The advent of biologic agents has allowed to reach new and ambitious outcomes in RA. Consistently, the cornerstone of the Treat To Target recommendations was the definition of an achievable treatment target, i.e. remission or at least low-disease activity .
DAS28-ESR < 2.6 has been the definition most widely used for remission in clinical practice. However, it has been suggested that disease activity could still be present in patients fulfilling that criterion. New ACR/EULAR definitions are more stringent and fewer patients are classified as being in remission using these concepts. Accordingly, barely half of patients with DAS28-ESR < 2.6 fulfilled SDAI or ACR/EULAR Boolean remission criteria in clinical practice . However, whether or not more stringent remission criteria provide better clinical and radiographic outcomes in the long term is still under debate. Selecting more stringent remission criteria implies, on one hand, fewer joint counts and less subclinical activity [15–16]. On the other hand, the more stringent is our target, the more we will step up the therapy to achieve the goal, with a subsequent higher risk of adverse events .
In this observational study of clinical practice, DAS28-ESR criterion identified remission three-fold as often as SDAI, CDAI, ACR/EULAR Boolean and PD remission criteria.
The number of patients classified in remission (27–31%) and the rate of change of therapy (31-33.3%) were not essentially different among SDAI, CDAI and Boolean criteria. Even radiographic progression, no matter the threshold used, was quite balanced among them. Therefore, ACR/EULAR remission definitions could be interchangeable, as it has been previously highlighted .
Remarkably, no significant differences were reached among SDAI, CDAI, Boolean criteria and DAS28-ESR criterion with regard to change of baseline therapy after 5 years of follow-up. Even radiographic progression was not substantially different. Previous studies also showed that the DAS28-ESR remission criterion had similar radiographic damage and disability than that seen with other criteria, and patient-reported outcomes were similar [19–20]. The global low level of radiographic progression, barely above one unit of mSHS per year, in part explained by the high use of biological therapy at baseline (60%), definitely influenced the low structural damage progression and hampered the comparison among groups. According to our results, patients in remission, whatever the concept used to define it, have no relevant radiological progression in the long-term.
The two main drawbacks of DAS28-ESR-based remission are, on one hand, the excessive weight in the formula for acute phase reactants, giving an advantage to IL-6-inhibiting agents . In this particular case, indexes such as CDAI or RAPID-3, not taking into account acute phase reactants, should be of first election [22–23]. On the other hand, a substantial amount of subclinical inflammation persists in patients in DAS28-ESR remission . It is important to highlight that clinical remission, no matter the definition employed, does not entirely correspond to imaging remission and some patients might experience structural damage progression [25–27]. However, very few patients of our cohort had significant radiographic progression as measured by mSHS (less than one unit per year), as it has seen in previous studies .
In order to discern which remission criterion is closer to arrest structural damage in our patients with established RA, we took different thresholds for radiographic progression. We observed that PD remission was related to better radiographic outcomes than exclusively clinical remission definitions, something already known for early rheumatoid arthritis . Ideally, achieving US remission and the complete abrogation of subclinical activity should be the ultimate goal for our RA patients. However, recent data from TASER , ARTIC  and IMAGINE-RA  trials showed that specifically targeting subclinical inflammation did not yield better clinical outcomes. This target could imply a risk of overtreating, with a higher use of biological therapy and more adverse events. No clear explanation exists for this. Maybe, Treat to Target strategies are not effective for treating subclinical inflammation or, alternatively, persistent subclinical synovitis does not imply worse clinical outcomes in the long-term. We previously have reported that, despite half of patients in remission still have US subclinical activity, the rate of radiographic progression was relatively low (10%) and, most probably, clinically irrelevant . Our results suggest that targeting remission whatever the concept selected, should be appropriate to achieve good clinical and radiological outcomes in a clinical care setting for patients with established RA.
Attending to our results, DAS28-ESR is not inferior to more stringent remission concepts in a clinical care setting after a long follow-up. SDAI, CDAI and ACR/EULAR Boolean criteria are definitely more appropriate for clinical trials, where comorbidities are specifically avoided, and patients’ assessments and acute phase reactants are related exclusively to RA and not to other extra-conditions seen in a real world-setting . For routine clinical practice, DAS28-ESR could be acceptable, achievable in a high percentage of patients and more suitable for “real” patients with comorbidities. Similar levels of serum calprotectin found across the five sets of remission, a biomarker strongly related to subclinical inflammation and radiological progression [13, 32], reinforces the idea of comparable outcomes for all remission definitions in the long-term. US remission yielded significantly better radiographic outcomes than clinical criteria. Due the uncertain value of structural damage associated with subclinical synovitis, this should not be an important limitation for the use of non-imaging criteria in clinical practice, especially in established RA.
If aiming for a state closer to normality (true remission), a concept of multi-dimensional remission (MDR) should be used, involving the achievement of different depths of remission, using clinical, imaging and additional serological, immunological or histological parameters . MDR has been shown to be related to better patient-reported outcomes, although prospective data is necessary to definitely address this issue.
This study has some limitations. The sample size was not big, and patient’s data was retrospectively collected from medical records, although the long-term follow-up and the objective outcomes selected, such as change of therapy and radiographic progression partially outweigh these drawbacks. Second, patients’ global assessment but neither pain assessment nor HAQ were recorded along the follow-up, since these two patient-related outcomes are not included in our routine monitoring of RA in clinical practice. In addition, since the current study was conducted in a clinical setting, we did not use a pre-established treatment protocol. Finally, few data on sustained remission was collected due to the reduced number of patients. This concept of persistent remission could be of relevance, since the continual fulfillment of any remission criteria has been strongly effective in preventing progression of functional disability .