Introduction
According to the treat-to-target principle, patients with rheumatoid arthritis (RA) should be monitored closely, with the goal of achieving clinical remission or low disease activity (LDA) within 6 months [
1,
2], and then regularly assessed for sustained remission [
3]. Various criteria have been used to formally define remission in clinical trials, of which the Disease Activity Score (DAS)28 (score of <2.6) has traditionally been used most frequently. However, patients in DAS28 remission may experience residual disease activity, as evidenced by swollen joint count (SJC) in particular [
4‐
7], which can lead to irreversible structural damage [
8,
9]. American College of Rheumatology (ACR)-European League Against Rheumatism (EULAR) recommendations [
2] advocate using more stringent remission criteria, namely the Simplified Disease Activity Index (SDAI) and a Boolean definition. Alternative definitions proposed for use in clinical practice, where measurement of acute-phase reactants is often unavailable, are the Clinical Disease Activity Index (CDAI) and a corresponding Boolean definition.
Abatacept is a biologic disease-modifying antirheumatic drug (DMARD) that selectively modulates T cell co-stimulation [
10] and has shown efficacy in several clinical trials, including the Abatacept study to Gauge Remission and joint damage progression in methotrexate (MTX)-naive patients with Early Erosive rheumatoid arthritis (AGREE) [
10‐
12].
The main objective of the present analysis was to explore remission in patients with early RA treated with abatacept plus MTX in light of the current, stringent ACR-EULAR definitions of remission [
2]. These new remission criteria are frequently believed to be difficult to achieve [
13,
14]. Therefore, we evaluated patients with early RA who had been treated with either MTX alone or abatacept plus MTX in the AGREE trial. We also investigated sustainability of initial remission and evaluated the relationship of disease activity with function and structure in these patients. As will be demonstrated, a considerable number of patients can indeed achieve (and sustain) remission, even when using the new and stringent remission criteria.
Methods
Patient population and study design
This post hoc analysis is based on data from the previously published AGREE Phase III study (ClinicalTrials.gov identifier NCT00122382), in which patients were randomized (1:1) to receive abatacept plus MTX or MTX alone over a 12-month, double-blind period [
15]. Patients were MTX naïve (or prior exposure was ≤10 mg/week for ≤3 months); had early RA (≤2 years); were positive for rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies; had evidence of erosive changes on hands, wrists or feet; and had tender joint count (TJC) ≥12, SJC ≥10 and C-reactive protein (CRP) ≥4.5 mg/dL.
Outcome measures
Individual core set variables [
16] were assessed monthly. Although DAS28 (CRP) <2.6 (DAS28 remission) [
17] at month 12 was a co-primary endpoint of the original study, in this post hoc analysis we calculated ACR-EULAR index-based remission rates, with remission defined as SDAI ≤3.3 and CDAI ≤2.8 (see Additional file
1: Table S1) [
2,
4,
18,
19]. Remission according to the ACR-EULAR Boolean definitions (clinical practice with 28-joint counts: TJC28 ≤1, SJC28 ≤1 and patient global assessment (PGA) ≤1; clinical trials with 28-joint counts and laboratory measures: TJC28 ≤1, SJC28 ≤1, CRP ≤1 mg/dL and PGA ≤1; clinical practice with 66/68-joint counts: TJC68 ≤1, SJC66 ≤1 and PGA ≤1; or clinical trials with 66/68-joint counts and laboratory measures: TJC68 ≤1, SJC66 ≤1, PGA ≤1 and CRP ≤1 mg/dL) was also evaluated post hoc [
2]. Level of disease activity was measured using DAS28 (CRP), SDAI and CDAI (low disease activity (LDA), SDAI >3.3–11, CDAI >2.8–10 or DAS28 ≤3.2; moderate disease activity (MDA), SDAI >11–26, CDAI >10–22, or DAS28 >3.2– ≤ 5.1; high disease activity (HDA), SDAI >26, CDAI >22, or DAS28 >5.1).
Functional disability was evaluated monthly using the Health Assessment Questionnaire-Disability Index (HAQ-DI). Structural damage progression was evaluated by radiographs at baseline and month 12, with changes over time evaluated according to the total Genant-modified Sharp score (TGSS) [
20] and non-progression defined as a mean change in TGSS of ≤0.
Statistical analyses
In the original study, DAS28 (CRP)-defined remission was evaluated for the intention-to-treat population, with patients who discontinued considered non-responders. For the purpose of this report, analyses were based on patients with DAS28 and SDAI data available at baseline, month 6 and month 12. Analyses were performed post hoc for patients who had received abatacept plus MTX or MTX alone in the double-blind period. The proportions of patients achieving remission and LDA according to DAS28 (CRP), SDAI and CDAI, and remission according to Boolean outcomes, were analyzed as point estimates with 95 % confidence intervals (CI). Analyses were performed to determine shifts in SDAI status (remission, LDA, MDA and HDA) from month 6 to 12, presented as the proportions of patients in each SDAI state at month 6 who achieved each SDAI state at month 12. Cumulative probability of time to achieve first remission/LDA and sustained first remission/LDA (defined as maintained at all subsequent visits up to month 12) according to DAS28, SDAI and CDAI were evaluated based on Kaplan–Meier estimation with 95 % CI. Patients who lost first remission/LDA status were censored at the time of loss.
The relationship between DAS28, SDAI and CDAI remission was investigated by determining the proportions (95 % CI) of patients in DAS28 remission who had also achieved SDAI or CDAI remission, and by evaluation of the median values of core set variables (TJC, SJC, PGA, evaluator’s global assessment (EGA), CRP, erythrocyte sedimentation rate (ESR)) for patients achieving remission. We also evaluated mean scores for core set variables for patients achieving remission at month 12 but not at month 6. Finally, we evaluated the relationship between disease activity at month 3 and functional and structural outcomes at month 12, including mean scores (SD) and mean changes (95 % CI) by disease activity status (remission, LDA or MDA and HDA pooled) at months 3 and 12. Mean changes, treatment differences and corresponding 95 % CI were adjusted based on an analysis of covariance model with treatment, baseline score and disease status as covariates.
Discussion
In the AGREE study, MTX-naïve patients with early RA who had been treated with abatacept plus MTX experienced clinical, functional and structural benefits, and improvements in disease activity, versus patients treated with MTX alone [
15]. In these post hoc analyses, high proportions of patients receiving abatacept plus MTX achieved remission at months 6 and 12 according to the stringent ACR-EULAR index-based SDAI (19 and 33 %, respectively) and CDAI (19 and 34 %, respectively) criteria. Higher proportions of patients achieved remission according to DAS28 (31 and 48 % at months 6 and 12) compared with SDAI, CDAI and Boolean criteria. This was not surprising as it is well established that DAS28 remission criteria frequently are afflicted with significant residual disease activity, both clinically and by sonography [
4‐
9]. Interestingly, the difference between DAS28 remission rates and SDAI/CDAI remission rates was generally smaller here [
21‐
24], presumably because abatacept, unlike some other biologic agents [
21], may not directly influence the acute-phase response, which is heavily weighted in the DAS28 formula. However, the DAS28 remission rates observed at 6 months were similar to those previously observed with other biologic agents. Rates for patients achieving Boolean-defined remission (with laboratory measures) were also relatively high for patients treated with abatacept plus MTX (15 and 24 % at months 6 and 12). These findings demonstrate that remission according to the stringent ACR-EULAR remission criteria (SDAI, CDAI and Boolean) is indeed frequently achievable in clinical trials in many MTX-naïve patients treated with MTX, and in even greater proportions of patients receiving biologic therapy (in this case abatacept) in combination with MTX. These results were not dissimilar to those observed in clinical practice, where SDAI and CDAI remission outcomes have been seen in approximately 20–25 % of patients [
25].
Analyses of disease activity based on different indices have been performed for other populations of patients treated with abatacept, including those with established RA refractory to MTX [
26,
27], and similar to other biologic agents, remission rates are lower for patients with refractory disease treated with abatacept plus MTX/DMARDs than for those in the MTX-naïve population, especially for achieving the stringent SDAI-derived criteria [
28,
29].
Cumulative probability plots have shown that patients receiving abatacept plus MTX reached stringent first remission targets at earlier time points than patients receiving MTX alone; this may have an impact on functional and structural outcomes, and so is important to evaluate [
2].
As anticipated, not all patients in DAS28 remission also achieved SDAI or CDAI remission, although a large proportion of patients were in SDAI or CDAI LDA, highlighting that it is more difficult to achieve remission according to these stringent criteria or that - in line with the data shown here - DAS28 "remission" comprises many patients with significant residual disease activity which are rightly captured as not being in remission by ACR-EULAR remission criteria and as being in an active disease state by SDAI and CDAI.
For abatacept plus MTX, the proportions of patients achieving stringent remission increased from month 6 to month 12 regardless of the index used, highlighting an increasing magnitude of response over time, even in this RA population with high risk of progression. Such observations, which have not been reported previously with other biologic agents, suggest that the efficacy of abatacept plus MTX may not peak at 6 months, but appears to continue to increase after month 6, allowing more patients to reach the therapeutic goals of SDAI and CDAI remission with continued therapy. These findings are supported by the recently updated EULAR recommendations for the management of RA with DMARDs, which state that individual patients may take longer than 6 months to achieve remission, and that in such cases change in disease activity from baseline should also be taken into consideration [
30]. Moreover, these findings highlight the value of the LDA target in the treat-to-target recommendations [
31‐
35] and also support the ACR-EULAR recommendations to report not only achievement but also maintenance of outcomes and sustainability of remission [
2].
Finally, we evaluated the association between remission of clinical disease activity at early time points (month 3) with functional and structural outcomes over the 12-month period. Patients who achieved clinical remission demonstrated numerically greater improvements in physical function, especially versus patients in MDA/HDA, regardless of the index used, supporting an association between early suppression of inflammation and long-term functional benefit. The best functional outcomes were achieved with SDAI and CDAI remission. Mean changes in radiographic score were numerically lower for patients in remission or LDA versus MDA/HDA; this difference was less pronounced for patients receiving abatacept plus MTX. Importantly, adjusted mean differences and exploratory
P values (i.e., not based on prespecified analyses) show a difference between patients in MDA/HDA treated with abatacept plus MTX versus MTX alone, suggesting a dissociation of the profound relationship between inflammation and destruction, as seen previously for tumor necrosis factor inhibitors, tocilizumab and rituximab [
31‐
35]. Altogether, these findings further highlight the value of targeting stringent remission outcomes, as recommended by ACR-EULAR [
2].
The limitations of this post hoc descriptive analysis should be taken into consideration when interpreting these data. The population analyzed here represents a subset of the original AGREE study, including only patients with complete datasets. The analyses were neither prespecified nor powered to detect between- or within-group differences. However, only 90/509 randomized patients were excluded from the analysis, which provides a relatively large sample size, and even if those patients excluded had been included and none had achieved remission, the overall proportion of patients achieving remission would likely have still been substantial, especially for patients treated with abatacept plus MTX. Nevertheless, the findings presented here would benefit from validation in a larger population.
Conclusions
In summary, in contrast to commonly held beliefs [
13,
14], relatively high proportions of patients can achieve at least low disease activity or remission by the ACR-EULAR criteria, despite, and at the same time because of, their stringency; this was seen for MTX and was more pronounced for treatment with abatacept plus MTX. In the AGREE study, many patients attained low disease activity, an alternative therapeutic target to remission. Furthermore, the regular assessment of remission in this study may have resulted in patients with transient fluctuations in disease activity failing to achieve the study definition of sustained remission (i.e., maintenance of first remission at all subsequent monthly visits up to month 12), and may have led to an underestimation of sustained remission. Some data suggest that higher rates of remission can be observed in observational datasets and clinical trials when a treat-to-target strategy is adopted [
25,
36]. More recent trials of abatacept in MTX-naïve patients with early progressive RA have reported higher rates of remission than reported here, even when using stringent remission criteria [
37]. This trend is thought to reflect the increasing use of biologic DMARDs earlier in the course of RA disease, patients entering clinical trials having shorter disease duration and lower disease activity at baseline. Nevertheless, these present analyses support the use of viable treatment targets in the therapy of patients with RA.
Acknowledgements
The AGREE study and subsequent statistical analyses were funded and performed by Bristol-Myers Squibb, which was involved in the design of the studies; in the collection, analysis and interpretation of data; in the writing of this manuscript; and in the decision to submit the manuscript for publication.
Professional medical writing and editorial assistance was provided by Eve Guichard, BSc (Hons), of Caudex Medical and was funded by Bristol-Myers Squibb.
Competing interests
JSS has received grant support, research fees, consulting fees or other remuneration from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Janssen, GlaxoSmithKline, Lilly, Pfizer, MSD, Novo-Nordisk, Roche, Sandoz and UCB. JW has received consulting fees/speaking fees/honoraria from AbbVie, Bristol-Myers Squibb, Chugai, Merck Sharp & Dohme, Pfizer and UCB. JJG-R reports consulting fees/speaking fees/honoraria from Bristol-Myers Squibb. WG has received consulting fees/speaking fees/honoraria from General Electric Medical Systems, Bristol-Myers Squibb, Merck Sharp & Dohme, UCB, AbbVie, Pfizer and Menarini. CG was an employee of Bristol-Myers Squibb during the time of this study. CP is contracted by Bristol-Myers Squibb. MLB is an employee of Bristol-Myers Squibb and has stock ownership in Bristol-Myers Squibb. RW has participated in a speaker’s bureau for Bristol-Myers Squibb, advisory boards for Galapagos and Janssen, and received research funding from Roche and UCB. No non-financial conflicts of interest exist for any of the authors.
Authors’ contributions
JSS participated in the design of the study, supervised data analysis and participated in the interpretation of data and writing of the manuscript. JW participated in the collection and interpretation of the data and review of the manuscript. JJG-R participated in the collection, analysis and interpretation of data, and review of the manuscript. WG participated in data collection and review of the manuscript. CG, CP and MLB participated in the design of post hoc analyses, interpretation of the data and writing of the manuscript. RW participated in the design of the study; the collection, analysis and interpretation of data; and writing of the manuscript. All authors read and approved the final manuscript.