Behcet's

Does this patient have Behçet’s Syndrome?

Behçet’s syndrome (BS) is a systemic inflammatory vasculitis characterized by recurrent oral aphthous ulcerations, genital ulcers, skin, and ocular lesions. BS is a heterogeneous syndrome which can affect the cardiovascular, gastrointestinal, renal, and nervous systems.

Oral ulcers

Recurrent oral ulcers are present in almost all BS patients. This is the earliest sign of disease and may precede other symptoms by years; most common sites are the gingival and buccal mucosa, tongue, and lips.

Genital ulcers

Genital ulcers are not as common as the oral ulcers and are present in 57-93% of patients. In many instances the diagnosis of genital herpes is considered first, and it is after ruling out this mimic and when the ulcers recur and other manifestations start to show the diagnosis of BS is considered. Ulcers are mainly on the scrotum in males; vulvar, vaginal and cervical lesions in females.

Cutaneous lesions

Cutaneous lesions occur in 38-90% of patients and are variable in appearance. Papulopustular lesions (acne like) are the most common and occur in usual sites of acne (face, upper chest, and back) as well as in atypical sites like the legs and arms. Erythema nodosum may affect different areas, mainly the lower extremities.

Pathergy reaction, which is a hyper-reactivity of skin in response to trauma; this can be elicited by skin prick by a 20 gauge need and observation of erythematous papular or pustular lesion that may appear 48 hours after routine blood draw. Cutaneous ulcers are much less frequent and occur only in 3% of patients; these usually heal with scarring.

Ocular manifestations

Ocular manifestations are very serious in BS and they occur in 30-70% of patients. Ocular disease in BS can cause blindness in 25% of patients. Ocular involvement is more severe in males from endemic countries. Clinical symptoms include photophobia, lacrimation, blurred vision, hyperemia, and pain.

Uveitis can be a bilateral chronic relapsing uveitis that can affect the anterior segment, posterior segment, or both. Inflammatory exudates may settle in a visible layer in the anterior chamber, forming the classic hypopyon. In addition to uveitis, retinal occlusive vasculitis occurs and involves the arteries and the veins

Oligoarthritis

The arthritis is typically a non-erosive, non-deforming oligoarthritis involving the knees, ankles, and wrists.

Systemic vasculitis

BS may include a peculiar systemic vasculitis that affects both the arterial and venous system. Veins are more commonly affected with deep or superficial thrombophlebitis; rarely thrombosis of the superior or inferior vena cava can occur; thrombosis may also involve hepatic veins leading to Budd-Chiari syndrome and can involve dural sinuses.

Arterial disease (manifested as aneurysms or occlusions) is less common but is associated with significant morbidity; arteries involved include the pulmonary arteries, abdominal aorta, carotid, femoral, popliteal, and rarely the coronaries.

Pulmonary artery aneurysm is a rare manifestation; it can present with hemoptysis and can be associated with deep vein thrombosis; this scenario can be easily misdiagnosed as pulmonary emboli given the similar clinical presentation and the association with venous thrombosis.

Neurologic manifestations

Neurologic manifestations are the most serious manifestation on BS and carry high mortality and morbidity. They occur in 5-10% of patients within 5 years of disease onset; more frequent in males. Two types of involvement are usually present: parenchymal disease manifesting as recurrent meningoencephalitis and cerebral venous thrombosis presenting as severe headaches. In contrary to other vasculitides, peripheral neuropathy is uncommon in BS.

Gastrointestinal manifestations

Gastrointestinal manifestations are more common among the Japanese BS population and Behcet patients in United States. It is frequently very challenging to differentiate from inflammatory bowel disease. In such circumstances, vascular involvement will be in favor of BS over IBD; however, vascular involvement is often a late manifestation of BS which adds to the challenge of the diagnosis.

Renal involvement

Renal involvement in BS is less frequent and less severe than in other forms of vasculitis. It can manifest as: AA amyloidosis; glomerulonephritis; vascular disease; and interstitial nephritis.

Diagnosis

The diagnosis of BS remains challenging given the diverse protean manifestations. Multiple disease mimics the syndrome. Diseases that affect the mucosa such as celiac disease, IBD, Stevens-Johnson syndrome, bullous skin disorder and venereal diseases should be ruled out. The arthritis of BS can mimic that of spondyloarthropathies.

Vascular involvement is peculiar giving that BS is a vasculitis that affects the venous and the arterial tree.

Recurrent ulcers can present years before any other manifestations, and it is not until visual, ophthalmologic or vascular manifestations occur for the diagnosis of BS to be raised.

What tests to perform?

The diagnosis of BS should be based on collective information gained from the pattern of clinical involvement, laboratory findings, tissue histology, and imaging.

An increase in the inflammatory markers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), leukocytes and platelets may be found during the active phase of the disease. These are not specific for the diagnosis but may indicate that an inflammatory status exits.

Different classification criteria have been developed in BS. These criteria were developed for research purposes and should not be used as diagnostic criteria.

The mostly used criteria are the International Study Group (ISG) criteria. They require the presence of recurrent oral aphthae (at least three times in 1 year) plus two of the following in the absence of other systemic diseases:

Recurrent genital aphthae, eye lesions (including anterior or posterior uveitis, cells in vitreous on slit lamp examination, or retinal vasculitis).
Skin lesions (including erythema nodosum, pseudo-vasculitis, papulopustular lesions, or acneiform nodules consistent with Behçet’s).
A positive pathergy test.

Pathologic diagnosis in BS is not a necessary test. Pathologic findings from aphthous ulcers are not specific and are not diagnostic. Findings of vasculitis from cutaneous biopsies should be interpreted in the context of other clinical findings to make the diagnosis of BS.

Generally, viral cultures and sometimes serologies should be done to exclude viral infection (including CMV and more common labial or genital herpes).

How should patients with Behçet’s Syndrome be managed?

Few randomized controlled trials have been performed in BS. Treatment of BS is based on the clinical presentation, affected site, and the severity of disease.

Articular disease is usually non-deforming and non-erosive, treatment is symptomatic; some patients need short term corticosteroid systemic or local injection therapy. Colchicine may be effective for arthritis in some patients with chronic inflammation.

Mucosal lesions

Mucosal lesions (oral and genital ulcers) are treated with topical corticosteroids. Other symptomatic treatments include lidocaine, chlorhexidine. Major oral or genital ulcers can be treated with intralesional steroids.

Colchicine is widely used for mucocutaneous lesions; its efficacy was shown only in genital ulcers and erythema nodosum in female patients. When oral and genital ulcerations are resistant to topical measures and colchicine, systemic glucocorticoids are utilized; Dapsone is effective for mucocutaneous manifestations. Methotrexate has as well been reported to be effective.

Resistant cases might warrant immunosuppressive therapy with azathioprine, cyclosporine A, IFN-alfa-2a or alfa-2b and TNF-blocking agents. Thalidomide has been used in refractory cases but its use is limited giving its adverse effects.

Apremilast is an emerging drug for the use of oral ulcers.

Ocular inflammatory disease

Topical corticosteroid and a dilating drop such as scopolamine may be used in the management of mild anterior uveitis. A short course of glucocorticoid therapy may be needed to control inflammation.

Posterior uveitis constitutes a serious threat to vision and requires intensive immunosuppression. A more aggressive management approach, including high dose glucocorticoid therapy in addition to another immunosuppressive agent, is needed in these patients.

Azathioprine was shown in a randomized controlled study to decrease the recurrence risk and severity of ocular disease in BS.

Azathioprine together with glucocorticoids is used for initial therapy by most centers; however, an expert panel from the American Uveitis Society recommends initial treatment with TNF-alpha inhibitors due to the observed improvement in ocular manifestations compared with other treatments. The data also suggest that infliximab and adalimumab may be more effective than etanercept.

Glucocorticoids are used as Prednisone (1 mg/kg per day for one month, with tapering thereafter as tolerated), or as intravenous methylprednisolone (1 g/day for three days) for sight-threatening disease. Intraocular triamcinolone may be beneficial for panuveitis.

Many large prospective case series demonstrated that anti–TNF therapy is effective in controlling resistant ocular disease in BS. In patients without an adequate response to initial therapy or with severe eye disease (defined as greater than two lines of drop in visual acuity on a 10/10 scale and/or retinal disease, such as retinal vasculitis or macular involvement), TNF-alpha inhibitor, most commonly infliximab, is added to Imuran.

Recently Adalimumab was shown to significantly lower the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. Further, adalimumab treatment controlled multiple aspects of uveitic inflammation without glucocorticoid support and was associated with a lower risk of uveitic flare and a longer time to a flare than placebo. This led to the FDA approval of Adalimumab for the treatment of noninfectious intermediate uveitis, posterior uveitis, and panuveitis in the United States.

Alternatively, Cyclosporine can be used as it was shown in a controlled trial to reduce the frequency of ocular exacerbations and improve visual acuity. Recently, Mycophenolate Mofetil (MFF) was shown to be safe and effective in controlling macular edema and uveitis relapses

Rituximab has also shown benefit in a small trial in patients with severe ocular manifestations resistant to cytotoxic agents.

GI manifestations

Corticosteroids, sulfasalazine, and azathioprine are the mainstay of treatment of GI manifestations. Successful treatment of GI manifestations of the disease has been reported with infliximab.

Vascular disease

Little data is available to direct the treatment of vascular disease in BS. A combined medical and surgical approach is needed in large arterial disease. High dose glucocorticoid therapy in addition to cyclophosphamide improves prognosis. Lower complication rates occur when surgical interventions are performed when the disease is inactive.

There is lack of consensus on the treatment of venous thrombosis in BS. Venous disease in Behçet’s syndrome is believed to result from endothelial inflammation leading to thrombosis. The treatment approach of preventing venous thrombotic events in Behçet’s syndrome is to control systemic inflammation. Nevertheless, when peripheral venous thrombotic events occur, patients are treated with anticoagulation. The use of immunosuppressants and glucocorticoids reduced risk of venous thrombotic relapse.

The management of cerebral sinus thrombosis and pulmonary vein thrombosis should be individualized. Systemic glucocorticoid treatment with or without other immune-modulating treatment is indicated; however, there is no consensus whether anticoagulation, the standard treatment for cerebral venous thrombosis, is beneficial in patients with Behçet’s associated cerebral vein thrombosis. Anticoagulation increases the risks of hemorrhage in patients with Behçet’s-associated aneurysms.

A special attention should be considered in patients with BS to minimize any invasive procedures or vascular manipulation. Patients with BS are at higher risk for pseudoaneurysm, phlebitis or thrombosis when the vessels are manipulated; this occurs mainly in patients who demonstrate positive pathergy test.

What happens to patients with Behçet’s Syndrome?

Typical age of onset of disease is the third or fourth decade of life.

BS has a more aggressive and severe course in young male adults in Eastern Mediterranean cohorts, Turkey, the Middle and Far East, and Japan than in Western populations. The greatest morbidity and mortality comes from neurologic, ocular, and large-vessel arterial or venous disease.

Mucocutaneous, articular, and ocular diseases are often at their worst in the early years of the syndrome. Neurologic and large vessel diseases usually present at a later stage of the disease. The disease activity may decline with passing years.

Survival from pulmonary artery aneurysms have dramatically improved due to earlier recognition and treatment using glucocorticoids and other immunosuppressives.

BS has a waxing and waning course characterized by relapses and remissions. Disease activity tends to lessen as time progress.

How to utilize team care?

BS patients are at risk of serious complications of the disease process. Close follow-up with an experienced team that includes rheumatologist, ophthalmologist and vascular specialist is required to identify early signs of disease activity and initiate the appropriate therapeutic strategy in order to prevent the dreaded complications of this disease.

Are there clinical practice guidelines to inform decision making?

EULAR (European League Against Rheumatism) guidelines for management of BS:

Mucocutaneous disease

Topical measures.
Erythema nodosum: colchicine.
Resistant cases: azathioprine, IFN-alfa-2a or alfa-2b, or anti-TNF agents.

Articular disease

Colchicine is the first choice.
Resistant cases: azathioprine, IFN-alfa-2a or alfa-2b, or anti-TNF agents.

Ocular disease

Azathioprine and local and systemic corticosteroids.

Refractory cases

Cyclosporine A or infliximab in combination with azathioprine and corticosteroids.
IFN-alfa-2a or alfa-2b alone or with corticosteroids.

Gastrointestinal disease

Sulfasalazine, corticosteroids, azathioprine, anti-TNF agents.
Surgery for perforation or intractable bleeding.

Major vessel disease

Acute deep vein thrombosis: corticosteroids, azathioprine, cyclophosphamide, or cyclosporine A.
Thrombosis of the vena cava and Budd-Chiari: Cyclophosphamide.
Arterial aneurysm: Corticosteroids and cyclophosphamide; surgery.

Neurologic disease

Parenchymal disease: corticosteroids, IFN-alfa-2a or alfa-2b, azathioprine, cyclophosphamide, methotrexate, or anti-TNF agents.
Dural sinus thrombosis: Corticosteroids.

Other considerations

Typical length of stay

Typical length of stay depends on the organ involved. Usually patients are hospitalized for major organ involvement such as GI, neurologic or vascular involvement.

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Rheumatology