Insights into the pathophysiology of Behçet’s disease & potential treatments
BARCELONA—Few conditions have as fascinating a global distribution as Behçet’s disease, which owes its distribution to the spread of genetic variants along the ancient trade route known as the Silk Road. The prevalence of the disease is currently highest in such countries as Turkey and Iran.1 Despite this geographic idiosyncrasy, cases of Behçet’s disease can be seen across the globe, and it’s important for all rheumatologists to understand the details of its diagnosis and treatment.
At EULAR 2025, during the plenary session, Behçet’s Disease: What Is New, Matteo Piga, MD, associate professor of rheumatology, the Department of Medical Science and Public Health, University of Cagliari, Italy, highlighted significant developments in the research literature from the past year.
Pathophysiology
Dr. Piga began by discussing new findings about the pathophysiology of Behçet’s disease, which can present with a variety of mucocutaneous, articular, ocular, vascular, neurological and gastrointestinal manifestations. As far back as the 1970s, researchers identified the human leukocyte antigen (HLA) region as the first genetic region with susceptibility for Behçet’s disease, specifically noting an association between HLA-B51 and the disorder. However, half a century after this discovery, the genetic architecture of the disease is still being explored.2
Dr. Piga noted that Behçet’s disease is a condition with both autoimmune and autoinflammatory features driven by neutrophil hyperactivity, T cell skewing and cytokine imbalance, infectious triggers and molecular mimicry, and endothelial dysfunction and thrombosis.3 Genome-wide association studies have identified at least 21 susceptibility loci—many of which influence immune pathways—that play a role in cytokine signaling, antigen processing and presentation, and innate immunity.2
Behçet’s Uveitis
Dr. Piga discussed a fascinating study that sought to evaluate the mechanisms that underlie the increased incidence, severity and poor prognosis of autoinflammatory Behçet’s uveitis in male patients. In this study, the researchers applied single-cell RNA sequencing to circulating neutrophils in the blood of patients with Behçet’s disease-associated uveitis. Proteomic analysis identified upregulation of pathways related to neutrophil extracellular trap formation and downregulation of nucleotide metabolism and apoptosis. Such upregulation was seen more in men than women in the study.
These findings suggest that sex-specific differences in neutrophil function contribute to the immunopathogenesis and clinical heterogeneity of Behçet’s uveitis, with men displaying a more proinflammatory neutrophil phenotype than women. This finding may explain the male-bias in disease severity.4
Advancements in Treatment
Dr. Piga next cited what he indicated was the most important clinical trial in Behçet’s disease of the past year. In a phase 2, multicenter, open-label, randomized controlled trial from Saadoun et al., 52 patients with severe Behçet’s disease (i.e., defined by major vascular or central nervous system involvement) were randomized to receive either 5 mg/kg of intravenous infliximab at weeks 0, 2, 6, 12 and 18 or 0.7 g/m2 or intravenous cyclophosphamide at weeks 0, 4, 8, 12, 16 and 20, with a maximum dose of 1.2 g/infusion. All patients also received the same background glucocorticoid regimen. The study’s primary outcome was complete response—defined as clinical, biological and radiological remission while on prednisone ≤0.1 mg/kg/day—at week 22.
At week 22, 81% of patients in the infliximab treatment group achieved complete response compared with 56% of those in the cyclophosphamide treatment group. Fewer adverse events were reported in patients who received infliximab than those who received cyclophosphamide (30% vs. 64%, respectively).5
In Dr. Piga’s view, this study clearly demonstrates that induction therapy with infliximab and glucocorticoids should be a first-line therapy in patients with organ- or life-threatening disease.
Other Promising Treatments
Additionally, Dr. Piga discussed other studies exploring treatment options for patients with Behçet’s disease.
A study from Moots et al. showed that in patients with active, refractory disease of all subtypes infliximab and interferon‑α2a demonstrated comparable efficacy and safety for inducing remission.6
A study from Zhong et al. showed that adalimumab plus corticosteroid treatment was superior to cyclosporine plus corticosteroids with respect to uveitis relapse rates in patients with severe Behçet’s disease who are naive to anti-tumor necrosis factor therapy.7
In a phase 3 study of 40 patients with active mucocutaneous lesions despite three or more months taking standard immunosuppressants, both infliximab and adalimumab were highly effective in inducing remission of the lesions and well-tolerated by patients. However, adalimumab demonstrated a significantly faster and higher response rate than infliximab.8
Finally, an observational study by Penuelas Leal et al. demonstrated that oral roflumilast—a phosphodiesterase-4 inhibitor often used in chronic obstructive pulmonary disease—had a potential benefit in reducing mucocutaneous and articular manifestations in patients with Behçet’s disease. However, the study authors note the agent remains investigational and is not established for severe, organ-threatening disease.9
Dr. Piga noted that upadacitinib is another medication that may show promise for the treatment of Behçet’s disease, but future studies into upadacitinib are needed.
Preventing Organ Damage
Throughout his talk, Dr. Piga repeated a key point: A window of opportunity to treat the inflammatory features of Behçet’s disease exists. If inflammation in the disease is not promptly identified and effectively intervened upon, then irreversible organ damage can ensue, causing long-term negative implications for patients.
Three main damage assessment tools are used for Behçet’s disease: the Vasculitis Damage Index (VDI), the Behçet’s Overall Damage Index (BODI) and the Behçet’s Disease Damage Index (BDI). Each tool is designed to assess irreversible organ damage, but they differ in scope, specificity and clinical utility. VDI is a generic tool developed for systemic vasculitides. Both BODI and BDI are specific to Behçet’s disease. According to Dr. Piga, BODI has the strongest evidence for validity and responsiveness in terms of assessing organ damage due to Behçet’s disease.
Gold standard tests that aid diagnosis of Behçet’s disease beyond the recognition of clinical symptoms and signs need to be established. Standardized treatment algorithms that can be broadly applied throughout the world need to be developed, and the application of uniform response criteria in clinical trials needs improvement.
Dr. Piga’s presentation was inspiring and helped the audience better understand this heterogeneous and complex condition. Whether you live near or far from what was once the Silk Road, we should keep these insights into Behçet’s disease in mind and, as Dr. Piga noted, keep an open eye for the condition wherever it may be lurking.
Jason Liebowitz, MD, FACR, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.
References
- Leonardo NM, McNeil J. Behcet’s disease: Is there geographical variation? a review far from the silk road. Int J Rheumatol. 2015;2015:945262.
- Ortiz-Fernández L, Sawalha AH. Genetics of Behçet’s disease: Functional genetic analysis and estimating disease heritability. Front Med (Lausanne). 2021 Feb 12;8:625710.
- Emmi G, Bettiol A, Hatemi G, et al. Behçet’s syndrome. Lancet. 2024 Mar 16;403(10431):1093–1108.
- Wang Q, Ma J, Gong Y, et al. Sex-specific circulating unconventional neutrophils determine immunological outcome of auto-inflammatory Behçet’s uveitis. Cell Discov. 2024 May 4;10(1):47.
- Saadoun D, Maalouf G, Vieira M, et al. Infliximab versus cyclophosphamide for severe Behçet’s syndrome. NEJM Evid. 2024 Nov;3(11):EVIDoa2300354.
- Moots RJ, Fortune F, Jackson R, et al. Infliximab vs. interferon-α in the treatment of Behçet’s syndrome: Clinical data from the BIO-BEHÇET’S randomized controlled trial. Rheumatology (Oxford). 2025 May 1;64(5):2882–2891.
- Zhong Z, Deng D, Gao Y, et al. Combinations of immunomodulatory agents for prevention of uveitis relapse in patients with severe Behçet’s disease already on corticosteroid therapy: A randomised, open-label, head-to-head trial. Lancet Rheumatol. 2024 Nov;6(11):e780–e790.
- Talarico R, Italiano N, Emmi G, et al. Efficacy and safety of infliximab or adalimumab in severe mucocutaneous Behçet’s syndrome refractory to traditional immunosuppressants: A 6-month, multicentre, randomised controlled, prospective, parallel group, single-blind trial. Ann Rheum Dis. 2024 Oct 17:ard-2024-226113.
- Peñuelas Leal R, Labrandero Hoyos C, Peñuelas Ruiz JA, et al. Treatment of Behçet disease with oral roflumilast: An observational study. Clin Exp Dermatol. 2024 Dec 23;50(1):62–68.
