Despite the identification of several promising drug targets and a vastly expanded understanding in the pathoetiology of the disease, no drug has ever been approved for the treatment of childhood-onset SLE (cSLE). Reasons for this profound dearth of approved treatments for cSLE include the lack of well validated, high-performing outcome and response measures for use in clinical trials to accurately capture relevant treatment benefits, both from a physician and a patient perspective. The objective of this application is to validate and calibrate measures of clinically relevant changes in cSLE as rated by the treating physician and patients with cSLE. The principal hypothesis to be tested is that improved response and outcome measures facilitate the accurate delineation of clinically relevant treatment effects in cSLE. In our approach to this study, we will take advantage of available longitudinal data from well-phenotyped cSLE cohorts from South America, the United States of America, and the United Kingdom (n= >1,800), besides prospectively collecting longitudinal data on 100 cSLE patients. We will test the principal hypothesis and achieve the objective of this application by pursuing the following specific aims: 1: To comprehensively validate the Preliminary Criteria of cSLE Flare, using prospective cSLE registries with the goal of achieving ACR/ EULAR endorsement.
Aim 2 : To provide enhanced tools for capturing clinically relevant Response to Therapy with cSLE.
Aim 3 : To develop an improved scoring algorithm for quantifying cSLE-associated Damage.
Aim 4 : To validate the PROMIS (Patient-Reported Outcomes Measurement Information System) Pediatric Short Forms in cSLE, focusing on clinically relevant changes over time. Upon completion of this research, enhanced outcome measures will be available that are ready for use as endpoints in clinical trials of cSLE. These are destined to simplify the conduct of adequately powered &less costly clinical trials of novel medications for children and adolescents with cSLE. Furthermore, we will delineate clinically relevant changes in cSLE from a patient perspective, capitalizing on the superior scaling properties offered by the NIH PROMIS Item Banks.
Our research is poised to have a major impact on the U.S. public health, because cost of care of cSLE is roughly 5 times higher than that of SLE in adults and in the realm of that of childhood-leukemia. Currently, all cSLE therapy is off-label and not based on high-level medical evidence. Like with other chronic diseases, this not only poses a risk on patient safety but also increases the cost of medical care while worsening the long- term medical outcomes of children and adolescents with cSLE, including their quality of life.