Behçet’s syndrome also known as an oculo-orogenital syndrome, malignant aphthosis is a rare multisystem inflammatory chronic remitting and relapsing auto-inflammatory systemic vascular disorder of the eye characterized by recurrent oral aphthous ulcers, genital ulcerations, ocular manifestations, and other systemic involvement, ulcers affecting the mouth and genitals, various skin lesions, oral and genital ulcerations, uveitis, and erythema nodosum and abnormalities affecting the eyes. Symptoms include mucous membrane lesions of the mouth (canker sores) and genitals (ulcers) that tend to disappear and recur spontaneously. Inflammation of the eyes (anterior uveitis, posterior uveitis, or panuveitis) also affects individuals with Behçet’s syndrome. Additional systems of the body may also be affected including the joints, blood vessels, central nervous system, and/or digestive tract. The exact cause of Behçet’s syndrome is unknown.
Symptoms
The earliest symptom of Behçet’s syndrome is usually painful canker sores on the mucous membranes that line the mouth (aphthous stomatitis). The sores are usually round or oval with reddish (erythematous) borders that may occur anywhere within the mouth. They may be shallow or deep and may appear as a single lesion or a cluster of multiple lesions. The sores typically heal within a few days, up to a week or more, without scarring, but frequently recur. They may precede other symptoms of Behçet’s syndrome by several years. Sometimes similar sores may appear on the genitals, specifically the scrotum and shaft of the penis in males and the vulva in females. The sores are also round and painful but may be larger and deeper than those affecting the mouth. These sores also recur, but unlike oral sores, may tend to scar.
Behçet’s syndrome may also affect the eyes. Symptoms may include inflammation of the back of the eye (posterior uveitis) and inflammation of the anterior chamber (anterior uveitis or iridocyclitis). Inflammation of the iris accompanied by pain, tearing (lacrimation), and the accumulation of pus (hypopyon iritis) may also occur. The retina may become inflamed resulting in blurred vision, abnormal sensitivity to light (photophobia), and/or, inflammation of the thin membranous layer of blood vessels behind the retina (chorioretinitis). Although the lesions that cause inflammation in various parts of the eyes may resolve, repeated recurrences may result in partial loss of vision (decreased visual acuity) or complete blindness if the disease is uncontrolled. In some cases, eye abnormalities may be the first symptom of Behçet’s syndrome. In other cases, they may not develop until several years later.
Individuals with Behçet’s syndrome may also exhibit the formation of small, pus-filled growths on the skin (pustules). Some affected individuals, especially females, may develop lesions that resemble those of erythema nodosum, a skin disorder characterized by the formation of tender, reddish, inflammatory nodules on the front of the legs. These nodules disappear on their own (spontaneously) sometimes leaving faint scars or discoloration (pigmentation). Some individuals with Behçet’s syndrome may develop small eruptions that resemble acne (acneiform eruptions) and/or inflammation that mistakenly appear to affect the hair follicles on the skin (pseudofolliculitis).
In approximately 50 percent of cases of Behçet’s syndrome, affected individuals experience pain (arthralgia) and swelling in various joints of the body (polyarthritis). This may occur before, during, or after the onset of the other symptoms associated with Behçet’s syndrome. Pain, which can range from mild to severe, typically affects the joints of the knees, wrists, elbows, and ankles, and may become chronic. Lasting damage to affected joints is extremely rare.
Individuals with Behçet’s syndrome may also have recurring ulcers in the digestive tract. Symptoms vary from mild abdominal discomfort to severe inflammation of the large intestine and rectum accompanied by diarrhea or bleeding.
Approximately 10%-20% of individuals with Behçet’s syndrome also have involvement in the central nervous system. These symptoms usually appear months or years after the initial symptoms of Behçet’s syndrome. Recurring attacks of inflammation involving the brain (parenchymal Neuro-Behçet) or the membranes that surround the brain or spinal cord (meningitis or meningoencephalitis) can result in neurological damage. Symptoms may include headache, the inability to coordinate voluntary movement (cerebellar ataxia), impaired muscle movements of the face and throat (pseudobulbar palsies), stroke, and/or rare, seizures.
Areas commonly affected by Behcet’s disease include:
- Mouth. Painful mouth sores that look similar to canker sores are the most common sign of Behcet’s disease. They begin as raised, round lesions in the mouth that quickly turn into painful ulcers. The sores usually heal in one to three weeks, though they do recur.
- Skin. Some people develop acne-like sores on their bodies. Others develop red, raised, and tender nodules on their skin, especially on the lower legs.
- Genitals. Red, open sores can occur on the scrotum or the vulva. The sores are usually painful and can leave scars.
- Eyes. Inflammation in the eye (uveitis) causes redness, pain, and blurred vision, typically in both eyes. In people with Behcet’s disease, the condition can come and go.
- Joints. Joint swelling and pain often affect the knees in people with Behcet’s disease. The ankles, elbows, or wrists also might be involved. Signs and symptoms can last one to three weeks and go away on their own.
- Blood vessels. Inflammation in veins and arteries can cause redness, pain, and swelling in the arms or legs when a blood clot results. Inflammation in the large arteries can lead to complications, such as aneurysms and narrowing or blockage of the vessel.
- Digestive system. A variety of signs and symptoms can affect the digestive system, including abdominal pain, diarrhea, and bleeding.
- Brain. Inflammation in the brain and nervous system can cause headaches, fever, disorientation, poor balance, or stroke.
Behçet’s syndrome causes inflammation of the blood vessels (vasculitis). The involvement of small vessels is thought to drive many of the problems that the disorder causes. In some instances, inflammation of the large veins, particularly those in the legs may occur along with the formation of blood clots (thrombophlebitis). The walls of an involved artery may bulge forming a sac (aneurysm). In very rare cases, blood clots from the veins travel to the lungs (pulmonary emboli) resulting in episodes of chest pain, coughing, difficult or labored breathing (dyspnea), and coughing up blood (hemoptysis).
Unlike most diseases which are classified as vasculitis, involvement of the kidneys or peripheral nerves is very rare.
It is especially important to identify Behçet’s disease when there is ocular, central nervous system or large blood vessel involvement as manifestations are usually the most serious.
Causes
The exact cause of Behçet’s syndrome is not known. Cell-mediated immunity plays a significant role in the pathogenesis of this disease. Type 1 helper T (Th1) cell activation leads to increased circulating levels of T-lymphocytes, accounting for various symptoms of Behcet disease. Pro-inflammatory cytokines, including IL-1, IL-8, IL-12, IL-17, IL-37, and TNF, are increased in Behcet disease and are thought to be involved in the pathogenesis. They may also serve as an indicator of disease severity. Increased macrophage activation, neutrophil chemotaxis, and phagocytosis have been observed in lesions of Behcet disease. Mucocutaneous lesions including oral aphthae, skin pustules, and erythema nodosum are thought to be a result of increased neutrophil activation leading to a neutrophilic vascular reaction that causes tissue injury.[rx] Circulating immune complexes play a role in causing the characteristic neutrophilic vascular reaction. Anti-endothelial cell antibodies and endothelial cell dysfunction are also thought to play a role in the pathogenesis of Behcet disease. [rx]
Studies suggest that some people may have a genetic predisposition to the condition. A genetic predisposition means that a person may carry a gene for a disease but it may not be expressed unless something in the environment triggers the disease. Researchers have demonstrated that certain individuals with Behçet’s syndrome, especially those of Middle Eastern and Asian descent, have an increased frequency of certain “human leukocyte antigens” (HLAs) in the blood. Individuals with Behçet’s syndrome are more likely to have HLA-B51 than the general population. The possible role of HLA-B51 in predisposing individuals to Behçet’s syndrome and its overall association with the disorder is unknown. Other genetic markers and their role in the development of Behçet’s disease are being studied. Viral or bacterial infections have also been suggested as a possible cause of the disorder. Still another theory is that the disease is an auto-inflammatory disorder in which the body loses the ability to appropriately regulate and control inflammation.
Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. While the investigation is ongoing, no autoantibodies to date have been identified to suggest that Behçet’s syndrome is an autoimmune disease.
Diagnosis
History and Physical
While mucocutaneous lesions are the hallmark of Behcet disease, the most severe manifestations are uveitis, large vessel, and neurological involvement.
Aphthae – Oral ulcers occur in 97% to 99% of patients with Behcet disease, and they often represent the initial clinical feature. Lesions are usually painful, recurrent, multiple, and may involve soft palate, hard palate, buccal mucosa, tongue, gingiva, lips, and tonsils. More than 90% of oral ulcers heal without scarring. Genital lesions are seen in more than 80% of patients with Behcet disease. These lesions are also recurrent, although, in contrast to oral lesions, more than 70% of genital lesions heal with scarring. Genital ulcers occur on the scrotum (90%) in males and the vulva or vagina in females.
Cutaneous Manifestations – Several cutaneous manifestations of Behcet disease have been described. Erythema nodosum-like lesions on the lower extremity are common. Behcet disease-related erythema nodosum lesions show a more vasculitic component compared to erythema nodosum which is idiopathic or from other causes.[rx] Superficial thrombophlebitis appearing as nodular lesions may be associated with deep vein thrombosis. Acneiform or pseudofolliculitis lesions are common but are non-specific and may be indistinguishable from ordinary acne.[rx] Other cutaneous manifestations that have been described include pyoderma gangrenosum-like lesions, pustular vasculitic lesions, cutaneous small-vessel vasculitis, and Sweet syndrome-like lesions.
A positive pathergy reaction characterized by the formation of erythematous papules or pustules 24 to 48 hours after needle insertion is thought to be very specific for Behcet disease. [rx] While it is seen in 60% to 70% of patients from Turkey and Japan, a positive pathergy reaction is very rarely observed in patients with Behcet disease who are from Northern Europe or the United States[rx].
Ocular Manifestations
More than 50% of patients with Behcet disease have eye involvement, although it is much more common in males and younger patients. Eye involvement is usually not the presenting feature of Behcet disease, but usually occurs within the initial few years of diagnosis, and is rare to occur late in the disease if not present earlier.[rx]
Uveitis that is relapsing, chronic, bilateral, and involves both anterior and posterior uveal tracts is common. Anterior uveitis causes erythema and photophobia, while posterior uveitis causes vision loss. Hypopyon-related uveitis is less common but very severe as it almost always accompanies severe retinal disease. Retinal involvement with retinal vasculitis can be seen and is a cause of blindness in these patients. Conjunctivitis and isolated anterior uveitis are rare.
Musculoskeletal Manifestations
Inflammatory, non-erosive, non-deforming arthritis is seen in 50% of patients with Behcet disease,[rx] more common in patients with acneiform lesions.[rx] It is usually oligoarthritis that is symmetric or asymmetric, but polyarthritis and monoarthritis can also be seen. Joint involvement is peripheral, and spine involvement or sacroiliitis is not usually seen, differentiating it from HLA-B27-associated erosive sacroiliitis. Knees are the most commonly involved joint, followed by ankles, wrists, and elbows.
Vascular Manifestations
The involvement of both arterial and venous tracts of all sizes is a hallmark of Behcet disease and can be seen in 25% of patients, more commonly in males. Superficial and deep thrombophlebitis of the lower extremities is the most common vascular manifestation. Rarely, Budd-Chiari syndrome or vena cava obstruction may be seen. Embolism of these thrombi is rare as the inflammatory thrombi tightly adhere to the diseased endothelium. Arterial vasculitis may involve any sized artery and may be accompanied by aneurysms or occlusions. Aortitis, as well as vasculitis of the carotid, femoral, and popliteal arteries, can be seen. Pulmonary artery involvement with aneurysm formation is unique to Behcet disease and is the leading cause of death in these patients.[rx]
Neurological Manifestations
Central nervous system involvement is seen in 5% to 10% of patients with Behcet disease, and 80% of it is parenchymal involvement most commonly of the brainstem that leads to cerebellar, pyramidal, and sensory signs and symptoms. The cerebrospinal fluid examination is sterile but may reveal elevated protein and/or cell count. Nonparenchymal involvement characterized by dural sinus thrombi is seen in 20% and leads to headaches and papilledema. Simultaneous parenchymal and nonparenchymal involvement, isolated cerebellar involvement, and cranial and peripheral nerve involvement are rare.[rx]
Gastrointestinal Manifestations
Mucosal ulcerations resembling the orogenital aphthae can be seen in the terminal ileum, cecum, colon, and esophagus. Extensive ulcerations, especially ileocecal lesions, may lead to perforation. Inflammatory bowel disease can present with similar gastrointestinal features in addition to extragastrointestinal features, including uveitis, erythema nodosum, oral ulcers, inflammatory arthritis, and pyoderma gangrenosum; and needs to be ruled out before confirming a diagnosis of Behcet disease.
Other Systemic Manifestations
Cardiac involvement, including pericarditis, myocarditis, endocarditis, coronary artery vasculitis, and coronary aneurysms, has been reported. Renal involvement is rare and may include AA-amyloidosis and glomerulonephritis. Epididymitis can also be seen.
Imaging
Diagnosis of Behcet is clinical and can be difficult due to the lack of any pathognomic laboratory findings. Laboratory findings are usually non-specific, including anemia of chronic disease, leukocytosis, and elevation in markers of inflammation. Imaging studies shall be directed at the organ involved and may include X-rays and arthrocentesis to assess arthritis, CT-scan to assess for bleeding, thrombosis, and ischemia, angiography to look for aneurysms, and lumbar puncture to evaluate meningitis. The rationale for carrying out these investigations is to rule out other causes of the clinical presentation. A careful ophthalmologic examination to evaluate ocular involvement shall be pursued at initial presentation, and cutaneous lesions shall be biopsied to confirm the cutaneous diagnosis.
Although several classification criteria have been published, they shall be used with caution in the clinical setting to make a diagnosis. The International Team for the Revision of International Criteria for Behçet Disease (ITR-ICBD) revised the established criteria in 2008. The revised criteria are point-based and give 1 point each to oral aphthosis, skin manifestations (pseudofolliculitis, skin aphthosis), vascular lesions (phlebitis, large vein thrombosis, aneurysm, arterial thrombosis), positive pathergy test and 2 points each to genital aphthosis and ocular lesions. 3 or more points are needed for the diagnosis of Behcet disease. Similar to previous classification criteria, there are some pitfalls with this criteria as well.
Patients with inflammatory bowel disease, systemic lupus erythematosus, reactive arthritis, and herpetic infections can mimic Behcet disease and shall be ruled out first.
Treatment
The treatment of Behçet’s syndrome is directed toward the specific symptoms that are apparent in each individual. Specific therapies for Behçet’s syndrome are symptomatic and supportive. The severity of the condition as well as the patient’s age and sex may all affect treatment decisions. Spontaneous remission over time is common for individuals with Behçet’s syndrome.
For recurrent ulcers, the application of corticosteroid-containing preparations to the affected areas may help abort developing attacks. Mouthwash containing a local anesthetic such as Xylocaine, lidocaine, or Benadryl may temporarily relieve pain. Arthritis associated with Behçet’s syndrome may be treated with colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs). Continuing therapy with the drug colchicine may be effective in preventing recurring attacks of oral and genital ulcers or arthritis.
- Mucocutaneous involvement: Topical corticosteroids, lidocaine-containing creams, or sucralfate suspension can be used for most minor orogenital lesions. For severe or refractory mucocutaneous lesions, colchicine, dapsone, thalidomide, methotrexate, prednisone, or interferon-alpha can be considered. Apremilast was approved for the treatment of oral ulcers in Behcet disease in 2019.
- Ocular involvement: Topical and/or systemic corticosteroids, in combination with azathioprine, is the first-line treatment recommended for uveitis, especially with posterior involvement. For severe or refractory eye disease, infliximab, adalimumab, mycophenolate mofetil, cyclosporine, or interferon-alpha can be considered.
- Musculoskeletal involvement: Arthritis can usually be managed with colchicine. Short courses of corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs) can be used for symptomatic relief. For patients with longer-lasting or frequently occurring attacks refractory to colchicine, the use of sulfasalazine, azathioprine, TNF-α antagonists, or interferon alfa can be considered.
- Vascular involvement: For venous involvement, corticosteroids, azathioprine, cyclosporine, and cyclophosphamide can be considered. For arterial involvement, cyclophosphamide, along with corticosteroids, is recommended. Data does not support the use of anticoagulants, antiplatelets, or fibrinolytic agents in patients with thrombosis.
- Neurologic involvement: Corticosteroids, azathioprine, interferon alfa, cyclophosphamide, methotrexate, or infliximab, can be used for parenchymal disease. For dural sinus thrombosis, corticosteroids can be used. Cyclosporine should be avoided in patients with CNS disease unless it is indicated for ocular involvement.
- Gastrointestinal involvement: To prevent recurrences, corticosteroids, sulfasalazine, 5-aminosalicylic acid, azathioprine, infliximab, and thalidomide can be considered.
Inflammation of the joints, skin, and/or mucous membranes or other organs may be reduced with oral corticosteroid drugs. However, corticosteroids do not prevent recurring episodes of symptoms and may not reduce damage when used alone. Therefore, immunosuppressive agents such as azathioprine, methotrexate, cyclosporine, or chlorambucil may be employed for improved control of inflammation and organ protection. Experience is evolving with the use of interferon-alpha and with agents which inhibit tumor necrosis factor (TNF) in the treatment of Behçet’s disease.
Surgical Intervention
Surgical interventions may be indicated in extensive vascular involvement refractory to medical management. Aneurysms tend to recur, and surgical intervention for aneurysms shall always accompany medical intervention to prevent recurrences. Surgery is also used to manage fistulas, intestinal stenosis, perforation, pulmonary artery aneurysms, glaucoma, cataracts, and CNS aneurysms.
Investigational Therapies
There are no FDA-approved therapies for the treatment of Behçet’s Syndrome. Immunosuppressive drugs such as azathioprine (Imuran), chlorambucil (Leukeran), cyclophosphamide (Cytoxan), cyclosporine (Sandimmune), interferon-alpha, and anti-TNF inhibitors have been studied for use as treatments for the disorder. It has been suggested that cyclosporine may be beneficial for the treatment of oral ulcers, skin lesions, and inflammation of the eyes, but the symptoms of Behçet’s syndrome return quickly when the drug is stopped. Apremilast (Otezla) is currently being studied for use in the treatment of recurrent oral and genital ulcerations as well as other manifestations.
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