REVIEWCurrent understanding of the pathophysiology of systemic juvenile idiopathic arthritis (sJIA) and target-directed therapeutic approaches

- Systemic JIA is the most severe form of juvenile idiopathic arthritis.
- The pathophysiology of sJIA remains largely unknown.
- Expression patterns of innate cytokines provide pathophysiological insights.
- Associated polymorphisms in single genes are too weak to confer sJIA.
- Modern treatment of sJIA includes target-directed cytokine-blocking strategies.

Because of its distinct clinical and laboratory features, reflecting systemic inflammation, sJIA can be distinguished from other forms of JIA which usually present as a milder phenotype. The exact pathophysiology of sJIA, however, remains unknown. Profound dysregulation of innate pro- and anti-inflammatory cytokines, and rapid clinical response to cytokine blocking strategies in sJIA patients suggest impaired control mechanisms in innate immune cells contributing to sJIA pathogenesis. Endogenous TLR ligands, such as S100 protein complexes, enhance the pro-inflammatory phenotype. Associations with polymorphisms in cytokine genes and their receptors suggest a genetic component. Furthermore, genetic associations that have been reported in familial hemophagocytic lympohistiocytosis also exist in patients with sJIA-associated macrophage activation syndrome, a severe complication of sJIA. Reported mutations in single genes, however, are too weak to confer sJIA, suggesting a multi-factorial mode of inheritance. We provide an overview of current pathophysiological concepts, state-of-the-art treatment regimens, and unanswered questions in sJIA.