Abstract
Background
Undifferentiated systemic autoinflammatory diseases (USAID) comprise a heterogeneous group of disorders characterized by recurrent systemic inflammation without an identifiable monogenic cause.Objective
To describe the phenotypic and therapeutic features of adult USAID and identify phenotypic clusters.Methods
We conducted a retrospective single-center study at the French Reference Center for Autoinflammatory Diseases between 2010 and 2025. USAID was defined as recurrent systemic attacks with ≥3 documented C-reactive protein (CRP) elevations and no pathogenic variant identified. Therapeutic response was classified as complete (CR) or partial (PR). Hierarchical cluster analysis included clinical and biological variables.Results
Among 150 patients (65.3% women; median age at onset 14 [0-64] years), recurrent attacks occurred in 87.3%. The most frequent manifestations were cutaneous (87.3%), fever (84%), asthenia (80%), musculoskeletal (79.3%), and abdominal involvement (63.3%). Colchicine was prescribed in 56.7% (CR 8.2%, PR 44.7%). Biologic therapies included anti-TNFα (n = 32; CR 21.9%, PR 31.3%), anti-IL-1 (n = 24; CR 25%, PR 16.7%), anti-IL-6 (n = 22; CR 31.8%, PR 31.8%), and JAK inhibitors (n = 16; CR 18.8%, PR 37.5%). Four clusters were identified: Cluster 1 (15.3%): fever, aphthous ulcers, pharyngitis, abdominal pain and lymphadenopathy. Cluster 2 (27.3%): brief attacks, urticaria and abdominal pain. Cluster 3 (19.3%): prolonged attacks, prominent arthralgia, arthritis, and myalgia. Cluster 4 (38%): predominantly men, older age at onset, frequent neutrophilic dermatoses. Treatment responses did not differ significantly between clusters.Conclusion
Adult USAID patients can be subdivided into four clusters. Phenotypic stratification may help structure diagnostic reasoning and guide future therapeutic research.