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Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
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Jihye Park1, Jae Hee Cheon1,2
Correspondence to: Correspondence to: Jae Hee Cheon
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:
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gut Liver 2018;12(6):623-632. https://doi.org/10.5009/gnl17462
Published online May 24, 2018, Published date November 15, 2018
Copyright © Gut and Liver.
Intestinal Behçet’s disease is a rare, immune-mediated chronic intestinal inflammatory disease; therefore, clinical trials to optimize the management and treatment of patients are scarce. Moreover, intestinal Behçet’s disease is difficult to treat and often requires surgery because of the failure of conventional medical treatment. Administration of anti-tumor necrosis factor–α, a potential therapeutic strategy, is currently under active clinical investigation, and evidence of its effectiveness for both intestinal Behçet’s disease and inflammatory bowel diseases has been accumulating. Here, we review updated data on current experiences and outcomes after the administration of anti-tumor necrosis factor–α for the treatment of intestinal Behçet’s disease. In addition to infliximab and adalimumab, which are the most commonly used agents, we describe agents such as golimumab, etanercept, and certolizumab pegol, which have recently been shown to be effective in refractory intestinal Behçet’s disease. This review also discusses safety issues associated with anti-tumor necrosis factor–α, including vulnerability to infections and malignancy.
Keywords: Behcet syndrome, Intestinal Behcet’s disease, Anti-tumor necrosis factor alpha, Infliximab, Adalimumab
Behçet’s disease (BD) is a chronic recurring multisystemic vasculitic disorder involving recurrent oral ulcers; genital ulcers; ocular lesions; skin manifestations; arthritis; and vascular, neurologic, and intestinal involvement.1,2 Intestinal BD is diagnosed when a patient with BD has both dominant gastrointestinal symptoms and typical intestinal ulcerative lesions on objective examinations.3 The intestinal involvement of BD is rare, ranging 5% to 20%, and it is more prevalent in East Asian countries, including Korea and Japan.4 Typical intestinal ulceration of intestinal BD is oval in shape and deep with discrete border located in the ileocecal area.5 It can cause diarrhea, abdominal pain, gastrointestinal bleeding, or bowel perforation.6,7
Intestinal BD has a heterogeneous range of clinical courses and symptoms, and a gold standard therapy remains elusive. Research on intestinal BD is relatively scarce because of the rarity of this disease.8 Moreover, intestinal BD is often refractory to conventional treatment such as corticosteroids and immunomodulators; therefore, alternative therapies are needed.9 Currently, anti-tumor necrosis factor-α (anti-TNF-α), a potential therapeutic strategy, is being evaluated, and evidence for its effectiveness has been accumulating. In Japan, anti-TNF-α has received approval to be used for the treatment of intestinal BD in cases where existing treatments are inadequate.10,11 One TNF-α receptor fusion protein (etanercept), three anti-TNF-α monoclonal antibodies (infliximab, adalimumab, and golimumab), and one anti-TNF-α PEGylated antigen-binding fragment (certolizumab pegol) are currently approved as anti-TNF-α therapies for several immune-mediated disorders.12 This article reviews the progress in the management of intestinal BD, focusing on current anti-TNF-α usage and possible future perspectives.
The pathogenesis of intestinal BD is still unclear; in addition to genetic factors, immune dysfunction and multiple cytokines are associated with the development and progression of disease.13 Several data suggest a role of TNF-α in the pathogenesis of intestinal BD. Inflammation in intestinal BD is thought to be mediated by cytokines derived from T helper type 1 (Th1) lymphocytes, including TNF-α.14 T cells at the intestinal mucosal level produce a large concentration of TNF-α, and T cells induce inflammation leading to mucosal damage through abnormal cytokine production, especially during the active phase of the disease.15,16 Recently, Emmi
Infliximab is a chimeric monoclonal antibody biologic drug that was first demonstrated in 2001 as an effective new therapy for patients with steroid-dependent intestinal BD.23 Infliximab is currently one of the most frequently described biologic agents for patients with intestinal BD. Infliximab was infused at 0, 2, and 6 weeks and every 8 weeks thereafter at 3–5 mg/kg in most studies (Table 1).24–30 Hassard
Combination therapy of infliximab and methotrexate was administered to 10 Japanese patients with refractory intestinal BD who failed to respond to conventional therapy, and it provided short- and long-term efficacy and tolerability as assessed by abdominal computed tomography (CT) and colonoscopy.24 Intestinal manifestations, including tenderness and bleeding, disappeared within 3 months, and improvement was confirmed at only 2 weeks after the initiation of infliximab infusions in all seven patients assessed on abdominal CT. Ileocecal ulceration disappeared in five patients (50%) at 6 months and nine patients (90%) at 12 months, as confirmed by colonoscopy. In a multicenter retrospective study, the primary outcome was reported using the disease activity index of intestinal Behçet’s disease (DAIBD) score with 28 Korean patients with moderate to severe intestinal BD.25,38 The clinical response rates, defined as a decrease in the DAIBD score of 20 points or more from the baseline value, were 75.0%, 64.3%, 50.0%, and 39.1% at 2, 4, 30, and 54 weeks, respectively. Old age at diagnosis (≥40 years), female sex, longer disease duration (≥5 years), concomitant immunomodulator use, and achievement of remission at week 4 were predictive factors for a sustained response to infliximab treatment. This study was meaningful in that it was the first paper to evaluate the efficacy of biologics in intestinal BD using the DAIBD score. Infliximab was administered to 15 Japanese patients with refractory intestinal BD at a single center.26 Clinical response, defined as a significant improvement in intestinal symptoms or a reduced CRP level, was observed in 12 (80%), 11 (64%), and eight (50%) patients at 10 weeks, 12 months, and 24 months, respectively. Clinical remission, defined as a significant improvement in intestinal symptoms and a reduced CRP level, was observed in four (27%), four (36%), and three (38%) patients at 10 weeks, 12 months, and 24 months, respectively. Zou
Unlike previous studies, only two out of six Japanese patients with refractory intestinal BD showed a good response, defined as improvement of endoscopic findings and successful tapering of corticosteroids.27 One of them achieved clinical remission of gastrointestinal involvement. Another two patients achieved a partial response, and the remaining two patients had progression of or unchanged gastrointestinal lesions.
Hibi
Currently, a prospective, open-label, single-arm, phase 3, multicenter clinical trial of infliximab in Korean patients with refractory intestinal BD is recruiting participants (
Adalimumab is a completely humanized IgG1 monoclonal anti-TNF-α antibody which could bind to TNF-α and prevent it from binding to its receptors. It was the third TNF-α inhibitor approved by the U.S. Food and Drug Administration (FDA), after infliximab and etanercept. Adalimumab has been approved for indications including juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease (CD), ulcerative colitis (UC), hidradenitis suppurativa, psoriasis, and panuveitis.39 It was recently approved and recommended as a standard therapy for intestinal BD in Japan, Taiwan, and South Korea.11,40
There are few available reports regarding adalimumab efficacy for intestinal BD (Table 2).41–44 In 2007, van Laar
There was a case report about the efficacy of adalimumab with combined hematologic disorders. Generally, patients with intestinal BD with myelodysplastic syndrome (MDS) involving trisomy 8 are refractory to conventional medical therapies and infliximab.47 Kimura
The relationship between adalimumab and pathologic finding has also been studied. Mizoshita
Tanida
Combination therapy of adalimumab with disease-modifying antirheumatic drugs does not appear to be significantly superior to adalimumab monotherapy.44 There were no differences between monotherapy and combination therapy in terms of efficacy, time to response, relapses, and adalimumab discontinuation in 100 consecutive patients with BD over a period of 24 months. Moreover, the frequency and time to response for adalimumab were not associated with a previous loss of response of other anti-TNF-α agents. Conversely, the relapse frequency and adalimumab discontinuation at the 2-month follow-up evaluation were significantly higher among patients that had previously experienced failure of an anti-TNF-α agent.
A prospective, multicenter clinical study on adalimumab lasting up to 50 weeks in Japanese patients with BD (NCT01243671) has been completed but has not yet been published. A prospective, open-label, single-arm, phase 3, multicenter clinical trial of adalimumab in Korean patients with intestinal BD is recruiting participants (
Etanercept is a dimeric humanized anti-TNF-α antibody, manufactured by recombinant DNA techniques, has a greater binding affinity by the combination of two naturally occurring soluble human TNF receptors linked to the Fc portion of an IgG1.50 Etanercept has been approved for indications including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis but not for inflammatory bowel diseases. Etanercept has proved to be effective in controlling intestinal BD with a good safety profile (Table 3).51–53 Watanabe
Golimumab is created with genetically engineered mice immunized with human TNF, resulting in the expression of fully humanized antibodies.61 Golimumab is approved for the treatment of UC by the U.S. FDA in 2013. Only a few data are available on golimumab in patients with intestinal BD (Table 3). Vitale
Certolizumab pegol is the only PEGylated anti-TNF-α biologic approved for the treatment of rheumatoid arthritis and CD. It is a humanized antigen-binding fragment of a monoclonal antibody which is conjugated to polyethylene glycol. Data about therapy with certolizumab pegol for BD are scarce (Table 3). Lopalco
Current knowledge about the complications of anti-TNF-α agents is mostly based on controlled clinical trials in treating IBD or rheumatoid diseases. Data derived from studies of their use for intestinal BD are scarce. Table 4 shows the complications associated with anti-TNF-α agents in recent studies including more than 10 patients with intestinal BD. There were no malignancies in these studies. There were some serious infections and infusion reactions, and tuberculosis was observed in one Japanese patient.41 Lee
Although the risk of lymphoma is an important concern associated with therapy for IBD, there are limited data on the risk of non-Hodgkin’s lymphoma (NHL) among anti-TNF-α agent users in IBD.63 The standardized incidence ratio (SIR) of NHL was 3.23 (95% confidence interval [CI], 1.5 to 6.9) in a previous meta-analysis that involved a majority of patients using infliximab with concomitant immunomodulators.64 In addition to NHL, the persistent use of anti-TNF-α beyond 1 year was associated with an even greater risk of melanoma skin cancer among patients with CD (adjusted odds ratio [OR], 3.23; 95% CI, 1.28 to 3.33).65 The greatest risk was evident in recent users of combined thiopurines and anti-TNF-α agents (adjusted OR, 5.85; 95% CI, 3.2 to 10.8). According to the European Crohn’s and Colitis Organisation guidelines, prolonged combination therapy of thiopurines and anti-TNF-α beyond 2 years in young men should be avoided to limit the risk of hepatosplenic T cell lymphoma.66 Intestinal BD is the most common along the ancient “Silk Road” route in the Far East and in the Mediterranean basin, and the prevalence of lymphoma and skin cancer is very low in this area.67 Current guidelines for malignancy in Asian patients with IBD focus on the surveillance of colorectal cancer.40 Patients with IBD are at increased risk for overall, intestinal, and hematological cancer.68 Likewise, intestinal BD is frequently associated with bone marrow disorders such as MDS and aplastic anemia.69 Therefore, close monitoring and identification of individual risk factors for malignancy is an important principle in biologic therapy for intestinal BD.
In terms of infection, analyses of infliximab safety data indicated no increase in infections during infliximab therapy in patients with CD or UC.70 The proportion of patients who experienced a serious infection was similar between infliximab group and the placebo group in five pivotal phase 3 IBD trials (ACCENT I, ACCENT II, SONIC, ACT 1, and ACT 2). A larger proportion of patients with UC, not CD, treated with infliximab with immunomodulator had at least one infection compared to the no immunomodulator treatment group. Especially, tuberculosis and viral hepatitis are endemic in East Asian countries. In a multicenter, observational Korean study, the adjusted SIR of tuberculosis was 41.7 (95% CI, 25.3 to 58.0), compared with that of the matched general population.71 Present or past hepatitis B infection was found in 40.62% of patients with IBD and in 27.58% of the patients without IBD in a Chinese study (p<0.001).72 Previous examination and vaccination before the use of anti-TNF-α and continuous evaluation for tuberculosis and hepatitis in patients with intestinal BD are mandatory.
Intestinal BD is a chronic, relapsing inflammatory disease that is associated with a severe disease course, such as perforation and bleeding. Many patients fail to respond to conventional treatments with corticosteroids and immunomodulatory agents, including thiopurines. Although the clinical remission rate at 1 month to corticosteroid therapy in intestinal BD was high, the response showed a decreasing at 1 year (46.3% vs 35.2%).10 Moreover, the cumulative relapse rates at 1, 2, 3, and 5 years were 5.8%, 28.7%, 43.7%, and 51.7% in patients with intestinal BD who received thiopurine therapy, respectively.73
Currently, anti-TNF-α agent therapy has demonstrated significantly favorable outcomes in patients with intestinal BD who are refractory to or intolerant to conventional therapy. Therefore, anti-TNF use will be gaining more popularity in terms of intestinal BD management in the near future. Its indications will also be more broadened. However, additional studies of larger cohorts of patients are needed to clarify the rationale underlying the outcomes observed in each of the previous small studies. Additionally, possible complications including infection, vaccination, and malignancy surveillance should be considered during biologic therapy for intestinal BD. It has not yet been determined if vedolizumab, a novel anti-integrin therapy for the treatment of IBD, could be a promising alternative therapeutic option for patients with intractable intestinal BD.
No potential conflict of interest relevant to this article was reported.
Infliximab Use in Patients with Intestinal Behçet’s Disease
Author (year) | Country | Method | Participants | Intervention | Outcomes |
---|---|---|---|---|---|
Iwata |
Japan | Retrospective, 1 center | 10 Patients with intestinal BD refractory to conventional therapy | IFX 3–5 mg/kg (wk 0, 2, 6) with methotrexate | Primary outcome
|
Lee |
Korea | Retrospective, 8 centers | 28 Patients with moderate to severe activity of intestinal BD (DAIBD ≥40) | IFX 5 mg/kg (wk 0, 2, 6) | Primary outcome
|
Kinoshita |
Japan | Retrospective, 1 center | 15 Patients with refractory intestinal BD to conventional therapy | IFX 5 mg/kg (wk 0, 2, 6) (n=10) IFX 5 mg/kg (wk 0, 2, 6) with azathioprine (n=5) |
Primary outcome
|
Ideguchi |
Japan | Retrospective, 1 center | 43 (6 Treated with infliximab for intestinal BD) patients with intestinal BD to conventional therapy | - | Good response in 2 patients, partial response in 2, and unchanged GI lesions in 2 patients |
Vallet |
France | Retrospective, 12 centers | 124 (9 Treated with infliximab for intestinal BD) | - | Primary outcome
|
Hibi |
Japan | Prospective, open-label, single-arm phase 3 study, 21 centers | 18 (11 With intestinal BD) patients with refractory intestinal BD to conventional therapy | IFX 5 mg/kg (wk 0, 2, 6) | Primary outcome
|
Zou |
China | Retrospective, 1 center | 27 Patients with moderate to severe activity of intestinal BD (DAIBD ≥40) | - | Primary outcome
|
BD, Behçet’s disease; IFX, infliximab; DAIBD, disease activity score for intestinal BD; CRP, C-reactive protein; GI, gastrointestinal.
Adalimumab Use in Patients with Intestinal Behçet’s Disease
Author (year) | Country | Method | Participants | Intervention | Outcomes |
---|---|---|---|---|---|
Tanida |
Japan | Prospective, open-label, uncontrolled, phase 3 study, 12 centers | 20 Patients with refractory intestinal BD to conventional therapy | ADA, 160 mg (wk 0), 80 mg (wk 2), 40 mg (wk 4) | Primary outcome
|
Tanida |
Japan | Retrospective, 1 center | 8 Patients with refractory intestinal BD to conventional therapy | ADA, 160 mg (wk 0), 80 mg (wk 2), 40 mg (wk 4) | Primary outcome
|
Inoue |
Japan | Prospective, open-label, uncontrolled, phase 3 study, 12 centers | 20 Patients with refractory intestinal BD to conventional therapy | ADA, 160 mg (wk 0), 80 mg (wk 2), 40 mg (wk 4) | Primary outcome
|
Vitale |
Italy | Retrospective, multicenter | 100 (13 With intestinal BD) patients with refractory intestinal BD to conventional therapy or previous anti-TNF α therapy | - | Primary outcome
|
BD, Behçet’s disease; ADA, adalimumab; TNF, tumor necrosis factor.
Etanercept, Golimumab, and Certolizumab Pegol Uses in Patients with Intestinal Behçet’s Disease
Author (year) | Country | Method | Participants | Intervention | Outcomes |
---|---|---|---|---|---|
Ma |
China | Retrospective, 1 center | 19 Patients treated with etanercept 19 Patients treated with conventional therapy (corticosteroid or methotrexate) | Etanercept 25 mg twice a wk with prednisolone 1 mg/kg/day and methotrexate 15 mg/wk | Primary outcome
|
Vitale |
Italy | Retrospective, 3 centers | 17 (6 Patients; GI tract involvement) patients treated with conventional therapy and at least another biological agent | Golimumab 50 mg every 30 day | BD Current Activity Form score: decreased significantly (p=0.002) |
Lopalco |
Italy | Retrospective, 1 center | 13 (5 Patients; GI tract involvement) patients treated with conventional therapy and at least another biological agent | Certolizumab 400 mg (0, 2, and 4 wk), 200 mg every 2 wk | Improvement of clinical manifestations: 53.84% |
BD, Behçet’s disease; GI, gastrointestinal.
Adverse Events of Biologics in Patients with Intestinal Behçet’s Disease
Author (year) | Country | Method | Intervention | Patients with malignancies | Patients with severe infection | Patients with infusion reaction | Adverse event of interest |
---|---|---|---|---|---|---|---|
Iwata |
Japan | Retrospective, 1 center | Infliximab | 0/10 | 0/10 | 0/15 | - |
Lee |
Korea | Retrospective, 8 centers | Infliximab | 0/28 | 1/28 | 6/28 | - |
Kinoshita |
Japan | Retrospective, 1 center | Infliximab | 0/15 | 0/15 | 1/15 | - |
Hibi |
Japan | Prospective, open-label, single-arm phase 3 study, 21 centers | Infliximab | 0/11 | 0/11 | 1/11 | - |
Zou |
China | Retrospective, 1 center | Infliximab | 0/27 | 1/27 | 0/27 | - |
Tanida |
Japan | Prospective, open-label, uncontrolled, phase 3 study, 12 centers | Adalimumab | 0/20 | 1/20 | 2/20 | 1 Tuberculosis |
Inoue |
Japan | Prospective, open-label, uncontrolled, phase 3 study, 12 centers | Adalimumab | 0/20 | 3/20 | 3/20 | - |
Vitale |
Italy | Retrospective, multicenter | Adalimumab | 0/13 | 0/13 | 1/13 | - |
Ma |
China | Retrospective, 1 center | Golimumab | 0/19 | 0/19 | 0/19 | - |
Gut and Liver 2018; 12(6): 623-632
Published online November 15, 2018 https://doi.org/10.5009/gnl17462
Copyright © Gut and Liver.
Jihye Park1, Jae Hee Cheon1,2
1Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea, 2Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
Correspondence to:Correspondence to: Jae Hee Cheon
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:
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Intestinal Behçet’s disease is a rare, immune-mediated chronic intestinal inflammatory disease; therefore, clinical trials to optimize the management and treatment of patients are scarce. Moreover, intestinal Behçet’s disease is difficult to treat and often requires surgery because of the failure of conventional medical treatment. Administration of anti-tumor necrosis factor–α, a potential therapeutic strategy, is currently under active clinical investigation, and evidence of its effectiveness for both intestinal Behçet’s disease and inflammatory bowel diseases has been accumulating. Here, we review updated data on current experiences and outcomes after the administration of anti-tumor necrosis factor–α for the treatment of intestinal Behçet’s disease. In addition to infliximab and adalimumab, which are the most commonly used agents, we describe agents such as golimumab, etanercept, and certolizumab pegol, which have recently been shown to be effective in refractory intestinal Behçet’s disease. This review also discusses safety issues associated with anti-tumor necrosis factor–α, including vulnerability to infections and malignancy.
Keywords: Behcet syndrome, Intestinal Behcet&rsquo,s disease, Anti-tumor necrosis factor alpha, Infliximab, Adalimumab
Behçet’s disease (BD) is a chronic recurring multisystemic vasculitic disorder involving recurrent oral ulcers; genital ulcers; ocular lesions; skin manifestations; arthritis; and vascular, neurologic, and intestinal involvement.1,2 Intestinal BD is diagnosed when a patient with BD has both dominant gastrointestinal symptoms and typical intestinal ulcerative lesions on objective examinations.3 The intestinal involvement of BD is rare, ranging 5% to 20%, and it is more prevalent in East Asian countries, including Korea and Japan.4 Typical intestinal ulceration of intestinal BD is oval in shape and deep with discrete border located in the ileocecal area.5 It can cause diarrhea, abdominal pain, gastrointestinal bleeding, or bowel perforation.6,7
Intestinal BD has a heterogeneous range of clinical courses and symptoms, and a gold standard therapy remains elusive. Research on intestinal BD is relatively scarce because of the rarity of this disease.8 Moreover, intestinal BD is often refractory to conventional treatment such as corticosteroids and immunomodulators; therefore, alternative therapies are needed.9 Currently, anti-tumor necrosis factor-α (anti-TNF-α), a potential therapeutic strategy, is being evaluated, and evidence for its effectiveness has been accumulating. In Japan, anti-TNF-α has received approval to be used for the treatment of intestinal BD in cases where existing treatments are inadequate.10,11 One TNF-α receptor fusion protein (etanercept), three anti-TNF-α monoclonal antibodies (infliximab, adalimumab, and golimumab), and one anti-TNF-α PEGylated antigen-binding fragment (certolizumab pegol) are currently approved as anti-TNF-α therapies for several immune-mediated disorders.12 This article reviews the progress in the management of intestinal BD, focusing on current anti-TNF-α usage and possible future perspectives.
The pathogenesis of intestinal BD is still unclear; in addition to genetic factors, immune dysfunction and multiple cytokines are associated with the development and progression of disease.13 Several data suggest a role of TNF-α in the pathogenesis of intestinal BD. Inflammation in intestinal BD is thought to be mediated by cytokines derived from T helper type 1 (Th1) lymphocytes, including TNF-α.14 T cells at the intestinal mucosal level produce a large concentration of TNF-α, and T cells induce inflammation leading to mucosal damage through abnormal cytokine production, especially during the active phase of the disease.15,16 Recently, Emmi
Infliximab is a chimeric monoclonal antibody biologic drug that was first demonstrated in 2001 as an effective new therapy for patients with steroid-dependent intestinal BD.23 Infliximab is currently one of the most frequently described biologic agents for patients with intestinal BD. Infliximab was infused at 0, 2, and 6 weeks and every 8 weeks thereafter at 3–5 mg/kg in most studies (Table 1).24–30 Hassard
Combination therapy of infliximab and methotrexate was administered to 10 Japanese patients with refractory intestinal BD who failed to respond to conventional therapy, and it provided short- and long-term efficacy and tolerability as assessed by abdominal computed tomography (CT) and colonoscopy.24 Intestinal manifestations, including tenderness and bleeding, disappeared within 3 months, and improvement was confirmed at only 2 weeks after the initiation of infliximab infusions in all seven patients assessed on abdominal CT. Ileocecal ulceration disappeared in five patients (50%) at 6 months and nine patients (90%) at 12 months, as confirmed by colonoscopy. In a multicenter retrospective study, the primary outcome was reported using the disease activity index of intestinal Behçet’s disease (DAIBD) score with 28 Korean patients with moderate to severe intestinal BD.25,38 The clinical response rates, defined as a decrease in the DAIBD score of 20 points or more from the baseline value, were 75.0%, 64.3%, 50.0%, and 39.1% at 2, 4, 30, and 54 weeks, respectively. Old age at diagnosis (≥40 years), female sex, longer disease duration (≥5 years), concomitant immunomodulator use, and achievement of remission at week 4 were predictive factors for a sustained response to infliximab treatment. This study was meaningful in that it was the first paper to evaluate the efficacy of biologics in intestinal BD using the DAIBD score. Infliximab was administered to 15 Japanese patients with refractory intestinal BD at a single center.26 Clinical response, defined as a significant improvement in intestinal symptoms or a reduced CRP level, was observed in 12 (80%), 11 (64%), and eight (50%) patients at 10 weeks, 12 months, and 24 months, respectively. Clinical remission, defined as a significant improvement in intestinal symptoms and a reduced CRP level, was observed in four (27%), four (36%), and three (38%) patients at 10 weeks, 12 months, and 24 months, respectively. Zou
Unlike previous studies, only two out of six Japanese patients with refractory intestinal BD showed a good response, defined as improvement of endoscopic findings and successful tapering of corticosteroids.27 One of them achieved clinical remission of gastrointestinal involvement. Another two patients achieved a partial response, and the remaining two patients had progression of or unchanged gastrointestinal lesions.
Hibi
Currently, a prospective, open-label, single-arm, phase 3, multicenter clinical trial of infliximab in Korean patients with refractory intestinal BD is recruiting participants (
Adalimumab is a completely humanized IgG1 monoclonal anti-TNF-α antibody which could bind to TNF-α and prevent it from binding to its receptors. It was the third TNF-α inhibitor approved by the U.S. Food and Drug Administration (FDA), after infliximab and etanercept. Adalimumab has been approved for indications including juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease (CD), ulcerative colitis (UC), hidradenitis suppurativa, psoriasis, and panuveitis.39 It was recently approved and recommended as a standard therapy for intestinal BD in Japan, Taiwan, and South Korea.11,40
There are few available reports regarding adalimumab efficacy for intestinal BD (Table 2).41–44 In 2007, van Laar
There was a case report about the efficacy of adalimumab with combined hematologic disorders. Generally, patients with intestinal BD with myelodysplastic syndrome (MDS) involving trisomy 8 are refractory to conventional medical therapies and infliximab.47 Kimura
The relationship between adalimumab and pathologic finding has also been studied. Mizoshita
Tanida
Combination therapy of adalimumab with disease-modifying antirheumatic drugs does not appear to be significantly superior to adalimumab monotherapy.44 There were no differences between monotherapy and combination therapy in terms of efficacy, time to response, relapses, and adalimumab discontinuation in 100 consecutive patients with BD over a period of 24 months. Moreover, the frequency and time to response for adalimumab were not associated with a previous loss of response of other anti-TNF-α agents. Conversely, the relapse frequency and adalimumab discontinuation at the 2-month follow-up evaluation were significantly higher among patients that had previously experienced failure of an anti-TNF-α agent.
A prospective, multicenter clinical study on adalimumab lasting up to 50 weeks in Japanese patients with BD (NCT01243671) has been completed but has not yet been published. A prospective, open-label, single-arm, phase 3, multicenter clinical trial of adalimumab in Korean patients with intestinal BD is recruiting participants (
Etanercept is a dimeric humanized anti-TNF-α antibody, manufactured by recombinant DNA techniques, has a greater binding affinity by the combination of two naturally occurring soluble human TNF receptors linked to the Fc portion of an IgG1.50 Etanercept has been approved for indications including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis but not for inflammatory bowel diseases. Etanercept has proved to be effective in controlling intestinal BD with a good safety profile (Table 3).51–53 Watanabe
Golimumab is created with genetically engineered mice immunized with human TNF, resulting in the expression of fully humanized antibodies.61 Golimumab is approved for the treatment of UC by the U.S. FDA in 2013. Only a few data are available on golimumab in patients with intestinal BD (Table 3). Vitale
Certolizumab pegol is the only PEGylated anti-TNF-α biologic approved for the treatment of rheumatoid arthritis and CD. It is a humanized antigen-binding fragment of a monoclonal antibody which is conjugated to polyethylene glycol. Data about therapy with certolizumab pegol for BD are scarce (Table 3). Lopalco
Current knowledge about the complications of anti-TNF-α agents is mostly based on controlled clinical trials in treating IBD or rheumatoid diseases. Data derived from studies of their use for intestinal BD are scarce. Table 4 shows the complications associated with anti-TNF-α agents in recent studies including more than 10 patients with intestinal BD. There were no malignancies in these studies. There were some serious infections and infusion reactions, and tuberculosis was observed in one Japanese patient.41 Lee
Although the risk of lymphoma is an important concern associated with therapy for IBD, there are limited data on the risk of non-Hodgkin’s lymphoma (NHL) among anti-TNF-α agent users in IBD.63 The standardized incidence ratio (SIR) of NHL was 3.23 (95% confidence interval [CI], 1.5 to 6.9) in a previous meta-analysis that involved a majority of patients using infliximab with concomitant immunomodulators.64 In addition to NHL, the persistent use of anti-TNF-α beyond 1 year was associated with an even greater risk of melanoma skin cancer among patients with CD (adjusted odds ratio [OR], 3.23; 95% CI, 1.28 to 3.33).65 The greatest risk was evident in recent users of combined thiopurines and anti-TNF-α agents (adjusted OR, 5.85; 95% CI, 3.2 to 10.8). According to the European Crohn’s and Colitis Organisation guidelines, prolonged combination therapy of thiopurines and anti-TNF-α beyond 2 years in young men should be avoided to limit the risk of hepatosplenic T cell lymphoma.66 Intestinal BD is the most common along the ancient “Silk Road” route in the Far East and in the Mediterranean basin, and the prevalence of lymphoma and skin cancer is very low in this area.67 Current guidelines for malignancy in Asian patients with IBD focus on the surveillance of colorectal cancer.40 Patients with IBD are at increased risk for overall, intestinal, and hematological cancer.68 Likewise, intestinal BD is frequently associated with bone marrow disorders such as MDS and aplastic anemia.69 Therefore, close monitoring and identification of individual risk factors for malignancy is an important principle in biologic therapy for intestinal BD.
In terms of infection, analyses of infliximab safety data indicated no increase in infections during infliximab therapy in patients with CD or UC.70 The proportion of patients who experienced a serious infection was similar between infliximab group and the placebo group in five pivotal phase 3 IBD trials (ACCENT I, ACCENT II, SONIC, ACT 1, and ACT 2). A larger proportion of patients with UC, not CD, treated with infliximab with immunomodulator had at least one infection compared to the no immunomodulator treatment group. Especially, tuberculosis and viral hepatitis are endemic in East Asian countries. In a multicenter, observational Korean study, the adjusted SIR of tuberculosis was 41.7 (95% CI, 25.3 to 58.0), compared with that of the matched general population.71 Present or past hepatitis B infection was found in 40.62% of patients with IBD and in 27.58% of the patients without IBD in a Chinese study (p<0.001).72 Previous examination and vaccination before the use of anti-TNF-α and continuous evaluation for tuberculosis and hepatitis in patients with intestinal BD are mandatory.
Intestinal BD is a chronic, relapsing inflammatory disease that is associated with a severe disease course, such as perforation and bleeding. Many patients fail to respond to conventional treatments with corticosteroids and immunomodulatory agents, including thiopurines. Although the clinical remission rate at 1 month to corticosteroid therapy in intestinal BD was high, the response showed a decreasing at 1 year (46.3% vs 35.2%).10 Moreover, the cumulative relapse rates at 1, 2, 3, and 5 years were 5.8%, 28.7%, 43.7%, and 51.7% in patients with intestinal BD who received thiopurine therapy, respectively.73
Currently, anti-TNF-α agent therapy has demonstrated significantly favorable outcomes in patients with intestinal BD who are refractory to or intolerant to conventional therapy. Therefore, anti-TNF use will be gaining more popularity in terms of intestinal BD management in the near future. Its indications will also be more broadened. However, additional studies of larger cohorts of patients are needed to clarify the rationale underlying the outcomes observed in each of the previous small studies. Additionally, possible complications including infection, vaccination, and malignancy surveillance should be considered during biologic therapy for intestinal BD. It has not yet been determined if vedolizumab, a novel anti-integrin therapy for the treatment of IBD, could be a promising alternative therapeutic option for patients with intractable intestinal BD.
No potential conflict of interest relevant to this article was reported.
Table 1 Infliximab Use in Patients with Intestinal Behçet’s Disease
Author (year) | Country | Method | Participants | Intervention | Outcomes |
---|---|---|---|---|---|
Iwata | Japan | Retrospective, 1 center | 10 Patients with intestinal BD refractory to conventional therapy | IFX 3–5 mg/kg (wk 0, 2, 6) with methotrexate | Primary outcome Rate of disappearance of ileocecal ulceration at 6 and 24 mo: 50% and 90% Dose of steroid tapered at 24 mo: 22.0–1.8 mg/day |
Lee | Korea | Retrospective, 8 centers | 28 Patients with moderate to severe activity of intestinal BD (DAIBD ≥40) | IFX 5 mg/kg (wk 0, 2, 6) | Primary outcome Clinical remission at 2, 4, 30, and 54 wk (DAIBD <20): 32.1%, 28.6%, 46.2%, and 39.1% Clinical response at 2, 4, 30, and 54 wk (ΔDAIBD ≥20): 75%, 64.3%, 50%, and 39.1% Biological response at 2, 4, 30, and 54 wk (CRP <3 mg/L): 82.1%, 57.1%, 53.8%, and 43.5% |
Kinoshita | Japan | Retrospective, 1 center | 15 Patients with refractory intestinal BD to conventional therapy | IFX 5 mg/kg (wk 0, 2, 6) (n=10) | Primary outcome Clinical remission at 10 wk, 12 mo, and 24 mo (improved symptom and normal CRP): 53%, 27%, and 38% Clinical response at 10 wk, 12 mo, and 24 mo (improved symptom or lower CRP): 27%, 36%, and 38% |
Ideguchi | Japan | Retrospective, 1 center | 43 (6 Treated with infliximab for intestinal BD) patients with intestinal BD to conventional therapy | - | Good response in 2 patients, partial response in 2, and unchanged GI lesions in 2 patients |
Vallet | France | Retrospective, 12 centers | 124 (9 Treated with infliximab for intestinal BD) | - | Primary outcome Complete response: 5/9 (55.6%) Improvement of clinical manifestations in BD patients treated by infliximab: 7/9 (77.8%) |
Hibi | Japan | Prospective, open-label, single-arm phase 3 study, 21 centers | 18 (11 With intestinal BD) patients with refractory intestinal BD to conventional therapy | IFX 5 mg/kg (wk 0, 2, 6) | Primary outcome Complete responder at 14, 30, and 54 wk (disappeared clinical symptom and healed or scarred ulcer): 55%, 55%, and 60% Dose reduction and withdrawal of steroids at 14, 30, 54 wk: 37.5%, 75.0%, and 100.0% |
Zou | China | Retrospective, 1 center | 27 Patients with moderate to severe activity of intestinal BD (DAIBD ≥40) | - | Primary outcome Clinical remission at 14, 30, and 52 wk (DAIBD <20): 69.2%, 40%, and 55% Clinical response at 14, 30, and 52 wk (ΔDAIBD ≥20): 84.6%, 70%, and 70% Mucosal healing at 14 wk: 72% |
BD, Behçet’s disease; IFX, infliximab; DAIBD, disease activity score for intestinal BD; CRP, C-reactive protein; GI, gastrointestinal.
Table 2 Adalimumab Use in Patients with Intestinal Behçet’s Disease
Author (year) | Country | Method | Participants | Intervention | Outcomes |
---|---|---|---|---|---|
Tanida | Japan | Prospective, open-label, uncontrolled, phase 3 study, 12 centers | 20 Patients with refractory intestinal BD to conventional therapy | ADA, 160 mg (wk 0), 80 mg (wk 2), 40 mg (wk 4) | Primary outcome Complete remission at 24 and 52 wk (marked improvement of global symptom and endoscopic assessment score): 20% and 20% Clinical response at 24 and 52 wk (marked improvement of global symptom or endoscopic assessment score): 45% and 60% |
Tanida | Japan | Retrospective, 1 center | 8 Patients with refractory intestinal BD to conventional therapy | ADA, 160 mg (wk 0), 80 mg (wk 2), 40 mg (wk 4) | Primary outcome Complete remission at 24 and 52 wk (marked improvement of global symptoms and endoscopic assessment score): 25% and 25% Clinical response at 24 and 52 wk (marked improvement of global symptom or endoscopic assessment score): 62.5% and 75% |
Inoue | Japan | Prospective, open-label, uncontrolled, phase 3 study, 12 centers | 20 Patients with refractory intestinal BD to conventional therapy | ADA, 160 mg (wk 0), 80 mg (wk 2), 40 mg (wk 4) | Primary outcome Complete remission at 52 and 100 wk (marked improvement of global symptom and endoscopic assessment score): 20% and 15% Clinical response at 52 and 100 wk (marked improvement of global symptom or endoscopic assessment score): 60% and 40% |
Vitale | Italy | Retrospective, multicenter | 100 (13 With intestinal BD) patients with refractory intestinal BD to conventional therapy or previous anti-TNF α therapy | - | Primary outcome Complete disappearance of BD-related clinical signs within the 12 wk from the start of adalimumab therapy: 81/100 patients Number of patients remaining on adalimumab therapy at the 24-mo follow-up visit: 67/100 patients |
BD, Behçet’s disease; ADA, adalimumab; TNF, tumor necrosis factor.
Table 3 Etanercept, Golimumab, and Certolizumab Pegol Uses in Patients with Intestinal Behçet’s Disease
Author (year) | Country | Method | Participants | Intervention | Outcomes |
---|---|---|---|---|---|
Ma | China | Retrospective, 1 center | 19 Patients treated with etanercept 19 Patients treated with conventional therapy (corticosteroid or methotrexate) | Etanercept 25 mg twice a wk with prednisolone 1 mg/kg/day and methotrexate 15 mg/wk | Primary outcome Complete disappearance of BD-related clinical signs within 12 wk from the start of adalimumab therapy: 81/100 patients Number of patients remaining on adalimumab therapy at 24-mo follow-up visit: 67/100 patients Sustained clinical benefit at the time of data enrollment: 12/17 (70.6%) BD-related manifestation at 3 mo: 16/17 (94.1%) |
Vitale | Italy | Retrospective, 3 centers | 17 (6 Patients; GI tract involvement) patients treated with conventional therapy and at least another biological agent | Golimumab 50 mg every 30 day | BD Current Activity Form score: decreased significantly (p=0.002) |
Lopalco | Italy | Retrospective, 1 center | 13 (5 Patients; GI tract involvement) patients treated with conventional therapy and at least another biological agent | Certolizumab 400 mg (0, 2, and 4 wk), 200 mg every 2 wk | Improvement of clinical manifestations: 53.84% |
BD, Behçet’s disease; GI, gastrointestinal.
Table 4 Adverse Events of Biologics in Patients with Intestinal Behçet’s Disease
Author (year) | Country | Method | Intervention | Patients with malignancies | Patients with severe infection | Patients with infusion reaction | Adverse event of interest |
---|---|---|---|---|---|---|---|
Iwata | Japan | Retrospective, 1 center | Infliximab | 0/10 | 0/10 | 0/15 | - |
Lee | Korea | Retrospective, 8 centers | Infliximab | 0/28 | 1/28 | 6/28 | - |
Kinoshita | Japan | Retrospective, 1 center | Infliximab | 0/15 | 0/15 | 1/15 | - |
Hibi | Japan | Prospective, open-label, single-arm phase 3 study, 21 centers | Infliximab | 0/11 | 0/11 | 1/11 | - |
Zou | China | Retrospective, 1 center | Infliximab | 0/27 | 1/27 | 0/27 | - |
Tanida | Japan | Prospective, open-label, uncontrolled, phase 3 study, 12 centers | Adalimumab | 0/20 | 1/20 | 2/20 | 1 Tuberculosis |
Inoue | Japan | Prospective, open-label, uncontrolled, phase 3 study, 12 centers | Adalimumab | 0/20 | 3/20 | 3/20 | - |
Vitale | Italy | Retrospective, multicenter | Adalimumab | 0/13 | 0/13 | 1/13 | - |
Ma | China | Retrospective, 1 center | Golimumab | 0/19 | 0/19 | 0/19 | - |