Remission is an unhelpful outcome measure in clinical trials in early rheumatoid arthritis and the 28 joint-count Disease Activity Score (DAS28) should be relegated to, at best, a secondary endpoint, a European task force has concluded.
It was responding to a draft guideline from the European Medicines Agency (EMA) which proposed remission as a primary endpoint, arguing that it is an established treatment target and that disease activity is routinely monitored in patients in European clinical practice.
“However…remission is still a relatively uncommon occurrence in clinical research, so that its power to detect differences in response between groups is reduced compared with the ACR20,” the task force has stated.
“Reaching such a challenging disease activity state would be likely to require increased numbers of patients for trials with the additional ethical concern that more individuals would be exposed to potentially ineffective treatment.”
Instead, the task force recommends choosing between either an appropriate improvement in disease activity, or a disease activity state that is feasible to reach by a substantial proportion of patients as a primary endpoint.
“For maximum discriminative power, this would be either the ACR20 or the profile of ACR response rates (none, 20, 50 and 70) tested together.
“We think that remission is currently more appropriate as a secondary endpoint in early RA clinical trials.”
DAS28 as a marker of remission is also problematic. While the EMA recommends a DAS28 of 2.6 or less as a threshold, this approach has already been abandoned by EULAR and the ACR.
In addition, DAS28 gives an excessive weight to acute phase reactants and ‘rewards’ biologics that reduce inflammatory markers without necessarily improving important clinical outcomes.
“Compelling evidence shows that the DAS28 might not provide a reliable definition of remission, or sometimes even low disease activity,” the task force wrote in the Annals of the Rheumatic Diseases.
Led by Professor Josef Smolen, it suggests that primary endpoints should include response defined by ACR criteria or the Simplified/Clinical Disease Activity Index (SDAI/CDAI), or a measure of low disease activity by any score.
It also recommended that patients to be enrolled in ‘early RA’ trials be defined as DMARD-naive and with a disease duration of no more than one year.