久松理一、平井郁仁、松本主之、小林清典、長堀正和、松下光伸、小林健二、小金井一隆、国崎玲子 岳野光洋、岸本暢将、上野文昭、田中正則 厚生労働科学研究 難治性疾患克服研究事業 原因不明小腸潰瘍症の実態把握、疾患概念、疫学、治療体系の確立に関する研究（研究代表者 日比紀文）平成2 4年度 総括・分担研究報告書（平成25年3月）.
Tadakazu Hisamatsu, Fumiaki Ueno, Takayuki Matsumoto, Kiyonori Kobayashi, Kazutaka Koganei, Reiko Kunisaki, Fumihito Hirai, Masakazu Nagahori, Mitsunobu Matsushita, Kenji Kobayashi, Mitsumasa Kishimoto, Mitsuhiro Takeno, Masanori Tanaka, Nagamu Inoue, Toshifumi Hibi
The 2nd edition of consensus statements for the diagnosis and management of intestinal Behçet's disease: indication of anti-TNFα monoclonal antibodies.
J Gastroenterol. 2014 Jan;49(1):156-62. doi: 10.1007/s00535-013-0872-4. Epub 2013 Aug 18.
Abstract/Text
BACKGROUND: Clinical evidence regarding intestinal Behçet's disease (BD) management is lacking and intestinal lesions are a poor prognostic factor. In 2007, the Japan consensus statement for diagnosis and management of intestinal BD was developed. Recently, the efficacy of anti-tumor necrosis factor (TNF)α monoclonal antibodies (mAbs), and infliximab (IFX) was reported and adalimumab (ADA) was approved for intestinal BD in Japan. This study renewed consensus-based practice guidelines for diagnosis and treatment of intestinal BD focusing on the indication of anti-TNFα mAbs.
METHODS: An expert panel of Japanese gastroenterology and rheumatology specialists was involved. Clinical statements for ratings were extracted from the literature, a professional group survey, and by an expert panel discussion, which rated clinical statements on a nine-point scale. After the first round of ratings, a panelist meeting discussed areas of disagreement and clarified areas of uncertainty. The list of clinical statements was revised after the panelist meeting and a second round of ratings was conducted.
RESULTS: Fifteen relevant articles were selected. Based on the first edition consensus statement, improved clinical statements regarding indications for anti-TNFα mAbs use were developed. After a two-round modified Delphi approach, the second edition of consensus statements was finalized.
CONCLUSIONS: In addition to standard therapies in the first edition, anti-TNFα mAbs (ADA and IFX) should be considered as a standard therapy for intestinal BD. Colchicines, thalidomide, other pharmacological therapy, endoscopic therapy, and leukocytapheresis were deemed experimental therapies.
石ヶ坪良明、岳野光洋、菊地弘敏、長堀正和、井上詠、黒沢美智子. 腸管ベーチェット病に対するインフリキシマブ治療の実態. 厚生労働科学研究 難治性疾患克服研究事業 ベーチェット病に関する調査研究(研究代表者 石ヶ坪良明) 平成2 3年度 総括・分担研究報告書（平成24年3月）.
M Naganuma, Y Iwao, N Inoue, T Hisamatsu, H Imaeda, H Ishii, T Kanai, M Watanabe, T Hibi
Analysis of clinical course and long-term prognosis of surgical and nonsurgical patients with intestinal Behçet's disease.
Am J Gastroenterol. 2000 Oct;95(10):2848-51. doi: 10.1111/j.1572-0241.2000.03198.x.
Abstract/Text
OBJECTIVE: Much remains unknown about the pathogenesis of intestinal Behçet's disease. The majority of these patients are treated with surgical intervention, although it has been recently reported that a number of medical treatments are sometimes effective. Only few studies, however, have ever been undertaken to analyze the long-term prognosis of this disease. In this study, we analyzed the clinical course and the recurrences after initial therapy in patients with intestinal Behçet's disease.
METHODS: We investigated 20 patients (surgical group, n = 8; nonsurgical group, n = 12) for whom the clinical courses were known for > or = 2 yr (2-23 yr).
RESULTS: The surgical group tended to have higher rates of complications such as ocular and ileal lesions than the nonsurgical group. In the surgical group, 75% of the patients recurred (and were readmitted) within 2 yr, and 37.5% of the patients required reoperation for intestinal obstruction because of ulcer at the anastomosis. The percentage of peripheral CD8+ DR+ lymphocytes in the recurrent group (10.4% +/- 2.5%) was significantly higher than that in the nonrecurrent group (4.3% +/- 1.2%, p < 0.05).
CONCLUSIONS: Our results indicate that more extensive disease involving the ileum and ocular lesions are markers of severity and progression to surgical crisis, and that patients requiring surgery suffer more frequent recurrences. Furthermore, an increased percentage of peripheral CD8+ DR+ lymphocytes may be a risk factor for disease recurrence.
Yoon Suk Jung, Jae Hee Cheon, Sung Pil Hong, Tae Il Kim, Won Ho Kim
Clinical outcomes and prognostic factors for thiopurine maintenance therapy in patients with intestinal Behcet's disease.
Inflamm Bowel Dis. 2012 Apr;18(4):750-7. doi: 10.1002/ibd.21757. Epub 2011 May 25.
Abstract/Text
BACKGROUND: To date, there have been no studies focusing on the efficacy of thiopurine therapy in intestinal Behcet's disease (BD). We conducted this study to investigate clinical outcomes and predictors of clinical relapse in intestinal BD patients receiving thiopurine maintenance therapy.
METHODS: We reviewed the medical records of all patients with intestinal BD who received thiopurine therapy in a single tertiary academic medical center between March 1986 and October 2010. The cumulative probabilities of clinical relapse after remission were calculated using the Kaplan-Meier method. Predictors of clinical relapse were identified by univariate analysis using the log-rank test and by multivariate analysis using Cox proportional hazards regression models.
RESULTS: Of a total of 272 patients with intestinal BD, 67 (24.6%) received their first course of thiopurine therapy at our center. Thirty-nine (58.2%) of the 67 patients constantly received thiopurines for maintaining medically or surgically induced remission. The cumulative relapse rates at 1 year, 2 years, 3 years, and 5 years after remission were 5.8%, 28.7%, 43.7%, and 51.7%, respectively. On multivariate analysis, a younger age (<25 years) at diagnosis and a lower hemoglobin level (<11 g/dL) were independent predictive factors for relapse in intestinal BD patients receiving thiopurine maintenance therapy.
CONCLUSIONS: Thiopurine therapy showed a relatively good effect for maintenance of remission in intestinal BD patients. However, a younger age at diagnosis and a lower hemoglobin level were associated with a poor response to thiopurines, necessitating early adoption of effective alternative therapeutic options in these risk groups.
Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
I J Choi, J S Kim, S D Cha, H C Jung, J G Park, I S Song, C Y Kim
Long-term clinical course and prognostic factors in intestinal Behçet's disease.
Dis Colon Rectum. 2000 May;43(5):692-700.
Abstract/Text
PURPOSE: The present study was aimed at evaluating the long-term course of intestinal Behçet's disease and determining predictive factors of prognosis.
METHODS: This report is a retrospective study based on the records of 43 patients with intestinal Behçet's disease. The mean follow-up duration was 73 +/- 60 months. We evaluated the efficacy of medical treatment for the intestinal lesion at initial eight weeks. The cumulative probabilities were calculated by using Kaplan-Meier method, and the results were compared by using the log-rank test.
RESULTS: Sixteen patients (38 percent) achieved a complete remission of intestinal lesions eight weeks after medical treatment had begun. The patients who achieved a complete remission had a lower probability of receiving an operation than those who had not (13 percent at 2 and 5 years vs. 36 and 43 percent, respectively; P = 0.028). The recurrence probability of intestinal lesions was 25 percent at two years and 49 percent at five years after complete remission with medical treatment. Patients who had a history of intestinal perforation or fistula had a higher probability of recurrence after operation than those without such history (59 vs. 33 percent at 2 years; 88 vs. 57 percent at 5 years; P = 0.020). Patients who had taken azathioprine had a lower probability of receiving reoperation than those who did not (7 vs. 25 percent at 2 years; 25 vs. 47 percent at 5 years; P = 0.035). The length of ileal resection and whether hemicolectomy was performed had no significant effect on the recurrence or reoperation rate.
CONCLUSIONS: Intestinal Behçet's disease frequently requires a surgical treatment and has a high recurrence rate. The patients who achieved a complete remission with medical treatment, who had no history of intestinal perforation, and who received azathioprine after operation showed better clinical courses. Resection of a short segment of bowel would be a more appropriate surgical procedure.
Satoshi Tanida, Nagamu Inoue, Kiyonori Kobayashi, Makoto Naganuma, Fumihito Hirai, Bunei Iizuka, Kenji Watanabe, Keiichi Mitsuyama, Takuya Inoue, Yoshiaki Ishigatsubo, Yasuo Suzuki, Masakazu Nagahori, Satoshi Motoya, Shiro Nakamura, Vipin Arora, Anne M Robinson, Roopal B Thakkar, Toshifumi Hibi
Adalimumab for the treatment of Japanese patients with intestinal Behçet's disease.
Clin Gastroenterol Hepatol. 2015 May;13(5):940-8.e3. doi: 10.1016/j.cgh.2014.08.042. Epub 2014 Sep 19.
Abstract/Text
BACKGROUND & AIMS: Behçet's disease is a chronic, relapsing inflammatory disease that can involve the mouth, skin, eyes, genitals, and intestines. Active intestinal Behçet's disease can be complicated by gastrointestinal (GI) bleeding and perforation. We performed a multicenter, open-label, uncontrolled study to evaluate the efficacy and safety of adalimumab, a fully human monoclonal antibody against tumor necrosis factor α, in patients with intestinal Behçet's disease who were refractory to corticosteroid and/or immunomodulator therapies.
METHODS: The study was conducted at 12 sites in Japan, from November 2010 through October 2012. Twenty patients were given 160 mg adalimumab at the start of the study and 80 mg 2 weeks later, followed by 40 mg every other week for 52 weeks; for some patients, the dose was increased to 80 mg every other week. A composite efficacy index, combining GI symptom and endoscopic assessments, was used to evaluate efficacy. The primary efficacy end point was the percentage of patients with scores of 1 or lower for GI symptom and endoscopic assessments at week 24. Secondary end points included complete remission and resolution of non-GI Behçet's-related symptoms.
RESULTS: Nine patients (45%) had GI symptom and endoscopic assessment scores of 1 or lower at week 24 of treatment, and 12 patients (60%) had these scores by week 52. Four patients (20%) achieved complete remission at weeks 24 and 52. Individual global GI symptom and endoscopic scores improved for most patients at weeks 24 and 52. Two thirds of patients with oral aphthous ulcers, skin symptoms, and genital ulcers, and 88% of patients with erythema nodosum had complete resolution of these conditions at week 52. A total of 9 of 13 patients (69%) taking steroids at baseline were able to taper (n = 1) or completely discontinue steroids (n = 8) during the study. No new safety signals were observed.
CONCLUSIONS: Adalimumab is a potentially effective treatment for intestinal Behçet's disease in Japanese patients who are refractory to conventional treatments. ClinicalTrials.gov number: NCT01243671.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
Makoto Naganuma, Atsushi Sakuraba, Tadakazu Hisamatsu, Hiroki Ochiai, Hirotoshi Hasegawa, Haruhiko Ogata, Yasushi Iwao, Toshifumi Hibi
Efficacy of infliximab for induction and maintenance of remission in intestinal Behçet's disease.
Inflamm Bowel Dis. 2008 Sep;14(9):1259-64. doi: 10.1002/ibd.20457.
Abstract/Text
BACKGROUND: Intestinal Behçet disease (BD) is characterized by intestinal inflammation with round and oval ulcers associated with gastrointestinal symptoms. Although several cases have been reported that infliximab is effective for induction of remission, the efficacy of infliximab for maintaining remission is unknown.
METHODS: Six cases with fulminant intestinal BD were treated with infliximab. All patients were steroid-dependent and refractory to immunosuppressants; 3 patients were treated with 6-mercaptopurine, 1 patient with azathioprine, 1 patient with cyclosporine A, and 1 patient with methotrexate.
RESULTS: Four patients achieved remission by infliximab and all of these patients maintained remission with scheduled treatments of infliximab, with the longest duration of remission being about 3 years. Another 2 patients with ileal ulceration required surgery; however, 1 patient has maintained remission by scheduled treatment of infliximab for 2 years after surgery.
CONCLUSIONS: Infliximab appears to offer an option for fulminant intestinal BD to induce and maintain remission, although a randomized control trial is needed.
Shigeru Iwata, Kazuyoshi Saito, Kunihiro Yamaoka, Shizuyo Tsujimura, Masao Nawata, Katsunori Suzuki, Yoshiya Tanaka
Effects of anti-TNF-alpha antibody infliximab in refractory entero-Behcet's disease.
Rheumatology (Oxford). 2009 Aug;48(8):1012-3. doi: 10.1093/rheumatology/kep126. Epub 2009 May 22.
Abstract/Text
Toshifumi Hibi, Shunsei Hirohata, Hirotoshi Kikuchi, Ukihide Tateishi, Noriko Sato, Kunihiko Ozaki, Kazuoki Kondo, Yoshiaki Ishigatsubo
Infliximab therapy for intestinal, neurological, and vascular involvement in Behcet disease: Efficacy, safety, and pharmacokinetics in a multicenter, prospective, open-label, single-arm phase 3 study.
Medicine (Baltimore). 2016 Jun;95(24):e3863. doi: 10.1097/MD.0000000000003863.
Abstract/Text
Behçet disease (BD) is a multisystem disease associated with a poor prognosis in cases of gastrointestinal, neurological, or vascular involvement. We conducted a multicenter, prospective, open-label, single-arm phase 3 study to determine the efficacy, safety, and pharmacokinetics of infliximab (IFX) in BD patients with these serious complications who had displayed poor response or intolerance to conventional therapy.IFX at 5 mg/kg was administered to 18 patients (11 intestinal BD, 3 neurological BD [NBD], and 4 vascular BD [VBD]) at weeks 0, 2, and 6 and every 8 weeks thereafter until week 46. In patients who showed inadequate responses to IFX after week 30, the dose was increased to 10 mg/kg. We then calculated the percentage of complete responders according to the predefined criteria depending on the symptoms and results of examinations (ileocolonoscopy, brain magnetic resonance imaging, computed tomography angiography, positron emission tomography, cerebrospinal fluid, or serum inflammatory markers), exploring the percentage of complete responders at week 30 (primary endpoint).The percentage of complete responders was 61% (11/18) at both weeks 14 and 30 and remained the same until week 54. Intestinal BD patients showed improvement in clinical symptoms along with decrease in C-reactive protein (CRP) levels after week 2. Consistently, scarring or healing of the principal ulcers was found in more than 80% of these patients after week 14. NBD patients showed improvement in clinical symptoms, imaging findings, and cerebrospinal fluid examinations. VBD patients showed improvement in clinical symptoms after week 2 with reductions in CRP levels and erythrocyte sedimentation rate. Imaging findings showed reversal of inflammatory changes in 3 of the 4 VBD patients. Irrespective of the type of BD, all patients achieved improvement in quality of life, leading to the dose reduction or withdrawal of steroids. IFX dose was increased to 10 mg/kg in 3 intestinal BD patients, resulting in the improvement of clinical symptoms, CRP levels, and visual analogue scale score. Safety and pharmacokinetics profiles were comparable to those in patients with rheumatoid arthritis or Crohn disease. These findings support IFX as a new therapeutic option for patients with intestinal BD, NBD, or VBD.
