History
Signs and symptoms of Behçet disease, which may be recurrent, may precede the onset of the mucosal membrane ulcerations by 6 months to 5 years.
Prior to the onset of Behçet disease, patients may experience a variety of symptoms, such as the following:
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Malaise
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Anorexia
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Weight loss
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Generalized weakness
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Headache
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Perspiration
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Decreased or elevated temperature
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Lymphadenopathy
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Pain of the substernal and temporal regions
A history of repeated sore throats, tonsillitis, myalgias, and migratory erythralgias without overt arthritis is common.
A diagnosis of Behçet disease is based on clinical criteria because of the absence of a pathognomonic laboratory test. The period between the appearance of an initial symptom and a major or minor secondary manifestation can be up to a decade in many cases.
The number of different criteria or classification systems that have been introduced over the past 25 years reflects the failure of any single one to meet clinical demands. The revised 1987 criteria of the Japanese group (Mizushima) have been widely applied. [67]
The diagnostic criteria of the International Study Group for Behçet Disease have been applied to establish a firmer diagnosis. They are the most widely used criteria. [68]
The major limitation of these criteria is the fact that recurrent oral ulceration is the characteristic symptom for the diagnosis of Behçet disease. For example, patients with uveitis and genital ulcers, without oral aphthosis, would not be considered to have Behçet disease, although this is, in fact, a far-advanced form of the disease.
International Criteria for Behçet Disease (ICBD) have been proposed by a collaborative study of 27 countries and includes a wide variety of symptoms, [69] putting in consideration that pathergy testing and oral ulcers are not mandatory for the diagnosis of Behçet disease, but a sum of a wide variety of symptoms should be considered, which increases its sensitivity. [69]
Diagnostic criteria from the Behçet syndrome research committee of Japan (1987 revision) [67]
Major features are as follows:
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Recurrent aphthous ulceration of the oral mucous membrane
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Skin lesions -Erythema nodosum –like lesions, subcutaneous thrombophlebitis, folliculitis (acneiform lesions), cutaneous hypersensitivity
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Eye lesions - Iridocyclitis, chorioretinitis, retinouveitis, definite history of chorioretinitis or retinouveitis
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Genital ulcer
Minor features are as follows:
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Arthritis without deformity and ankylosis
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Gastrointestinal lesions characterized by ileocecal ulcers
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Epididymitis
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Vascular lesions
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Central nervous system symptoms
Diagnosis is as follows:
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Complete - Four major features
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Incomplete - (1) 3 major features, (2) 2 major and 2 minor features, or (3) typical ocular symptom and 1 major or 2 minor features
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Possible - (1) 2 major features or (2) 1 major and 2 minor features
International criteria for the classification of Behçet disease (1990) [68]
Recurrent oral ulceration
Minor aphthous or major aphthous or herpetiform ulceration is observed by a physician or reported reliably by a patient, and it recurs at least 3 times in one 12-month period, plus 2 of the following:
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Recurrent genital ulceration - Recurrent genital aphthous ulceration or scarring, especially males, observed by a physician or reliably reported by a patient
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Eye lesions - (1) Anterior uveitis, posterior uveitis, and cells in vitreous upon slit-lamp examination or (2) retinal vasculitis observed by physician (ophthalmologist)
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Skin lesions - (1) Erythema nodosum–like lesions observed by physician or reliably reported by a patient, pseudofolliculitis, and papulopustular lesions or (2) acneiform nodules consistent with Behçet disease, observed by a physician, and in postadolescent patients not receiving corticosteroids
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Positive pathergy test - An erythematous papule larger than 2 mm at the prick site 48 hours after the application of a 20- to 22-gauge sterile needle, which obliquely penetrated avascular skin to a depth of 5 mm as read by a physician at 48 hours
Findings are applicable if no other clinical explanation is present.
ICBD 2013 [69]
A score of 4 or more from the following point system indicates a Behçet disease diagnosis:
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Ocular lesions: 2 points
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Genital aphthosis: 2 points
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Oral aphthosis: 2 points
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Skin lesions: 1 point
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Neurological manifestations: 1 point
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Vascular manifestations: 1 point
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Positive pathergy test: 1 point
Physical Examination
Oral ulcers
Oral aphthae that occur in patients with Behçet disease are indistinguishable from common aphthae (canker sores). They are one of the most frequent symptoms occurring in Behçet disease, with a frequency of about 97-100%. [70] Aphthae may be more extensive, more painful, more frequent, and evolve quickly from a pinpoint flat ulcer to a large sore. Lesions can be shallow or deep (2-30 mm in diameter) and usually have a central, yellowish, necrotic base and a punched-out, clean margin. They can appear singly or in crops, are located anywhere in the oral cavity, persist for 1-2 weeks, and subside without leaving scars.
The most common sites are the tongue, lips, buccal mucosa, and gingiva; the tonsils, palate, and pharynx are less common sites. The interval between recurrences ranges from weeks to months.
Oral ulcers can be classified into 3 types: minor, major, and herpetiform.
Minor ulcers are 1-5 small, moderately painful ulcers persisting for 4-14 days (see the image below).
Major ulcers are 1-10 very painful ulcers, measuring 10-30 mm, persisting up to 6 weeks, and possibly leaving a scar upon healing (see the image below).
Herpetiform ulcers are a recurrent crop of as many as 1000 small and painful ulcers (see the image below).
In patients with recurrent aphthous ulcers, minor trauma such as eating foods with a rough texture, brushing teeth, and chewing gum may trigger the development of a new aphthous lesion. [71]
Genital manifestations
Genital ulcers resemble their oral counterparts but may cause greater scarring. They have been found in 56.7-97% of cases, but their appearance is mostly a secondary symptom that accompanies oral ulcers. In males, the ulcers usually occur on the scrotum (see the image below), penis, and groin.
In females, they occur on the vulva (see the image below), vagina, groin, and cervix.
The lesions start as a papule or pustules and evolve into painful ulcers. The ulcers have sharp, punched-out borders, with surrounding edema. Healing usually occurs within 2-4 weeks. [72] It was reported that ulcers smaller than 1 cm in diameter can cause scarring in about 49% of patients, while larger ulcers healed with scar in about 89% of cases. About 60% of ulcers in women located on the labia majora and inguinal region showed scar formation after healing. [73]
Ulcers have also been found in the urethral orifice and perianal area. Epididymitis may arise and is a minor diagnostic criterion for the disease according to the Behçet Disease Research Committee of Japan. An additional genital symptom is orchiepididymitis, observed in 10.8% of men.
Cutaneous manifestations
A variety of skin lesions may appear in patients with Behçet disease (58.6-97%).
Erythema nodosum–like lesions are noted in about half the patients with Behçet disease, more commonly in females. They present as erythematous painful nodules, usually located on the pretibial surface of the lower limbs, but they may occur on the arms and thighs. [74] Healing occurs with hyperpigmentation in about 6 weeks. Unlike erythema nodosum occurring with other diseases, lesions associated with Behçet disease often ulcerate, owing to the underlying medium-vessel vasculitis. [75] See the image below.
A retrospective study in Tunisia that included 213 Behçet disease patients revealed that patients with erythema nodosum–like lesions or neurological manifestations are prone to develop cardiac and vascular complications. [76]
Papulopustular eruptions are observed in 30-90% of cases. [56] The acneiform lesions are composed of papules, pustules, and noninflammatory comedones. They are polymorphic in nature. Unlike acne vulgaris, the acneiform lesions are found commonly on the chest, back, and shoulders and less commonly on the face. See the images below.
Acneiform lesions in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
Acneiform lesions in a patient with Behçet disease (an inflamed nodule and noninflammatory comedones). Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
The mean age of development of these lesions is about 30 years. The international study group diagnostic criteria consider that postadolescent patients who develop acneiform lesions with no history of intake of systemic steroids are presenting a sign of Behçet disease. Most pustules are sterile, but coagulase-negative staphylococci and Prevotella species have been isolated from individual lesions. Papulopustular lesions are commonly associated with the presence of arthritis. [77] See the image below.
Erythema multiforme–like lesions are a reported cutaneous manifestation.
Thrombophlebitis is noted commonly in males. [74] See the images below.
Superficial thrombophlebitis in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
Postphlebitic limb in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
Extragenital ulcers are rare but are reported to occur in axillary, inframammary, and interdigital areas of the feet. [78] Cutaneous ulcers affect approximately 3% of Behçet disease patients and are usually recurrent. [78] Necrotic ulcerations of fingers and toes with underlying necrotizing vasculitis have been reported. [79]
Other cutaneous lesions include subungual infarcts, palpable purpura, and erythema multiforme–like lesions. The presence of HLA-b51 and other signs of Behçet disease help establish the diagnosis. [80]
Lesions resembling Sweet syndrome are seen in about 4% of cases of Behçet disease. [74] See the image below.
Bullous necrotizing vasculitis and pyoderma gangrenosum are reported.
Pathergy is nonspecific skin inflammatory reactivity that is observed to occur following any scratches or intradermal saline injection. The puncture site becomes inflamed and develops a small sterile pustule from hyperactivity of the skin to any intracutaneous insult. The pustular reaction of the skin is thought to denote increased neutrophil chemotaxis.
Higher positivity (84-98%) is found in Mediterranean areas and the Middle East than in the Far East (40-70%), with Western countries having significantly lower positivity than the other regions. [81] Surgical interventions in these Behçet disease patients may result in severe and nonspecific inflammatory reactions. [82] See the image below.
Abnormalities in nail fold capillaries can be seen using nail fold capillaroscopy in Behçet disease patients, mainly capillary dilatations and microhemorrhages. [83] They were noted in 75% of patients in a study that included 33 patients with Behçet disease. [84] and in 40% of Iranian patients in a study that included 128 Behçet disease patients. [85]
Uncommon skin manifestations may include perniolike lesions, neutrophilic eccrine hidradenitis, ulcus cruris, and Kaposi sarcoma. [86]
Lesions often occur in combination (eg, erythema nodosum–like lesions and papulopustular eruptions). Follicle-based pustules or acne lesions are not considered specific lesions of Behçet disease.
Ocular manifestations
Ocular involvement is the major cause of morbidity and the most dreaded complication because it occasionally progresses rapidly to blindness. It is reported in 47-65% of patients with Behçet disease, with more aggressive forms and high rates of blindness reported in Turkey compared with the American patients, in whom blindness is a rare complication of uveitis. [87] Childhood-onset Behçet uveitis is more common in males. [88]
Anterior uveitis presents mainly with photophobia and may progress to hypopyon.
Posterior uveitis (retinal vasculitis) is reported. Involvement of the retina may be severe, with papilledema, retinal exudates, and hemorrhages, and it may lead to blindness if therapy is delayed.
Panuveitis may occur. Involvement of the entire uveal tract was found to be the most common ocular lesion in a study that included 880 Turkish patients. [89]
Iridocyclitis, chorioretinitis, scleritis, keratitis, and optic neuritis are also reported ocular manifestations.
Retinal vein thrombosis can occur and lead to sudden blindness.
Ocular surface lesions in the form of dry eye syndrome, conjunctival lesions, and corneal ulceration have all been reported as ocular manifestations in Behçet disease patients. [90]
See the image below.
Saadoun et al found that cerebral venous thrombosis (CVT) was present in 7.8% of a large cohort of patients with Behçet disease. The main complication of CVT was severe visual loss from optic atrophy. Papilledema and concurrent prothrombotic risk factors were independently associated with the occurrence of sequelae; peripheral venous thrombosis and concurrent prothrombotic risk factors were associated with relapse of thrombosis. Anticoagulant therapy proved safe and effective in up to 90% of patients. [91]
Vascular involvement
Vascular involvement is a common complication in Behçet disease, affecting about 40% of patients and making the prognosis for Behçet disease worse. It affects mainly young men.
Vascular involvement includes both the venous and arterial systems, affecting all sizes of vessels (large, medium, and small). [92]
Arterial system
Arterial involvement occurs in about 2-17% of patients with Behçet disease. [92]
Aneurysm is the most serious arterial complication. It affects large vessels, including the aorta (thoracic and abdominal) and pulmonary, femoral, iliac, and peripheral arteries. Rupture of a pulmonary artery aneurysm may present with hemoptysis and can be fatal, making the early diagnosis and treatment of vascular complications vital.
Arterial stenosis may manifest clinically as medial thickening, along with perivascular round cell infiltration found histologically. Depending on the site, different clinical presentations occur. Hypertension can originate from renal artery stenosis. Femoral artery stenosis and intermittent claudication cause avascular necrosis of the femoral head.
Arterial occlusion may be caused by thrombosis or progression of stenosis. Pulseless disease can result from subclavian artery occlusion. Atherosclerosis is not increased in Behçet disease. [93]
Arteritis may occur. Pulmonary vasculitis can produce dyspnea, chest pain, cough, or hemoptysis. Aortitis is a rare serious complication. Aortic regurgitation has been reported as a result of aortitis that causes sinus of Valsalva dilatation. Patients with Behçet disease undergoing valve replacement were reported to have complications from valve detachment compared with other patients. [94] Coronary artery vasculitis may cause acute myocardial infarction, but this is rare. [93]
See the images below.
Radial artery aneurysm with its effect distally on index finger in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
CT angiogram showing pulmonary artery aneurysm in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
Venous system
Venous involvement is noted in about 40% of patients. Superficial and deep venous systems are affected. [92]
Superficial and deep veins of the lower limbs are the most frequently affected. Involvement of large vessels, including the superior vena cava, inferior vena cava, deep femoral vein, subclavian vein, cerebral veins, and pulmonary veins, accounts for one third of venous thrombosis in Behçet disease patients. Budd-Chiari syndrome, is a very serious complication that increases the mortality rate 9 times. [92] Recurrent superficial and deep venous thrombosis in the lower extremities may be complicated by postthrombophlebitic syndrome. [95] Although thrombosis is a common complication in Behçet disease, the strong adherence of the thrombus to the vessel makes the frequency of thromboembolism in these patients very low. [56]
Chronic venous disease in Behçet patients is more common in men, frequently bilateral disease, with earlier age of onset of thrombosis. A severe disease course is common, and 51% of Behçet disease patients develop severe postthrombotic syndrome, while 32% develop venous claudication. These complications occur in 8% and 12%, respectively, in patients with venous disease who do not have Behçet disease. [96]
Cardiac involvement
Cardiac complications occur in about 6% of patients with Behçet disease. Involvement of all layers of the heart is noted. It includes pericarditis, increased thickness of epicardial fat, myocardial lesions including myocarditis, myocardial fibrosis and infarction, and endocardial involvement including aortic and mitral regurgitation and intracardiac thrombosis. [92]
Cardiac and pulmonary inflammatory masses have been reported and may mimic metastatic disease. [97]
Gastrointestinal involvement
The clinical spectrum of gastrointestinal effects [98] is enormously varied and occurs in more than 10% of patients with Behçet disease. Gastrointestinal involvement is noted in one third of Behçet disease patients in Japan, whereas it is less frequent in the Mediterranean area. [56] Anorexia, vomiting, dyspepsia, diarrhea, abdominal distention, and abdominal pain all may occur. Terminal ileum and ileocecal regions were reported to be frequently complicated by deep penetrating ulcers, ischemic infarctions, and thrombosis; these symptoms may mimic those of inflammatory bowel disease. [99]
Joint manifestations
More than half the patients develop signs or symptoms of synovitis, arthritis (asymmetrical, nonerosive, and nondeforming), and/or arthralgia during the course of the disease. [100] The most frequent minor feature in childhood-onset Behçet disease is reported to be arthritis, occurring in 11 of 40 patients. Multiple-joint involvement is common. Clinical features have been reported as pain, tenderness, swelling, limitation of joint movement, warmth, and morning stiffness.
Neurologic manifestations
The rate of neurologic involvement in persons with Behçet disease varies from 3.2-49% according to the reports of different populations. It is more frequent in men aged 20-40 years. [101] Neurological involvement can be parenchymal and nonparenchymal.
Parenchymal involvement includes brain stem involvement manifesting as cranial neuropathy, ophthalmoparesis, and cerebellar or pyramidal dysfunction. It also includes cerebral hemisphere involvement manifesting as hemiparesis, hemisensory loss, seizures, encephalopathy, dysphasia, psychosis, and cognitive dysfunction. [101] Finally, it includes spinal cord involvement presenting by sensory, motor, or sphincter dysfunction. Pseudotumoral brain lesions have been noted. [102]
Nonparenchymal affection includes intracranial and extracranial aneurysms and cerebral venous thrombosis. It carries a better prognosis than that of parenchymal affection. [101]
Neurologic involvement is one of the most serious complications, leading to severe disability and a high fatality rate. Neurologic manifestations usually occur within 5 years of disease onset. Severe headache is the most frequent initial neurological symptom.
Carpal tunnel syndrome can occur in Behçet disease patients as a result of inflammation of tendons, connective tissue, and vessels. It is reported in about 0.8% of patients with Behçet disease. [103]
Neuropsychiatric involvement
This affects a minority of patients, about 2%. [104] Symptoms such as hypersomnia, bipolar disorder, and acute psychosis have been reported, and some reports relate it to exacerbation of the disease. It may occur as a result of the associated neuroinflammatory process that occurs during disease activity.
A study showed that about 59% of patients with Behçet disease experience poor sleep quality often related to the depression, anxiety, painful genital ulcers, and arthritis present in Behçet disease patients. [105]
Pregnancy-associated manifestations
Estrogen and progesterone exert an immunomodulatory effect on pregnant women with Behçet disease, typically making the disease activity regress during pregnancy. [106] However, a paradoxical disease flare was reported in about 8% of pregnant patients with Behçet disease in one study, occurring mainly in the first trimester. [107]
Exacerbations mostly occur in the form of recurrent oral and genital ulcer. [108]
Hypercoagulability in pregnancy may increase the vascular complications, mainly the thrombotic complications. Budd-Chiari syndrome and cerebral venous thrombosis have been reported in pregnant women with Behçet disease. [109]
Fetal complications can include intrauterine growth restriction and miscarriage, reportedly mostly related to impaired function of vascular endothelial cells. [110]
The rate of cesarean delivery and medical termination of pregnancy was found to be higher in pregnant women with Behçet disease compared with other pregnant patients. [110]
Close follow-up is necessary to monitor the health of the mother and baby.
Childhood disease
Childhood Behçet disease is not uncommon; it accounts 3.3-26% of patients with Behçet disease. A large cohort study in Iran included 6500 patients and showed that 5.1% of patients had disease onset at age ten 10 years and 25.3% at age 11-20 years. [111] The disease may start as early as the neonatal period, and this usually occurs in children of mothers with active Behçet disease during pregnancy. [112] The neonatal form presents mainly with mucocutaneous manifestations that regress in the first months of life but may have a more prolonged course (>1 y).
Childhood Behçet disease differs in presentation, with girls having more genital ulcers and boys experiencing more eye and neurological complications. [113]
A family history of Behçet disease is noted in 9-30% [114] and 42% in a Turkish study. [115]
Recurrent mouth ulcers are the first manifestation of the disease in 87-98% of cases, [114] with an average age of onset of 7.4 years. They present mainly on the lips, cheeks, tongue, and lips. They should be investigated to eliminate other causes of recurrent mouth ulcers.
Genital ulcers are the second most common sign after mouth ulcers (60-83% of patients). They often appear after puberty, more frequently among girls [114] and usually affect the vulva. In males, the scrotum, penis, and perianal region are affected. Deep ulcers may leave scars on after healing. [116]
Skin lesions are noted in about 92% of patients, starting on average at age 13 years. Pseudofolliculitis (40-60%) and erythema nodosum (40%) are the most frequently seen cutaneous manifestations. Necrotic pseudofolliculitis occurs mainly in males. [114]
Ocular involvement affects 60% of children with Behçet disease. [114] The predominant ocular disease in children is panuveitis. [117] Anterior uveitis frequently occurs before age 1- years. [115] Retinal vasculitis and retinitis more readily affect older adolescents (16-20 y) but have a better prognosis than that in adults. [117]
Neurological involvement includes headaches, which are common. Cerebral venous thrombosis [118] and paralysis of cranial nerve VI, which may cause diplopia, are reported frequently. Behavioral disorders and problems learning in school are reported complications. [119]
Other organ manifestations
Cases with renal involvement, such as mild asymptomatic glomerulonephritis, have also been reported. Mediastinal lymphadenopathy, pleural effusions, and pericardial effusions may be observed. [120]
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Minor aphthous ulcer.
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Major aphthous ulcer.
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Herpetiform oral ulcer.
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A characteristic genital ulcer on scrotum.
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A single ulcer on vulva.
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Erythema nodosum–like lesions on skin.
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Papulopustular eruptions.
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Sweet syndrome–like lesion.
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Typical positive pathergy reaction at injection site.
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Ocular involvement showing posterior uveitis.
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CT angiogram showing pulmonary artery aneurysm in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
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Acneiform lesions in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
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Superficial thrombophlebitis in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
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Postphlebitic limb in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
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Acneiform lesions in a patient with Behçet disease (an inflamed nodule and noninflammatory comedones). Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
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Radial artery aneurysm with its effect distally on index finger in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
