Evaluation of vitamin D and vitamin B12 levels in children with Familial Mediterranean Fever

Evaluation of vitamin D and vitamin B12 levels in children with Familial Mediterranean Fever | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluation of vitamin D and vitamin B12 levels in children with Familial Mediterranean Fever AYŞE GÜNGÖR, AYŞE OFLU, HİLAL KOYUNCU, AYSUN SOYUGÜZEL, NUR ÖNEN, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7914184/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: This study aimed to determine the Vitamin D and Vitamin B12 levels in pediatric cases diagnosed with Familial Mediterranean Fever (FMF) and compare these levels with those of healthy controls. Methods This retrospective study included pediatric FMF patients aged 0 to 18 years admitted to a tertiary care hospital and healthy children of similar age and gender. Data were obtained through review of patients' electronic medical records. Results A total of 71 FMF patients were included in the study group and 141 healthy children in the control group. The mean age was 10.5 ± 4.2 years in the study group and 10.2 ± 4.2 years in the control group. There was no significant difference between the groups in terms of age and gender (p > 0.05). When the groups were compared in terms of vitamin D deficiency, the frequency was found to be higher in the study group with a ratio of 57.7% (p = 0.009). There was no significant difference between the groups in terms of vitamin B12 deficiency (p > 0.05). Conclusion This study revealed that vitamin D levels were lower in FMF patients compared to healthy controls, but there was no significant difference in vitamin B12 levels. This finding highlights the importance of screening and monitoring vitamin D levels in FMF patients. Child Familial Mediterranean Fever Vitamin D Vitamin B12 What is Known Vitamin D deficiency is related to increase disease activity in autoimmune and autoinflammatory diseases. Vitamin B12 levels may decrease in chronic inflammatory diseases. Vitamin D deficiency and vitamin B12 deficiency may occur in FMF cases. What is New Vitamin D deficiency is common in children with FMF, but not directly related to disease severity and activity. Vitamin B12 levels do not differ in children with FMF. Vitamin D deficiency is more common in FMF patients with joint symptoms. Introduction Familial Mediterranean Fever (FMF) is an autosomal recessively inherited autoinflammatory disease characterized by recurrent attacks of fever, abdominal pain, and polyserositis. It is endemic, particularly among Eastern Mediterranean populations, Jews, Armenians, Turks, and North African Arabs, with a prevalence of 1:300–1:2000 [ 1 ]. This disease presents with a range of clinical signs and a dramatic increase in acute-phase reactants, with flares of systemic inflammation followed by periods of remission of variable duration. Rash, serositis (peritonitis, pleuritis), lymphadenopathy, and arthritis are the main clinical manifestations [ 2 , 3 ]. The gene responsible for the disease is the MEFV gene, located on the short arm of chromosome 16, which encodes the 781-amino acid pyrin protein. Approximately 300 different mutations of the MEFV gene that can cause FMF have been identified [ 4 , 5 ]. Of these mutations, V726A, M680I, E148Q, M694V, and M694I account for approximately 70% to 80% of cases. Approximately 10% of patients diagnosed with clinical FMF do not have mutations in the MEFV gene. The MEFV gene carrier rate can reach as high as one-third in some regions [ 5 , 6 ]. Colchicine has been used in the treatment of FMF since 1972, and it can reduce both the frequency and number of attacks and prevent complications of the disease [ 7 – 9 ]. Although colchicine is an essentially safe drug with few side effects, such as diarrhea and abdominal distension, numerous animal and human studies indicate that it may impair intestinal absorption of vitamin B12 and is considered a potential agent for vitamin deficiency [ 10 – 12 ]. Colchicine may reduce vitamin B12 absorption by decreasing the receptor level of the B12-intrinsic factor (IF) complex on mucosal cells [ 11 , 13 ]. Recent research has increasingly focused on the potential role of vitamin D, a secosteroid hormone essential for calcium homeostasis and immunomodulation, in the pathophysiology of FMF [ 14 ]. Studies have also found that vitamin D deficiency is more common in patients with FMF and is associated with greater disease severity, pain, and impaired quality of life [ 15 – 18 ]. This deficiency may be linked to the proinflammatory state of FMF, as vitamin D is known to exert anti-inflammatory effects through the inhibition of proinflammatory cytokines such as IL-1, IL-6, and TNF-α [ 19 – 21 ]. Chronic inflammation, reduced sun exposure due to lifestyle changes during exacerbations, and possible genetic predispositions may contribute to lower serum vitamin D levels [ 22 ] Additionally, medications such as colchicine, a cornerstone of FMF management, may further exacerbate the deficiency by interfering with vitamin D metabolism [ 23 ]. To this end, routine screening for vitamin D levels is recommended in pediatric FMF patients [ 15 ]. In this study, we aimed to compare children with FMF with healthy children in terms of vitamin D and vitamin B12 deficiency and to examine the relationship between vitamin D and vitamin B12 deficiency and the clinical features of the disease. Methods Study Design and Participants This retrospective study was conducted between October 15, 2024, and December 15, 2024. Patients diagnosed with FMF (case group) aged 0-18 years who were admitted to a tertiary university hospital between June 2020 and June 2024, and healthy children admitted to the hospital for well-child follow-up on the same date (control group) were included in the study. The control group was twice the size of the case group and was almost matched for age and sex. Cases with chronic kidney or liver disease, malnutrition, metabolic bone disease, or other comorbidities, and those using any medication that affects vitamin D or vitamin B12 levels were excluded from the study. Data Collection Data on sociodemographic characteristics such as age, gender, season of admission, reasons for admission, and final diagnoses were obtained from hospital electronic file records. Cases were classified as infants (1 month-2 years), preschoolers (3-5 years), middle childhood (6-10 years), and adolescents (11-18 years). Seasons were classified as "Spring" (March-April-May), "Summer" (June-July-August), "Autumn" (September-October-November), and "Winter" (December-January-February). Vitamin D and vitamin B12 levels were evaluated in both groups. 25(OH)D values <12 ng/mL were classified as deficiency, 12-20 ng/mL as insufficiency[24]. B12 values <200 pg/mL were classified as deficiency, 200-300 pg/mL as insufficiency [25]. Clinical characteristics of the case group, including age at diagnosis, disease duration, colchicine treatment duration, symptoms and signs and disease severity score [26] and laboratory findings (Presence of anemia, presence of leukocytosis, presence of platelet abnormality, increased sedimentation rate, increased fibrinogen, presence of proteinuria and presence of MEFV mutation) were also collected. Anemia was defined according to the lower limit of hemoglobin for age and gender; leukocyte, fibrinogen and sedimentation values were evaluated and values above the upper limit were considered as leukocytosis, increased sedimentation rate and increased fibrinogen, respectively [27]. Ethical Approval It was received from the Afyonkarahisar Health Sciences University Ethics Committee on date: 06.09.2024 with decision no: 2024/311. All study procedures were performed in accordance with the Declaration of Helsinki. Statistical Analysis Statistical evaluation was performed using the IBM SPSS Statistics for Windows, Version 22.0. (Armonk, NY: IBM Corp.) program. Data were analyzed using descriptive statistical methods. Normality tests, including Kolmogorov-Smirnov and Shapiro-Wilk tests, were used to determine the distribution of quantitative data. Normally distributed data were expressed as mean ±standard deviation, and non-normally distributed data were expressed as median and minimum-maximum values. Categorical variables were expressed as percentage (%) and number (n). The Mann-Whitney U test was used to compare quantitative data between groups because the distribution of the data was not normal. Chi Square test and Fisher’s Exact test were used for categorical variables. Results A total of 71 case and 142 healthy controls were included in the study. 54.9% of the participants in the case group and 61.3 % in the control group were male. In the case group, the mean age ±standard deviation (SD) was determined as 10.5 ±4.2 years, median age [minimum and maximum (min-max)] was determined as 10.0 (1.6-18.0) years, while in the control group, the mean age ±SD was determined as 9.9 ±4.2, median age (min-max) was determined as 9.9 (1.6-18.0) years. There was no difference between the case and control groups in terms of age, age group, gender and the season when vitamin levels are tested (p>0.5). Table 1 shows the comparison of case group and control group in terms of general characteristics. When both groups were compared in terms of the frequency of low serum vitamin D levels (insufficiency and deficiency) (<20 ng/ml), it was found to be higher in the case group (57.7 %) than in the control group (38.7 %) (p=0.009). The median and the mean ±SD serum vitamin D level was also lower in the case group as 18.1 ng/mL and 19.4±9.5 ng/mL, respectively (p=0.018). When the groups were compared in terms of low serum vitamin B12 levels, no significant difference was found (p>0.05). Table 2 shows the comparison of the case and the control group in terms of presence of low vitamin D and vitamin B12 and also serum vitamin D and vitamin B12 levels. In case group, the median age (min-max) at diagnosis was 6.0 (2.0-12.0) years, the median (min-max) duration of the disease was 3.5 (1.0-12.0) years. When the demographic and clinical characteristics of the cases were compared with the presence of low vitamin D, it was found that the presence of vitamin D deficiency or insufficiency was more common in cases with pleuritis, myalgia, arthralgia and arthritis (p=0.044, p=0.014, p=0.037, p=0.014, respectively). Demographic characteristics of the cases, laboratory findings and severity of disease did not change according to the presence of low vitamin D (p>0.05). When the demographic and clinical characteristics of the cases were compared with the presence of low vitamin B12, any parameter changed according to the presence of low vitamin B12 (p>0.05). Table 3 shows the comparison of demographic and clinical characteristics with the presence of vitamin D and vitamin B12 deficiency or insufficiency in FMF patients. Discussion Our study revealed that vitamin D deficiency is common in patients followed up with a diagnosis of FMF. Vitamin D is essential not only for bone health but also for immune system regulation and inflammation control. Vitamin D deficiency has been shown to increase disease activity in autoimmune and autoinflammatory diseases, trigger the production of proinflammatory cytokines, and impair immune tolerance [28]. In our study, the ratio of vitamin D deficiency was found to be higher in children with FMF than in healthy controls. This finding is consistent with previous studies in the literature highlighting vitamin D deficiency in FMF patients [21, 29, 30]. In a 1983 study conducted by Adams and colleagues, seven patients with sarcoidosis and two with idiopathic pulmonary fibrosis were examined, demonstrating the effects of active vitamin D on the immune system and its importance in autoimmune diseases [31]. This pioneering study highlighted the immunomodulatory role of vitamin D and led to numerous studies today. Following this important study, research has been conducted on the relationship between vitamin D and autoimmune and autoinflammatory diseases [30, 32, 33]. Active vitamin D and its analogs have been shown to prevent lupus-like symptoms and reduce the development of inflammatory bowel disease [34]. Increasing evidence suggests that vitamin D is important in the onset and progression of many autoimmune diseases[35]. Although vitamin D deficiency has been shown to be common in patients with FMF there are conflicting results in the literature regarding the relationship between this deficiency and disease severity and activity (21,29,30). In our study, no significant relationship was found between vitamin D levels, disease severity, or colchicine treatment. Anık et al. also reported that vitamin D levels were low in children with FMF, but there was no significant relationship with disease severity [29]. In a study by Yılmaz et al., no correlation was found between vitamin D levels and disease severity; however, all FMF patients with mild, moderate, or severe symptom scores had low vitamin D levels [30]. In our study, no significant correlation was also found between vitamin D levels and serum acute-phase reactants level. This result is consistent with the results of Anık et al. [29], who found no significant relationship between serum vitamin D levels and serum acute-phase reactants levels. Erten et al. reported a relationship between elevated inflammatory markers (ESR and fibrinogen) and low vitamin D levels in FMF patients [21]. Causes of vitamin D deficiency in patients with FMF include chronic inflammation due to the disease itself, colchicine treatment affecting intestinal absorption, and reduced physical activity and sunlight exposure. There are conflicting results in the literature regarding the effect of colchicine treatment on vitamin D levels. While Karatay et al.'s [36] study on patients with Behçet's disease suggested that colchicine treatment might reduce vitamin D levels, a study by Anık et al. found that vitamin D levels in children with FMF were inversely proportional to the cumulative colchicine dose [29]. In our study, no significant relationship was found between colchicine dose and duration and vitamin D levels. The most common clinical presentations of FMF patients are recurrent fever, abdominal pain, and joint symptoms. In this study, patients presenting with joint symptoms at presentation had significantly lower vitamin D levels than those presenting with abdominal pain and fever. This result suggests that the risk of vitamin D deficiency is higher in FMF patients with joint involvement. Similarly, a study by Erten et al. [21] reported that vitamin D levels were significantly lower in FMF patients with joint symptoms at presentation than in those presenting with abdominal pain. The findings of both studies highlight that vitamin D insufficiency is more common in patients presenting with joint complaints in FMF. In our study, no significant difference was found between vitamin D levels and different MEFV gene mutations. This finding suggests that genotype alone is not the sole determinant in the pathogenesis of FMF, but that environmental factors (sun exposure, dietary habits, physical activity) and inflammatory processes also contribute significantly. Indeed, the literature has reported that vitamin D levels in patients with FMF do not show a clear relationship with genotype. Onur et al., in their study investigating the relationship between vitamin D status and disease activity in their patients, demonstrated that low vitamin D levels can be observed regardless of genotype [37]. This suggests that vitamin D deficiency in FMF may be related to the inflammatory processes and environmental factors that accompany the disease, and therefore, clinical management should consider not only genetic subtype but also biochemical and environmental parameters. Vitamin B12 is essential for DNA synthesis, erythropoiesis, and nervous system function. Although it has been suggested that vitamin B12 levels may decrease in chronic inflammatory diseases, studies specifically on FMF are quite limited. In our study, no significant difference in vitamin B12 levels was found between children with FMF and healthy controls. In the study conducted by Başaran et al., it was reported that vitamin B12 levels in children with FMF were not significantly different from healthy controls, but vitamin B12 levels were found to be significantly lower in patients receiving high-dose treatment, even though they were within normal limits and did not cause anemia [38]. This finding suggests that vitamin B12 deficiency in FMF does not play a decisive role in the pathogenesis or clinical course of the disease. However, colchicine used in treatment may affect intestinal mucosal function and reduce serum vitamin B12 levels. A study by Yılmaz et al. showed that long-term colchicine administration led to a deficiency in serum vitamin B12 levels [10, 39] Our study has several limitations. These include being a single-center, cross-sectional study and not having detailed assessments of factors that could affect vitamin D levels, such as participants' dietary habits, sunlight exposure, and physical activity levels. Furthermore, the study population largely originating from a single geographic region may limit the generalizability of the findings to larger populations with different genetic backgrounds and environmental factors. A key strength of our study is that it is one of the few studies to investigate vitamin D deficiency and vitamin B12 deficiency together in patients with FMF. Conclusion While vitamin D deficiency is common in children with FMF, it is not directly related to disease severity and activity. Vitamin B12 levels, however, do not differ in children with FMF compared to healthy controls. While this study highlights the need for routine monitoring of vitamin D levels in children with FMF, the same conclusion cannot be drawn for vitamin B12. However, prospective studies with larger samples are needed to assess whether vitamin D supplementation can effectively reduce the frequency and severity of FMF attacks and its impact on disease activity and prognosis. Declarations Author Contribution All authors contributed to the study conception and design. Material preparation, data collection were performed by Ayşe Güngör, Aysun Soyugüzel, Hilal Koyuncu and Nur Önen. Analysis were performed by Ayşe Güngör. Literature review was done by Ayşe Güngör, Hilal Koyuncu and Aysun Soyugüzel. The first draft of the manuscript was written by Ayşe Güngör and, Ayşe Oflu. The article was edited and checked by Ayşe Oflu . Ayşe Güngör, Ayşe Oflu, Ayşegül Bükülmez, A.Afşin Kundak and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. References Lidar M, Livneh A (2007) Familial Mediterranean fever: clinical, molecular and management advancements. Neth J Med 65(9):318–324 Terreri MTR et al (2016) Guidelines for the management and treatment of periodic fever syndromes familial Mediterranean fever. Revista Brasileira de Reumatologia (English Edition) 56(1):37–43 Livneh A et al (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthr Rhuem 40(10):1879–1885 Consortium IF (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90(4):797–807 Touitou I (2001) The spectrum of familial Mediterranean fever (FMF) mutations. Eur J Hum Genet 9(7):473–483 Ehrenfeld M et al (1982) Gastrointestinal effects of long-term colchicine therapy in patients with recurrent polyserositis (familial Mediterranean fever). Digestive diseases and sciences, 27(8): pp. 723–727 Ozen S et al (2025) EULAR/PReS endorsed recommendations for the management of familial Mediterranean fever (FMF): 2024 update. Annals of the rheumatic diseases Goldfinger S (1972) Colchicine for familial Mediterranean fever. Shinar Y et al (2000) Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rhuematol 27(7):1703–1707 Stopa E, O'Brien R, Katz M (1979) Effect of colchicine on guinea pig intrinsic factor-vitamin B12 receptor. Gastroenterology 76(2):309–314 Webb DI et al (1968) Mechanism of vitamin B12 malabsorption in patients receiving colchicine. N Engl J Med 279(16):845–850 Davis RE Clinical chemistry of vitamin B12. Advances in clinical chemistry, 1985. 24: pp. 163–216 Race T, Paes I, Faloon W (1970) Intestinal malabsorption induced by oral colchicine. Comparison with neomycin and cathartic agents. Am J Med Sci 259(1):32–41 Ozdogan H, Ugurlu S (2019) Familial mediterranean fever. La Presse Médicale 48(1):e61–e76 Turhan T et al (2018) Vitamin D status, serum lipid concentrations, and vitamin D receptor (VDR) gene polymorphisms in Familial Mediterranean fever. Bosnian J Basic Med Sci 18(1):21 Orhan C et al (2020) Vitamin D binding protein genotype frequency in familial Mediterranean fever patients. Scand J Rheumatol 49(6):484–488 Eloi M et al (2017) 25-Hydroxivitamin D serum concentration, not free and bioavailable vitamin D, is associated with disease activity in systemic lupus erythematosus patients. PLoS ONE 12(1):e0170323 Alesh MB et al (2022) Hidden threat in familial Mediterranean fever: subclinical inflammation, oxidative stress and their relationship with vitamin D status. Turk J Med Sci 52(1):67–75 Escobedo-Monge MF et al (2024) Calcium, phosphate, and vitamin d in children and adolescents with chronic diseases: a cross-sectional study. Nutrients 16(9):1349 Saedmocheshi S et al (2024) The effect of vitamin D consumption on pro-inflammatory cytokines in athletes: A systematic review of randomized controlled trials. Sports 12(1):32 Erten Ş et al (2012) Low plasma vitamin D levels in patients with familial Mediterranean fever. Rheumatol Int 32(12):3845–3849 Mansueto P et al (2022) Familial Mediterranean fever and diet: a narrative review of the scientific literature. Nutrients 14(15):3216 Ozer I et al (2015) Association between colchicine resistance and vitamin D in familial Mediterranean fever. Ren Fail 37(7):1122–1125 Munns CF et al (2016) Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metabolism 101(2):394–415 Green R et al (2017) Vitamin B12 deficiency. Nat reviews Disease primers 3(1):1–20 Pras E et al (1998) Clinical differences between North African and Iraqi Jews with familial Mediterranean fever. Am J Med Genet 75(2):216–219 Fish JD, Lipton JM, Lanzkowsky P (2021) SPEC–Lanzkowsky's Manual of Pediatric Hematology and Oncology, 12-Month Access, eBook: SPEC–Lanzkowsky's Manual of Pediatric Hematology and Oncology, 12-Month Access, eBook. academic Aranow C (2011) Vitamin D and the immune system. J Investig Med 59(6):881–886 Anık A et al (2014) Decreased vitamin D levels in children with familial M editerranean fever. Int J Rheum Dis 17(3):321–326 Yilmaz R et al (2014) Hypovitaminosis D in children with familial Mediterranean fever. Clin Invest Med 37(4):E211–E216 Adams JS et al (1983) Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Investig 72(5):1856–1860 Gallo D et al (2023) How does vitamin D affect immune cells crosstalk in autoimmune diseases? Int J Mol Sci 24(5):4689 Zhao SS et al (2023) Associations between vitamin D and autoimmune diseases: Mendelian randomization analysis . in Seminars in arthritis and rheumatism . Elsevier Shevchuk S et al (2023) Vitamin D level in patients with systemic lupus erythematosus: its relationship to disease course and bone mineral density, vol 10. Lupus Science & Medicine, 2 Cutolo M, Gotelli E (2023) The 2023’s growing evidence confirming the relationship between vitamin D and autoimmune diseases. Nutrients 15(22):4760 Karatay S et al (2011) Vitamin D status in patients with Behcet's Disease. Clinics 66:721–723 Onur H et al (2016) Vitamin D levels in children with familial Mediterranean fever. Pediatr Rheumatol 14(1):28 Başaran Ö, Uncu N (2018) Kolşisin tedavisi altındaki ailevi akdeniz ateşi tanısı ile takip edilen çocuk hastalarda vitamin B12 düzeylerinin değerlendirilmesi. Güncel Pediatri 16(2):86–92 Yilmaz R et al (2011) Serum Vitamin B12 Status in Children with Familial Mediterranean Fever Receiving Colchicine Treatment 對秋水仙堿治療家族性地中海熱兒童後血清維生素 B12 水平的研究. HK J Paediatr (new series) 16(1):3–8 Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files tables.docx 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7914184","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":539052635,"identity":"e390b9a4-5d84-4f51-8bbc-abb0fb849f81","order_by":0,"name":"AYŞE GÜNGÖR","email":"data:image/png;base64,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","orcid":"","institution":"Afyonkarahisar University of Health Sciences Faculty of Medicine","correspondingAuthor":true,"prefix":"","firstName":"AYŞE","middleName":"","lastName":"GÜNGÖR","suffix":""},{"id":539052643,"identity":"9e4f2afc-809a-4f7e-b2c3-71361bfca252","order_by":1,"name":"AYŞE OFLU","email":"","orcid":"","institution":"Afyonkarahisar University of Health Sciences Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"AYŞE","middleName":"","lastName":"OFLU","suffix":""},{"id":539052647,"identity":"9bae0831-d061-4136-a792-25b3d0ca5dbb","order_by":2,"name":"HİLAL KOYUNCU","email":"","orcid":"","institution":"Afyonkarahisar University of Health Sciences Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"HİLAL","middleName":"","lastName":"KOYUNCU","suffix":""},{"id":539052652,"identity":"8c7ec9dc-d36b-43a5-9456-4183d6b68c8c","order_by":3,"name":"AYSUN SOYUGÜZEL","email":"","orcid":"","institution":"Afyonkarahisar University of Health Sciences Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"AYSUN","middleName":"","lastName":"SOYUGÜZEL","suffix":""},{"id":539052654,"identity":"127d2396-1ea0-4ca3-84a2-99c6f48aa7de","order_by":4,"name":"NUR ÖNEN","email":"","orcid":"","institution":"Afyonkarahisar University of Health Sciences Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"NUR","middleName":"","lastName":"ÖNEN","suffix":""},{"id":539052657,"identity":"40dc10b9-86da-4383-b464-71d003bb778b","order_by":5,"name":"AYŞEGÜL BÜKÜLMEZ","email":"","orcid":"","institution":"Afyonkarahisar University of Health Sciences Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"AYŞEGÜL","middleName":"","lastName":"BÜKÜLMEZ","suffix":""},{"id":539052658,"identity":"acd250ef-4459-432f-8fb2-bd73dc13791e","order_by":6,"name":"AFŞİN KUNDAK","email":"","orcid":"","institution":"Afyonkarahisar University of Health Sciences Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"AFŞİN","middleName":"","lastName":"KUNDAK","suffix":""}],"badges":[],"createdAt":"2025-10-21 11:53:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7914184/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7914184/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":95220419,"identity":"efb7495d-c09a-4eed-8907-a165a7cb4e6a","added_by":"auto","created_at":"2025-11-05 15:54:07","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":49522,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-7914184/v1/ccc3402bd6484fb00b7243c4.docx"},{"id":95228805,"identity":"9ad9b0f0-4d78-41ca-83f8-da27faac4050","added_by":"auto","created_at":"2025-11-05 16:34:09","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":8059,"visible":true,"origin":"","legend":"","description":"","filename":"ce1cad51274d40ef87dfc65269994fdc.json","url":"https://assets-eu.researchsquare.com/files/rs-7914184/v1/b3da08c4cec19859d4319c97.json"},{"id":95220421,"identity":"a03cc765-e580-44d3-9656-976c0521884f","added_by":"auto","created_at":"2025-11-05 15:54:07","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":70045,"visible":true,"origin":"","legend":"","description":"","filename":"ce1cad51274d40ef87dfc65269994fdc1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7914184/v1/ecdb101abea33323d8d46495.xml"},{"id":95220423,"identity":"8e3e3dbe-866f-492d-8739-9b8757c5d93f","added_by":"auto","created_at":"2025-11-05 15:54:07","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":68022,"visible":true,"origin":"","legend":"","description":"","filename":"ce1cad51274d40ef87dfc65269994fdc1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7914184/v1/662e5c27bb867146aae6d868.xml"},{"id":95220422,"identity":"c66f43bc-32fe-4376-84a0-c59d22a8fd9d","added_by":"auto","created_at":"2025-11-05 15:54:07","extension":"html","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":76079,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7914184/v1/891b530df1a3e3d4f5e93e5a.html"},{"id":95654944,"identity":"fa7f8770-0d28-43d5-b23c-3b80d482429d","added_by":"auto","created_at":"2025-11-11 16:13:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":358811,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7914184/v1/6e56070c-5ece-4732-a56e-4a3763cf45cf.pdf"},{"id":95220424,"identity":"a38e1c2f-56a0-4584-ba7e-665e7b5ee3ad","added_by":"auto","created_at":"2025-11-05 15:54:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":47176,"visible":true,"origin":"","legend":"","description":"","filename":"tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7914184/v1/7df90e15916aa2229972acdc.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluation of vitamin D and vitamin B12 levels in children with Familial Mediterranean Fever","fulltext":[{"header":"What is Known","content":"\u003cp\u003eVitamin D deficiency is related to increase disease activity in autoimmune and autoinflammatory diseases.\u003c/p\u003e\n\u003cp\u003eVitamin B12 levels may decrease in chronic inflammatory diseases.\u003c/p\u003e\n\u003cp\u003eVitamin D deficiency and vitamin B12 deficiency may occur in FMF cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is New\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVitamin D deficiency is common in children with FMF, but not directly related to disease severity and activity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVitamin B12 levels do not differ in children with FMF.\u003c/p\u003e\n\u003cp\u003eVitamin D deficiency is more common in FMF patients with joint symptoms.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eFamilial Mediterranean Fever (FMF) is an autosomal recessively inherited autoinflammatory disease characterized by recurrent attacks of fever, abdominal pain, and polyserositis. It is endemic, particularly among Eastern Mediterranean populations, Jews, Armenians, Turks, and North African Arabs, with a prevalence of 1:300\u0026ndash;1:2000 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This disease presents with a range of clinical signs and a dramatic increase in acute-phase reactants, with flares of systemic inflammation followed by periods of remission of variable duration. Rash, serositis (peritonitis, pleuritis), lymphadenopathy, and arthritis are the main clinical manifestations [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The gene responsible for the disease is the MEFV gene, located on the short arm of chromosome 16, which encodes the 781-amino acid pyrin protein. Approximately 300 different mutations of the MEFV gene that can cause FMF have been identified [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Of these mutations, V726A, M680I, E148Q, M694V, and M694I account for approximately 70% to 80% of cases. Approximately 10% of patients diagnosed with clinical FMF do not have mutations in the MEFV gene. The MEFV gene carrier rate can reach as high as one-third in some regions [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Colchicine has been used in the treatment of FMF since 1972, and it can reduce both the frequency and number of attacks and prevent complications of the disease [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Although colchicine is an essentially safe drug with few side effects, such as diarrhea and abdominal distension, numerous animal and human studies indicate that it may impair intestinal absorption of vitamin B12 and is considered a potential agent for vitamin deficiency [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Colchicine may reduce vitamin B12 absorption by decreasing the receptor level of the B12-intrinsic factor (IF) complex on mucosal cells [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecent research has increasingly focused on the potential role of vitamin D, a secosteroid hormone essential for calcium homeostasis and immunomodulation, in the pathophysiology of FMF [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Studies have also found that vitamin D deficiency is more common in patients with FMF and is associated with greater disease severity, pain, and impaired quality of life [\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This deficiency may be linked to the proinflammatory state of FMF, as vitamin D is known to exert anti-inflammatory effects through the inhibition of proinflammatory cytokines such as IL-1, IL-6, and TNF-α [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Chronic inflammation, reduced sun exposure due to lifestyle changes during exacerbations, and possible genetic predispositions may contribute to lower serum vitamin D levels [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] Additionally, medications such as colchicine, a cornerstone of FMF management, may further exacerbate the deficiency by interfering with vitamin D metabolism [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. To this end, routine screening for vitamin D levels is recommended in pediatric FMF patients [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In this study, we aimed to compare children with FMF with healthy children in terms of vitamin D and vitamin B12 deficiency and to examine the relationship between vitamin D and vitamin B12 deficiency and the clinical features of the disease.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study was conducted between October 15, 2024, and December 15, 2024. Patients diagnosed with FMF (case group) aged 0-18 years who were admitted to a tertiary university hospital between June 2020 and June 2024, and healthy children admitted to the hospital for well-child follow-up on the same date (control group) were included in the study. The control group was twice the size of the case group and was almost matched for age and sex. Cases with chronic kidney or liver disease, malnutrition, metabolic bone disease, or other comorbidities, and those using any medication that affects vitamin D or vitamin B12 levels were excluded from the study. \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData on sociodemographic characteristics such as age, gender, season of admission, reasons for admission, and final diagnoses were obtained from hospital electronic file records. Cases were classified as infants (1 month-2 years), preschoolers (3-5 years), middle childhood (6-10 years), and adolescents (11-18 years). Seasons were classified as \"Spring\" (March-April-May), \"Summer\" (June-July-August), \"Autumn\" (September-October-November), and \"Winter\" (December-January-February). Vitamin D and vitamin B12 levels were evaluated in both groups. \u0026nbsp;25(OH)D values \u0026lt;12 ng/mL were classified as deficiency, 12-20 ng/mL as insufficiency[24]. B12 values \u0026lt;200 pg/mL were classified as deficiency, 200-300 pg/mL as insufficiency [25]. Clinical characteristics of the case group, including age at diagnosis, disease duration, colchicine treatment duration, symptoms and signs and disease severity score [26] and laboratory findings (Presence of anemia, presence of leukocytosis, presence of platelet abnormality, increased sedimentation rate, increased fibrinogen, presence of proteinuria and presence of MEFV mutation) were also collected. Anemia was defined according to the lower limit of hemoglobin for age and gender; leukocyte, fibrinogen and sedimentation values were evaluated and values above the upper limit were considered as leukocytosis, increased sedimentation rate and increased fibrinogen, respectively [27].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt was received from the Afyonkarahisar Health Sciences University Ethics Committee on date: 06.09.2024 with decision no: 2024/311. All study procedures were performed in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical evaluation was performed using the IBM SPSS Statistics for Windows, Version 22.0. (Armonk, NY: IBM Corp.) program. Data were analyzed using descriptive statistical methods. Normality tests, including Kolmogorov-Smirnov and Shapiro-Wilk tests, were used to determine the distribution of quantitative data. Normally distributed data were expressed as mean ±standard deviation, and non-normally distributed data were expressed as median and minimum-maximum values. Categorical variables were expressed as percentage (%) and number (n). The Mann-Whitney U test was used to compare quantitative data between groups because the distribution of the data was not normal. Chi Square test and Fisher’s Exact test were used for categorical variables.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 71 case and 142 healthy controls were included in the study. 54.9% of the participants in the case group and 61.3 % in the control group were male. In the case group, the mean age ±standard deviation (SD) was determined as 10.5 ±4.2 years, median age [minimum and maximum (min-max)] was determined as 10.0 (1.6-18.0) years, while in the control group, the mean age ±SD was determined as 9.9 ±4.2, median age (min-max) was determined as 9.9 (1.6-18.0) years. There was no difference between the case and control groups in terms of age, age group, gender and the season when vitamin levels are tested (p\u0026gt;0.5). Table 1 shows the comparison of case group and control group in terms of general characteristics.\u003c/p\u003e\n\u003cp\u003eWhen both groups were compared in terms of the frequency of low serum vitamin D levels (insufficiency and deficiency) (\u0026lt;20 ng/ml), it was found to be higher in the case group (57.7 %) than in the control group (38.7 %) (p=0.009). The median and the mean ±SD serum vitamin D level was also lower in the case group as 18.1 ng/mL and 19.4±9.5 ng/mL, respectively (p=0.018). When the groups were compared in terms of low serum vitamin B12 levels, no significant difference was found (p\u0026gt;0.05). Table 2 shows the comparison of the case and the control group in terms of presence of low vitamin D and vitamin B12 and also serum vitamin D and vitamin B12 levels.\u003c/p\u003e\n\u003cp\u003eIn case group, the median age (min-max) at diagnosis was 6.0 (2.0-12.0) years, the median (min-max) duration of the disease was 3.5 (1.0-12.0) years. When the demographic and clinical characteristics of the cases were compared with the presence of low vitamin D, it was found that the presence of vitamin D deficiency or insufficiency was more common in cases with pleuritis, myalgia, arthralgia and arthritis (p=0.044, p=0.014, p=0.037, p=0.014, respectively). Demographic characteristics of the cases, laboratory findings and severity of disease did not change according to the presence of low vitamin D (p\u0026gt;0.05). When the demographic and clinical characteristics of the cases were compared with the presence of low vitamin B12, any parameter changed according to the presence of low vitamin B12 (p\u0026gt;0.05). Table 3 shows the comparison of demographic and clinical characteristics with the presence of vitamin D and vitamin B12 deficiency or insufficiency in FMF patients.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study revealed that vitamin D deficiency is common in patients followed up with a diagnosis of FMF. Vitamin D is essential not only for bone health but also for immune system regulation and inflammation control. Vitamin D deficiency has been shown to increase disease activity in autoimmune and autoinflammatory diseases, trigger the production of proinflammatory cytokines, and impair immune tolerance [28]. In our study, the ratio of vitamin D deficiency was found to be higher in children with FMF than in healthy controls. This finding is consistent with previous studies in the literature highlighting vitamin D deficiency in FMF patients [21, 29, 30]. In a 1983 study conducted by Adams and colleagues, seven patients with sarcoidosis and two with idiopathic pulmonary fibrosis were examined, demonstrating the effects of active vitamin D on the immune system and its importance in autoimmune diseases [31]. This pioneering study highlighted the immunomodulatory role of vitamin D and led to numerous studies today. Following this important study, research has been conducted on the relationship between vitamin D and autoimmune and autoinflammatory diseases [30, 32, 33]. Active vitamin D and its analogs have been shown to prevent lupus-like symptoms and reduce the development of inflammatory bowel disease [34]. Increasing evidence suggests that vitamin D is important in the onset and progression of many autoimmune diseases[35]. Although vitamin D deficiency has been shown to be common in patients with FMF there are conflicting results in the literature regarding the relationship between this deficiency and disease severity and activity (21,29,30). In our study, no significant relationship was found between vitamin D levels, disease severity, or colchicine treatment. Anık et al. also reported that vitamin D levels were low in children with FMF, but there was no significant relationship with disease severity [29]. In a study by Yılmaz et al., no correlation was found between vitamin D levels and disease severity; however, all FMF patients with mild, moderate, or severe symptom scores had low vitamin D levels [30]. In our study, no significant correlation was also found between vitamin D levels and serum acute-phase reactants level. This result is consistent with the results of Anık et al. [29], who found no significant relationship between serum vitamin D levels and serum acute-phase reactants levels. Erten et al. reported a relationship between elevated inflammatory markers (ESR and fibrinogen) and low vitamin D levels in FMF patients [21].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Causes of vitamin D deficiency in patients with FMF include chronic inflammation due to the disease itself, colchicine treatment affecting intestinal absorption, and reduced physical activity and sunlight exposure. There are conflicting results in the literature regarding the effect of colchicine treatment on vitamin D levels. While Karatay et al.'s [36] study on patients with Behçet's disease suggested that colchicine treatment might reduce vitamin D levels, a study by Anık et al. found that vitamin D levels in children with FMF were inversely proportional to the cumulative colchicine dose [29]. \u0026nbsp;In our study, no significant relationship was found between colchicine dose and duration and vitamin D levels.\u003c/p\u003e\n\u003cp\u003eThe most common clinical presentations of FMF patients are recurrent fever, abdominal pain, and joint symptoms. In this study, patients presenting with joint symptoms at presentation had significantly lower vitamin D levels than those presenting with abdominal pain and fever. This result suggests that the risk of vitamin D deficiency is higher in FMF patients with joint involvement. Similarly, a study by Erten et al. [21] reported that vitamin D levels were significantly lower in FMF patients with joint symptoms at presentation than in those presenting with abdominal pain. The findings of both studies highlight that vitamin D insufficiency is more common in patients presenting with joint complaints in FMF. In our study, no significant difference was found between vitamin D levels and different MEFV gene mutations. This finding suggests that genotype alone is not the sole determinant in the pathogenesis of FMF, but that environmental factors (sun exposure, dietary habits, physical activity) and inflammatory processes also contribute significantly. Indeed, the literature has reported that vitamin D levels in patients with FMF do not show a clear relationship with genotype. Onur et al., in their study investigating the relationship between vitamin D status and disease activity in their patients, demonstrated that low vitamin D levels can be observed regardless of genotype [37]. This suggests that vitamin D deficiency in FMF may be related to the inflammatory processes and environmental factors that accompany the disease, and therefore, clinical management should consider not only genetic subtype but also biochemical and environmental parameters.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Vitamin B12 is essential for DNA synthesis, erythropoiesis, and nervous system function. Although it has been suggested that vitamin B12 levels may decrease in chronic inflammatory diseases, studies specifically on FMF are quite limited. In our study, no significant difference in vitamin B12 levels was found between children with FMF and healthy controls. In the study conducted by Başaran et al., it was reported that vitamin B12 levels in children with FMF were not significantly different from healthy controls, but vitamin B12 levels were found to be significantly lower in patients receiving high-dose treatment, even though they were within normal limits and did not cause anemia [38]. This finding suggests that vitamin B12 deficiency in FMF does not play a decisive role in the pathogenesis or clinical course of the disease. However, colchicine used in treatment may affect intestinal mucosal function and reduce serum vitamin B12 levels. A study by Yılmaz et al. showed that long-term colchicine administration led to a deficiency in serum vitamin B12 levels [10, 39]\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Our study has several limitations. These include being a single-center, cross-sectional study and not having detailed assessments of factors that could affect vitamin D levels, such as participants' dietary habits, sunlight exposure, and physical activity levels. Furthermore, the study population largely originating from a single geographic region may limit the generalizability of the findings to larger populations with different genetic backgrounds and environmental factors. A key strength of our study is that it is one of the few studies to investigate vitamin D deficiency and vitamin B12 deficiency together in patients with FMF.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWhile vitamin D deficiency is common in children with FMF, it is not directly related to disease severity and activity. Vitamin B12 levels, however, do not differ in children with FMF compared to healthy controls. While this study highlights the need for routine monitoring of vitamin D levels in children with FMF, the same conclusion cannot be drawn for vitamin B12. However, prospective studies with larger samples are needed to assess whether vitamin D supplementation can effectively reduce the frequency and severity of FMF attacks and its impact on disease activity and prognosis.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection were performed by Ayşe G\u0026uuml;ng\u0026ouml;r, Aysun Soyug\u0026uuml;zel, Hilal Koyuncu and Nur \u0026Ouml;nen. Analysis were performed by Ayşe G\u0026uuml;ng\u0026ouml;r. Literature review was done by Ayşe G\u0026uuml;ng\u0026ouml;r, Hilal Koyuncu and Aysun Soyug\u0026uuml;zel. The first draft of the manuscript was written by Ayşe G\u0026uuml;ng\u0026ouml;r and, Ayşe Oflu. The article was edited and checked by Ayşe Oflu . Ayşe G\u0026uuml;ng\u0026ouml;r, Ayşe Oflu, Ayşeg\u0026uuml;l B\u0026uuml;k\u0026uuml;lmez, A.Afşin Kundak and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLidar M, Livneh A (2007) Familial Mediterranean fever: clinical, molecular and management advancements. Neth J Med 65(9):318\u0026ndash;324\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTerreri MTR et al (2016) Guidelines for the management and treatment of periodic fever syndromes familial Mediterranean fever. Revista Brasileira de Reumatologia (English Edition) 56(1):37\u0026ndash;43\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLivneh A et al (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthr Rhuem 40(10):1879\u0026ndash;1885\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eConsortium IF (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90(4):797\u0026ndash;807\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTouitou I (2001) The spectrum of familial Mediterranean fever (FMF) mutations. Eur J Hum Genet 9(7):473\u0026ndash;483\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEhrenfeld M et al (1982) \u003cem\u003eGastrointestinal effects of long-term colchicine therapy in patients with recurrent polyserositis (familial Mediterranean fever).\u003c/em\u003e Digestive diseases and sciences, 27(8): pp. 723\u0026ndash;727\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOzen S et al (2025) EULAR/PReS endorsed recommendations for the management of familial Mediterranean fever (FMF): 2024 update. Annals of the rheumatic diseases\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGoldfinger S (1972) \u003cem\u003eColchicine for familial Mediterranean fever.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShinar Y et al (2000) Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rhuematol 27(7):1703\u0026ndash;1707\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStopa E, O'Brien R, Katz M (1979) Effect of colchicine on guinea pig intrinsic factor-vitamin B12 receptor. Gastroenterology 76(2):309\u0026ndash;314\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWebb DI et al (1968) Mechanism of vitamin B12 malabsorption in patients receiving colchicine. N Engl J Med 279(16):845\u0026ndash;850\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDavis RE \u003cem\u003eClinical chemistry of vitamin B12.\u003c/em\u003e Advances in clinical chemistry, 1985. 24: pp. 163\u0026ndash;216\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRace T, Paes I, Faloon W (1970) Intestinal malabsorption induced by oral colchicine. Comparison with neomycin and cathartic agents. Am J Med Sci 259(1):32\u0026ndash;41\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOzdogan H, Ugurlu S (2019) Familial mediterranean fever. La Presse M\u0026eacute;dicale 48(1):e61\u0026ndash;e76\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTurhan T et al (2018) Vitamin D status, serum lipid concentrations, and vitamin D receptor (VDR) gene polymorphisms in Familial Mediterranean fever. Bosnian J Basic Med Sci 18(1):21\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOrhan C et al (2020) Vitamin D binding protein genotype frequency in familial Mediterranean fever patients. Scand J Rheumatol 49(6):484\u0026ndash;488\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEloi M et al (2017) 25-Hydroxivitamin D serum concentration, not free and bioavailable vitamin D, is associated with disease activity in systemic lupus erythematosus patients. PLoS ONE 12(1):e0170323\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlesh MB et al (2022) Hidden threat in familial Mediterranean fever: subclinical inflammation, oxidative stress and their relationship with vitamin D status. Turk J Med Sci 52(1):67\u0026ndash;75\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEscobedo-Monge MF et al (2024) Calcium, phosphate, and vitamin d in children and adolescents with chronic diseases: a cross-sectional study. Nutrients 16(9):1349\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSaedmocheshi S et al (2024) The effect of vitamin D consumption on pro-inflammatory cytokines in athletes: A systematic review of randomized controlled trials. Sports 12(1):32\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eErten Ş et al (2012) Low plasma vitamin D levels in patients with familial Mediterranean fever. Rheumatol Int 32(12):3845\u0026ndash;3849\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMansueto P et al (2022) Familial Mediterranean fever and diet: a narrative review of the scientific literature. Nutrients 14(15):3216\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOzer I et al (2015) Association between colchicine resistance and vitamin D in familial Mediterranean fever. Ren Fail 37(7):1122\u0026ndash;1125\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMunns CF et al (2016) Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metabolism 101(2):394\u0026ndash;415\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGreen R et al (2017) Vitamin B12 deficiency. Nat reviews Disease primers 3(1):1\u0026ndash;20\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePras E et al (1998) Clinical differences between North African and Iraqi Jews with familial Mediterranean fever. Am J Med Genet 75(2):216\u0026ndash;219\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFish JD, Lipton JM, Lanzkowsky P (2021) SPEC\u0026ndash;Lanzkowsky's Manual of Pediatric Hematology and Oncology, 12-Month Access, eBook: SPEC\u0026ndash;Lanzkowsky's Manual of Pediatric Hematology and Oncology, 12-Month Access, eBook. academic\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAranow C (2011) Vitamin D and the immune system. J Investig Med 59(6):881\u0026ndash;886\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAnık A et al (2014) Decreased vitamin D levels in children with familial M editerranean fever. Int J Rheum Dis 17(3):321\u0026ndash;326\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYilmaz R et al (2014) Hypovitaminosis D in children with familial Mediterranean fever. Clin Invest Med 37(4):E211\u0026ndash;E216\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAdams JS et al (1983) Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Investig 72(5):1856\u0026ndash;1860\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGallo D et al (2023) How does vitamin D affect immune cells crosstalk in autoimmune diseases? Int J Mol Sci 24(5):4689\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhao SS et al (2023) \u003cem\u003eAssociations between vitamin D and autoimmune diseases: Mendelian randomization analysis\u003c/em\u003e. in \u003cem\u003eSeminars in arthritis and rheumatism\u003c/em\u003e. Elsevier\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShevchuk S et al (2023) Vitamin D level in patients with systemic lupus erythematosus: its relationship to disease course and bone mineral density, vol 10. Lupus Science \u0026amp; Medicine, 2\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCutolo M, Gotelli E (2023) The 2023\u0026rsquo;s growing evidence confirming the relationship between vitamin D and autoimmune diseases. Nutrients 15(22):4760\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKaratay S et al (2011) Vitamin D status in patients with Behcet's Disease. Clinics 66:721\u0026ndash;723\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOnur H et al (2016) Vitamin D levels in children with familial Mediterranean fever. Pediatr Rheumatol 14(1):28\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBaşaran \u0026Ouml;, Uncu N (2018) Kolşisin tedavisi altındaki ailevi akdeniz ateşi tanısı ile takip edilen \u0026ccedil;ocuk hastalarda vitamin B12 d\u0026uuml;zeylerinin değerlendirilmesi. G\u0026uuml;ncel Pediatri 16(2):86\u0026ndash;92\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYilmaz R et al (2011) Serum Vitamin B12 Status in Children with Familial Mediterranean Fever Receiving Colchicine Treatment 對秋水仙堿治療家族性地中海熱兒童後血清維生素 B12 水平的研究. HK J Paediatr (new series) 16(1):3\u0026ndash;8\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\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":"Child, Familial Mediterranean Fever, Vitamin D, Vitamin B12","lastPublishedDoi":"10.21203/rs.3.rs-7914184/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7914184/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e\u003cp\u003eThis study aimed to determine the Vitamin D and Vitamin B12 levels in pediatric cases diagnosed with Familial Mediterranean Fever (FMF) and compare these levels with those of healthy controls.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis retrospective study included pediatric FMF patients aged 0 to 18 years admitted to a tertiary care hospital and healthy children of similar age and gender. Data were obtained through review of patients' electronic medical records.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 71 FMF patients were included in the study group and 141 healthy children in the control group. The mean age was 10.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2 years in the study group and 10.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2 years in the control group. There was no significant difference between the groups in terms of age and gender (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). When the groups were compared in terms of vitamin D deficiency, the frequency was found to be higher in the study group with a ratio of 57.7% (p\u0026thinsp;=\u0026thinsp;0.009). There was no significant difference between the groups in terms of vitamin B12 deficiency (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis study revealed that vitamin D levels were lower in FMF patients compared to healthy controls, but there was no significant difference in vitamin B12 levels. This finding highlights the importance of screening and monitoring vitamin D levels in FMF patients.\u003c/p\u003e","manuscriptTitle":"Evaluation of vitamin D and vitamin B12 levels in children with Familial Mediterranean Fever","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-05 15:54:03","doi":"10.21203/rs.3.rs-7914184/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":"4cf62f2d-61c1-4b7e-a245-75dac5bc67ff","owner":[],"postedDate":"November 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-10T20:23:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-05 15:54:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7914184","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7914184","identity":"rs-7914184","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}