The Safety Of Abatacept in patients with active rheumatoid arthritis and an inadequate response to Anti-TNF therapy: Results from the ARRIVE Trial - OP0121
Authors: M. Schiff, C. Pritchard, J. Teng, K. Bahrt, M. Genovese
Background:
An earlier study of Abatacept in TNF inadequate responders, ATTAIN, was conducted in patients with RA who were washed out of their TNF antagonists before beginning therapy with abatacept. In clinical settings, a prolonged washout period may not be feasible due to ongoing disease activity of patients and a need to initiate a new therapy. However, there are concerns that the TNF antagonist may exhibit a “carry over” effect especially in terms of safety. Prior studies evaluating the combination of abatacept with other biological DMARDS has shown an increase in infections in patients compared to abatacept in combination with nonbiological DMARDS (http://www.hopkins-arthritis.org/physician-corner/education/eular2005/ra-treatments-ctla4.html). Evaluating the safety of abatacept in patients introduced shortly after discontinuation of a TNF antagonist is an important clinical question. This study was designed to assess the clinical safety and tolerability of abatacept with a shorter TNF antagonist washout period.
Methods:
This was a subanalysis of 842 US pts from an international, 6-month, open-label Phase IIIb ARRIVE (Abatacept Researched in Rheumatoid arthritis patients with an Inadequate anti-TNF response to Validate Effectiveness) trial of 1285 pts with active RA and an inadequate response to ≥3 months of TNF antagonist therapy. Patients had either: (1) discontinued TNF antagonist therapy ≥2 months before screening due to lack of clinical response or an inadequate response and persistent disease activity (Prior users); or (2) received TNF antagonist therapy within 2 months of screening, without a clinical response, or had an insignificant response and a persistent DAS28 (C-reactive protein [CRP]) score of ≥5.6 (Current users). Unlike in the ATTAIN trial, patients were also eligible if they had discontinued TNF antagonists primarily for safety reasons. All Current users started ABA at their next scheduled TNF antagonist dose. Patients received a fixed dose of ABA (approximately 10 mg/kg, according to weight range) on Days 1, 15 and 29, and every 4 weeks thereafter, plus stable background non-biologic DMARD therapy. Safety results are presented for the Prior vs Current user groups.
Results:
Out of 1043 enrolled US pts, 842 were treated and evaluated for safety (370 Prior and 472 Current users). Overall, baseline characteristics were similar in both groups (mean DAS28 [CRP] of 6.2). Mean disease duration was 12.7 and 10.4 years in Prior and Current users, respectively. At 6 months, the frequency of adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs/SAEs, infections, neoplasms and deaths were similar in Prior and Current users (Table below). Serious infections were similar in Prior vs Current users (2.2 vs 2.3%, respectively); the most frequent (occurring in ≥2 pts) were pneumonia (4 [0.8%] Current pts) and lobar pneumonia (2 [0.5%] Prior pts). No serious opportunistic infections, including tuberculosis, occurred in either group. One death due to congestive heart failure was reported in a Prior user (not considered related to ABA therapy).
Events (Days 1-169), n (%) |
ABA + DMARDs |
||
|
Prior users |
Current users |
Overall |
|
(n=370) |
(n=472) |
(n=842) |
Deaths |
1 (0.3) |
0 |
1 (0.1) |
SAEs |
34 (9.2) |
36 (7.6) |
70 (8.3) |
Discontinuations due to SAEs |
8 (2.2) |
4 (0.8) |
12 (1.4) |
AEs |
284 (76.8) |
363 (76.9) |
647 (76.8) |
Discontinuations due to AEs |
15 (4.1) |
19 (4.0) |
34 (4.0) |
Infections |
149 (40.3) |
181 (38.3) |
330 (39.2) |
Serious infections |
8 (2.2) |
11 (2.3) |
19 (2.3) |
Neoplasms* |
3 (0.8) |
2 (0.4) |
5 (0.6) |
*SAEs (benign, malignant and unspecified).
Conclusion:
ABA was generally safe and well tolerated in this subset of US pts with active RA and an inadequate response to anti-TNF therapy, regardless of whether or not patients had a washout period, supporting direct switching to ABA from anti-TNF therapy as an option in clinical practice.
Editorial Comment:
Understanding the safety of switching patients from one form of therapy to another is an important clinical question that is not necessarily answered in standard clinical trials, which typically have well defined criteria for washout of background medications. In clinical practice, however, this is not often the case with patients failing to respond to one agent and needing a new therapeutic strategy for disease control. Previous studies have raised concerns of concomitantly administered biological agents with infection risks increased. This study provides some information in terms of the timing of abatacept after a TNF antagonist. The two groups of patients studied (those more than or less than 2 months from their last TNF antagonist dose), are quite similar in terms of AEs, SAEs, infections, serious infections and neoplasms. These data thus provide some comfort in initiating a change in therapeutic class to abatacept soon after discontinuation of a TNF antagonist. Whether there are differences between different TNF antagonists is not known from this study. Similar types of studies will be very important with future therapies especially as the numbers of different classes of targeted therapies expands and the possibilities of switches from one to another increase. Even with data such as this study, clinicians should always be alert to the possibility of additive toxicities whenever combining or cycling immunomodulatory agents.