Anti-Angiogenic Effects of Anti–Tumor Necrosis Factor α Agents in the Treatment of Behçet Disease

Abstract

There are accumulating evidences on the role of dysregulated angiogenesis in Behçet disease. By considering that encouraging results are accumulating about the role of anti–tumor necrosis factor α (TNF-α) agents in the treatment of Behçet disease and that there are evidences of a role of anti-TNF-α agents in angiogenesis inhibition, it is conceivable that antiangiogenic effects of anti-TNF-α agents may contribute to the efficacy of these therapeutic arms in Behçet disease.

Behçet disease is a chronic autoimmune disease, characterized by mucocutaneous, ocular, gastrointestinal, vascular, and central nervous system manifestations. ¹ By considering its systemic involvement, Behçet disease is classified in the group of vasculitides. There are accumulating evidences on the role of dysregulated angiogenesis in Behçet disease. ² In fact, increased levels of angiogenic factors, such as vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein 1 (MCP-1), have been found in serum samples obtained from patients affected by Behçet disease. ³ Increased VEGF levels have been observed in oral aphthous lesions and in the ocular inflammation.^4,5 Moreover, other factors, such as interleukin 8 (IL-8) and angiopoietin 1 (Ang-1), which are responsible for endothelial cell proliferation and migration and angiogenesis, are probably involved in the pathogenesis of Behçet disease. In fact, IL-8 has been found overexpressed in synovial fluids in patients affected by Behçet disease. ⁶ Nevertheless, contrasting results have been found regarding Ang-1 levels. On one hand, Choe et al ⁷ have found increased Ang-1 expression in Behçet disease compared with healthy controls. On the other hand, Bassyouni et al ⁸ have recently demonstrated low levels of Ang-1 in patients with Behçet disease, in particular in patients with vascular involvement. These contrasting results may be related to different clinical expressions of Behçet disease in the patients of these studies and anyway suggest a dysregulation of this important angiogenic factor. Moreover, Behçet disease is characterized by increased serum levels of soluble form of vascular endothelial cadherin adhesion molecule (sVE-cadherin), which is involved in inducing angiogenesis and vascular stability. ⁹ However, antiangiogenic factors, such as angiostatin, have been found overexpressed in Behçet disease, especially in patients with active disease, with a direct correlation with deep vein thrombosis, arthritis, and uveitis. ¹⁰

As demonstrated by case reports and short-term trials, encouraging results are accumulating about the role of anti–tumor necrosis factor α (TNF-α) agents in the treatment of Behçet disease. ¹¹ Moreover, there are accumulating evidences of a role of these agents in angiogenesis inhibition. By considering that TNF-α is involved in the expression of important angiogenic factors, such as VEGF, Ang-1, and Ang-2 (angiopoietin 2), ¹² numerous studies have suggested a role for TNF-α inhibitors in angiogenesis inhibition. In fact, topical application of infliximab or etanercept has been successfully used in animal models of corneal neovascularization.^13–17 Infliximab treatment has been correlated to a reduction in serum VEGF levels in patients affected by chronic arthritides, such as rheumatoid arthritis and psoriatic arthritis (PSA).^18–21 A reduction in VEGF levels has been seen in skin lesions of patients affected by PSA after infliximab treatment. ²¹ A reduced angiogenesis has been demonstrated in synovial tissue obtained from patients with PSA treated with infliximab. ²² An antiangiogenic effect in psoriatic skin has been shown after 12 weeks of treatment with etanercept by videocapillaroscopic evaluation of psoriatic plaque. ²³ Immunohistochemical investigations confirmed a reduction in VEGF levels in patients with PSA after etanercept treatment.^16,23 The efficacy of adalimumab has been established in neovascular age-related macular degeneration refractory to anti-VEGF therapy. ²⁴ Infliximab and adalimumab have shown antiangiogenic activity in Crohn disease and psoriasis.^25,26 Moreover, golimumab has demonstrated a role in angiogenesis inhibition in tetratricopeptide repeats 2 (IFIT2)-depleted metastatic oral squamous cell carcinoma cells. ²⁷ Finally, a role in the inhibition of TNF-α–dependent angiogenesis has been demonstrated in vitro also for certolizumab pegol. ²⁸

By considering these evidences, it is conceivable that antiangiogenic effects of anti–TNF-α agents may contribute to the efficacy of these therapeutic arms in Behçet disease. Nevertheless, to date, very few studies are available about the role of angiogenesis in Behçet disease, and no studies have ever been performed about the role of anti–TNF-α agents in angiogenesis during Behçet disease. Therefore, to our opinion, further studies are needed to better define the exact role of angiogenesis inhibition in Behçet disease and to clarify whether TNF-α inhibitors may play antiangiogenic effects in this disease.