Background/Purpose: Syndrome of Undifferentiated Recurrent Fevers (SURF) refers to patients with recurrent fevers who do not meet clinical or classification criteria for Periodic Fevers, Aphthous stomatitis, Pharyngitis, and Adenitis (PFAPA) syndrome or Hereditary Recurrent Fever syndromes (HRFs). Most studies on patients with SURF reveal heterogeneous presentations and responses to treatment. The aims of this study were to define endotype groups within SURF, and their treatment responses.

Methods: SURF was defined as at least 3 stereotypical recurrent fever episodes not fitting clinical criteria for PFAPA or HRFs. Patient data were collected from Cincinnati Children’s Hospital Medical Center (CCHMC), University of Michigan (UofM), Texas Children’s Hospital (TCH), and Boston Children’s Hospital (BCH). Cytokine analysis was performed on available samples. Patients were clustered using age and clinical characteristics by Partitioning Around Medoids (PAM), Hierarchical, and K-prototype clustering methods. Characteristics associated with treatment responses were analyzed using univariable and multivariable regression.

Results: A total of 110 patients were included (CCHMC=65, UofM=15, BCH=15, TCH=15). PAM clustering showed three main groups: group 1 (n=57) largely resembled PFAPA but with frequent abdominal pain and myalgia; group 2 (n=30) had rash and arthralgias; and group 3 (n=23) was fever predominant. Cytokine analysis of these clusters showed elevated levels of IFN- β in group 3, a group that was also more likely to have complete response to on demand steroids. Regression analyses supported that patients without musculoskeletal complaints tended to have a complete response to on demand steroids, patients without GI complaints tended to have complete response to colchicine, patients with anorexia tended to have a complete response to tonsillectomy/adenoidectomy, and that patients with headache and arthralgias tended to receive anti-IL1 treatment and have a complete response. Genetic analysis showed high enrichment for genes associated with innate immunity in Groups 1 and 2 (enrichment score 5.75 and 4.72, respectively).

Conclusion: We found three distinct groups of SURF patients: 1. PFAPA-like, 2. rash and arthralgias, and 3. fever predominant. This third group was immunologically distinct and most likely to respond to on-demand steroids. Groups 1 and 2 tended to have high enrichment scores for genes important in innate immunity. Larger prospective studies are needed to better define the groups that exist within SURF.

Patient Demographics

PAM Cluster Analysis of age and clinical characteristics

Treatment responses per cluster

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinct-endotypes-of-surf-associated-with-clinical-phenotypes-inflammatory-cytokines-and-treatment-responses/