Discussion
The prevalence of remission and MDA after 6 months of treatment with anti-TNF in RA patients differed largely between criteria, according to the results of this study. MDA and DAS-28 <2.6 were quite lenient, with 26–33% of patients being in remission at 6 months and ACR/EULAR remission criteria were quite strict, with 6% of patients being in remission at 6 months.
Obviously, residual disease activity occurred more frequently in the more lenient criteria. For DAS-28 <2.6 and MDA criteria, most residual disease activity was present in the VAS GH >1 cm, up to 69% of patients in MDA. In the ACR/EULAR remission criteria, no residual disease activity was seen on the PRO because VAS GH <1 cm was part of the criteria. The majority of patients with no swollen or tender joints and a CRP ≤1 mg/dl, who may be considered to be in clinical remission to an important extent, were not classified as being in remission according to the ACR/EULAR remission criteria because of their VAS score >1 cm. Another striking result is that patients who score 1 on every item of the ACR/EULAR remission criteria have a DAS-28 of 2.8, which is higher than the cut-point of DAS-28 remission. Due to these results, and in addition to the VAS GH being the variable with the most residual disease activity in DAS-28 <2.6 and MDA, it appears that the low cut-point (≤1 cm) in the PRO of the ACR/EULAR remission criteria is too strict to be applied in daily clinical practice. When the criteria were modified by varying the cut-point of VAS GH stepwise to 4, the prevalence of remission increased to ~18%.
Our last objective, to evaluate the relation between residual disease activity and disability, showed that more residual disease activity also led to increased disability scores. This was shown when comparing ACR/EULAR remission with the more lenient criteria, but also in the increasing HAQ when modifying the cut-point of VAS in the ACR/EULAR remission criteria.
As RA patients may have a different prognosis for joint damage progression, based on the presence of e.g. shared epitope, anti-CCP positivity or RF positivity, this implies that ACR/EULAR remission must not be the most appropriate treatment target for all RA patients. In the presence of less favourable prognostic factors such as anti-CCP and residual presence of swollen joints, pharmacological treatment may be intensified if not leading to unacceptable toxicity.
The prevalence of remission and MDA differs between health care systems and countries. The prevalence of 25% in DAS-28 <2.6 as found in our study falls well within the range of prevalences found in other daily practice studies of anti-TNF that varied from 16 to 32%. The differences in prevalence may depend on follow-up time, disease duration and baseline disease activity. MDA is less frequently reported than DAS-28 <2.6 in clinical studies. Three trials with adalimumab and abatacept showed a prevalence of MDA of 15–31%. In two cohorts of RA patients using non-biologic DMARDs, a prevalence of MDA was found of 20–23%. Prevalence of ACR/EULAR remission in cross-sectional analysis in cohorts of daily practice was 7.5–8.8%.
Residual disease activity, especially of swollen joints, is a known feature in DAS-28 <2.6. This is explained by the fact that low scores in one variable can compensate for high scores in others and the relatively low weight for swollen joints in the DAS-28 formula. In our cohort 51% of patients had one or more swollen joint, which is higher than the range 9–30% found in the literature. Twenty-five per cent of patients with tender joints when DAS-28 was <2.6 is in agreement with 8–40% of patients with DAS-28 <2.6 in other studies. Residual disease activity in MDA or ACR/EULAR remission criteria was not previously published.
In the literature, the HAQ score accepted as remission is 0.5, representing hardly any difficulties in daily activities. HAQ of 1.0 represents mild disability with some difficulties in all activities. The median HAQ score of patients in ACR/EULAR remission is below the cut-point of 0.5. After modification of the VAS cut-point to 3 or 4, the median HAQ did not exceed 0.5. The IQR of the HAQ became larger, but does not exceed the cut-point for mild disability.
Treatment targets for RA are shifting. True clinical remission, which can be defined as the complete absence of clinical signs and symptoms, is still difficult to reach. MDA or DAS-28 <2.6 might be a more reachable treatment target in practice. MDA and DAS-28 <2.6 appear to perform quite similarly, with regard to prevalence as well as the occurrence of residual disease activity. Given the amount of residual disease activity allowed for in DAS-28 <2.6, it proposedly rather describes a state of near remission or minimal disease activity just like MDA does.
ACR/EULAR remission criteria were developed to define a strict, though achievable target that distinguishes remission from low disease activity. By its construction, the ACR/EULAR remission criteria effectively decrease the presence of residual disease activity as measured by tender, swollen joints and acute-phase reaction, but they seem hard to achieve.
It is debatable whether or not a PtGA ≤1 is mandatory for remission of disease activity. Obviously, a low PtGA is aimed at when the goal is to restore health. According to the authors, a PRO should be included in the definition, as was shown by a CART analysis, however, the cut-point for PtGA was chosen for practical reasons. However, there are reasons to regard the cut-point of 1 cm as inappropriately low. First, the cut-point of 1 assumes that PtGA in non-RA patients would be ≤1. However, 45% of the normal population aged ≥50 has a VAS GH score of >2/10. Secondly, the PtGA might unjustly be interpreted as measuring only RA disease activity. The PRO is included in the definition of ACR/EULAR remission because it should convey morning stiffness, fatigue and other not objectively assessable disease activity. High correlations between VAS disease activity, pain and general health show that it is difficult for patients to distinguish RA activity from other ailments like accompanying OA or myalgia. Additionally, several mechanisms separated from arthritis do influence patients' evaluation of their health, such as recalibration of the VAS after treatment (response shift), patients being more sensitive to losses than to gains (loss aversion) and the tendency of people not to rate extremes (end of scale aversion) and apparently are not considered in the choice for the cut-point. Due to this unrealistically low cut-point, this variable has a very heavy weight in the ACR/EULAR definition of remission and remission is hard to achieve.
Remission as the ultimate goal in RA is questionable, because the definition of remission is still a matter of discussion. More important is to have reachable treatment targets based on disease outcomes such as functionality. When PtGA is modified in the criteria, prevalence increases considerably, but disability score also increases. This shows that it is desirable to include a PRO in the definition of remission. However, it is unknown to what extent variation in the VAS cut-point compromises the validity of the criteria.
The results presented concern a cohort of patients with established RA and a median disease duration of 6 years. However, from a treatment viewpoint it is highly relevant to try to reach remission in early RA. Moreover, remission, notably with the ACR/EULAR remission criteria, may be more easily reached in early RA. The time point of 6 months that was chosen for our analyses may be perceived to be short. However, this time point was chosen because the largest decrease in disease activity in patients with established RA occurred in the first 6 months after starting anti-TNF treatment and the average level of disease activity stays stable after 6 months. Illustratively, occurrence of remission was not different between 6 and 12 months of follow-up. We also regarded that 6 months is a meaningful time point to show the much-wished-for beneficial effect of anti-TNF in RA patients failing DMARD therapy.
Due to the large amount of missing data of the variables Physician Global Assessment and PtGA for disease activity in the DREAM data set, we used only the DAS-28-based definitions of MDA and the ACR/EULAR remission criteria based on SJC-28, TJC-28, CRP and PtGA. This is a limitation of our study. Further, the PtGA rating was substituted by VAS GH in our calculation of ACR/EULAR remission criteria. The concept rated by the VAS GH is not the same as the concept rated by the VAS disease activity, because general health can also be caused by factors other than disease activity. However, VAS GH and PtGA by the patient were closely correlated and there was no systematic difference between the two variables. Therefore, we regard that at least in our study the ACR/EULAR remission criteria would not have performed differently with PtGA instead of general health.
In the definition of MDA, ESR is used as acute-phase reactant, whereas in ACR/EULAR remission CRP is chosen. Therefore, the criteria are difficult to compare on the acute-phase reactant. The aim of our study was to compare three different criteria, not to compare performance of CRP with that of ESR. We chose to present residual activity of both variables because of difference in common use or preference of rheumatologists.
In conclusion, MDA and DAS-28 <2.6 are reachable treatment targets in daily clinical practice for anti-TNF treatment of RA. However, both are associated with the presence of residual disease activity. In contrast, ACR/EULAR remission criteria show limited residual disease activity, but are not easily reached in clinical practice mainly because of the strict cut-point on PtGA ≤1 cm.