Phenotypic Dichotomy in Behçet’s Disease: Insights into Vascular,Neurological,and Ocular Subtypes

Behçet’s Disease (BD) is a form of variable vessel vasculitis characterised by multisystem involvement. A distinguishing feature of BD—unlike other types of vasculitides—is its unique vascular involvement. This vascular form of the disease, known as vascular Behçet’s disease (VBD), affects both veins and arteries, presenting with a wide range of manifestations such as superficial thrombophlebitis, deep vein thrombosis, aneurysms, stenosis, and vaso-occlusive lesions. Numerous studies have shown that VBD is more commonly seen in males and is associated with higher disease activity. ¹ It is also a significant contributor to both morbidity and mortality in BD. Among the vascular complications, involvement of large veins such as the superior or inferior vena cava, hepatic vein thrombosis (as seen in Budd–Chiari syndrome), and aneurysms or pseudoaneurysms in major arteries like the abdominal aorta, femoral artery, or pulmonary artery are particularly severe and potentially life-threatening.^2,3 In addition to vascular involvement, neuro-Behçet’s disease (NBD) is a rare but serious form of BD that affects the nervous system. It carries a high risk of relapse, long-term neurological complications, and mortality. ⁴ Similarly, ocular BD, another rare and severe form of the disease, primarily affects young adult males and can lead to significant visual impairment or blindness. ⁵ All these severe manifestations of BD—whether vascular, neurological, or ocular—can be organ-threatening or life-threatening. Therefore, early diagnosis and timely initiation of aggressive immunosuppressive therapy are crucial to prevent irreversible damage. Diagnosis of BD is entirely clinical due to the absence of specific serological markers or definitive histopathological features, which distinguishes it from other vasculitides. This makes diagnosis particularly challenging, considering that in a significant proportion of cases of these subtypes of BD, such as vascular, neuro, or ocular BD, manifestations can occur in isolation without other systemic signs. Given these challenges, there is a pressing need to identify prognostic markers in patients with VBD, NBD, or ocular involvement. These markers could help clinicians identify high-risk patients who may benefit from more aggressive treatment strategies at an earlier stage.

In this context, the study by Hussein et al., which examines the relationship between VBD, NBD, and ocular involvement in BD, is particularly relevant. ⁶ Earlier, Düzgün et al., in an analysis of 180 BD patients, found that those with vascular involvement had significantly less ocular involvement compared to patients without vascular disease. ⁷ A similar observation was later reported by Fei et al. in a retrospective study of 796 BD patients. ² However, neither of these studies explored the deeper nuances of the VBD–ocular BD relationship, unlike the study by Hussein et al.

Hussein et al. stratified VBD patients into high-risk (Hr-VBD) and low-risk (Lr-VBD) groups. They found that the overall frequency of ocular manifestations—including uveitis and retinal vasculitis—was significantly lower in VBD patients. Notably, retinal vasculitis, the most severe ocular complication, was inversely associated with Hr-VBD, with a 42% reduction in its risk. ⁶

The authors also investigated the link between VBD and NBD, an area with previously conflicting data. Torgutalp et al. observed a numerically higher, though statistically non-significant, frequency of NBD in VBD patients (8.7% vs. 6.4%). ⁸ Conversely, Fei et al. reported a lower frequency among VBD patients (3.9% vs. 5.5%; P = .640). ² In comparison, Hussein et al. found a higher, yet again statistically non- significant, frequency of NBD among VBD patients (13.5% vs. 8.2%; P = .2), aligning more closely with Torgutalp’s findings. Crucially, they further analysed the incidence of NBD across the Hr-VBD and Lr-VBD subgroups and found that the presence of NBD was associated with a 27% reduction in Hr-VBD risk.

Based on these findings, Hussein et al. proposed that vascular and oculo/neuro-Behçet’s manifestations may represent opposing poles of the disease spectrum, possibly driven by distinct pathogenic mechanisms. Nonetheless, further research is needed to validate this hypothesis. Overall, their study underscores the complex interplay between the different phenotypic presentations of BD and adds valuable insight into its underlying pathophysiology.