Our studies in children with rheumatic diseases have led to the identification of two of the oldest cytokines, type I interferon (IFN) and interleukin 1 (IL-1), as important pathogenic players in systemic lupus erythematosus (SLE) and systemic onset juvenile arthritis (SoJIA), respectively. These findings were obtained by studying the transcriptional profiles of patient blood cells and by assessing the biological and transcriptional effect(s) of active patient sera on healthy blood cells. We also identified a signature that can be used to promptly diagnose SoJIA from other febrile conditions. Finally, our pilot clinical trials using IL-1 blockers have shown remarkable clinical benefits in SoJIA patients refractory to other medications.