Behçet’s disease (BD) is a multisystemic disorder of unknown etiology mainly defined by recurrent oral aphthosis, genital ulcers, and chronic relapsing bilateral uveitis, all of which represent the “stigmata” of disease. However, many other organs including the vascular, neurological, musculoskeletal, and gastrointestinal systems can be affected. The gastrointestinal involvement in Behçet’s disease (GIBD), along with the neurological and vascular ones, represents the most feared clinical manifestation of BD and shares many symptoms with inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis. Consequently, the differential diagnosis is often a daunting task, albeit the presence of typical endoscopic and pathologic findings may be a valuable aid to the exact diagnosis. To date, there are no standardized medical treatments for GIBD; therefore therapy should be tailored to the single patient and based on the severity of the clinical features and their complications. This work provides a digest of all current experience and evidence about pharmacological agents suggested by the medical literature as having a potential role for managing the dreadful features of GIBD.
Behçet’s disease (BD) is a rare relapsing systemic inflammatory disorder of unknown etiology characterized by recurrent oral ulcers, genital sores, and ocular lesions; however many other organs including the vascular, neurological, and musculoskeletal systems as well as the gastrointestinal system can be involved [
Although oral aphthae and genital ulcers are the earliest and the most frequent manifestations of BD, anticipating by many years other typical BD clinical symptoms, GIBD is one of the major causes of morbidity and mortality, often leading to severe complications. GIBD occurs in 3–60% of patients, on average 4.5–6 years after the onset of oral ulcerations [
Main clinical, endoscopic, and pathological features of gastrointestinal involvement in Behçet’s disease and most common localization.
Behçet’s disease | Crohn’s disease | Ulcerative colitis | |
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Gastrointestinal manifestations | Anorexia, vomiting, dyspepsia, diarrhoea, abdominal pain, melena, hematochezia, fever | Anorexia, vomiting, dyspepsia, diarrhea, gastrointestinal bleeding, abdominal pain, fever | Rectal bleeding, |
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Pathological features | Vasculitis of the | Transmural mucosal inflammation, | Distortion of crypt architecture, |
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Endoscopic findings | Round or oval ulcers, punched-out lesions with discrete margins (>1 cm), focal distribution (<5 ulcers) | Longitudinal ulcers, cobblestone appearance, aphthous ulcers showing longitudinal array | Mucosal erythema, fine granularity, loss of vascular marking, erosions, ulcers, spontaneous bleeding, luminal narrowing with pseudopolyps |
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Localization | Terminal ileum, ileocecal region, colon | Small bowel, upper-gastrointestinal tract | Starts in the rectum and extends proximally in a continuous manner through the entire colon |
Gastrointestinal lesions are typically irregular, round or oval, punched-out, large (>1 cm), single to a few in number, deep, and with discrete margins in a focal distribution [
Although a wide number of conventional immunosuppressive drugs have been used to induce remission in GIBD, several failures have been reported. This article reviews the progress in the management of GIBD focusing on current treatment strategies and possible future perspectives. An electronic literature search was conducted using the PubMed database and the clinicaltrials.gov search engine. We looked for all studies published in the last years, including case reports, clinical trials, and cohort studies (Table
Overview of studies derived from the medical literature reporting treatment indications of gastrointestinal lesions in Behçet’s disease.
Drugs | Dose | Authors (year) | Number of patients | Type of study | Outcomes |
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5-ASA/SSZ | 2.4–4 g/day | Jung et al. | 143/292 | Retrospective cohort study | Positive effect in maintaining remission |
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THD | 2-3 mg/kg/day | Yasui et al. | 7 | Case series | Dramatic improvement in clinical symptoms |
— | Lee et al. | 4 | Case series | 3/4 patients had a clinical improvement and all discontinued steroid therapy | |
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THD/IFX/ADA/ | THD 50–100 mg/day | Hatemi et al. (2015) | 13/64 | Observational study | Remission obtained with TNF- |
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AZA or 6-MP | AZA 2–2.5 mg/kg/day | Jung et al. | 67/272 | Retrospective study | Relative good effect for maintenance of remission |
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AZA or 6-MP | AZA 2–2.5 mg/kg/day | Lee et al. | 77 | Retrospective observational study | The rates of reoperation, readmission, and death were not significantly different between the 5-ASA and thiopurine groups |
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MTX + IFX | MTX - | Iwata et al. | 10 | Observational study | Long-term alleviation of entero-BD and excellent tolerability with combination of IFX and MTX |
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INF- | 6 × 106 IU per day for 14 days | Grimbacher et al. | 1 | Case report | Complete remission of Behçet’s retinal infiltrates and BD-related colitis |
3 × 106 IU/day 3 times/week increased to 6 × 106 IU/day 3 times/week | Monastirli et al. | 1 | Case report | Complete remission of all clinical manifestations | |
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IVIg | 400 mg/kg/day for 5 days per month | Cantarini et al. | 1/4 | Case series | Complete disease remission of gastrointestinal, manifestations |
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IFX | — | Ideguchi et al. | 7/43 | Retrospective observational study | Good response in two patients, remission in one, partial response in two, and unchanged GI lesions in two patients |
5 mg/kg/every 8 weeks | Lee et al. | 28 | Multicenter retrospective study | IFX efficacy for patients with moderate-to-severe intestinal BD | |
5 mg/kg every 8 weeks | Kinoshita et al. | 15/43 | Retrospective cohort study | Acceptable efficacy of IFX in BD patients refractory to conventional treatments | |
5 mg/kg every 8 weeks | Hibi et al. | 11/18 | Open-label study | IFX efficacy in the treatment of intestinal BD | |
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ADA | 160 mg at week 0 and 80 mg at week 2, followed by 40 mg every other week | Tanida et al. | 20 | Multicenter, open-label, uncontrolled study | ADA effectiveness in inducing and maintaining clinical improvement and remission in patients with intestinal BD |
160 mg at week 0 and 80 mg at week 2, followed by 40 mg every other week | Tanida et al. | 8 | Retrospective observational study | Long-term efficacy and safety of ADA for the treatment of intestinal BD in the clinical setting | |
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ETA | 25 mg twice a week | Ma et al. | 19/35 | Observational study | The relapse rate for etanercept therapy was reduced significantly when compared with conventional therapy |
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ANA | 100 mg/day | Cantarini et al. | 3/9 | Case series | Complete resolution of abdominal pain in two patients, |
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CANA | 150 mg every 8 weeks | Vitale et al. | 2/3 | Case series | Complete resolution of abdominal pain |
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TCZ | 8 mg/kg/ every 4 weeks | Deroux et al. | 3/4 | Case series | Less effective for arthralgia and abdominal pain |
ADA, adalimumab; ANA, anakinra; anti-TNF-
As underlined in the guidelines of the European League Against Rheumatism (EULAR) for the management of BD, evidence-based recommendations regarding GIBD are not provided due to the poor amount of published clinical trials [
Nevertheless GIBD management is still largely empirical due to the lack of not yet standardized medical treatments, the heterogeneity of this disorder, and the unpredictable exacerbations of BD. To date, several conventional immunosuppressive drugs may be employed, although none of them has been proven actually effective in preventing disease relapse.
CC are the first-line therapy, especially in patients with severe systemic symptoms, recurrent gastrointestinal bleeding, or when treatment with 5-aminosalicylic acid (5-ASA)/SSZ is not enough [
5-ASA/SSZ is indicated in all cases of GIBD due to its safety profile and current limited therapeutic options [
THD is an immunomodulatory drug, used mainly in the treatment of specific tumors. It is usually considered the last-line therapy for GIBD, albeit its use is well-documented [
Yasui et al. reported the benefits of THD in 7 juvenile‐onset patients with severe, recurrent GIBD who had previously failed immunosuppressant treatments and developed significant CC toxicity. THD was given at the initial dose of 2 mg/kg per day and was increased to 3 mg/kg per day if necessary. All patients showed dramatic improvement in clinical symptoms, and CC were successfully withdrawn [
Despite the efficacy and safety profile reported in several bodies of evidence of the literature [
Thiopurines including 6-mercaptopurine (6-MP) and its prodrug AZA have been traditionally thought to decrease reoperation rate in patients with GIBD who already had undergone surgical interventions [
Yet, a recent retrospective observational study was carried out to assess the efficacy of postoperative thiopurine therapy in 77 patients with GIBD; although a lower postoperative recurrence was found in patients who received thiopurines than those taking 5-ASA, the rates of reoperation, readmission, and death were not significantly different between the 5-ASA and thiopurine groups [
Evidence concerning the efficacy of methotrexate combined with infliximab (IFX) in refractory entero-BD has been also reported in 9 out of 10 patients who experienced the disappearance of ileocecal ulcerations at 12 months of therapy [
Interferon (IFN) is a cytokine able to render cells resistant to infection by many viruses. It was introduced for the treatment of BD by Tsambaos in 1986, because of its antiviral and antiproliferative properties [
During the last few decades intravenous immunoglobulins (IVIg) have been increasingly administered for a wide number of autoimmune and systemic inflammatory diseases. To the best of our knowledge, IVIg have so far been evaluated in few patients with GIBD. In this regard, the efficacy of IVIg has been reported in a patient with BD-related colitis who initially had failed under CC and immunosuppressive therapy [
Several data suggest a role of TNF-
Yet, a Korean multicenter retrospective study aimed at investigating the response to IFX in 28 patients with GIBD showed a clinical response rate of 64.3% with a clinical remission rate of 28.6% at week 4, following IFX infusion. Furthermore, an older age at diagnosis (≥40 years), the female sex, a longer disease duration (≥5 years) as well as the concomitant immunomodulator use, and achievement of remission at week 4 were regarded as predictive factors of sustained response [
The efficacy of IFX in GIBD has also been corroborated by a retrospective cohort study on 15 patients with active disease refractory to conventional medications. 80% of patients exhibited a good response to IFX and 53% of them achieved remission after 10 weeks. Moreover 64% and 50% of patients maintained the response to IFX at 12 and 24 months, respectively [
Finally, an interventional open-label single-arm study testing the efficacy of IFX by assessing the mean decrease in DAIBD score in patients with active intestinal disease refractory to conventional therapies is currently recruiting participants (ClinicalTrials.gov,
To date, few data are available regarding ADA efficacy in GIBD, although the proofs of its usefulness are increasing [
However, the most consistent evidence regarding ADA efficacy derives from a phase 3, multicenter, open-label uncontrolled study evaluating Japanese patients with active intestinal BD nonresponsive to standard therapies. Twenty patients received induction treatment with ADA (160 mg at week 0, baseline, and 80 mg at week 2, followed by 40 mg every other week for 52 weeks); a composite index, combining GI symptoms and endoscopic assessments, was used to evaluate the efficacy of treatment. A marked improvement, defined as values ≤1 for both the global GI symptoms and endoscopic assessment scores, was seen in 60% of patients at week 52. Interestingly 20% of patients achieved a complete remission, defined as global GI symptoms and endoscopic scores of 0, at weeks 24 and 52, suggesting that ADA was an effective therapy to induce and maintain clinical improvement and remission in patients with GIBD [
Less experience has been gained focusing on the management of GIBD with ETA treatment [
Although the employment of anti-IL-1 agents on various BD manifestations has been well-documented [
Haematopoietic stem cell transplantation (HSCT) has been used in the treatment of severe autoimmune and inflammatory conditions unresponsive to conventional therapy. Although several treatment options, including biologic agents, are till now available for BD management, there is still an unmet need for more effective therapies for patients who are refractory to conventional treatments. In this regard encouraging results derive from several case reports describing HSCT in GIBD patients transplanted for accompanying haematological conditions. A complete remission of GI findings was observed after HSCT and there was no need to treat patients with any medications [
Surgery is indicated when patients with GIBD are refractory to medical treatment or serious complications, such as when gastrointestinal bleeding, perforation, fistulae, obstructions, and abdominal masses occur [
BD is a complex syndrome characterized by significant heterogeneity of clinical manifestations with usually frequent relapses. GIBD is one of the most severe manifestations of this disease, causing serious complications such as perforation and gastrointestinal bleeding. GIBD shares many clinical features with inflammatory bowel diseases, and for this reason it represents a pitfall for physicians regarding differential diagnosis at the first presentation. Nevertheless, a careful evaluation of endoscopic findings may help in the diagnostic interpretation, whereas the endoscopic biopsy is necessary to confirm a histopathologic diagnosis. Treatments have been largely unsatisfactory, creating significant unmet needs, and the lack of evidence-based treatment makes the management of GIBD very challenging. Currently, several immunosuppressive drugs such as SSZ, CC, and AZA are generally well-tolerated but often associated with increased risk of disease relapses as a result of which surgery is required in many patients. In the last years, new pathogenetic hypotheses supported the use of biotechnological drugs, mostly TNF-
The authors declare that there is no conflict of interests regarding the publication of this paper.
Giuseppe Lopalco and Donato Rigante equally contributed to this manuscript.