Behçet's syndrome within the spectrum of systemic vasculitides.

Recurrent skin mucosa lesions and sight-threatening panuveitis have been recognized as the ‘classic triad’ ever since the first description. BS can also affect locomotor, cardiovascular, gastrointestinal, and central nervous systems, creating a wide range of clinical phenotypes[ 1 20 21 22 46 ] [ Figure 1 ]. The demographic and clinical features, the management strategies, and the prognosis may differ among phenotypes. In addition, the clinical spectrum may also extend from a rare presentation of an isolated single organ involvement to multiple systemic manifestations depending on genetic and epigenetic background and even geographical differences. Behcet syndrome- phenotypes: Different demographic features, clinical presentation, prognosis and treatment response

The diagnosis of BS remains primarily clinical due to the absence of specific laboratory tests. Classification and diagnostic criteria, such as the International Study Group for Behçet’s Disease (ISG)[ 23 ] and the International Criteria for Behçet’s Disease (ICBD),[ 24 ] have been developed to improve diagnosis. These criteria emphasize recurrent mucocutaneous lesions, eye involvement, and pathergy testing, with the ICBD incorporating vascular and neurological involvement, as well. The ICBD exhibits higher sensitivity (94.8%; 95% CI: 93.4–95.9) than the ISG criteria (85.0%) while maintaining acceptable specificity (90.5%; 95% CI: 87.9–92.8), compared to the ISG’s higher specificity (96.0%).[ 24 ] Despite their utility, both of the criteria face several limitations. A major criticism is the reliance on the pathergy test, which has shown declining sensitivity over time.[ 25 ] This is also true for the complete BS with “original triad,” which has become less common over recent decades.[ 26 ] Thus, diagnostic criteria might be prone to skip cases with incomplete presentation, such as isolated ocular or vascular involvement. This limitation is particularly important when criteria are applied in routine clinical evaluations while planning management in an individual patient rather than in academic research settings. Fortunately, one might not find it difficult to make a differential diagnosis in the majority of cases in BS, as major organ involvement could be quite specific despite the low specificity of skin-mucosa lesions.[ 1 ] For instance, in the case of a patient presenting with nongranulomatous panuveitis with veno-occlusive features and a relapsing course, the presence or absence of typical skin-mucosa lesions may not significantly influence diagnosis.[ 27 ] Similarly, in Hughes–Stovin syndrome, the presence of pulmonary artery aneurysms (PAA) with venous thrombosis should prompt urgent treatment despite the absence of skin-mucosa lesions.[ 28 ] On the other hand, gastrointestinal involvement, which on its own is difficult to discern from CD, without typical skin-mucosa findings.[ 29 ] Meanwhile, given the severity of the situation, as long as immunosuppressive treatments, such as antitumor necrosis factor (TNF) agents, are initiated, whether the condition is CD or BS would also not matter. Efforts have been made to develop organ-specific diagnostic criteria, particularly for ocular involvement. Tugal-Tutkun et al . tried to define the sensitivity and specificity of ocular lesions in diagnosing Behçet’s uveitis using color fundus photographs and also proposed an algorithm for diagnosis based solely on ophthalmological findings.[ 30 31 ] However, more efforts are needed for organ-specific criteria.

BS is most prevalent along the historic “Silk Road,” extending from the Mediterranean to the Far East, where HLA-B51 (a MHC Class I variant allele) prevalence is also high.[ 10 ] Turkey has the highest prevalence at 421 per 100,000 people.[ 11 ] Clinical manifestations, particularly, vascular and gastrointestinal involvement, vary between geographical regions, reflecting genetic and environmental influences.

Gastrointestinal (GI) system involvement is present in approximately 10%–20% of BS patients, with a significant geographical variation. Intestinal manifestations tend to develop 4–6 years after disease onset without substantial gender predilection.[ 95 96 ] The differential diagnoses include CD, intestinal tuberculosis, nonsteroidal anti-inflammatory drug-induced enteropathy, and neoplasia.[ 95 ] The differentiation from CD poses a challenge.[ 29 95 ] Large, deep, round, or oval-shaped ulcers with discrete borders, commonly described as “punch-out” ulcers in the ileocecal region, are characteristic of BS.[ 95 96 97 ] Unlike CD, cobblestone appearance, granulomatous inflammation, and stricture formation are quite rare in BS.[ 34 95 96 ] Instead, neutrophilic phlebitis has been implicated in the mucosal inflammation in GI involvement due to BS.[ 35 95 ] Ulcers of BS can lead to perforation, fistula formation, and bleeding, necessitating emergency surgical intervention.[ 95 96 ] Age under 25 at diagnosis, history of laparotomy, and volcano-shaped ulcers on colonoscopy were identified as risk factors for perforation.[ 98 ] Mesenteric arteries can also be involved in the disease process, potentially leading to intestinal ischemia and infarction.

The prognosis is highly variable and depends on the severity of organ involvement, demographic factors, and timely initiation of treatment. More severe disease is observed in endemic regions such as Turkey and Middle Eastern countries, and men generally have a worse prognosis. Mortality is primarily driven by vascular and neurological complications, with PAA, BCS, p-NBS, and frequent disease exacerbations being the most significant contributors.[ 22 99 ] Long-term studies report varying mortality rates, ranging from 5% over a median follow-up of 7.7 years to 10% after 20 years.[ 22 99 ] Advances in imaging, early diagnosis, and biologic therapies have significantly reduced overall mortality and morbidity.

NBS affects approximately 5%–10% of BS patients, with a higher prevalence in men and younger individuals.[ 1 22 ] The mean age of neurological involvement is typically in the third or fourth decades, occurring about 3–6 years after the initial diagnosis of BS.[ 35 ] NBS characteristically presents frequently in two major forms: parenchymal NBS (p-NBS) accounting for about 80% of cases and nonparenchymal such as CVST.[ 35 ] While parenchymal form clusters with ocular involvement, CVST frequently coexists with venous vascular involvement.[ 46 62 ] P-NBS primarily involves the brainstem, diencephalon, and basal ganglia.[ 35 88 89 ] Spinal cord involvement occurs in approximately 10% of NBS cases.[ 90 ] Clinically, p-NBS manifests as acute or subacute brainstem syndromes, presenting with headache, cranial nerve palsies, ataxia, dysarthria, and behavioral changes. Magnetic resonance imaging (MRI) studies frequently reveal T2 hyperintense lesions in the brainstem, often extending into the diencephalon and basal ganglia.[ 35 89 90 91 ] Acute disease is marked by extensive perilesional edema, indicating perivenular inflammation and vasogenic edema.[ 35 ] These lesions typically resolve or leave minimal residual changes, similar to the healing process of venous infarctions. Spinal cord lesions are usually longitudinally extensive, affecting multiple segments, with a preference for the cervical and thoracic parts.[ 90 ] The “Bagel Sign,” a T2-weighted MRI pattern, is typical for spinal involvement. Diffusion tensor imaging has demonstrated significant microstructural alterations in white matter tracts, strongly correlated with cognitive impairments and disease severity in BS patients with p-NBS.[ 92 ] Similarly, milder white matter changes were observed in patients without neurological involvement, suggesting possible subclinical involvement. p-NBS is associated with significant motor and cognitive impairments. Early intervention is critical, as the rate of severe disabling sequels or death in p-NBS is around 25% after a median follow-up of 6 years.[ 93 ] Male sex, early disease onset, paresis at the onset of disease, relapsing course, and brainstem lesions are significantly associated with poor outcomes. Patients often exhibit subacute or chronic onset, presenting with symptoms of increased intracranial pressure.[ 94 ] Typically, the superior sagittal and transverse sinuses are affected. Unlike other CVSTs due to other causes, focal neurological deficits and venous infarctions are uncommon. Relapses are rare, and prognosis is good; however, occasionally, optic atrophy may occur.[ 94 ] The differential diagnosis of p-NBS includes multiple sclerosis, neuro-sarcoidosis, neuromyelitis optica spectrum disorders, CNS vasculitis, lymphoma, glial tumor, and infectious conditions such as tuberculosis or herpes simplex encephalitis.[ 35 ] Multiple sclerosis remains the most challenging one, particularly in regions where both diseases are prevalent. Diagnosis relies on systemic BS features and distinct radiologic patterns [ Figure 5 ]. CVST should be differentiated from other thrombophilia syndromes [ Table 2 ]. Magnetic resonance imaging findings of neurological involvement in Behcet syndrome. (a) MIP image of contrast-enhanced MR venography showing irregularity and narrowing of left transvers sinus suggesting cerebral venous sinus thrombosis, (b) Sagittal T2W and, (c) Axial T2-weighted images showing left mesodiencephalic increased signal intensity lesion which is typical for parenchymal neuro-Behcet syndrome

Ocular involvement is the most common major organ manifestation in BS. Its prevalence varies by clinical setting, ranging between 35% and 90%.[ 60 ] Uveitis typically develops within 2–4 years of skin-mucosa lesions but can present as the initial symptom in up to 20% of cases.[ 60 ] Cluster studies suggest that eye disease can occur as a distinct phenotype; however, an association with parenchymal neuro-Behçet’s syndrome (NBS) has been also reported [ Figure 1 ].[ 46 58 59 61 62 ] Men and younger patients tend to experience more severe disease and are at a higher risk for vision loss.[ 1 20 21 22 60 63 64 ] It is characterized by bilateral, nongranulomatous panuveitis and retinal vasculitis, most commonly presenting as periphlebitis.[ 27 ] The hallmark features include relapsing retinal inflammation, vitritis, macular edema, and occlusive retinal vasculitis.[ 27 ] Retinal vascular involvement is seen in about one-third of the cases and involves most commonly branch retinal vein and peripheral retinal veins.[ 65 ] These occlusions are associated with a poorer prognosis and significant visual impairment. Histopathological examination discloses obliterative periphlebitis and venous thrombosis accompanied by inflammatory cell infiltration.[ 66 ] Complications such as optic atrophy, macular scarring, and neovascularization may occur, leading to irreversible tissue damage and a significant decrease in visual acuity.[ 63 ] A total of 23% of the patients developed legal blindness after a mean of 10.3 ± 8.4 years follow-up in a multicenter study including 1465 patients.[ 64 ] Patients with BS have a 10-fold higher risk of complete vision loss risk and a 4.9-fold higher risk of visual impairment compared to the general population.[ 67 ] Imaging techniques such as fluorescein angiography, the gold standard for evaluating retinal and choroidal vascular changes, and optical coherence tomography, which detects early retinal thickness changes, are essential for monitoring disease progression.[ 68 ] Advances in biologic therapies, particularly anti-TNF agents, have significantly improved visual outcomes by effectively controlling inflammation.[ 68 ] A study comparing BS uveitis patients from 2009–2015 to 2016–2021 revealed a lower overall complication rate in the latter group, highlighting the positive impact of the increased use of biologics.[ 69 ] Despite these advances, early diagnosis and treatment are critical to prevent permanent damage.

The etiopathogenesis of BS remains unclear, but it is likely triggered by an exaggerated inflammatory response driven by enhanced innate immune activation to nonspecific stimuli in genetically predisposed individuals.[ 4 7 8 12 ] HLA-B51-a MHC Class I allele-is identified as the strongest susceptibility factor.[ 7 8 ] Genetic studies also highlight the role of endoplasmic reticulum aminopeptidase gene polymorphisms in HLA-B51-positive patients and other non-HLA genetic associations (such as IL23R and IL10), linking BS to spondyloarthropathies (SpA), particularly Crohn’s disease (CD).[ 8 13 14 15 ] In this setting, the recently suggested concept of MHC-I-opathy links BS to SpA based on shared immunopathogenic mechanisms involving MHC Class I molecules and overlapping clinical features.[ 6 ] MHC-I-opathies are characterized by tissue-specific inflammation at barrier sites and stress-prone areas. Innate and adaptive immune responses, particularly involving CD8 + T cells and the IL-23–IL-17 axis, are suggested to contribute to their pathogenesis. There are several issues with the inclusion of BS in this concept, the most important being its association with HLA-B51.[ 1 16 ] Although BS is strongly associated with HLA-B51, this allele’s role in disease pathogenesis is complex and does not conform to the patterns observed in other MHC-I-opathies. Only about half of BS patients carry HLA-B51, suggesting a weak predictive value and among the carriers, HLA-B51 exhibits a limited association with specific BS manifestations.[ 10 17 ] A recent meta-analysis indicated that the HLA–B51/B5 allele is responsible for 32%–52% of BS cases across different geographic subgroups.[ 10 ] Moreover, a consistent and significant MHC-I association has not been demonstrated, particularly in patients from nonendemic regions, where the prevalence of HLA-B51 is notably lower.[ 18 ] Other than the HLA-B51 issue, unlike typical MHC-I-opathies, BS does not exhibit characteristic axial or enthesitis-dominant features. Instead, it presents a broader range of clinical manifestations, including vascular, neurological, and mucocutaneous involvement, which are marked by innate immune dysregulation and prominent venous inflammation. BS shares several characteristics with autoinflammatory conditions, most notably familial Mediterranean fever (FMF).[ 4 19 ] Both diseases have ancient origins, are prevalent in Middle Eastern and Mediterranean populations, and respond to colchicine treatment. Unlike classical autoimmune diseases, they lack autoantibodies, antigen-specific T cells, and hyperactive B cells, instead exhibiting heightened innate immune responses. It is important to note that BS and FMF are completely different diseases with unique clinical features. However, episodic, self-limited attacks are common to both, although BS presents with more complex lesions and risks permanent damage. Studies further indicate that BS and FMF may co-occur more often than expected, and both conditions are strongly associated with MHC Class I-related disorders.[ 20 ] Pathogenic variants, such as p.Met694Val, which activate the inflammasome complex, are more frequent in BS patients with vascular involvement and positive pathergy but are associated with lower eye disease.[ 19 ] These suggest a potential role for MEFV variants in regional phenotypical differences.

Vascular involvement primarily affects young males, runs a relapsing course, exhibits a marked tendency for thrombosis, and demonstrates a predilection for venous involvement. It typically occurs within the first 5 years of disease onset and could be initial disease manifestation in about one-third.[ 22 70 ] Vascular involvement is an entirely distinct phenotype in BS [ Figure 1 ], appearing without the concomitant presence of mucocutaneous lesions or uveitis.[ 32 46 58 59 ] A well-recognized example is Hughes–Stovin syndrome (see diagnosis), now considered an incomplete form of BS.[ 28 ] The main types, specific features, and complications associated with vascular involvement are shown in Table 2 . Differential features and specific complications of various clinical forms CTEPH: Chronic thromboembolic pulmonary hypertension, IVC: Inferior vena cava, DVT: Deep vein thrombosis, CVST: Cerebral venous sinus thrombosis All types of veins and arteries can be involved in BS; however, lower extremity deep venous thrombosis (DVT) with or without superficial vein involvement is the most common vascular manifestation comprising up to 80% of all vascular events.[ 70 ] While not specific to BS, the relapsing course reaching up to 45% within 2 years, along with its bilateral involvement, affecting both deep and superficial veins and diffusely extending nature of thrombosis, particularly in young males, is characteristic.[ 71 72 ] The presence of recurrent superficial thrombophlebitis should prompt consideration of BS, even in patients with incomplete ISG criteria. DVT may lead to postthrombotic syndrome, intractable stasis ulcers, and chronic venous insufficiency, significantly impairing quality of life.[ 71 73 ] Thromboses of major veins, such as the superior or inferior vena cava (IVC) and hepatic veins, are also common.[ 74 ] IVC involvement is typically seen in the infra-hepatic part as a silent progression of iliofemoral vein thrombosis [ Figure 3 ]. Despite the conspicuous thrombotic tendency in BS, thromboembolic events are rare because vascular involvement is commonly associated with intense inflammatory thrombosis, which is strictly adhered to the vessel wall.[ 34 75 76 ] Less commonly, Budd–Chiari syndrome (BCS) can be seen due to hepatic or supra-hepatic IVC thrombosis and is associated with grave outcome.[ 77 ] Although silent forms of BCS are associated with better prognosis. Superior vena cava thrombosis may lead to complications such as sleep apnea and persistent pleural effusions.[ 78 ] Cerebral venous sinus thrombosis (CVST) takes a major part in the vascular phenotype, often clustering with DVT, IVC, and pulmonary artery involvement (See Neurological manifestations).[ 70 79 ] While CVST is the initial vascular event in juvenile patients and exhibits a low relapse rate, it can predict the development of other major vascular complications during follow-up, particularly in young males. On the other hand, CVST may present as the sole vascular involvement in female patients. Venous involvement in Behcet syndrome. (a) Collaterals due to Vena Cava Superior Thrombosis (red arrows), (b) Stasis Dermatitis and Venous Ulcer (red circle), (c) Superficial Thrombophlebitis (red arrows), (d) Jugular Vein Distension due Vena Cava Superior Thrombosis (red arrow) Arterial involvement is less common but potentially life-threatening. It is characterized by aneurysms and in situ thrombosis. Pulmonary arteries are more likely to be affected compared to aorta or peripheral arteries.[ 22 70 75 ] While PAA is the hallmark of BS, recent studies indicate that isolated in situ pulmonary artery thrombosis became the dominant presenting form, whereas PAA is less common [ Figure 4 ].[ 80 81 ] Major complications include chronic thromboembolic pulmonary hypertension, pneumothorax caused by large cavities, and bronchial artery enlargement.[ 75 82 ] Nonpulmonary arterial involvement tends to occur later in the disease course, presenting with symptoms such as claudication, pulsatile masses, or ischemic manifestations.[ 83 ] In addition, peripheral artery aneurysms are sometimes incidentally detected on computed tomography imaging performed for unrelated indications, often without accompanying symptoms. Cardiac involvement, although rare, encompasses a spectrum of conditions, including intracardiac thrombosis, aortic regurgitation, pericarditis, myocarditis, and coronary artery aneurysms.[ 76 84 ] These manifestations may appear as the initial presentation of BS. Intracardiac thrombosis distinctly occurs on the right side, is often associated with pulmonary arterial involvement and could develop into endomyocardial fibrosis, leading to severe right heart failure.[ 76 ] Arterial involvement in Behcet syndrome. (a) Left Common Femoral Artery Aneurysm (red circle), (b) Venous Infarcts due Pulmonary Artery Thrombosis (red arrows), (c) Pulmonary Artery Thrombosis (red arrow), (d) Pericardial Effusion (red arrows), (e) Pulmonary Artery Thrombosis with Mural Thrombi (red circle) (f) Intracardiac Thrombosis (red arrow) Growing evidence indicates that VWT in the lower extremity veins is increased in BS compared to other inflammatory diseases and healthy controls as assessed by the US.[ 36 37 38 39 40 ] VWT is particularly elevated in BS patients without overt vascular involvement, implying that it may serve as an early marker of subclinical vascular inflammation.[ 36 ] Measurements of VWT, particularly using a cutoff value of 0.5 mm for the common femoral vein, have shown potential as a diagnostic tool to differentiate BS from other conditions.[ 38 ] A recent study using this time MR venography observed that there is diffuse and generalized venous system pathology, with significant vein wall thickening and perivascular abnormalities in BS patients compared to controls.[ 41 ] Having said that, the clinical utility of VWT remains controversial due to variability in sensitivity, specificity, and measurement techniques across US studies.[ 36 37 38 39 40 85 86 ] In addition, lower diagnostic performance in nonendemic regions may limit its widespread application.[ 87 ] The pathological significance of increased VWT also remains unclear – whether it represents active inflammation, chronic fibrosis, or a predisposition to thrombosis is yet to be determined.

Behçet’s syndrome (BS) is a complex inflammatory disorder of unknown etiology.[ 1 ] It is distinguished by its unique geographical distribution, relapsing course, severe disease course among young males, and an increased tendency for thrombosis, particularly in the veins. It has been difficult to categorize BS and place it rightfully into a specific cluster. Scholars have long debated whether it is an autoimmune or autoinflammatory disease or a member of the spondyloarthropathy family or more recently a MHC-1-opathy.[ 2 3 4 5 6 7 ] Evidence suggests it incorporates aspects of all these conditions, with genetic predisposition playing a crucial role in its pathogenesis.[ 8 ] Although it is currently classified as a variable vasculitis,[ 9 ] its precise categorization within the spectrum of systemic vasculitides remains also challenging. This review aims to discuss the problems with these classifications, particularly within the spectrum of systemic vasculitides and outlines distinctive clinical features in light of current evidence.

BS has been classified as a variable vessel vasculitis. However, this categorization, like other classification attempts, seems to fail. Unlike classical vasculitides, BS is characterized by neutrophil-dominant inflammation, prominent venous involvement, and frequent thrombosis without typical histopathological features such as fibrinoid necrosis, granulomatous inflammation, or immune complex deposition. Besides venous thrombosis, small vein or venule inflammation appears to be the primary pathological mechanism affecting many organ systems. Recent findings of increased VWT in patients without overt vascular involvement further support the primary role of venous pathology in BS. However, the link between venous involvement and enhanced innate immunity response remains incompletely understood. Emerging studies on the contribution of neutrophils and NETs to thrombogenesis may provide some critical insights. BS also shares genetic and clinical traits with MHC-I-opathies and autoinflammatory diseases, such as its relapsing course and predilection for young males, yet remains unique. Adding to this complexity, there are multiple distinct clinical phenotypes, each with its own demographic, clinical, prognostic, and therapeutic characteristics, suggesting that this condition may not be a single pathological entity. Thus, further research is needed to clarify its complex pathogenesis. There are no conflicts of interest.