Behçet's Disease

Behçet's disease is a complex multi-system disorder of unknown aetiology characteristically presenting with recurrent oral ulcers. It is presumed to be an autoimmune disease and includes involvement of the mucocutaneous, ocular, cardiovascular, renal, gastrointestinal, pulmonary, vascular, musculoskeletal, urological and central nervous systems.

• Prevalence is 0.3-6.6 cases per 100,000 population. The prevalence is highest in the Middle East, China and Japan.¹
• Most common among patients aged 15-45 years. An age of onset younger than 25 years is associated with a higher prevalence of eye disease and active clinical disease.
• Males are affected more commonly than females.²
• Behçet's disease is associated with HLA-B51. Familial cases have been reported, but inheritance is probably not Mendelian.³

• Non-specific symptoms include tiredness, malaise, muscle pains, and transient fevers.
• Headaches are common.⁵
• Skin and mucous membranes:
  • Painful aphthous ulcers occur in any part of the mouth. The ulcers may last as long as 3 weeks.
    
    
    
    
    
    
  • Skin lesions occur in the genital regions.
    
    
    
    
    
    
  • Painful nodules occur due to erythema nodosum; patients often present with acne-like or pustular lesions.
    
    
    
    
    
    
• Ocular lesions include anterior uveitis, posterior uveitis, hypopyon, cataracts, glaucoma, retinal vasculitis, retinal haemorrhage, retinal detachment.
• Neurological: Central nervous system involvement occurs late in the disease, e.g. meningoencephalitis, pyramidal tract lesions, cranial nerve lesions, behaviour changes and dementia. Thrombosis within the dural venous sinuses may also occur. Peripheral nerve involvement is rare.⁶
• Cardiovascular:
  • Vascular lesions include vasculitis of the small and large vessels, deep vein thrombosis and superficial thrombophlebitis, arterial occlusions and aneurysms.
  • Cardiac lesions include arrhythmias, pericarditis, vasculitis of the coronary arteries, endomyocardial fibrosis, and granulomas in the endocardium.
• Arthritis: Arthritis and arthralgias are common; arthritis is usually acute and not deforming and most often affects lower limbs, especially the knee. Back pain due to sacroiliitis may also occur.
• Gastrointestinal: Dysphagia, flatulence, abdominal pain, vomiting, diarrhoea or gastrointestinal bleeding. Ulcerative lesions may occur in any part of the gastrointestinal tract.
• Other manifestations include epididymitis, glomerulonephritis, lymphadenopathy, myositis, and polychondritis. Amyloidosis may occur but is uncommon.

The International Study Group criteria are currently used to define the illness:⁷

• At least 3 episodes of oral ulceration must occur in a 12-month period. They may be herpetiform or aphthous in nature.
• At least 2 of the following must occur:
  • Recurrent, painful genital ulcers that heal with scarring.
  • Ophthalmic lesions, including anterior or posterior uveitis, hypopyon, or retinal vasculitis.
  • Skin lesions, including erythema nodosum, pseudofolliculitis, or papulopustular lesions (may also include atypical acne).
  • Pathergy: Defined as a sterile erythematous papule larger than 2 mm in size appearing 48 hours after skin pricks with a sharp, sterile needle (a dull needle may be used as a control).

• Depends on which systems are involved.
• Differential diagnosis of oral or genital ulcers includes Herpes simplex , hand-foot-and-mouth disease, herpangina, chancre , histoplasmosis, squamous cell carcinoma.

• Full blood count may show mild anaemia and raised white cell count.
• Non-specific inflammatory markers: CRP, ESR, complement and acute-phase reactants may all be elevated during an acute attack.
• Antiphospholipid antibodies are positive in 25% patients.
• Pathergy test: Minor skin trauma induces an inflammatory papule or pustule after 24-48 hours (as defined above).
• Synovial fluid is usually cloudy with raised white cell count.
• Cerebrospinal fluid: Often find increased white cell counts (lymphocyte predominance) and elevated protein and immunoglobulin levels.
• Imaging studies, including CT and/or MRI scan, single-photon emission computed tomography (SPECT), may be required.
• Angiography is required to identify and assess aneurysms.
• Biopsy: Relevant tissue biopsy, e.g. renal biopsy, may be indicated.

• Local therapy:⁸
  • Dissolved tetracycline held in the mouth for approximately two minutes is the the drug of choice for aphthous stomatitis and oral ulcers.
  • Topical corticosteroids are effective for oral or genital ulcerations if they are applied during the prodromal stage of ulceration.
• Systemic manifestations:
  • Continual use of immunosuppressive medications may be required to suppress disease.
  • Corticosteroids are the mainstay of treatment; they are effective for acute manifestations but there is no evidence of any beneficial effect on disease progression.⁸
  • Methotrexate, colchicine or azathioprine can be effective.⁹ Dapsone, thalidomide (use is strictly limited because of its teratogenicity) and levamisole may also be useful.²
  • Tumour necrosis factor antagonists, e.g. etanercept or infliximab, may be effective.^10,11
• Mucocutaneous lesions and joint involvement:⁸
  • May respond to NSAIDs, prednisolone, levamisole, colchicine, dapsone, or sulfapyridine and thalidomide.
  • In most patients, arthritis can be managed with colchicine.¹² Local corticosteroid injections may also be used.
  • Immunosuppressive therapy with azathioprine, chlorambucil or cyclophosphamide may be effective.
• Major vessel disease:¹²
  • Vasculitis is treated with immunosuppressive medication, e.g. cyclophosphamide.²
  • Acute deep vein thrombosis: Immunosuppressive agents such as corticosteroids, azathioprine, cyclophosphamide or ciclosporine A.
  • Pulmonary and peripheral arterial aneurysms, cyclophosphamide and corticosteroids are recommended.
  • There is no evidence of benefit of anticoagulants, antiplatelet or antifibrinolytic agents in the management of deep vein thrombosis or for the use of anticoagulation for the arterial lesions.
• Ocular disease: Treatment includes topical mydriatic and corticosteroid drops. Successful immunosuppression is achieved with azathioprine or systemic corticosteroids.¹²
• Erythema nodosum: Colchicine or dapsone are effective.
• Central nervous system:¹²
  • For parenchymal involvement, corticosteroids, IFNa, azathioprine, cyclophosphamide, methotrexate and TNFa antagonists should be tried.
  • For dural sinus thrombosis, corticosteroids are recommended.
• Gastrointestinal lesions: Agents such as sulfasalazine, corticosteroids, azathioprine,
  TNF antagonists or thalidomide should be tried first before surgery, except in emergencies.¹²

Surgical

May be required for:

• Gastrointestinal complications, e.g. perforation and peritonitis.
• Aneurysms or ischaemic tissues affected by vasculitis or thrombosis.
• Ventricular aneurysms and coronary thrombosis.
• Eye involvement, e.g. glaucoma, cataracts or retinal detachment.
• Central nervous system aneurysms or clots.

• Vasculitis, rupture of aneurysms and thrombosis may all lead to potentially fatal cardiovascular complications.
• Central nervous system involvement can lead to permanent deficits.
• Eye involvement may result in blindness.

• Very variable course of recurrences and remissions lasting for years.
• Prognosis will depend on which systems are involved. Men tend to have a poorer prognosis.¹³
• Mortality is usually low but death may occur as a result of neurological involvement, vascular disease, bowel perforation, cardiopulmonary disease, or as a complication of immunosuppressive therapy.