Macaraeg Marci, Baker Elizabeth, Handorf Elizabeth, Matt Michael, Baker Elizabeth K, Brunner Hermine, Grom Alexei A, Henrickson Michael, Huggins Jennifer, Zhang Wenying, Lee Pui, Marsh Rebecca, Schulert Grant S
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Arthritis Rheumatol. 2025 May;77(5):596-605. doi: 10.1002/art.43065. Epub 2024 Dec 29.
Syndrome of undifferentiated recurrent fevers (SURF) is characterized by recurrent fevers and autoinflammation without a confirmed molecular diagnosis of a hereditary recurrent fever syndrome, and not fulfilling criteria for periodic fever, adenitis, pharyngitis, aphthous stomatitis syndrome (PFAPA). The goal of this study was to characterize clinical features of patients with SURF compared to patients with PFAPA and to analyze their cytokine signature, genetic variations, and responses to treatment.
We enrolled 46 patients observed at Cincinnati Children's Hospital Medical Center. Baseline data and inflammatory cytokines were collected at enrollment, and their clinical course was followed. Cytokine analysis was performed using a cytokine multiplex assay. Many patients had specific or whole exome genetic testing.
The prevalence of rash and arthralgias were higher in patients with SURF compared to patients with PFAPA. Pharyngitis and adenopathy were less frequent. A subset of patients with SURF clustered together with elevated proinflammatory cytokines and more frequently required biologic therapy. Focused analysis of whole exome sequencing data revealed that variants of unknown clinical significance (VUCS) were frequently identified in genes implicated in B cell development, immunodeficiencies, and inflammatory bowel disease risk. Treatments for patients with SURF commonly included on-demand steroids, colchicine, and anti-interleukin-1 therapy.
Our findings suggest SURF is a heterogeneous group but has distinct clinical and immunologic features from disorders such as PFAPA. Patients have frequent VUCS, which may have relevance to disease pathogenesis. A subset of patients showed more inflammation and an increased need for biologic therapy. Further research is necessary to define whether there exist distinct SURF endotypes and to better predict treatment outcomes.
未分化型复发性发热综合征（SURF）的特征为反复发热和自身炎症反应，且未确诊为遗传性复发性发热综合征，也不符合周期性发热、腺炎、咽炎、口疮性口炎综合征（PFAPA）的标准。本研究的目的是比较SURF患者与PFAPA患者的临床特征，并分析他们的细胞因子特征、基因变异及对治疗的反应。
我们纳入了在辛辛那提儿童医院医疗中心观察的46例患者。在入组时收集基线数据和炎性细胞因子，并跟踪他们的临床病程。使用细胞因子多重检测法进行细胞因子分析。许多患者进行了特定或全外显子组基因检测。
与PFAPA患者相比，SURF患者皮疹和关节痛的发生率更高。咽炎和腺病较少见。一部分SURF患者聚集在一起，促炎细胞因子升高，更频繁地需要生物治疗。对全外显子组测序数据的重点分析显示，在与B细胞发育、免疫缺陷和炎症性肠病风险相关的基因中经常发现临床意义不明的变异（VUCS）。SURF患者的治疗通常包括按需使用类固醇、秋水仙碱和抗白细胞介素-1治疗。
我们的研究结果表明，SURF是一个异质性群体，但具有与PFAPA等疾病不同的临床和免疫学特征。患者常有VUCS，这可能与疾病发病机制有关。一部分患者表现出更多炎症，对生物治疗的需求增加。有必要进一步研究以确定是否存在不同的SURF内型，并更好地预测治疗结果。
