Abstract
Objective: Behcet’s disease (BD) is a chronic multisystem inflammatory disease classified as Variable Vessel Vasculitis with unclear etiology. We designed this systematic review and meta-analysis to evaluate vitamin D status in Behcet’s disease patients with this background.
Methods: We performed this systematic review and meta-analysis according to PRISMA guidelines. We included all observational studies in humans published in English, evaluating the association of 25(OH)D concentrations in Behcet’s patients. Two reviewers (HRK and AE) independently searched the databases and screened articles based on their titles and abstracts. A third reviewer resolved all disagreements. We performed analysis using Cochrane Program Review Manager Version 5.3. The protocol for this review was registered on PROSPERO (CRD42020197426).
Results: A total of 341 publications were initially identified according to the search strategy. Finally, 12 publications were included in the meta-analysis. We performed this meta-analysis on 1265 participants from different studies with a sample size ranging from 63 to 224 individuals. In studies comparing active and inactive subgroups of patients with Behcet’s disease, we found a significantly lower serum level of vitamin D in patients with Active BD (-0.4; 95% CI: -0.61, -0.25; p<0.001). We found that the serum level of vitamin D in Behcet’s disease is significantly higher than in health controls (0.5; 95% CI: 0.15, 0.50; p=0.001).
Conclusion: We demonstrated that the existing evidence is consistent with the hypothesis that an increased serum level of vitamin D would be associated with a substantially lower risk of active Behcet’s disease.
Keywords: Behcet’s disease, vitamin D deficiency, vasculitis, oral aphthosis, rheumatology, genital ulcer.
Graphical Abstract
[1]
Abdou MMS, Sheta MM, Effat DA, Haikal AE. Assessment of 25-hydroxyvitamin D level in patients with Behçet’s disease and its correlation with disease activity and severity. Egypt Rheumatol Rehabil 2017; 44(1): 30-8.
[http://dx.doi.org/10.4103/1110-161X.198429]
[http://dx.doi.org/10.4103/1110-161X.198429]
[2]
Davatchi F, Chams-Davatchi C, Shams H, et al. Behcet’s disease: Epidemiology, clinical manifestations, and diagnosis. Expert Rev Clin Immunol 2017; 13(1): 57-65.
[http://dx.doi.org/10.1080/1744666X.2016.1205486] [PMID: 27351485]
[http://dx.doi.org/10.1080/1744666X.2016.1205486] [PMID: 27351485]
[3]
Calamia KT, Kaklamanis PG. Behçet’s disease: Recent advances in early diagnosis and effective treatment. Curr Rheumatol Rep 2008; 10(5): 349-55.
[http://dx.doi.org/10.1007/s11926-008-0057-y] [PMID: 18817637]
[http://dx.doi.org/10.1007/s11926-008-0057-y] [PMID: 18817637]
[4]
Adeeb F, Khan MU, Li X, Stack AG, Devlin J, Fraser AD. High vitamin D levels may downregulate inflammation in patients with Behçet’s disease. Int J Inflam 2017; 2017: 8608716.
[http://dx.doi.org/10.1155/2017/8608716] [PMID: 28660088]
[http://dx.doi.org/10.1155/2017/8608716] [PMID: 28660088]
[5]
Calamia KT, Wilson FC, Icen M, Crowson CS, Gabriel SE, Kremers HM. Epidemiology and clinical characteristics of Behçet’s disease in the US: A population-based study. Arthritis Rheum 2009; 61(5): 600-4.
[http://dx.doi.org/10.1002/art.24423] [PMID: 19405011]
[http://dx.doi.org/10.1002/art.24423] [PMID: 19405011]
[6]
Can M, Gunes M, Haliloglu OA, et al. Effect of vitamin D deficiency and replacement on endothelial functions in Behçet’s disease. Clin Exp Rheumatol 2012; 30(3)(Suppl. 72): S57-61.
[PMID: 23020973]
[PMID: 23020973]
[7]
Aslan N, Demirci K, Güler T, Dörtbaş F, Kale E. The effect of vitamin D on clinical manifestations and activity of Behçet’s disease. Postepy Dermatol Alergol 2017; 34(1): 15-20.
[http://dx.doi.org/10.5114/pdia.2016.57222] [PMID: 28261027]
[http://dx.doi.org/10.5114/pdia.2016.57222] [PMID: 28261027]
[8]
Do JE, Kwon SY, Park S, Lee ES. Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behcet’s disease. Rheumatology (Oxford) 2008; 47(6): 840-8.
[http://dx.doi.org/10.1093/rheumatology/ken109] [PMID: 18411217]
[http://dx.doi.org/10.1093/rheumatology/ken109] [PMID: 18411217]
[9]
Al-Nahas Z, Fawzy M, El Menyawi M, Shaker O, Ragab G. 25-hydroxyvitamin D3 deficiency and vitamin D receptor polymorphisms in Egyptian patients with Behçet’s disease: A pilot study. Int J Clin Rheumatol 2017; 12(2): 20.
[10]
Khodadadi H, Khabazi A, Ghaderian SMH, et al. Molecular analysis of vitamin D receptor gene polymorphisms rs2228570 (FokI) and rs1544410 (BsmI) in patients with Behcet’s Disease. Life Sci J 2013; 10(4): 608-15.
[11]
Tizaoui K, Kaabachi W, Ouled Salah M, Ben Amor A, Hamzaoui A, Hamzaoui K. Vitamin D receptor TaqI and ApaI polymorphisms: A comparative study in patients with Behçet’s disease and rheumatoid arthritis in Tunisian population. Cell Immunol 2014; 290(1): 66-71.
[http://dx.doi.org/10.1016/j.cellimm.2014.05.002] [PMID: 24880677]
[http://dx.doi.org/10.1016/j.cellimm.2014.05.002] [PMID: 24880677]
[12]
Tian Y, Wang C, Ye Z, Xiao X, Kijlstra A, Yang P. Effect of 1,25-dihydroxyvitamin D3 on Th17 and Th1 response in patients with Behçet’s disease. Invest Ophthalmol Vis Sci 2012; 53(10): 6434-41.
[http://dx.doi.org/10.1167/iovs.12-10398] [PMID: 22918640]
[http://dx.doi.org/10.1167/iovs.12-10398] [PMID: 22918640]
[13]
Choi B, Lee E-S, Sohn S. Vitamin D3 ameliorates herpes simplex virus-induced Behçet’s disease-like inflammation in a mouse model through down-regulation of Toll-like receptors. Clin Exp Rheumatol 2011; 29(4)(Suppl. 67): S13-9.
[PMID: 21269574]
[PMID: 21269574]
[14]
Yazici H, Seyahi E, Hatemi G, Yazici Y. Behçet syndrome: A contemporary view. Nat Rev Rheumatol 2018; 14(2): 107-19.
[http://dx.doi.org/10.1038/nrrheum.2017.208] [PMID: 29296024]
[http://dx.doi.org/10.1038/nrrheum.2017.208] [PMID: 29296024]
[15]
Dal NE, Cerci P, Olmez U, Keskin G. The role of vitamin D receptor gene polymorphisms in the pathogenesis of Behçet’s disease: A case-control study in Turkish population. Ann Hum Genet 2019; 83(3): 177-86.
[http://dx.doi.org/10.1111/ahg.12301] [PMID: 30730049]
[http://dx.doi.org/10.1111/ahg.12301] [PMID: 30730049]
[16]
Mirfeizi Z, Tabaei S, Ravanshad Y, Hashemzadeh K, Kharazmi E, Mehrad-Majd H. Associations between vitamin D receptor polymorphisms and susceptibility to Behcet’s disease: A meta-analysis. Immunol Invest 2018; 47(4): 389-402.
[http://dx.doi.org/10.1080/08820139.2018.1430827] [PMID: 29388852]
[http://dx.doi.org/10.1080/08820139.2018.1430827] [PMID: 29388852]
[17]
Wells G, Shea B. The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomized studies in meta-analysis. Appl Eng Agric 2014; 18(6): 727-34.
[18]
Pearson ES. The percentage limits for the distribution of range in samples from a normal population (n⩽100.). Biometrika 1932; 24(3/4): 404-17.
[http://dx.doi.org/10.2307/2331974]
[http://dx.doi.org/10.2307/2331974]
[19]
Ganeb SS, Sabry HH, El-Assal MM, Kamal HM, Fayed AA. Vitamin D levels in patients with Behçet’s disease: Significance and impact on disease measures. Egypt Rheumatol 2013; 35(3): 151-7.
[http://dx.doi.org/10.1016/j.ejr.2013.01.006]
[http://dx.doi.org/10.1016/j.ejr.2013.01.006]
[20]
Djeraba Z, Benlabidi F, Djaballah-Ider FZ, et al. Vitamin D status in Algerian Behçet’s disease patients: An immunomodulatory effect on NO pathway. Immunopharmacol Immunotoxicol 2017; 39(4): 243-50.
[http://dx.doi.org/10.1080/08923973.2017.1327967] [PMID: 28532201]
[http://dx.doi.org/10.1080/08923973.2017.1327967] [PMID: 28532201]
[21]
Faezi ST, Ansari N, Paragomi P, Akhlaghi M, Ghanavat M, Davatchi F. Vitamin D deficiency in patients with Behcet’s disease. J Diabetes Metab Disord 2014; 13(1): 18.
[http://dx.doi.org/10.1186/2251-6581-13-18] [PMID: 24451043]
[http://dx.doi.org/10.1186/2251-6581-13-18] [PMID: 24451043]
[22]
Karatay S, Yildirim K, Karakuzu A, et al. Vitamin D status in patients with Behcet’s disease. Clinics (São Paulo) 2011; 66(5): 721-3.
[PMID: 21789370]
[PMID: 21789370]
[23]
Khabbazi A, Rashtchizadeh N, Ghorbanihaghjo A, et al. The status of serum vitamin D in patients with active Behcet’s disease compared with controls. Int J Rheum Dis 2014; 17(4): 430-4.
[http://dx.doi.org/10.1111/1756-185X.12153] [PMID: 24118939]
[http://dx.doi.org/10.1111/1756-185X.12153] [PMID: 24118939]
[24]
Kul A, Erdal A. Bone mineral density and vitamin D values in Behçet’s disease. Turk Osteoporoz Dergisi 2018; 24(3): 78-83.
[http://dx.doi.org/10.4274/tod.galenos.2018.16362]
[http://dx.doi.org/10.4274/tod.galenos.2018.16362]
[25]
Hamzaoui K, Ben Dhifallah I, Karray E, Sassi FH, Hamzaoui A. Vitamin D modulates peripheral immunity in patients with Behçet’s disease. Clin Exp Rheumatol 2010; 28(4)(Suppl. 60): S50-7.
[PMID: 20868571]
[PMID: 20868571]
[26]
Kandi B, Cicek D, Ilhan N. Vitamin levels in Behçet’s disease. J Dermatolog Treat 2007; 18(2): 69-75.
[http://dx.doi.org/10.1080/09546630601156355] [PMID: 17520462]
[http://dx.doi.org/10.1080/09546630601156355] [PMID: 17520462]
[27]
Zhong Z, Su G, Du L, Zhou Q, Li F, Chi W, et al. Higher 25-hydroxyvitamin D level is associated with increased risk for Behçet’s disease. Clin Nutr 2020; 40(2): 518-24.
[PMID: 32593521]
[PMID: 32593521]
[28]
Alpsoy E, Donmez L, Onder M, et al. Clinical features and natural course of Behçet’s disease in 661 cases: A multicentre study. Br J Dermatol 2007; 157(5): 901-6.
[http://dx.doi.org/10.1111/j.1365-2133.2007.08116.x] [PMID: 17711526]
[http://dx.doi.org/10.1111/j.1365-2133.2007.08116.x] [PMID: 17711526]
[29]
Yu S, Cantorna MT. The vitamin D receptor is required for iNKT cell development. Proc Natl Acad Sci USA 2008; 105(13): 5207-12.
[http://dx.doi.org/10.1073/pnas.0711558105] [PMID: 18364394]
[http://dx.doi.org/10.1073/pnas.0711558105] [PMID: 18364394]
[30]
Pitukweerakul S, Sinyagovskiy P, Prachuapthunyachart S. The association between vitamin D level and Behcet’s disease: A meta-analysis. Int J Rheum Dis 2017; 20(12): 2217-8.
[http://dx.doi.org/10.1111/1756-185X.13108] [PMID: 28608505]
[http://dx.doi.org/10.1111/1756-185X.13108] [PMID: 28608505]
[31]
Tang J, Zhou R, Luger D, et al. Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. J Immunol 2009; 182(8): 4624-32.
[http://dx.doi.org/10.4049/jimmunol.0801543] [PMID: 19342637]
[http://dx.doi.org/10.4049/jimmunol.0801543] [PMID: 19342637]
[32]
Adorini L. Selective immunointervention in autoimmune diseases: Lessons from multiple sclerosis. J Chemother 2001; 13(3): 219-34.
[http://dx.doi.org/10.1179/joc.2001.13.3.219] [PMID: 11450879]
[http://dx.doi.org/10.1179/joc.2001.13.3.219] [PMID: 11450879]
[33]
Adorini L. Immunomodulatory effects of vitamin D receptor ligands in autoimmune diseases. Int Immunopharmacol 2002; 2(7): 1017-28.
[http://dx.doi.org/10.1016/S1567-5769(02)00049-8] [PMID: 12188026]
[http://dx.doi.org/10.1016/S1567-5769(02)00049-8] [PMID: 12188026]
[34]
Jurutka PW, Remus LS, Whitfield GK, et al. The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol 2000; 14(3): 401-20.
[http://dx.doi.org/10.1210/mend.14.3.0435] [PMID: 10707958]
[http://dx.doi.org/10.1210/mend.14.3.0435] [PMID: 10707958]
[36]
Baeke F, Korf H, Overbergh L, et al. Human T lymphocytes are direct targets of 1,25-dihydroxyvitamin D3 in the immune system. J Steroid Biochem Mol Biol 2010; 121(1-2): 221-7.
[http://dx.doi.org/10.1016/j.jsbmb.2010.03.037] [PMID: 20302932]
[http://dx.doi.org/10.1016/j.jsbmb.2010.03.037] [PMID: 20302932]
[37]
Orbach H, Zandman-Goddard G, Amital H, et al. Novel biomarkers in autoimmune diseases: Prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases. Ann N Y Acad Sci 2007; 1109(1): 385-400.
[http://dx.doi.org/10.1196/annals.1398.044] [PMID: 17785327]
[http://dx.doi.org/10.1196/annals.1398.044] [PMID: 17785327]
[38]
Güngör Ş, Gökdemir G, Çiçek YG, Topal İO, Canat D. The effect of 25(OH)D on endothelial and immunological markers in Behçet’s disease. J Dermatolog Treat 2016; 27(3): 254-9.
[http://dx.doi.org/10.3109/09546634.2015.1093585] [PMID: 26368304]
[http://dx.doi.org/10.3109/09546634.2015.1093585] [PMID: 26368304]
Article Metrics
41
2
