This study compared a treatment strategy that is intensive in treatment target and in the medications used with an up-to-date regular treatment strategy, with DMARD-free sustained remission as long-term outcome. An intensive treatment strategy was not associated with a higher prevalence of DMARD-free sustained remission, nor after correction for baseline differences, nor after correction for a propensity score. Stratification for ACPA revealed that ACPA-positive RA patients in the intensive treatment group achieved DMARD-free remission more often but also had a higher rate of late flares. Therefore, our current results do not provide evidence for long-term benefits of an intensive DAS-steered treatment regimen with regard to achieving DMARD-free sustained remission.
While a randomized trial would have been the best method to compare the two treatment strategies because of the element of randomization, the present study does have some important advantages. The first is the long-term follow-up duration. Trials often have a limited follow-up duration which hampers the evaluation of long-term outcomes. In the IMPROVED trial, the follow-up was restricted to 5 years. The median follow-up in this study was almost 8 years as patients were followed-up in the EAC cohort after conclusion of the trial, and some patients had a follow-up of > 10 years.
A second strength of our study is that the whole source population of RA patients newly classified with RA in a time-period in one center was studied. Trials include sets of patients with certain characteristics, hampering extrapolation to the general population of RA-patients. Furthermore, the IMPROVED trial did not include a regular treatment arm [18]. Comparing RA patients treated in this trial with RA patients treated by the same team of rheumatologists according to routine care allowed to evaluate whether an intensive trial regimen is favorable for the long-term outcome studied. As mentioned previously, an important issue is why almost half of the recent-onset RA patients that met the inclusion criteria of the IMPROVED study did not participate. Reasons for not participating were not routinely documented and may be related to willingness of the patient or preference of the rheumatologist. Relatively few differences in patient characteristics were observed between the two groups. The most important difference was the prevalence of ACPA; possibly rheumatologists or patients themselves were less motivated in case of ACPA negativity. Since ACPA has been associated with a lower hazard on achieving DMARD-free remission [10, 13], analyses were repeated after stratification by ACPA status to prevent bias. In the whole group, multivariable models corrected for baseline differences as well as for a propensity score were performed in order to reduce bias caused by confounding by indication. Altogether, the issue of non-comparability might not be completely prevented in this way. However, although there may still be unmeasured confounding, there are also many important similarities between the two groups. These include similarities in patient characteristics, inclusion period, center, and team of treating rheumatologists. This suggests that the differences observed could be largely attributed to the most important difference between the groups, namely the treatment strategy that was applied.
The outcome DMARD-free sustained remission is infrequently studied. A previous study from our center evaluated the difference in DMARD-free remission during 5 years of follow-up in patients with DAS-driven versus non-DAS-driven therapy [22]. Here, the DAS-driven group was derived from the BeSt-trial [21]. Because of stringent inclusion criteria, a rather severe set of RA patients was included in the trial. As shown by the many differences in baseline characteristics between both treatment groups [22], non-comparability was a larger issue in this previous study than in the present investigation.
Despite some methodological limitations, data from this previous study suggested that ACPA-positive patients had a greater advantage of DAS-driven therapy [22]. Also, in our data, ACPA-positive patients achieved DMARD-free remission more often in the intensive therapy group. However, after considering the late flares, there was no significant difference in the DMARD-free remission that was sustained over time. It is possible that the remaining difference would have reached statistical significance if the sample size would have been larger. In contrast, late flares occurred more often in ACPA-positive patients after having achieved DMARD-free remission. Consequently, it is also possible that after a longer follow-up, the rate of late flares would increase especially in the ACPA-positive group, diminishing the difference between the intensive treatment group and routine care in ACPA-positive RA. Hence, the present data do not allow to conclude that ACPA-positive RA patients benefit from an intensive treatment strategy with regard to achieving and sustaining DMARD-free remission.
Although the long follow-up duration is advantageous and allowed to study the occurrence of late flares, some late flares occurred several years after DMARD cessation. Possibly, the currently observed percentage of patients achieving late flares is underestimated. In addition, some late flares may have been missed as patients in sustained remission can be referred to the GP with instructions to return if symptoms reoccur. Despite these instructions and the fact that early access for RA patients is promoted in several ways, including the presence of screening clinics [23], we cannot exclude that some patients were not referred back to our outpatient clinic in case of recurring symptoms. However, we do not expect that these issues, if present, depend on treatment strategy or ACPA status. Similarly, the amount of patients achieving DMARD-free sustained remission could be either an underestimation (as more patients may achieve this after longer follow-up) or an overestimation (as patients already having achieved this outcome could experience a recurrence of clinical synovitis). However, as follow-up duration was similar in both treatment arms, we do not expect this would change the results.
Differences in treatment strategy between the two groups were not only the difference in treatment target (DAS < 1.6 instead of 2.4), but also the initial high dose of prednisone (60 mg/day), and the possibility to switch to biologicals after 4 months. In regular care, prednisone was occasionally started next to MTX, but not in a high dose and biologics were only allowed after failure of > 2 cDMARDS, which (if necessary) generally took place at a longer disease duration. In contrast to the patients treated in the trial, treatment changes in the regular care group were also made at non-protocolized visits and a larger variety of DMARDs were possible. This hampered a detailed registration of all DMARDs used in the regular care group. Additionally, it is possible that in routine care, rheumatologists were more reluctant to taper and stop DMARDs. However, despite all the differences in treatment strategy between the groups, no important differences in DMARD-free sustained remission were observed.
The IMPROVED study had a duration of 5 years; thereafter, patients were treated according to the best insights of the treating rheumatologist. Thus, after 5 years of treatment, the strategies became similar between both groups. This may have resulted in a reduction of initial contrasts between the groups [24].
The percentage of patients achieving DMARD-free sustained remission was relatively high, but similar to previous studies on this outcome [13]. Local treatment guidelines comprise tapering and stopping of DMARDs also in regular care [13]. This may differ from routine care elsewhere, especially since EULAR guidelines are cautious with regard to tapering and subsequent stopping of DMARDs [2, 16]. Now, several studies have revealed that DMARD-free remission is an achievable outcome; more research on tapering and stopping DMARDs is warranted.
