Predictive factors for therapeutic response and cluster analysis in syndrome of undifferentiated recurrent fever (SURF)

Abstract

Introduction: Syndrome of undifferentiated recurrent fever (SURF) refers to a group of recurrent fevers without a clear monogenic cause. Clinical spectrum, treatment response predictors and management strategies remain unclear.

Objective: This study aims to longitudinally analyse a homogeneously selected cohort of 101 SURF patients, to identify factors associated with colchicine resistance and to evaluate the efficacy of interleukin-1 (IL-1) inhibitors.

Methods: Patients were enrolled in the Eurofever Registry, carefully excluding those with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA); familial Mediterranean fever and other known monogenic recurrent fevers. Demographic, clinical and treatment data were analysed to identify predictors of colchicine resistance and define subgroups through cluster analysis.

Results: Common symptoms included fever, arthralgia, abdominal pain and myalgia, with PFAPA-like features (lymphadenopathy, tonsillitis, oral aphthae) observed in one-third of cases, sporadically. Colchicine efficacy, assessed in 77 patients, revealed complete response in the majority of patients (61%). Univariable analysis identified PFAPA-like features, including aphthous stomatitis (p=0.001), cervical lymphadenopathy (p=0.012) and exudative tonsillitis (p=0.004), as associated with colchicine resistance. Multivariable analysis confirmed aphthous stomatitis as an independent predictor of resistance (p=0.014). Tonsillectomy was ineffective. IL-1 inhibitors (anakinra, canakinumab) were beneficial in refractory cases. Cluster analysis revealed three distinct subgroups with varying symptoms and colchicine responses.

Conclusions: These findings provide new insights into SURF, identifying predictors of colchicine resistance and supporting the efficacy of IL-1 blockade. Cluster analysis suggests the heterogeneity within SURF, reinforcing the need for refined diagnostic criteria and personalised treatment strategies.

Keywords: Biological Therapy; Hereditary Autoinflammatory Diseases; Immune System Diseases; Inflammation.

Figure 1. Clinical characteristics of the 101 described patients. The X-axis represents the number of patients. The frequency of each symptom, listed on the Y-axis, is shown as a percentage and stratified in green for symptoms present ‘Always’ and in light blue for symptoms present ‘Often/Sometimes’.

Figure 2. Colchicine treatment in the cohort: (A) Efficacy at last follow-up in 77 SURF patients (complete efficacy in green, partial in blue, inefficacy in black). Data are shown as percentages, with patient numbers in parentheses. (B) Colchicine efficacy observed at 1 year, 2 years and 5 years after treatment initiation, categorised as complete efficacy (green), partial efficacy (blue) and inefficacy (red), with percentages indicated on the bars. (C) Reasons for colchicine discontinuation in the 40 patients who stopped treatment. Data are shown as percentages, with patient numbers in parentheses. (D) Kaplan-Meier survival estimates for complete response to colchicine in the cohort (n=77), showing the probability of achieving and maintaining a complete response over time, with the 95% CI shaded. SURF, syndrome of undifferentiated recurrent fever.

Figure 3. Cluster analysis in the SURF cohort. (A) Histograms showing symptom frequency across three clusters, with black indicating presence and grey absence. Clinical features and patient numbers are listed. (B) Kaplan-Meier survival estimates for complete colchicine response across clusters, showing a trend for better response in Cluster 3, followed by Cluster 1 and Cluster 2 (p=0.1096). Abd, abdominal; Cerv. Lymph, cervical lymph nodes; Eryth, erythematous; Ex, exudative; SURF, syndrome of undifferentiated recurrent fever.