Background Preliminary definitions of improvement (DOIs) for adult dermatomyositis (DM), polymyositis (PM) and juvenile dermatomyositis (JDM) have been developed in 2004 by International Myositis Assessment and Clinical Studies (IMACS) group based on the existing core set activity measures (CSMs). Pediatric Rheumatology International Trials Organization (PRINTO) has also provided provisional data-driven definition of improvement for JDM in 2010. However, these DOIs defined only minimal clinical improvement and were in need of further validation. Therefore, the goal was to develop new consensus DOIs for minimal, moderate and major improvement for the use in therapeutic trials.
Methods Patient profiles from natural history and/trial data were rated by adult and pediatric myositis experts and consensus (≥70% agreement) was reached in 91% and 98% respectively (adult experts: 157 minimal, 72 moderate and 12 major improvement; pediatric 247 minimal, 174 moderate and 84 major improvement). Conjoint analysis was performed on forced-choice surveys (using 1000Minds software). Candidate DOIs based on changes in CSMs were generated as follows: A) 21 previously-published DOIs; B) 428 DOIs developed using expert survey and variations of published DOIs; C) 204DOIs derived from logistic regression; D) 18 DOIs derived from a Conjoint Analysis survey that yielded scores with different levels of improvement in different CSMs; E) 18 DOIs drafted by combining changes in each CSM with respective Conjoint Analysis weights; and F) 183 DOIs drafted by applying weights from Conjoint Analysis to the base DOIs. Relative and absolute percentage change DOIs were tested for minimal, moderate and major improvement. The consensus patient profiles were then used to test DOIs for their validity, including sensitivity, specificity, kappa, OR and area under the curve (AUC). High performing DOIs were externally validated using Rituximab in Myositis (RIM) trial data (N=200) and PRINTO JDM (n=139) trials, followed by a consensus meeting using nominal group technique (NGT).
Results A final ranking of the top DOIs from the adult and pediatric working groups yielded >90% consensus for a Conjoint Analysis hybrid model DOI using relative % change in CSMs (adult group) or absolute % change in CSMs (pediatric group). NGT discussion with the adult and pediatric working groups yielded consensus (91% agreement) in use of a Conjoint Analysis hybrid DOI for both adult DM/PM and JDM clinical trials using absolute % change with different cut points for minimal, moderate and major improvement (Table). Total improvement score is a sum of scores achieved in six CSMs based on the predefined absolute percentage level of improvement in each CSM - MD global, patient/parent global, MMT/CMAS, HAQ/CHAQ, muscle enzyme/CHQ-PF50, and extra muscular VAS/DAS.
Conclusion A Conjoint Analysis-driven hybrid definition with a continuous score of improvement based on absolute % change in CSMs with different cut points for minimal, moderate and major improvement was selected by a data and consensus-driven process as a final DOI to be used for clinical trials in adult DM/PM and juvenile DM. Criteria for major improvement in adult group is considered preliminary.
*ACR-EULAR Myositis Response Criteria Project N Ruperto, R Aggarwal, AA Amato, N Bayat, R Cimaz, RG Cooper, R Cuttica, H Chinoy, K Danko, M Dastmalchi, B Erman, B Feldman, D Fiorentino, A Huber, D Isenberg, JD Katz, S Knupp de Oliveira, I Lundberg, C Lindsley, A Mammen, CV Oddis, C Pilkington, M Punaro, A Ravelli, A Reed, K Rouster-Stevens, A van Royen, J Vencovsky, M de Visser, SR Ytterberg, A Pistorio, L Villa, M Rinaldi, H Rockette, P Lachenbruch, F Miller, L Rider.
Disclosure of Interest None declared