—Melissa Weiss and Ronald Butendieck, MD
Behçet disease (BD) is thought to be a form of vasculitis that affects multiple organ systems. The classic symptoms of BD are uveitis and oral and genital ulcers, also known as the triple symptom complex, but patients can also present with neurological, musculoskeletal, and gastrointestinal symptoms.1 While only one therapy is FDA-approved for the treatment of BD, several therapeutic options have shown success in treating the many signs and symptoms of this disease.
Similar to other conditions that impact multiple organ systems, there are many of challenges in treating BD. “In a perfect world, we want a medication that is well-tolerated, efficacious, and with little to no adverse effects,” said Dr Butendieck. Due to the rarity of this disease, few large-scale clinical trials have been conducted to test the efficacy and safety of older and newer medications. Likewise, the lack of trials and funding for this rare disease can make it difficult for clinicians to prescribe therapies, as barriers such as cost affect whether a patient can access these life-altering medications. Furthermore, the lack of familiarity of BD in the United States poses a unique challenge for both diagnosing and treating BD.
In an interview with the Autoimmune Learning Network, Ronald Butendieck, MD, reviewed some of the challenges and treatment options for BD, as well as areas of future research, highlighting the need for clinicians to be highly suspicious when assessing a patient with suspected BD.
One major challenge is the difficulty of diagnosing a patient with BD. “Since the disease is quite rare in the West, most physicians (rheumatologists included) have a lack of experience with seeing patients with true Behçet disease,” said Dr Butendieck. There are multiple infectious, autoimmune, and environmental conditions that can mimic BD, including inflammatory bowel disease, systemic lupus erythematous and rheumatoid arthritis.1,2
In addition, the multiple manifestations of BD can make selecting the best treatment option difficult, and patients often require combination therapy to address their multiple symptoms. “Clinicians must take into consideration drug-drug interactions, medication tolerability, potential adverse effects, and monitor appropriate labors,” he added. Another challenge is limited data on the efficacy of therapies, including older options, due to the rarity of this disease. The majority of medications used to treat BD are based on clinical experience, case reports and series, and observational studies published in the literature.1
One barrier to investigating possible new and already existing therapies is the limited understanding of BD pathogenesis. While there is a large body of literature on the possible mechanisms of action and pathways of BD, “our understanding of whether these mechanisms are influenced by environmental, genetic, or other factors is still very limited,” said Dr Butendieck. Similar to lupus, BD is a multifaceted, multisystem process that can present with various manifestations. “One pathway may not explain the entirety of this disease,” he said. For example, HLA-B51 is considered a genetic marker of BD, but individuals with BD from Western countries tend to not have this genetic variant.3 In addition, patients from Western countries tend not to have positive responses on a pathergy test.2 “This makes diagnosing BD additionally challenging,” he added.
Treatment Plans and Options
Developing a treatment plan for patients with BD, like other chronic diseases, involves controlling the disease in order to improve quality of life and prevent long-term complications. One barrier to treating BD is access to therapies that can effectively treat certain manifestations of the disease. The majority of treatment options for BD, which include oral, topical, intravenous and subcutaneous injection therapies, are used off-label. “Clinicians should make sure that the therapy they want to use is available for patients and addresses the particular clinical manifestations of concern,” suggested Dr Butendieck.
Oral and cutaneous signs
Mucocutaneous disease is one of the most prominent features among patients with BD in the West, noted Dr Butendieck. Topical corticosteroids are considered first-line treatment for oral and genital ulcerations, especially those with mild disease.1 Colchicine is also commonly used to treat mucocutaneous manifestations, with one clinical trial showing significant improvement in overall disease activity index scores compared with placebo.4 Other therapies that have demonstrated efficacy in improving mucosal and cutaneous manifestations of BD include azathioprine, cyclosporine, thalidomide, interferon alpha, and topical triamcinolone acetonide cream.1,5
There are safety concerns for thalidomide and cyclosporine. While thalidomide was shown to be effective for treating BD, one study reported 84% of patients experienced at least one adverse event and 21% of these patients experienced a severe adverse event.6 Cyclosporine is effective for BD, but it was also found to be associated with an increased risk for parenchymal neurological involvement.7
Apremilast is the first and only FDA-approved therapy for the treatment of oral ulcers associated with BD.8 A phase 3, randomized, double-blind, placebo-controlled trial showed statistically significant improvements in pain and oral ulcer clearance among patients treated with apremilast compared with placebo. Similar to other indications for apremilast, the most common adverse events associated with treatment included diarrhea, nausea, headache, upper respiratory tract infection, and viral upper respiratory tract infection.9
Overall, apremilast is generally well-tolerated and safe and does not lower the immune system or interact much with other medications, said Dr Butendieck. The latter is important for patients who may need to take more than one therapy to manage this disease or other comorbidities. While the trial included a subset of patients with other cutaneous manifestations of BD (eg, genital ulcers), it was not designed to assess the efficacy of apremilast for treating these areas.9
In addition, anti-tumor necrosis factor (TNF) alpha inhibitors have been found to be effective among patients with refractory mucocutaneous diseases, such as infliximab and etanercept.1
According to Dr Butendieck, nonsteroidal anti-inflammatory drugs are first-line options for patients with arthritis symptoms. Similar to mucocutaneous manifestations, colchicine, anti-TNF inhibitors, methotrexate, and azathioprine have also been shown to be effective for treating arthritic symptoms.1
Ocular manifestations can be managed by an ophthalmologist. Typically, topical steroid drops are used to manage uveitis, said Dr Butendieck, but systemic steroids, azathioprine, anti-TNF inhibitors, and cyclosporine can also be prescribed.1 A retrospective analysis of severe uveitis in 157 patients showed 92.9% of patients treated with corticosteroids and azathioprine achieved either complete or partial control, as well as saw a decreased use in the mean oral prednisone dosage after treatment.10
Central nervous system involvement occurs in less than 20% of patients.1 Patients with neurological manifestations of BD fall within two subtypes, parenchymal and nonparenchymal involvement, that are managed aggressively to prevent life-threatening complications.11
Parenchymal BD, which presents as brainstem, hemispheric, spinal, and meningoencephalitis manifestations and can cause stroke-like symptoms, are treated with high-dose glucocorticoids alone or in combination with azathioprine.11 Anti-TNF inhibitors have also been found to be effective for neurological complications.1,11,12 In patients with nonparenchymal BD, which presents as central venous sinus thrombosis and arterial involvement in the brain, are also treated with high-dose steroids or immunosuppressive therapies with or without with anticoagulation therapy.11,12
“For non-life-threatening or organ-threatening disease, azathioprine can be used, but with neurological manifestations of Behçet disease, we usually go for the ‘big guns,’” explained Dr Butendieck.
The Next Potential Big Game Changer: Anti-TNF inhibitors
Anti-TNF inhibitors, arguably one of the biggest therapeutic breakthroughs for other inflammatory autoimmune diseases, are also demonstrating efficacy among patients with BD. Case reports and observational studies have shown patients with various manifestations of BD and refractory disease are responding to anti-TNF inhibitors.1 “What really appears to be the most beneficial is the monoclonal anti-TNF inhibitors, such as infliximab and adalimumab,” stated Dr Butendieck.
A recent multicenter observational study showed infliximab and adalimumab were highly effective among patient with refractory vascular BD, with 80% of patients achieving clinical remission within 3 months of initiating therapy.13 Adalimumab was also found to improve arthritis and mucocutaneous symptoms.14 In a 1-year study on the efficacy of infliximab, 18 of 21 patients with BD that was refractory to standard immunosuppressive therapies achieved total remission of ocular and neurological symptoms.15 In addition, a multicenter study with 124 patients showed all severe and/or refractory BD manifestations were effectively treated with either infliximab or adalimumab.16
Ustekinumab was also found to improve BD-related oral ulcers in two separate studies.17,18 Other anti-TNF inhibitors under investigation include secukinumab, golimumab, certolizumab pegol, and etanercept.19-22
Clinical trials are needed to determine whether apremilast is effective for other manifestations of BD, including cutaneous disease and arthritis. Also, more studies are needed to confirm the findings from case reports and observational studies on the efficacy of anti-TNF inhibitors for BD. “It would be of enormous benefit to have these therapies formally studied and potentially approved by the FDA to increase access to these medications for appropriate patients,” said Dr Butendieck.
In addition, more studies are needed to elaborate on the pathology of the disease, mechanisms of action, and why patients can present with different manifestations in order to identify other therapeutic targets and improve treatment. While there are two available international classification criteria for diagnosing BD,23,24 these have limitations. Updated classification criteria are needed with better sensitivity and specificity to improve clinicians’ ability to diagnose BD, added Dr Butendieck.
With the approval of apremilast, the interest in BD has grown. However, Dr Butendieck cautions physicians to be careful when evaluating a patient with suspected BD to avoid over diagnosing the disease. He recommends physicians who are not comfortable making the diagnosis refer patients to those with experience in treating this disease.
1. Rokutanda R, Kishimoto M, Okada M. Update on the diagnosis and management of Behçet's disease. Open Access Rheumatol. 2015;7:1-8. doi:10.2147/OARRR.S46644
2. Kokturk A. Clinical and pathological manifestations with differential diagnosis in Behçet's disease. Patholog Res Int. 2012;2012:690390. doi:10.1155/2012/690390
3. Alpsoy E. Behçet’s disease: a comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions. J Dermatol. 2016;43(6):620-632. doi:10.1111/1346-8138.13381
4. Davatchi F, Sadeghi Abdollahi B, Tehrani Banihashemi A, et al. Colchicine versus placebo in Behçet's disease: randomized, double-blind, controlled crossover trial. Mod Rheumatol. 2009;19(5):542-549. doi:10.1007/s10165-009-0200-2
5. Fani MM, Ebrahimi H, Pourshahidi S, Aflaki E, Shafiee Sarvestani S. Comparing the effect of phenytoin syrup and triamcinolone acetonide ointment on aphthous ulcers in patients with Behcet’s syndrome. Iran Red Crescent Med J. 2012;14(2):75-78.
6. Hello M, Barbarot S, Bastuji-Garin S, Revuz J, Chosidow O. Use of thalidomide for severe recurrent aphthous stomatitis: a multicenter cohort analysis. Medicine (Baltimore). 2010;89(3):176-182. doi:10.1097/MD.0b013e3181dfca14
7. Akman-Demir G, Ayranci O, Kurtuncu M, Vanli EN, Mutlu M, Tugal-Tutkun I. Cyclosporine for Behçet's uveitis: is it associated with an increased risk of neurological involvement? Clin Exp Rheumatol. 2008;26(4 Suppl 50):S84-S90.
8. FDA approves Otelza (apremilast) for the treatment of oral ulcers associated with Behçet’s disease. News release. Celgene; July 19, 2019. Accessed July 29, 2020. 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
9. Hatemi G, Mahr A, Ishigatsubo Y, et al. Trial of apremilast for oral ulcers in Behçet’s syndrome. N Engl J Med. 2019;381(20):1918-1928. doi:10.1056/NEJMoa1816594
10. Saadoun D, Wechsler B, Terrada C, et al. Azathioprine in severe uveitis of Behçet’s disease. Arthritis Care Res (Hoboken). 2010;62(12):1733-1738. doi:10.1002/acr.20308
11. Borhani-Haghighi A, Kardeh B, Banerjee S, et al. Neuro-Behcet's disease: an update on diagnosis, differential diagnoses, and treatment. Mult Scler Relat Disord. 2019;39:101906. doi:10.1016/j.msard.2019.101906
12. Kidd DP. Neurological complications of Behçet's syndrome. J Neurol. 2017;264(10):2178-2183. doi:10.1007/s00415-017-8436-9
13. Aksoy A, Yazici A, Omma A, et al. Efficacy of TNFα inhibitors for refractory vascular Behçet's disease: a multicenter observational study of 27 patients and a review of the literature. Int J Rheum Dis. 2020;23(2):256-261. doi:10.1111/1756-185X.13778
14. Braun-Moscovici Y, Tavor Y, Markovits D, et al. The effects of adalimumab in Behçet disease patients on clinical manifestations and on pro-inflammatory cytokines milieu: long-term follow-up. Isr Med Assoc J. 2020;22(5):289-293.
15. Giardina A, Ferrante A, Ciccia F, Vadalà M, Giardina E, Triolo G. One year study of efficacy and safety of infliximab in the treatment of patients with ocular and neurological Behçet's disease refractory to standard immunosuppressive drugs. Rheumatol Int. 2011;31(1):33-37. doi:10.1007/s00296-009-1213-z
16. Vallet H, Riviere S, Sanna A, et al. Efficacy of anti-TNF alpha in severe and/or refractory Behçet’s disease: multicenter study of 124 patients. J Autoimmun. 2015;62:67-74. doi:10.1016/j.jaut.2015.06.005
17. Mirouse A, Barete S, Desbois AC, et al. Long-term outcome of ustekinumab therapy for Behçet’s disease. Arthritis Rheumatol. 2019;71(10):1727-1732. doi:10.1002/art.40912
18. Mirouse A, Barete S, Monfort JB, et al. Ustekinumab for Behçet’s disease. J Autoimmun. 2017;82:41-46. doi:10.1016/j.jaut.2017.05.002
19. 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
20. 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
21. Lopalco G, Emmi G, Gentileschi S, et al. Certolizumab pegol treatment in Behcet’s disease with different organ involvement: a multicenter retrospective observational study. Mod Rheumatol. 2017;27(6):1031-1035. doi:10.1080/14397595.2017.1285857
22. Melikoglu M, Fresko I, Mat C, et al. Short-term trial of etanercept in Behçet’s disease: a double blind, placebo controlled study. J Rheumatol. 2005;32(1):98-105.
23. International Study Group for Behçet's Disease. Criteria for diagnosis of Behçet's disease. Lancet. 1990;335(8697):1078-1080. doi:10.1016/0140-6736(90)92643-V
24. International Team for the Revision of the International Criteria for Behçet's Disease (ITR-ICBD). The International Criteria for Behçet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol. 2014;28(3):338-347. doi:10.1111/jdv.12107