Introduction
Presently, in patients with newly diagnosed rheumatoid arthritis (RA), achieving remission is a realistic goal [
1,
2]. Even sustained and drug-free remission is proven to be feasible [
3,
4]. This has been achieved during the last decades by early and efficient use of synthetic and biological disease-modifying anti-rheumatic drugs (DMARDs) and by applying treat-to-target (T2T) approaches. In randomised controlled clinical trials, with strict selection of patients and controlled conditions, T2T aiming at remission or low disease activity results in good clinical outcomes [
5‐
7]. It has also been shown that implementation of T2T, especially when using a protocolled treatment strategy, is more effective than a traditional routine care approach [
7‐
9]. Therefore, T2T is now recommended for patients with early RA by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) [
10‐
12].
Implementing and retaining T2T in daily clinical practice may, however, be a challenge for rheumatologists as well as their patients. Barriers that are frequently mentioned are the complex medication schedules and fear of side effects, doubts about the reliability and validity of composite measurements of disease activity, the applicability of a target of low disease activity for some patients and restrictions in time and resources as well as other logistical aspects [
13,
14]. However, in previous publications on the Dutch RhEumatoid Arthritis Monitoring (DREAM) remission induction cohort, successful implementation of T2T in daily clinical practice was demonstrated. Achieving remission within the first year of treatment was shown to be a realistic goal for an important proportion of patients. [
2] Furthermore, in most patients, remission was sustained for 6 months or longer during an initial follow-up of 3 years. In addition, patients suffered only limited radiographic damage over this period of time, while physical capacity and health-related quality of life significantly improved [
15], illustrating that not only the disease but also the patient benefits from the T2T approach. Adherence to the T2T recommendations was high, which comprised regular assessment of disease activity and protocolled treatment adjustments regarding subsequent disease activity-driven therapeutic steps [
16].
Data on long-term results of continuous application of T2T in daily practice are scarce. While many observational studies have evaluated the long-term outcomes of RA, these originate mainly from before the introduction of targeted therapy and the availability of biologicals [
1]. Long-term data from more recent randomised controlled clinical trials, using a T2T approach and biologicals, have shown good clinical outcomes [
17‐
20]. However, the generalisability of these results is hampered by the selection of specific patient groups in clinical trials and strict exclusion criteria. Patients seen in real-life practice may differ substantially from those in randomised clinical trials [
21]. In this observational study, we therefore describe the 5-year disease and patient-related outcomes of continuous application of a T2T strategy in patients with early RA in daily clinical practice.
Discussion
This study confirms the favourable long-term outcomes of a continuous treat-to-target approach in RA patients in daily clinical practice. Mean disease activity decreased quickly and remained low for the remainder of the follow-up period. The majority of patients reached at least one period of sustained remission in most cases while on conventional synthetic DMARDs. Also, a substantial number of patients achieved drug-free remission. Similarly, functional disability decreased and physical health-related quality of life improved and remained so. The overall use of biological DMARDs was low.
Observational studies in early RA from 1996 to 2007, with a follow-up of 5–10 years, have shown endpoint DAS remission percentages of 23–30% [
1]. One of these studies contained a population comparable to our DREAM cohort with regard to baseline disease activity and autoantibody status. This study, in which treatment consisted mainly of methotrexate and sulfasalazine without the application of a T2T principle, demonstrated DAS remission rates of 25 and 20% after 3 and 5 years, respectively [
27]. In comparison with these results, our data from the DREAM registry illustrates the major improvement in the management of RA in daily clinical practice that has been realised over the last decades. This improvement has most likely been realised by applying the T2T approach and therefore the efficient use of conventional and biological DMARDs.
There have been several randomised controlled clinical trials, which have proven the effectiveness of T2T strategies. In the CAMERA study, MTX-based tight control during the first 2 years was compared with MTX-based conventional treatment. After 5 years of follow-up, the mean DAS28 decreased from 5.60 to 2.68 and from 5.60 to 2.75 for both treatment arms, respectively [
19]. In the BeST study, there were no differences in remission rates after 5 years of follow-up between MTX-based sequential monotherapy, step-up combination therapy, initial combination therapy with prednisone or initial combination therapy with MTX and tumour necrosis factor alpha inhibitors [
20]. The total combined DAS remission rate after 5 years was 48% in the BeST study. The difference between this remission rate and the results of our DREAM cohort might be explained by the higher disease activity at baseline, the more stringent inclusion and exclusion criteria and the target of low disease activity in the BeST study.
To date, there is no consensus on how to define sustained remission or drug-free remission, which makes comparison of our results with existing data difficult. In a large Canadian prospective early RA cohort (
N = 1840) with a follow-up of 5 years in which patients were treated to the discretion of the treating rheumatologist (45.8% MTX combination therapy and 31.7% MTX monotherapy), sustained remission (the more stringent Boolean clinical practice definition; tender joint count ≤ 1 using 28 joints, swollen joint count ≤ 1 using 28 joints and patient global assessment ≤ 1 on a 0–10 scale) for ≥ 6 months was achieved in 25% of the patients [
28]. Long-term 10-year follow-up data from the observational Leiden Early Arthritis Cohort and the British Early Rheumatoid Arthritis Study (both started before the use of biologicals and without the T2T principle) showed that sustained DMARD-free remission (the sustained absence of synovitis for at least 1 year after discontinuation of therapy with DMARDs) occurred in 9–15% of RA patients [
29]. In the BeST study, after 5 years, 23% of patients achieved drug-free remission (every patient who was able to stop medication regardless of the duration of remission thereafter) with no significant differences between the treatment arms [
30].
Our study describes long-term outcome of implementation and continuous application of T2T to RA patients in daily clinical practice. The outcomes are similar to or even better than the results of T2T randomised clinical trials, in which strict selection of patients and controlled conditions were followed. These ‘real-life data’ are of important additional value in the evidence for the effectiveness of a T2T approach in RA patients [
31]. The strengths of our study lie in its setting and design. Patients were treated according to current guidelines, and the strategy complied with (Dutch) reimbursement regulations regarding prescription of TNFi. Patients with comorbidities and contraindications for medication did not have to be excluded because deviations from the protocol were allowed. Therefore, results are more likely to be generalisable to other RA populations in the same settings.
Any observational study like this has potential limitations in terms of the possibility of missing data and susceptibility to bias and confounding by indication. The first limitation of our study is the proportion of patients which was lost to follow-up and the amount of missing values. One of the reported reasons for loss to follow-up was sustained remission, which might have led to an underestimation of the actual remission rates. In addition, we were confronted with missing DAS28 values, largely due to less frequent visits to the clinic in case of remission or low disease activity. Linear mixed modelling was used for analysis of the DAS28 course because of the advantage of this method in dealing with missing values. For determining the occurrence of sustained remission, imputation was used by last observation carried forward under the assumption that patients will visit the clinic when the disease flares.
Second, the proportion of patients with positive auto-antibodies rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) in our study is lower than in some recent clinical trials [
32,
33], which could be interpreted as a limitation or cast doubt on the accuracy of diagnosis. However, the aim of our study was to describe outcomes of up-to-date treatment of early rheumatoid arthritis in real-life practice. For that reason, we included all patients with a clinical diagnosis of RA made by an experienced rheumatologist after careful consideration of clinical symptoms, laboratory findings and imaging closely mirroring daily practice. In most clinical trials, patients which are diagnosed with RA were selected based on fulfilment of the revised 1987 American College for Rheumatology classification criteria (1987 ACR criteria), including rheumatoid factor. As a consequence, this has likely led to a higher proportion of patients with positive auto-antibodies in these trials. In addition, trials that included early RA patients (diagnosis according to the 1987 ACR criteria) presented proportions of positive auto-antibodies close to our data. For example, the COBRA-light study reported 62% anti-CCP positivity and 58% RF positivity [
34] and the BeSt study reported 62% anti-CCP positivity and 66% RF positivity [
35].
Third, our target of DAS28-based remission criterion has been criticised regarding its ability to reflect a state of true remission [
10]. However, the DAS28 is an applicable and widely used instrument to assess disease activity in daily practice and part of most international reimbursement guidelines for biologicals [
36]. Furthermore, our data clearly show that this target resulted in favourable outcomes from the medical as well as the patient perspective.
Finally, this study reports only the results of the implementation of initial step-up MTX monotherapy while in the meantime randomised clinical trials have proven initial combination therapy with different regimes of glucocorticoid use to be superior [
33,
37]. Forthcoming cohort studies will have to show whether adjustment of the treatment strategy in daily clinical practice will lead to further improvements.
Implementation and retention of a strict T2T approach in patients with newly diagnosed RA in daily clinical practice leads over a follow-up of 5 years to favourable disease and patient-related outcomes.