Autoinflammatory Diseases: New Insights into Pathophysiology and Diagnosis

Abstract

Autoinflammatory diseases (AIDs) are a heterogeneous group of rare disorders characterized by inappropriate activation of the innate immune system, leading to recurrent or persistent episodes of sterile systemic inflammation. Major advances in molecular genetics and next-generation sequencing have substantially improved our understanding of these disorders, enabling the identification of numerous monogenic forms and the development of a classification based on the underlying pathogenic pathways. In children, AIDs represent an important cause of unexplained recurrent fever and chronic inflammation, with highly variable clinical presentations involving the skin, joints, gastrointestinal tract, serosal membranes, eyes, central nervous system, lungs, or blood vessels.

Inflammasomopathies, including familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency, PAPA syndrome, and disorders associated with NLRC4, NLRP1, or NLRP12, result from excessive inflammasome activation and increased production of interleukin-1β and/or interleukin-18. Type I interferonopathies, such as Aicardi-Goutières syndrome, STING-associated vasculopathy with onset in infancy, and CANDLE/PRAAS, are characterized by persistent activation of the type I interferon pathway. NF-κB-related disorders, cytokine dysregulation syndromes, TNF receptor-associated periodic syndrome, deficiency of adenosine deaminase 2, and disorders affecting ubiquitination, cell death, or cytoskeletal regulation further broaden the pathophysiological spectrum of AIDs.

Diagnosis relies on a structured approach integrating careful phenotypic assessment, exclusion of major differential diagnoses, biological evaluation of inflammation, and the appropriate use of orienting biomarkers, including serum amyloid A, interleukin-18, and the type I interferon signature. Multigene panels, whole-exome sequencing, and, in selected cases, whole-genome sequencing play an increasingly important role in diagnostic confirmation. However, variants of uncertain significance require cautious interpretation based on clinical, biological, familial, and functional data. Identification of the underlying molecular mechanism now allows the use of targeted therapies, particularly interleukin-1 inhibitors, tumor necrosis factor inhibitors, and Janus kinase inhibitors, paving the way toward precision medicine in children with autoinflammatory diseases.