Clinical Manifestations and Treatment Response of Patients With Syndrome of Undifferentiated Recurrent Fever ( SURF )

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Systemic autoinflammatory diseases (AIDs) are a heterogeneous group of inborn errors of immunity characterized by episodes of sterile inflammation without evidence of pathogenic autoantibodies or autoreactive T lymphocytes [1]. The most known manifestation of AIDs is recurrent fever, often associated with inflammatory involvement of joints, brain, eyes, skin, and serous membranes. Peripheral serum inflammatory markers, as C reactive protein and serum amyloid A, always increase during attacks [2]. AIDs are rare (incidence of < 1/2000 individuals) [3], although they are increasingly recognized worldwide. Most AIDs are caused by a single genetic variant, although some may result from somatic mosaicism or low-penetrance variants [4, 5]. Genetic testing is necessary for molecular diagnosis, which is confirmed in patients with typical symptoms and pathogenic variants [1]. Among patients with clinical signs of AIDs, at least 40% have no molecular diagnosis, and approximately 50% have no pathogenic variants in AID-related genes analyzed with targeted next-generation sequencing panels [6]. Most of these patients meet classification criteria for periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome [7]. PFAPA syndrome is the most common polygenic AID, characterized by recurrent episodes of oral ulcers, bilateral cervical lymphadenopathy, and/or exudative tonsillitis. PFAPA syndrome has a self-limiting clinical course, with remission during late childhood. In cases of frequent and/or severe inflammatory attacks that cause significant discomfort to the patient, tonsillectomy is suggested, with a high rate of efficacy (75%–90%). Diagnostic criteria for PFAPA syndrome have been published elsewhere [8]. Another group of patients presenting with recurrent fever and negative or inconclusive genetic tests for AIDs has been classified under the term syndrome of undifferentiated recurrent fever (SURF) [9]. SURF patients do not carry variants in monogenic AIDs-associated genes and do not fulfill the diagnostic criteria for PFAPA syndrome or other inherited recurrent fever syndromes. Despite evolving knowledge of the molecular mechanisms underlying AIDs, it remains unclear whether SURF represents a distinct clinical entity with complex, polygenic inheritance or a heterogeneous group of patients with similar manifestations and what is the most effective treatment for these patients. In this study, we performed a systematic review with meta-analysis to highlight the clinical features and the best treatment options in SURF patients. We searched all original English studies in PubMed database (https://pubmed.ncbi.nlm.nih.gov; accessed on 2 June 2023) with the queries: “SURF” AND “fever”; “undefined/undifferentiated” AND “recurrent/periodic fever”; “unclassified autoinflammatory disease”; “undefined systemic autoinflammatory disorders”. The search was conducted independently by two authors (E.L. and R.P.). The libraries “meta” and “metafor” of R (version 4.3.2) were used to perform the meta-analysis of those studies that fulfilled the criteria reported above. The efficacy rates (number of responders to treatment/number of treated patients) of steroids, colchicine, anakinra, NSAIDs, DMARDs, and tonsillectomy were determined from each study separately. Outcomes are presented as proportions and their 95% confidence intervals (CI). Heterogeneity across studies was evaluated by using the I2-statistic, with I2 > 50% indicating substantial heterogeneity [10]. Given the heterogeneity of the selected studies, a random-effects (RE) analysis was chosen for all meta-analyses. Of the 264 articles initially identified, 21 met the inclusion criteria (Figure S1) [11-31]. The main characteristics of these studies are summarized in Table S1. A total of 665 SURF patients are described; 40% (266/665 patients) are female. The largest cohort is from the international EUROFEVER registry, and additional cohorts are from the Netherlands, Italy, and the Middle East. The largest ethnic groups are Caucasian and Middle Eastern. Most patients present with symptoms during childhood, with 73/665 patients (10.9%) having onset in adulthood. We found relatives with a history of recurrent fevers of unknown origin in 69/665 patients (10.4%). The median age at disease onset is 6.4 years (±10.6) and the median age at study enrolment is 8.3 years (±4.1). The median delay in diagnosis is 3.4 years (±1.3). The clinical features of SURF are presented in Figure 1. Inflammatory attacks show a median duration of 5.5 days (±2.9) and a median relapse of 40 days (8.8 ± 3.1 attacks/year). Fever is reported in 607/665 (91.3%) patients. The most frequently reported symptoms during attacks are arthralgia, abdominal pain, and oral ulcers (almost 50% of patients). Myalgia and lymphadenopathy are reported by almost 30% of patients, while rash/erythema, pharyngitis, and headache are reported less frequently (22%–26% of patients). Fatigue, malaise, nausea/vomiting, diarrhea, and arthritis are reported in 10%–20% of patients, and chest pain, pericarditis, hepatosplenomegaly, and ocular manifestations in less than 10%. Urethritis/cystitis, scrotal pain, genital ulcers, sinusitis, febrile convulsions, neck stiffness, proteinuria, amyloidosis, and sensorineural deafness have been anecdotally reported. Treatment response comparisons in SURF patients estimated by RE analysis are shown in Figure 2. Detailed forest plots showing pooled estimates are presented in Figures S2–S7. On-demand steroidal and nonsteroidal anti-inflammatory drugs show similar results (0.68 [95% CI: 0.44–0.89] and 0.69 [95% CI: 0.27–0.99], respectively). The most commonly used long-term drugs are colchicine and the interleukin-1 inhibitor anakinra with quite similar results (0.59 [95% CI: 0.45–70] and 0.68 [95% CI: 0.30–0.98], respectively). DMARDs and tonsillectomy are used less frequently (0.18 [95% CI: 0.00–0.49] and 0.22 [95% CI: 0.00–0.72], respectively). SURF is an umbrella clinical entity recently included in AIDs and defined by recurrent fever attacks without any overt infectious disease, absent criteria for PFAPA syndrome, and negative genetic tests for monogenic AIDs. This clinical and laboratory classification of exclusion allows clinicians to study and follow a group of patients who present evidence of autoinflammation without treatment guidelines. The term allows to clearly differentiate these patients from those with evidence of tonsils as triggers of inflammatory flares even in the case of incomplete PFAPA criteria, also known as incomplete PFAPA patients, for which tonsillectomy is commonly effective [32]. Key findings of our study are reported in Table 1. The present study highlights the efficacy rate of long-term use of colchicine and anakinra in previously published SURF cohorts. Further studies in different ethnic groups are warranted to confirm this observation. Furthermore, a regular follow-up aimed at capturing evidence of newly emerging symptoms suggestive of a well-defined AID and a regular genetic re-screening are warranted. In fact, the number of monogenic diseases associated with recurrent fever is increasing, and some SURF patients can be molecularly defined with new sequencing techniques (i.e., multiplex ligation-dependent probe amplification, long-read sequencing) in the future. In the meantime, SURF classification allows for the study more deeply, even with omics techniques, a condition that appears to be polygenic in nature. Our study has several limitations. Some authors included in SURF cohorts also included patients without overt fever during flares (about 10%), suggesting different manifestations used to suspect an autoinflammatory process (i.e., positive inflammatory markers, etc.). These criteria of suspicion are not usually reported, introducing a possible enrolment bias affecting the interpretation of pooled data. Furthermore, different techniques of genetic sequencing used across different studies ma

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