To guide clinicians in evaluating treatment responses in daily practice and to define remission in clinical trials, standardized measures for remission have been formulated by the American College of Rheumatology (ACR), the European League against Rheumatism (EULAR) and the US Food and Drug Administration (FDA). The ACR criteria for remission include six core variables, of which five must be fulfilled for at least two consecutive months. These include fatigue, joint pain, joint tenderness, joint swelling, duration of morning stiffness, joint swelling, and ESR [21
]. The EULAR response criteria use an index of disease activity (the disease activity score (DAS)), which is determined by a mathematical formula [22
] (Table ). The initial DAS counted 44 joints on swelling and included the Ritchie articular index for tender joints. The DAS28 uses an abbreviated 28-joint count for tender and swollen joints, omitting, among others, the feet [22
]. Using the original DAS (44 joints), low disease activity is defined by a score between 1.6 and 2.4, and remission is defined by a score below 1.6. When the DAS28 is applied, a score between 2.6 and 3.2 indicates low disease activity, and a score lower than 2.6 points to remission. In a Spanish random sample of 788 RA patients, the positive predictive value of each of the DAS28 indices was assessed: the positive predictive value for remission of a normal ESR was 7%, of morning stiffness <15 minutes 8%, of the absence of fatigue 9%, of the absence of joint tenderness 13%, of the absence of joint swelling 16% and of the absence of joint pain by anamnesis 28% [23
]. The FDA has formulated the most rigorous definition for remission. These guidelines require that the ACR criteria for remission are met in addition to a radiological arrest (Sharp-van der Heijde or Larsen method) over a period of six following months in the absence of DMARDs [24
]. Two less stringent response criteria were also formulated, complete clinical response and major clinical response [24
]; according to this classification, complete clinical response is similar to remission while continuing antirheumatic therapy (Table ).
Definition of remission as treatment outcome/disease state in RA
It has been argued that the ACR criteria for remission are difficult to apply for clinical trials, as patients do not easily fulfill these criteria due to the time requirement of two months and the inclusion of fatigue. Therefore, most recent trials currently use a DAS-based definition of remission or use the ACR70 response criteria. However, the ACR70 response criteria are not an adequate measure for remission as the concordance between ACR70 and DAS remission is low and ACR70 responders have a higher number of tender or swollen joints or ESR than patients in DAS remission [25
]. Several studies have compared the DAS-defined remissions with the ACR criteria for remission or the DAS remission with remission according to the DAS28. Although it is reported that a DAS28 < 2.6 corresponds to the ACR remission criteria [26
], a recent report showed that DAS remission is more conservative than DAS28 remission and concludes that a DAS28 cutoff of 2.6 has insufficient validity to use in clinical trials [27
]. A Finish comparison of remission according to the DAS28 and ACR criteria showed that a DAS cutoff value of 2.3 corresponds to the ACR criteria and that, even among patients with a DAS < 2.3, tender joints were present in 19%, swollen joints in 11% and both swollen and tender joints in 7% [28
]. The FDA clinical response criteria include a time requirement of six months; the percentage of patients achieving remission according to this definition is lower than the percentages when remission was assessed at one time point [25
]. This time requirement seems relevant given data that show that when remission is based on a single time measurement disease progression can occur [29
]. The most likely explanation for this observation is that either subclinical disease is present or the waxing and waning disease activity of a low disease activity state is measured at the lowest level thereby creating 'false-positive remissions'.
In conclusion, the DAS and ACR criteria are both an important outcome measure for treatment response in clinical trials. The ACR and FDA criteria contain a time constraint that results in a lower percentage of remissions in comparison with the assessment of remission at one time point. Obviously, a time constraint in the definition of remission leads to less 'false-positive' findings of remission in patient management. Therefore, in our opinion, the presence of a time condition in the definition of remission enhances the significance of the remission for use as an outcome measure in clinical trials, and when a DAS-based definition of remission is used, the study should consider repeating it over time in order to calculate the mean and standard deviation of the disease activity.