What is the history, physical exam, etiology, diagnosis approach, differential diagnosis, management, complications, and prognosis of Behcet disease?

Behçet's Disease: Comprehensive Overview

Behçet's disease is a chronic, relapsing, systemic vasculitis characterized by oral and genital ulcers, skin lesions, and potential involvement of multiple organ systems that requires individualized treatment based on organ involvement and disease severity. 1, 2

Epidemiology and Etiology

• Behçet's disease is most prevalent along the ancient "Silk Road," with highest prevalence in Turkey (80-370 cases per 100,000 persons) compared to only 1-3 cases per million in the United States 1, 2
• The disease typically appears in the third or fourth decade of life with roughly equal gender distribution, though men often experience more severe disease 3, 4
• Etiology involves a complex interplay between genetic predisposition (particularly HLA-B51) and environmental triggers leading to dysregulated immune responses 2, 5
• Genetic factors are key drivers of pathogenesis, with HLA-B51 being the strongest genetic susceptibility factor 3, 4
• Streptococcus sanguinis or microbiome changes can trigger innate immune system-mediated inflammation sustained by adaptive immune responses 3

Clinical Manifestations and Diagnosis

History and Physical Examination

• Recurrent oral aphthous ulcers (painful, round/oval ulcers with erythematous borders) are the hallmark manifestation 1, 3
• Genital ulcers (similar to oral ulcers but may leave scars) commonly affect the scrotum in men and labia in women 1, 3
• Skin lesions include erythema nodosum, papulopustular lesions, and pathergy (hyperreactivity of skin to minor trauma) 1, 4
• Ocular involvement presents as uveitis, retinal vasculitis, and may lead to blindness if untreated 1, 6
• Vascular involvement occurs in approximately one-third of patients, affecting both arteries and veins 1, 2
• Neurological manifestations include parenchymal disease and cerebral venous thrombosis 7, 6
• Gastrointestinal involvement presents with abdominal pain and ulcerations, most commonly in the ileocecal region 8
• Arthritis typically affects large joints such as knees and ankles, usually non-erosive and non-deforming 6

Diagnostic Criteria

• Diagnosis requires recurrent oral aphthous ulcers plus at least two of: recurrent genital ulceration, uveitis/retinal vasculitis, or specific skin lesions 7
• The pathergy test (formation of a papule or pustule 24-48 hours after skin prick) may support diagnosis 7, 4

Laboratory and Imaging

• No specific diagnostic laboratory test exists; ESR and CRP may be elevated during active disease 7
• HLA-B51 testing has moderate positive predictive value (55%) and high negative predictive value (84-90%) but should not be used as a standalone diagnostic test 7
• Organ-specific imaging is necessary based on clinical manifestations:
  • MRI with contrast for neurological involvement 7
  • Doppler ultrasound, CT angiography, or MR angiography for vascular manifestations 7

Differential Diagnosis

• Recurrent aphthous stomatitis (lacks systemic manifestations) 4
• Inflammatory bowel disease (particularly for gastrointestinal involvement) 8
• Multiple sclerosis (for neurological manifestations) 7
• Other vasculitides (granulomatosis with polyangiitis, polyarteritis nodosa) 4
• Sarcoidosis 7

Management

General Principles

• Treatment should be tailored to specific organ involvement and disease severity 1, 6
• The goal is to promptly suppress inflammatory exacerbations to prevent irreversible organ damage 1
• Young men with early disease onset have higher risk of severe disease and may benefit from early aggressive immunosuppression 6

Treatment Based on Organ Involvement

Mucocutaneous Manifestations

• Topical corticosteroids are first-line for isolated oral and genital ulcers 1, 6
• Colchicine (1-2 mg/day) should be tried first for recurrent mucocutaneous lesions, especially erythema nodosum and genital ulcers 1, 6
• For resistant cases, consider azathioprine, thalidomide, interferon-alpha, or TNF-alpha inhibitors 1, 6
• Papulopustular or acne-like lesions are treated with topical or systemic measures as used in acne vulgaris 1

Ocular Involvement

• Any patient with posterior segment inflammation should receive azathioprine (2.5 mg/kg/day) and systemic corticosteroids 1, 6
• For severe eye disease, add either cyclosporine A or infliximab to the regimen 6
• Regular ophthalmologic examinations are essential for monitoring 7, 6

Vascular Involvement

• For acute deep vein thrombosis, use immunosuppressive agents such as corticosteroids, azathioprine, cyclophosphamide, or cyclosporine A 6
• For pulmonary and peripheral arterial aneurysms, high-dose glucocorticoids and cyclophosphamide are recommended 6
• Anticoagulants should generally be avoided in Behçet's disease with venous thrombosis due to bleeding risk, especially with coexisting pulmonary arterial aneurysms 6

Neurological Involvement

• Acute parenchymal attacks should be treated with high-dose glucocorticoids followed by slow tapering, together with immunosuppressives such as azathioprine 6
• For cerebral venous thrombosis, high-dose glucocorticoids followed by tapering is recommended 6
• Avoid cyclosporine A in patients with central nervous system involvement due to potential neurotoxicity 6

Gastrointestinal Involvement

• Medical treatment with sulfasalazine, corticosteroids, azathioprine should be tried before surgery, except in emergencies 6
• For severe/refractory cases, consider TNF-alpha antagonists and/or thalidomide 6

Steroid Dosing Regimen

• For acute attacks requiring systemic therapy, start with oral prednisolone at 1 mg/kg/day followed by gradual taper over 2-3 months 6
• For posterior segment inflammation, consider intravenous methylprednisolone pulses (1 g/day for 3-7 days) 6
• After achieving clinical response, taper prednisolone by 5-10 mg every 10-15 days, aiming for a maintenance dose of 5-10 mg/day 6
• Always combine systemic corticosteroids with appropriate steroid-sparing agents 6

Complications and Prognosis

• Untreated eye, vascular, nervous system, and gastrointestinal involvement can cause serious damage and even death 1, 3
• The disease is associated with higher mortality in young male patients 3
• Large-vessel, neurological, gastrointestinal, and cardiac involvement are the most important causes of death 3
• Post-thrombotic syndrome is frequent with recurrent deep vein thrombosis and may result in difficult-to-treat leg ulcers 6
• Disease manifestations typically ameliorate over time in many patients 1
• Regular monitoring of inflammatory markers and organ-specific evaluations are essential for assessing disease activity and treatment response 7, 6