Periodic fever syndromes in Chinese children and adolescents: a single-centre cohort study

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We aimed to evaluate the clinical and genetic characteristics of patients with periodic fever syndrome. And to evaluate the safety and efficacy of colchicine in the treatment of PFS. Methods : This study included patients diagnosed with PFS between April 2021 and January 2024 at Bei Jing Children's Hospital, Immunology Department. We retrospectively analyzed the clinical data (clinical features, laboratory findings and genetic features). The onset of the disease and adverse events following the use of colchicine were also analysed. Results : A total of 130 patients were included in this study, with a male to female ratio of 1.2:1. The mean (95% CI) ages at symptom onset and diagnosis were 3.59(3.06-4.11) years and 5.33(4.79-5.87) years, respectively. The average duration of the febrile episode is 3.92 days and the average frequency of the febrile episode is 3.44 weeks. During PFS flares, leukocytes, neutrophils, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were significantly higher than in inter-episode periods. The most frequently detected gene mutation is MEFV. Thirty-five patients were free of clinical symptoms 5 month after taking colchicine. Conclusion : We present a cohort of children and adolescence with periodic fever syndrome. The most common PFS is PFAPA and the most common gene mutation in PFS patients is MEFV. Colchicine is a safe and effective drug for the treatment of PFS. Periodic fever syndromes genetic features children colchicine Figures Figure 1 Figure 2 Introduction Fever is one of the most common symptoms in patients and most frequently is caused by infections. However, when infections are excluded, the remaining differential diagnosis includes malignancy, immunodeficiency, and inflammatory conditions, and if the fever is recurrent or periodic, auto-inflammatory conditions come to mind first. [ 1 ] Recurrent or periodic fever syndromes are defined by 3 or more episodes of unexplained fever in a 6-month period, occurring at least 7 days apart [ 2 ] . Periodic fever syndromes (PFS) are a group of disorders of innate immunity that cause multisystem inflammation and present as unexplained fluctuations or recurrent episodes of fever usually accompanied with inflammation in the joints, eyes, skin or serosal surfaces. Some of the patients may have other accompanying symptoms, such as oropharyngeal, gastrointestinal, dermatological or musculoskeletal manifestations. Although patients present with fever, they do not require antibiotics, anti-inflammatory drugs or other immunotherapies, and the fever resolves spontaneously over a period of time. Periodic fever syndromes are the most common type of autoinflammatory diseases. It is mediated by overactivation of the innate immune system in the absence of autoreactive antibodies or antigen-specific T cells [ 3 ] . The features of PFS are clinical inflammation, which varies according to the underlying genetic defect, and patients always have elevated acute phase reactants during the inflammatory episodes, manifesting mainly as an increase in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum amyloid A (SAA) [ 4 , 5 ] . The most common monogenic periodic fever syndromes are familial Mediterranean fever(FMF), mevalonate kinase deficiency/hyper immunoglobulin D syndrome(HIDS), cryopyrin-associated periodic syndrome(CAPS), periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, and tumor necrosis factor receptor-associated periodic syndrome(TRAPS). The clinical features of PFS are repeated febrile episodes lasting for a few days and accompanied by systemic inflammation. Treatment and management of patients with PFS is similar. Colchicine is recommended for FMF patients. It prevents febrile episodes, subclinical inflammation, and secondary amyloidosis, and has also been used in the treatment of PAFPA to prevent attacks [ 6 ] . Studies have shown that tonsillectomy is a highly effective surgical treatment option, curing more than 90% of PFAPA patients [ 7 ] . Glucocorticoids lead to the resolution of symptoms, but they also have side effects that we need to consider. Nonsteroidal anti-inflammatory drugs (NSAIDs) and IL-1 blockade may also be an option. Anakinra and Canakinumab were reported to provide response in patients with CAPS [ 8 ] . Anakinra is effective as well as safe in TRAPS [ 9 ] . The aim of our study was to evaluate clinical and genetic features in a large, well-characterised cohort of patients with periodic fever syndrome and to evaluate the safety and efficacy of colchicine in the treatment of PFS. Materials and methods Study population and the definitions This is a retrospective study. Patients who were diagnosed with periodic fever syndrome between April 2021 and January 2024 at Bei Jing Children’s Hospital, Immunology Department were enrolled. Demographic data, clinical characteristics, laboratory outcomes were documented by medical file screening. Gene variant analysis was performed with Sanger sequencing. The frequency, duration and adverse reactions of the patients before and after taking colchicine were analyzed by telephone follow-up. The diagnosis of FMF is made based on clinical findings rather than genetic testing. Currently, the internationally accepted diagnostic criteria for FMF is “Yalcinkaya-Ozen” criteria [10] ,it requires recurrent (≥3) attacks with at least 2 of the following 5 features: fever lasting between 12 and 72 hours, abdominal pain, chest pain, arthritis, and a positive family history for FMF. Diagnosis of PFAPA syndrome established according to modified Marshall criteria [11] ,regularly recurrent fever, absence of upper respiratory tract infection and at least one of the following clinical signs: pharyngitis, aphthous stomatitis or cervical adenitis, completely asymptomatic intervals between febrile episodes, normal growth and development. The diagnosis of CAPS depends mainly on clinical manifestations (the common clinical features are fever, urticarial rash, musculoskeletal symptoms, elevated acute phase reactants, and conjunctivitis) and genetic testing(pathogenic variants including R260W,D303N, L305P, E311K, T348M, L353P, A439V) [12] . Unclassified periodic fever syndrome was defined as recurrent episodes (with either strict periodicity or irregular intervals) lasting days to weeks, in which fever is the cardinal feature and other associated features are similar and predictable, with intervening intervals of weeks to months characterised by complete well-being. [1] . Ethics approval and consent to participate The study was approved by the Ethics Committee of Beijing Children's Hospital (Institutional Review Board (IRB) approved protocol [2022]-E-177-Y), and written informed consent was waived. Statistical analysis Statistical analyses were performed using the SPSS software version 26. Continuous and categorical variables are presented as mean±2SD(standard deviation) or number (percentage). We analysed the differences in the laboratory outcomes by using two-sample t-tests. Comparisons of non-normally distributed data were performed using the Mann Whiney U rank test. A two-tailed p-value of 0.05 was considered to be statistically significant. Results Patient characteristics A total of 130 patients (59 girls, 71 boys) were enrolled in the study between April 2021 and January 2024 in our pediatric immunology department. The demographic and clinical features of these patients are presented in Table 1. The mean age at symptom onset was 3.59 years. And the mean age at diagnosis was 5.33 years. The average time from symptom onset to diagnosis was 1.74 years. The mean duration of a febrile episode was 3.9 days with an interval between episodes of 3.4 weeks. All patients were asymptomatic during the afebrile period and showed normal growth and development. The maximum temperature during the episode was 39.9℃. The most common symptoms were Pharyngitis (74.6 %) and Cervical adenitis (40.8 %). Digestive symptoms (abdominal pain, nausea and vomiting or diarrhea) were also presented in some patients. Skin rash was mainly seen in patients with CAPS. The most common type of periodic fever syndrome is PFAPA (52.3%). Periodic fever is characteristic in a subset of patients (39.2%), but it is difficult to further differentiate the disease types. Oral corticosteroids (3.1%), colchicine (28.5%), thalidomide (2.3%) and NSAIDs (1.5%) were recommended to patients. But most patients did not accept any treatment (62.3%). Family medical history (first and second degree relatives) was found in 11 (8.5%) patients. Gene variant analysis was performed in 87 patients. No positive mutation was found in 38 patients (29.23%). In patients with positive mutations, MEFV was the most common mutation. Table 1 Demographic and clinical characteristics of patients Characteristics, n(%) or mean(95%CI) patients (n=130) Gender, male 71（54.6%） Age at symptom onset, years 3.59(3.06-4.11) Age at diagnosis, years 5.33(4.79-5.87) Time between onset and diagnosis，years 1.74(1.37-2.11) Fever Duration of the febrile episode, days 3.92(3.29-4.55) Frequency of the febrile episode, weeks 3.44(3.22-3.65) Cardinal features Pharyngitis 97(74.6%) Cervical adenitis 53(40.8%) Oral aphthosis 40(30.8%) Abdominal pain 11(8.5%) Nausea and vomiting or diarrhea 5(3.8%) Skin rash 3(2.3%) Maximal temperature，℃ 39.9(39.8-40.0) Types of disease FMF 4(3.1%) PFAPA 68(52.3%) CAPS 4(3.1%) HIDS 3(2.3%) Unclassified 51(39.2%) Treatment Corticosteroids 4(3.1%) Tonsillectomy 3(2.3%) Colchicine 38(29.2%) Thalidomide 3(2.3%) NSAID 2(1.5%) No treatment 80(61.6%) Family history 11(8.5%) Gene mutation Negative 38(29.23%) MEFV 33(25.38%) MVK 3(2.31%) NLRP3 4(3.08%) NLRP12 4(3.08%) NLRC4 1(0.77%) NOD2 1(0.77%) TNFAIP3 1(0.77%) PLCG2 1(0.77%) PIPK1 1(0.77%) MEFV mutation analysis MEFV mutations were detected in 33 patients, 21 patients(63.6%) were PFAPA. In PFAPA, FMF and other periodic fever syndromes, the p.E148Q(c.442G＞C) mutation was the most common type of mutation and was detected in 26 patients (78.79%). Other mutations, such as p.R408Q, p.P369S, p.c304R and p.R408Gln were also detected. The results of the MEFV mutation analysis are given in Table 2. Table 2 MEFV mutation analyses of the study population Types of disease Nucleotide Amino Acid Number of patients PFAPA(n=21) c.442G＞C p.E148Q 16 c.910G＞A c.1223G＞A c.1105C＞T p.c304R p.R408Q p.P369S 4 c.1105C＞T c1223G＞A p.R408Gln 1 FMF（n=3） c.442G＞C p.E148Q 3 Unclassified（n=9） c.442G＞C p.E148Q 7 c.1105C＞T p.P369S 2 Laboratory outcomes Findings of laboratory data during PFS flares and inter-episode periods are presented in Table 3. During flares, leukocytes, neutrophils, ESR and CRP were significantly higher than during inter-episode periods. But there were no significant differences in lymphocytes, monocytes, haemoglobin between flares and inter-episode periods. Table 3 Laboratory Findings During Episode and Inter-Episode Periods Parameter During Episodes Inter- Episodes P* Leukocytes（×10^9/L） 12.94±11.3 7.25±6.95 0.0001 Neutrophils（×10^9/L） 8.10±9.57 3.67±4.38 0.0001 Lymphocytes（×10^9/L） 3.26±3.85 3.04±4.06 0.724 Monocytes（×10^9/L） 1.09±1.32 94.62±339.68 0.135 Haemoglobin（g/L） 116.55±67.54 112.43±48.66 0.824 C-reactive protein(CRP, mg/L) 68.64±83.29 8.52±9.29 0.0001 Erythrocyte sedimentation rate(ESR ,mm/h) 40.07±41.10 11.12±15.32 0.0001 Efficacy and safety of Colchicine As showed at figure 1. Thirty-eight patients were treated with colchicine. Fourteen patients are PFAPA, 4 patients are FMF, 19 patients are other PFS(unclassified),1 patient is HIDS. One patient developed abdominal pain and alopecia after taking colchicine, which was severe, and the use of colchicine was suspended. One patient had abdominal pain, nausea, and dizziness after taking colchicine, one had abdominal pain and constipation after taking colchicine, and one had diarrhea after taking colchicine. But they continued to take colchicine. After taking colchicine, there was no significant difference in urea, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (gamma-GT), lactate dehydrogenase (LDH), creatine kinase lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), leukocytes, neutrophils, lymphocytes, monocytes, platelets, haemoglobin, CRP and ESR compared with those before taking colchicine. However, alkaline phosphatase (APS) and creatine kinase (CK) were significantly higher after taking colchicine than before(Table 4). Of the 37 patients who adhered to oral colchicine, 17 patients were free of clinical symptoms 1 month after taking colchicine. After 3 months of taking colchicine, 25 patients achieved clinical remission. After 5 months of follow-up, only 2 patients were not in remission and were considered ineffective (Figure 2). Table 4 Differences in laboratory outcomes before and after taking colchicine Before taking colchicine After taking colchicine P Urea（mmol/L） 3.75±0.97 4.49±1.18 0.063 Creatinina（umol/L） 29.84±10.00 33.34±10.19 0.341 ALT（U/L） 12.61±5.19 16.20±10.28 0.274 AST（U/L） 27.44±8.42 28.82±6.24 0.469 gamma-GT（U/L） 13.99±4.46 14.72±8.77 0.695 APS（U/L） 210.93±71.35 248.10±58.02 0.012* LDH（U/L） 215.85±47.72 214.71±34.66 0.322 CK（U/L） 72.30±36.18 107.67±41.61 0.003* CK-MB（U/L） 17.52±6.92 19.90±4.44 0.066 Leukocytes（×10^9/L） 7.846±2.55 9.26±3.78 0.159 Neutrophils（×10^9/L） 3.29±2.03 4.93±3.20 0.106 Lymphocytes（×10^9/L） 3.80±1.99 3.50±1.37 0.945 Monocytes（×10^9/L） 0.54±0.19 0.63±0.34 0.304 platelets（×10^9/L） 366.63±129.49 320.57±128.52 0.313 Haemoglobin（g/L） 120.9±12.26 128.19±9.30 0.053 CRP（mg/L） 10.57±10.19 12.57±11.18 0.569 ESR（mm/h） 20.11±21.99 14.48±13.02 0.204 gamma-GT: gamma glutamyl transpeptidase AST: Aspartate aminotransferase ALT: Alanine aminotransferase LDH: lactate dehydrogenase APS: Alkaline phosphatase CK: creatine kinase CK-MB: creatine kinase-MB Gene mutation analyses of the patients who taking colchicine Thirty-eight patients who took colchicine, their gene mutations are shown in Table 5. Twenty-one patients found no gene mutation or gene data were not available. Twelve patients had MEFV mutations, most of the MEFV mutations were p.E148Q. Other mutations included NLRP1, NLRP12,MVK and PIPK1. Table 5 Gene mutation analyses of the patients who taking colchicine Types of disease Nucleotide Amino Acid Number of patients Negative/NA - - 21 c.1105C＞T c1223G＞A p.R408Gln 1 c.1105C＞T c.442G＞C p.P369S p.E148Q 1 MEFV c.1105C＞T c.442G＞C p.Pro369Ser p.Glu148Gln 1 MEFV c.442G＞C p.E148Q 9 MEFV c.1105C＞T p.P369S 1 MEFV NLRP1 c.442G＞C c.3607C＞T p.E148Q p.H1203Y 1 NLRP12 c.1732A＞G S578G 1 MVK c.655G＞A p.Gly219Arg 1 PIPK1 c.1335T＞A p.H445Q 1 NA: Not available. Discussion Periodic fever syndromes (PFS) are a wide group of autoinflammatory diseases characterized by recurrent episodes of fever in the absence of microbial, autoimmune or malign conditions [13] . It is difficult to diagnose PFS in a large population, there is a lack of criteria for the diagnosis of PFS, and there can be considerable overlap in the clinical presentation of different diseases. The diagnosis of PFS depends on clinical symptoms, so there is an inevitable delay in diagnosis. Many patients have seen five or more hospital specialities before a diagnosis is made [14] . For doctors, knowing whether a patient has PFS means ruling out some common clinical problems such as infection, malignancy, immunodeficiency and inflammatory conditions. It is clear that autoinflammation can result from various pathogenic mechanisms. The most common mechanism is dysregulation of interleukin 1(IL-1) secretion, as seen in FMF and CAPS. In this study, the clinical findings, gene mutation analysis and treatment responses are elaborated in a large cohort of pediatric PFS patients. In our cohort, the male to female ratio was 1.2. In other studies, FMF incidence was reported to be equal between male and female [15, 16] ,and in PFAPA patients the male to female ratio was 1.2-1.6 [17, 18] .In our study, the mean age of disease onset and the mean age of disease diagnosed are 3.59 years and 5.33 years, respectively. In two studies conducted in Turkey, the mean age at disease onset was 5.3–5.4 years and mean age at diagnosis was 7.6–8.4 years in FMF patients [19, 20] .In a study from western Sweden, the median age of disease onset was 2 years (range 0.1–16 years) in PFAPA patients [21] . The most common symptom in our cohort was pharyngitis, which may be related to the fact that the majority of patients in our cohort were PFAPA. Skin rash, Nausea and vomiting or diarrhea are mostly seen in CAPS. In our study, MEFV variants were detected in 21 PFAPA patients, 3 FMF patients and 9 other PFS patients. This is similar to a previous study that found MEFV variants in 32.5% of PFAPA patients [22] . Mehmet et al showed that most PFAPA patients have heterozygous MEFV gene mutations [22] . MEFV mutations are also found in FMF patients, in some studies from Turkey, about 20% of general population in Turkey is carrier of a MEFV mutation. And the most common mutations are M694V, E148Q, M680I, V726A, and M694I [24-26] . In our study, CRP and ESR show elevations during episodes, along with leukocytosis. But Procalcitonin had normal values, which means infections are excluded. These are similar to the studies about PFAPA and FMF [27, 28] .CRP and ESR are acute phase reactants, patients with persistent elevations of these inflammatory markers between episodes are considered to be at higher risk for systemic amyloid deposition [29] . In a previous study, Kenan Barut et al found that patients with the homozygous M694V mutation also had elevated CRP and ESR between episodes [28] . Anemia is also reported in some studies that patients with recurrent FMF attacks [30] .However, there was no statistically difference in hemoglobin during episodes and Inter- Episodes of patients in our study. In the current study, neutrophils and leukocytes were higher during PFS flare, and the same results have been seen in other studies [31] . Colchicine is recommended for the treatment of FMF. In many studies, the effect of colchicine therapy has been well established in randomized trials [32, 33] . And it has been shown to be safe for the prophylaxis of acute episodes of FMF and for the prevention of amyloidosis in FMF. [31] .Colchicine binds in equimolar and a poorly reversible manner to soluble non-polymerized tubulin, forming a tubulin-colchicine complex [34] .This complex can change the structure and the function of the cytoskeleton, thereby influencing neutrophil immigration and adhesion [34, 35] . Colchicine has not been examined systematically in PFAPA and other PFS. In some studies, colchicine may be effective in the treatment of PFAPA [36, 37] . The study by Yonatan Butbul Aviel et al also demonstrated a statistically significant reduction in the frequency of PFAPA episodes following colchicine administration [38] .Our study is the first to demonstrate the efficacy and safety of colchicine in the treatment of PFS. In our study, 37 patients were treated with colchicine and 35 of them achieved clinical remission. Adverse events are also reported in our patients, but only one patient discontinued taking colchicine due to a serious adverse event. Other therapies such as corticosteroids, thalidomide and NSAIDs are also effective in controlling symptoms during an active episode. However, corticosteroids do not prevent relapses and may even increase the frequency of relapses, and patients' concerns about the side effects of the drugs may make them reluctant to use corticosteroids and look for other ways to prevent relapses [39] . Our study has identified an additional or alternative approach to the treatment of PFS. Colchicine may have a good safety profile to treat patients with PFS, especially those with frequent episodes. Conclusion The current diagnosis of PFAPA, FMF or other periodic fever syndrome is based on the patient's clinical symptoms. Our results indicated that the mean age of disease onset was 3.59 years old, but the average age at diagnosis was 5.33 years old. Previously, they were basically considered to have an infection and were treated with antibiotics. The most common PFS is PFAPA and the most common gene mutation in PFS patients is MEFV. Colchicine is a safe and effective drug for the treatment of PFS. Declarations Ethics approval and consent to participate The study was approved by the Ethics Committee of Beijing Children's Hospital (Institutional Review Board (IRB) approved protocol [2022]-E-177-Y), and written informed consent was waived. Consent for publication Not applicable. Availability of data and materials All data generated or analyzed during this study are included in this published article. Competing interests The authors declare that they have no competing interests. Funding Not applicable. Author’s contributions Xiongbin Chen proposed the study and wrote the first draft. Yulu Li, Mengyang Yang, Zhou Shu collected and analyzed the data. Huawei Mao guided the design of the study and helped to draft the manuscript. All authors read and approved the final manuscript. References Soon G S, Laxer R M. Approach to recurrent fever in childhood[J]. Can Fam Physician, 2017,63(10):756-762. John C C, Gilsdorf J R. Recurrent fever in children[J]. Pediatr Infect Dis J, 2002,21(11):1071-1077. Gattorno M, Hofer M, Federici S, et al. Classification criteria for autoinflammatory recurrent fevers[J]. Ann Rheum Dis, 2019,78(8):1025-1032. Hull K M, Shoham N, Chae J J, et al. 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Acta Paediatr, 2008,97(8):1090-1092. Padeh S, Brezniak N, Zemer D, et al. Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome[J]. J Pediatr, 1999,135(1):98-101. Butbul A Y, Tatour S, Gershoni B R, et al. Colchicine as a therapeutic option in periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome[J]. Semin Arthritis Rheum, 2016,45(4):471-474. Tasher D, Somekh E, Dalal I. PFAPA syndrome: new clinical aspects disclosed[J]. Arch Dis Child, 2006,91(12):981-984. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4411739","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":304178783,"identity":"5564b794-b738-43e2-aa7f-7f5852ab6d69","order_by":0,"name":"Xiongbin Chen","email":"","orcid":"","institution":"Department of Immunology, National Center for Children's Health, Beijing Children's Hospital of Capital Medical University, Beijing","correspondingAuthor":false,"prefix":"","firstName":"Xiongbin","middleName":"","lastName":"Chen","suffix":""},{"id":304178786,"identity":"241787e9-94a2-4b12-a5af-c194feb63873","order_by":1,"name":"Yulu Li","email":"","orcid":"","institution":"Department of Immunology, National Center for Children's Health, Beijing Children's Hospital of Capital Medical University, Beijing","correspondingAuthor":false,"prefix":"","firstName":"Yulu","middleName":"","lastName":"Li","suffix":""},{"id":304178788,"identity":"85d44342-4c32-41bd-aa35-ec3aa1024ece","order_by":2,"name":"Mengyang Yang","email":"","orcid":"","institution":"Department of Immunology, National Center for Children's Health, Beijing Children's Hospital of Capital Medical University, Beijing","correspondingAuthor":false,"prefix":"","firstName":"Mengyang","middleName":"","lastName":"Yang","suffix":""},{"id":304178790,"identity":"98ffc944-6a96-4714-aeee-cf7e1f084193","order_by":3,"name":"Zhou Shu","email":"","orcid":"","institution":"Department of Immunology, National Center for Children's Health, Beijing Children's Hospital of Capital Medical University, Beijing","correspondingAuthor":false,"prefix":"","firstName":"Zhou","middleName":"","lastName":"Shu","suffix":""},{"id":304178792,"identity":"5a46b1ab-988e-426e-b76c-89490651e544","order_by":4,"name":"Huawei Mao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAnElEQVRIiWNgGAWjYHACNiCWkCNdizHJWhgSG4hWr9t++NhjngqL9L7jCYwfPuYQocXsTFq6Mc8ZidyZZx4wS87cRoyWAzlm0rltErkbbiSwMfMSpeX8G6CWfxLpBsRruQGypUEigRQtz9Kk/xyTMJx55mEzkX45n3xMckZNnTzf8eSDHz4SowUBDpAQNTAtCaTqGAWjYBSMgpECAC+PNmcwawZwAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Immunology, National Center for Children's Health, Beijing Children's Hospital of Capital Medical University, Beijing","correspondingAuthor":true,"prefix":"","firstName":"Huawei","middleName":"","lastName":"Mao","suffix":""}],"badges":[],"createdAt":"2024-05-13 08:27:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4411739/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4411739/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57517659,"identity":"d0cdcab2-9b94-4aac-a011-a439b1c882c3","added_by":"auto","created_at":"2024-05-31 20:24:22","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":26181,"visible":true,"origin":"","legend":"\u003cp\u003ePatient taking colchicine\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4411739/v1/1b237cad45999d6bcb7a23b8.jpg"},{"id":57517660,"identity":"f764b8b3-bb87-4e23-a2e0-19af6c95cdbd","added_by":"auto","created_at":"2024-05-31 20:24:23","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":40400,"visible":true,"origin":"","legend":"\u003cp\u003ePatient response to colchicine\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4411739/v1/97aa0c6886277f3c26cea56d.jpg"},{"id":68709367,"identity":"2d620ad6-1035-471d-a1f9-19ad363701f9","added_by":"auto","created_at":"2024-11-11 08:53:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":600584,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4411739/v1/0e614392-9756-4f79-959f-7cae98dec276.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Periodic fever syndromes in Chinese children and adolescents: a single-centre cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFever is one of the most common symptoms in patients and most frequently is caused by infections. However, when infections are excluded, the remaining differential diagnosis includes malignancy, immunodeficiency, and inflammatory conditions, and if the fever is recurrent or periodic, auto-inflammatory conditions come to mind first.\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003eRecurrent or periodic fever syndromes are defined by 3 or more episodes of unexplained fever in a 6-month period, occurring at least 7 days apart\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Periodic fever syndromes (PFS) are a group of disorders of innate immunity that cause multisystem inflammation and present as unexplained fluctuations or recurrent episodes of fever usually accompanied with inflammation in the joints, eyes, skin or serosal surfaces. Some of the patients may have other accompanying symptoms, such as oropharyngeal, gastrointestinal, dermatological or musculoskeletal manifestations. Although patients present with fever, they do not require antibiotics, anti-inflammatory drugs or other immunotherapies, and the fever resolves spontaneously over a period of time.\u003c/p\u003e \u003cp\u003ePeriodic fever syndromes are the most common type of autoinflammatory diseases. It is mediated by overactivation of the innate immune system in the absence of autoreactive antibodies or antigen-specific T cells\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. The features of PFS are clinical inflammation, which varies according to the underlying genetic defect, and patients always have elevated acute phase reactants during the inflammatory episodes, manifesting mainly as an increase in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum amyloid A (SAA) \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. The most common monogenic periodic fever syndromes are familial Mediterranean fever(FMF), mevalonate kinase deficiency/hyper immunoglobulin D syndrome(HIDS), cryopyrin-associated periodic syndrome(CAPS), periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, and tumor necrosis factor receptor-associated periodic syndrome(TRAPS). The clinical features of PFS are repeated febrile episodes lasting for a few days and accompanied by systemic inflammation.\u003c/p\u003e \u003cp\u003eTreatment and management of patients with PFS is similar. Colchicine is recommended for FMF patients. It prevents febrile episodes, subclinical inflammation, and secondary amyloidosis, and has also been used in the treatment of PAFPA to prevent attacks \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Studies have shown that tonsillectomy is a highly effective surgical treatment option, curing more than 90% of PFAPA patients\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Glucocorticoids lead to the resolution of symptoms, but they also have side effects that we need to consider. Nonsteroidal anti-inflammatory drugs (NSAIDs) and IL-1 blockade may also be an option. Anakinra and Canakinumab were reported to provide response in patients with CAPS\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Anakinra is effective as well as safe in TRAPS\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe aim of our study was to evaluate clinical and genetic features in a large, well-characterised cohort of patients with periodic fever syndrome and to evaluate the safety and efficacy of colchicine in the treatment of PFS.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population and\u0026nbsp;the\u0026nbsp;definitions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a retrospective study. Patients who were diagnosed with periodic fever syndrome between April 2021 and January 2024 at Bei Jing Children’s Hospital, Immunology Department were enrolled. Demographic data, clinical characteristics, laboratory outcomes were documented by medical file screening. Gene variant analysis was performed with Sanger sequencing. The frequency, duration and adverse reactions of the patients before and after taking colchicine were analyzed by telephone follow-up.\u003c/p\u003e\n\u003cp\u003eThe diagnosis of FMF is made based on clinical findings rather than genetic testing. Currently, the internationally accepted diagnostic criteria for FMF is “Yalcinkaya-Ozen” criteria\u003csup\u003e[10]\u003c/sup\u003e,it requires recurrent (≥3) attacks with at least 2 of the following 5 features: fever lasting between 12 and 72 hours, abdominal pain, chest pain, arthritis, and a positive family history for FMF.\u003c/p\u003e\n\u003cp\u003eDiagnosis of PFAPA syndrome established according to modified Marshall criteria\u003csup\u003e[11]\u003c/sup\u003e,regularly recurrent fever, absence of upper respiratory tract infection and at least one of the following clinical signs: pharyngitis, aphthous stomatitis or cervical adenitis, completely asymptomatic intervals between febrile episodes, normal growth and development.\u003c/p\u003e\n\u003cp\u003eThe diagnosis of CAPS depends mainly on clinical manifestations (the common clinical features are fever, urticarial rash, musculoskeletal symptoms, elevated acute phase reactants, and conjunctivitis) and genetic testing(pathogenic variants including R260W,D303N, L305P, E311K, T348M, L353P, A439V)\u003csup\u003e[12]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eUnclassified periodic fever syndrome was defined as recurrent episodes (with either strict periodicity or irregular intervals) lasting days to weeks, in which fever is the cardinal feature and other associated features are similar and predictable, with intervening intervals of weeks to months characterised by complete well-being.\u003csup\u003e[1]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of Beijing Children's Hospital (Institutional Review Board (IRB) approved protocol [2022]-E-177-Y), and written informed consent was waived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed using the SPSS software version 26. Continuous and categorical variables are presented as mean±2SD(standard deviation) or number (percentage). We analysed the differences in the laboratory outcomes by using two-sample t-tests. Comparisons of non-normally distributed data were performed using the Mann Whiney U rank test. A two-tailed p-value of 0.05 was considered to be statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 130 patients (59 girls, 71 boys) were enrolled in the study between April 2021 and January 2024 in our pediatric immunology department. The demographic and clinical features of these patients are presented in Table 1. The mean age at symptom onset was 3.59 years. And the mean age at diagnosis was 5.33 years. The average time from symptom onset to diagnosis was 1.74 years. The mean duration of a febrile episode was 3.9 days with an interval between episodes of 3.4 weeks. All patients were asymptomatic during the afebrile period and showed normal growth and development. The maximum temperature during the episode was 39.9℃. The most common symptoms were Pharyngitis (74.6 %) and Cervical adenitis (40.8 %). Digestive symptoms (abdominal pain, nausea and vomiting or diarrhea) were also presented in some patients. Skin rash was mainly seen in patients with CAPS.\u003c/p\u003e\n\u003cp\u003eThe most common type of periodic fever syndrome is PFAPA (52.3%). Periodic fever is characteristic in a subset of patients (39.2%), but it is difficult to further differentiate the disease types. Oral corticosteroids (3.1%), colchicine (28.5%), thalidomide (2.3%) and NSAIDs (1.5%) were recommended to patients. But most patients did not accept any treatment (62.3%). Family medical history (first and second degree relatives) was found in 11 (8.5%) patients. Gene variant analysis was performed in 87 patients. No positive mutation was found in 38 patients (29.23%). In patients with positive mutations, MEFV was the most common mutation.\u003c/p\u003e\n\u003cp\u003eTable 1 Demographic and clinical characteristics of patients\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eCharacteristics, n(%) or mean(95%CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003epatients (n=130)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eGender, male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e71（54.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eAge at symptom onset, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e3.59(3.06-4.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eAge at diagnosis, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e5.33(4.79-5.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eTime between onset and diagnosis，years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e1.74(1.37-2.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eFever\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Duration of the febrile episode, days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e3.92(3.29-4.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Frequency of the febrile episode, weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e3.44(3.22-3.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eCardinal features\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003ePharyngitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e97(74.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Cervical adenitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e53(40.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Oral aphthosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e40(30.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eAbdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e11(8.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eNausea and vomiting or diarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e5(3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eSkin rash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e3(2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eMaximal temperature，℃\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e39.9(39.8-40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eTypes of disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eFMF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e4(3.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003ePFAPA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e68(52.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; CAPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e4(3.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; HIDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e3(2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Unclassified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e51(39.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Corticosteroids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e4(3.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Tonsillectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e3(2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Colchicine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e38(29.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Thalidomide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e3(2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; NSAID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e2(1.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;No treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e80(61.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eFamily history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e11(8.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003eGene mutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Negative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e38(29.23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; MEFV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e33(25.38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;MVK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e3(2.31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; NLRP3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e4(3.08%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;NLRP12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e4(3.08%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; NLRC4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e1(0.77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;NOD2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e1(0.77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; TNFAIP3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e1(0.77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;PLCG2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e1(0.77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.983050847457626%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; PIPK1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.016949152542374%\" valign=\"top\"\u003e\n \u003cp\u003e1(0.77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMEFV mutation analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMEFV mutations were detected in 33 patients, 21 patients(63.6%) were PFAPA. In PFAPA, FMF and other periodic fever syndromes, the p.E148Q(c.442G＞C) mutation was the most common type of mutation and was detected in 26 patients (78.79%). Other mutations, such as p.R408Q, p.P369S, p.c304R and p.R408Gln were also detected. The results of the MEFV mutation analysis are given in Table 2.\u003c/p\u003e\n\u003cp\u003eTable 2 \u0026nbsp;MEFV mutation analyses of the study population\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003eTypes of disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003eNucleotide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003eAmino Acid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePFAPA(n=21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003ec.442G＞C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003ep.E148Q\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.51231527093596%\" valign=\"top\"\u003e\n \u003cp\u003ec.910G＞A\u003c/p\u003e\n \u003cp\u003ec.1223G＞A\u003c/p\u003e\n \u003cp\u003ec.1105C＞T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.832512315270936%\" valign=\"top\"\u003e\n \u003cp\u003ep.c304R\u003c/p\u003e\n \u003cp\u003ep.R408Q\u003c/p\u003e\n \u003cp\u003ep.P369S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.6551724137931%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.51231527093596%\" valign=\"top\"\u003e\n \u003cp\u003ec.1105C＞T\u003c/p\u003e\n \u003cp\u003ec1223G＞A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.832512315270936%\" valign=\"top\"\u003e\n \u003cp\u003ep.R408Gln\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.6551724137931%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003eFMF（n=3）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003ec.442G＞C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003ep.E148Q\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eUnclassified（n=9）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003ec.442G＞C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003ep.E148Q\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.51231527093596%\" valign=\"top\"\u003e\n \u003cp\u003ec.1105C＞T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.832512315270936%\" valign=\"top\"\u003e\n \u003cp\u003ep.P369S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.6551724137931%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFindings of laboratory data during PFS flares and inter-episode periods are presented in Table 3. During flares, leukocytes, neutrophils, ESR and CRP were significantly higher than during inter-episode periods. But there were no significant differences in lymphocytes, monocytes, haemoglobin between flares and inter-episode periods.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3 \u0026nbsp;Laboratory Findings During Episode and Inter-Episode Periods\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"510\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003eDuring Episodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.607843137254903%\" valign=\"top\"\u003e\n \u003cp\u003eInter- Episodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.176470588235293%\" valign=\"top\"\u003e\n \u003cp\u003eP*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eLeukocytes（\u0026times;10^9/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e12.94\u0026plusmn;11.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.607843137254903%\" valign=\"top\"\u003e\n \u003cp\u003e7.25\u0026plusmn;6.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.176470588235293%\" valign=\"top\"\u003e\n \u003cp\u003e0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eNeutrophils（\u0026times;10^9/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e8.10\u0026plusmn;9.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.607843137254903%\" valign=\"top\"\u003e\n \u003cp\u003e3.67\u0026plusmn;4.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.176470588235293%\" valign=\"top\"\u003e\n \u003cp\u003e0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eLymphocytes（\u0026times;10^9/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e3.26\u0026plusmn;3.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.607843137254903%\" valign=\"top\"\u003e\n \u003cp\u003e3.04\u0026plusmn;4.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.176470588235293%\" valign=\"top\"\u003e\n \u003cp\u003e0.724\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eMonocytes（\u0026times;10^9/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e1.09\u0026plusmn;1.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.607843137254903%\" valign=\"top\"\u003e\n \u003cp\u003e94.62\u0026plusmn;339.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.176470588235293%\" valign=\"top\"\u003e\n \u003cp\u003e0.135\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eHaemoglobin（g/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e116.55\u0026plusmn;67.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.607843137254903%\" valign=\"top\"\u003e\n \u003cp\u003e112.43\u0026plusmn;48.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.176470588235293%\" valign=\"top\"\u003e\n \u003cp\u003e0.824\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eC-reactive protein(CRP, mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e68.64\u0026plusmn;83.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.607843137254903%\" valign=\"top\"\u003e\n \u003cp\u003e8.52\u0026plusmn;9.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.176470588235293%\" valign=\"top\"\u003e\n \u003cp\u003e0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eErythrocyte sedimentation rate(ESR ,mm/h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e40.07\u0026plusmn;41.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.607843137254903%\" valign=\"top\"\u003e\n \u003cp\u003e11.12\u0026plusmn;15.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.176470588235293%\" valign=\"top\"\u003e\n \u003cp\u003e0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy and safety of Colchicine\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs showed at figure 1. Thirty-eight patients were treated with colchicine. Fourteen patients are PFAPA, 4 patients are FMF, 19 patients are other PFS(unclassified),1 patient is HIDS. One patient developed abdominal pain and alopecia after taking colchicine, which was severe, and the use of colchicine was suspended. One patient had abdominal pain, nausea, and dizziness after taking colchicine, one had abdominal pain and constipation after taking colchicine, and one had diarrhea after taking colchicine. But they continued to take colchicine. After taking colchicine, there was no significant difference in urea, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (gamma-GT), lactate dehydrogenase (LDH), creatine kinase lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), leukocytes, neutrophils, lymphocytes, monocytes, platelets, haemoglobin, CRP and ESR compared with those before taking colchicine. However, alkaline phosphatase (APS) and creatine kinase (CK) were significantly higher after taking colchicine than before(Table 4).\u003c/p\u003e\n\u003cp\u003eOf the 37 patients who adhered to oral colchicine, 17 patients were free of clinical symptoms 1 month after taking colchicine. After 3 months of taking colchicine, 25 patients achieved clinical remission. After 5 months of follow-up, only 2 patients were not in remission and were considered ineffective (Figure 2).\u003c/p\u003e\n\u003cp\u003eTable 4 Differences in laboratory outcomes before and after taking colchicine\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"top\"\u003e\n \u003cp\u003eBefore taking colchicine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"top\"\u003e\n \u003cp\u003eAfter taking colchicine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eUrea（mmol/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e3.75\u0026plusmn;0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e4.49\u0026plusmn;1.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.063\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eCreatinina（umol/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e29.84\u0026plusmn;10.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e33.34\u0026plusmn;10.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.341\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eALT（U/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e12.61\u0026plusmn;5.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e16.20\u0026plusmn;10.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.274\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eAST（U/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e27.44\u0026plusmn;8.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e28.82\u0026plusmn;6.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.469\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003egamma-GT（U/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e13.99\u0026plusmn;4.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e14.72\u0026plusmn;8.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.695\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eAPS（U/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e210.93\u0026plusmn;71.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e248.10\u0026plusmn;58.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.012*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eLDH（U/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e215.85\u0026plusmn;47.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e214.71\u0026plusmn;34.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.322\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eCK（U/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e72.30\u0026plusmn;36.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e107.67\u0026plusmn;41.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eCK-MB（U/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e17.52\u0026plusmn;6.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e19.90\u0026plusmn;4.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eLeukocytes（\u0026times;10^9/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e7.846\u0026plusmn;2.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e9.26\u0026plusmn;3.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.159\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eNeutrophils（\u0026times;10^9/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e3.29\u0026plusmn;2.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e4.93\u0026plusmn;3.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.106\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eLymphocytes（\u0026times;10^9/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e3.80\u0026plusmn;1.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e3.50\u0026plusmn;1.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.945\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eMonocytes（\u0026times;10^9/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.54\u0026plusmn;0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.63\u0026plusmn;0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.304\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eplatelets（\u0026times;10^9/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e366.63\u0026plusmn;129.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e320.57\u0026plusmn;128.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.313\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eHaemoglobin（g/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e120.9\u0026plusmn;12.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e128.19\u0026plusmn;9.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eCRP（mg/L）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"bottom\"\u003e\n \u003cp\u003e10.57\u0026plusmn;10.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"bottom\"\u003e\n \u003cp\u003e12.57\u0026plusmn;11.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.569\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.143712574850298%\" valign=\"top\"\u003e\n \u003cp\u003eESR（mm/h）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.13572854291417%\" valign=\"top\"\u003e\n \u003cp\u003e20.11\u0026plusmn;21.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.343313373253494%\" valign=\"top\"\u003e\n \u003cp\u003e14.48\u0026plusmn;13.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.377245508982035%\" valign=\"top\"\u003e\n \u003cp\u003e0.204\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003egamma-GT: gamma glutamyl transpeptidase\u003c/p\u003e\n\u003cp\u003eAST: Aspartate aminotransferase\u003c/p\u003e\n\u003cp\u003eALT: Alanine aminotransferase\u003c/p\u003e\n\u003cp\u003eLDH: lactate dehydrogenase\u003c/p\u003e\n\u003cp\u003eAPS: Alkaline phosphatase\u003c/p\u003e\n\u003cp\u003eCK: creatine kinase\u003c/p\u003e\n\u003cp\u003eCK-MB: creatine kinase-MB\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGene mutation analyses of the patients who taking colchicine\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThirty-eight patients who took colchicine, their gene mutations are shown in Table 5. Twenty-one patients found no gene mutation or gene data were not available. Twelve patients had MEFV mutations, most of the MEFV mutations were p.E148Q. Other mutations included NLRP1, NLRP12,MVK and PIPK1.\u003c/p\u003e\n\u003cp\u003eTable 5 Gene mutation analyses of the patients who taking colchicine\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003eTypes of disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003eNucleotide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003eAmino Acid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNegative/NA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.51231527093596%\" valign=\"top\"\u003e\n \u003cp\u003ec.1105C＞T\u003c/p\u003e\n \u003cp\u003ec1223G＞A\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.832512315270936%\" valign=\"top\"\u003e\n \u003cp\u003ep.R408Gln\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.6551724137931%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.51231527093596%\" valign=\"top\"\u003e\n \u003cp\u003ec.1105C＞T\u003c/p\u003e\n \u003cp\u003ec.442G＞C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.832512315270936%\" valign=\"top\"\u003e\n \u003cp\u003ep.P369S\u003c/p\u003e\n \u003cp\u003ep.E148Q\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.6551724137931%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003eMEFV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003ec.1105C＞T\u003c/p\u003e\n \u003cp\u003ec.442G＞C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003ep.Pro369Ser\u003c/p\u003e\n \u003cp\u003ep.Glu148Gln\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003eMEFV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003ec.442G＞C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003ep.E148Q\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003eMEFV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003ec.1105C＞T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003ep.P369S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003eMEFV\u003c/p\u003e\n \u003cp\u003eNLRP1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003ec.442G＞C\u003c/p\u003e\n \u003cp\u003ec.3607C＞T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003ep.E148Q\u003c/p\u003e\n \u003cp\u003ep.H1203Y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003eNLRP12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003ec.1732A＞G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003eS578G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003eMVK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003ec.655G＞A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003ep.Gly219Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003ePIPK1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.53531598513011%\" valign=\"top\"\u003e\n \u003cp\u003ec.1335T＞A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003ep.H445Q\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.925650557620816%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eNA: Not available.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePeriodic fever syndromes (PFS) are a wide group of autoinflammatory diseases characterized by recurrent episodes of fever in the absence of microbial, autoimmune or malign conditions\u003csup\u003e[13]\u003c/sup\u003e.\u0026nbsp;It is difficult to diagnose PFS in a large population, there is a lack of criteria for the diagnosis of PFS, and there can be considerable overlap in the clinical presentation of different diseases. The diagnosis of PFS depends on clinical symptoms, so there is an inevitable delay in diagnosis. Many patients have seen five or more hospital specialities before a diagnosis is made\u003csup\u003e[14]\u003c/sup\u003e. For doctors, knowing whether a patient has PFS means ruling out some common clinical problems such as infection, malignancy, immunodeficiency and inflammatory conditions. It is clear that autoinflammation can result from various pathogenic mechanisms. The most common mechanism is dysregulation of interleukin 1(IL-1) secretion, as seen in FMF and CAPS.\u003c/p\u003e\n\u003cp\u003eIn this study, the clinical findings, gene mutation analysis and treatment responses are elaborated in a large cohort of pediatric PFS patients.\u0026nbsp;In our cohort, the male to female ratio was 1.2. In other studies, FMF incidence was reported to be equal between male and female\u003csup\u003e[15, 16]\u003c/sup\u003e,and in PFAPA patients the male to female ratio was 1.2-1.6\u003csup\u003e[17, 18]\u003c/sup\u003e.In our study, the mean age of disease onset and the mean age of disease diagnosed are 3.59 years and 5.33 years, respectively.\u0026nbsp;In two studies conducted in Turkey, the mean age at disease onset was 5.3\u0026ndash;5.4\u0026nbsp;years and mean age at diagnosis was 7.6\u0026ndash;8.4\u0026nbsp;years in FMF patients\u003csup\u003e[19, 20]\u003c/sup\u003e.In a study from western Sweden, the median age of disease onset was 2 years (range 0.1\u0026ndash;16 years) in PFAPA patients\u003csup\u003e[21]\u003c/sup\u003e. The most common symptom in our cohort was pharyngitis, which may be related to the fact that the majority of patients in our cohort were PFAPA.\u0026nbsp;Skin rash, Nausea and vomiting or diarrhea are mostly seen in CAPS.\u003c/p\u003e\n\u003cp\u003eIn our study, MEFV variants were detected in 21 PFAPA patients, 3 FMF patients and 9 other PFS patients. This is similar to a previous study that found MEFV variants in 32.5% of PFAPA patients\u003csup\u003e[22]\u003c/sup\u003e.\u0026nbsp;Mehmet et al showed that most PFAPA patients have heterozygous MEFV gene mutations\u003csup\u003e[22]\u003c/sup\u003e.\u0026nbsp;MEFV mutations are also found in FMF patients, in some studies from Turkey, about 20% of general population in Turkey is carrier of a MEFV mutation. And the most common mutations are M694V, E148Q, M680I, V726A, and M694I\u003csup\u003e[24-26]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn our study, CRP and ESR show elevations during episodes,\u0026nbsp;along with leukocytosis. But Procalcitonin had normal values, which means infections are excluded.\u0026nbsp;These are similar to the studies about PFAPA and FMF\u003csup\u003e[27, 28]\u003c/sup\u003e.CRP and ESR are acute phase reactants,\u0026nbsp;patients with persistent elevations of these inflammatory markers between episodes are considered to be at higher risk for systemic amyloid deposition\u003csup\u003e[29]\u003c/sup\u003e. In a previous study, Kenan Barut et al found that patients with the homozygous M694V mutation also had elevated CRP and ESR between episodes\u0026nbsp;\u003csup\u003e[28]\u003c/sup\u003e.\u0026nbsp;Anemia is also reported in some studies that patients with recurrent FMF attacks\u003csup\u003e[30]\u003c/sup\u003e.However, there was no statistically difference in hemoglobin during episodes and Inter- Episodes of patients in our study.\u0026nbsp;In the current study, neutrophils and leukocytes were higher during PFS flare, and the same results have been seen in other studies\u003csup\u003e[31]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eColchicine is recommended for the treatment of FMF. In many studies, the effect of colchicine therapy has been well established in randomized trials\u003csup\u003e[32, 33]\u003c/sup\u003e. And it has been shown to be safe for the prophylaxis of acute episodes of FMF and for the prevention of amyloidosis in FMF.\u0026nbsp;\u003csup\u003e[31]\u003c/sup\u003e.Colchicine binds in equimolar and a poorly reversible manner to soluble non-polymerized tubulin, forming a tubulin-colchicine complex\u003csup\u003e[34]\u003c/sup\u003e.This complex can change the structure and the function of the cytoskeleton, thereby influencing neutrophil immigration and adhesion\u003csup\u003e[34, 35]\u003c/sup\u003e. Colchicine has not been examined systematically in PFAPA and other PFS. In some studies, colchicine may be effective in the treatment of PFAPA\u003csup\u003e[36, 37]\u003c/sup\u003e.\u0026nbsp;The study by\u0026nbsp;Yonatan Butbul Aviel et al also\u0026nbsp;demonstrated a statistically significant reduction in the frequency of PFAPA episodes following colchicine administration\u003csup\u003e[38]\u003c/sup\u003e.Our study is the first to demonstrate the efficacy and safety of colchicine in the treatment of PFS.\u0026nbsp;In our study, 37 patients were treated with colchicine and 35 of them achieved clinical remission.\u0026nbsp;Adverse events are also reported in our patients, but only one patient discontinued taking colchicine due to a serious adverse event. Other therapies such as corticosteroids, thalidomide and NSAIDs are also effective in controlling symptoms during an active episode. However, corticosteroids do not prevent relapses and may even increase the frequency of relapses, and patients\u0026apos; concerns about the side effects of the drugs may make them reluctant to use corticosteroids and look for other ways to prevent relapses\u003csup\u003e[39]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOur study has identified an additional or alternative approach to the treatment of PFS. Colchicine may have a good safety profile to treat patients with PFS, especially those with frequent episodes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe current diagnosis of PFAPA, FMF or other periodic fever syndrome is based on the patient\u0026apos;s clinical symptoms. Our results indicated that the mean age of disease onset was 3.59 years old, but the average age at diagnosis was 5.33 years old. Previously, they were basically considered to have an infection and were treated with antibiotics. The most common PFS is PFAPA and the most common gene mutation in PFS patients is MEFV. Colchicine is a safe and effective drug for the treatment of PFS.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of Beijing Children\u0026apos;s Hospital (Institutional Review Board (IRB) approved protocol [2022]-E-177-Y), and written informed consent was waived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXiongbin Chen proposed the study and wrote the first draft. Yulu Li, Mengyang Yang, Zhou Shu collected and analyzed the data. Huawei Mao guided the design of the study and helped to draft the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSoon G S, Laxer R M. Approach to recurrent fever in childhood[J]. Can Fam Physician, 2017,63(10):756-762.\u003c/li\u003e\n\u003cli\u003eJohn C C, Gilsdorf J R. Recurrent fever in children[J]. Pediatr Infect Dis J, 2002,21(11):1071-1077.\u003c/li\u003e\n\u003cli\u003eGattorno M, Hofer M, Federici S, et al. Classification criteria for autoinflammatory recurrent fevers[J]. Ann Rheum Dis, 2019,78(8):1025-1032.\u003c/li\u003e\n\u003cli\u003eHull K M, Shoham N, Chae J J, et al. The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations[J]. Curr Opin Rheumatol, 2003,15(1):61-69.\u003c/li\u003e\n\u003cli\u003eKastner D L, Aksentijevich I, Goldbach-Mansky R. 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International Retrospective Chart Review of Treatment Patterns in Severe Familial Mediterranean Fever, Tumor Necrosis Factor Receptor-Associated Periodic Syndrome, and Mevalonate Kinase Deficiency/Hyperimmunoglobulinemia D Syndrome[J]. Arthritis Care Res (Hoboken), 2017,69(4):578-586.\u003c/li\u003e\n\u003cli\u003eEl-Shanti H, Majeed H A, El-Khateeb M. Familial mediterranean fever in Arabs[J]. Lancet, 2006,367(9515):1016-1024.\u003c/li\u003e\n\u003cli\u003eJarjour R A, Al-Berrawi S. Familial Mediterranean fever in Syrian children: phenotype-genotype correlation[J]. Rheumatol Int, 2015,35(4):629-634.\u003c/li\u003e\n\u003cli\u003ePerko D, Debeljak M, Toplak N, et al. Clinical features and genetic background of the periodic Fever syndrome with aphthous stomatitis, pharyngitis, and adenitis: a single center longitudinal study of 81 patients[J]. Mediators Inflamm, 2015,2015:293417.\u003c/li\u003e\n\u003cli\u003eLazea C, Damian L, Vulturar R, et al. PFAPA Syndrome: Clinical, Laboratory and Therapeutic Features in a Single-Centre Cohort[J]. Int J Gen Med, 2022,15:6871-6880.\u003c/li\u003e\n\u003cli\u003eEce A, \u0026Ccedil;akmak E, Uluca \u0026Uuml;, et al. The MEFV mutations and their clinical correlations in children with familial Mediterranean fever in southeast Turkey[J]. Rheumatol Int, 2014,34(2):207-212.\u003c/li\u003e\n\u003cli\u003eOzturk C, Halicioglu O, Coker I, et al. Association of clinical and genetical features in FMF with focus on MEFV strip assay sensitivity in 452 children from western Anatolia, Turkey[J]. Clin Rheumatol, 2012,31(3):493-501.\u003c/li\u003e\n\u003cli\u003eRydenman K, Fjeld H, H\u0026auml;tting J, et al. Epidemiology and clinical features of PFAPA: a retrospective cohort study of 336 patients in western Sweden[J]. Pediatr Rheumatol Online J, 2022,20(1):82.\u003c/li\u003e\n\u003cli\u003eKaynak D, Yildiz M, Sahin S, et al. NLRP3 gene variants and serum NLRP3 levels in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome[J]. Clin Rheumatol, 2023,42(1):245-251.\u003c/li\u003e\n\u003cli\u003eCeliksoy M H, Ogur G, Yaman E, et al. Could familial Mediterranean fever gene mutations be related to PFAPA syndrome?[J]. Pediatr Allergy Immunol, 2016,27(1):78-82.\u003c/li\u003e\n\u003cli\u003eYilmaz E, Ozen S, Balci B, et al. Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population[J]. Eur J Hum Genet, 2001,9(7):553-555.\u003c/li\u003e\n\u003cli\u003eTouitou I. Standardized testing for mutations in familial Mediterranean fever[J]. Clin Chem, 2003,49(11):1781-1782.\u003c/li\u003e\n\u003cli\u003eYigit S, Bagci H, Ozkaya O, et al. MEFV mutations in patients with familial Mediterranean fever in the Black Sea region of Turkey: Samsun experience [corrected][J]. J Rheumatol, 2008,35(1):106-113.\u003c/li\u003e\n\u003cli\u003eAdrovic A, Sahin S, Barut K, et al. Familial Mediterranean fever and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: shared features and main differences[J]. Rheumatol Int, 2019,39(1):29-36.\u003c/li\u003e\n\u003cli\u003eBarut K, Sahin S, Adrovic A, et al. Familial Mediterranean fever in childhood: a single-center experience[J]. Rheumatol Int, 2018,38(1):67-74.\u003c/li\u003e\n\u003cli\u003eBayram M T, \u0026Ccedil;ankaya T, Bora E, et al. Risk factors for subclinical inflammation in children with Familial Mediterranean fever[J]. Rheumatol Int, 2015,35(8):1393-1398.\u003c/li\u003e\n\u003cli\u003eCelkan T, Celik M, Kasap\u0026ccedil;opur O, et al. The anemia of familial Mediterranean fever disease[J]. Pediatr Hematol Oncol, 2005,22(8):657-665.\u003c/li\u003e\n\u003cli\u003eKolly L, Busso N, von Scheven-Gete A, et al. Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1\u0026beta; production[J]. J Allergy Clin Immunol, 2013,131(6):1635-1643.\u003c/li\u003e\n\u003cli\u003eZemer D, Revach M, Pras M, et al. A controlled trial of colchicine in preventing attacks of familial mediterranean fever[J]. N Engl J Med, 1974,291(18):932-934.\u003c/li\u003e\n\u003cli\u003eDinarello C A, Wolff S M, Goldfinger S E, et al. Colchicine therapy for familial mediterranean fever. A double-blind trial[J]. N Engl J Med, 1974,291(18):934-937.\u003c/li\u003e\n\u003cli\u003eBhattacharyya B, Panda D, Gupta S, et al. Anti-mitotic activity of colchicine and the structural basis for its interaction with tubulin[J]. Med Res Rev, 2008,28(1):155-183.\u003c/li\u003e\n\u003cli\u003eRavelli R B, Gigant B, Curmi P A, et al. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain[J]. Nature, 2004,428(6979):198-202.\u003c/li\u003e\n\u003cli\u003eTasher D, Stein M, Dalal I, et al. Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes[J]. Acta Paediatr, 2008,97(8):1090-1092.\u003c/li\u003e\n\u003cli\u003ePadeh S, Brezniak N, Zemer D, et al. Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome[J]. J Pediatr, 1999,135(1):98-101.\u003c/li\u003e\n\u003cli\u003eButbul A Y, Tatour S, Gershoni B R, et al. Colchicine as a therapeutic option in periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome[J]. Semin Arthritis Rheum, 2016,45(4):471-474.\u003c/li\u003e\n\u003cli\u003eTasher D, Somekh E, Dalal I. PFAPA syndrome: new clinical aspects disclosed[J]. Arch Dis Child, 2006,91(12):981-984.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Periodic fever syndromes, genetic features, children, colchicine","lastPublishedDoi":"10.21203/rs.3.rs-4411739/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4411739/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e: Periodic fever syndromes (PFS) are a broad group of autoinflammatory diseases characterised by recurrent episodes of fever in the absence of microbial, autoimmune or malignant conditions. We aimed to evaluate the clinical and genetic characteristics of patients with periodic fever syndrome. And to evaluate the safety and efficacy of colchicine in the treatment of PFS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: This study included patients diagnosed with PFS between April 2021 and January 2024 at Bei Jing Children's Hospital, Immunology Department. We retrospectively analyzed the clinical data (clinical features, laboratory findings and genetic features). The onset of the disease and adverse events following the use of colchicine were also analysed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A total of 130 patients were included in this study, with a male to female ratio of 1.2:1. The mean (95% CI) ages at symptom onset and diagnosis were 3.59(3.06-4.11) years and 5.33(4.79-5.87) years, respectively. The average duration of the febrile episode is 3.92 days and the average frequency of the febrile episode is 3.44 weeks. During PFS flares, leukocytes, neutrophils, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were significantly higher than in inter-episode periods. The most frequently detected gene mutation is MEFV. Thirty-five patients were free of clinical symptoms 5 month after taking colchicine.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: We present a cohort of children and adolescence with periodic fever syndrome. The most common PFS is PFAPA and the most common gene mutation in PFS patients is MEFV. Colchicine is a safe and effective drug for the treatment of PFS.\u003c/p\u003e","manuscriptTitle":"Periodic fever syndromes in Chinese children and adolescents: a single-centre cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-31 20:24:11","doi":"10.21203/rs.3.rs-4411739/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d2ef393a-adb4-4646-a49c-22bca81dac88","owner":[],"postedDate":"May 31st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-11T08:53:11+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-31 20:24:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4411739","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4411739","identity":"rs-4411739","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}