Entero-Behcet: A Challenging Aspect of Behçet’s Disease

Abstract

Behcet disease is a proteiform vasculitis, and it can have multiple presentations. One of these presentations is digestive involvement commonly known as entero-Behcet. It is a challenging presentation of Behcet disease, because of its similarity with other inflammatory digestive diseases, especially Crohn disease, which makes its diagnosis difficult and uncertain in many cases. It is also challenging to treat, and its treatment can go from corticosteroids and immunosuppressive therapy to biologics. The absence of a standardized protocol to treat patients can be confusing for practitioners treating entero-Behcet. This incites doctors treating entero-Behcet to have multidisciplinary meetings to discuss patients’ cases. This review will give an insight into pathophysiology, diagnosis, and management of entero-Behcet to help practitioners taking care of this challenging aspect of entero-Behcet.

1. Introduction

Behcet disease (BD) is a primitive vasculitis from unknown origin, characterized by recurrent oral and/or genital aphthosis, ocular manifestations, and arthritis. Intestinal presentation of BD is rare, its prevalence is up to 5–10% [1], but can be very severe and difficult to diagnose and to differentiate from an inflammatory bowel disease, especially when it is the initial manifestation. East Asian countries have a higher frequency of intestinal manifestation in BD compared with Western or Middle Eastern countries [2]. Intestinal involvement in BD is known as entero-Behcet (EB), and it is defined when a patient presenting with BD has intestinal symptoms associated to aphthous ulceration confirmed by endoscopic exploration [3] and unexplained by infectious or toxic causes or another inflammatory disease. Intestinal involvement in BD usually occurs 4–6 years after the onset of oral ulcers [4]. Intestinal manifestations as well as vascular involvement are more common after the age of 40 [5]. The digestive symptoms are essentially abdominal pain, nausea, vomiting, and diarrhea. Ulcers can even lead to gastrointestinal bleeding and to intestinal perforation. In equivalence with BD, the pathophysiology of EB is not fully understood; it is also a multifactorial disease, implying genetic, environmental, and immune factors.

Similar to Crohn disease (CD), EB is characterized by a prevalence for the ileoceocal area; however, every segment of the digestive tract can be affected [3, 6]; they present with some similarities concerning the genetic basis and pathophysiology; therefore, the treatment for EB is modeled on the CD one, such as corticosteroids, immunosuppressors, and biologics. But there is still no consensus for management of intestinal Behcet’s disease to date.

It is essential that every specialist caring for patients with BD should know every aspect of the clinical manifestations, the diagnostic work-up, and the up-to-date management strategies available for EB. This review will give an insight into pathophysiology, diagnosis, and management of EB to help practitioners taking care of this challenging aspect of BD.

2. Pathophysiology

Human leukocyte antigen (HLA)-B51 allele, ERAP 1, and MHC class I-related gene A (MICA) are the classical genetic factors of BD, which have not been identified in CD [1, 7]. The interleukin (IL) 10 and the IL23R-IL12RB2 loci that were recently identified, on the contrary, are associated with both BD and CD [1]. On the immune level, Th1, Th17, CD4+, and CD8+ T cell, and γδ + T cell activities, as well as IL-12, IL-23, IL-27 and tumor necrosis factor alpha (TNF-α) levels, were increased in patients with BD as well as in CD [1]. A study has recently reported that the IL-12B levels correlated with the clinical and endoscopic disease activities of EB and CD [8].

Genetic factors cannot completely explain the emergence of BD; therefore, additional factors are essential for the pathogenesis of BD/EB. Among these factors, environmental triggers have been suspected to be associated with BD, especially microbiological agents such as streptococcal antigens and herpes simplex virus (HSV) [7]. A molecule mimicry between those microbial agents and human peptides such as the heat shock proteins (HSPs) can be also a triggering factor [7, 9]. The role of microbiota has been emphasized in recent studies, where an unbalanced gut microbiome with reduced intestinal microbial diversity has been found in BD patients, marked by a decreased butyrate production, which has been suggested to induce inflammation [7].

On the nosological level, there are two forms of EB: neutrophilic phlebitis that leads to mucosal inflammation and ulcer formation and large vessel disease (i.e., mesenteric arteries) that results in intestinal ischemia and infarction [6]. A recent study has demonstrated that thrombophlebitis in the mesenteric veins and not arteries plays a central role in the perforation in EB, suggesting that there might be distinct mechanisms of pathogenesis for EB, including mucosal inflammation and infarction due to venous obstruction [10].

3. Diagnosis

Esophageal involvement is unusual [11]. The clinical presentations are essentially ulcers, stenosis, perforation, varices, and decreased motility. The patient will present with retrosternal chest pain, dysphagia, odynophagia, hematochezia, and melena [6, 11].

The stomach is presumably the least involved gastrointestinal organ in EB. Commonly, patients present with dyspepsia and epigastric pain. Bleeding can occur on ulcers that can be found in the stomach or the duodenum [6].

Intestinal ulcerations are the main pathological features of EB [12]. Most common complication of intestinal BD was found to be perforation (12.7%), followed by fistula (7.6%), stricture (7.2%), and abscess (3.3%) [13]. The most common location of perforation is reported to be terminal ileum, ileoceocal valve, and ascending colon [6].

Pancreas, liver, and biliary system are rarely involved, the underlying phenomenon is usually vasculitis. The most prominent complication of the hepatobiliary system in BD is Budd-Chiari syndrome [6].

There are no pathognomonic tests for EB. Recently, novel diagnostic criteria and a disease activity index have been proposed in the diagnosis of intestinal BD [14, 15]. These criteria are based on endoscopic features and clinical patterns. Similar to CD, a diagnosis of EB combines clinical, endoscopic, pathological, and radiological criteria [1]. The disease activity index for intestinal Behcet’s disease (DAIBD) is categorized as quiescent, mild, moderate, and severe disease based on the total score (≤19, 20 ∼ 39, 40 ∼ 74, and ≥ 75, respectively), DAIBD includes clinical features that have been present over the preceding 7 days such as the general condition of patient, extraintestinal manifestations, intestinal complications, abdominal symptoms, fever, and stool frequency not requiring laboratory data or endoscopic findings [15]. Future studies are needed to confirm its interest in different populations and ethnics.

4. Diagnostic modalities

Studies have found that the levels of fecal calprotectin and serum anti-α-enolase antibody were significantly correlated with the disease activity of EB [16]. The rate of anti-Saccharomyces cerevisiae antibodies (ASCA) detection is remarkably higher in patients with BD, especially in patients with gastrointestinal involvement, than in controls [2]. But these biological parameters are not commonly used to assess EB in daily practice to date.

Capsule endoscopy has a major role in detecting small bowel lesions including reddened lesions, erosions, and ulcers, especially when conventional exploration remains negative [17]. Endoscopic exploration remains the gold standard in exploring EB. The typical endoscopic features found are oval-shaped large intestinal ulcerations in the ileoceocal area with deep and discrete borders. These features can vary from aphthous to deep penetrating volcano-shaped ulcerations and ulcerations with a more frequent focal to less frequently diffuse distribution, in contrast with CD [1, 6]. In this regard, a valuable diagnostic algorithm using a classification analysis of the lesions has been proposed in order to differentiate between EB and CD [18].

There are no pathognomonic histologic findings for EB. Vasculitis, which is the main characteristic of BD, can affect small veins and venules in intestinal mucosa. But histology often shows nonspecific inflammation (lymphocytic or neutrophilic infiltrations) rather than vasculitis [2]. The absence of granuloma is in favor of EB rather than CD. Nevertheless, granulomas can be absent in CD. Transmural inflammation, chronicity, and focality are not discriminatory because they are observed in both EB and CD. Normal circumferential mucosa surrounding a large ulceration is one of the characteristic histologies of intestinal BD [2, 18].

5. Differential diagnosis

EB and CD share the majority of extraintestinal manifestations, essentially oral aphthous ulcers, arthritis, uveitis, cutaneous symptoms such as erythema nodosum and pyoderma gangrenosum, and thromboembolic events. But these features have some specificities when happening in BD, which can help to differentiate EB from CD, especially on the initial setting. So, in BD, uveitis is more severe and recurrent, and it is often characterized by chronic posterior uveitis or panuveitis with necrotizing retinal vasculitis and can frequently lead to cecity if it is not correctly treated. Articular manifestations in BD commonly include arthralgia, oligoarthritis, and polyarthritis, in contrast with CD, where the most common joint features are spondyloarthritis. Genital ulcers, neurologic and vascular involvement are more common in BD [2, 13, 15]. On the intestinal level, both diseases affect the ileoceocal region with predilection. Anal complications (stricture, fistula, and abscess formation), which are frequently observed in CD, are rare in EB [15].

The endoscopic findings in EB include round/oval ulcers, punched-out lesions with discrete margins (>1 cm), focal distribution (<5 ulcers), in contrast with CD, where the ulcers are more longitudinal with cobblestone appearance. A classification score was suggested in a Korean study to help distinguish EB from CD, where it was stated that irregular/geographic-shaped ulcers and focal distributions are suggestive of EB, while segmental/diffuse lesions suggest more CD [18]. Similarly, the pathological features are slightly different between both diseases. Thus, in EB, it comprises vasculitis of the small veins and venules with deep ulcerations, without granulomas or cobblestoning, ischemic perforation, and thrombosis. In CD, transmural mucosal inflammation is noted with inflammatory cell infiltrate (lymphocytes, plasma cells) with focal crypt irregularity and granulomas [12, 15].

In addition to CD, intestinal tuberculosis is also commonly cited on the differential diagnosis, but practitioners should be aware of the existence of other less commonly cited diagnoses such as NSAID-induced ulcers of the gastrointestinal tract, which can be widely used in BD [6].

6. Management

Concerning the management of EB, there is a lack of randomized controlled studies. Knowing that EB and CD share a considerable number of genetic backgrounds, pathogenesis, and clinical features, current therapeutic strategies for EB are molded on those proposed for CD.

7. Medical management

Studies found that 5-ASA and sul-fasalazine should only be used in patients with mild to moderate disease, as the risk of relapse on ASA or sulfasalazine monotherapy increased significantly at higher disease activity levels [19]. In moderate to severe cases, corticosteroids are generally recommended as the first-line treatment for EB [20]. Treatment response to steroids generally induces remission in almost half of cases and lowers the risk of surgery [6]. Azathioprine and methotrexate are recommended in third-line treatment in patients with moderate to severe EB, who are resistant to both corticosteroids and TNF-inhibitors. The use of thiopurines after surgery has an interest in preventing recurrence in intestinal BD patients [6, 21]. The use of thalidomide, mycophenolate, and tacrolimus was reported in some case reports/series, but these are not included in current consensus statements for medical management [1, 6].

8. Anti-TNF-alpha agents

Many reports confirmed the efficacy of anti-TNF-α antibody (infliximab/adalimumab) in the treatment of EB, where the remission rate can reach 80–89% [22, 23, 24]. There are also reports on the long-term efficacy of anti-TNF-α antibodies in treating EB [22]. Anti-TNF-α antibodies were also effective in preventing postoperative recurrence with a recurrence-free state for 2–3 years. Studies have reported that infliximab at 5 mg/kg is effective in improving ulcers and subsequently maintaining remission in patients with ulcers occurring at the anastomotic site within 2 weeks after ileoceocal resection who fail to respond to conventional therapy with prednisolone, azathioprine, mesalamine, and colchicine [25].

In a recent study, authors administered anti-TNF-α antibody to 49 patients with refractory EB and demonstrated its high efficacy based on both endoscopy results and a quantitative disease activity index, with a beneficial effect on sparing corticosteroids. Besides, anti-TNF-α antibodies demonstrated sufficient efficacy to control disease activity without concomitant corticosteroids in some patients [26].

9. Tocilizumab

In a recent review, that has included 20 publications about 47 BS patients with different organ involvements refractory to previous treatment with conventional immunosuppressives and biologic agents, tocilizumab failed to improve patients with gastrointestinal involvement, with even exacerbation of symptoms in some patients [27].

10. Secukinumab

In a multicenter, retrospective study of 15 BS patients with refractory manifestations secukinumab led to a complete or partial response in 90% during a follow-up of 18 months [23]. Interestingly, 60% of these patients had intestinal involvement, and they responded completely to secukinumab, an agent that paradoxically may induce or aggravate Crohn’s disease. Thus, more research is necessary to understand the role of IL-17 in the pathogenesis of BD [5].

11. Tofacitinib

A retrospective study from China looked at the efficacy of tofacitinib 5 mg twice daily in 13 BD patients with refractory vascular, gastrointestinal, or articular involvement. In this study, tofacitinib had no effect on intestinal involvement. This was attributed to the resemblance of pathophysiology between EB and CD for which tofacitinib is already known to be ineffective [28].

12. Apremilast

This treatment led to rapid improvement of oral and genital ulcers and reduction of glucocorticoid dose with no difference between monotherapy and combination therapy. Other BS manifestations such as intestinal symptoms also improved [29], but apremilast can frequently present with severe gastrointestinal adverse effects [30], which can be limiting of its use in EB in the future.

13. Surgery

Surgical management in EB is required in cases complicated with perforation and massive bleeding and can be salutary in some cases of abdominal abscess, fistula, and stricture. Additionally, patients who are refractory to medical treatment will benefit from surgical treatment [31]. Surgery in EB will be less and less used with the rising usage of biologics.

14. Prognosis and follow-up

Clinical remission has been a long-standing goal of therapy in patients with EB, but recently, with analogy to CD, researchers are paying increasing attention to endoscopic remission, which is also termed as mucosal healing [16], which would be in the future a major therapeutic target, especially with the advent of biologics. Mucosal healing is defined as the complete absence of inflammatory and ulcerative lesions in all segments of the gut on endoscopic examination [16].

The occurrence of intestinal involvement is generally considered an indicator of poor prognosis with increased morbidity and mortality, due the important prevalence of digestive bleeding, intestinal perforation, fistulas, which will often require surgery. Risk factors for developing intestinal manifestations were found to be male gender, elevated ESR, CRP, IL-6 and decreased hemoglobin [6]. The relapses were also studied and were more likely to occur in patients with intestinal ulcers in the ileoceocal and colorectal regions or in patients with poor compliance [32]. To date, there are no established guidelines for surveillance.

15. Conclusion

Entero-Behcet can be a challenging aspect of Behcet’s disease to diagnose and to treat. It can also bear a poor prognosis. Many efforts were made to help the diagnosis, especially to distinguish it from Crohn disease, by developing classification scores and severity disease index. Treatment strategies have also benefited from the rise of biologics use with advantageous results, which has permitted to target not only clinical remission but also mucosal healing. But there is a need to provide more robust evidence-based therapeutic protocols and to establish guidelines for endoscopic surveillance.