KJIM The Korean Journal of Internal MedicineKorean J Intern Med 1226-3303 2005-6648 The Korean Association of Internal Medicine 10.3904/kjim.2017.377 kjim-2017-377 Review Updated treatment strategies for intestinal Behçet’s disease ParkYong Eun 1 CheonJae Hee 1 2 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea Correspondence to Jae Hee Cheon, M.D. Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: +82-2-2228-1990 Fax: +82-2-393-6884 E-mail: geniushee@yuhs.ac

This paper was contributed by Korean Association for the Study of Intestinal Diseases.

 1 2018 8 12 2017 33 1 1 19 17 11 2017 20 11 2017 Copyright © 2018 The Korean Association of Internal Medicine 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Behçet’s disease (BD) is a chronic, idiopathic, relapsing immune-mediated disease involving multiple organs, and is characterized by recurrent oral and genital ulcers, ocular disease, gastrointestinal ulcers, vascular diseases, and skin lesions. In particular, gastrointestinal involvement in BD is followed by severe complications, including massive bleeding, bowel perforation, and fistula, which can lead to significant morbidity and mortality. However, the management of intestinal BD has not yet been properly established. Intestinal BD patients with a severe clinical course experience frequent disease aggravations and often require recurrent corticosteroid and/or immunomodulatory therapies, or even surgery. However, a considerable number of patients with intestinal BD are often refractory to conventional therapies such as corticosteroids and immunomodulators. Recently, there has been a line of evidence suggesting that biologics such as infliximab and adalimumab are effective in treating intestinal BD. Moreover, new biologics targeting proteins other than tumor necrosis factor α are emerging and are under active investigation. Therefore, in this paper, we review the current therapeutic strategies and new clinical data for the treatment of intestinal BD.

 Intestinal Behcet disease Biological products Tumor necrosis factor-alpha Infliximab Adalimumab INTRODUCTION

Behçet’s disease (BD) is a chronic, multi-systemic immune disorder with an unknown etiology, characterized by recurrent oral and genital aphthous ulcerations, arthritis, and skin manifestations, with ocular, vascular, neurological, and gastrointestinal (GI) involvement [1,2]. The diagnosis of intestinal BD is based on GI symptoms in BD patients and typical intestinal ulcerative lesions documented by objective measures [3]. Although the GI symptoms can range from asymptomatic or mild abdominal discomfort to severe abdominal pain, involvement of the GI tract often leads to severe morbidity and mortality [4]. Additionally, these patients can have further complications such as massive hemorrhage, fistula, or bowel perforation [3,5]. Similar to inflammatory bowel disease (IBD), intestinal BD is accompanied by different clinical courses [6] with chronic continuous symptoms or repeated episodes of relapse and remission [7,8]. Along with proper intervention with surgical management, the appropriate use of medical therapy given the life-long duration of the disease is of great importance in the management of intestinal BD [9,10]. Empirical medical therapies include 5-aminosalicylic acids (5-ASAs), corticosteroids, immunomodulators such as azathioprine and 6-mercaptopurine (6-MP), thalidomide, and anti-tumor necrosis factor α (TNF-α) agents. Therefore, we will cover and review the current optimal medical treatment options and recent data relevant to patients with intestinal BD. Furthermore, new treatment modalities that might have the potential to be developed as novel therapeutic agents in the near future will also be discussed.

 PRINCIPLES OF APPROACH TO THE MANAGEMENT OF INTESTINAL BD

According to the 2008 European League Against Rheumatism (EULAR) guidelines, there are unfortunately no evidence-based treatment guidelines that can be recommended for the management of intestinal BD [11]. There are a few large, randomized and controlled trials of potential management for patients with intestinal BD. Therefore, the management of intestinal BD has been empirically based on the treatment guidelines for Crohn’s disease (CD) following opinions of expert physicians [2]. Correspondingly, according to the Japanese consensus of intestinal BD published in 2007, 5-ASAs, corticosteroids, immunomodulators, enteral nutrition, total parenteral nutrition, and surgical therapy were included in standard therapy for intestinal BD [12]. In addition, in 2014, the 2nd edition of consensus statements for intestinal BD suggested that anti-TNF-α agents such as adalimumab and infliximab should be considered as standard therapy for intestinal BD [13]. Cheon and Kim [2] and Lee et al. [14] proposed a treatment algorithm for intestinal BD based on expert opinion and accumulated published data (Fig. 1).

 MEDICAL TREATMENT 5-Aminosalicylic acids

5-ASAs can reduce inflammation and have immunomodulatory actions in the intestine [15]. 5-ASAs widely used for IBD are sulfasalazine and mesalamine [15]. Although evidence of efficacy in intestinal BD is still insufficient, the Japanese consensus statements recommended 5-ASA as a first option for induction and maintenance therapy for mild or moderate intestinal BD [13]. 5-ASA is usually administered at a dose of 2 to 4 g/day [2]. Sulfasalazine, a colon-selective drug that contains a sulfa group, is usually administered 3 to 4 g/day in intestinal BD [2].

In 1997, a case study reported that sulfasalazine use was associated with clinical improvement in 79% (11 of 14, p < 0.005) of intestinal BD patients in Korea [16]. In contrast, Matsukawa et al. [17] reported the ineffectiveness of 5-ASA in recurrent intestinal ulcers. However, Jung et al. [18] showed that 5-ASA/sulfasalazine therapy has a positive effect on maintaining remission in Korean patients with intestinal BD, although younger age (< 35 years), higher C-reactive protein (CRP) level, and higher disease activity were associated with a poor response to 5-ASA/sulfasalazine. Another retrospective study on the effect of 5-ASA compounds reported that among 16 patients who were treated with 5-ASA compounds, 62.5% (n = 10) achieved clinical remission with a disease-free duration of 89.3 ± 64.5 months (Table 1) [13,16,18-34]. This discrepancy between studies possibly originates from differences in disease heterogeneity, especially disease severity.

 Corticosteroids

Corticosteroids are fast-acting anti-inflammatory drugs that have been commonly used for patients with acutely moderate-to-severe and refractory intestinal BD [13,20-22,35]. However, evidence on the efficacy of corticosteroids in intestinal BD also remains insufficient, because prospective/randomized studies are lacking. Treatment with corticosteroids is considered the first-line therapy during the acute phase of the disease, initially at doses of 0.5 to 1.0 mg/kg/day of prednisolone for 1 to 2 weeks with tapering by 5 mg each week and stoppage within 3 months (Table 1) [2,36-38]. Prolonged use of prednisolone in excess of 10 mg/day is not recommended. Some case studies have reported the efficacy of an intravenous administration of a lipid emulsion of dexamethasone [20,21]. However, corticosteroid use was paradoxically associated with increased risk of GI bleeding and perforation [39]. Additionally, Park et al. [40] reported that corticosteroid use was significantly associated with re-bleeding in patients with intestinal BD. Despite these side effects, Park et al. [23] in 2010 performed a retrospective study of clinical outcomes after corticosteroid use in patients with moderate-to-severe intestinal BD. A total of 54 patients were enrolled and the median corticosteroid dosage was 0.58 mg/kg (interquartile range, 0.39 to 1.20). In this study, 46.3% of patients (n = 25) achieved complete remission after 1 month of treatment. Three months after treatment, 40.7% of patients (n = 22) showed treatment response. After 1 year, 48.1% (n = 26) remained responsive to treatment. However, after 1 year, 35.2% of the patients (n = 19) exhibited corticosteroid dependency, and 7.4% (n = 4) received surgery. Treatment response at three months was independently associated with a decreased risk of surgery in the long term (p = 0.009). Therefore, the authors suggested that short-term response rate to initial corticosteroid therapy was high in patients with intestinal BD [23]. Given this background, the Japanese consensus recommended that corticosteroids should be considered for induction therapy when patients have severe symptoms such as abdominal pain, diarrhea, or GI bleeding due to deep ulcers [13].

 Immunomodulators

Immunomodulators included in this review are thiopurines (6-mercaptopurine, 6-MP, and its prodrug azathioprine), methotrexate, tacrolimus, interferon, cyclosporin, and intravenous immunoglobuilin [41].

Thiopurines

Thiopurines are the most commonly prescribed immunomodulators for patients with intestinal BD, especially those with moderate-to-severe disease and those who are corticosteroid-dependent/resistant or secondarily lose response to anti-TNF-α agents (Table 1) [1,2,13,24].

Thiopurine drugs such as azathioprine and 6-MP are also used in postoperative patients after intestinal resection to reduce the postoperative recurrence rate [25], and they were reported to be relatively useful in the maintenance of remission after surgery in intestinal BD patients [26]. The initial dose of azathioprine is 25 to 50 mg/day, and if the azathioprine therapy is tolerated without side effects such as leukopenia and liver dysfunction, the dose can be gradually increased every 2 to 3 weeks up to 2.0 to 2.5 mg/kg [13,26,42]. The dose for the initial use of 6-MP is 0.5 mg/kg, which can also be gradually increased up to 1.0 to 1.5 mg/kg in a similar manner to that of azathioprine [26]. Jung et al. [26] reported positive effects of thiopurine maintenance therapy in patients with intestinal BD in Korea. They retrospectively evaluated patients with intestinal BD who received prolonged thiopurine monotherapy for over 6 months in a tertiary single center [26]. Of the 272 patients with intestinal BD, 67 patients (24.6%) received thiopurine therapy, and 39 of these 67 patients (58.2%) maintained medically or surgically induced remission. However, a younger age at diagnosis and a lower hemoglobin level were significantly associated with a poor response to thiopurines in this study [26].

Choi et al. [24] and Lee et al. [25] independently reported the effects of postoperative thiopurine use in patients with intestinal BD (Table 1). Choi et al. [24] compared the reoperation rate between azathioprine users and non-users. Reoperation rates were significantly lower in azathioprine users (7%) than in non-users (25%) at 2 years, and 25% and 47% at 5 years, respectively [24]. In addition, Lee et al. [25] investigated the postoperative protective effect of thiopurine. In their study, the postoperative recurrence rate was significantly lower in patients who received postoperative thiopurines (p = 0.050) [25].

The most common side effect of thiopurine drugs was leukopenia, which is defined as a white blood cell (WBC) count lower than 3,000 or 4,000 cells/mm3 [26,27]. Following the American Gastroenterological Association recommendations, it is suggested that when patients are treated with azathioprine or 6-MP, routine laboratory monitoring, including complete blood count, should be frequently performed [43]. Park et al. [27] reported that lower WBC count during thiopurine maintenance therapy was associated with prolonged remission.

 Methotrexate

The efficacy of other immunomodulators has also been reported. The use of methotrexate in patients with intestinal BD remains relatively poorly understood; however, Iwata et al. [44] reported the efficacy and safety of the combination of infliximab and methotrexate in 10 patients with refractory intestinal BD. All the 10 patients had improved symptoms and disease-related complications within 4 weeks. In addition, 50% of the patients (five of 10) showed disappearance of ileocecal valve ulcers at 6 months, and 90% of the patients (nine of 10) showed disappearance of the ulcers at 12 months (Table 2) [44-67]. Recently, Park et al. (unpublished data) also reported the efficacy of methotrexate in patients with intestinal BD as either mono- or combination therapy with adalimumab. In a retrospective review of 10 intestinal BD patients who received methotrexate treatment, four of the 10 patients received methotrexate monotherapy and the other six patients received combination therapy with adalimumab. In methotrexate monotherapy, three patients (30%) had steroid-free remission at 3 months, and four patients (50%) did at 6 months (unpublished data) (Table 1).

 Tacrolimus

Oral tacrolimus is a macrolide antibiotic with potent immunosuppressive activity [68], and it is widely used for the prevention of allograft rejection in patients who underwent organ transplantation [28]. Matsumura et al. [28] reported improvement after using tacrolimus in a patient refractory to conventional therapeutic agents such as 5-ASA, corticosteroids, immunomodulators, and infliximab. In our experience at Severance Hospital, four patients underwent tacrolimus therapy after failure of conventional agents, but none had a response to that drug (unpublished data).

 Interferon

In 1957, Isaacs and Lindenmann [69] first introduced interferon (IFN), a large family of glycoproteins known to produce cellular responses to various antigens such as microbes, viruses, and tumors [70,71]. Several studies reported the efficacy of IFN alfa-2a in the treatment of BD, especially in patients with mucocutaneous lesions, arthritis, and ocular manifestations [70,72,73]. Alpsoy et al. [70] reported a randomized, placebo-controlled, and double-blind study in 50 patients with BD. Of the 50 patients, 23 received IFN alfa-2a therapy, two of whom showed complete response while another 13 showed partial response. Eight patients showed no response. Grimbacher et al. [74] reported the efficacy of IFN alfa-2a in a patient who had eye and GI tract involvement. The patient experienced improved retinal infiltrates, skin lesions, and abdominal complaints within 2 weeks of treatment [74]. Monastirli et al. [75] presented a case demonstrating improvement of clinical symptoms in a patient who had intestinal BD and acute myelitis that were initially unresponsive to high-dose steroids; the patient remained drug-free until 12 months of follow-up. However, until now, there has been little research on the effect of IFN in patients with intestinal BD, and therefore it is difficult to clearly define the effect of IFN on intestinal BD.

 Cyclosporin

Cyclosporin is one of the most potent immunosuppressive agents, which decreases T-cell activity and blocks the immune response of inflammatory cytokines [76]. Several studies reviewed the positive effect of cyclosporin on the ocular manifestations of BD [11,77,78]. Following the EULAR guidelines, cyclosporin should not be used in BD patients with central nervous system involvement [11]. With regard to intestinal BD, Bayraktar et al. [7] reported cyclosporin had no benefit on intestinal BD. Therefore, further study is needed to clarify the efficacy of cyclosporin in intestinal BD.

 Intravenous immunoglobulin

Since 1952, immune globulin products from human plasma have been used to treat immune deficiency [29,79]. Intravenous immunoglobulin (IVIG) is an immunomodulating agent that has multiple activities and has been used for autoimmune and systemic inflammatory diseases [29]. There are a limited number of studies regarding the role of the IVIG in intestinal BD. Beales [30] reported a case of IVIG treatment without additional corticosteroids in a BD patient with colon involvement after initial failed treatment with corticosteroids and other immunomodulators. She significantly improved after IVIG initiation, and bowel lesions disappeared after 6 weeks. Cantarini et al. [29] reported successful treatment with IVIG in patients with severe and resistant BD. Of four patients, all had mucocutaneous involvement with BD and one patient had intestine involvement (Table 1) [29]. Therefore, the effect of IVIG on intestinal BD still warrants further study.

 Thalidomide

Thalidomide, a synthetic derivative of glutamic acid, was first introduced in 1957 and used as a sedative agent with a teratogenic side effects; however, recent research has shown growing interest in its anti-inflammatory and immunomodulatory properties [2,31]. Therefore, there have been several studies of thalidomide treatment in pediatric patients with BD who were refractory to other immunomodulators, or those who developed undesirable side effects [80,81].

Sayarlioglu et al. [32] reported beneficial effects of thalidomide on recurrent perforating intestinal ulcers in an adult patient with BD. Additionally, Yasui et al. [31] reviewed a case of thalidomide for the treatment of juvenile-onset intestinal BD, which included seven patients with severe and recurrent intestinal involvement. The initial dose of thalidomide was 2 mg/kg/day, with dose adjustment according to response; if necessary, the dose of thalidomide was increased up to 3 mg/kg/day or decreased to 0.5 to 1 mg/kg/day [31]. All the seven patients achieved clinical improvement and were allowed to stop corticosteroid therapy [31]. In Korea, Lee et al. [33] also reported the efficacy of thalidomide in four patients who had chronic relapse of intestinal BD that repeatedly required corticosteroids and was refractory to conventional therapy such as 5-ASA and immunomodulators. Three of the four patients showed clinical symptom improvements; however, two of the four patients had to stop the therapy due to side effects such as general edema, leukopenia, and sepsis (Table 1).

It has been reported that thalidomide reduces TNF-α levels via degradation of its encoding messenger RNA, and thus shows immunomodulatory effects [82]. Hatemi et al. [83] investigated 13 patients with intestinal BD who were refractory to conventional therapy were treated with anti-TNF-α and/or thalidomide. Of those, 10 patients (75%) achieved clinical and endoscopic remission [83]. Therefore, thalidomide may become a therapeutic option for intestinal BD, but it should be carefully selected and monitored due to its teratogenicity and side effects such as edema, leukopenia, and sepsis. Further well-designed studies are necessary to conduct proper use.

 Others Colchicine

Colchicine is an anti-inflammatory drug that suppresses the secretion of cytokines and chemokines, and is used for the management of patients with gout and BD [35,84]. Some studies reported the improvement of arthralgia and erythema nodosum in patients with BD, but the effect on mucocutaneous manifestations was controversial in several studies [85-87]. Therefore, the EULAR recommended that colchicine is preferred when the dominant lesion is erythema nodosum [11]. However, currently, there is no evidence on the use of colchicine for intestinal BD. Choi et al. [24] suggested that there are no beneficial effects on intestinal lesions from their retrospective study. There is an insufficient number of studies to prove efficacy of colchicine in intestinal BD.

 Stem cell transplantation and leukocytapheresis

Hematopoietic stem cell transplantation (HSCT) has been used to treat severe autoimmune and inflammatory conditions that are unresponsive to traditional therapies [38,88]. HSCT in patients with BD has been reported several times in forms of case reports either for refractory BD or patients with associated hematological conditions such as aplastic anemia or myelodysplastic syndrome (MDS) [88-90]. This treatment is based on the rationale that a vigorous immunoablative regimen can remove autoaggressive lymphocyte clones [2]. Yamato [89] and Rossi et al. [90] reported cases of successful stem cell transplantation for MDS with BD and severe/refractory BD. HSCT could be an alternative therapy in BD patients with severe organ involvement, including GI involvement, that is refractory to immunomodulators [88]. Allo-stem cell transplants have high transplant-related morbidity and mortality; therefore, autologous transplants have been performed more frequently in BD patients, and non-myeloablative regimens may be preferred over myeloablative ones [88].

According to the Japanese consensus statements for intestinal BD in 2014 [13], leukocytapheresis was classified into an experimental treatment to mechanically remove WBCs in patients with intestinal BD who are steroid-dependent or resistant [2]. This is because activated neutrophils in patients with severe intestinal BD increase leukocytosis or cytokines [91]. However, this procedure also warrants further well-designed studies [2].

 Anti-TNF-α agents and biologics

Intestinal BD is associated with abnormal T-cell immune response and T helper type 1-associated cytokines such as TNF-α, IFN-γ, interleukin-12 (IL-12), and IL-18, which play a critical role in disease pathogenesis [92,93]. In patients with BD, the number of γδ cells producing TNF-α increases, TNF-α and its receptor levels are elevated in the blood, and the expression of TNF-α increases when the clinical course becomes worse [93]. Therefore, the importance of anti-TNF-α agents has been reported in several studies based on this background (Table 2) [45,46,67,94-97]. According to the Japanese consensus [13], anti-TNF-α mAbs (infliximab and adalimumab) should be considered as the standard therapy in patients with intestinal BD [2,13]. Infliximab is a chimeric monoclonal antibody against TNF-α [2] that can be considered for induction therapy with 5 mg/kg at 0, 2, and 6 weeks [13]. Responders should be administered maintenance therapy with infliximab every 8 weeks [13]. Adalimumab is a fully human anti-TNF-α monoclonal antibody [48], and can also be used for induction therapy with a dose of 160 mg at week 0 (baseline), 80 mg at week 2, and 40 mg at week 4 subcutaneously. Responders should be considered for maintenance therapy every other week at a dose of 40 mg [13]. In addition, several studies on the effects of various biologics such as etanercept, anakinra, canakinumab, and tocilizumab have been conducted [49-52].

Infliximab

Hassard et al. [53] reviewed a patient with chronically active, steroid-dependent intestinal BD who received 4 doses of infliximab during 6 months. The patient achieved remission, with a reduced Crohn’s Disease Activity Index score (from 270 to 13) at 2 weeks of infliximab use, and maintained remission after 10 weeks (Table 2) [53]. Naganuma et al. [54] also reported on the efficacy of infliximab induction and maintenance therapy. Four of six patients with intestinal BD achieved remission, and all four patients maintained remission with infliximab therapy (Table 2) [54]. In 2013, Lee et al. [45] reported a multicenter retrospective study of 28 patients with active moderate-to-severe intestinal BD who had been treated with infliximab at eight tertiary hospitals in Korea. At 2, 4, 30, and 54 weeks post-infliximab infusion, patients showed clinical response rates of 75%, 64.3%, 50%, and 39.1%, and clinical remission rates of 32.1%, 28.6%, 46.2%, and 39.1%, respectively. In addition, independent factors of maintenance response were older age at diagnosis (≥ 40 years), female sex, a longer disease duration (≥ 5 years), concomitant immunomodulator use, and achievement of remission at week 4 on multivariate analysis (Table 2) [45]. In a prospective open-label, single-arm phase 3 study in Japan, 18 patients with BD were enrolled, including 11 patients with intestinal BD, three patients with neurological BD, and four patients with vascular BD with poor response or resistance to conventional therapy [47]. Induction infliximab therapy was administered at 5 mg/kg at weeks 0, 2, and 6, with maintenance therapy every 8 weeks thereafter until week 46. Eleven of 18 of the patients (61%) were complete responders at weeks 14 and 30 and remained in remission until week 54. In addition, laboratory findings such as CRP levels were diminished, and 80% of patients showed healing or scarring ulceration at week 14. However, three patients with intestinal BD had to increase the dose of infliximab up to 10 mg/kg after week 30 due to loss of response, and two of three patients had symptoms that could not be controlled and worsened (Table 2) [47].

The efficacy of infliximab induction and maintenance therapy for intestinal BD has been widely accepted in many studies [13,47,55]. However, there is still insufficient evidence on the effect of combination therapy with immunomodulators as well as whether it can be used as a postoperative therapy in patients who underwent bowel resection. Byeon et al. [56] reviewed a patient with an unhealed postoperative anastomotic site and recurrent ulcers after a distal ileocecectomy, and reported endoscopic remission after 15 days of infliximab infusion. Iwata et al. [44] reported that concomitant therapy of infliximab with methotrexate was effective to achieve short-term remission and long-term response until 24 months. Well-designed further studies are needed.

 Adalimumab

Adalimumab is a humanized anti-TNF-α monoclonal antibody [98] and is widely used in patients with rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, psoriasis, juvenile idiopathic arthritis, uveitis, and IBD [48,57,99]. In 2011, De Cassan et al. [58] first reported adalimumab efficacy in patients with intestinal BD with repeated steroid-dependent flares and failure of conventional therapy. After that, several studies showed the efficacy of adalimumab in patients with intestinal BD. Tanida et al. [48] performed a multicenter, open-label, uncontrolled study of adalimumab for the treatment of Japanese patients with intestinal BD who were refractory to conventional therapy, including corticosteroids and/or immunomodulators. A total of 20 patients with intestinal BD were treated with adalimumab with dose of 160 mg at induction, 80 mg 2 weeks later, and 40 mg every other week for 52 weeks; for some patients with incomplete response, the dose of adalimumab increased up to 80 mg every other week. After 24 weeks of adalimumab therapy, nine of 20 patients (45%) had alleviated GI symptoms and diminished endoscopic assessment scores to 1 or lower than at pre-treatment. In addition, 12 of 20 patients (60%) had reduced endoscopic assessment scores at week 52. Additionally, no newly discovered safety problems or deaths were reported (Table 2) [48]. Recently, Inoue et al. [46] published an open-label phase 3 study (NCT01243671) in Japan to evaluate the safety and efficacy of adalimumab for the treatment of the same patients included in the 52 week follow-up study from weeks 52 to 100. Long-term efficacy of adalimumab was assessed on the basis of marked improvement, defined as both a GI symptom score of ≤ 1 (did not affect patient’s daily life) and an endoscopic score of ≤ 1 (largest ulcer is ≤ 1/4 original size), and complete remission, defined as a GI symptom score of 0 (symptom-free) and an endoscopic score of 0 (complete ulcer healing). At weeks 52 and 100, 12 of 20 patients (60%) and eight of 20 patients (40%) showed marked improvement, while four of 20 patients (20%) and three of 20 patients (15%) showed complete remission, respectively (Table 2) [46]. In addition, Kimura et al. [95] reported that a patient with intestinal BD and MDS successfully improved in GI symptoms, CRP levels, leukocytopenia, and anemia 4 months after starting adalimumab.

Combination therapy with adalimumab and immunomodulators has not yet been established, but Vitale et al. [59] conducted a multicenter retrospective study with 100 BD patients for the comparison of adalimumab monotherapy and combination therapy with disease modifying anti-rheumatic drugs. Although the study was not limited to patients with intestinal BD, it did not show a significant difference in clinical outcomes between adalimumab monotherapy and combination therapy (Table 2) [59].

 Etanercept

Etanercept is a dimeric human TNF receptor (TNFR) p75-Fc fusion protein that inhibits TNF-α activity [100,101]. Only a few studies have focused on etanercept as a treatment option for intestinal BD [49]. Ma et al. [49] reported on the outcomes of etanercept in the treatment of intestinal BD with 19 patients who were refractory to conventional therapy. Etanercept (25 mg twice a week for 3 months) was compared with conventional therapy, and the etanercept group showed significantly greater healing of ulceration, remission, and recovery of the erythrocyte sedimentation rate and CRP levels [49]. However, etanercept was not effective for the treatment of IBD, unlike other anti-TNF agents such as infliximab and adalimumab [102,103]. Sandborn et al. [102] conducted a randomized, double-blind, placebo-controlled trial in patients with active CD using etanercept. Forty-three patients were enrolled; however, 39% of the etanercept-treated patients had a clinical response compared with 45% of the placebo group (p = 0.763) at week 4 [102]. Furthermore, some recent studies have suggested a paradoxical development of IBD in patients receiving etanercept therapy. Forty-four (41 CD, three ulcerative colitis [UC]) of 443 cases (297 CD, 146 UC) were reported to develop de novo IBD after the initiation of etanercept, and 43 cases of flares of existing IBD patients were reported in association with etanercept therapy [104]. Therefore, the therapeutic efficacy of etanercept in patients with intestinal BD is also questionable.

 Anakinra

Anakinra is a recombinant version of the IL-1 receptor antagonist (IL1-RA) and a biologic agent used to modify the immune response of IL-1 [105]. Although the exact etiology of BD is still unclear, it has been reported that IL-1 is a proinflammatory cytokine [106] which can be increased in patients with BD. Zou and Guan [106] reported increased susceptibility to BD due to polymorphisms in the IL-1-related gene. Cantarini et al. [50] reported on the effects of anakinra in patients with conventional therapy-resistant BD. Nine patients were refractory to anti-TNF agents and conventional therapy, and most of them received anakinra (100 mg daily) with low doses of corticosteroids. Eight of nine patients had symptom improvement after using anakinra; however, the eight had recurrence over time and 15% of patients experienced adverse events (AEs) [50]. Although the efficacy of anakinra has been shown in a few studies, the long-term effect is unclear and most of the studies were not limited to patients with intestinal BD; therefore, more studies are required to clarify the relationship between recurrence and dosage, and to determine the exact efficacy in intestinal BD.

 Canakinumab

Canakinumab is a fully human anti-IL-1β antibody which could also be considered as a therapeutic option for resistant or refractory BD [51,60]. Vitale et al. [51] reported successful use of canakinumab in three patients with BD. Two patients had GI involvement and had failed to respond to conventional therapy such as sulfasalazine, methotrexate, cyclosporin, azathioprine, corticosteroids, anti-TNF agents, and anakinra (100 mg/day). Therefore, canakinumab was used at a dose of 150 mg every 6 (case 2) and/or 8 weeks (case 1) by subcutaneous injection, which led to clinical improvement and achieved clinical remission [51]. Recently, Emmi et al. [60] reported outcomes on the use of IL-inhibitors including canakinumab in patients with BD. Three patients used canakinumab (150 mg every 6 to 8 weeks for 12 months) and achieved complete remission at 12 months with no serious AEs (Table 2) [60]. However, the study was not limited to intestinal BD. Therefore, further studies are required.

 Tocilizumab

Tocilizumab is a recombinant-humanized anti-human IL-6 receptor monoclonal antibody [107]. IL-6 is a cytokine that plays an important role in immune function, and some studies have shown that circulating IL-6 level is elevated in patients with BD [52,108]. Deroux et al. [52] reported four experienced cases using tociliziumab and reviewed the cases in the literature to evaluate the safety and efficacy of tocilizumab in patients with refractory BD. Three of the four patients were BD patients with GI involvement and all patients were previously unresponsive to conventional therapy. All patients received tocilizumab (8 mg/kg every 4 weeks) and experienced significantly decreased disease activity [52]. However, tocilizumab failed in clinical trials for patients with CD because of serious adverse effects such as bowel perforation and abscess [109,110]. This is because IL-6 is known to play an important role in stimulating intestinal epithelial proliferation and repairing intestinal injury [111]. Therefore, we should pay attention to the use of tocilizumab in patients with intestinal BD in whom intestinal perforation is one of the important complications, and further studies are required.

 CONCLUSIONS

Although intestinal BD is not common, GI manifestation occurs more frequently in East Asia, including Korea, than in the Mediterranean region [2,36,112,113]. In addition, complications such as intestinal perforation and bleeding considerably increase morbidity and mortality [2,3]; therefore, it is important to manage and treat patients properly. Appropriate medical therapy in intestinal BD is important to prevent poor outcomes such as frequently recurred ulcer, surgery, complications, and mortality. 5-ASA, corticosteroids, immunomodulators, and anti-TNF agents have been proposed as standard therapy in intestinal BD. However, there is still no definite guideline for established medical therapy because of its rarity and lack of clinical data. Studies on the pathogenesis of BD have been carried out, and studies on new therapies such as the therapeutic effects of related biological agents have been actively under investigation. We anticipate more advanced treatment strategies and established treatment guidelines in intestinal BD in the near future.

No potential conflict of interest relevant to this article was reported.

This study was supported by a grant (NRF-2017R1A1A1A05001011) from the Basic Science Research Program through the National Research Foundation of Korea, which is funded by the Ministry of Science, ICT, and Future Planning; and a faculty research grant (2012-31-0477) from the Department of Internal Medicine, Yonsei University College of Medicine.

 REFERENCES HisamatsuT HayashidaM Treatment and outcomes: medical and surgical treatment for intestinal Behcet’s disease Intest Res 2017 15 318 327 CheonJH KimWH An update on the diagnosis, treatment, and prognosis of intestinal Behcet’s disease Curr Opin Rheumatol 2015 27 24 31 LeeHJ CheonJH Optimal diagnosis and disease activity monitoring of intestinal Behcet’s disease Intest Res 2017 15 311 317 KimDH CheonJH Intestinal Behcet’s disease: a true inflammatory bowel disease or merely an intestinal complication of systemic vasculitis? Yonsei Med J 2016 57 22 32 ParkJJ KimWH CheonJH Outcome predictors for intestinal Behcet’s disease Yonsei Med J 2013 54 1084 1090 JungYS CheonJH ParkSJ HongSP KimTI KimWH Clinical course of intestinal Behcet’s disease during the first five years Dig Dis Sci 2013 58 496 503 BayraktarY OzaslanE Van ThielDH Gastrointestinal manifestations of Behcet’s disease J Clin Gastroenterol 2000 30 144 154 GriggEL KaneS KatzS Mimicry and deception in inflammatory bowel disease and intestinal Behcet disease Gastroenterol Hepatol (N Y) 2012 8 103 112 JungYS YoonJY LeeJH Prognostic factors and long-term clinical outcomes for surgical patients with intestinal Behcet’s disease Inflamm Bowel Dis 2011 17 1594 1602 BaekSJ KimCW ChoMS Surgical treatment and outcomes in patients with intestinal Behcet disease: long-term experience of a single large-volume center Dis Colon Rectum 2015 58 575 581 HatemiG SilmanA BangD EULAR recommendations for the management of Behcet disease Ann Rheum Dis 2008 67 1656 1662 KobayashiK UenoF BitoS Development of consensus statements for the diagnosis and management of intestinal Behcet’s disease using a modified Delphi approach J Gastroenterol 2007 42 737 745 HisamatsuT UenoF MatsumotoT The 2nd edition of consensus statements for the diagnosis and management of intestinal Behcet’s disease: indication of anti-TNFα monoclonal antibodies J Gastroenterol 2014 49 156 162 LeeHW KimWH CheonJH The medical treatments of intestinal Behcet’s disease: an update Intest Res 2013 11 155 160 LimWC WangY MacDonaldJK HanauerS Aminosalicylates for induction of remission or response in Crohn’s disease Cochrane Database Syst Rev 2016 7 CD008870 YooHM HanKH KimPS Clinical features of intestinal Behet’s disease and therapeutic effects of sulfasalazine Korean J Gastroenterol 1997 29 465 472 MatsukawaM YamasakiT KoudaT KuriharaM Endoscopic therapy with absolute ethanol for postoperative recurrent ulcers in intestinal Behcet’s disease, and simple ulcers J Gastroenterol 2001 36 255 258 JungYS HongSP KimTI KimWH CheonJH 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 46 e38 e45 HatemiI EsatogluSN HatemiG ErzinY YaziciH CelikAF Characteristics, treatment, and long-term outcome of gastrointestinal involvement in Behcet’s syndrome: a strobe-compliant observational study from a dedicated multidisciplinary center Medicine (Baltimore) 2016 95 e3348 NakaseH OkazakiK KawanamiC Therapeutic effects on intestinal Behcet’s disease of an intravenous drug delivery system using dexamethasone incorporated in lipid emulsion J Gastroenterol Hepatol 2001 16 1306 1308 TodaK ShiratoriY YasudaM Therapeutic effect of intraarterial prednisolone injection in severe intestinal Behcet’s disease J Gastroenterol 2002 37 844 848 YasuoM MiyabayashiH OkanoT AokiH IchikawaK HiroseY Successful treatment with corticosteroid in a case of Behcet’s syndrome with multiple esophageal ulcerations Intern Med 2003 42 696 699 ParkJJ CheonJH MoonCM W1321 long-term clinical outcomes after the first course of corticosteroid therapy in patients with moderate to severe intestinal Behcet’s disease Gastroenterology 2010 138 5 Suppl 1 S698 S699 ChoiIJ KimJS ChaSD Long-term clinical course and prognostic factors in intestinal Behcet’s disease Dis Colon Rectum 2000 43 692 700 LeeHW CheonJH LeeHJ Postoperative effects of thiopurines in patients with intestinal Behcet’s disease Dig Dis Sci 2015 60 3721 3727 JungYS CheonJH HongSP KimTI KimWH Clinical outcomes and prognostic factors for thiopurine maintenance therapy in patients with intestinal Behcet’s disease Inflamm Bowel Dis 2012 18 750 757 ParkMS KimDH KimDH Leukopenia predicts remission in patients with inflammatory bowel disease and Behcet’s disease on thiopurine maintenance Dig Dis Sci 2015 60 195 204 MatsumuraK NakaseH ChibaT Efficacy of oral tacrolimus on intestinal Behcet’s disease Inflamm Bowel Dis 2010 16 188 189 CantariniL StromilloML VitaleA Efficacy and safety of intravenous immunoglobulin treatment in refractory Behcet’s disease with different organ involvement: a case series Isr Med Assoc J 2016 18 238 242 BealesIL Gastrointestinal involvement in Behcet’s syndrome Am J Gastroenterol 1998 93 2633 YasuiK UchidaN AkazawaY Thalidomide for treatment of intestinal involvement of juvenile-onset Behcet disease Inflamm Bowel Dis 2008 14 396 400 SayarliogluM KotanMC TopcuN BayramI ArslanturkH GulA Treatment of recurrent perforating intestinal ulcers with thalidomide in Behcet’s disease Ann Pharmacother 2004 38 808 811 LeeHJ CheonJH LeeKJ Clinical experience of thalidomide in the treatment of Korean patients with intestinal Behcet’s disease: pilot experience in a single center Intest Res 2010 8 63 69 SontaT ArakiY KoubokawaM The beneficial effect of mesalazine on esophageal ulcers in intestinal Behcet’s disease J Clin Gastroenterol 2000 30 195 199 SalehZ ArayssiT Update on the therapy of Behcet disease Ther Adv Chronic Dis 2014 5 112 134 KaklamaniVG VaiopoulosG KaklamanisPG Behcet’s disease Semin Arthritis Rheum 1998 27 197 217 SakaneT TakenoM SuzukiN InabaG Behcet’s disease N Engl J Med 1999 341 1284 1291 LopalcoG RiganteD VeneritoV Update on the medical management of gastrointestinal Behcet’s disease Mediators Inflamm 2017 2017 1460491 NarumS WestergrenT KlempM Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis BMJ Open 2014 4 e004587 ParkJ CheonJH ParkYE Risk factors and outcomes of acute lower gastrointestinal bleeding in intestinal Behcet’s disease Int J Colorectal Dis 2017 32 745 751 ShararaAI When to start immunomodulators in inflammatory bowel disease? Dig Dis 2016 34 125 131 KimB ParkSJ HongSP CheonJH KimTI KimWH Overlooked management and risk factors for anemia in patients with intestinal Behcet’s disease in actual clinical practice Gut Liver 2015 9 750 5 FeuersteinJD NguyenGC KupferSS Falck-YtterY SinghS American Gastroenterological Association Institute Clinical Guidelines Committee American Gastroenterological Association Institute Guideline on therapeutic drug monitoring in inflammatory bowel disease Gastroenterology 2017 153 827 834 IwataS SaitoK YamaokaK Efficacy of combination therapy of anti-TNF-α antibody infliximab and methotrexate in refractory entero-Behcet’s disease Mod Rheumatol 2011 21 184 191 LeeJH CheonJH JeonSW Efficacy of infliximab in intestinal Behcet’s disease: a Korean multicenter retrospective study Inflamm Bowel Dis 2013 19 1833 1838 InoueN KobayashiK NaganumaM Long-term safety and efficacy of adalimumab for intestinal Behcet’s disease in the open label study following a phase 3 clinical trial Intest Res 2017 15 395 401 HibiT HirohataS KikuchiH 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 95 e3863 TanidaS InoueN KobayashiK Adalimumab for the treatment of Japanese patients with intestinal Behcet’s disease Clin Gastroenterol Hepatol 2015 13 940 948 MaD ZhangCJ WangRP WangL YangH Etanercept in the treatment of intestinal Behcet’s disease Cell Biochem Biophys 2014 69 735 739 CantariniL VitaleA ScaliniP Anakinra treatment in drug-resistant Behcet’s disease: a case series Clin Rheumatol 2015 34 1293 1301 VitaleA RiganteD CasoF Inhibition of interleukin-1 by canakinumab as a successful mono-drug strategy for the treatment of refractory Behcet’s disease: a case series Dermatology 2014 228 211 214 DerouxA ChiquetC BouilletL Tocilizumab in severe and refractory Behcet’s disease: four cases and literature review Semin Arthritis Rheum 2016 45 733 737 HassardPV BinderSW NelsonV VasiliauskasEA Anti-tumor necrosis factor monoclonal antibody therapy for gastrointestinal Behcet’s disease: a case report Gastroenterology 2001 120 995 999 NaganumaM SakurabaA HisamatsuT Efficacy of infliximab for induction and maintenance of remission in intestinal Behcet’s disease Inflamm Bowel Dis 2008 14 1259 1264 TravisSP CzajkowskiM McGovernDP WatsonRG BellAL Treatment of intestinal Behcet’s syndrome with chimeric tumour necrosis factor alpha antibody Gut 2001 49 725 728 ByeonJS ChoiEK HeoNY Antitumor necrosis factor-alpha therapy for early postoperative recurrence of gastrointestinal Behcet’s disease: report of a case Dis Colon Rectum 2007 50 672 676 TanidaS MizoshitaT NishieH Long-term efficacy of adalimumab in patients with intestinal Behcet’s disease: eight consecutive cases J Clin Med Res 2016 8 334 337 De CassanC De VroeyB DussaultC HachullaE BucheS ColombelJF Successful treatment with adalimumab in a familial case of gastrointestinal Behcet’s disease J Crohns Colitis 2011 5 364 368 VitaleA EmmiG LopalcoG Adalimumab effectiveness in Behcet’s disease: short and long-term data from a multicenter retrospective observational study Clin Rheumatol 2017 36 451 455 EmmiG TalaricoR LopalcoG Efficacy and safety profile of anti-interleukin-1 treatment in Behcet’s disease: a multicenter retrospective study Clin Rheumatol 2016 35 1281 1286 KramMT MayLD GoodmanS MolinasS Behcet’s ileocolitis: successful treatment with tumor necrosis factor-alpha antibody (infliximab) therapy. Report of a case Dis Colon Rectum 2003 46 118 121 UgrasM ErtemD CelikelC PehlivanogluE Infliximab as an alternative treatment for Behcet disease when other therapies fail J Pediatr Gastroenterol Nutr 2008 46 212 215 MaruyamaY HisamatsuT MatsuokaK A case of intestinal Behcet’s disease treated with infliximab monotherapy who successfully maintained clinical remission and complete mucosal healing for six years Intern Med 2012 51 2125 2129 KinoshitaH KunisakiR YamamotoH Efficacy of infliximab in patients with intestinal Behcet’s disease refractory to conventional medication Intern Med 2013 52 1855 1862 IdeguchiH SudaA TakenoM Gastrointestinal manifestations of Behcet’s disease in Japan: a study of 43 patients Rheumatol Int 2014 34 851 856 ShimizuY TakedaT MatsumotoR Clinical efficacy of adalimumab for a postoperative marginal ulcer in gastrointestinal Behcet disease Nihon Shokakibyo Gakkai Zasshi 2012 109 774 780 LeeJH KimTN ChoiST Remission of intestinal Behcet’s disease treated with anti-tumor necrosis factor alpha monoclonal antibody (Infliximab) Korean J Intern Med 2007 22 24 27 MatsuokaK SaitoE FujiiT Tacrolimus for the treatment of ulcerative colitis Intest Res 2015 13 219 226 IsaacsA LindenmannJ Virus interference. I. The interferon Proc R Soc Lond B Biol Sci 1957 147 258 267 AlpsoyE DurusoyC YilmazE Interferon alfa-2a in the treatment of Behcet disease: a randomized placebo-controlled and double-blind study Arch Dermatol 2002 138 467 471 KotterI GunaydinI ZierhutM StubigerN The use of interferon alpha in Behcet disease: review of the literature Semin Arthritis Rheum 2004 33 320 335 ZouboulisCC OrfanosCE Treatment of Adamantiades-Behcet disease with systemic interferon alfa Arch Dermatol 1998 134 1010 1016 TsambaosD EichelbergD GoosM Behcet’s syndrome: treatment with recombinant leukocyte alpha-interferon Arch Dermatol Res 1986 278 335 336 GrimbacherB WengerB DeibertP NessT KoetterI PeterHH Loss of vision and diarrhoea Lancet 1997 350 1818 MonastirliA ChroniE GeorgiouS Interferon-α treatment for acute myelitis and intestinal involvement in severe Behcet’s disease QJM 2010 103 787 790 MatsudaS KoyasuS Mechanisms of action of cyclosporine Immunopharmacology 2000 47 119 125 OzdalPC OrtacS TaskintunaI FiratE Long-term therapy with low dose cyclosporin A in ocular Behcet’s disease Doc Ophthalmol 2002 105 301 312 OzyazganY YurdakulS YaziciH Low dose cyclosporin A versus pulsed cyclophosphamide in Behcet’s syndrome: a single masked trial Br J Ophthalmol 1992 76 241 243 HooperJA Intravenous immunoglobulins: evolution of commercial IVIG preparations Immunol Allergy Clin North Am 2008 28 765 778 ShekLP LeeYS LeeBW LehmanTJ Thalidomide responsiveness in an infant with Behcet’s syndrome Pediatrics 1999 103 6 Pt 1 1295 1297 KariJA ShahV DillonMJ Behcet’s disease in UK children: clinical features and treatment including thalidomide Rheumatology (Oxford) 2001 40 933 938 MoreiraAL SampaioEP ZmuidzinasA FrindtP SmithKA KaplanG Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation J Exp Med 1993 177 1675 1680 HatemiI HatemiG PamukON ErzinY CelikAF TNF-alpha antagonists and thalidomide for the management of gastrointestinal Behcet’s syndrome refractory to the conventional treatment modalities: a case series and review of the literature Clin Exp Rheumatol 2015 33 6 Suppl 94 S129 S137 AtasH CemilBC CanpolatF GonulM The effect of colchicine on mean platelet volume in Behcet’s disease Ann Clin Lab Sci 2015 45 545 549 YurdakulS MatC TuzunY A double-blind trial of colchicine in Behcet’s syndrome Arthritis Rheum 2001 44 2686 2692 AktulgaE AltacM MuftuogluA A double blind study of colchicine in Behcet’s disease Haematologica 1980 65 399 402 HatemiG SilmanA BangD Management of Behcet disease: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for the management of Behcet disease Ann Rheum Dis 2009 68 1528 1534 SoysalT SalihogluA EsatogluSN Bone marrow transplantation for Behcet’s disease: a case report and systematic review of the literature Rheumatology (Oxford) 2014 53 1136 1141 YamatoK Successful cord blood stem cell transplantation for myelodysplastic syndrome with Behcet disease Int J Hematol 2003 77 82 85 RossiG MorettaA LocatelliF Autologous hematopoietic stem cell transplantation for severe/refractory intestinal Behcet disease Blood 2004 103 748 750 NambaK SonodaKH KitameiH Granulocytapheresis in patients with refractory ocular Behcet’s disease J Clin Apher 2006 21 121 128 GulA Behcet’s disease: an update on the pathogenesis Clin Exp Rheumatol 2001 19 5 Suppl 24 S6 S12 LeeCK KimHJ Pathogenesis and treatment of intestinal Behcet’s disease Korean J Gastroenterol 2007 50 3 8 ValletH RiviereS SannaA Efficacy of anti-TNF alpha in severe and/or refractory Behcet’s disease: multicenter study of 124 patients J Autoimmun 2015 62 67 74 KimuraM TsujiY IwaiM Usefulness of adalimumab for treating a case of intestinal Behcet’s disease with trisomy 8 myelodysplastic syndrome Intest Res 2015 13 166 169 IshiokaM OnochiK SuzukiY Successful treatment with infliximab for refractory para-ileostomal ulceration in a patient with Behcet’s disease Clin J Gastroenterol 2015 8 193 196 ZouJ JiDN CaiJF GuanJL BaoZJ Long-term outcomes and predictors of sustained response in patients with intestinal Behcet’s disease treated with infliximab Dig Dis Sci 2017 62 441 447 ParkJ CheonJH Could adalimumab be used safely and effectively in intestinal Behcet’s disease refractory to conventional therapy? Intest Res 2017 15 263 265 WuKC RanZH GaoX Adalimumab induction and maintenance therapy achieve clinical remission and response in Chinese patients with Crohn’s disease Intest Res 2016 14 152 163 HaraouiB BykerkV Etanercept in the treatment of rheumatoid arthritis Ther Clin Risk Manag 2007 3 99 105 CantariniL TinazziI CaramaschiP BellisaiF BrognaA GaleazziM Safety and efficacy of etanercept in children with juvenile-onset Behcets disease Int J Immunopathol Pharmacol 2009 22 551 555 SandbornWJ HanauerSB KatzS Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial Gastroenterology 2001 121 1088 1094 Van den BrandeJM BraatH van den BrinkGR Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease Gastroenterology 2003 124 1774 1785 O’TooleA LucciM KorzenikJ Inflammatory bowel disease provoked by etanercept: report of 443 possible cases combined from an IBD referral center and the FDA Dig Dis Sci 2016 61 1772 1774 MertensM SinghJA Anakinra for rheumatoid arthritis Cochrane Database Syst Rev 2009 1 CD005121 ZouJ GuanJL Interleukin-1-related genes polymorphisms in Turkish patients with Behcet disease: a meta-analysis Mod Rheumatol 2014 24 321 326 KoryurekOM KalkanG A new alternative therapy in dermatology: tocilizumab Cutan Ocul Toxicol 2016 35 145 152 HamzaouiK HamzaouiA GuemiraF BessioudM HamzaM AyedK Cytokine profile in Behcet’s disease patients. Relationship with disease activity Scand J Rheumatol 2002 31 205 210 CoskunM VermeireS NielsenOH Novel targeted therapies for inflammatory bowel disease Trends Pharmacol Sci 2017 38 127 142 DaneseS VermeireS HellsternP 764 Results of andante, a randomized clinical study with an anti-IL6 antibody (PF-04236921) in subjects with Crohn’s disease who are anti-TNF inadequate responders Gastroenterology 2016 150 4 Suppl 1 S155 KuhnKA ManieriNA LiuTC StappenbeckTS IL-6 stimulates intestinal epithelial proliferation and repair after injury PLoS One 2014 9 e114195 YaziciY YurdakulS YaziciH Behcet’s syndrome Curr Rheumatol Rep 2010 12 429 435 YiSW CheonJH KimJH The prevalence and clinical characteristics of esophageal involvement in patients with Behcet’s disease: a single center experience in Korea J Korean Med Sci 2009 24 52 56 Figure and Tables

A proposed algorithm for the treatment of intestinal Behçet’s disease. Adapted from Lee et al. [14. 5-ASA, 5-aminosalicylic acid; anti-TNF, anti-tumor necrosis factor.

Studies of medical treatments of intestinal BD: 5-ASA, corticosteroids, immunomodulators, thalidomide, IVIG

Drugs Study Type of study No. of patients or articles Dose of medication Indication/Outcomes
5-ASA Yoo et al. (1997) [16] Case report Total: 31 Sulfasalazine user: 14 1 g/day → 2–4 g/day → 1–2 g/day (maintenance) Symptom improved: 79%
Sonta et al. (2000) [34] Case report Total: 1 1,200 mg/day Lesion: esophageal ulcers
Positive clinical efficacy
Jung et al. (2012) [18] Retrospective cohort study Total: 292 - Maintaining remission; mild-to-moderate intestinal BD
Clinical remission: 143
Hisamatsu et al. (2014) [13] Japanese consensus statements Relevant articles: 15 5-ASA: 2.25–3.00 g/day Indication: maintenance therapy
Sulfasalazine: 3–4 g/day
Hatemi et al. (2016) [19] Retrospective cohort study Total: 60 - Remission: 10 of 16 patients (62.5%)
5-ASA user: 16 Disease free duration: 89.3 ± 64.5 months
Corticosteroids Nakase et al. (2001) [20] Case report Total: 2 Case 1: PD 30 mg → 40 mg → no improved: IV 2.5 mg dexamethasone every 2 weeks Case 1: after IV corticosteroid use, oral, abdominal pain improved & inflammatory parameters: normalized
Case 2: PD 40 mg → 25 mg/ day → recur: IV 2.5 mg limethasone every 2 weeks Case 2: after IV corticosteroid use, abdominal symptoms disappeared & inflammatory parameters: normalized
Toda et al. (2002) [21] Case report Total: 1 1 g/day of IV methylpred- nisolone, 3 days → IV PD 40 mg/day → 20 mg PD IA injection Disease remission
Yasuo et al. (2003) [22] Case report Total: 1 PD 0.5 mg/kg daily Lesion: esophageal ulcer
Symptom improved & esophagoscopy after 4 weeks: mucosa healing
Park et al. (2010) [23] Retrospective cohort study Total: 54 Median dosage: 0.58 mg/kg (range, 0.39–1.20) Clinical remission: 25 (46.3%)
1 Year treatment response: 26 (48.1%)
Cumulative probability of surgery: 17.5% at 1 year; 49.1% at 3 years
Hisamatsu et al. (2014) [13] Japanese consensus statements Relevant articles: 15 The initial dose of corticosteroids: 0.5–1 mg/kg/day for 1–2 weeks Indication: induction therapy
Clinical improvement → tapered by 5 mg every week & stopped Severe symptoms (i.e., abdominal pain, diarrhea, GI bleeding)
Immunomodulators Choi et al. (2000) [24] Retrospective cohort study Total: 43 AZA: 50 mg/day Re-operation rates: decreased in AZA user group (7% vs. 25% at 2 years; 25% vs. 47% at 5 years) maintenance ther- apy in patients who require surgery
Remission: 16 (38%)
Matsumura et al. (2010) [28] Case report Total: 1 Oral tacrolimus: 10–12 ng/mL (induction) → 5–10 ng/mL (maintenance) Refractory case to 5-ASA, steroid, immunomodulators, thalidomide, infliximab
Remission: 33 months after starting tacrolimus
Jung et al. (2012) [26] Retrospective cohort study Total: 272 AZA: Initial dose 25 or 50 mg daily → 2.0–2.5 mg/kg (gradually increased every 2–4 weeks) Indication: maintenance therapy
AZA user: 67 (24.6%) Remission: 39 (58.2%) of 67 (maintaining medically or surgically induced remission)
6-MP: Initial dose 0.5 → 1.0–1.5 mg/kg (gradually increased) Clinical relapse: 13 (33.3%) of 39
Relapse risk factors: younger age (< 25 years) at diagnosis, lower hemoglobin level (< 11 g/dL)
Hisamatsu et al. (2014) [13] Japanese consensus statements Relevant articles: 15 AZA: Initial dose 25–50 mg/day Indication: corticosteroid- dependent, corticosteroid- resistant, or anti-TNF-α mAb-resistant
Lee et al. (2015) [25] Retrospective cohort study Total: 77 AZA: 2–2.5 mg/kg/day Postoperative recurrence rate: lower in patients who received post-operative thiopurines than 5-ASA user (p = 0.050)
Thiopurine user: 27 (35.1%) 6-MP: 1–1.5 mg/kg/day
Park et al. (2015) [27] Retrospective cohort study Total: 196 (IBD) AZA: 2–2.5 mg/kg/day Cumulative relapse-free survival rate: higher in the leukopenic group than in the non-leukopenic group (p < 0.001)
Intestinal BD: 83 6-MP: converted to an equivalent AZA dose by multiplying by 2.08
Hatemi et al. (2016) [19] Retrospective cohort study Total: 44 AZA Remission and no relapse: 24 (65%)
Mean follow-up duration: 68.6 ± 43.6 months
Park et al. (2017) (unpublished data) Retrospective cohort study Total: 10 MTX: various dose (subcutaneously & oral) Steroid free remission: 3 patients (30%) at 3 months, 4 patients (50%) at 6 months
MTX monotherapy: 4 MTX + ADA: 6 ADA: 160 mg in week 0, 80 mg in week 2, and 40 mg every other week CRP levels: significantly decreased at 6 months com- pared with the baseline (p = 0.039).
Thalidomide Sayarlioglu et al. (2004) [32] Case report Total: 1 100 mg/day Lesion: recurrent intestinal perforation cecum, transverse colon, terminal ileum
Remission: 4 months follow-up
Yasui et al. (2008) [31] Case report Total: 7 Initial dose: 2 mg/kg/day → if necessary, 3 mg/kg/day (increase) or 1–0.5 mg/kg/ day (decreased) Inclusion case: conventional therapy failure, severe steroid toxicity
Clinical improvement: all patients
Lee et al. (2010) [33] Case report Total: 4 Case 1: 200 mg/day Inclusion case: refractory to steroid, 5-ASA, immunomodulators
Case 2: 100 mg/day Clinical improvement: 3 of 4
Case 3: 100 mg/day
Case 4: 50 → 100 mg/day
IVIG Beales (1998) [30] Case report (letters) Total: 1 400 mg/kg/day for 5 days Lesion: oral, genital ulcer, uveitis, acneiform rash, arthralgia, intestine
Previous therapy: cyclosporine, thalidomide maintenance → IV methyl PD, oral mesala- mine add → no effect
Clinical improvement: after 30 months
Cantarini et al. (2016) [29] Case report Total: 4 Case 3: 400 mg/kg/day for 5 days per month Lesion: mucocutaneous, ocular, neurological, GI
GI BD: 1 Previous therapy: prednisone, cyclosporine, AZA, mesalazine
Clinical improvement: after 14 months

BD, Behçet’s disease; 5-ASA, 5-aminosalicylic acid; IVIG, intravenous immunoglobulin; PD, prednisolone; IV, intravenous; IA, intra-arterial; GI, gastrointestinal; AZA, azathioprine; 6-MP, 6-mercaptopurine; TNF-α, tumor necrosis factor α; mAb, monoclonal antibody; IBD, inflammatory bowel disease; MTX, methotrexate; ADA, adalimumab; CRP, C-reactive protein.

Studies of medical treatment of intestinal BD: anti-TNF agents and biologics

Drugs Study Type of study No. of patients Dose of medication Outcomes
Infliximab Hassard et al. (2001) [53] Case report Total: 1 5 mg/kg, at 0, 2, 7, and 23 weeks Disease activity: CDAI 270 (baseline) → 13 (at 2 weeks)
Remission: after 10 weeks
Travis et al. (2001) [55] Case report Total: 2 Case 1: 3 mg/kg (dose reduced because of recent sepsis) Case 1: CRP 72 mg/L → 45 (on steroids) → 70 (sepsis) → 29 (on infliximab) → 12 (12 weeks later)
Case 2: 5 mg/kg Case 2: CRP 109 mg/L → 25 (on steroids) → 73 (recur) → 53→ < 6 (on infliximab)
Kram et al. (2003) [61] Case report Total: 1 5 mg/kg dose over a 6-week period (3 infusions) CRP 18.7 → normal (on infliximab) → 22.5 mg/mL (relapse) → normal (on infliximab + MTX)
Lee et al. (2007) [67] Case report Total: 1 5 mg/kg CRP: 70 → 6.7 mg/L (on infliximab) CDAI: 183 → 88 (on infliximab)
HBI: 10 → 2 (on infliximab)
Byeon et al. (2007) [56] Case report Total: 1 5 mg/kg Lesion: unhealed anastomosis site, early recurrent ulcers after a distal ileocecectomy
Remission: on endoscopy at 15 days after the infliximab infusion
Ugras et al. (2008) [62] Case report Total: 1 5 mg/kg at weeks 0, 2, and 6 Remission: 7 months
Naganuma et al. (2008) [54] Case report Total: 6 5 mg/kg at 0, 2, 6 weeks (induction) & every 8 weeks (maintain) Clinical remission: 4 of 6 (induction), 4 of 4 (maintain)
Surgery: 2 of 6 (case 5-ileum ulceration, case 6-ileum ulceration with internal fistula)
Maruyama et al. (2012) [63] Case report Total: 1 5 mg/kg at 0, 2, and 6 weeks (induction) & every 8 weeks (maintain) Remission: 6 years
Iwata et al. (2011) [44] Retrospective study Total: 10 Infliximab (3 mg/kg at 0, 2, and 6 weeks & every 8 weeks) + MTX (3 mg/kg to 200 mg) Short-term response: improved clinical symptoms & decreased ESR, CRP within 4 weeks
Long-term response: remain remission at 6, 12, and 24 months
Lee et al. (2013) [45] Retrospective multicenter study Total: 28 5 mg/kg at weeks 0,2, and 6 & every 8 weeks Moderate to severe disease
Clinical response: 2 weeks (75%), 4 (64.3%), 30 (50%), 54 (39.1%)
Clinical remission: 2 (32.1%), 4 (28.6%), 30 (46.2%), 54 (39.1%)
Biological response rate: 2 (82.1%), 4 (57.1%), 30 (53.8%), 54 (43.5%)
Sustained response: 15 (53.6%)
Kinoshita et al. (2013) [64] Retrospective study Total: 15 5 mg/kg at 0, 2 and 6 weeks & every 8 weeks Short-term response at week 10: 12 of 15 (80%)
Clinical remission: 8 of 15 (53%)
Clinical response: 4 of 15 (27%)
Long-term response after 12 months: 7 of 11 (64%)
Clinical remission: 3 of 11 (27%)
Clinical response: 4 of 11 (36%)
After 24 months: 4 of 8 (50%)
Clinical remission & response: 3 of 8 (38%)
Ideguchi et al. (2014) [65] Retrospective study Total: 43 Infliximab user: 7 - 1 of 7: remission
2 of 7: insufficient efficacy
1 of 7: AE, sepsis
2 of 7: unchanged
1 of 7: for concurrent rheumatoid arthritis
Hibi et al. (2016) [47] Prospective, open-label, single-arm phase 3 study Total: 18 Intestinal BD (11), NBD (3), VBD (4) 5 mg/kg at weeks 0, 2, 6 (induction) & every 8 weeks (maintain) until week 46 Complete responder: 61% (11 of 18)
10 mg/kg (patients who showed inad- equate responses after week 30) Intestinal BD: improvement in clinical symptoms & decrease in CRP levels after week 2
ADA De Cassan et al. (2011) [58] Case report Total: 2 Induction dose of 160 mg subcutaneously 80 mg 2 weeks later Intestinal BD
Maintenance: 40 mg every other week Repeated steroid-dependent flares and failure of maintenance
Clinical response, remission: 1-year follow-up
Shimizu et al. (2012) [66] Case report Total: 1 40 mg every other week Lesion: marginal ulcer after surgery (total gastrectomy) in stomach
Improvement: after 3 months
Tanida et al. (2015) [48] Multicenter, open-label, uncontrolled study Total: 20 160 mg at the start Intestinal BD
80 mg at 2 weeks Symptom relief & endoscopic assessment scores of 1 or lower at week 24 of treatment: 9 of 20 (45%)
40 mg, every other week & 80 mg for inadequate response/flare for 52 weeks At week 52: 12 patients (60%)
Tanida et al. (2016) [57] Case report Total: 8 ADA: 160 mg in week 0, 80 mg in week 2, 40 mg every other week over 52 weeks Refractory intestinal BD (failed to respond to conventional treatments)
Primary outcome
MI: at 10 weeks; 5 of 8 (62.5%); at 52 weeks; 6 of 8 (75%)
Improvement of Global GI symptoms to score 0: at 10 weeks; 3 of 8 (37.5%); at 52 weeks; 4 of 8 (50%)
Vitale et al. (2017) [59] Multicenter retrospective observational study Total: 100 40 mg subcutane- ously every 14 days (5 patients: initially treated with 40 mg every 7 days) GI involvement: 47 of 100
At 12 weeks: ADA induced clinical efficacy in 81 patients
At 24 months: 67 of 100 patients were still on ADA therapy
Combination therapy with DMARDs: no significantly superior to monotherapy
Inoue et al. (2017) [46] Open label study following a phase 3 clinical trial Total: 20 Initiated at 160 mg; 2 weeks, 80 mg, followed by 40 mg every other week until the study end Intestinal BD
Study completion: 15 Incidence of AEs through week 100; 544.4 events/100 person-years
MI at weeks 52: 60.0%
MI at weeks 100: 40.0%
CR at weeks 52: 20.0%
CR at weeks 100: 15.0%
Etanercept Ma et al. (2014) [49] Retrospective comparative study based on observation Total: 54 Etanercept, subcutaneously at the dose of 25 mg twice a week Intestinal BD
Conventional therapy: 35 Primary outcome: 4 criteria for diagnosis of BD
Etanercept: 19 Remission rate, ulcer healing, recovery rate of ESR and CRP: significantly higher in Etanercept group than conventional group.
Less adverse reactions in intestinal BD: etanercept group
ANA/CAN Cantarini et al. (2015) [50] Case report Total: 9 ANA, 100 or 150 mg/day GI involvement BD: 3 of 9
With prednisone (5–25 mg/day) On refractory to TNF blockers, standardized therapies
Response to ANA: 8 of 9
Relapse: 8 of 9
Remain completely under control on ANA monotherapy: 1 patient
Emmi et al. (2016) [60] Retrospective study Total: 30 ANA, 100 mg/day, subcutaneously GI involvement BD: 13% (4 of 30)
ANA: 27 CAN, 150 mg, subcutaneously every 6–8 weeks CR at 12 months: 13 of 27
CAN: 3 Maintain therapy: 6 of 13
Maintained the same drug: 1 of 6
Shifted from ANA to CAN: 6
AE: ANA, 4 of 27 (15%); CAN, 0 of 27
Vitale et al. (2014) [51] Case report Total: 3 CAN, 150 mg every 6 weeks Case 1: GI involve (+), symptom-free, 6-month follow-up
Case 2: GI involve (+), symptom-free, 12-month follow-up
Case 3: GI involve (–), symptom-free, 6-month follow-up
Tocilizumab Deroux et al. (2015) [52] Case report & literature review Total: 15 8 mg/kg every 4 weeks or 2 weeks Refractory BD
Case: 4 GI involvement: 3 of 4 (case)/1 of 11 (literature)
Literature review related case: 11 In 4 cases: BD activity decreased significantly
In literature review (11 previous cases): 8 of 11, improvement; 3 of 11, without efficacy

BD, Behçet’s disease; TNF, tumor necrosis factor; CDAI, Crohn’s Disease Activity Index; CRP, C-reactive protein; MTX, methotrexate; HBI, Harvey-Bradshaw Index; ESR, erythrocyte sedimentation rate; AE, adverse event; BD, Behçet’s disease; NBD, neurological Behçet’s disease; VBD, vascular Behçet’s disease; ADA, adalimumab; GI, gastrointestinal; DMARD, disease modifying anti-rheumatic drug; MI, marked improvement; CR, complete remission; ANA, anakinra; CAN, canakinumab.