Introduction
Early diagnosis and rapid initiation of treatment has become the mission in rheumatoid arthritis (RA).
Several composite indices are used for measuring disease activity, response and remission. The disease activity score based on 28-joint count (DAS28) is a validated method of outcome measures in clinical trials and clinical practice [
1]. The DAS28 score, European League Against Rheumatism (EULAR) response criteria, and low disease activity criteria were developed originally using the erythrocyte sedimentation rate (ESR) as an element of the four-variable score (DAS28(4v)-ESR) [
2,
3]. Later findings highlighted the importance of C-reactive protein (CRP) – being an acute-phase reactant, it might give better estimation of short-term changes in disease activity – and therefore CRP was used in disease assessment as a useful outcome measure in the four-variable DAS28 including CRP (DAS28(4v)-CRP) [
4].
Remission criteria using DAS28(4v)-ESR are well known and the most widely used in clinical practice. DAS28-CRP gives a good estimation of DAS28-ESR on a group level [
5]. Further recommendations were made on the application of DAS28(4v)-CRP, setting similar cutoff values to the DAS28(4v)-ESR for definitions of disease remission as well as low, moderate or high disease activity [
6]. Originally, the remission threshold was set to DAS28(4v)-CRP <2.6, equal to DAS28(4v)-ESR, although some earlier results suggest that DAS-28(4v)-CRP levels and their cutoff values for remission or response are lower [
2,
6,
7]. At present, DAS28 criteria are widely used in formulas either with the ESR or CRP.
More effective drugs and treatment strategies allowed remission to become the treatment target in RA, although even in remission patients can experience radiographic progression [
8‐
10]. Limitations of the previous remission criteria and the ultimate goal of treating to remission urged the collaboration to establish a new composite tool for measuring remission in RA. New RA remission criteria were developed by the American College of Rheumatology (ACR)/EULAR in 2011 on the basis of using data from four clinical trials and need to be validated using different datasets in clinical practice [
11]. To be classified as in remission according to these criteria, patients must have swollen joint count out of 28 joints (SJC28), tender joint count out of 28 joints (TJC28), CRP (mg/dl) and patient global health assessment (PGH) on a 0 to 10 visual analogue scale of 1 or less [
11].
Previous findings showed that, despite minimal disease activity, patients might not fulfil the ACR/EULAR remission criteria, mainly because these RA patients regularly do not meet the PGH criterion of the provisional ACR/EULAR Boolean-based definition despite a good clinical disease state [
12]. Prince and colleagues compared the performance of ACR/EULAR Boolean and Simplified Disease Activity Index (SDAI) remission criteria with DAS28(4v)-ESR criteria and DAS28(4v)-CRP <2.6 or <2.3 criteria [
7]. They suggested that overall just a small portion of patients reached and remained in remission in the long term, and fewer patients reached ACR/EULAR remission than any DAS28 remission [
7]. The objective of this study was to examine the performance of the ACR/EULAR Boolean and the DAS28(4v)-CRP remission status in a routine clinical setting involving biologic-treated RA patients.
Discussion
Remission-orientated treatment is the principal target either with disease-modifying antirheumatic drugs or biological therapy in RA [
18,
19]. Several composite indices have been introduced to evaluate disease activity in rheumatology practice (DAS28, SDAI, Clinical Disease Activity Index) [
20]. Increasing postulation for early diagnosis and aggressive treatment has created a demand for more stringent measures of response, especially remission in disease development. In addition, it has been suggested that it is possible to predict early response to TNFi therapies using a mathematical model [
21]. Previous remission criteria have been used in daily practice and clinical trials, of which DAS28 remission criteria are the most commonly used and reliable in clinical practice [
22]. The need for other stringent remission criteria created a collaboration by ACR, EULAR and the Committee of Outcome Measures in Rheumatology Initiative (OMERACT) group to work out the new ACR/EULAR remission criteria in 2011 [
11]. In this observational cohort we examined the frequency and sustainability of remission according to the new criteria and the DAS28(4v)-CRP-based criteria.
We followed a biologic-naive RA group being unresponsive for different disease-modifying agents (disease-modifying antirheumatic drugs), having high disease activity and requiring the initiation of biological therapy. The examined patients were started on TNFi therapy that is unique in terms of the homogenicity of the RA group. Investigations were made in a clinical setting.
Boolean remission criteria allow fewer patients into remission than DAS28(4v)-CRP criteria, and hence the highest possible score for any subcriteria is ≤1; however, DAS28 allows wide varieties also in TJC, SJC, CRP and PGH. ACR/EULAR remission criteria are more stringent in terms of allowing fewer patients into remission, and in the view of these results fewer patients can reach this requirement due to higher TJC28, SJC28, CRP or PGH values at any timepoint. For the same reason, Boolean remission patients were better responders on a group basis than DAS28 remission patients. Recently de Punder and colleagues found that anti-tumour necrosis factor-treated patients who score 1 on every item of the ACR/EULAR remission criteria had a DAS28(4v)-ESR higher (2.8) than the cutoff point for their DAS28(4v)-ESR remission (<2.6) [
23]. Hirabayashi and Ishii revealed that the DAS28-ESR cutoff point necessary to predict remission was <1.54 under the new criteria in clinical settings for tocilizumab-treated patients; a DAS28-ESR cutoff point <2.0 was previously examined as a candidate definition of remission by ACR/EULAR [
11,
24].
Several published reports have examined the effect of PGH on ACR/EULAR criteria for clinical trials, and emphasise that missing the PGH criteria by ≤1 frequently leaves patients in a nonremission status. Otherwise these patients demonstrate a good clinical disease activity [
12]. Similar observations were also confirmed in a solely clinical setting of the ACR/EULAR criteria, neglecting CRP from the definition of remission [
6]. We present the first PGH data on a biologic naive cohort starting TNFi treatment. In patients missing Boolean remission due to one subcriterion, PGH was found to be the strongest contributory factor raising disease activity above the cutoff in this cohort. In accordance with this, DAS28 remission patients missing Boolean remission status have higher post-treatment disease activity, primarily due to increased PGH. Previous findings suggest that the assessment of PGH may raise difficulties in defining remission in clinical practice. Originally, the ACR/EULAR remission criteria were developed for clinical trials. The literature reflects that clinical trial conditions are different from routine clinical practice and that patients may score PGH differently depending on their original disease activity [
12]. Modification of PGH subcriteria to PGH ≤2 has been proposed to allow more patients to reach ACR/EULAR remission [
25]. The limitation in clinical application of the new remission criteria is that patients may score a high PGH for reasons other than RA disease activity, raising the opportunity for overtreatment; in contrast, minimisation of latent disease activity may ensure better long-term radiographic outcomes.
We confirmed that despite remission rates being lower in Boolean remission status, the majority of patients gave at least moderate response to therapy and good response improved from 3 to 12 months. One-fifth of our patients presented low disease activity post treatment at any timepoint and both the DAS28 and Boolean remission statuses improved from 3 to 12 months of therapy.
The feasibility of more stringent remission criteria hides inherent challenges as age, comorbidities and nondisease-related factors may significantly influence measurement of remission. In this study we confirmed that younger age and lower baseline TJC28 were predictors for both DAS28 and Boolean remission status compared with nonremission, which is consistent with previous findings that gave impact for these predictors in DAS28 remission [
26]. Age has a further impact on remission status, younger patients being more likely to reach Boolean remission compared with DAS28 remission, which supports earlier aggressive treatment as it offers a higher probability of sustained remission.
The drawbacks to our study are that calculations with the Clinical Disease Activity Index and SDAI were not calculated due to lack of data. We did not compare remission criteria in the case of patients on solely disease-modifying agents (disease-modifying antirheumatic drugs) and we did not analyse according to different TNFi therapies, although most studies to date have failed to show differences in efficacy across the class. Our observational study did not extend to data analysis on the predictive value of remission criteria for further synovitis, bone marrow oedema or radiographic progression. There is evidence that a longer period in remission results in less radiographic progression [
10]. Additionally, several studies confirm that subclinical disease activity, and possibly further radiological progression, may be detectable despite clinical remission, and applying stricter remission criteria should guard against this happening [
27]. Zhang and colleagues examined the radiologic and functional outcome of RA patients 1 year after treatment initiation and found that Boolean and SDAI/Clinical Disease Activity Index definitions made better prediction for good outcomes than DAS-based definitions [
28]. Lillegraven and colleagues first evaluated the relationship between the time in remission and radiographic joint damage comparing ACR/EULAR with DAS28-CRP-based remission on a clinical observational RA cohort. Their findings suggest that the Boolean-based definition has the highest, and the DAS28-CRP-based definition has the lowest, likelihood ratio for good radiographic outcome, therefore verifying the validity of new remission criteria in clinical settings [
10]. Sakellariou and colleagues also confirmed the higher probability of ultrasound-detected synovitis for DAS28 remission than ACR/EULAR remission [
29]. However, we did not examine ultrasound/magnetic resonance imaging-detected synovitis. Existing subclinical disease activity in clinical remission establishes the demand for further observational studies in the state of remission to introduce new recommendations including imaging follow-up strategies. Identifying predictors of remission will help to achieve a better radiographic and functional outcome [
30].
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
All authors contributed to the acquisition and interpretation of data, and drafting the manuscript. In addition, EB, JMD, UF and DJV made substantial contributions to the study conception, data analysis and revision of manuscript. CO, RM and LH participated in patient recruitment and data analysis. AK, OF, PG, MMo, EO’F, PM, LM, MO’N and MMu contributed to patient recruitment and data capturing. All authors read and approved the final manuscript.