Abatacept retention and clinical outcomes in rheumatoid arthritis: real-world data from the German cohort of the ACTION study and a comparison with other participating countries

Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease causing progressive joint damage and subsequently impaired physical function, and requires long-term management. Treatment of RA includes both conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), the most widely used of which is methotrexate, and biologic (bDMARDs), predominantly tumor necrosis factor inhibitors (TNFis) [1]. Current treatment guidelines for RA recommend a “treat-to-target” principle to achieve remission or low disease activity (LDA) [2]. While adherence and continuation of antirheumatic therapy are necessary to achieve optimal outcomes, real-world studies have reported discontinuation rates for TNFi therapy of 30–50% at 2 years [3]. Factors influencing adherence and continuation of therapy include treatment response and safety or tolerability, and there is considerable interest in identifying patient and disease characteristics that may influence efficacy and safety in individual patients.

While randomized controlled trials for biologic agents have contributed a wealth of efficacy and safety data, some patients with RA do not meet the stringent inclusion criteria (e.g., age, comorbid conditions, and active disease measurement requirements) for such trials, thereby reducing their generalizability. As such, real-world data supplement evidence from interventional studies by providing clinically relevant and valuable insights into bDMARD use in representative and heterogeneous patient populations. In addition, differences between countries are important considerations when analyzing data from international studies. It has been reported that variations in patient characteristics, prescribing or health-care system reimbursement may have contributed to the geographical differences in response to and retention of the selective T cell co-stimulation modulator abatacept in patients with RA reported previously [4]. Notably, it was shown that greater accessibility to bDMARDs was associated with lower abatacept retention [4].

AbataCepT In rOutiNe clinical practice (ACTION) was a 2-year, observational, prospective study of patients with moderate-to-severe RA who initiated intravenous abatacept therapy during routine clinical practice [4‐7]. The study was carried out across Europe (Austria, Belgium, Czech Republic, Denmark, France, Germany, Greece, Italy, Netherlands, Spain, and Switzerland) and Canada from May 2008 to December 2013 and included patients who initiated abatacept as a first-, second-, or further-line biologic. In the overall ACTION study population, higher abatacept retention rates were seen in earlier versus later lines of treatment; however, variations by country have been noted [4, 8]. Notably, biologic-naïve patients in Canada, Greece, and Italy were found to be less likely to discontinue treatment at 2 years than those in Germany [8]. Therefore, to provide a real-world, local perspective and to explore differences between Germany and other countries further, we report the results of a 2-year post hoc analysis of retention rates and clinical outcomes by treatment line in the German cohort of patients enrolled in the ACTION study. We also compare outcomes in biologic-naïve patients from Germany with those in the pooled cohort of biologic-naïve patients from other countries in ACTION.

In the German cohort of the ACTION study, abatacept retention rates at 2 years were similar in the biologic-naïve and biologic-failure cohorts (~ 40%), and were both lower than in the biologic-naïve cohort of patients from other participating countries (59%). In contrast, clinical outcomes were generally better in biologic-naïve than biologic-failure patients within the German cohort. A non-specific trend for lower good/moderate EULAR response and LDA/remission rates was seen in biologic-naïve patients from Germany versus those pooled from other countries. Abatacept was well tolerated, and the safety profile was consistent with previous published data, with no new safety signals.

The finding of lower 2-year retention rates in biologic-naïve patients from Germany versus those from other participating countries is interesting. Considerable regional variation in abatacept retention was seen in the overall ACTION study cohort, with 2-year retention rates in biologic-naïve patients ranging from 42.1% in Germany to 67.8% in Italy. Furthermore, in biologic-naïve patients, residence in Germany versus Canada, Greece, and Italy was found to be a significant predictor of abatacept discontinuation at 1 and 2 years [5, 8]. The 2-year analysis of the biologic-naïve or biologic-failure cohort only of the ACTION study also reported a similar finding in biologic-failure patients [4]. In the present analysis, we confirmed that in biologic-naïve patients, not only was retention lower in the German cohort versus the pooled other countries cohort, but that this was accompanied by a trend for poorer clinical outcomes at 2 years.

Variations in abatacept retention rates by country were also reported in an analysis of nine European registries [16]. Geographical differences in retention and response are likely due to numerous factors, including genetic variation [17] and differences in health-care systems. All residents in Germany are legally required to have health insurance; statutory health insurance which covers the cost of most prescription medications with very low out-of-pocket costs is used by most. Despite widespread acceptance of EULAR guidelines for the treatment of RA [1, 18] at a local level [19], the availability, reimbursement and uptake/treatment patterns of newer agents, particularly bDMARDs, does vary greatly between European countries [20‐22]. Indeed, lower abatacept retention in countries with greater access to bDMARDs has been described [16], which may partly explain the differences in retention between Germany and other participating countries reported here.

Differences in patient characteristics which could affect the results should also be considered. Compared with the pooled other countries cohort of the ACTION study, a slightly lower proportion of the German cohort was biologic naïve (25.3% vs. 30.0%). This anomaly may be explained by the high level of accessibility to bDMARDs in Germany; although a minimum level of disease activity is required for bDMARD reimbursement in 86% of European countries, this is not the case in Germany [22] and so patients may initiate bDMARD treatment earlier in their disease course. Among biologic-naïve patients, the proportion who had received > 3 prior csDMARDs was significantly higher among those recruited in Germany compared with the other countries, and differences in treatment with specific csDMARDs were noted. Longer disease duration and treatment history, in particular, may have influenced physicians’ decisions to change therapy. Patients with RA who have erosions and are seropositive for RF and/or anti-CCP are generally associated with a poorer prognosis. In ACTION, factors such as RF/anti-CCP seropositivity and comorbidities have been shown to impact abatacept retention [8]. For example, RF/anti-CCP double positivity predicted higher retention and remained associated with higher retention in patients with erosive disease [5]. In the Italian cohort, RF/anti-CCP seropositivity versus double seronegativity was associated with higher retention [23]. Here, we found that a greater proportion of patients was seropositive at baseline in the German cohort than in the pooled other countries cohort, despite retention rates being lower in the German cohort. Of note, abatacept monotherapy was prescribed more frequently in the German than the other countries cohort, yet discontinuations due to inefficacy were less frequent in the German cohort. Biologic monotherapy may have been prescribed for several reasons, including intolerance of or non-compliance with methotrexate [24]. These results demonstrate the complex interplay between many different factors influencing drug retention in RA.

In contrast to findings for the overall ACTION population [8], in the German cohort, there was no significant difference between 2-year retention rates in biologic-naïve versus biologic-failure patients. Prior exposure to biologic agents was also shown to negatively influence abatacept retention in clinical practice by Finckh et al. [16]. In this pan-European study, variation in retention was explained primarily by differences in access to bDMARDs, rather than patient or disease characteristics. No specific switching criteria for bDMARDs are in place in Germany [22]; therefore, patients may change treatments more frequently, due to factors such as adverse events or early perceived lack of efficacy, than in other locations.

Clinical outcomes for patients in the German cohort of the ACTION study were similar to those in the overall ACTION study cohort [5, 8], with improved outcomes being associated with earlier treatment line. This finding is consistent with abatacept’s mechanism of action as an upstream regulator that interferes with the underlying disease process of T cell activation [25]. Interestingly, there was a trend for lower remission/LDA and EULAR response rates among biologic-naïve patients in the German cohort than in the other countries cohort, although this did not reach statistical significance for any outcome measure. Differences in abatacept retention rates previously observed across European countries were associated with national economic features (e.g., GDP per capita); however, the effects of socioeconomic features (e.g., education level) were less clear [16]. The lower overall retention rate observed in the German cohort compared with that in other countries could be due to preferential or earlier switching of therapy by biologic-naïve patients not reaching LDA/remission based on either patient choice and/or physician expectation, possibly due to the greater access to alternative treatment options in Germany.

These real-world data from local, heterogeneous patient populations that represent patients in routine care are clinically relevant and supplement existing knowledge on the use of abatacept in routine practice. However, the data presented here should be interpreted within the context of the study limitations. Analyses based on real-world studies, although of value, are affected by inherent limitations such as non-randomization, observational trial design, clinician- rather than protocol-led treatment decisions, the potential for referral and channeling bias, the lack of an active comparator, and loss of patients to follow-up. Also, these were subgroup analyses of a larger study and analyses were post hoc in nature. Nonetheless, the random selection of participating study sites ensured that these were representative of each country.

Abatacept retention at 2 years in the German cohort from the ACTION study was similar in biologic-naïve versus biologic-failure patients. However, clinical outcomes were generally better in biologic-naïve than biologic-failure patients. In addition, abatacept retention was lower in biologic-naïve patients in the German cohort than in those from other participating countries. This analysis of a national cohort provides important information on local treatment patterns and raises awareness of the potential impact of these on outcomes. Importantly, these findings indicate that data from large international studies may not be directly applicable to individual countries and that this should be taken into consideration when extrapolating data from such studies to the local level. Similarly, data derived from one country are not necessarily generalizable to other countries.