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Systemic JIA (SJIA) is distinguished from other forms of JIA by the prevalence of the severe, life-threatening complications macrophage activation syndrome (SJIA-MAS) and lung disease (SJIA-LD). Alternative therapeutics are urgently needed, as disease pathogenesis diverges from what is observed in SJIA, and currently available biologics are insufficient. SJIA-MAS, defined by a cytokine storm and dysregulated proliferation of T-lymphocytes, and SJIA-LD which presents with lymphocytic interstitial inflammation and pulmonary alveolar proteinosis, are both thought to be driven by IFNs, in particular the type II IFN-γ. Involvement of IFNs and a possible crosstalk of type I IFNs with existing biologics indicate a distinct role for the JAK-STAT signalling pathway in the pathogenesis of SJIA-MAS and SJIA-LD. Here, we review this role of JAK-STATs and IFNs in SJIA complications and discuss how new insights of ongoing research are shaping future therapeutic advances in the form of JAK inhibitors and antibodies targeting IFNs. [ABSTRACT FROM AUTHOR]

Rationale: IL-18 is a member of the IL-1 cytokine family, and elevated blood IL-18 concentrations associate with disease activity in macrophage activation syndrome (MAS) and poor clinical outcomes in severe inflammatory and septic conditions.Objectives: Although recent investigations provide mechanistic evidence for a contribution of IL-18 to inflammation and hyperinflammation in sepsis and MAS, we sought to study regulatory mechanisms underlying human IL-18 expression.Methods: Samples from in vivo and in vitro endotoxin rechallenge experiments, patients with inflammatory disease, and isolated human monocytes treated with various stimulants and drugs were tested for cytokine gene and protein expression. Serum IL-18 expression with or without JAK/STAT inhibition was analyzed in two MAS mouse models and in a patient with recurrent MAS.Measurements and Main Results: Peripheral blood and monocytic IL-18 expression escaped LPS-induced immunoparalysis. LPS-stimulated primary human monocytes revealed specific IL-18 expression kinetics controlled by IFNα/β signaling. JAK/STAT inhibition or IFNβ neutralization during LPS stimulation blunted cytokine expression. Similarly, microtubule-destabilizing drugs abrogated LPS-induced IL18 expression, but this effect could be fully reversed by addition of IFNα/β. Ex vivo analysis of inflammatory disease patients' whole blood revealed strong correlation of type I IFN score and IL18 expression, whereas JAK/STAT inhibition strongly reduced IL-18 serum levels in two MAS mouse models and in a patient with recurrent MAS.Conclusions: Our data indicate that IL-18 (but not IL-1β) production from human monocytes requires cooperative Toll-like receptor and IFNα/β signaling. Interference with IFNα/β expression or signaling following JAK/STAT inhibition may control catastrophic hyperinflammation in MAS. [ABSTRACT FROM AUTHOR]