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

Abstract

Background: Methotrexate (MTX) remains the anchor drug in rheumatoid arthritis (RA) treatment, but is poorly tolerated or contraindicated in some patients. There is a wealth of data supporting the use of abatacept in combination with MTX, but data on alternative conventional synthetic disease-modifying antirheumatic drug (csDMARD) combinations with abatacept are scarce.

Methods: In this post-hoc exploratory analysis, efficacy and safety data were extracted from abatacept RA studies in which combination with csDMARDs other than MTX was permitted: three interventional trials (ATTAIN, ASSURE, and ARRIVE) and one real-world study (ACTION). Patients with moderate-to-severe RA received abatacept in combination with MTX, hydroxychloroquine, sulfasalazine, azathioprine, or leflunomide for 6 months to 2 years according to the study design. Change from baseline in physical function (Health Assessment Questionnaire-Disability Index (HAQ-DI); all studies) and 28-joint Disease Activity Score (C-reactive protein) (DAS28 (CRP); ATTAIN, ARRIVE, and ACTION), American College of Rheumatology response rates (ATTAIN), and safety were assessed for individual and pooled csDMARD combinations for each trial. A meta-analysis was also performed on pooled data for HAQ-DI and DAS28 (CRP) across interventional trials.

Results: Across all four studies, 731 patients received abatacept plus one non-MTX csDMARD (hydroxychloroquine n = 152; sulfasalazine n = 123; azathioprine n = 59; and leflunomide n = 397) and 2382 patients received abatacept plus MTX. Mean changes from baseline in HAQ-DI scores for abatacept plus MTX (all csDMARDs pooled) vs abatacept plus a non-MTX csDMARD were -0.54 vs -0.44 (ATTAIN), -0.43 vs -0.43 (ASSURE), and -0.39 vs -0.36 (ARRIVE). Mean changes from baseline in DAS28 (CRP) and ACR response rates were also similar with abatacept plus MTX or non-MTX csDMARDs. Data for individual non-MTX csDMARDs (pooled across studies) and real-world data were consistent with these findings. Rates of treatment-related adverse events and serious adverse events, respectively, for abatacept plus one non-MTX csDMARD vs abatacept plus MTX were 35.7% vs 41.7% and 2.4% vs 2.3% (ATTAIN), 58.0% vs 55.9% and 4.2% vs 1.7% (ASSURE), and 38.1% vs 44.3% and 0.6% vs 2.9% (ARRIVE).

Conclusions: Abatacept in combination with non-MTX csDMARDs is clinically effective and well tolerated in patients with moderate-to-severe RA, providing similar benefits to those seen with abatacept plus MTX.

Trial registration: ClinicalTrials.gov NCT00048581 . Registered 2 November 2002. ClinicalTrials.gov NCT00048932 . Registered 11 November 2002. ClinicalTrials.gov NCT00124982 . Registered 30 June 2005. ClinicalTrials.gov NCT02109666 . Registered 8 April 2014.

Keywords: Abatacept; Azathioprine; Conventional synthetic disease-modifying antirheumatic drug; Hydroxychloroquine; Leflunomide; Methotrexate; Rheumatoid arthritis; Sulfasalazine.

Conflict of interest statement

Ethics approval and consent to participate

All of the studies were approved by institutional review boards and independent ethics committees at participating sites and were conducted in accordance with the Declaration of Helsinki (registration numbers: ATTAIN, ClinicalTrials.gov NCT00048581; ATTEST, ClinicalTrials.gov NCT00048932; ARRIVE, ClinicalTrials.gov NCT00124982; ACTION, ClinicalTrials.gov NCT02109666).

Because this was a post-hoc analysis, no specific consent was obtained above that received for each individual trial. All patients provided written informed consent prior to randomization.

Consent for publication

Not applicable.

Competing interests

RA has received research grants and speaker’s honoraria from Bristol-Myers Squibb (BMS). AR-R has received honoraria for consultation and lectures from BMS. KK has received consulting fees and speakers honoraria from BMS. REV has received honoraria and/or grant support from AbbVie, BMS, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda. JR has received speaker fees and honoraria from AbbVie, BMS, MSD, Novartis, Pfizer, Roche, and Sanofi. HB has received honoraria and grant support from BMS, Novartis, Pfizer, Roche, MSD, AbbVie, Sanofi, Chugai, and UCB. EF has received honoraria and grant support from BMS, Novartis, Pfizer, Roche, MSD, AbbVie, and Sanofi. YE has received consultancy fees from BMS. CR is an employee and shareholder of BMS.

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Figures

Fig. 1

Mean change from baseline in HAQ-DI scores in response to abatacept administered in combination with one csDMARD (a) All non-MTX csDMARDs pooled in individual interventional studies. (b) Data from the observational ACTION study. (c) Pooled analysis from the ATTAIN, ASSURE, and ARRIVE studies for individual csDMARDs. Error bars show 95% CI. ABA abatacept, AZA azathioprine, csDMARD conventional synthetic disease-modifying antirheumatic drug, HAQ-DI Health Assessment Questionnaire—Disability Index, HCQ hydroxychloroquine, LEF leflunomide, MTX methotrexate, SSZ sulfasalazine

Fig. 2

Mean change from baseline in DAS28 (CRP) in response to abatacept administered in combination with one csDMARD. (a) Pooled for all non-MTX csDMARDs in individual interventional studies. (b) Data from the observational ACTION study (DAS28 (ESR, otherwise CRP)). (c) Pooled analysis from the ATTAIN and ARRIVE studies. Error bars show 95% CI. ABA abatacept, AZA azathioprine, CRP C-reactive protein, csDMARD conventional synthetic disease-modifying antirheumatic drug, DAS28 28-joint Disease Activity Score, ESR erythrocyte sedimentation rate, HCQ hydroxychloroquine, LEF leflunomide, MTX methotrexate, SSZ sulfasalazine

Fig. 3

ACR response rates for abatacept administered in combination with (a) MTX vs any one non-MTX csDMARD (pooled analysis) and (b) individual csDMARDs at 6 months in the ATTAIN study. Excludes patients on multiple background csDMARDs. Error bars show 95% CI. ABA abatacept, ACR20/50/70, ≥ 20%/≥ 50%/≥ 70% improvement in American College of Rheumatology criteria, AZA azathioprine, csDMARD conventional synthetic disease-modifying antirheumatic drug, HCQ hydroxychloroquine, LEF leflunomide, MTX methotrexate, SSZ sulfasalazine