Current Understandings in Behçet Disease
- 1. Department of Paediatrics, The Hospital for Sick Children, Canada
- 2. Department of Paediatric Emergency Medicine, Paediatrics, The Hospital for Sick Children, Canada
- 3. Department of Paediatrics, University of Toronto, Canada
- 4. Department of Paediatrics, St. Joseph’s Health Centre, Canada
- 5. Departments of Rheumatology, Paediatrics, The Hospital for Sick Children, Canada
- 6. Department of Newborn and Developmental Pediatrics, Sunnybrook Health Sciences Centre, Canada
Behçet disease (BD) is a relapsing inflammatory disorder characterized by mucocutaneous ulcers 9both oral and genital) and often involves the neurological, ophthalmological, musculoskeletal, gastrointestinal and vascular systems. While the pathoetiology of BD is not yet known, its features are thought to be related to an underlying systemic vasculitis. Research that focuses on the immunological phenomena that drive this disease aims to better understand current treatments and uncover new therapies. With recent data suggesting that biologics may be beneficial in managing the life-threatening complications of BD, particularly its vascular complications, there is increasing evidence to support the use of biologics, including the TNF-a inhibitors, as first-line therapy.
She D, Soon GS, Banihani R, Etoom Y (2018) Current Understandings in Behçet Disease. JSM Arthritis 3(1): 1028
- Behçet Disease
Once known as Adamantiades-Behçet disease, the condition now referred to as BD was first described by Benediktos Adamantiades in 1930  and HulusiBehçet in 1937  who each identified syndromic co-presentations of aphthous ulcers and hypopyon. Curth  went on to develop the first known diagnostic criteria, which included mucocutaneous findings such as oral ulcers, eye involvement, rheumatic pain, cutaneous infections, genital ulcerations and pathergy. While there have since been at least 16 sets of diagnostic criteria that have attempted to characterize the condition [4-13], the exact underlying pathophysiological mechanisms and their clinical manifestations remain unknown. Since this clinical entity imparts significant morbidity and mortality, there remains on going interest in developing refined diagnostic criteria and improved treatment options to best manage these patients.
This article reviews current understandings in BD, including its clinical presentation, pathophysiology, treatment options and prognosis.
PRESENTATION AND EPIDEMIOLOGY
BD tends to present in the fourth and fifth decades of life, with increased incidence along the geographical origins and historical route of the Silk Road from Japan to the eastern edge of the Mediterranean Sea. There is comparatively lower prevalence in North America and northern Europe . Although the gender distribution is roughly equal on a global scale, there is particular gender prevalence depending on country of origin , with increased female prevalence in eastern Asia, northern Europe and the United States [16-18] (though one cohort study in China found a very slight predominance of males in their sample ) and increased male prevalence in the Middle East .
Despite the differences among stvarious sets of diagnostic criteria, BD remains classically described as a combination of aphthous ulcers (with oral lesions often as the first presentation  and genital lesions a more specific finding ) with systemic involvement that may include ophthalmological findings , the central and peripheral nervous systems , the gastrointestinal system [14,22], vascular pathways (both arterial and venous)  and arthritis . More rarely, the renal [25,26] and cardiopulmonary systems  may be involved. There is notably some gender difference in the prevalence of these presentations, with ophthalmological, vascular and neurological presentations more common in males while mucocutaneous lesions and joint involvement are more common in females .
The clinical manifestations of BD are thought to be related to an underlying vasculitis, which is unique in its propensity to involve blood vessels of all sizes (small, medium and large) in both the arterial and venous systems . Large vessel disease can be seen in up to half of patients diagnosed with BD, with veins being more commonly affected . Venous complications often present as superficial thrombophlebitis, though rarer involvement of the large veins (such as the vena cavae and hepatic veins) has also been described. Large artery complications (such as the pulmonary arteries and abdominal aorta) involve aneurysm development secondary to inflammation , with pulmonary artery aneurysms being the most common cause of mortality [30,31]. Critically, many of the other involved systems exhibit evidence of vascular involvement, with their clinical manifestations as secondary sequelae.
Ophthalmological features of BD are well described, perhaps owing to their history as some of the primary findings originally linked to the mucocutaneous symptoms of the condition . All parts of the eye can become involved; findings may include anterior and posterior uveitis, retinal vasculitis and cataract development .
Neurological involvement in BD often foretells severe disability, with Noel et al., reporting a significant portion of patients becoming dependent or deceased after a median follow-up of 73 months . Pathologically, clinical symptoms occur secondary to parenchymal inflammation with meningoencephalitis seen on histopathology, though non-parenchymal disease has also been observed. Central nervous system involvement often presents as movement disorder-like symptoms, such as chorea and dystonia, as well as cognitive dysfunction . Second only to pulmonary artery aneurysms, central nervous system involvement is the most common cause of mortality in BD [30,31].
Gastrointestinal involvement in BD can present non-specifically, with symptoms including abdominal discomfort and pain, nausea, vomiting, diarrhea and gastrointestinal bleeding. Symptoms often manifest 5-6 years following initial presentation . Gastrointestinal involvement has been described as evolving in one of two fashions: 1 ulceration (often in the ileocecal region though the entire alimentary tract can become involved) and large vessel disease, causing downstream intestinal ischemia; or  neutrophilic phlebitis which provokes mucosal inflammation . Clinically, patients with BD present similarly to the initial course of Crohndisease; as such, efforts have been made to define significant differences between the two entities to ensure better clinical delineation, including the use of endoscopy and radiographic findings .
Musculoskeletal involvement in the form of joint symptoms can be seen in over half and nearly up to 75% of patients, with 10% reporting joint involvement as the initial finding . Acute knee mono arthritis is the most common presentation  though elbow and radiocarpal joint involvement is often described. Ankylosing spondylitis is also documented  though less commonly than monoarthritis .
In contrast to the prior systems described, renal and cardiac disease tends to be uncommon in BD. Renal involvement may manifest in different ways including renal tubular acidosis, renal artery stenosis, renal vein thrombosis and chronic glomerulonephritis, with end stage renal disease being quite rare . Cardiac symptoms include chest pain, myocardial infarction and heart failure, though these typically occur in a very small subset of patients .
Despite nearly 90 years of clinical awareness, the precise pathophysiology of BD remains unexplained . Though there are multiple associations, including a number of clinical and biochemical findings, there is ongoing uncertainty regarding the precise nature of the disease mechanisms and their clinical manifestations.
Genetically, BD has been found to be closely associated with immune-function related genes, specifically HLA-B5 and HLA-B51, the former being more prevalent in the Far East and Mediterranean populations while the latter is more common among East Asian patients . Interestingly, environmental interaction with HLA-B51 appears to play a key role in influencing development of the disease; certain ethnic populations, such as in the Italian and Portuguese populations, have a similar distribution of HLA-B51 and yet notably less incidence of BD in comparison to those ethnic groups distributed along the Silk Road . Beyond HLA-B5 and HLA-B51, the advent of genome wide association studies has also highlighted several other genes that appear to be significantly associated with BD including HLA-A26 , IL-10, IL-23R, IL-12B2 , and STAT4 . BD also shares loci implicating high risk with other autoimmune diseases such as inflammatory bowel disease (in the form of IL-10 and IL-23R) and ankylosing spondylitis (via MHC class I region and ERAP1- pathway related genes) . Familial inheritance has also been demonstrated, with evidence of genetic anticipation and later generations presenting with symptoms at earlier ages .
It is important to recognize that many of the genes above are implicated in the biological processes the govern Th1 and Th17 regulation. At the cellular level, activated lymphocytes, including Th1, appear to drive the inflammatory processes that cause some of the clinical manifestations through the release of pro-inflammatory cytokines . Recent studies have suggested that Th17 and IL-17 may also play contributory roles in promoting neutrophil infiltration into disease-affected tissues, thus aggravating or potentially initiating certain disease features . Cell studies involving peripheral blood samples from BD patients have demonstrated that the pro-inflammatory effects of IL-17 and IL-21 drive the maturation of Th1 and Th17 cells while dysregulating T-regulatory cell development, which in turn were associated with BD patient disease severity; interestingly, IL-21 blockade in vitro was seen to reverse this trend .
As early as Behçet’s initial description of the disease, there has also been speculation that an infectious agent may play a role in its etiology [2,3] with studies having found higher levels of antibodies against S. pyogenes and S. sanguinisin BD patients as well as higher scores on dental plaque indices  and a higher incidence of oral ulcer development following dental work in BD patients . From a mechanism perspective, it is thought that microbial by-products, such as heat shock proteins (HSPs), can effectively activate two pathways that can promote the development of BD. In one pathway, detection of bacterial HSPs by HSP-specific T cells through molecular mimicry can promote Th1 cytokine release (including IFN-γ and TNF-α)and cell-mediated cytotoxicity. From an adaptive immunity standpoint, BD patients appear to possess a larger quantity of antibodies against HSP molecules as released by S. pyogenes and S. sanguinis, which in vivo mouse models have shown can induce T-cell activation and cause some of the clinical features of BD to appear such as uveitis . It is also interesting to note that HSP60 has been implicated in inducing T-cell damage to endothelial cells, which stimulates VEGF expression and provoking vasculitis and thrombosis .
The implication of current pathophysiological research suggests that an interaction between the Th1 and Th17 pathway and an environmental stressor (such as dental work leading to exposure to S. sanguinis) creates a pro-inflammatory state that leads to VEGF expression and subsequently vascular inflammation; the downstream effects to end-organs constitute the myriad presentations of BD.
Despite the improved understanding of the pathophysiology of BD, the precise mechanisms by which these findings translate to the clinical manifestations and their complications remain unknown. Further research is required to better understand the features and potential targets for treatment of the disease.
There are many sets of proposed diagnostic criteria that have been developed across multiple patient populations in varying geographical regions to identify patients with BD. Since there is currently no pathognomonic finding or laboratory test to provide a definitive diagnosis, the impetus to describe the features that constitute a diagnosis remains critical to understanding the nature of the disease.
Limitations in many of the diagnostic criteria sets exist because they were developed in patient populations within varying geographical boundaries. More recently, however, criteria were developed to overcome these geographical limitations by the International Study Group (ISG) for BD in 1990 [50,51] and the International Criteria for BD (ICBD), which was created in 2006 ; the latter have subsequently been revised, most recently in 2014  utilizing patient datasets across multiple international centres and validated across multiple patient cohorts .
The ISG criteria suggest a diagnosis of BD when the clinical history is suggestive of:
- Recurrent oral ulceration (minor aphthous, major aphthous or herpetic form ulceration recurring at least three times in one 12-month period, observed by physician or patient)
AND at least ≥2 of the following:
- Recurrent genital ulceration (aphthous ulceration or scarring observed by physician or patient)
- Eye lesions (anterior uveitis, posterior uveitis, cells in the vitreous on slit-lamp examination or retinal vasculitis detected by an ophthalmologist)
- Skin lesions (erythema nodosum observed by physician or patient, pseudofolliculitis, papulopustular lesions or acnei form nodules observed by physician or postadolescent patient not receiving corticosteroids
- Pathergy (skin reaction to a needle prick observed by physician at 24-48h)
According to the ICBD criteria, a diagnosis is based on a score ≥4 points using the following criteria (with point values as indicated):
- Recurrent oral aphthous ulcers – 2 points
- Skin lesions (papulopustules, erythema nodosum, thrombophlebitis) – 1 point
- Vascular involvement (arterial or venous thromboses, aneurysms) – 1 point
- Recurrent genital aphthous ulcers – 2 points
- Ocular involvement (hypopyon-iritis, uveitis) – 2 points
- Central nervous system involvement – 1 point
- Positive pathergy test – 1 point
Davatchi et al., tested the ISG and ICBD across several international patient cohorts and found that the ISG was more specific, but less sensitive, with the ICBD exhibiting the inverse . Regardless, there is an ongoing need for further testing of these criteria across additional patient cohorts to better assess the suitability of these criteria.
There is no curative treatment for BD. The goal rather is to control acute exacerbations and prevent organ damage. Presently, the treatment of BD focuses largely on active symptoms such as topical corticosteroids for oral and genital ulcers and ocular inflammation. There remains poor consensus on the selection of agents such as oral colchicine, dapsone, azathioprine or systemic steroids. Given the multiple organ systems that may be involved in the disease, an individualized team approach is recommended, with care providers and specialists providing specific management plans as appropriate.
A Cochrane review conducted in 2000 evaluating 10trials and 679 patients found that many of the treatments considered standard for symptoms of BD were not effective. There was some evidence to support treatment of eye-related complications with cyclosporine and azathioprine and arthritis with benzathinepenicillin, but ultimately the review called for further clinical trials to better assess the suitability of alternate treatments . As such, management of BD requires ongoing research to explore potential evidence-driven first line agents.
Biologics have recently become a focused interest in the treatment of BD, particularly in those instances where patients are refractory to conventional therapy . Studies reviewing the safety and efficacy of TNF-α inhibitors to treat severe complications of BD are becoming more readily available , with infliximab having been shown across several case studies of exhibiting effectiveness in the treatment of BD [58,59,60]. While most studies examining the use of biologics focus on anti-TNF-α therapies, one more recent trial has shown effectiveness of phosphodiesterase-4 inhibitors in treating BD-related oral ulcers . There has also been adoption of other monoclonal antibodies in the treatment in BD. Alemtuzumab, a monoclonal antibody that binds to CD52 and targets CD52-bearing lymphocytes for destruction, is an agent of interest in patients refractory to other treatments, though this seems limited to the subcutaneous form of delivery .
Given the evidence of the role of IL-6 and IL-27 in promoting disease activity as part of the Th17 pathway, there is also interest in IL-21 blockade with ustekinumabas a potential treatment to reverse the promotion of Th17 and restore T-regulatory cell activity [46,63]. It has also been suggested that treatment refractory BD may reflect that different organ system presentations may constitute disease states that involve over-expression of specific cytokines in the Th1 and Th17 pathway; as such, some groups have investigated the use of other biologics in various organ presentations of BD to determine if improved outcomes are possible. To date, some success has been seen with tocilizumab in ocular BD  and abatacept in one case study of a woman suffering from both ocular and skin-based manifestations of the disease .
Surgical treatment remains an important option for some subsets of patients. Intestinal involvement, for example, may require surgical management depending on the complications that a rise such as fistula formation, continued failure of medical therapy or severe gastrointestinal bleeding that cannot be medically controlled. However, although gastrointestinal involvement in BD has been clinically compared to inflammatory bowel disease, knowledge translation has proven difficult, with noconsensus regarding the precise surgical approach in these patients [66,67].
A diagnosis of BD carries an increased risk of morbidity and mortality from its associated complication . Multivariate analyses have been performed, evaluating for risk factors correlating with mortality in BD, and have generally found that male gender, arterial involvement, and those with an increased number of disease flares were found to be significantly and independently associated with increased mortality . This increased risk is likely in keeping with pulmonary artery aneurysms occurring almost exclusively in males . In addition, males who presented with more organ system involvement were found by Ugurlu et al., to also be associated with the development of more severe disease .
BD is a systemic vasculitis with characteristic mucocutaneous findings and often multi-organ involvement. The condition often presents in the fourth and fifth decades of life and equally among males and females, though regional differences in prevalence do exist. Diagnosis can be challenging, with validation studies of the ISG and ICBD diagnostic criteria ongoing to allow improved recognition and thus early intervention of the disease.
Patients with BD can expect their outcomes to improve following diagnosis, although this is dependent on early identification and management of critical complications of the disease. Current studies have shown that male patients, arterial involvement and increased frequency of flares is associated with worse prognosis; as such, care providers should individualize management strategies to recognize that this subset of patients will require increased vigilance with respect to identifying and treating potential complications early in the disease course.
Research in BD continues to investigate the immunological profile of the disorder to better understand the pathophysiology of the disease and evaluate new treatments aimed at the most severe complications. Many studies have begun to show promise with respect to the use of TNF-α inhibitors as a means of treating life-threatening complications, and newer studies are demonstrating that other biologic agents may prove to be useful in managing organ-specific symptoms of the disorder. Innovative strategies and ongoing evaluation will be required to assess whether biologics may one day become first-line treatment of patients with BD.
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