Background
Psoriatic arthritis (PsA) is a chronic inflammatory autoimmune disease with a range of clinical manifestations affecting skin and musculoskeletal systems [
1]. Health-related quality of life (HRQoL) can vary greatly according to a patient’s specific symptoms; hence, assessing treatment effects using patient-reported outcomes (PROs) is particularly important in PsA [
2‐
6]. Several PRO instruments have been validated in PsA, including the Health Assessment Questionnaire-Disability Index (HAQ-DI) [
4,
7] and Short Form-36 (SF-36) [
5,
6].
Abatacept, a selective T-cell co-stimulation modulator [
8], has a distinct mechanism of action upstream of currently available agents, and is approved for treatment of rheumatoid arthritis and juvenile idiopathic arthritis, and recently for active PsA in adults [
9]. In the phase 3 Active pSoriaTic aRthritis rAndomizEd triAl (ASTRAEA, NCT01860976), subcutaneous (SC) abatacept 125 mg weekly significantly increased the proportion of patients achieving ≥ 20% improvement in the American College of Rheumatology criteria (ACR20) compared with placebo at week 24 (primary endpoint: 39.4% vs 22.3%;
P < 0.001) and was well tolerated in patients with active PsA [
10]. A numerically higher proportion of patients with HAQ-DI responses (reductions from baseline ≥ 0.35) was evident with abatacept versus placebo (
P > 0.05). Abatacept treatment also reduced progression of structural damage with an overall beneficial effect on musculoskeletal symptoms. However, due to the hierarchical testing procedure employed, it was not possible to attribute significance to endpoints ranked below HAQ-DI responses in the hierarchical testing [
10].
The effect of factors associated with poor prognosis and treatment resistance, such as elevated C-reactive protein (CRP) levels and prior exposure to tumour necrosis factor inhibitors (TNFi) [
11], was also evaluated in ASTRAEA. Higher ACR20 responses were observed with abatacept versus placebo in both TNFi-naïve and TNFi-exposed subpopulations at week 24, with the largest treatment differences seen in TNFi-naïve patients [
10]. Moreover, patients with baseline CRP ≥ upper limits of normal (ULN) had the highest ACR20 responses at week 24 with abatacept versus placebo [
10].
The goal of the analyses reported here was to examine the impact of abatacept versus placebo treatment on PROs in ASTRAEA for the overall population and in subgroups by baseline CRP levels and previous TNFi exposure.
Discussion
These analyses demonstrated that abatacept treatment generally improved PROs in patients with active PsA in the phase 3 ASTRAEA trial, particularly in those who were TNFi-naïve and/or with elevated CRP at baseline
. In the overall population at week 16, prior to EE, abatacept administration was associated with improved PROs compared with placebo; significant improvements with abatacept versus placebo were reported in SF-36 PCS, PF, BP and VT domain scores as well as DLQI, reflecting those areas of HRQoL most impacted by PsA. At week 24 in the non-EE responder analysis, a potential benefit of abatacept treatment was evident compared with placebo, with significantly greater improvements reported in physical function (by HAQ-DI) and dermatological manifestations (by DLQI). The proportion of patients with clinically meaningful HAQ-DI responses (reductions from baseline score ≥ 0.35) at week 24 was numerically higher with abatacept versus placebo: 31.0% versus 23.7%; however, as this did not reach statistical significance, it was not possible to definitively attribute significance to lower-ranking secondary endpoints in the hierarchical testing (nominal
P values only were generated; 95% CIs were not overlapping) [
10]. Notably, significant improvements in DLQI, the only PRO investigated here that directly measures the skin domain in PsA, were reported by those patients with a background of an overall modest skin response (by Psoriatic Area and Severity Index) in ASTRAEA at week 24 [
10]. Nevertheless, as the week 24 analysis included only non-EE responders, the placebo arm comprised patients who reported responses to placebo. Therefore, it may be expected that differences between treatment groups would be less obvious at week 24 than week 16. In addition, the number of patients analysed at this time point was lower than at week 16.
Comparisons of the proportion of patients reporting improvements ≥ MCID is considered a clinically meaningful estimate of therapy effects [
22]. Overall, the proportion of abatacept-treated patients reporting improvements ≥ MCID in PROs exceeded the proportion of placebo-treated patients: at week 16, 41.8–58.2% of abatacept-treated patients across different PROs reported clinically meaningful improvements in HAQ-DI, SF-36 PCS and MCS, individual SF-36 domains and FACIT-F scores compared with 33.6–47.9% of those treated with placebo.
In addition to the overall population analysis, PROs were analysed in subpopulations of patients by baseline CRP, as elevated CRP is an identified poor prognostic factor [
11]. There was a non-statistically significant trend towards improved PROs in patients with elevated baseline CRP regardless of treatment arm at week 16. However, among patients with elevated CRP, those receiving abatacept reported greater improvements compared with placebo. Similarly, in the main ASTRAEA study, the highest ACR20 responses with abatacept versus placebo were seen in patients with CRP > ULN at baseline [
10], suggesting that these patients may be particularly responsive to abatacept. Our results suggest that baseline CRP should be taken into consideration when evaluating the clinical efficacy of different treatments. PROs were also analysed in subpopulations by previous exposure to TNFi treatment. At week 16, improvements were greater with abatacept than with placebo in both TNFi-naïve and TNFi-exposed subpopulations. However, in abatacept-treated patients, reported improvements in PROs were generally larger in the TNFi-naïve versus TNFi-exposed subpopulations. Indeed, greater efficacy would be expected in TNFi-naïve than in TNFi-exposed patients [
23]. These findings are in line with clinical outcomes observed with abatacept in this trial, which were generally better in patients with elevated CRP at baseline and TNFi-naïve patients [
10]. The PRO data reported here support previous results that abatacept may be particularly effective in certain subpopulations of patients.
The effects of other DMARDs, including TNFi agents, on PROs in patients with active PsA have been investigated previously, with most studies assessing effects over 24 or 48 weeks. Statistically and clinically meaningful improvements in SF-36 PCS and MCS and all individual domain scores from baseline to week 24 have been reported with etanercept [
24]; clinically meaningful improvements in PROs including HAQ-DI and SF-36 PCS scores have also been reported over 48 weeks of treatment [
25]. Similarly, adalimumab has been shown to improve HRQoL, based on SF-36 PCS, HAQ-DI, FACIT-F and DLQI scores, after 48 weeks of treatment [
26]. The effects of the newer interleukin inhibitors on PROs have also been studied. Ustekinumab, an anti-interleukin-12 and -23 agent, improved physical function (by SF-36 PCS and HAQ-DI) and dermatological manifestations (by DLQI) at week 24 [
27,
28]. Beneficial effects on PROs have also been reported after 24 weeks with the anti-interleukin-17A agent secukinumab [
29,
30]. Furthermore, apremilast, a phosphodiesterase 4 inhibitor, was shown to significantly improve HAQ-DI scores by week 16 compared with placebo in a 24-week trial in which < 10% of patients had previously failed a biologic therapy [
31]. In the current study, improvements in PROs achieved with abatacept appeared less marked than that reported with other biologic DMARDs (bDMARDs) in earlier studies; however, differences in trial design and patient populations preclude comparisons of efficacy between abatacept and other bDMARDs based on currently available evidence.
The therapeutic options for PsA have greatly increased over the past 10 years and, as more new treatments are introduced, assessing responses to therapy including PROs will become increasingly important, aiding treatment choices. A recent literature review provided an evidence-based overview of 44 instruments per core PsA outcome domain to ascertain applicability and best instrument for each domain of the many available PROs [
32]. However, further research is warranted to develop and validate specific PRO measures that better capture the impact of all PsA symptoms [
33]. In the meantime, using a combination of instruments and/or the best available instrument per domain, as in this trial, provides a more complete picture [
33].
A number of study limitations should be considered. First, subpopulation comparisons and ascertainment of scores ≥ MCID and ≥ normative values were post hoc in nature. Second, owing to the particular trial design, a high proportion of patients were subject to EE at week 16; as such, week 24 analyses included a limited number of patients who were still receiving blinded treatment in either arm of the trial. Only nominal P values were provided for endpoints that ranked lower in the statistical hierarchy than the first secondary endpoint, which did not reach statistical significance at the 5% level. For other endpoints, only 95% CIs of differences between abatacept and placebo arms were generated, without associated P values. In addition, due to the low patient numbers, the reported data for subpopulations were difficult to interpret, particularly at week 24. Finally, certain PROs may improve less rapidly over time and thus the week 16 time point may have not allowed maximal effects of abatacept treatment to be observed. In addition, although some statistically significant improvements were noted with abatacept, these may not necessarily be clinically important.
Acknowledgements
Under the direction of the authors, Katerina Kumpan, PhD, of Caudex, Oxford, UK (funded by Bristol-Myers Squibb), provided medical writing assistance for the development of this manuscript. Sandra Overfield, Protocol Manager, Bristol-Myers Squibb, assisted in initial design and operational aspects of the study.
Competing interests
VS reports receiving consulting fees from AbbVie, Amgen Corporation, AstraZeneca, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Corrona, Crescendo/Myriad Genetics, EMD Serono, Genentech/Roche, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sandoz, Sanofi and UCB. EA, TL, AJ, SB and HAA are employees of Bristol-Myers Squibb and report holding stock in Bristol-Myers Squibb. PJM reports receiving consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Janssen, Lilly, Merck, Novartis, Pfizer, Sun, UCB and Zynerba; and speaker fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Novartis, Pfizer and UCB.