Are You Confident of the Diagnosis?
Behçet’s syndrome is a chronic, relapsing, multisystemic, autoimmune vasculitis. The clinical presentation varies depending on which organ systems are involved (mucocutaneous, ocular, cardiovascular, musculoskeletal, gastrointestinal or neurologic). The international criteria for diagnosis require oral aphthous ulcers 3 times in 12 months (Figure 1) plus any two including genital ulcers, uveitis or retinal vasculitis, skin lesions, or positive skin pathergy. Thus, this can fall under the purview of a dermatologist with multiple potential presentations.
The mucous membrane lesions are typically confined to oral and genital aphthous ulcers. The skin lesions, however, can be quite heterogeneous and include pustular vasculitis/pseudo-folliculitis, erythema nodosum and acneiform eruptions.
Characteristic findings on physical examination
If a patient meets the criteria for Behçet’s syndrome with multisystem involvement, no specific dermatologic investigation may be needed. In the setting of aphthous ulcers, a detailed history and clinical examination may be sufficient. Aphthous ulcers present as painful, well-demarcated ulcers with an erythematous ring and pseudomembranous slough at the base. Lesions have a subtle 1-2 days prodrome, last 7 to 10 days and resolve without scarring.
If biopsies are performed, pathology would be the nonspecific findings of an aphthous ulcer (a mixed, reactive, dermal infiltrate beneath (including neutrophils, macrophages, and lymphocytes) a disrupted epithelium) (Figure 2). In general, a neutrophilic vascular reaction pattern is considered representative of the cutaneous lesions of Behçet’s syndrome. A test for pathergy may assist in confirming the diagnosis.
Depending on the initial presenting symptom(s) or sign(s), the differential diagnoses for Behçet’s syndrome are too varied to list. However, the most common initial manifestation is oral aphthous ulcers; therefore, the main differential diagnosis is that of recurrent aphthous stomatitis (herpes simplex, varicella zoster, hand, foot and mouth disease, erythema multiforme, bullous disorders, pyostomatitis vegetans, syphilis, lichen planus, lupus erythematosus, celiac disease, nutritional deficiencies, and oral cancers).
Biopsies for H&E and direct immunofluorescence can rule out bullous disease and cancer. Other items in the differential can be ruled out using serologic testing (ESR, ANA, TSH, IgA and IgG tissue transglutaminase, RPR and HIV), determination of B12, folate, and PCR (HSV and VZV).
Who is at Risk for Developing this Disease?
The likelihood of a patient with oral aphthous ulcers evolving into a patient meeting the criteria for Behçet’s syndrome will vary greatly depending on geography. The highest prevalence of Behçet’s syndrome occurs in the populations along the historical Silk Road trading route stretching from the Mediterranean through the Middle East to the Far East. Behçet’s syndrome is quite rare in the United States. Males are more frequently involved than females, with ratios varying depending on the population studied. Onset can occur at any age but is most common in the third decade.
Severe disease is associated with being male and young age at onset with higher frequency of major organ involvement and mortality. Smoking cessation in patients with Behçet’s syndrome can increase the number and frequency of mucocutaneous lesions, especially oral aphthae.
What is the Cause of the Disease?
Behçet’s syndrome is an autoimmune, inflammatory condition of unknown etiology. The pathophysiology is likely multifactorial. There is a genetic tendency with a strong association to HLA-B51. Dysregulated immune responses to infectious triggers or trauma have been postulated but not proven.
Systemic Implications and Complications
Behçet’s syndrome is a multisystem disease; therefore, extracutaneous implications are many and varied. However, ocular involvement, experienced by up to 80% of patients, is the leading cause of morbidity. Referral to ophthalmology and close monitoring are of paramount importance. Early identification and aggressive treatment of ocular disease can prevent blindness.
There is no cure for Behçet’s syndrome so treatment is aimed at symptom control. Because flares and remissions are expected, treatment may not need to be continuous.
APHTHOUS ULCER TREATMENT
Can be approached in the same way as those of recurrent aphthous stomatitis, the main difference being that an ointment is the preferred vehicle for application to the genitals.
Oral Hygiene Products (oral aphthae)
Sodium laurel sulfate (SLS)-free toothpaste (Rembrandt Canker Sore Toothpaste, Tom’s of Maine SLS-free toothpastes, plain baking soda)
Topical Medications for Symptomatic Relief (Oral Aphthae)
Lidocaine viscous solution 15 ml swish and spit every 3 hours as necessary, not to exceed 8 doses in 24 hours
Lidocaine 2% gel applied to the lesions every 3 hours as necessary, not to exceed 8 doses in 24 hours
Sucralfate 1G/10 ml solution 10 ml swish and spit, 2-4 times a day
Tetracycline 250 mg/5 ml was used 4 times daily, suspension to be held in the mouth for 2 minutes and then swallowed
Chlorhexidine gluconate 0.2% mouthwash 3 times daily for 6 weeks
Topical Medications for Symptomatic Relief (Genital Aphthae)
Lidocaine 2% jelly applied to lesions every 3 hours, not to exceed 8 applications in 24 hours
Topical Treatments (Oral Aphthae)
Fluocinonide or clobetasol gel applied 2-3 times a day
Dexamethasone solution 0.5 mg/ml, 5 ml swish and spit 2-3 times a day
Triamcinolone intralesional injection 0.1 ml to 0.5 ml of 10 mg/ml solution
Amlexanox 5% paste up to 4 times per day (currently discontinued in the US)
Topical Treatments (Genital Aphthae)
Clobetasol ointment applied to the lesions 2 to 3 times a day
Pimecrolimus applied to the lesions 2 times daily for 1 week
Over-the-Counter Systemic Treatment (Oral Aphthae)
Vitamin B12 1000 μg daily
Prescription Systemic Treatments (Oral and Genital Aphthae)
Zinc sulfate 100 mg 3 times daily
Prednisone 40-60 mg start tapered over 1-2 weeks (goal is steroid-sparing therapy)
Colchicine 0.6 mg 3 times a day (often used in combination with dapsone)
Dapsone 100-150 mg daily
Pentoxifylline 400 mg 3 times a day
Clofazamine 100 mg daily for 1 month, then 100 mg every other day
Methotrexate 10-15 mg/week (folic acid 1 mg daily)
Cyclosporine 1-3 mg/kg/day (short term, monitoring blood pressure and kidney function)
Apremilast 30 mg twice a day for 12 weeks (single trial thus far)
Aggressive Prescription Systemic Treatments (Oral and Genital Aphthae)
Anti-TNF-alpha inhibitors etanercept and adalimumab (for severe and refractory cases given the side effects and expense)
Thalidomide (for severe and refractory cases given the side effects)
IFN-alpha (for severe and refractory disease given the side effects)
ERYTHEMA NODOSUM TREATMENT
Rest and elevation
Nonsteroidal anti-inflammatory medications (indomethacin, naprosyn)
Erythromycin (single case report)
Other Mucocutaneous Manifestations
Colchicine, which inhibits neutrophilic inflammation, may be effective
Systemic immunosuppressive medications (azathioprine, mycophenolate mofitel, methotrexate) may be utilized as wel
Optimal Therapeutic Approach for this Disease
The aggressiveness of treatment should be titrated to the aggressiveness of active disease. Fear of potential disease severity should not lead to aggressive treatment as there is no proven long-term benefit to this approach. Additionally, the risk of morbidity from medication side effects should always be considered. The organ system in which unchecked inflammation has the greatest potential morbidity should dictate treatment. Thus, the dermatologist’s role in treatment may be secondary to another specialist (e.g., ophthalmologist, neurologist, or rheumatologist).
In mild mucocutaneous disease, topical corticosteroids and NSAIDs may prove sufficient. If systemic medications are required, colchicine is a simple first-line drug that may benefit multiple disease manifestations and does not require blood work. Most patients can tolerate twice daily dosing of colchicine and many can tolerate three pills daily if dosed as one in the morning and two at bedtime. Pentoxifylline is a less expensive but likely less effective alternative.
Managing a patient with Behçet’s syndrome requires a collaborative effort amongst specialists. The clinicians involved are determined by the organ system involvement. Their degree of individual involvement may vary with the course of the disease.
Unusual Clinical Scenarios to Consider in Patient Management
A multisystem inflammatory disease with a relapsing/remitting nature unfortunately dictates an unpredictable clinical course for most patients.
What is the Evidence?
Taylor, J, Glenny, AM, Walsh, T, Brocklehurst, P. “Interventions for the management of oral ulcers in Behçet's disease”. Cochrane Database Syst Rev. vol. 9. 2014 Sep 25. pp. CD011018(Comprehensive Cochrane review of 15 trials with over 800 randomised patients were used to compare various therapies including topical and systemic but given high risk of bias a meta-analysis could not be conducted.)
Hatemi, G, Seyahi, E, Fresko, I, Talarico, R. “Behçet's syndrome: a critical digest of the 2014-2015 literature”. Clin Exp Rheumatol. vol. 33. 2015 Nov-Dec. pp. S3-14. (A condensed summary of trials including emphasis on epidemiology, systemic manifestation of the disease and novel therapeutic in 2014-15.)
Hatemi, G, Melikoglu, M, Tunc, R, Korkmaz, C. “Apremilast for Behçet's Syndrome – A Phase 2, Placebo-Controlled Study”. New England Journal of Medicine N Engl J Med. vol. 372. 2015. pp. 1510-1518. (A small phase II trial with less than 120 patients showing efficacy of Apremilast in management of Behçet's disease.)
Saleh, Z, Arayssi, T. “Update on the therapy of Behçet's disease”. Therapeutic Advances in Chronic Disease. vol. 5. 2014. pp. 112-134. (Brief over disease followed by comprehensive review of therapeutic options of disease.)
Alexoudi, I, Kapsimali, V, Vaiopoulos, A, Kanakis, M. “Evaluation of the current therapeutic strategies in Behçet's disease”. Clin Rheumatol. vol. 30. 2011. pp. 30-157. (Current therapeutic recommendations for skin involvement as well as other organ systems.)
Areda, A, Fragiadaki, K, Sfikakis, PP. “Anti-TNF agents for Behçet's disease: analysis of published data on 369 patients”. Semin Arthritis Rheum 2010 Dec 16 (epub). (Extensive review of literature regarding the use of anti-TNF agents in Behçet's syndrome.)
Davatchi, F, Shahram, F, Chams-Davatchi, C, Shams, H. “Behçet's disease: from East to West”. Clin Rheumatol. vol. 29. 2010. pp. 29-823. (Epidemiologic comparison across five populations. Study of disease evolution in a Japanese population.)
Ideguchi, H, Suda, A, Takeno, M, Ueda, A. “Behçet disease: evolution of clinical manifestations”. Medicine. vol. 90. 2011. pp. 90-125. (Observational analysis of the presentation and evolution of Behçet's syndrome over time in a Japanese population.)
McCarty, MA, Garton, RA, Jorizzo, JL. “Complex aphthosis and Behçet's disease”. Dermatol Clin. vol. 21. 2003. pp. 41-8. (Clinically useful review from the perspective of a dermatologist.)
Soy, M, Erken, E, Konca, K, Ozbek, S. “Smoking and Behçet's disease”. Clin Rheumatol. vol. 19. 2000. pp. (508)-9. (Small 1-week controlled study assessing effects of smoking cessation on symptoms in patients with Behçet's syndrome.)
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