The American College of Rheumatology response criteria for systemic lupus erythematosus clinical trials: Measures of overall disease activity

Objective. Improved standards for the evaluation of therapeutic interventions in systemic lupus erythematosus (SLE) are needed. The purpose of this study by a committee of the American College of Rheumatology was to define clinically meaningful improvement, no change, or worsening in 6 existing clinical measures of SLE disease activity. This represents an important step in a disease in which some organ symptoms get better and others get worse. It is intended to help investigators develop sample size estimates based on meaningful effect sizes and to gauge the clinical relevance of any observed change in disease activity. Methods. Medical records from 310 patients drawn from 3 sources were abstracted into a standard format. Each vignette included clinical and laboratory data obtained during 2-3 visits. Ratings on the following 6 instruments were obtained for the same patients during the visit or retrospectively: the British Isles Lupus Assessment Group (BILAG), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the revised Systemic Lupus Activity Measure (SLAM-R), the European Consensus Lupus Activity Measure (ECLAM), the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA)-SLEDAI, and the Responder Index for Lupus Erythematosus (RIFLE). From this pool of vignettes, 5 common vignettes and 10 randomly selected vignettes were rated through a secure Web site by 88 international experts on SLE. The experts, who were blinded to the activity measure scores, were asked to rate each patient's clinical condition as worsened, improved, or unchanged relative to the previous visit. These ratings were transformed by statistical procedures into performance characteristic curves that related a change on a particular SLE activity measure to the physicians' agreement on whether that patient had worsened, improved, or remained the same clinically. These were discussed by the committee members, who were blinded to the actual instrument used. The committee then voted on what level of expert agreement would be used to determine clinically meaningful change. Results. The physician ratings on the 5 common vignettes revealed considerable variation in their clinical appraisals. Overall, the 6 SLE activity measures showed excellent separation of clinical conditions as being worsened, improved, or the same. The committee voted to take 70% agreement by physicians as the point on the performance characteristic curves at which meaningful change in a score could be identified. For each instrument, we computed the units of change required to indicate improvement or worsening. Conclusion. To our knowledge, these are the first response criteria in any disease where a clinically relevant change has been determined a priori and mapped to standardized measures. This criterion should aid the clinical evaluation of new therapies, improve comparability between trials, and facilitate innovative trial designs.