Assessment of response to therapy in rheumatoid arthritis (RA) has evolved over the past two decades. Although in earlier years observation of response was considered a sufficient treatment success, more recently the importance of achieving a low or “good” state of disease activity has moved into the foreground. These developments peaked in the publication of the “treat-to-target” principle for RA, which clearly defined disease activity states as important targets for RA patients. Around the same time, the first joint effort of the ACR and the European League Against Rheumatism (EULAR) resulted in recommendations for reporting clinical trial outcomes that included proportions of patients achieving low disease activity and remission in addition to standard “response” end points.
The ACR and EULAR have defined remission using Boolean- or index-based criteria (i.e., a Simplified Disease Activity Index [SDAI] score of ≤3.3). The researchers undertook this study to compare definitions of remission to inform choice of end points for future rheumatoid arthritis (RA) clinical trials, and included in their comparison the remission criterion of a score of ≤2.8 on the Clinical Disease Activity Index (CDAI).
Methods: The authors performed post hoc analyses on clinical remission rates using data from two infliximab trials (the ASPIRE [Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset] and ATTRACT [Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy] trials) and one golimumab trial (the GO-FORWARD trial). They investigated stringency of the different remission definitions, their power to discriminate between active drug and comparator, and aspects of their internal and external validity. The investigators also investigated population determinants of discriminatory power for a particular remission end point.
Results: In patients with early RA (the ASPIRE trial), ACR/EULAR Boolean, CDAI, and SDAI remission rates at six to seven months were 4–6% for methotrexate (MTX) alone vs. 11–14% for infliximab plus MTX. In patients with MTX-refractory active RA (the ATTRACT and GO- FORWARD trials), remission rates were ≤1% for comparator (add-on of placebo) versus 4–6% for add-on of infliximab in the ATTRACT trial and ≤3% for comparator (add-on of placebo) vs. 11–13% for add-on of golimumab in the GO-FORWARD trial. Existing remission cut points of different measures were generally comparable, with the Boolean criteria being somewhat more stringent than the SDAI and CDAI criteria. Remission rates were similar across definitions, as was average statistical power (CDAI, 55.6%; Boolean, 59.9%; SDAI, 62.6%).
Conclusion: Significant advances have been made in the treatment of RA over the past 20 years, and with the hope of developing even more effective therapeutics, achieving a very low level of disease activity like remission is an important outcome to be examined. Remission is an ambitious primary end point for RA clinical trials to be reserved for selected scenarios based on power considerations. The analyses of these researchers help inform the use of the more recent ACR/EULAR-endorsed definitions of remission as an end point in RA clinical trials and substantiate remission as an ambitious primary end point for such trials, particularly in situations where large sample sizes are acceptable from an ethical and financial perspective. The ACR/EULAR definitions are interchangeable, with slightly higher stringency of Boolean criteria over index-based criteria.
Excerpted and adapted from:
Mack ME, Hsia E, Aletaha D. Comparative assessment of the different American College of Rheumatology/European League Against Rheumatism remission definitions for rheumatoid arthritis for their use as clinical trial end points. Arthritis Rheumatol. 2017 Mar;69(3):tktk.