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Abstract Background Systemic autoinflammatory disorders (SAIDs) represent a growing spectrum of diseases characterized by dysregulation of the innate immune system. The most common pediatric autoinflammatory fever syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), has well defined clinical diagnostic criteria, but there is a subset of patients who do not meet these criteria and are classified as undefined autoinflammatory diseases (uAID). This project, endorsed by PRES, supported by the EMERGE fellowship program, aimed to analyze the evolution of symptoms in recurrent fevers without molecular diagnosis in the context of undifferentiated AIDs, focusing on PFAPA and syndrome of undifferentiated recurrent fever (SURF), using data from European AID registries. Methods Data of patients with PFAPA, SURF and uSAID were collected from 3 registries including detailed epidemiological, demographic and clinical data, results of the genetic testing and additional laboratory investigations with retrospective application of the modified Marshall and PRINTO/Eurofever classification criteria on the cohort of PFAPA patients and preliminary SURF criteria on uSAID/SURF patients. Results Clinical presentation of PFAPA is variable and some patients did not fit the conventional PFAPA criteria and exhibit different symptoms. Some patients did not meet the criteria for either PFAPA or SURF, highlighting the heterogeneity within these groups. The study also explored potential overlaps between PFAPA and SURF/uAID, revealing that some patients exhibited symptoms characteristic of both conditions, emphasizing the need for more precise classification criteria. Conclusions Patients with recurrent fevers without molecular diagnoses represent a clinically heterogeneous group. Improved classification criteria are needed for both PFAPA and SURF/uAID to accurately identify and manage these patients, ultimately improving clinical outcomes.

Abstract Background Among the various numbers of different autoinflammatory diseases (AIDs), the absolute majority of them remains rare, with a single representative in large populations. This project, endorsed by PRES, supported by the EMERGE fellowship program, and performed in line with the Metadata registry for the ERN RITA (MeRITA), has the objective of performing a data synchronization attempt of the most relevant research questions regarding clinical features, diagnostic strategies, and optimal management of autoinflammatory diseases. Results An analysis of three large European registries: Eurofever, JIR-cohort and AID-Net, with a total coverage of 7825 patients from 278 participating centers from different countries, was performed in the context of epidemiological and clinical data merging. The data collected and evaluated in the registries does not cover only pediatric patients, but also adults with newly diagnosed AIDs. General aspects of the existing epidemiological data have been discussed in the context of patient global distribution, potential diagnostic delays, access to genetic testing, and the availability of the treatment. Conclusions In general, the results indicate a great potential for upcoming collaborative work using existing data in cohorts that enhance the quality of medical care performed for patients with autoinflammatory diseases.