{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T15:31:30Z","timestamp":1784302290160,"version":"3.55.0"},"reference-count":30,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T00:00:00Z","timestamp":1682467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Takeda Japan Medical Office","award":["20K16961"],"award-info":[{"award-number":["20K16961"]}]},{"name":"JSPS KAKENHI","award":["20K16961"],"award-info":[{"award-number":["20K16961"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Mediterranean fever (MEFV) gene mutations are responsible for familial Mediterranean fever (FMF) and associated with other inflammatory diseases. However, the effects of MEFV gene mutations on intestinal Beh\u00e7et\u2019s disease (BD) are unknown. In this study, we investigated these mutations and clinical features in patients with intestinal BD. Methods: MEFV gene analysis was performed in 16 patients with intestinal BD, 10 with BD without intestinal lesions, and 50 healthy controls. Clinical features of patients with intestinal BD were retrospectively assessed. Results: The rates of MEFV gene mutations in patients with intestinal BD, BD without intestinal lesions, and healthy controls were 75%, 50%, and 38%, respectively. Only 2 of 12 patients with intestinal BD harboring MEFV gene mutations (17%) were controlled without immunosuppressive treatment, while 8 patients (67%) required therapy with tumor necrosis factor (TNF) inhibitors. Among patients with intestinal BD without MEFV gene mutations (four patients), three (75%) were controlled by the administration of 5-aminosalicylic acid with or without colchicine, and one (25%) required TNF inhibitors. All patients who underwent intestinal resection had MEFV gene mutations. Immunohistochemical analysis and in situ hybridization with interleukin-1\u03b2 (IL-1\u03b2) showed a high expression of IL-1\u03b2 only in injured areas, suggesting that IL-1\u03b2 may be involved in the formation of ulcers in patients with intestinal BD carrying MEFV gene mutations. Conclusion: Mutations in the MEFV gene may be associated with intestinal lesions of BD and refractoriness to treatment.<\/jats:p>","DOI":"10.3390\/jcm12093131","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T01:44:42Z","timestamp":1682473482000},"page":"3131","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Possible Association of Mutations in the MEFV Gene with the Intestinal Phenotype of Beh\u00e7et\u2019s Disease and Refractoriness to Treatment"],"prefix":"10.3390","volume":"12","author":[{"given":"Yoki","family":"Furuta","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Gushima","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Naoe","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munenori","family":"Honda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuiko","family":"Tsuruta","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7152-6101","authenticated-orcid":false,"given":"Katsuya","family":"Nagaoka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8990-9496","authenticated-orcid":false,"given":"Takehisa","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakuni","family":"Tateyama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahoko","family":"Fujimoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Hirata","sequence":"additional","affiliation":[{"name":"Department of Hematology, Rheumatology and Infectious Diseases, School of Medicine, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiko","family":"Miyagawa","sequence":"additional","affiliation":[{"name":"Department of Hematology, Rheumatology and Infectious Diseases, School of Medicine, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komei","family":"Sakata","sequence":"additional","affiliation":[{"name":"Department of Hematology, Rheumatology and Infectious Diseases, School of Medicine, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Mizuhashi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Rheumatology and Infectious Diseases, School of Medicine, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikako","family":"Iwakura","sequence":"additional","affiliation":[{"name":"Department of Hematology, Rheumatology and Infectious Diseases, School of Medicine, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Murai","sequence":"additional","affiliation":[{"name":"Department of Hematology, Rheumatology and Infectious Diseases, School of Medicine, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0473-754X","authenticated-orcid":false,"given":"Masao","family":"Matsuoka","sequence":"additional","affiliation":[{"name":"Department of Hematology, Rheumatology and Infectious Diseases, School of Medicine, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9723-0846","authenticated-orcid":false,"given":"Yoshihiro","family":"Komohara","sequence":"additional","affiliation":[{"name":"Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2473-6966","authenticated-orcid":false,"given":"Yasuhito","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s10238-004-0033-4","article-title":"Behcet\u2019s disease","volume":"4","author":"Suzuki","year":"2004","journal-title":"Clin. Exp. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"318","DOI":"10.5217\/ir.2017.15.3.318","article-title":"Treatment and outcomes: Medical and surgical treatment for intestinal Behcet\u2019s disease","volume":"15","author":"Hisamatsu","year":"2017","journal-title":"Intestig. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1007\/s00296-013-2838-5","article-title":"Gastrointestinal manifestations of Behcet\u2019s disease in Japan: A study of 43 patients","volume":"34","author":"Ideguchi","year":"2014","journal-title":"Rheumatol. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1007\/s00535-016-1300-3","article-title":"Incidence and clinical outcomes of intestinal Behcet\u2019s disease in Korea, 2011\u20132014: A nationwide population-based study","volume":"52","author":"Han","year":"2017","journal-title":"J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3349\/ymj.1997.38.6.411","article-title":"Epidemiological features of Adamantiades-Behcet\u2019s disease in Germany and in Europe","volume":"38","author":"Zouboulis","year":"1997","journal-title":"Yonsei Med. J."},{"key":"ref_6","first-page":"658","article-title":"Behcet\u2019s disease in Saudi Arabia","volume":"21","author":"Bohlega","year":"1994","journal-title":"J. Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.lfs.2012.03.017","article-title":"Interactions between IL17A, IL23R, and STAT4 polymorphisms confer susceptibility to intestinal Behcet\u2019s disease in Korean population","volume":"90","author":"Kim","year":"2012","journal-title":"Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"174","DOI":"10.5606\/tftrd.2017.72681","article-title":"Coexistence of familial Mediterranean fever and Behcet\u2019s disease: A case report","volume":"63","author":"Guler","year":"2017","journal-title":"Turk. J. Phys. Med. Rehabil."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ejim.2016.10.011","article-title":"Behcet\u2019s disease and familial Mediterranean fever: Two sides of the same coin or just an association? A cross-sectional study","volume":"39","author":"Watad","year":"2017","journal-title":"Eur. J. Intern. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8134","DOI":"10.1073\/pnas.1306352110","article-title":"Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behcet disease","volume":"110","author":"Kirino","year":"2013","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"El Roz, A., Ghssein, G., Khalaf, B., Fardoun, T., and Ibrahim, J.N. (2020). Spectrum of MEFV Variants and Genotypes among Clinically Diagnosed FMF Patients from Southern Lebanon. Med. Sci., 8.","DOI":"10.3390\/medsci8030035"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/S1097-2765(03)00056-X","article-title":"Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis","volume":"11","author":"Chae","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.1002\/acn3.50937","article-title":"MEFV gene mutations in neuro-Behcet\u2019s disease and neuro-Sweet disease","volume":"6","author":"Ishikawa","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1016\/S0140-6736(12)61377-4","article-title":"Mediterranean mimicker","volume":"380","author":"Arasawa","year":"2012","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1159\/000502640","article-title":"MEFV Gene-Related Enterocolitis Account for Some Cases Diagnosed as Inflammatory Bowel Disease Unclassified","volume":"101","author":"Saito","year":"2019","journal-title":"Digestion"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1007\/s12328-021-01497-1","article-title":"Mediterranean fever gene-associated enterocolitis in an elderly Japanese woman","volume":"14","author":"Shibata","year":"2021","journal-title":"Clin. J. Gastroenterol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1007\/s00535-013-0872-4","article-title":"The 2nd edition of consensus statements for the diagnosis and management of intestinal Behcet\u2019s disease: Indication of anti-TNFalpha monoclonal antibodies","volume":"49","author":"Hisamatsu","year":"2014","journal-title":"J. Gastroenterol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1093\/rheumatology\/ken162","article-title":"Behcet\u2019s disease associated with bone marrow failure in Korean patients: Clinical characteristics and the association of intestinal ulceration and trisomy 8","volume":"47","author":"Ahn","year":"2008","journal-title":"Rheumatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/s41590-020-0705-6","article-title":"Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis","volume":"21","author":"Park","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/ng.624","article-title":"Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet\u2019s disease susceptibility loci","volume":"42","author":"Mizuki","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/ng.625","article-title":"Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet\u2019s disease","volume":"42","author":"Remmers","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/j.immuni.2019.03.012","article-title":"Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity","volume":"50","author":"Mantovani","year":"2019","journal-title":"Immunity"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.autrev.2017.12.006","article-title":"Behcet\u2019s disease: New insights into pathophysiology, clinical features and treatment options","volume":"17","author":"Greco","year":"2018","journal-title":"Autoimmun. Rev."},{"key":"ref_24","first-page":"345","article-title":"Elevated serum interleukin 1 receptors and interleukin 1B in patients with Behcet\u2019s disease: Correlations with disease activity and severity","volume":"31","author":"Yosipovitch","year":"1995","journal-title":"Isr. J. Med. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1007\/s10067-013-2443-8","article-title":"Anakinra treatment in drug-resistant Behcet\u2019s disease: A case series","volume":"34","author":"Cantarini","year":"2015","journal-title":"Clin. Rheumatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s10067-016-3506-4","article-title":"Interleukin (IL)-1 inhibition with anakinra and canakinumab in Behcet\u2019s disease-related uveitis: A multicenter retrospective observational study","volume":"36","author":"Fabiani","year":"2017","journal-title":"Clin. Rheumatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/nm.4307","article-title":"Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease","volume":"23","author":"West","year":"2017","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1038\/s41591-021-01520-5","article-title":"IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies","volume":"27","author":"Friedrich","year":"2021","journal-title":"Nat. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1056\/NEJM199910213411707","article-title":"Behcet\u2019s disease","volume":"341","author":"Sakane","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/art.1780380321","article-title":"Excessive function of peripheral blood neutrophils from patients with Behcet\u2019s disease and from HLA-B51 transgenic mice","volume":"38","author":"Takeno","year":"1995","journal-title":"Arthritis. Rheum."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/9\/3131\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:23:41Z","timestamp":1760124221000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/9\/3131"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,26]]},"references-count":30,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["jcm12093131"],"URL":"https:\/\/doi.org\/10.3390\/jcm12093131","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,26]]}}}