—Melissa Weiss and Delfin Santos, MD
Behçet disease (BD), also known as Behçet (pronounced beh-SHETS) syndrome, is a rare inflammatory condition that presents a serious conundrum for those who treat it. Its etiology is largely unknown, and the diagnosis is made entirely through exclusion of other autoimmune, infectious, and environmental conditions. The lack of diagnostic tests, including genetic and other biomarkers, and rarity of this disease in the United States presents a significant challenge for patients and physicians.
“What we really need to do is increase awareness,” said Delfin Santos, MD, director of Rochester Rheumatology in Rochester Hills, MI, and member of the American Behçet Disease Association medical advisory board, in an interview. Dr Santos has been involved in the BD community for more than 20 years and lectures on this disease across the country. “I come across a lot of physicians around the country who are not familiar with this condition,” he said. While many physicians learn about BD in medical school, just as many report that they have never seen a case. “I wonder if they have never seen a case or if they missed the diagnosis,” said Dr Santos.
Raising awareness and teaching physicians about this rare disease is only half the battle for improving patients’ quality of life. Therapies for BD are limited, and there is a need for greater interest in the research and pharmaceutical spheres to increase both awareness and therapeutic options.
History, Clinical Characteristics, Risk Factors
BD can affect multiple organ systems. It was first described in 1937 by the Turkish dermatologist Hulusi Behçet.1 The most characteristic signs of BD, also known as the triple symptom complex, are inflammation of the eyes and oral and genital ulcers. While these are considered classic symptoms of BD, patients can also have vascular, cutaneous, neurologic, arthritic, and gastrointestinal symptoms.1
Typically, BD presents during a patient’s second, third, or fourth decade of life.2 There are some reports of BD in children, although this is uncommon, and it is very rare for new-onset BD to occur in individuals aged 55 years and older.3 In addition, symptoms of BD can develop over time. “Patients who present with only mucocutaneous symptoms take longer to diagnose than those with more serious manifestations of the disease, most patients do not present with the classic ‘triple symptom complex’,” said Dr Santos.
Other symptoms associated with BD include erythema nodosum, folliculitis, acneiform-like lesions, nonerosive arthritis and ulceration and inflammation in the gastrointestinal tract. Some patients can have central nervous system involvement, which can include meningoencephalitis, central sinus thrombosis neurologic deficits, and psychiatric symptoms.1
Aneurysms and deep vein thrombosis are other complications of BD that can be potentially life-threatening.1 “Blood clots caused by BD are different from typical blood clots,” said Dr Santos. He explained that these clots in patients with BD adhere to the vascular wall due to the inflammation and immune process. For these patients, treatment with immunosuppressive agents is more important than anti-coagulation. “When a patient with Behcet’s disease presents with an acute deep vein thrombosis, a health care practitioner has to rule out the presence of peripheral, pulmonary or aortic aneurysms because anti-coagulation therapy could cause them to hemorrhage and die,” said Dr Santos. In addition, BD-caused uveitis can lead to blindness.2 “However, the incidence of blindness is low in the US,” stated Dr Santos.
A diagnosis of BD is based primarily on excluding all other possible options because many of the aforementioned symptoms can mimic other diseases. A patient who presents with oral ulcers will need to be assessed for multiple conditions including herpes simplex infection, syphilis, recurrent aphthous stomatitis, pemphigus, and systemic lupus erythematosus (SLE).3 Genital ulcers can be caused by Crohn disease, many infectious diseases such as syphilis, chancre and herpes. Similarly, uveitis is also a clinical characteristic of SLE, rheumatoid arthritis, vasculitis, and sarcoidosis. The skin manifestations of BD are also found in patients with SLE, hidradenitis suppurativa, and acne, as well as cutaneous reactions to medications.3
“We need the help of other specialists to help us rule out other conditions,” said Dr Santos. He has seen patients referred for an evaluation of possible BD who actually had skin cancer or viral conditions, such as Epstein-Barr virus. A multidisciplinary approach and high suspicion for other possible diseases is necessary to prevent both overdiagnosing and underdiagnosing patients with BD.
There are no blood, genetic, or specific diagnostic tests available for BD.1-3 Biopsies of the ulcers and skin lesions can be performed, but “it really serves to differentiate BD from other conditions,” said Dr Santos.
In addition, pathergy tests can be used to help identify a patient with BD, but its prevalence outside of countries along the Silk Road is low.3 The formation of a sterile pustule or erythematous small papule after 24 to 48 hours of a needle prick is considered a positive response and a possible sign of active BD. However, there is wide variability based on geographic location of positive test results among patients with BD. Mediterranean and Middle/Far Eastern countries have the highest percentages of positive pathergy tests, whereas Western countries and the US have the lowest.3
There are two diagnostic criteria available for BD: International Study Group (ISG) and International Behçet Criteria (ICBD).4,5 The ISG criteria was established in 1990 and developed for research classification purposes. A patient using the ISG criteria can only be diagnosed with BD if they have recurrent oral ulceration, occurring at least three times in 12 months, and two of the following: recurrent genital ulcerations, eye lesions, cutaneous lesions, and a positive pathergy test.4
In 2013, the ICBD was developed to address some of the limitations of the ISG criteria.5 The Table outlines the point system to diagnose a patient with suspected BD. After excluding other possible conditions, if a patient has a score of 4 or more in the ICBD, then they are diagnosed with BD.5
Prevalence and Genetic Risk Factors
While it is considered a rare disease in the US, estimated to affect only 5.2 per 100,000 individuals, BD is much more common in countries along the historic Silk Road, including China, Turkey, Iran, and Japan.6 In Turkey, the estimated prevalence is 42 per 10,000.7
A potential genetic risk factor for BD, HLA-B51, was identified among patients in Mediterranean and Eastern Countries, such as Turkey.1 The prevalence of HLA-B51 gene is over 50% among patients with BD in Turkey; however, the prevalence is less than 20% of patients in the US.8 In addition, a study conducted in a rheumatology office in New Mexico that analyzed patients for HLA-B51 showed about 25% of patients met the criteria for BD but 33% had other autoimmune diseases, such as rheumatoid lupus, dermatomyositis, and ankylosing spondylitis.9
Infectious agents have also been implicated in the development of BD, including Streptococcus sanguis, herpes simplex virus, and hepatitis viruses.1 An animal model showed mice with certain genes knocked out and infected with the herpes virus had similar symptoms to BD.10 “While herpes virus and other infectious agents are suspected, they have not definitively been proven as etiologic factors,” said Dr Santos.
A major obstacle for treating patients with BD is the lack of FDA-approved therapies. Aside from apremilast, which was approved in 2019 for oral ulcers associated with BD, all other therapeutic options are prescribed off-label.11 These include older therapies, such as steroids, methotrexate, azathioprine, cyclosporine, and colchicine, which treat many of the symptoms and inflammation of BD.1,12 Newer therapies that have been used with anecdotal reports of success include tumor necrosis factor (TNF) inhibitors, such as adalimumab, etanercept, certolizumab pegol, infliximab, and golimumab.13-17 Also, IL-17 and IL-12/IL-23 inhibitors have shown some efficacy for patients with BD.18,19 “However, it is difficult for physicians to prescribe these medications for their patients because of the limited data on their efficacy and lack of FDA approval,” said Dr Santos.
“We need better biomarkers to help diagnose and monitor BD, we also need more research to help determine the etiologic factors associated with this disease,” said Dr Santos. In addition, more efficacious therapies, with better patient access are needed to improve both the treatment of BD and patients’ quality of life.
“Patients with Behçet’s disease can present to any subspecialty of medicine. Awareness of this condition by physicians in various fields of medicine will help with early diagnosis and help reduce the complications of more advanced disease,” said Dr Santos. Increased awareness and interest in the medical community and pharmaceutical industry is needed to improve the diagnosis, management, and treatment of BD. The approval of apremilast is the first step towards achieving this goal. Since the approval of apremilast, Dr Santos has seen more physicians learning about and discussing BD at meetings. This is an encouraging sign for patients with this rare disease.
To learn more and become involved, visit the American Behçet Disease Association website.
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11. FDA approves Otelza (apremilast) for the treatment of oral ulcers associated with Behçet’s disease [press release]. Summit, NJ: Celgene; July 19, 2019. https://ir.celgene.com/press-releases-archive/press-release-details/2019/FDA-Approves-OTEZLA-apremilast-for-the-Treatment-of-Oral-Ulcers-Associated-with-Behets-Disease/default.aspx
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17. Vitale A, Emmi G, Lopalco G, et al. Long-term efficacy and safety of golimumab in the treatment of multirefractory Behçet's disease. Clin Rheumatol. 2017;36(9):2063-2069. doi:10.1007/s10067-017-3627-4
18. Di Scala G, Bettiol A, Cojan RD, Finocchi M, Silvestri E, Emmi G. Efficacy of the anti-IL 17 secukinumab in refractory Behçet's syndrome: a preliminary study. J Autoimmun. 2019;97:108-113. doi:10.1016/j.jaut.2018.09.002
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