[What is an undifferentiated systemic autoinflammatory disease in adults?]

Systemic autoinflammatory diseases (SAIDs) are associated with a dysregulation of innate immunity leading to recurrent or chronic inflammation. There are both well-characterized monogenic forms, such as familial Mediterranean fever, cryopyrinopathies and VEXAS syndrome, and multifactorial forms defined by classification criteria, such as Still's disease, Schnitzler syndrome and SITRAME. However, a significant proportion of patients, estimated at up to 73% in some series, present with an autoinflammatory phenotype without any identified pathogenic variant or established diagnosis based on classification criteria. These situations are grouped under the term undifferentiated systemic autoinflammatory diseases (USAID). In adults, the most common manifestations are recurrent fever, fatigue, myalgia, arthralgia, cutaneomucous and digestive features, ENT or ocular involvement. Clinical heterogeneity contributes to delayed diagnosis, which can take several years. Diagnosis is based on repeated documentation of a biological inflammatory syndrome, the progression of symptoms over at least six months, the exclusion of common differential diagnoses (infections, cancers, haematological disorders or autoimmune diseases) and the absence of criteria allowing to classify the patient to a defined entity. Investigations include repeated biological tests, screening for immune deficiencies or autoantibodies, and sometimes genetic testing to detect monogenic diseases with either germinal or somatic variants. In the absence of specific criteria, response to treatments targeting innate immunity, such as colchicine or cytokine inhibitors (IL-1, IL-6, TNF, JAK), may confirm the diagnosis. USAID in adults is an emerging entity, on the borderline between monogenic and multifactorial diseases, the recognition of which is essential to reduce diagnostic uncertainty and adapt management.