今日の臨床サポート

ベーチェット病

著者: 金子駿太 JCHO 東京山手メディカルセンター

監修: 金子礼志 国立国際医療研究センター 膠原病科

著者校正/監修レビュー済:2022/08/03
参考ガイドライン:
  1. 日本ベーチェット学会:ベーチェット病診療ガイドライン2020
  1. 欧州リウマチ学会:2018 update of the EULAR recommendations for the management of Behçet’s syndrome
患者向け説明資料

概要・推奨   

  1. 再発性・多発性の口腔内アフタ、結節性紅斑様皮疹、ぶどう膜炎、外陰部潰瘍などを認めた場合、ベーチェット病を想起する。
  1. 診断基準に含まれる主症状・副症状ともに、ベーチェット病に対する特異性は高くないこと、鑑別すべき疾患が多いことを認識する必要がある。
  1. 患者ごとに、治療の対象となる病変の重症度および後遺症を残す可能性の有無により治療の優先順位を決め、治療にあたることが大事である。
アカウントをお持ちの方はログイン
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要とな
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
金子駿太 : 特に申告事項無し[2022年]
監修:金子礼志 : 特に申告事項無し[2022年]

  1. 2020年に新たにベーチェット病診療ガイドラインが作成された。それを元に新しいエビデンスを追記した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. ベーチェット病とは、皮膚粘膜病変を特徴とする、原因不明の自己炎症性疾患で、診断基準をもとに診断される状態である。
  1. 1937年、トルコの皮膚科医Hulsi Behçetによって提唱された。
  1. 口腔内アフタ性潰瘍(口腔内アフタ)、結節性紅斑などの皮膚症状、ぶどう膜炎などの眼症状、外陰部潰瘍の4つが主症状である。副症状に、関節炎や副睾丸炎、特殊病型として腸管・血管・神経病変がある。
  1. 上記症状が出現と消退を繰り返すことが特徴である。
  1. 地域的分布をみると、世界的にはシルクロードに沿った地域(地中海沿岸、中東から東アジア)に多く、日本では北高南低の分布を示し、北海道や東北に多いとされている。
  1. 好発年齢は20~40歳で、男女比は約1:1である。重症例は男性に多い。
  1. 厚生労働省の全国疫学調査によると、現在、日本における患者数は約18,000人と考えられている。
  1. 病因はいまだ不明だが、遺伝素因に病原微生物をはじめとした環境因子が関わり、自己免疫異常や好中球機能過剰に代表される自然免疫系の異常を引き起こし、発症に至ると考えられている。
  1. ベーチェット病では、HLA-B51保有率が高く(50~70%)、発病にHLA-B51やこれに連鎖する因子の役割が重視されている。日本人の場合、健常者でも15%程度で陽性になるが、それでもなお、日本人のHLA-B51保有者におけるベーチェット病に罹患する相対危険率は7.9と高い。
  1. HLA-B51以外にも、HLA-A26などいくつかの遺伝子多型や、新たにIL10およびIL23R/IL12RB2の2つの遺伝子領域の一塩基多型が疾患感受性遺伝子であることが報告された。その後も、免疫応答や炎症に関わる遺伝子(ERAP1など)が、次々と同定されている。
  1. 診断には、わが国の厚生労働省研究班による診断基準(2010年改訂)が用いられる(診断基準: >詳細情報 )。
  1. 4主症状すべてを満たせば完全型ベーチェット病と診断されるが、3主症状、眼症状+1主症状、2主症状+2副症状、眼症状+2副症状という組み合わせの場合、不全型ベーチェット病と診断される。患者数としては不全型の方が多い。
  1. 特殊病型(腸管・血管・神経)は、ベーチェット病(完全型・不全型)と診断されている例が前提である。
  1. ベーチェット病は、指定難病であり、重症度基準Ⅱ度以上の場合などでは、申請し認定されると保険料の自己負担分の一部が公費負担として助成される。(平成27年1月施行
  1. 難病法に基づく医療費助成制度
病歴・診察のポイント  
ポイント:
  1. 診断基準に含まれる主症状・副症状ともに、ベーチェット病に対する特異性は高くないこと、鑑別すべき疾患が多いことを認識する必要がある。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
常時アップデートされており、最新のエビデンスを各分野のエキスパートが豊富な図表や処方・検査例を交えて分かりやすく解説。日常臨床で遭遇するほぼ全ての症状・疾患から薬剤・検査情報まで瞬時に検索可能です。

まずは15日間無料トライアル
本サイトの知的財産権は全てエルゼビアまたはコンテンツのライセンサーに帰属します。私的利用及び別途規定されている場合を除き、本サイトの利用はいかなる許諾を与えるものでもありません。 本サイト、そのコンテンツ、製品およびサービスのご利用は、お客様ご自身の責任において行ってください。本サイトの利用に基づくいかなる損害についても、エルゼビアは一切の責任及び賠償義務を負いません。 また、本サイトの利用を以て、本サイト利用者は、本サイトの利用に基づき第三者に生じるいかなる損害についても、エルゼビアを免責することに合意したことになります。  本サイトを利用される医学・医療提供者は、独自の臨床的判断を行使するべきです。本サイト利用者の判断においてリスクを正当なものとして受け入れる用意がない限り、コンテンツにおいて提案されている検査または処置がなされるべきではありません。 医学の急速な進歩に鑑み、エルゼビアは、本サイト利用者が診断方法および投与量について、独自に検証を行うことを推奨いたします。

文献 

Haruko Ideguchi, Akiko Suda, Mitsuhiro Takeno, Atsuhisa Ueda, Shigeru Ohno, Yoshiaki Ishigatsubo
Behçet disease: evolution of clinical manifestations.
Medicine (Baltimore). 2011 Mar;90(2):125-32. doi: 10.1097/MD.0b013e318211bf28.
Abstract/Text Clinical phenotypes of Behçet disease (BD) vary among ethnic groups. We chronologically analyzed the clinical manifestations of BD in 412 patients meeting the Japanese criteria for BD seen at 2 Yokohama City University hospitals from July 1991 to December 2007. We examined the onset of individual symptoms in each patient. A single initial symptom appeared earlier than any other manifestation in 78% of the patients. Time from the initial symptom to diagnosis was 8.6 ± 10.1 years. Oral ulcer, the most common initial manifestation, preceded the diagnosis by 7.5 ± 10.2 years. Genital ulcer and eye and skin involvement appeared 1 or 2 years before diagnosis, whereas gastrointestinal, central nervous system, or vascular involvement developed later. The frequency of eye involvement was significantly higher in patients with neurologic lesions, but significantly lower in those with gastrointestinal or vascular involvement. However, no particular combination of major symptoms predicted the development of organ involvement. There has been a recent decrease in the rate of "complete" BD (patients having all 4 of the major symptoms of oral ulcers, genital ulcers, and eye and skin lesions), whereas the frequencies of arthritis, gastrointestinal, and vascular involvement have been increasing. Further assessment may allow the detection of early predictors of the more aggressive disease, which requires more intensive treatment.

PMID 21358436
D Lê Thi Huong, B Wechsler, T Papo, J C Piette, O Bletry, J M Vitoux, E Kieffer, P Godeau
Arterial lesions in Behçet's disease. A study in 25 patients.
J Rheumatol. 1995 Nov;22(11):2103-13.
Abstract/Text OBJECTIVE: To identify the prognostic indicators of patients with Behçet's disease complicated with arterial lesions.
METHODS: Retrospective chart analysis of 25 consecutive patients with Behçet's disease and angiographically proven arterial lesions.
RESULTS: Occlusive lesions were present in 7 patients, aneurysms in 3, and both occlusive and aneurysmal lesions in 15. High dose corticosteroids were not effective in isolated occlusive lesions and probably contributed to one fatal infection. Death was related to aneurysms in 5 patients. Twenty-seven vascular surgical procedures were performed in 15 patients. Arterial lesions recurred in all patients who did not received postoperative corticosteroids. Within a 2 yr period after operation, the rate of therapy failure was lower in the group of patients treated with a postoperative combination of corticosteroids and immunosuppressive drugs, compared to the group treated with corticosteroids alone. In patients treated for lower limb arterial lesions, the rate of relapse was similar whether venous autologous or prosthetic grafts were used. Graft thrombosis occurred in 3/7 patients given anticoagulants and in 3/4 patients with no antiaggregant or anticoagulant therapy.
CONCLUSION: Aneurysms have a worse prognosis than occlusive lesions. High dose corticosteroids should not be systematically prescribed for isolated occlusive lesions. Surgery, when feasible, is indicated for aneurysms because they entail a high risk of rupture. Postoperative corticosteroids are necessary to prevent arterial relapse. A combination of corticosteroids and immunosuppressive therapy is more effective than corticosteroids alone. After bypass for lower limb arterial lesions, anticoagulation is warranted to prevent graft thrombosis.

PMID 8596152
V Hamuryudan, S Yurdakul, F Moral, F Numan, H Tüzün, N Tüzüner, C Mat, Y Tüzün, Y Ozyazgan, H Yazïci
Pulmonary arterial aneurysms in Behçet's syndrome: a report of 24 cases.
Br J Rheumatol. 1994 Jan;33(1):48-51.
Abstract/Text Pulmonary arterial involvement is an important complication of Behçet's syndrome (BS). Among 2179 patients with BS, 24 (1.1%) were diagnosed as having pulmonary arterial aneurysms (PAAs). Haemoptysis was the presenting symptom in all but one. All were male. The mean age at the time of the diagnosis of PAA was 30 +/- 11 S.D. yr (range 17-59 yr). Their mean disease duration was 5 +/- 4 yr (range 3 months-16 yr). There was a high prevalence of thrombophlebitis (21/24, 88%). Histopathological examination showed pulmonary vasculitis involving all layers of pulmonary arteries and veins. Twelve patients (50%) died after a mean of 9.5 +/- 11 S.D. months (range 1-36 months) after the onset of haemoptysis. The mean duration of follow-up of the remaining 12 patients was 25.5 +/- 24 S.D. months (range 1-78 months). The treatment consisted mainly of pulsed or oral cyclophosphamide alone or with prednisolone. As is true with other severe manifestations of Behçet's syndrome, PAAs are more common among males. They are associated with a prevalence of thrombophlebitis and there is high mortality despite treatment.

PMID 8162457
Alexandra Varol, Oliver Seifert, Chris D Anderson
The skin pathergy test: innately useful?
Arch Dermatol Res. 2010 Apr;302(3):155-68. doi: 10.1007/s00403-009-1008-9. Epub 2009 Dec 12.
Abstract/Text Pathergy is the term used to describe hyper-reactivity of the skin that occurs in response to minimal trauma. A positive skin pathergy test (SPT), characterised by erythematous induration at the site of the needle stick with a small pustule containing sterile pus at its centre, is among the criteria required for a diagnosis of Behçet's disease (BD) and in certain population has been shown to be highly specific for this condition. Problems with standardising the induction manoeuvre for the SPT as well as the method of assessment of the response have limited the usefulness of the SPT in the clinical setting. Extensive investigation into histopathological and immunological aspects of pathergy has led to a number of hypotheses relating to the aetiology of the skin pathergy reaction and the disease itself, but the cause is considered to be unknown. Pathergy lesions, the development of new skin lesions or the aggravation of existing ones following trivial trauma, are also reported in pyoderma gangrenosum and has been noted in other neutrophilic dermatoses such as Sweet's syndrome. The response of such patient groups to the systematic application of the SPT has not been described. We propose that a new way of considering the pathergy reaction is to see it as an aberration of the skin's innate reactivity from a homeostatic reactive mode closely coupled to tissue healing to an abnormal destructive/inflammatory mode. Our understanding of BD and other similar conditions would profit by more detailed mechanistic knowledge of skin homeostasis to minimal trauma in both health and disease through a more structured and systematic use of the SPT.

PMID 20012749
Kaori Aramaki, Hirotoshi Kikuchi, Shunsei Hirohata
HLA-B51 and cigarette smoking as risk factors for chronic progressive neurological manifestations in Behçet's disease.
Mod Rheumatol. 2007;17(1):81-2. doi: 10.1007/s10165-006-0541-z. Epub 2007 Feb 20.
Abstract/Text
PMID 17278029
H Yazici, H Pazarli, C G Barnes, Y Tüzün, Y Ozyazgan, A Silman, S Serdaroğlu, V Oğuz, S Yurdakul, G E Lovatt
A controlled trial of azathioprine in Behçet's syndrome.
N Engl J Med. 1990 Feb 1;322(5):281-5. doi: 10.1056/NEJM199002013220501.
Abstract/Text Cytotoxic agents have long been used in Behçet's syndrome, especially for eye involvement, but their effectiveness has been uncertain. We conducted a two-year randomized, placebo-controlled, double-blind trial of azathioprine (2.5 mg per kilogram of body weight per day) in Turkish men with Behçet's syndrome without eye disease (group 1; n = 25) or with eye disease (group 2; n = 48). Corticosteroid treatment remained available to all the patients. All six patients withdrawn from the study because of severe eye disease were receiving placebo (P less than 0.001). Azathioprine was superior to placebo in the prevention of new eye disease in group 1 (1 vs. 8 patients; P less than 0.01) and in group 2 among the 14 patients who at entry had disease in only one eye (P less than 0.001). There were fewer episodes of hypopyon uveitis (1 vs. 15; P less than 0.001) among the group 2 patients who took azathioprine. The patients taking azathioprine also had less frequent oral ulcers, genital ulcers, and arthritis. There were no serious side effects attributable to azathioprine. We conclude that azathioprine is effective in controlling the progression of Behçet's syndrome, especially its most serious manifestation, eye disease.

PMID 2404204
V Hamuryudan, Y Ozyazgan, N Hizli, C Mat, S Yurdakul, Y Tüzün, M Senocak, H Yazici
Azathioprine in Behcet's syndrome: effects on long-term prognosis.
Arthritis Rheum. 1997 Apr;40(4):769-74. doi: 10.1002/1529-0131(199704)40:4<769::AID-ART24>3.0.CO;2-E.
Abstract/Text OBJECTIVE: To assess the effect of azathioprine (AZA) treatment on long-term prognosis in Behçet's syndrome.
METHODS: Patients (all male) who took part in a double-blind, placebo-controlled trial of AZA a mean +/- SD of 94 +/- 10 months previously were reevaluated.
RESULTS: The emergence of blindness (log rank chi2 = 5.6, P = 0.02) and a 2-line drop in the visual acuity of the right eye (log rank chi2 = 5.9, P = 0.015) occurred significantly more frequently among the patients originally allocated to the placebo group compared with patients who originally received AZA, despite posttrial treatment for patients in both groups when needed. There was also a trend toward more frequent occurrence of extraocular complications in the placebo group. The beneficial effect of AZA was especially pronounced among patients who had eye involvement of short duration prior to their entry into the trial.
CONCLUSION: Early treatment with AZA tends to favorably affect the long-term prognosis of Behçet's syndrome.

PMID 9125262
P P Sfikakis, N Markomichelakis, E Alpsoy, S Assaad-Khalil, B Bodaghi, A Gul, S Ohno, N Pipitone, M Schirmer, M Stanford, B Wechsler, C Zouboulis, P Kaklamanis, H Yazici
Anti-TNF therapy in the management of Behcet's disease--review and basis for recommendations.
Rheumatology (Oxford). 2007 May;46(5):736-41. doi: 10.1093/rheumatology/kem034. Epub 2007 Apr 2.
Abstract/Text
PMID 17403712
N Matsumura, Y Mizushima
Leucocyte movement and colchicine treatment in Behcet's disease.
Lancet. 1975 Oct 25;2(7939):813.
Abstract/Text
PMID 78172
I Kötter, H Dürk, J Saal, G Fierlbeck, U Pleyer, M Ziehut
Therapy of Behçet's disease.
Ger J Ophthalmol. 1996 Mar;5(2):92-7.
Abstract/Text Behçet's disease (BD) is a multisystem vasculitis of unknown origin. In this retrospective study we analyzed the therapy of 32 patients seen between 1978 and 1993 at the Departments of Rheumatology, Ophthalmology, and Dermatology of the Tübingen University Clinic. The aim of this study was to evaluate the efficacy of different therapeutic strategies concerning different organ manifestations of the disease, especially eye disease. A total of 20 patients had cutaneous manifestations or arthritis. Whereas treatment with colchicine (Col), azathioprine (AZA), cyclosporine (CSA), or steroids (Ster) produced only partial remissions, a combination of CSA, AZA, and steroids led to complete remissions. Interferon-gamma (IFN-gamma) therapy led to remission rates of 60% (complete) and 20% (partial). In all, 22 patients had uveitis (posterior or panuveitis). Steroids were effective in only 50% of the patients and Col was partially effective in 66%. AZA induced a remission in 71% of cases and CSA was partial effective in 60%. The threshold combination of AZA, CSA, and Ster induced a complete remission in 66% of the patients. IFN-gamma was ineffective in 80%. IFN-alpha was used in one patient only and induced a complete remission. These results demonstrate that although our patient group is too small to allow significant conclusions to be drawn, in terms of the literature, for mucocutaneous disease and arthritis, IFNs might be the best therapy, whereas for uveitis as well as other more severe features of the disease, CSA or AZA + Ster should be used. If the latter are ineffective, the threefold combination (AZA, CSA, Ster) is probably the most effective alternative. The significance of IFN-alpha will be evaluated in further studies.

PMID 8741153
Shigeaki Ohno, Satoshi Nakamura, Sadao Hori, Machiko Shimakawa, Hidetoshi Kawashima, Manabu Mochizuki, Sunao Sugita, Satoki Ueno, Kazuyuki Yoshizaki, Goro Inaba
Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behçet's disease with refractory uveoretinitis.
J Rheumatol. 2004 Jul;31(7):1362-8.
Abstract/Text OBJECTIVE: Behçet's disease (BD) with uveoretinitis is a chronic refractory disease accompanied by ocular attacks. As the decrease in visual acuity due to ocular attack is seriously life-threatening, development of a new drug is anticipated. Since tumor necrosis factor-a (TNF-a) is involved in the symptoms of BD, particularly the activity of ocular symptoms, suppression of TNF-a might be effective in treating BD with uveoretinitis. We conducted a clinical trial of infliximab, an anti-TNF-a chimeric monoclonal antibody, in patients with BD.
METHODS: In this open label trial, the efficacy, safety, and pharmacokinetics of repeated administration of infliximab were evaluated in 13 patients with BD accompanied by refractory uveoretinitis. Infliximab was administered 4 times at Weeks 0, 2, 6, and 10 at doses of either 5 or 10 mg/kg by intravenous drip infusion. Frequency of ocular attacks was used as the primary index for evaluation of efficacy, with visual acuity and extraocular symptoms as secondary indices.
RESULTS: The mean numbers of ocular attacks, converted to frequency per 14 weeks, were 3.96 times for the 5 mg/kg group and 3.79 times for the 10 mg/kg group during the observation period. Following treatment with infliximab, they decreased to 0.98 times and 0.16 times, respectively. A serious adverse event, tuberculosis, was observed in one case in the 10 mg/kg group. Serum infliximab concentration increased with dosage.
CONCLUSION: Administration of infliximab in patients with BD with refractory uveoretinitis suppressed the frequency of ocular attacks, and multiple administration was well tolerated, suggesting that infliximab is effective for this condition.

PMID 15229958
Claudia Fabiani, Antonio Vitale, Giacomo Emmi, Lorenzo Vannozzi, Giuseppe Lopalco, Silvana Guerriero, Ida Orlando, Rossella Franceschini, Daniela Bacherini, Luca Cimino, Alessandra Soriano, Bruno Frediani, Mauro Galeazzi, Florenzo Iannone, Gian Marco Tosi, Carlo Salvarani, Luca Cantarini
Efficacy and safety of adalimumab in Behçet's disease-related uveitis: a multicenter retrospective observational study.
Clin Rheumatol. 2017 Jan;36(1):183-189. doi: 10.1007/s10067-016-3480-x. Epub 2016 Nov 16.
Abstract/Text The study aim was to evaluate the efficacy of adalimumab (ADA) in a large series of Behçet's disease (BD)-related uveitis. We performed a multicenter retrospective observational study including 40 selected patients (66 eyes) receiving ADA. Clinical data were retrospectively analyzed at baseline, at 3 and 12 months of treatment. Primary end point was reduction of ocular inflammatory flares. Secondary end points were improvement of best corrected visual acuity (BCVA), reduction of macular thickness measured by optical coherence tomography (OCT), reduction in the occurrence of vasculitis assessed by fluorescein angiography (FA), and evaluation of statistically significant differences between patients treated with ADA monotherapy and those undergoing ADA plus DMARDs and in patients firstly treated with ADA compared to patients previously administered with other biologics; ADA steroid sparing effect was also evaluated. During the first 12 months of ADA therapy, the number of flares significantly decreased from 200 flares/100 patients/year to 8.5 flares/100 patients/year (p < 0.0001). Similarly, BCVA improved if compared to baseline (7.4 ± 2.9 versus 8.5 ± 2.1, p = 0.03). OCT findings significantly improved showing a mean reduction of central macular thickness (CMT) of 27.27 ± 42.8 μm at the end of follow-up (p < 0.006). FA identified retinal vasculitis in 22 cases at baseline (55%), 8 (20%) cases after 3 months, and in only one (2.5%) case at 12-month follow-up. FA improvement was highly significant at 3- and 12-month follow-up if compared to baseline (p < 0.0001 and p = 0.006, respectively). ADA is highly effective and safe for the treatment of BD-related uveitis, providing a long-term control of ocular inflammation.

PMID 27853889
Y Ozyazgan, S Yurdakul, H Yazici, B Tüzün, A Işçimen, Y Tüzün, T Aktunç, H Pazarli, V Hamuryudan, A Müftüoğlu
Low dose cyclosporin A versus pulsed cyclophosphamide in Behçet's syndrome: a single masked trial.
Br J Ophthalmol. 1992 Apr;76(4):241-3.
Abstract/Text A single masked trial of cyclosporin A 5 mg/kg/day versus monthly 1 g intravenous boluses of cyclophosphamide was conducted among 23 patients with Behçet's syndrome and active, potentially reversible uveitis. The trial was unmasked after a mean of 12 (SD 2) months for the cyclosporin A group (n = 12) and a mean of 10 (SD 3) months for the cyclophosphamide group (n = 11). During the initial 6 months the visual acuity significantly improved (p < 0.001) in the cyclosporin A group whereas this was not observed in the cyclophosphamide group. The subsequent follow-up of patients up to 24 months suggested that the initial improvement in visual acuity with cyclosporin A was not sustained. More extensive and especially long-term studies of cyclosporin A in the uveitis of Behçet's syndrome are warranted.

PMID 1390495
D BenEzra, E Cohen, T Chajek, G Friedman, S Pizanti, C de Courten, W Harris
Evaluation of conventional therapy versus cyclosporine A in Behçet's syndrome.
Transplant Proc. 1988 Jun;20(3 Suppl 4):136-43.
Abstract/Text When ocular structures are affected in Behçet's syndrome, a rapid loss of vision has been the rule regardless of the type of treatment--corticosteroids, Leukeran, Imuran, colchicine. The objectives of the present study were to compare, in a masked manner, conventional treatment (corticosteroids/Leukeran) to treatment with CsA. Forty patients suffering from Behçet's syndrome with active ocular inflammatory reactions were included in the study. These were randomly assigned to conventional or CsA regimens and were regularly examined by a multidisciplinary group of physicians. The unmasked internist modulated the treatment and recorded systemic manifestations. The masked ophthalmologists recorded the ocular findings without knowledge of the assigned type of treatment. An analysis of the results 3 years after initiation of the study shows that CsA is more effective than conventional therapy in decreasing the active ocular inflammatory processes and arresting the deterioration of visual acuity. Regarding the extraocular symptoms, however, conventional therapy is superior to CsA, especially for the control of skin lesions and arthritis. Side effects were recorded in a much higher incidence among patients receiving CsA. However, tight and constant control of the CsA dosage as performed in this study has, so far, prevented clinical and biochemical nephrotoxic manifestations in patients assigned to this treatment.

PMID 3381269
K Masuda, A Nakajima, A Urayama, K Nakae, M Kogure, G Inaba
Double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behçet's disease.
Lancet. 1989 May 20;1(8647):1093-6.
Abstract/Text The efficacy and safety of oral cyclosporin 10 mg/kg per day in Behçet's disease were compared in a randomised double-masked study with those of colchicine, 1 mg orally per day, and were also investigated in a long-term open study. The double-masked study showed that cyclosporin was effective in treating not only the ocular manifestations of Behçet's disease but also oral aphthous ulcer, dermal lesions, and genital ulceration. Efficacy did not weaken during long-term treatment.

PMID 2566048
Takahide Matsuda, Shigeaki Ohno, Shunsei Hirohata, Yoshitaka Miyanaga, Hiroshi Ujihara, Goro Inaba, Satoshi Nakamura, Shun-Ichi Tanaka, Mitsuko Kogure, Yutaka Mizushima
Efficacy of rebamipide as adjunctive therapy in the treatment of recurrent oral aphthous ulcers in patients with Behçet's disease: a randomised, double-blind, placebo-controlled study.
Drugs R D. 2003;4(1):19-28.
Abstract/Text BACKGROUND: Behçet's disease (BD) is a recurrent inflammatory disease involving chronic recurrent oral aphthous ulcers (aphthae), uveitis, skin lesions and genital ulcers. We prospectively investigated the efficacy of rebamipide, a gastroprotective drug, against oral aphthous ulcers in BD patients.
METHODS: In a multicentre, double-blind, placebo-controlled study, 35 patients with BD, having as the main symptom oral aphthosis, were randomised to receive rebamipide 300 mg/day or placebo for 12 to 24 weeks between August 1994 and December 1996. Oral aphthosis must have occurred within 4 weeks prior to enrolment and must have been visible for at least 7 days during that time. Oral aphthae count and pain scores were recorded daily in a diary by the patients themselves. Monthly aphthae count and pain scores were defined as the sum of aphthae count and pain scores for a month, respectively. Investigators rated the global improvement in aphthae count and pain using a 6-point scale. The rate of change in monthly aphthae count and pain scores in the first 3 and last 3 months of treatment were assessed in patients with more severe symptoms whose aphthae count and pain score were >28 at baseline (trial entry).
RESULTS: The rate of moderate or marked improvement in aphthae count and pain was 36% (5 of 14 subjects) in the placebo group and 65% (11 of 17 subjects) in the rebamipide group. During months 2 to 6 of treatment, aphthae count tended to increase and reached a peak at month 4 in the placebo group but decreased in the rebamipide group. Pain score decreased to the same extent in both groups for the first 3 months of treatment; however, in the fourth to sixth months of treatment, the pain score tended to increase in the placebo group but decreased in the rebamipide group. In patients with a monthly aphthae pain score >28 at baseline, pain and count scores decreased throughout the 6 months of rebamipide treatment but increased during the last 3 months of treatment in the placebo group (p < 0.01 for the between-group comparisons).
CONCLUSIONS: Rebamipide is well tolerated and improves the aphthae count and pain score in BD patients. It may therefore be useful in the treatment and prevention of frequently recurrent oral aphthous ulcers (not restricted to BD). Administration of rebamipide is not cumbersome, and it does not cause any discomfort, which corticosteroid ointments for example may do; furthermore, there are no specific adverse drug reactions. Rebamipide is therefore recommended as a long-term treatment for recurrent oral aphthous ulcers.

PMID 12568631
Erkan Alpsoy, Cicek Durusoy, Ertan Yilmaz, Yilmaz Ozgurel, Oya Ermis, Sahin Yazar, Erdal Basaran
Interferon alfa-2a in the treatment of Behçet disease: a randomized placebo-controlled and double-blind study.
Arch Dermatol. 2002 Apr;138(4):467-71.
Abstract/Text OBJECTIVE: To determine the therapeutic efficacy of interferon alfa-2a in the treatment of Behçet disease.
DESIGN: A randomized placebo-controlled and double-blind study.
SETTING: University referral center.
PATIENTS: Fifty patients with Behçet disease were involved in the study.
INTERVENTION: The patients were given interferon alfa-2a, 6 x 10(6) IU, subcutaneously 3 times per week or placebo for 3 months, and examined clinically at weekly intervals.
MAIN OUTCOME MEASURES: For each mucocutaneous lesion and articular symptom, the mean frequency and duration were evaluated during the 3-month pretreatment, treatment, and follow-up periods. Pain for oral and genital ulcers was scored on a scale of 0 to 3. The ocular inflammatory score, the frequency of attacks, and changes in visual acuities for patients with ocular involvement were assessed before the study, at the end of treatment, and during the follow-up periods. In addition, overall responses at the end of the treatment period were graded as follows: complete remission, disappearance of all clinical signs and symptoms during treatment; partial remission, greater than a 50% decrease in the frequency, duration, and severity of pain for oral and genital ulcers and/or a decrease in the severity and frequency of ocular attacks; stable disease, less than a 50% change in the clinical signs and symptoms; and no effect or deterioration, ineffectiveness or worsening of clinical signs and symptoms.
RESULTS: Twenty-three interferon alfa-2a- and 21 placebo-treated patients, ranging in age from 16 to 55 years (mean +/- SD age, 32.38 +/- 7.94 years), were evaluable for efficacy. Interferon alfa-2a treatment significantly decreased the duration (P=.02) and pain (P=.01) of oral ulcers and the frequency of genital ulcers (P=.03) and papulopustular lesions (P=.01). The mean frequency and duration of erythema nodosum-like lesions (P=.77 and.27, respectively), thrombophlebitis (P=.29 and.61, respectively), and articular symptoms (P=.92 and.74, respectively) also decreased. But there were no statistically significant differences. An improvement in the severity and the frequency of ocular attacks occurred in 5 of 6 patients in the interferon alfa-2a-treated group and in 1 of 3 patients in the placebo-treated group. Of the 23 patients in the interferon alfa-2a-treated group, 15 responded to treatment (2 complete and 13 partial responses); and of the 21 patients in the placebo group, 3 responded to treatment (3 partial responses) (P<.005).
CONCLUSION: Interferon alfa-2a is an effective alternative treatment for Behçet disease, particularly for the management of the mucocutaneous lesions of the disease.

PMID 11939808
Ina Kötter, Ilhan Günaydin, Manfred Zierhut, Nicole Stübiger
The use of interferon alpha in Behçet disease: review of the literature.
Semin Arthritis Rheum. 2004 Apr;33(5):320-35.
Abstract/Text OBJECTIVES: To evaluate the efficacy and safety of interferon (IFN) alpha for the treatment of Behçet's disease (BD) and discuss its possible mechanisms of action.
METHODS: Reports published until July 2002 in all languages were identified by the PubMed Database and the BD conference proceedings and abstract booklets. The indexing terms used were "Behçet" and "interferon."
RESULTS: Thirty-two original reports and 4 selected abstracts were included in the analysis. Systemic IFN-alpha was administered to 338 patients. One hundred eighty-two patients with acute ocular disease were treated with IFN-alpha. Two hundred sixty-four patients received IFN-alpha2a, and 74 received IFN-alpha2b. Eighty-six percent of the patients with mucocutaneous symptoms, 96% with arthritis, and 94% with uveitis exhibited a partial or complete response. Higher IFN doses were more effective than low-dose regimens and led to up to 56% long-term remissions after discontinuation of IFN-alpha were reported. IFN-alpha2a apparently was superior to IFN-alpha2b, with more complete remissions, but this probably was the result of a bias caused by the larger number of patients treated with IFN-alpha2a. Side effects were dose-dependent and similar to those noted in patients with hepatitis C.
CONCLUSIONS: Although the comparability of the studies is hampered because of different study designs, IFN-alpha is effective for the treatment of BD. It was beneficial even in resistant posterior uveitis, in which long-term remissions with preservation of visual acuity was achieved. In contrast, mostly partial remissions were reported for mucocutaneous symptoms.

PMID 15079763
Gulen Hatemi, Melike Melikoglu, Recep Tunc, Cengiz Korkmaz, Banu Turgut Ozturk, Cem Mat, Peter A Merkel, Kenneth T Calamia, Ziqi Liu, Lilia Pineda, Randall M Stevens, Hasan Yazici, Yusuf Yazici
Apremilast for Behçet's syndrome--a phase 2, placebo-controlled study.
N Engl J Med. 2015 Apr 16;372(16):1510-8. doi: 10.1056/NEJMoa1408684.
Abstract/Text BACKGROUND: Oral ulcers, the hallmark of Behçet's syndrome, can be resistant to conventional treatment; therefore, alternative agents are needed. Apremilast is an oral phosphodiesterase-4 inhibitor that modulates several inflammatory pathways.
METHODS: We conducted a phase 2, multicenter, placebo-controlled study in which 111 patients with Behçet's syndrome who had two or more oral ulcers were randomly assigned to receive 30 mg of apremilast twice daily or placebo for 12 weeks. This regimen was followed by a 12-week extension phase in which the placebo group was switched to apremilast and a 28-day post-treatment observational follow-up phase. The patients and clinicians were unaware of the study assignments throughout the trial. The primary end point was the number of oral ulcers at week 12. Secondary outcomes included pain from these ulcers (measured on a 100-mm visual-analogue scale, with higher scores indicating worse pain), the number of genital ulcers, overall disease activity, and quality of life.
RESULTS: The mean (±SD) number of oral ulcers per patient at week 12 was significantly lower in the apremilast group than in the placebo group (0.5±1.0 vs. 2.1±2.6) (P<0.001). The mean decline in pain from oral ulcers from baseline to week 12 was greater with apremilast than with placebo (-44.7±24.3 mm vs. -16.0±32.5 mm) (P<0.001). Nausea, vomiting, and diarrhea were more common in the apremilast group (with 22, 9, and 12 incidents, respectively, among 55 patients) than in the placebo group (with 10, 1, and 2 incidents, respectively, among 56 patients), findings that were similar to those in previous studies of apremilast. There were two serious adverse events in patients receiving apremilast.
CONCLUSIONS: Apremilast was effective in treating oral ulcers, which are the cardinal manifestation of Behçet's syndrome. This preliminary study was neither large enough nor long enough to assess long-term efficacy, the effect on other manifestations of Behçet's syndrome, or the risk of uncommon serious adverse events. (Funded by Celgene; ClinicalTrials.gov number, NCT00866359.).

PMID 25875256
S Yurdakul, C Mat, Y Tüzün, Y Ozyazgan, V Hamuryudan, O Uysal, M Senocak, H Yazici
A double-blind trial of colchicine in Behçet's syndrome.
Arthritis Rheum. 2001 Nov;44(11):2686-92.
Abstract/Text OBJECTIVE: Colchicine is a widely used treatment for Behçet's syndrome, even though in a previous 6-month controlled study, it was shown to be effective only in controlling erythema nodosum and arthralgias. We reassessed the effect of colchicine in Behçet's syndrome in a study conducted among a larger group of patients for 2 years.
METHODS: We randomized 116 patients with Behçet's syndrome (60 male/56 female), who had active mucocutaneous disease without eye or major organ involvement, to receive either placebo or colchicine (1-2 mg/day, adjusted to body weight) in a double-blind trial for 2 years. The primary outcome measure was the sustained absence of any lesions during treatment (complete response). The secondary outcome measure was the difference in the number of mucocutaneous lesions or arthritic joints between the active drug and placebo arms. Women and men were analyzed separately.
RESULTS: Eighty-four patients (72%; 45 male, 39 female) completed the 24-month study. Kaplan-Meier analyses showed significantly more complete responses in the colchicine treatment group in terms of reduced occurrence of genital ulcers (P = 0.004), erythema nodosum (P = 0.004), and arthritis (P = 0.033) among the women, and reduced occurrence of arthritis (P = 0.012) among the men. The mean numbers of genital ulcers (P = 0.001), erythema nodosum lesions (P = 0.002), and arthritic joints (P = 0.014) among the women were less in the colchicine group, and the mean number of arthritic joints (P = 0.026) among the men was less in the colchicine group. Adverse effects were similar in both groups.
CONCLUSION: Colchicine may be useful for treating some of the manifestations of Behçet's syndrome, especially among women. This might be a reflection of less severe disease among the women.

PMID 11710724
E Aktulga, M Altaç, A Müftüoglu, Y Ozyazgan, H Pazarli, Y Tüzün, B Yalçin, H Yazici, S Yurdakul
A double blind study of colchicine in Behçet's disease.
Haematologica. 1980 Jun;65(3):399-402.
Abstract/Text
PMID 6778795
C Estrach, S Mpofu, R J Moots
Behçet's syndrome: response to infliximab after failure of etanercept.
Rheumatology (Oxford). 2002 Oct;41(10):1213-4.
Abstract/Text
PMID 12364656
Aikaterini Arida, Kalliopi Fragiadaki, Eirini Giavri, Petros P Sfikakis
Anti-TNF agents for Behçet's disease: analysis of published data on 369 patients.
Semin Arthritis Rheum. 2011 Aug;41(1):61-70. doi: 10.1016/j.semarthrit.2010.09.002. Epub 2010 Dec 17.
Abstract/Text OBJECTIVE: Off-label use of anti-tumor necrosis factor (TNF) agents for Behçet's disease (BD) is increasing. We evaluated published data on their efficacy and safety for patients with unmet medical needs due to severe disease manifestations, including ocular, gastrointestinal, and central nervous system involvement.
METHODS: Peer-reviewed articles on anti-TNF agents for BD appearing in Medline/PubMed through March 2010 were identified using the appropriate indexing terms.
RESULTS: We found 88, 12, and 13 primary articles from 20 countries on infliximab, etanercept, and adalimumab, reporting on 325, 37, and 28 patients, respectively. All patients were inadequately controlled with, or intolerant to, other immunosuppressive regimens, including interferon; 20 patients received more than 1 anti-TNF agent. In the only randomized placebo-controlled trial, 4-week administration of etanercept was effective in suppressing most of the mucocutaneous manifestations. In 16 open prospective studies evaluating the effect of repetitive infliximab injections (174 patients in total, men:women = 3:1, median follow-up = 16.2 months), sustained organ-specific, clinical responses were evident in 90%, 89%, 100%, and 91% of patients with resistant mucocutaneous, ocular, gastrointestinal, and central nervous system involvement, respectively. Combination of infliximab with azathioprine and/or cyclosporine-A appeared superior to monotherapy for sustained ocular remission. However, due to the fact that necessary data were lacking, formal estimation of anti-TNF treatment effect on the disease activity indexes for different organ involvement was not possible.
CONCLUSIONS: Although more controlled data are needed, there is enough published experience to suggest that TNF blockade represents an important therapeutic advancement for patients with severe and resistant, or intolerant, to standard immunosuppressive regimens BD.

Copyright © 2011 Elsevier Inc. All rights reserved.
PMID 21168186
Hasan Tuzun, Emire Seyahi, Caner Arslan, Vedat Hamuryudan, Kazim Besirli, Hasan Yazici
Management and prognosis of nonpulmonary large arterial disease in patients with Behçet disease.
J Vasc Surg. 2012 Jan;55(1):157-63. doi: 10.1016/j.jvs.2011.07.049. Epub 2011 Sep 23.
Abstract/Text OBJECTIVE: The purpose of this study was to evaluate and report our treatment policies in the management of nonpulmonary arterial aneurysms in Behçet disease and to assess the prognosis in a cohort of 25 patients diagnosed between 1996 and 2007 by formally reassessing their outcome at the present time.
METHODS: We identified 25 patients (24 men/1 woman) with Behçet disease with nonpulmonary aneurysms (n = 23) or occlusions (n = 2) between 1996 and 2007. All patients fulfilled the International Study Group Criteria for Behçet disease. Aneurysms were demonstrated with contrast-enhanced computed tomography (CT) or magnetic resonance angiography (MRA) after first-line ultrasonography. Standard surgical procedures were carried out in 22 patients. One patient with a nonruptured saccular aortic aneurysm and 2 patients with carotid aneurysms were managed only medically. For the patients with aneurysms located in the aortic bifurcation, we preferred aorto-bi-iliac bypasses; for the six extremity aneurysms, we were able to ligate the arteries; and for the other 10 extremity aneurysms we used polytetrafluoroethylene (PTFE) grafts for bypass procedures. All patients received immunosuppression with cyclophosphamide and corticosteroids before the operation and were continued in the postoperative period. All patients were examined between January and December 2010 paying special attention for new and anastomotic aneurysms and graft patency.
RESULTS: There was one death and 1 patient was lost to follow-up. The remaining 23 patients (92%) were under follow-up after a mean of 7.4 ± 2.9 years after their operation. Four PTFE grafts (40%) inserted for extremity aneurysms occluded with no disabling consequences. Also, 6 patients who were treated with ligation postoperatively began to complain of mild to moderate claudication. In 2 patients, aneurysms recurred at the anastomotic site, whereas in 3 patients, new aneurysms developed at other sites.
CONCLUSION: The surgical management of large, nonpulmonary arterial disease of Behçet disease is currently quite satisfactory. When the false aneurysm is in the infrarenal aorta, aorto-bi-iliac bypass is the preferred surgical intervention. Extremity aneurysms can be treated with synthetic graft insertion. In selected cases, ligation can give satisfactory results; however, postoperative claudication is common. In some patients with small intact saccular aneurysms, surgery may not be necessary. Patients must be prescribed immunosuppressive therapy with cyclophosphamide and corticosteroids before and after the surgical intervention in order to avoid Behçet disease activation.

Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.
PMID 21944910
Qi Liu, Wei Ye, Changwei Liu, Yongjun Li, Rong Zeng, Leng Ni
Outcomes of vascular intervention and use of perioperative medications for nonpulmonary aneurysms in Behçet disease.
Surgery. 2016 May;159(5):1422-9. doi: 10.1016/j.surg.2015.11.022. Epub 2016 Jan 5.
Abstract/Text BACKGROUND: Aneurysms attributable to Behçet disease (BD) are not common but are associated with a poor prognosis because of a high risk of rupture. Special considerations are required for vascular intervention, because the intense local inflammation may increase complications. The aim of this study was to assess the outcome of operative intervention and the use of perioperative medical therapy for aneurysms in patients with BD.
MATERIALS AND METHODS: We reviewed retrospectively the medical records of patients with BD admitted to Peking Union Medical College Hospital between January 1995 and January 2015.
RESULTS: Among 874 patients diagnosed with BD, 176 patients had vascular involvement, of whom 59 had arterial aneurysms. Thirty-six patients with 51 arterial aneurysms underwent operative intervention. The 51 primary operative interventions included 20 open operations and 31 endovascular interventions. Eleven (22 %) recurrent aneurysms developed in 10 patients and 5 (10%) thrombosis occurred in 5 patients. Of the 19 endovascular stents placed for aortic aneurysms, 1 type I endoleak, 1 graft occlusion, 3 recurrent aneurysms, and 1 recurrent aneurysmal rupture occurred. Among the revascularization procedures for extremity arteries, there were more complications with endovascular intervention than with open surgery. The cumulative risk of recurrent aneurysmal formation at the operative site was significantly less in patients treated with operative intervention combined with use of immunosuppressants than those treated with operative intervention alone (P = .01).
CONCLUSION: In patients with BD, an endovascular approach is feasible and effective for aortic aneurysms, whereas bypass surgery appears to provide better outcomes for extremity arterial aneurysms than placement of endovascular stents. The administration of corticosteroids combined with cyclophosphamide perioperatively decreases the cumulative risk of recurrent aneurysm.

Copyright © 2016 Elsevier Inc. All rights reserved.
PMID 26765098
Vedat Hamuryudan, Emire Seyahi, Serdal Ugurlu, Melike Melikoglu, Gulen Hatemi, Yesim Ozguler, Canan Akman, Hasan Tuzun, Sebahattin Yurdakul, Hasan Yazici
Pulmonary artery involvement in Behçet׳s syndrome: Effects of anti-Tnf treatment.
Semin Arthritis Rheum. 2015 Dec;45(3):369-73. doi: 10.1016/j.semarthrit.2015.06.008. Epub 2015 Jun 18.
Abstract/Text OBJECTIVES: Anti-TNF agents are being increasingly used in patients with Behçet׳s syndrome (BS) when conventional immunosuppressives fail. However, experience with anti-TNF treatment on pulmonary artery involvement (PAI) of BS is limited.
METHODS: A chart review revealed 13 patients with PAI (all men) treated with anti-TNF agents (12 infliximab and 1 adalimumab) following an inadequate response to immunosuppressives for 12.2 ± 9.5 SD months and 2 male patients who developed PAI while receiving infliximab for large vein thrombosis for 10 months and for parenchymal central nervous system involvement for 2 years, respectively.
RESULTS: The first patient developing PAI while receiving infliximab responded to cyclophosphamide and prednisolone but the second died with hemoptysis within 1 month. At the end of the survey, 6 of the 13 patients with PAI were continuing these agents for 25.5 ± 16.2 SD months with good response, 4 stopped anti-TNF treatment after a mean of 23 ± 9.8 SD months after achieving clinical and radiologic response and 1 patient with good response went to another center after receiving infliximab for 10 months and the remaining 2 experienced serious infections (lung tuberculosis and aspergillosis) necessitating early withdrawal. Two patients relapsed within 3 years after stopping anti-TNF agents and concomitant azathioprine. One developed mesenteric vein thrombosis necessitating bowel resection and the second developed new PAI that was controlled with cyclophosphamide and prednisolone after short courses of infliximab, adalimumab, and canakinumab.
CONCLUSION: Anti-TNF treatment seems to be effective for refractory PAI of BS but may not prevent its development. Relapses can be seen after withdrawal. Caution is required for their serious adverse effects.

Copyright © 2015 Elsevier Inc. All rights reserved.
PMID 26190564
Estee Chan, Shirish R Sangle, J Gerry Coghlan, David D D'Cruz
Pulmonary artery aneurysms in Behçet's disease treated with anti-TNFα: A case series and review of the literature.
Autoimmun Rev. 2016 Apr;15(4):375-8. doi: 10.1016/j.autrev.2016.01.003. Epub 2016 Jan 8.
Abstract/Text Behçet's disease (BD) is a systemic inflammatory disorder of unknown aetiology. Pulmonary haemorrhage from ruptured pulmonary artery aneurysms (PAA) in this condition carries a high mortality but treatment has largely been empiric with use of glucocorticoids and cyclophosphamide. Tumour necrosis factor α (TNF-α) was recently recognised as a mediator in the pathogenesis of BD inflammatory lesions. TNFα inhibitors have been shown in various case reports/series to have beneficial effects in uveoretinitis, entero-Behçet's, neuro-Behçet's and BD arthritis. We describe the efficacy and tolerability of infliximab in 2 patients with Behçet's disease complicated by pulmonary vasculitis admitted to our unit during the years 2004-2015, and discuss the previously published data in this area.

Copyright © 2016 Elsevier B.V. All rights reserved.
PMID 26777307
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.

PMID 27310969
G Hatemi, A Silman, D Bang, B Bodaghi, A M Chamberlain, A Gul, M H Houman, I Kötter, I Olivieri, C Salvarani, P P Sfikakis, A Siva, M R Stanford, N Stübiger, S Yurdakul, H Yazici, EULAR Expert Committee
EULAR recommendations for the management of Behçet disease.
Ann Rheum Dis. 2008 Dec;67(12):1656-62. doi: 10.1136/ard.2007.080432. Epub 2008 Jan 31.
Abstract/Text OBJECTIVES: To develop evidence-based European League Against Rheumatism (EULAR) recommendations for the management of Behçet disease (BD) supplemented where necessary by expert opinion.
METHODS: The multidisciplinary expert committee, a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), consisted of nine rheumatologists (one who was also a clinical epidemiologist and one also a Rehabilitation Medicine doctor), three ophthalmologists, one internist, one dermatologist and one neurologist, representing six European countries plus Tunisia and Korea. A patient representative was also present. Problem areas and related keywords for systematic literature research were identified. Systematic literature research was performed using Medline and the Cochrane Library databases from 1966 through to December 2006. A total of 40 initial statements were generated based on the systematic literature research. These yielded the final recommendations developed from two blind Delphi rounds of voting.
RESULTS: Nine recommendations were developed for the management of different aspects of BD. The strength of each recommendation was determined by the level of evidence and the experts' opinions. The level of agreement for each recommendation was determined using a visual analogue scale for the whole committee and for each individual aspect by the subgroups, who consider themselves experts in that field of BD. There was excellent concordance between the level of agreement of the whole group and the "experts in the field".
CONCLUSION: Recommendations related to the eye, skin-mucosa disease and arthritis are mainly evidence based, but recommendations on vascular disease, neurological and gastrointestinal involvement are based largely on expert opinion and uncontrolled evidence from open trials and observational studies. The need for further properly designed controlled clinical trials is apparent.

PMID 18245110
Yoon Suk Jung, Sung Pil Hong, Tae Il Kim, Won Ho Kim, Jae Hee Cheon
Long-term clinical outcomes and factors predictive of relapse after 5-aminosalicylate or sulfasalazine therapy in patients with intestinal Behcet disease.
J Clin Gastroenterol. 2012 May-Jun;46(5):e38-45. doi: 10.1097/MCG.0b013e3182431d56.
Abstract/Text BACKGROUND: Currently, 5-aminosalicylic acid (5-ASA)/sulfasalazine is used to empirically treat patients with intestinal Behcet disease (BD) without clear clinical evidence. In this study, we investigated long-term clinical outcomes and predictors of clinical relapse in patients with intestinal BD receiving 5-ASA/sulfasalazine maintenance therapy.
METHODS: We reviewed the medical records of all the patients with intestinal BD, who received 5-ASA/sulfasalazine therapy in a single tertiary academic medical center between March 1986 and January 2011. 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: Among the 143 patients enrolled, 46 (32.2%) had a clinical relapse while they were being treated with 5-ASA/sulfasalazine therapy. The cumulative relapse rates at 1, 3, 5, and 10 years after remission were 8.1%, 22.6%, 31.2%, and 46.7%, respectively. By multivariate analysis, a younger age (<35 y) at the time of diagnosis, higher C-reactive protein level (≥1.5 mg/dL), and a higher disease activity index for intestinal Behcet disease score (≥60) at the time of 5-ASA/sulfasalazine initiation were independent predictors of relapse in patients with intestinal BD receiving 5-ASA/sulfasalazine maintenance therapy.
CONCLUSIONS: This study has shown that 5-ASA/sulfasalazine therapy has a positive effect in maintaining remission in patients with intestinal BD. However, a younger age (<35 y), higher C-reactive protein level (≥1.5 mg/dL), and a higher disease activity index for intestinal Behcet disease score (≥60) were associated with a poor response to 5-ASA/sulfasalazine therapy, making careful observation and intensive treatment necessary in these risk groups.

PMID 22298088
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.
PMID 21618352
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.

PMID 10826433
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.
PMID 25245624
Shunsei Hirohata, Hirotoshi Kikuchi, Tetsuji Sawada, Hiroko Nagafuchi, Masataka Kuwana, Mitsuhiro Takeno, Yoshiaki Ishigatsubo
Analysis of various factors on the relapse of acute neurological attacks in Behçet's disease.
Mod Rheumatol. 2014 Nov;24(6):961-5. doi: 10.3109/14397595.2014.891496. Epub 2014 Mar 19.
Abstract/Text OBJECTIVES: To investigate the influences of various factors on the relapse of acute neurological attacks in patients with Behçet's disease (BD).
METHODS: Sixty-one patients, who met the international classification criteria for BD, had attacks of acute neuro-Behçet's disease (NBD) and could be followed up at least for 2 months, including 60 patients in our multicenter retrospective survey on BD patients in 2011. The factors associated with relapse of acute neurological attacks were assessed.
RESULTS: Twenty-one of 61 patients had been taking cyclosporine A (CyA) at the onset of acute NBD. All the 21 patients with CyA and 33 of the 40 patients without CyA had eye involvement. There were no significant differences in demographic features, clinical symptoms, MRI findings, the need for, and responses to corticosteroid therapy including pulse therapy between patients with CyA and those without CyA. CyA was withdrawn in 19 of 21 patients with CyA. Of note, patients with CyA showed significantly lower relapse rates than those without CyA (HR 0.1283, 95% CI: 0.0788-0.7836, p = 0.0186 as calculated by log-rank test). Moreover, colchicine was found to reduce the relapse rates in patients with acute NBD without CyA (HR 0.2771, 95% CI: 0.0827-0.9422, p = 0.0450 [log-rank test]).
CONCLUSION: These results indicate that CyA-related acute neurological manifestations are almost identical with CyA-unrelated acute events of NBD, except for the paucity of relapse on withdrawal of CyA. The data also demonstrate that colchicine is effective to prevent relapses of acute neurological attacks especially in patients with CyA-unrelated acute NBD.

PMID 24645723
K Fujikawa, K Aratake, A Kawakami, T Aramaki, N Iwanaga, Y Izumi, K Arima, M Kamachi, M Tamai, M Huang, H Nakamura, Y Nishiura, T Origuchi, H Ida, K Eguchi
Successful treatment of refractory neuro-Behcet's disease with infliximab: a case report to show its efficacy by magnetic resonance imaging, transcranial magnetic stimulation and cytokine profile.
Ann Rheum Dis. 2007 Jan;66(1):136-7. doi: 10.1136/ard.2006.056804.
Abstract/Text
PMID 17178762
Massimiliano Di Filippo, Maria Di Gregorio, Carlotta Nannini, Lorenzo Gaetani, Cristina Gallina, Piero Floridi, Paola Sarchielli, Paolo Calabresi, Fabrizio Cantini
Infliximab monotherapy for neuro-Behçet's disease: a case report.
J Neurol Sci. 2014 Dec 15;347(1-2):389-90. doi: 10.1016/j.jns.2014.09.052. Epub 2014 Oct 7.
Abstract/Text
PMID 25456463
S Hirohata, H Suda, T Hashimoto
Low-dose weekly methotrexate for progressive neuropsychiatric manifestations in Behcet's disease.
J Neurol Sci. 1998 Aug 14;159(2):181-5. doi: 10.1016/s0022-510x(98)00165-8.
Abstract/Text The most serious central nervous system (CNS) manifestation in Behcet's disease is a slowly progressive dementia (progressive NB), which may ultimately lead to the deterioration of the personality of patients. An open trial was designed to investigate the efficacy of low dose weekly methotrexate (MTX) therapy for progressive NB. Six patients with Behcet's disease, whose neuropsychiatric manifestations were judged to be progressive (4 females and 2 males, aged 55.0+/-8.2 years), were given oral MTX (7.5-12.5 mg/week) until the end of the 12-month trial. The clinical responses of the patients to MTX were judged by neuropsychiatric findings, intelligence test, brain MRI scans and cerebrospinal fluid (CSF) IL-6 levels. After the 12-month trial, CSF IL-6 levels were found to be significantly decreased. Accordingly, the neuropsychological manifestations as well as the findings on MRI scans and intelligence quotients were not significantly worsened after the trial. Three patients presented with mild liver dysfunction, which returned to normal by decreasing the dose of MTX. However, 6 months after discontinuation of MTX, all the six patients showed significant exacerbation of the manifestations as evidenced by a decrease in verbal intelligence quotients along with the marked elevation of CSF IL-6. These results suggest that low dose weekly MTX therapy might have a beneficial effect in the treatment of progressive NB, although a trial for a longer period would be necessary.

PMID 9741405
Hirotoshi Kikuchi, Kaori Aramaki, Shunsei Hirohata
Low dose MTX for progressive neuro-Behçet's disease. A follow-up study for 4 years.
Adv Exp Med Biol. 2003;528:575-8. doi: 10.1007/0-306-48382-3_117.
Abstract/Text
PMID 12918768
Shunsei Hirohata, Hirotoshi Kikuchi, Tetsuji Sawada, Hiroko Nagafuchi, Masataka Kuwana, Mitsuhiro Takeno, Yoshiaki Ishigatsubo
Clinical characteristics of neuro-Behcet's disease in Japan: a multicenter retrospective analysis.
Mod Rheumatol. 2012 Jun;22(3):405-13. doi: 10.1007/s10165-011-0533-5. Epub 2011 Sep 21.
Abstract/Text To delineate the clinical characteristics of neuro-Behçet's disease (NBD), a multicenter retrospective survey was performed in BD patients who had presented any neurological manifestations between 1988 and 2008. The diagnosis of acute NBD, chronic progressive (CP) NBD, and non-NBD was confirmed by retrospective review of clinical records. Data on a total of 144 patients were collected; 76 with acute NBD, 35 with CP NBD, and 33 with non-NBD. High-intensity lesions on T2-weighted magnetic resonance imaging (MRI) were found in 60.5% of the patients with acute NBD, 54.2% with CP NBD, and 42.4% with non-NBD, whereas brainstem atrophy was observed in 7.5% with acute NBD, 71.4% with CP NBD, and 9.0% with non-NBD. The cerebrospinal fluid (CSF) cell count was prominently elevated in patients with acute NBD, but was normal in about 15% of those with CP NBD. The sensitivity and specificity of the CSF cell count for the diagnosis of acute NBD versus non-NBD were 97.4 and 97.0%, respectively (cut-off 6.2/mm(3)). The sensitivity and specificity of CSF interleukin (IL)-6 for the diagnosis of CP NBD versus the recovery phase of acute NBD were 86.7 and 94.7%, respectively (cut-off 16.55 pg/ml). The results indicate that elevation of the CSF cell count and CSF IL-6 and the presence of brainstem atrophy on MRI are useful for the diagnosis of NBD.

PMID 21935641
Hirotoshi Kikuchi, Kaori Aramaki, Shunsei Hirohata
Effect of infliximab in progressive neuro-Behçet's syndrome.
J Neurol Sci. 2008 Sep 15;272(1-2):99-105. doi: 10.1016/j.jns.2008.05.002. Epub 2008 Jun 11.
Abstract/Text Recent studies have shown the beneficial effect of infliximab in ocular manifestation of Behçet's disease. The current studies examined the efficacy of infliximab in progressive neuro-Behçet's syndrome (NB) refractory to methotrexate (MTX). Five male patients with progressive NB with sustained elevation of cerebrospinal fluid (CSF) IL-6 (over 20 pg/ml) despite administration of MTX and steroid, were given intravenous infusion of 5 mg/kg infliximab at weeks 0, 2, 6, and 14 with MTX (10-17.5 mg/week) and prednisolone (<10 mg/day) at the same doses. The clinical responses were judged by neuropsychiatric findings, revised Wechsler adult intelligence scale (WAIS-R), and brain magnetic resonance imaging (MRI) scans at 24 weeks. In all the 5 patients, CSF IL-6 were markedly decreased by 1/2-1/37 on the next day of the first infusion and remained below 20 pg/ml before the last infusion at 14 weeks, whereas CSF TNF-alpha were not significantly changed at any time point. At 24 weeks from the initial infusion, none of the 5 patients showed exacerbation (3 patients significantly improved). Nor did the atrophy in midbrain, pons and medulla on brain MRI scans show significant progression. These results suggest that infliximab might have a beneficial effect in the treatment of progressive NB by reducing CSF IL-6 levels but not TNF-alpha. Since infliximab has been shown to have cytotoxic effects on monocytes/macrophages, the rapid fall of CSF IL-6 after the infusion suggest that infliximab might directly act on such inflammatory cells producing IL-6.

PMID 18550081

ページ上部に戻る

戻る

さらなるご利用にはご登録が必要です。

こちらよりご契約または優待日間無料トライアルお申込みをお願いします。

(※トライアルご登録は1名様につき、一度となります)


ご契約の場合はご招待された方だけのご優待特典があります。

以下の優待コードを入力いただくと、

契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから