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Abstract

Behcet’s disease (BD) is a chronic and recurrent systemic vasculitis involving large, medium and small blood vessels as well as arteries and veins. BD with predominant gastrointestinal manifestations is diagnosed as intestinal BD, which is associated with severe complications such as massive gastrointestinal hemorrhage, perforation, and obstruction. Recently, treat-to-target (T2T) strategies have been successfully used in many chronic diseases and been suggested in the management of BD, while there are no related reviews about the global treatment strategy including treatment principles and targets for intestinal BD in detail. Herein, we review the treatment principles from the aspects of departments of Rheumatology and Gastroenterology. In addition, treatment targets of intestinal BD are reviewed from three aspects such as evaluable markers, effective markers and potency-ratio markers. Some definitions and conceptions from inflammatory bowel disease (IBD) bring us reference and enlightenments.

Keywords

intestinal Behcet’s disease treat-to-target treatment principles treatment targets

Introduction

Behcet’s disease (BD) is a chronic recurrent systemic vasculitis involving large, medium and small vessels as well as arteries and veins. It was first reported in 1937 by Hulusi Behcet, a Turkish dermatologist. This disease has a high prevalence along the Silk Road, including Japan, Korea, the Middle East, and the Mediterranean region. The most widely accepted criteria include the criteria published by the International Study Group for BD in 1990 and The International Criteria for Behcet’s Disease developed from the collaboration of experts from 27 nations. The sensitivity and specificity of the former are 85 and 96%, respectively, while the latter are 94.8 and 90.5%, respectively.^1,2 BD can involve multiple organs, including skin, mucosa, eyes, cardiovascular system, nervous system, gastrointestinal tract, joints, lungs, kidneys, etc. Patients with involvement of important organs usually have poor outcomes.^3,4

Gastrointestinal involvement of BD is termed as intestinal Behcet’s disease (intestinal BD). It may cause serious complications including perforation, obstruction, fistula formation and gastrointestinal bleeding in some cases, showing high rates of disability and mortality. The prevalence of gastrointestinal involvement in BD is about 3–60% and it shows regional differences, with approximately 2.8–4.0% in Turkey, India and Saudi Arabia, 10% in China, 38–53% in Japan and 50–60% in the UK.⁵ It is noteworthy that intestinal BD can present with or without other organ involvement, with volcano-shaped ulcers in ileocecal area as the typical finding.^6,7 Up to now, the diagnosis of intestinal BD mainly depends on clinical manifestations without specific laboratory index. And in a few cases, it is hard to differentiate intestinal BD from other inflammatory gastrointestinal diseases such as Crohn’s disease (CD), intestinal tuberculosis. Japanese and Korean guidelines for intestinal BD have proposed algorithms for definite diagnosis.^8,9 Recently, our team also summarized the key points of differential diagnosis among intestinal BD, CD and intestinal tuberculosis in a review about clinical characteristics, diagnosis and evaluation of intestinal BD.¹⁰

The management of intestinal BD is mainly carried out in the Departments of Rheumatology and Gastroenterology, which are complementary to each other. The European League Against Rheumatism (EULAR) updated the recommendations for the management of BD published in 2018, which first proposed that gastrointestinal involvement of BD should be confirmed by endoscopy and/or imaging.¹¹ Evidence-based Diagnosis and Clinical Practice Guidelines (EDGs) for intestinal BD published by the Japanese Society for Behcet’s Disease (JSBD) in 2020 clearly presented the diagnostic criteria and algorithm.⁸ Recently, the Inflammatory Enteropathy Group, Chinese Medical Association (IEGCMA) published a Chinese consensus on diagnosis and treatment of intestinal BD in 2022.⁷

Recently, treat-to-target (T2T) strategies have been embraced in many chronic diseases, such as hypertension, diabetes, rheumatoid arthritis, and inflammatory bowel disease (IBD), including ulcerative colitis (UC) and CD. T2T strategies have improved long-term outcomes of related diseases.¹² With a deeper understanding of BD and the development of diagnosis, evaluation and treatment methods, Hatemi proposed for the first time in 2022 to implement a T2T strategy in the management of BD.¹³ To date, there is no related reviews about the treatment principles and targets of intestinal BD in detail. Therefore, we review intestinal BD with treatment principles and targets to improve the clinicians’ understanding.

Treatment principles

Severity of disease and previous treatment principles

In the past decade, significant research results on BD have been published enabling a deeper understanding of disease behavior and management. Studies showed that any part of the alimentary tract can be affected in intestinal BD while the ileocecal area was the most frequently involved location.⁴ Deep ulcers in intestinal BD were responsible for severe complications such as perforation, gastrointestinal bleeding and obstruction, which indicated that gastrointestinal involvement in BD was a predictive factor for a poor prognosis.¹⁴ For example, Yook et al.¹⁵ in 2013 conducted a retrospective analysis of 124 patients with intestinal BD and found that the incidence of intestinal perforation, fistula, stenosis and abscess was 12.7, 7.6, 7.2, and 3.3%, respectively. Hatemi et al.⁶ reviewed the charts of all BD patients in their BD clinic in 2016 and found that 32% patients (N = 60) suffered from acute abdominal pain. 8 of these patients had massive bleeding while the other 11 patients had perforations. Another study in 2017 also showed that 11.2% patients (N = 588) with acute lower gastrointestinal bleeding were identified in patients with intestinal BD. Therefore, it was necessary to prompt timely treatment of intestinal BD to prevent severe complications and to achieve favorable prognosis.¹⁶

In the field of rheumatology, the EULAR recommendations for the management of BD in 2008 and the guidelines for the diagnosis and treatment of BD published by the Rheumatology Society of Chinese Medical Association (RSCMA) in 2011 put forward the treatment principles in detail. The aim of BD treatment is to control symptoms and prevent irreversible organ damage. In addition, multisystem involvement mandates collaboration between different specialties.^17,18 In the field of gastroenterology, Japanese gastroenterologists used to have extensively studied intestinal BD. The Japanese consensus statement for the diagnosis and management of intestinal BD was established and updated in 2007 and 2014, which paid more attention to the treatment goals than to the treatment principles. The EDGs for intestinal BD published by the JSBD in 2020 and Chinese consensus on intestinal BD published by the IEGCMA in 2022 also focused on the treatment goals.^7,8,19,20

Updated treatment methods and treatment principles

The appropriate adoption of medical therapy was of great importance in intestinal BD as well as proper intervention with surgical management.¹⁷ Conventional medications included 5-aminosalicylic acids, corticosteroids, immunomodulators such as azathioprine, thalidomide, which were capable of inducing and maintaining remission without the need for surgery in some patients. These drugs acted as key components of the standard therapy for intestinal BD according to the Japanese consensus of intestinal BD published in 2007.⁹ However, some patients with intestinal BD were refractory to conventional treatment. Park et al.¹⁸ performed a study regarding clinical outcomes after corticosteroid use in patients with moderate-to-severe intestinal BD. A total of 54 patients were enrolled and 46.3% of whom achieved complete remission after 1 month of treatment and 48.1% remained responsive to therapy after 1 year of treatment. Yet it was worth noting that 35.2% of these patients developed corticosteroid dependency and 7.4% received surgery after 1 year. The adoption of biological agents such as anti-tumor necrosis factor (TNF) agents in intestinal BD allowed for effective treatment of these corticosteroid-dependent and other complicated cases. Kinoshita et al.¹⁹ reported that 15 Japanese patients with refractory intestinal BD who showed poor response to corticosteroid and conventional immunosuppressive agents received therapy of an anti-TNF agent (infliximab) at a single center and exhibited significant clinical response with 80% patients at 10 weeks, 64.0% at 12 months, and 50.0% at 24 months. Furthermore, in 2013 Lee et al.²¹ conducted a Korean multicenter retrospective study of 28 patients with intestinal BD who received infliximab therapy. They showed that patients at 2, 4, 30, and 54 weeks after treatment presented a clinical response rate of 75.0, 64.3, 50, and 39.1%, and a clinical remission rate of 32.1, 28.6, 46.2, and 39.1%, respectively. It was suggested that infliximab was a well-tolerated and effective therapy for patients with moderate-to-severe intestinal BD.²²

According to these studies, the EULAR and RSCMA updated the guidelines in 2018 and 2021, respectively. The updated treatment principles can be summarized as follows: (1) The key point is to promptly suppress inflammatory exacerbations and prevent recurrences. (2) The prevention of irreversible organ damage and disease progression is the final goal. (3) A multidisciplinary approach and individualized treatment based on patient status, severity of organ involvement, and patient preferences are necessary.^11,23 To some extent, it is similar to the principles of treatment for IBD, which aims for early induction of remission and long-term maintenance to prevent relapse.²⁴

Treatment targets

The treatment principles and targets complement each other and act as global treatment strategy. Up to now, the medical treatment target for intestinal BD is to prompt timely suppression of inflammation and maintenance of disease remission. Here, we elaborate the treatment target from three aspects as follows: evaluable markers, effective markers, and potency-ratio markers. Considering that there is a lack of high-quality research in the field of intestinal BD, some definitions and conceptions are cited from IBD.¹²

Evaluable markers: Where should we pick up treatment targets from?

Clinical manifestations

In 2011, Cheon et al.²⁵ first proposed the Disease Activity Index for Intestinal BD (DAIBD) to evaluate the disease activity of intestinal BD. The DAIBD provides a score between 0 and 325 based on an 8-point index that includes symptoms and signs of patients. It classifies disease activity as quiescent (⩽19), mild (20–39), moderate (40–74) and severe (⩾75). The study enrolled a total of 110 patients with intestinal BD, and the results revealed that the DAIBD showed much higher responsiveness than the Crohn’s Disease Activity Index (CDAI) (r = 0.81 versus 0.65, respectively). Park et al.²⁶ in 2013 reported that DAIBD had predictive value for prognosis and outcome of intestinal BD: ① DAIBD ⩾ 70 was a predictive factor for surgical intervention [Hazard ratio (HR) 5.43; 95% CI 2.65–11.10]; ② DAIBD ⩾ 60 was an independent factor associated with relapse for patients during 5-ASA therapy (HR 2.30; 95% CI 1.10–4.83); ③ DAIBD ⩾ 40 at the time of diagnosis was independently associated with a more severe clinical course (OR 6.20; 95% CI 1.10–33.50). However, some studies have shown that a portion of patients with intestinal BD in clinical remission (DAIBD ⩽ 19) still have endoscopic disease activity.²⁷

Endoscopy

Endoscopic evaluation of intestinal BD mainly includes gastroscopy, colonoscopy, enteroscopy and capsule endoscopy. According to the guidelines established by the IBD Study Group of the Korean Association of the Study of Intestinal Diseases, the typical ulcerations of intestinal BD were described as few in number (⩽5), large, discrete, and round or oval-shaped ulcerations in the ileocecal area (Figure 1(a)). The other types of ulcers include small aphthous ulcerations to multiple irregularly shaped ulcerations and are defined as atypical ulcerations.⁹ A multivariate regression analysis of 167 intestinal BD patients conducted by Lee et al.²⁷ revealed that the number of intestinal ulcers (⩾2, p = 0.031) and volcano-shaped ulcers (p = 0.001) were predictive factors for severe DAIBD scores and disease activity. Mucosal healing (MH) has been one of the main therapeutic targets stipulated by recent authoritative recommendations and guidelines in IBD and is associated with better long-term outcomes.^24,28 The definition of MH currently lacks consensus. A Mayo endoscopic subscore of 0 or 1 or an SES-CD (simple endoscopic score for CD) less than 3 is recognized by most experts as an acceptable measure of MH and has been widely used in UC and CD.^29,30 With a deep understanding of intestinal BD, recent studies suggest that MH is a potential predictive factor for the long-term prognosis of intestinal BD (Figure 1(b)). A meta-analysis by Wu et al.³¹ in 2020 revealed that MH is associated with a decreased risk of disease recurrence (RR 0.41; 95% CI 0.30–0.57) and surgery (RR 0.33; 95% CI 0.17–0.63) in intestinal BD. However, in clinical practice, there are contraindications for endoscopic examination of some patients, as it is invasive. To date, there are no surrogate noninvasive markers of endoscopy.

Figure 1.

Endoscopic findings of intestinal Behcet’s disease. (a) Typical ulcer in ileocecal area before treatment; (b) Mucosal healing of ulcer in ileocecal area after treatment.

Radiology

The radiologic evaluation of intestinal BD is mainly based on computed tomography enterography (CTE). On CTE, intestinal BD commonly manifests as geographic, relatively large, and deep penetrating ulcers with bowel wall thickening and mural hyperenhancement in the ileocecal region. Occasionally, intestinal BD manifests as a cecal mass or an aneurysmal dilatation of the terminal ileum masquerading as a malignant tumor. Patients with gastrointestinal complications such as intestinal perforation, fistula, stenosis and abscess may have corresponding imaging findings (Figure 2).³² Recently, magnetic resonance enterography and bowel ultrasonography have also been increasingly used in the diagnosis and treatment of chronic intestinal inflammatory disease.³³ One study by Peker et al.³⁴ revealed that a polypoid pattern and homogeneous mural enhancement were the findings seen more frequently in BD (p < 0.001) than in CD (p = 0.003). Another study by Ma et al.³⁵ in 2021 showed that focal lesions (OR 0.16, 95% CI: 0.04–0.56) and large ulcers (OR 0.06; 95% CI: 0.01–0.55) were independent predictors of intestinal BD over CD in bowel ultrasonography. Transmural healing (TH) refers to healing of the full-thickness bowel wall under radiology. At present, there is no internationally recognized definition, and most studies use bowel wall thickness (usually 3 mm or less as the critical value) for evaluation.³³ There were more significant research results for TH in CD than in UC: ① A study of 218 CD patients who completed a 2-year treatment course with anti-TNF-α agents showed that TH was associated with longer intervals until clinical relapse (HR 0.87, p = 0.01), hospitalization (HR 0.88, p = 0.002) and surgery (HR 0.94, p = 0.008) than MH.³⁶ ② There is controversy regarding the correlation between TH and MH in CD. In two studies of CD patients (N = 66 and N = 90), a good correlation was observed between MH and TH (k = 0.63, p < 0.001; k = 0.64, p < 0.001).^37,38 Another study of CD patients (N = 214) revealed that TH and MH are associated with improved long-term outcomes in CD, but there was poor correlation between TH and MH.³⁹ ③ An update on the Selecting Therapeutic Targets in IBD (STRIDE-II) conducted by the International Organization for the Study of IBD in 2021 recommended that TH should be used as an adjunct to MH to represent a deeper level of healing in CD.¹² We speculate that this may be related to the pathophysiological mechanism of CD as full-thickness inflammation.

Figure 2.

Radiological findings of intestinal Behcet’s disease with complications. (a) Wall thickening of ileocecal area with luminal stenosis and mural hyperenhancement; (b) Intestinal- abdominal fistula and mural abscess.

Histology

The main techniques to obtain pathology of intestinal BD include surgical resection and endoscopic biopsy. It has been shown in typical surgical pathology results that vasculitis, such as fibrinoid necrosis and inflammatory cell infiltration of small blood vessels in the bowel and mesentery, could be found (Figure 3(a)). It is relatively hard to obtain evidence of vasculitis in endoscopic biopsy, as the material is usually from the mucosal layer of pathological tissue (Figure 3(b)).^23,40 Histological healing (HH) refers to the histopathology that indicates the improvement of inflammation and the repair of damaged structures. The research results of HH in UC were similar to those of TH in CD, which showed that HH may be superior to MH in long-term remission and cancer prevention.^41–43 HH is also recommended as an adjunct to MH in UC in the STRIDE-II consensus.¹² In my opinion, this may be related to the fact that the pathophysiological mechanism of UC is superficial intestinal inflammation, which makes it easier to see bowel wall inflammation in the mucosal samples obtained by endoscopic biopsy.

Figure 3.

Pathological findings of tissue specimens in ileocecal area of intestinal Behcet’s disease. (a) (from right hemicolectomy): Ulceration of ileocecal region and abscess formation with thickening of vascular wall and swelling of endometrium; (b) (from colonoscopy biopsy): Nonspecific mucosal inflammation and cryptitis.

Biomarkers

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are important biomarkers for evaluating disease activity in intestinal BD despite the lack of specific factors to date. Bai et al.⁴⁴ conducted a retrospective study of patients with intestinal BD (N = 29) in 2007 and revealed that ESR and CRP increased significantly during disease activity (92.3 and 92.0%). Two studies by Jung YS et al.^45,46 in 2011 and 2012 revealed that a CRP level ⩾ 0.4 mg/dL was an independent predictive factor for postoperative recurrence and reoperation, while a CRP level ⩾ 1.5 mg/dL was associated with a poor response to 5-ASA therapy. The important role of fecal calprotectin (FC) in the evaluation of chronic intestinal inflammatory diseases such as IBD has been proven in previous studies.^47,48 In recent years, increasingly more studies have shown that FC is helpful in the diagnosis of intestinal BD and associated with disease activity.^49–51 Further research is needed for large-scale clinical application in consideration of the variable cutoff values, false positive by drug interference and storage at room temperature.⁵² In addition, FC may be a potential noninvasive biomarker of MH and is correlated with TH and HH in IBD according to some research, and it is also worth further attention and research in intestinal BD.^53–56

Effective markers: How should we pick up effective treatment targets?

According to the characteristics of the above evaluable marker and relevant research, the EDGs for intestinal BD by the JSBD in 2020 and the RSCMA guidelines for BD in 2021 updated the treatment targets that clinical remission and the normalization of CRP are the initial targets, and MH was recommended as a further target, which was supported by the Chinese consensus on intestinal BD published by the IEGCMA in 2022.^7,8,23 TH and HH, which indicated deeper remission, were not included in the guidelines as treatment targets due to a lack of relevant research in intestinal BD. We speculate that TH may be more promising in the further study of intestinal BD than HH, considering that intestinal BD is more similar to CD in its clinical symptoms, imaging findings and endoscopic characteristics than UC.¹³ It is worth noting that some studies in IBD revealed that the combination of evaluable markers (e.g. CRP and FC, CDAI and FC) may be promising treatment targets according to the effectiveness of disease-activity evaluation.^57,58 This new idea is worthy of reference for intestinal BD. In clinical practice, some patients with vasculitis, such as BD, may suffer from irreversible damage to the involved organs and blood vessels, such as coronary artery stenosis and ischemia, pulmonary hypertension, renal insufficiency and so on, while inflammation is well controlled. Moreover, it is well known that ischemia of blood-supply mesenteric vessels is the cause of ischemic bowel disease and one of the causes of refractory duodenal ulcer.⁵⁹ Therefore, we suggest that future studies should focus on whether the definition of MH in intestinal BD needs to be adjusted or modified.

Potency-ratio markers: Why should we weigh the pros and cons of different treatment targets?

The concept ‘the deeper the remission, the better the outcomes’ has been recognized by an increasing number of clinicians engaged in chronic intestinal inflammatory diseases.¹² However, immunosuppressive drugs such as glucocorticoids, traditional immunosuppressants, and biological agents have their related adverse drug reactions, which may be life-threatening in serious conditions. In addition, some drugs are relatively expensive.^60–62 Therefore, seeking deeper remission may be associated with more adverse reactions and costs, especially for patients with advanced age, immunosuppressed conditions, underlying diseases, high risk of treatment and poor economic status. Consequently, the EDG for intestinal BD in 2020 by the JSBD emphasized that adverse events due to enhanced treatment must be comprehensively considered before upgrading the treatment target.⁸ In addition, a simple algorithm for the treatment goals in UC and CD suggested by the STRIDE-II consensus is worthy of reference for clinicians engaged in the field of intestinal BD. The key points are summarized as follows: ① It is emphasized that it is necessary to balance the benefits and risks before adjusting the treatment targets; ② the treatment targets are stratified according to time, which means that remission of clinical symptoms and biomarkers presents as early and initial goals, while deep remission acts as a late and final goal; ③ the treatment targets are individualized based on the disease characteristics such as MH and HH for UC and MH and TH for CD.¹²

Key points to be made clear

What’s more, there were several key points which should be made clear in our review. It was listed in a table form as follows (Table 1): ① Application: as we all knew, intestinal BD was gastrointestinal involvement of BD while BD was an autoimmune disease with multiple organ involvement. For patients with BD, skin, mucosa, and joint involvement could cause impairment of quality of life but do not cause permanent damage whereas untreated eye, vascular, nervous system, and gastrointestinal system involvement could cause serious damage and even death.⁶³ And it was worth noting for clinicians in disease assessment that the treatment targets mentioned in our review applied to gastrointestinal assessment of BD after treatment especially presenting mainly with gastrointestinal involvement. The treatment targets for BD needed to be multidimensional as it was a systemic vasculitis which can affect multiple organs with different course and prognostic importance¹²; ② Reference: in consideration of lack of high-quality research in the field of intestinal BD and clinical similarity between intestinal BD and IBD to some extent, we reviewed the treatment targets of intestinal BD by mentioning several definitions and conceptions in IBD for partial reference. However, it was also worth noting that intestinal BD and IBD were clearly different kinds of diseases. The former was the gastrointestinal manifestations of chronic recurrent systemic vasculitis while the latter was a disease of nonspecific chronic inflammation confined to the intestine with different which could have extraintestinal manifestations during the clinical course.^40,64 Therefore, as we mentioned above, further studies should be conducted to explore whether the definitions and conceptions from IBD needed to be adjusted or modified in intestinal BD; ③ Significance: we reviewed the treatment principles and targets of intestinal BD, aiming to improve clinicians’ global understanding of the disease treatment. Certainly, the concrete medical treatment plans in intestinal BD such as reduction strategies of corticosteroid, advantages and disadvantages of different drugs, and application of biologic agents and conventional immunosuppressive agents were of the same importance which needs further discussion in the future.^65,66

Table 1.

Key points to be made clear.

Key points	Explanation
Application	1. The treatment principles and targets mentioned in our review applied to gastrointestinal assessment of BD after treatment especially presenting mainly with gastrointestinal involvement.
Application	2. The treatment targets for BD needed to be multidimensional as it can affect multiple organs with different course and prognostic importance.
Reference	1. Several definitions and conceptions of the treatment targets mentioned in our review for intestinal BD refer to inflammatory bowel disease due to lack of high-quality studies and clinical similarity between these two diseases.
Reference	2. Further studies should be conducted to explore whether the definitions and conceptions from inflammatory bowel disease needed to be adjusted or modified in intestinal BD in consideration that they were clearly different kinds of diseases.
Significance	1. Our review focused on the treatment principles and targets and aimed to help clinicians for global understanding of the disease.
Significance	2. The concrete medical treatment plans in intestinal BD were as important as global treatment principles and targets which needed further discussion in the future.

BD, Behcet’s disease.

Conclusion

In summary, BD is a systemic vasculitis with multiple organ involvement. For intestinal BD namely BD with predominant gastrointestinal manifestations, we review the global treatment strategy with treatment principles and targets. The key points of the treatment principles of intestinal BD focus on prompt suppression of inflammatory exacerbations and prevention of recurrences to prevent irreversible organ damage and disease progression. As for treatment targets in intestinal BD, further seeking MH is expected to have a better prognosis after achieving remission of clinical symptoms and normalization of CRP. Subsequent multicenter, prospective and large-sample-size studies are needed for further exploration of treatment targets, such as noninvasive markers and whether TH and HH can improve the long-term prognosis of intestinal BD.

Footnotes

Acknowledgements

The authors would like to thank Dr. Yabing Wang for the comments of the manuscript and Dr. Xiaxiao Yan for figure making.

Declarations

ORCID iD

Dong Wu

References

Criteria for diagnosis of Behcet’s disease. International Study Group for Behcet’s Disease. Lancet 1990; 335(8697): 1078–1080.

International Team for the Revision of the International Criteria for Behcet’s D. The International Criteria for Behcet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 2014; 28(3): 338–347.

Hatemi

Seyahi

Fresko

, et al. Behcet’s syndrome: one year in review 2022. Clin Exp Rheumatol 2022; 40(8): 1461–1471.

Nguyen

Upadhyay

Javaid

, et al. Behcet’s disease: an in-depth review about pathogenesis, gastrointestinal manifestations, and management. Inflamm Intest Dis 2021; 6(4): 175–185.

Skef

Hamilton

Arayssi

Gastrointestinal Behcet’s disease: a review. World J Gastroenterol 2015; 21(13): 3801–3812.

Hatemi

Esatoglu

Hatemi

, et al. 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(16): e3348.

Inflammatory Enteropathy Group. Gastroenterology Branch, Chinese Medical Association. Chinese consensus on diagnosis and treatment of intestinal Behcet’s disease (in Chinese). Chin J Dig 2022; 42(10): 649–658.

Watanabe

Tanida

Inoue

, et al. Evidence-based diagnosis and clinical practice guidelines for intestinal Behcet’s disease 2020 edited by Intractable Diseases, the Health and Labour Sciences Research Grants. J Gastroenterol 2020; 55(7): 679–700.

Cheon

Shin

Kim

, et al. [Diagnosis of intestinal Behcet’s disease]. Korean J Gastroenterol 2009; 53(3): 187–193.

10.

Clinical characteristics, diagnosis and evaluation of intestinal Behcet’s disease (in Chinese). Chin J Gen Pract 2022; 21(11): 1101–1106.

11.

Hatemi

Christensen

Bang

, et al. 2018 update of the EULAR recommendations for the management of Behcet’s syndrome. Ann Rheum Dis 2018; 77(6): 808–818.

12.

Turner

Ricciuto

Lewis

, et al. STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology 2021; 160(5): 1570–1583.

13.

Hatemi

A treat-to-target approach is needed for Behcet’s syndrome. Curr Opin Rheumatol 2022; 34(1): 39–45.

14.

Hisamatsu

Naganuma

Matsuoka

, et al. Diagnosis and management of intestinal Behcet’s disease. Clin J Gastroenterol 2014; 7(3): 205–212.

15.

Jung

Cheon

Park

, et al. Long-term clinical outcomes of Crohn’s disease and intestinal Behcet’s disease. Inflamm Bowel Dis 2013; 19(1): 99–105.

16.

Park

Cheon

Park

, et al. Risk factors and outcomes of acute lower gastrointestinal bleeding in intestinal Behcet’s disease. Int J Colorectal Dis 2017; 32(5): 745–751.

17.

Hatemi

Silman

Bang

, et al. EULAR recommendations for the management of Behcet disease. Ann Rheum Dis 2008; 67(12): 1656–1662.

18.

Rheumatology society of Chinese Medical Associaton. Guidelines for the diagnosis and treatment of Behcet’s disease (in Chinese). Chin J Rheumatol 2011; (05): 345–347.

19.

Hisamatsu

Ueno

Matsumoto

, et al. The 2nd edition of consensus statements for the diagnosis and management of intestinal Behcet’s disease: indication of anti-TNFalpha monoclonal antibodies. J Gastroenterol 2014; 49(1): 156–162.

20.

Kobayashi

Ueno

Bito

, et al. Development of consensus statements for the diagnosis and management of intestinal Behcet’s disease using a modified Delphi approach. J Gastroenterol 2007; 42(9): 737–745.

21.

Lee

Cheon

Jeon

, et al. Efficacy of infliximab in intestinal Behcet’s disease: a Korean multicenter retrospective study. Inflamm Bowel Dis 2013; 19(9): 1833–1838.

22.

Park

Cheon

JH.

Update on the treatment of Behcet’s disease of the small bowel with biologic agents. Curr Gastroenterol Rep 2020; 22(5): 24.

23.

Zheng

Zhang

Zhu

, et al. Recommendations for the diagnosis and treatment of Behcet’s syndrome in China (in Chinese). Chin J Intern Med 2021; 60(10): 860–867.

24.

Nakase

Uchino

Shinzaki

, et al. Evidence-based clinical practice guidelines for inflammatory bowel disease 2020. J Gastroenterol 2021; 56(6): 489–526.

25.

Cheon

Han

Park

, et al. Development, validation, and responsiveness of a novel disease activity index for intestinal Behcet’s disease. Inflamm Bowel Dis 2011; 17(2): 605–613.

26.

Park

Kim

Cheon

JH.

Outcome predictors for intestinal Behcet’s disease. Yonsei Med J 2013; 54(5): 1084–1090.

27.

Lee

Kim

Jang

, et al. Correlations between endoscopic and clinical disease activity indices in intestinal Behcet’s disease. World J Gastroenterol 2012; 18(40): 5771–5778.

28.

Maaser

Sturm

Vavricka

, et al. ECCO-ESGAR guideline for diagnostic assessment in IBD part 1: initial diagnosis, monitoring of known IBD, detection of complications. J Crohns Colitis 2019; 13(2): 144–164.

29.

Boal Carvalho

Cotter

. Mucosal healing in ulcerative colitis: a comprehensive review. Drugs 2017; 77(2): 159–173.

30.

Klenske

Bojarski

Waldner

, et al. Targeting mucosal healing in Crohn’s disease: what the clinician needs to know. Therap Adv Gastroenterol 2019; 12: 1756284819856865.

31.

Gong

Zhang

Sun

, et al. Mucosal healing in intestinal Behcet’s disease: a systematic review and meta-analysis. J Dig Dis 2021; 22(2): 83–90.

32.

Park

Lim

JS.

Computed tomography enterography for evaluation of inflammatory bowel disease. Clin Endosc 2013; 46(4): 327–366.

33.

Zacharopoulou

Craviotto

Fiorino

, et al. Targeting the gut layers in Crohn’s disease: mucosal or transmural healing? Expert Rev Gastroenterol Hepatol 2020; 14(9): 775–787.

34.

Peker

Erden

, et al. Intestinal Behcet disease: evaluation with MR enterography – a case-control study. AJR Am J Roentgenol 2018; 211(4): 767–775.

35.

Wang

, et al. Pilot case-control study to explore the value of intestinal ultrasound in the differentiation of two common diseases involving the ileocecal region: intestinal Behcet’s disease and Crohn’s disease. Quant Imaging Med Surg 2021; 11(7): 3200–3208.

36.

Castiglione

Imperatore

Testa

, et al. One-year clinical outcomes with biologics in Crohn’s disease: transmural healing compared with mucosal or no healing. Aliment Pharmacol Ther 2019; 49(8): 1026–1039.

37.

Castiglione

Mainenti

Testa

, et al. Cross-sectional evaluation of transmural healing in patients with Crohn’s disease on maintenance treatment with anti-TNF alpha agents. Dig Liver Dis 2017; 49(5): 484–489.

38.

Castiglione

Testa

Rea

, et al. Transmural healing evaluated by bowel sonography in patients with Crohn’s disease on maintenance treatment with biologics. Inflamm Bowel Dis 2013; 19(9): 1928–1934.

39.

Fernandes

Rodrigues

Bernardo

, et al. Transmural healing is associated with improved long-term outcomes of patients with Crohn’s disease. Inflamm Bowel Dis 2017; 23(8): 1403–1409.

40.

Kim

Cheon

JH.

Intestinal Behcet’s disease: a true inflammatory bowel disease or merely an intestinal complication of systemic vasculitis?

Yonsei Med J 2016; 57(1): 22–32.

41.

Korelitz

BI.

Mucosal healing as an index of colitis activity: back to histological healing for future indices. Inflamm Bowel Dis 2010; 16(9): 1628–1630.

42.

Peyrin-Biroulet

Bressenot

Kampman

Histologic remission: the ultimate therapeutic goal in ulcerative colitis?

Clin Gastroenterol Hepatol 2014; 12(6): 929.e2–934.e2.

43.

Riley

Mani

Goodman

, et al. Microscopic activity in ulcerative colitis: what does it mean? Gut 1991; 32(2): 174–178.

44.

Bai

. Clinical characteristics of intestinal Behcet’s disease. Chinese Academy of Medical Sciences and Peking Union Medical College, 2007.

45.

Jung

Hong

Kim

, et al. 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(5): e38–e45.

46.

Jung

Yoon

Lee

, et al. Prognostic factors and long-term clinical outcomes for surgical patients with intestinal Behcet’s disease. Inflamm Bowel Dis 2011; 17(7): 1594–1602.

47.

Ayling

Kok

Fecal calprotectin. Adv Clin Chem 2018; 87: 161–190.

48.

Ometto

Friso

Astorri

, et al. Calprotectin in rheumatic diseases. Exp Biol Med (Maywood) 2017; 242(8): 859–873.

49.

Esatoglu

Hatemi

Ozguler

, et al. Faecal but not serum calprotectin levels look promising in predicting active disease in Behcet’s syndrome patients with gastrointestinal involvement. Clin Exp Rheumatol 2018; 36(6 Suppl 115): 90–96.

50.

Kim

Park

Kim

, et al. Fecal calprotectin as a non-invasive biomarker for intestinal involvement of Behcet’s disease. J Gastroenterol Hepatol 2017; 32(3): 595–601.

51.

Ozseker

Sahin

Ozseker

, et al. The role of fecal calprotectin in evaluating intestinal involvement of Behcet’s disease. Dis Markers 2016; 2016: 5423043.

52.

Ricciuto

Griffiths

AM.

Clinical value of fecal calprotectin. Crit Rev Clin Lab Sci 2019; 56(5): 307–320.

53.

Carlsen

Riis

Elsberg

, et al. The sensitivity of fecal calprotectin in predicting deep remission in ulcerative colitis. Scand J Gastroenterol 2018; 53(7): 825–830.

54.

Mak

Buisson

Andersen

Jr. , et al. Fecal calprotectin in assessing endoscopic and histological remission in patients with ulcerative colitis. Dig Dis Sci 2018; 63(5): 1294–1301.

55.

Weinstein-Nakar

Focht

Church

, et al. Associations among mucosal and transmural healing and fecal level of calprotectin in children with Crohn’s disease. Clin Gastroenterol Hepatol 2018; 16(7): 1089.e4–1097.e4.

56.

Zittan

Kelly

Kirsch

, et al. Low fecal calprotectin correlates with histological remission and mucosal healing in ulcerative colitis and colonic Crohn’s disease. Inflamm Bowel Dis 2016; 22(3): 623–630.

57.

Reinisch

Panaccione

Bossuyt

, et al. Biomarker correlation with endoscopic outcomes in patients with Crohn’s disease: data from calm. Gastroenterology 2018; 154(6): S-587.

58.

Chen

Liu

Gao

, et al. Efficacy of noninvasive evaluations in monitoring inflammatory bowel disease activity: a prospective study in China. World J Gastroenterol 2017; 23(46): 8235–8247.

59.

Kim

HU.

Diagnostic and treatment approaches for efractory peptic ulcers. Clin Endosc 2015; 48(4): 285–290.

60.

Frauman

AG.

An overview of the adverse reactions to adrenal corticosteroids. Adverse Drug React Toxicol Rev 1996; 15(4): 203–206.

61.

Meyer

Decker

Baughman

Toxicity and monitoring of immunosuppressive therapy used in systemic autoimmune diseases. Clin Chest Med 2010; 31(3): 565–588.

62.

Thomas

PWA

Romkens

TEH

West

, et al. Discrepancy between patient- and healthcare provider-reported adverse drug reactions in inflammatory bowel disease patients on biological therapy. United European Gastroenterol J 2021; 9(8): 919–928.

63.

Karadag

Bolek

. Management of Behcet’s syndrome. Rheumatology (Oxford)2020; 59(Suppl 3): iii108–iii17.

64.

Hatemi

Seyahi

Fresko

, et al. Behcet’s syndrome: one year in review 2022. Clin Exp Rheumatol 2022; 40(8): 1461–1471.

65.

Ozguler

Ozdede

Hatemi

. Recent Insights into the Management of Behcet Syndrome. J Inflamm Res 2021; 14: 3429–3441.

66.

Alibaz-Oner

Direskeneli

. Biologic treatments in Behcet’s disease. Eur J Rheumatol 2021; 8(4): 217–222.

The treatment principles and targets for intestinal Behcet’s disease

Abstract

Keywords

Introduction

Treatment principles

Severity of disease and previous treatment principles

Updated treatment methods and treatment principles

Treatment targets

Evaluable markers: Where should we pick up treatment targets from?

Clinical manifestations

Endoscopy

Radiology

Histology

Biomarkers

Effective markers: How should we pick up effective treatment targets?

Potency-ratio markers: Why should we weigh the pros and cons of different treatment targets?

Key points to be made clear

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References