Anti-TNF-α agents in vascular Behçet's disease

Response to: Thrombotic therapy in patients with Behçet’s disease. Expert Rev. Cardiovasc. Ther. 12(4), 413–414 (2014).

We really thank the authors for their comments to our article titled ‘Vascular Behçet’s disease: new insights in the management of thrombosis’, recently published in this journal [1], allowing us to make more detailed considerations.

Behçet's disease (BD) is a multisystemic inflammatory condition characterized by a diverse spectrum of clinical manifestations including cardiovascular ones, which affect up to 45% of BD patients. Due to its relevant impact on patients’ prognosis, vascular involvement was added to the 2006 International Criteria for Behçet’s disease (ICBD) [2,3]. Venous thrombosis is the more common vascular manifestation: it occurs more frequently in male patients with active disease, tends to recur and is an important cause of morbidity and mortality. Systemic inflammation is the main trigger of thrombosis in BD, and endothelial cell dysfunction certainly seems to be a characteristic feature of BD and to play a key role in the pathogenesis of thrombotic manifestations [1]. In recent years, there is a growing interest for endothelial damage biomarkers, and some authors suggest that, along with VEGF, von Willebrand factor, thrombomodulin, and some adhesion molecules [4], also serum endocan levels and mean platelet volume could represent new markers of endothelial cell dysfunction [5,6].

Cases of angio-Behçet patients resistant or intolerant to conventional immunosuppressive therapy successfully treated with anti-TNF-α agents have been increasingly reported over the last years. However, experience with anti-TNF-α therapy for major vessel involvement is limited to case reports. In an analysis of 369 BD patients treated with anti-TNF-α agents in 20 different countries [7], only few cases of BD with vascular complications treated with anti-TNF-α monoclonal antibodies were described. Infliximab was the most used anti-TNF-α agent, and a good clinical response with an acceptable safety profile was reported [8]. Recently also for adalimumab, a fully human anti-TNF-α antibody, a rapid beneficial effect on some clinical involvements (mostly ocular and mucocutaneous manifestations) was described in 19 BD patients, with no specific data about its efficacy in vascular complications [9].

Data reported in our article are referred to the last update of our BD patient database on May 2013; in our cohort, 28 BD patients presented vascular manifestations, with a male/female ratio of about 1:1 (13 males and 15 females), but the most severe manifestations were observed in younger males. The main age of onset was in the second to third decade of life, and no familial clustering was reported in these patients. Neither HLA B 51 allele positivity (53% of patients) nor positive pathergy test (3 positive, 16 negative, 9 unknown) seems to have a strict relationship with vascular involvement in our BD patients. Of note, 24 patients were from Center-South Italy, while only 4 patients were from North Italy, according to the recent data of an increased prevalence of BD in southern versus northern regions of Italy reported by Olivieri et al. [10]. Mucocutaneous lesions (oral and genital ulcerations, pseudo-folliculitis and erythema nodosum) and articular involvement were the most common clinical manifestations of these 28 patients with angio-Behçet: bipolar aphthosis occurred in 57% of patients, whereas 25% presented only oral ulcerations. Skin manifestations were present in 57% and arthritis in 46% of them. Finally, uveitis and CNS involvement were observed in seven and three patients, respectively. We observed 10 BD patients with vascular involvement, treated with adalimumab, given at the dose of 40 mg/every other week, with a good clinical response, a low rate of recurrence and good safety profile; the major reason to start this therapy in our cohort had been refractory disease to other treatments [1].

BD represents a systemic disorder with a poorly understood pathogenesis; the discovery of new pathways in BD immunopathogenesis could help to better understand the mechanisms of action of the new biological treatments, and in particular of anti-TNF-α agents [11].

Thrombosis in BD patients is a serious disorder requiring an early and aggressive treatment and, according to the European League Against Rheumatism recommendations, classical immunosuppressive therapy represents the treatment choice [12]. In our view, in the near future, anti-TNF-α agents might be used as first-line treatment in severe vascular conditions, especially in young patients with life-threatening complications.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.