ベーチェット病（指定難病56）．難病情報センター． [Internet]. Available from: https://www.nanbyou.or.jp/entry/187
Ideguchi H, Suda A, Takeno M, Ueda A, Ohno S, Ishigatsubo Y.
Behçet disease: evolution of clinical manifestations.
Medicine (Baltimore). 2011 Mar;90(2):125-132. 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.
Lê Thi Huong D, Wechsler B, Papo T, Piette JC, Bletry O, Vitoux JM, Kieffer E, Godeau P.
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.
Hamuryudan V, Yurdakul S, Moral F, Numan F, Tüzün H, Tüzüner N, Mat C, Tüzün Y, Ozyazgan Y, Yazïci H.
Pulmonary arterial aneurysms in Behçet's syndrome: a report of 24 cases.
Br J Rheumatol. 1994 Jan;33(1):48-51. doi: 10.1093/rheumatology/33.1.48.
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.
Varol A, Seifert O, Anderson CD.
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.
Aramaki K, Kikuchi H, Hirohata S.
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
Yazici H, Pazarli H, Barnes CG, Tüzün Y, Ozyazgan Y, Silman A, Serdaroğlu S, Oğuz V, Yurdakul S, Lovatt GE.
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.
Hamuryudan V, Ozyazgan Y, Hizli N, Mat C, Yurdakul S, Tüzün Y, Senocak M, Yazici H.
Azathioprine in Behcet's syndrome: effects on long-term prognosis.
Arthritis Rheum. 1997 Apr;40(4):769-74. doi: 10.1002/art.1780400425.
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.
Sfikakis PP, Markomichelakis N, Alpsoy E, Assaad-Khalil S, Bodaghi B, Gul A, Ohno S, Pipitone N, Schirmer M, Stanford M, Wechsler B, Zouboulis C, Kaklamanis P, Yazici H.
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
Matsumura N, Mizushima Y.
Leucocyte movement and colchicine treatment in Behcet's disease.
Lancet. 1975 Oct 25;2(7939):813. doi: 10.1016/s0140-6736(75)80031-6.
Abstract/Text
Kötter I, Dürk H, Saal J, Fierlbeck G, Pleyer U, Ziehut M.
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.
小竹聡, 市石昭, 小阪祥子, 吉川浩二, 皆川玲子, 松田 英彦： ベーチェット病の眼症状に対する低用量シクロスポリン 療法. 日眼会誌 1992 96: 1290-1294.
Ohno S, Nakamura S, Hori S, Shimakawa M, Kawashima H, Mochizuki M, Sugita S, Ueno S, Yoshizaki K, Inaba G.
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.
Fabiani C, Vitale A, Emmi G, Vannozzi L, Lopalco G, Guerriero S, Orlando I, Franceschini R, Bacherini D, Cimino L, Soriano A, Frediani B, Galeazzi M, Iannone F, Tosi GM, Salvarani C, Cantarini L.
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.
Ozyazgan Y, Yurdakul S, Yazici H, Tüzün B, Işçimen A, Tüzün Y, Aktunç T, Pazarli H, Hamuryudan V, Müftüoğlu A.
Low dose cyclosporin A versus pulsed cyclophosphamide in Behçet's syndrome: a single masked trial.
Br J Ophthalmol. 1992 Apr;76(4):241-3. doi: 10.1136/bjo.76.4.241.
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.
BenEzra D, Cohen E, Chajek T, Friedman G, Pizanti S, de Courten C, Harris W.
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.
Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, Inaba G.
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. doi: 10.1016/s0140-6736(89)92381-7.
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.
Matsuda T, Ohno S, Hirohata S, Miyanaga Y, Ujihara H, Inaba G, Nakamura S, Tanaka S, Kogure M, Mizushima Y.
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. doi: 10.2165/00126839-200304010-00002.
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.
Alpsoy E, Durusoy C, Yilmaz E, Ozgurel Y, Ermis O, Yazar S, Basaran E.
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. doi: 10.1001/archderm.138.4.467.
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.
Kötter I, Günaydin I, Zierhut M, Stübiger N.
The use of interferon alpha in Behçet disease: review of the literature.
Semin Arthritis Rheum. 2004 Apr;33(5):320-35. doi: 10.1016/j.semarthrit.2003.09.010.
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.
Hatemi G, Melikoglu M, Tunc R, Korkmaz C, Turgut Ozturk B, Mat C, Merkel PA, Calamia KT, Liu Z, Pineda L, Stevens RM, Yazici H, Yazici Y.
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.).
Yurdakul S, Mat C, Tüzün Y, Ozyazgan Y, Hamuryudan V, Uysal O, Senocak M, Yazici H.
A double-blind trial of colchicine in Behçet's syndrome.
Arthritis Rheum. 2001 Nov;44(11):2686-92. doi: 10.1002/1529-0131(200111)44:11<2686::aid-art448>3.0.co;2-h.
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.
Aktulga E, Altaç M, Müftüoglu A, Ozyazgan Y, Pazarli H, Tüzün Y, Yalçin B, Yazici H, Yurdakul S.
A double blind study of colchicine in Behçet's disease.
Haematologica. 1980 Jun;65(3):399-402.
Abstract/Text
Melikoglu M, Fresko I, Mat C, Ozyazgan Y, Gogus F, Yurdakul S, Hamuryudan V YH. Short-term trial of etanercept in Behçet’s disease: a double blind, placebo controlled study. J Rheumatol. 2005;32(1):98-105.
Estrach C, Mpofu S, Moots RJ.
Behçet's syndrome: response to infliximab after failure of etanercept.
Rheumatology (Oxford). 2002 Oct;41(10):1213-4.
Abstract/Text
Arida A, Fragiadaki K, Giavri E, Sfikakis PP.
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.
Tuzun H, Seyahi E, Arslan C, Hamuryudan V, Besirli K, Yazici H.
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.
Liu Q, Ye W, Liu C, Li Y, Zeng R, Ni L.
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.
Hamuryudan V, Seyahi E, Ugurlu S, Melikoglu M, Hatemi G, Ozguler Y, Akman C, Tuzun H, Yurdakul S, Yazici H.
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.
Chan E, Sangle SR, Coghlan JG, D'Cruz DD.
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.
Hibi T, Hirohata S, Kikuchi H, Tateishi U, Sato N, Ozaki K, Kondo K, Ishigatsubo Y.
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.
Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain AM, Gul A, Houman MH, Kötter I, Olivieri I, Salvarani C, Sfikakis PP, Siva A, Stanford MR, Stübiger N, Yurdakul S, Yazici H; 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.
Jung YS, Hong SP, Kim TI, Kim WH, Cheon JH.
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.
Jung YS, Cheon JH, Hong SP, Kim TI, Kim WH.
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.
Choi IJ, Kim JS, Cha SD, Jung HC, Park JG, Song IS, Kim CY.
Long-term clinical course and prognostic factors in intestinal Behçet's disease.
Dis Colon Rectum. 2000 May;43(5):692-700. doi: 10.1007/BF02235590.
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.
Tanida S, Inoue N, Kobayashi K, Naganuma M, Hirai F, Iizuka B, Watanabe K, Mitsuyama K, Inoue T, Ishigatsubo Y, Suzuki Y, Nagahori M, Motoya S, Nakamura S, Arora V, Robinson AM, Thakkar RB, Hibi T.
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.
Hirohata S, Kikuchi H, Sawada T, Nagafuchi H, Kuwana M, Takeno M, Ishigatsubo Y.
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.
Fujikawa K, Aratake K, Kawakami A, Aramaki T, Iwanaga N, Izumi Y, Arima K, Kamachi M, Tamai M, Huang M, Nakamura H, Nishiura Y, Origuchi T, Ida H, Eguchi K.
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
Di Filippo M, Di Gregorio M, Nannini C, Gaetani L, Gallina C, Floridi P, Sarchielli P, Calabresi P, Cantini F.
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
Hirohata S, Suda H, Hashimoto T.
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.
Kikuchi H, Aramaki K, Hirohata S.
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
Hirohata S, Kikuchi H, Sawada T, Nagafuchi H, Kuwana M, Takeno M, Ishigatsubo Y.
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.
Kikuchi H, Aramaki K, Hirohata S.
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.
