It is widely recognized and recommended that current treatment of rheumatoid arthritis should be targeted to disease remission or, if this is not achievable, to minimal disease activity. In agreement with such recommendation, evaluation of remission and low disease activity are always included among efficacy end points of confirmatory trials of novel anti-rheumatic agents. However, this raises the problem of using a shared definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials.
Remission has been commonly defined as a DAS28 lower than 2.6. However, in theory, this goal can be achieved even if more than 10 joints are swollen. Apparently joint erosion can continue progressing even when the DAS28 remission definition is met. In the last few year, the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) have focused on a definition of remission that reflects a state of absence of disease activity. In 2011, The ACR/EULAR proposed two options for assessing remission in clinical trials, a Boolean or an index based definition (Felson et al, Arth Rheumatism 2011;63:573-86). The Boolean definition requires that all following criteria show a score £ 1: swollen and tender joints, serum C-reactive protein (CRP) (mg/dl), patient global assessment (0 to 10). The index based definition requires a Simplified Disease Activity Index (SDAI) score £ 3.3. The ACR/EULAR have requested that both definitions are tested in future clinical trials and validated in observational datasets. Interestingly, the ACR/EULAR recommendation has been included in the revised European Medicines Agency (EMA) guidance on clinical trials in rheumatoid arthritis (CPMP/EWP/556/95 rev. 2, draft 2011), where remission or low disease activity are indicated as potential primary study end points, with remission in particular representing an optimal primary end point for trials in early rheumatoid arthritis. The EMA guidance also makes reference to the definitions of remission proposed by the ACR/EULAR.
In agreement with the ACR recommendation, data from previous clinical trials have been re-evaluated to compare the remission outcome based on the different definitions. For example, results from the TAMARA phase IIIB study (tocilizumab in patients with active disease despite stable dose of conventional or biological disease-modifying anti-rheumatic drug (DMARD) were analyzed to assess remission according to the new ACR criteria and to compare the results with the original analysis of DAS28-erythrocyte sedimentation rate (ESR) remission (Ilking-Konert et al, Ann Rheum Dis 2011;70:1986-90). At week 24, while nearly 50% of patients (47.6%) had achieved a DAS28 < 2.6, only 20.3% had attained the Boolean defined remission and 25.2% the index based remission (SDAI £ 3.3). As expected, the more stringent criteria of Boolean remission led to a considerable reduction of remission rate, that was consistent with the SDAI and with the Clinical Disease Activity Index (CDAI) remission (24.1% with CDAI < 2.8). This result indicates that Boolean criteria represent a remission model closer to what is to be intended as remission in the clinical practice, as compared with DAS28. A similar comparison was conducted in patients with early rheumatoid arthritis, for whom remission should be the primary therapy goal. Again, Boolean remission was attained by less than half of the patients compared to those that achieved a DAS28-CRP < 2.6. The new remission criteria are also being evaluated in observational or cohort studies, like the BRASS (Prince et al, Arthr Res Ther 2012;14:R68), the ESPOIR (Zhang et al, Arthr Res Ther. 2012;14:R156), early rheumatoid arthritis cohort studies (Kuriya et al, J Rheumatol. 2012;39:1155-8; Vermeer et al, Rheumatol. 2012;51:1076-80) and others. Data so far tends to confirm that the new Boolean and the SDAI remission criteria are better predictors of stability of joint damage progression compared with DAS28. Due to ACR/EULAR Boolean stringent criteria, remission may not be an achievable goal for many patients, with a number of swollen and tender joints as well as patient global assessment £ 1 being the main limiting factors.
New criteria are being evaluated in recently initiated clinical trials, in addition to DAS28, SDAI or CDAI criteria. Results from these studies may provide useful information on the performance and feasibility of the new ACR definition of remission and, most important, on the possibility of using this definition as a primary end point in future clinical trials, particularly in very early or early rheumatoid arthritis.
In the future, imaging may be included among the criteria for remission. In fact there is evidence that synovitis can still be found in patients in clinical remission and may lead to adverse functional and clinical outcome. Many questions concerning use of imaging for evaluating remission are yet to be answered, for example: the type of imaging method, the joints to be evaluated, the acceptable level of inflammation, and the impact of imaging remission on patient’s outcome.