Behcet Disease was first described in 1937 by Hulusi Behçet from Istanbul, who described three patients with oral and genital ulcerations, uveitis, and erythema nodosum. Other clinical features were identified later and were added to the disease spectrum.[1] Behcet disease is an auto-inflammatory systemic vasculitis of unknown etiology. It is characterized by mucocutaneous manifestations, including recurrent oral and genital ulcerations, ocular manifestations, especially chronic relapsing uveitis and systemic vasculitis involving arteries and veins of all sizes. It is also known as Behcet syndrome and malignant aphthosis.
Causes of Behcet Disease
The exact etiological basis of Behcet disease remains unknown, although genetics and environmental factors have been found to play a role.
Increased prevalence along the “Silk Route” and familial aggregation suggest a genetic element, although Behcet disease does not follow a mendelian inheritance. The most frequent association is with carriers of HLA-B51/B5, who are at high risk for developing Behcet disease compared to non-carriers. [2] HLA B51 is a common genetic factor prevalent in Japanese, middle eastern, and Turkish populations. Several other genes have been identified, including tumor necrosis factor (TNF), heat shock proteins, and major histocompatibility complex class I chain-related genes. Still, their independent contribution to the development of Behcet disease is debatable.[3]
Exposure to infectious agents, especially hypersensitivity to Streptococcus sanguis antigens, has suggested a pathological role. [4][5] While many other infectious agents, including Staphylococcus aureus, Herpes simplex virus type 1, and Prevotella species, have been suggested as potential culprits, their direct association with the development of Behcet disease has not been confirmed.[6] The current belief is that exposure to an infectious agent or an external agent somehow initiates an auto-inflammatory response in genetically predisposed individuals.
Pathophysiology
Behcet disease is an auto-inflammatory vasculitis involving arteries and veins of all sizes and types. In contrast to other vasculitides, vasculitic lesions in Behcet disease lack necrotizing vasculitis or giant cell formation. Venular involvement and formation of pulmonary and arterial aneurysms are unique to Behcet disease.[10] Furthermore, patients with Behcet disease lack specific autoantibodies, as seen in other autoimmune disorders such as systemic lupus erythematous.
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.[11] 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. [12]
Diagnosis of Behcet Disease
Histopathology
Histopathological features of the disease are vasculitis and thrombosis. Biopsy of the mucocutaneous lesions shows a neutrophil-predominant reaction with endothelial swelling, extravasation of RBCs, and leukocytoclastic vasculitis with fibrinoid necrosis of the blood vessel walls. The presence of lymphocytic vasculitis represents older lesions [13], and a neutrophilic vascular reaction is considered to be the most predominant reaction in Behcet disease. The involvement of vasa vasorum (vasculitis) may result in the formation of aneurysms in the large arteries. Synovial fluid analysis in Behcet disease reveals neutrophil predominant leucocyte counts varying from 300 cells/mm3 to more than 30,000 cells/mm3.[14]
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 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 that is idiopathic or from other causes.[15] 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.[13] 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. [16] 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[17].
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.[18]
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 the 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,[19] more common in patients with acneiform lesions.[20] 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.[21]
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.[22]
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.
Evaluation
Diagnosis of Behcet is clinical and can be difficult due to the lack of any pathognomic laboratory finding. 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 of Behcet Disease
Medical Intervention
Treatment is aimed at preventing organ damage. The treatment strategy is decided based on organ involvement, severity, and prognostic factors.
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 anticoagulant, antiplatelet, 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.
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.
Differential Diagnosis
Behcet disease is a clinical diagnosis. There are several other diseases that can mimic clinical features, which are seen in Behcet disease, all of which should be ruled out before confirming a diagnosis of Behcet disease.
1. Inflammatory bowel disease (IBD): In addition to gastrointestinal involvement, IBD and Behcet disease share several similar clinical features, which include oral ulcers, uveitis, inflammatory arthritis, erythema nodosum, and pyoderma gangrenosum. Colon biopsies may not be adequate in differentiating these diseases. However, sacroiliitis and axial inflammatory arthritis can be seen in IBD but not in Behcet disease. Posterior uveitis and panuveitis are rare in IBD. Vascular inflammation leading to aneurysms, venous thrombosis, CNS involvement, and pathergy test are also a feature of IBD. Without the presence of these other extragastrointestinal clinical features, it is not easy to differentiate these two conditions.
2. Seronegative arthritis: Reactive arthritis is another major differential diagnosis, as it can also cause peripheral inflammatory arthritis, ocular inflammation, and skin disease. As in IBD, posterior uveitis and panuveitis are rare in reactive arthritis and vascular, or CNS involvement is also rare. Sacroiliitis and axial involvement are common in reactive arthritis while not in Behcet disease. Urethritis, penile lesions on the glans penis, and conjunctivitis, which are features of reactive arthritis, are not usually seen in Behcet disease.
3. The systemic lupus erythematosus (SLE): SLE can have a very similar presentation to Behcet disease and can involve all the organs involved in Behcet disease in a similar fashion. However, inflammatory thrombi are not usually seen in SLE, and the SLE-specific autoantibodies can help differentiate these two conditions.
4. Herpetic infections: Oral and genital lesions can be seen in herpetic infections, and when appropriate, a culture shall be done from the lesion to rule out herpes before considering Behcet.
Other differential diagnoses that shall be considered (depending on organ involvement) include sarcoidosis, other systemic vasculitides, relapsing polychondritis, and multiple sclerosis.
Complications
Besides increased mortality, Behcet disease is associated with several potential lifelong complications, most of which are a result of ocular or neurologic involvement. Patients with hypopyon-related uveitis and retinal involvement are at a high risk of blindness.
Coronary or pulmonary arterial aneurysmal rupture is also associated with Behcet disease, which carries a high mortality risk.
Centraal nervous involvement can lead to significant morbidity, permanent deficits, and death. Ocular involvement, in the form of anterior and posterior uveitis, may result in permanent blindness.
Another complication of Behcet disease is an increased incidence of miscarriages due to the vasculitis of the placenta.
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