New genes, pathways and therapeutic targets in autoinflammatory diseases

Studies in 2023 have described eight new monogenic autoinflammatory diseases and their accompanying disease-causing mutations, uncovering clinical phenotypes, pathogenic mechanisms and therapeutic targets. Researchers have identified autoinflammatory pathways linked to mitochondrial dysfunction or overactivation of SRC family kinases.

Key advances

• Characterization of a new autoinflammatory disease, loss of IL-1 receptor sensitivity to its antagonist (LIRSA), highlights the role of IL-1 in sterile bone inflammation and led to the development of an IL-1 inhibitor⁴.

• Newly discovered ARF1 mutations cause an ARF-dependent type interferonopathy, the characterization of which provides pathogenic insight and supports a link between type I interferon signalling, mitochondrial dysfunction and neurological impairment⁷.

• Three family carrying autosomal dominant mutations in STAT4 present with disabling pansclerotic morphea partially responsive to ruxolitinib, demonstrating the potential of JAK inhibition in this previously untreatable disorder⁸.

• Gain-of-function mutation in LYN, which encodes a SRC tyrosine kinase, is associated with an autoinflammatory disease responsive to TNF inhibition and the SRC kinase inhibitor dasatinib, adding to an emerging group of diseases known as kinasopathies⁹.