. In the subgroup of patients with COPD, respiratory system–related AEs and SAEs were reported in a greater proportion of patients in the abatacept group compared with the placebo group, although the overall number of patients with COPD in this study was small. Nonetheless, the findings in this study indicate that abatacept should be used with caution and with close monitoring of respiratory status in patients with RA and COPD.
The ASSURE trial involved 1 year of observation; however, greater clinical experience over longer periods of observation and in larger populations of patients with comorbidities is required to validate these findings. An important finding in this study was the number of serious infections observed when abatacept was combined with other biologic therapies. This confirms the findings of a smaller phase II study in which abatacept (2 mg/kg) in combination with the anti-TNF agent etanercept was associated with a higher rate of serious infections than was etanercept plus placebo after 1 year of double-blind therapy (Weinblatt M, et al: unpublished observations). In contrast, across clinical trials of abatacept in combination with nonbiologic therapy, the reported incidence of serious infections was lower than that reported here for patients receiving abatacept in combination with biologic background therapy. Genovese et al (6) reported that among patients who experienced an inadequate response to anti-TNF therapy, at 6 months the number of serious infections was comparable in patients receiving abatacept plus DMARDs and in those receiving placebo plus DMARDs (2.3% for both). More recently, among a group of patients with an inadequate response to MTX, serious infections in the abatacept group were of a similar magnitude to those in patients with an inadequate response to anti-TNF therapy (3.9% and 2.3%, respectively, for patients receiving abatacept plus MTX and those receiving placebo plus MTX) (12).
Although efficacy was not a primary end point of the ASSURE trial, and as such this study was not designed to prospectively assess the efficacy of abatacept between subgroups, the benefit seen with abatacept in terms of physical function and physician- and patient-reported pain and global assessment tended to be less in patients receiving background biologic therapy compared with those receiving background nonbiologic therapy. A post hoc analysis was used to assess each efficacy outcome according to background therapy; although post hoc analyses may not be deemed optimal, the lack of clinical benefit seen here in the group of patients receiving abatacept plus biologic therapy is consistent with that seen in the phase II study of abatacept in combination with etanercept.
Coupled with the less favorable safety profile seen in patients receiving abatacept on a background of biologic therapy, these findings are consistent with the lack of added benefit and increased rate of infection seen when other biologic agents were used in combination (e.g., etanercept plus anakinra) (13). In that study, patients receiving etanercept plus anakinra had a higher frequency of serious infection compared with those receiving etanercept alone (3.7–7.4% versus 0%), and the number of ACR responders was lower (13). Based on the results of the ASSURE trial and the phase II study evaluating the concomitant use of abatacept and etanercept, a favorable benefit-to-risk ratio with abatacept in combination with other biologic therapies is not apparent; therefore, use of abatacept in combination with biologic therapies is not advised.
The safety and tolerability of abatacept in the ASSURE trial was favorable when abatacept was given in combination with nonbiologic DMARDs; the number of good clinical outcomes was also greater in this subgroup over the course of 1 year. Selective costimulation modulation with abatacept is an effective therapy for RA, with an acceptable safety profile when used in combination with a variety of background nonbiologic DMARDs.