The meaning of clinical remission in polyarticular juvenile idiopathic arthritis: gene expression profiling in peripheral blood mononuclear cells identifies distinct disease states.

Objective—The development of biomarkers to predict response to therapy in polyarticular juvenile idiopathic arthritis (JIA) is an important issue in pediatric rheumatology. An critical step in this process is determining whether there is biological meaning to clinically derived terms such as “active disease” and “remission.” We used a systems biology approach to address this question. Methods—We performed gene transcriptional profiling on children who fit criteria for specific disease states as defined by consensus criteria developed by Wallace et al. (J Rheumatol 2005). Children with active disease (AD, n=14), clinical remission on medication (CRM, n=9) and clinical remission off medication (CR, n=6) were studied, in addition to healthy control children (n=13). Transcriptional profiles in peripheral blood mononuclear cells (PBMC) were obtained using Affymetrix U133 Plus 2.0 Arrays. Results—Hierarchical cluster analysis and predictive modeling demonstrated that the clinicallyderived criteria represent biologically-distinct states. Minimal differences were seen between children with AD and those with CRM. Thus, underlying immune/inflammatory abnormalities persist despite response to therapy. The PBMC transcriptional profiles of children in remission did not return to normal, but revealed networks of pro- and anti-inflammatory genes suggesting that “remission” is a state of homeostasis, not a return to normal. Conclusions—Gene transcriptional profiling of PBMC reveals that clinically-derived criteria for JIA disease states reflect underlying biology. We also demonstrate that neither CRM nor CR states result in resolution of the underlying inflammatory process, but are more likely to be states of balanced homeostasis between pro- and anti-inflammatory mechanisms.