Abatacept used in combination with non-methotrexate disease-modifying antirheumatic drugs: a descriptive analysis of data from interventional trials and the real-world setting

Efficacy and safety data for patients with moderate-to-severe RA who received abatacept or placebo in combination with MTX, HCQ, SSZ, azathioprine (AZA), or LEF were extracted from the ATTAIN (ClinicalTrials.gov NCT00048581), ASSURE (ClinicalTrials.gov NCT00048932), ARRIVE (ClinicalTrials.gov NCT00124982), and ACTION (ClinicalTrials.gov NCT02109666) studies. Details of the designs, patient populations, and primary results for these studies have been published previously [17, 21, 22]. Briefly, ATTAIN was a 6-month, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of abatacept added to background DMARDs in patients with active RA who had an inadequate response to TNFi therapy [17]. ASSURE was a 1-year, multinational, multicentre, randomized, double-blind, two-arm, parallel-dosing trial to assess the safety of abatacept in patients with active RA during 1 year of abatacept treatment added to background therapy with ≥ 1 csDMARD or bDMARD [22]. ARRIVE was an international, 6-month, open-label trial in patients with active RA who had an inadequate response to TNFi therapy for ≥ 3 months and 28-joint Disease Activity Score (C-reactive protein) (DAS28 (CRP)) ≥ 5.1 and were switched to abatacept directly from their TNFi or after completing washout of TNFi therapy within 2 months of screening [21]; background csDMARDs were continued after the switch. ACTION was a prospective, observational study in patients with RA who initiated intravenous abatacept in Europe and Canada between May 2008 and January 2013 to assess retention, effectiveness, safety, and tolerability of abatacept in a real-world setting. The population included patients enrolled in Cohort A (May 2008–December 2010) who were naïve to bDMARDs or who had previously failed treatment with ≥ 1 bDMARD—most (1009/1131 (89.2%)) had experienced prior biologic failure [13, 20].

ACR response rates reflect improvements in the signs and symptoms of RA; specifically, tender and swollen joints, and three of the five remaining core data set measures: patient global assessment of pain, patient global assessment of disease activity, physician global assessment of disease activity, patient assessment of physical function (Health Assessment Questionnaire—Disability Index (HAQ-DI)), and an acute-phase reactant value, CRP. In the ATTAIN study, ACR response rates of ≥ 20%, ≥ 50%, and ≥ 70% improvement (ACR20, ACR50, and ACR70), the mean change from baseline in DAS28 (CRP), the HAQ-DI score, and safety were assessed at 6 months [17]. In the ASSURE study, the mean change from baseline in HAQ-DI score was measured at 6 and 12 months, and the safety of abatacept added to a background of ≥ 1 csDMARD was assessed [22]. In the ARRIVE study, DAS28 (CRP) and HAQ-DI score were determined and safety was assessed in all patients who received ≥ 1 dose of study drug at 6 months [21]. In the ACTION study, mean change from baseline in DAS28 (CRP) and HAQ-DI score was determined at 6, 12, and 24 months, and safety was assessed in accordance with local regulations [20].

Safety data were summarized by treatment (individual and pooled for all non-MTX csDMARDs) for the ATTAIN, ASSURE, and ARRIVE studies. In the ACTION study, safety data for individual csDMARDs were not assessed; therefore, the safety profiles of abatacept in combination with MTX or other csDMARDs could not be compared.

Available baseline disease characteristics and demographics were reported for each treatment (abatacept or placebo plus MTX or other csDMARD) using descriptive statistics, including sample size, proportions or means, and standard deviations (SDs).

Comparison of efficacy and safety outcomes for abatacept vs placebo could not be performed for combination therapy with any csDMARD other than with MTX due to low numbers of patients who received these therapies. Furthermore, formal comparisons between abatacept plus MTX vs a non-MTX csDMARD could not be conducted due to large imbalances in patient numbers between treatment groups and very small patient numbers for some csDMARDs. Therefore, only outcomes for abatacept plus MTX or other csDMARD were reported, with results analysed descriptively.

Efficacy outcomes were investigated at specific time points (6, 12, and/or 24 months) according to the follow-up available in each study. For the interventional studies, within-trial efficacy data were pooled and reported for abatacept plus any one non-MTX csDMARD for each available outcome from that trial. Efficacy data from the ACTION study were also reported for abatacept plus MTX or abatacept plus any non-MTX csDMARD given as first-line or later-line therapy. In addition, efficacy results for abatacept with MTX or one other csDMARD were pooled across studies when an outcome was included in more than one interventional study (ATTAIN, ASSURE, or ARRIVE). Integrated HAQ-DI data across the three interventional studies (ATTAIN, ASSURE, and ARRIVE) and DAS28 (CRP) data across two studies (ATTAIN and ARRIVE) were pooled for individual csDMARDs. The pooled variance method was used to estimate means and proportions with 95% confidence intervals (CIs) combined from multiple studies, in order to shorten the CI widths and consequently increase statistical precision due to the greater number of patients when combining multiple studies.

Safety outcomes were assessed at 6 months in the ATTAIN and ARRIVE studies and at 12 months in the ASSURE study, representing the short-term/double-blind periods of these studies.

Across all four studies, 2382 patients included in the analysis received abatacept plus MTX and 731 received abatacept plus one non-MTX csDMARD (HCQ n = 152; SSZ n = 123; AZA n = 59; LEF n = 397) (Table 1). Baseline characteristics for patients, by csDMARD subgroup, are presented in Table 2; there were no major differences between groups or studies. The mean dose of each csDMARD used in combination with abatacept was similar across the three interventional trials (Table 3). In the ACTION study, csDMARDs were used according to the label.

Mean change from baseline in HAQ-DI scores was available for all four studies. In patients treated with abatacept plus MTX vs abatacept plus any csDMARD other than MTX (pooled by study), the mean changes from baseline (95% CI) in HAQ-DI scores to month 6 were, respectively: –0.54 (–0.63, –0.45) vs –0.44 (–0.59, –0.29) (ATTAIN), –0.43 (–0.48, –0.38) vs –0.43 (–0.48, –0.37) (ASSURE), and –0.39 (–0.44, –0.33) vs –0.36 (–0.43, –0.29) (ARRIVE) (Fig. 1a). In the ACTION study, similar reductions in HAQ-DI scores were observed for abatacept administered in combination with MTX vs non-MTX csDMARDs, respectively, at 12 and 24 months (Fig. 1b); this finding was consistent, regardless of whether abatacept was given as first-line (12 months -0.54 vs –0.49; 24 months –0.76 vs –0.75) or second-line (12 months –0.41 vs –0.51; 24 months –0.48 vs –0.61) therapy (95% CIs overlapped; Fig. 1b).

In a pooled analysis of data from the three interventional studies (ATTAIN, ASSURE, and ARRIVE), patients treated with abatacept plus MTX had a mean change from baseline in HAQ-DI scores to month 6 of –0.43 (Fig. 1c); for individual non-MTX csDMARDs, this value ranged from –0.35 to –0.49 (Fig. 1c). When each csDMARD and interventional study were analysed separately, reductions in HAQ-DI scores with abatacept plus the non-MTX csDMARDs HCQ, SSZ, AZA, and LEF were similar to those observed with abatacept plus MTX, although 95% CIs were large for all treatments other than MTX (Additional file 1).

Mean changes from baseline in DAS28 (CRP) were available for the ATTAIN, ARRIVE, and ACTION (DAS28 (erythrocyte sedimentation rate, otherwise CRP)) studies only. In the individual trials (pooled non-MTX csDMARD analysis), mean changes from baseline (95% CI) in DAS28 (CRP) for abatacept plus MTX vs abatacept plus any non-MTX DMARD were: –2.05 (–2.28, –1.81) vs –1.78 (–2.16, –1.40) (ATTAIN) and –2.03 (–2.16, –1.90) vs –2.00 (–2.18, –1.82) (ARRIVE) (Fig. 2a). In the ACTION study, similar reductions in DAS28 (CRP) were observed for abatacept administered in combination with MTX or non-MTX csDMARDs, respectively, at both 12 and 24 months, and irrespective of whether abatacept was given as first-line (12 months –2.03 vs –1.16; 24 months –2.74 vs –2.27) or second-line (12 months –1.73 vs –2.11; 24 months –2.02 vs –2.61) therapy (95% CIs overlapped; Fig. 2b).

In the pooled analysis of data from the ATTAIN and ARRIVE studies, the mean change from baseline in DAS28 (CRP) in patients treated with abatacept plus MTX was –2.04. In those treated with abatacept plus a csDMARD other than MTX, the mean change from baseline in DAS28 (CRP) ranged from –1.65 to –2.37 (Fig. 2c). Consistent with the effects of treatment on HAQ-DI, improvements in DAS28 (CRP) with abatacept plus individual csDMARDs were similar to those observed with abatacept plus MTX in the individual ATTAIN and ARRIVE studies (Additional file 2).

ACR20/50/70 response rates were assessed only in the ATTAIN study (Fig. 3). ACR20 response rates for abatacept plus MTX were 58.8% and for any other non-MTX csDMARD (pooled) were 55.8%. While there were numerical differences in ACR50 and ACR70 response rates for abatacept plus MTX vs abatacept plus any non-MTX csDMARD when data were pooled, 95% CIs overlapped between the two groups.

Adverse events (AEs) in patients treated with abatacept administered in combination with MTX or with a non-MTX csDMARD (pooled data) for the ATTAIN, ASSURE, and ARRIVE studies are presented in Table 4. The incidence of any AE or serious AE (SAE), related AEs or SAEs, and discontinuation due to AEs or SAEs among patients who received abatacept plus MTX or those who received abatacept plus any non-MTX csDMARDs (pooled data) were similar within each study (Table 4).

The rates of treatment-related AEs in patients who received abatacept plus MTX were 41.7% (ATTAIN), 55.9% (ASSURE), and 44.3% (ARRIVE), and in patients who received abatacept plus any non-MTX csDMARD were 35.7% (range 25.0–40.0%; ATTAIN), 58.0% (range 50.0–59.7%; ASSURE), and 38.1% (range 28.1–46.7%; ARRIVE; Table 4 and Additional file 3). The rates of treatment-related SAEs with abatacept plus MTX were 2.3% (ATTAIN), 1.7% (ASSURE), and 2.9% (ARRIVE), and with abatacept plus any non-MTX csDMARD were 2.4% (range 0.0–25.0%; ATTAIN), 4.2% (range 0.0–10.0%; ASSURE), and 0.6% (range 0–1.5%; ARRIVE). Rates of discontinuations due to AEs and SAEs are also presented in Table 4.

The number of deaths was very low across the studies. In patients receiving abatacept, there was one death in the ATTAIN study (abatacept plus SSZ), four in the ASSURE study (three with abatacept plus MTX and one with abatacept plus LEF), and one in the ARRIVE study (abatacept plus MTX). Infections and infestations were the most common AEs by system organ class. Rates were 38.3%, 54.6%, and 41.4%, respectively, for abatacept plus MTX in the ATTAIN, ASSURE, and ARRIVE studies, and 40.5% (range 10.0–64.7%) in ATTAIN, 62.9% (range 47.2–71.0%) in ASSURE, and 35.8% (range 25.0–46.7%) in ARRIVE for abatacept plus non-MTX csDMARDs (Table 4). For all safety outcomes, the broad ranges of AE rates for non-MTX csDMARDs reflected very low patient numbers in these groups.