JAK inhibitors in autoinflammation

Abstract

Interferonopathies are a subset of autoinflammatory disorders with a prominent type I IFN gene signature. Treatment of these patients has been challenging, given the lack of response to common autoinflammatory therapeutics including IL-1 and TNF blockade. JAK inhibitors (Jakinibs) are a family of small-molecule inhibitors that target the JAK/STAT signaling pathway and have shown clinical efficacy, with FDA and European Medicines Agency (EMA) approval for arthritic and myeloproliferative syndromes. Sanchez and colleagues repurposed baricitinib to establish a significant role for JAK inhibition as a novel therapy for patients with interferonopathies, demonstrating the power of translational rare disease research with lifesaving effects.

Figure 1. Disease mechanisms and new therapeutic strategy for the interferonopathies.

The interferonopathies including SAVI, CANDLE, and AGS are associated with overproduction of type I IFNs, IFN-α and IFN-β, through diverse mechanisms including pathways involving nucleic acid sensing and intracellular stress. These cytokines bind to the common IFN a/β receptor, leading to phosphorylation and activation of the JAK/STAT pathway, with phosphorylation and translocation of STAT proteins to the nucleus. The STATs subsequently stimulate transcription of several IFN-induced genes that are part of a clinically validated IFN gene signature. Like other autoinflammatory diseases, IFNs stimulate the further expression and release of IFNs, thereby amplifying inflammation. JAK inhibitors (Jakinibs) block the activation of JAK, preventing the expression of IFN-induced genes and the autoinflammatory loop. IRE, IFN-regulatory element; IRF3, IFN-regulatory factor 3; TBK1, TANK-binding kinase 1.