Behcet Disease

Hippocrates may have described Behçet disease in the fifth century BCE. In 1930, the Greek ophthalmologist Benediktos Adamantiades reported a patient with inflammatory arthritis, oral and genital ulcers, phlebitis, and iritis.[4] The disease is named after the Turkish dermatologist Hulusi Behçet, who identified it in a patient in 1924 and published a description of the disease in 1937.[5]

Starting in 1946, numerous sets of diagnosis/classification criteria for Behçet disease have been proposed. The International Criteria for Behcet's Disease (ICBD), published in 2006, remains the most widely used.[6]

 

Theories behind the pathogenesis of Behçet disease currently suggest an autoimmune etiology. It is thought that in genetically predisposed individuals, exposure to an infectious agent or an environmental antigen triggers the autoimmune response.

Infectious triggers

Exposure to an infectious agent may trigger a cross-reactive immune response. Proposed infectious agents have included the following:

• Herpes simplex virus (HSV)
• Streptococcus species
• Staphylococcus species
• Escherichia coli

The International Study Group for Behçet's Disease has emphasized the presence of recurrent oral ulcers as a primary consideration in the diagnosis of Behçet disease.[3] In response, the pathogens above have been targeted for study, with the hope of establishing a direct link between their presence and disease activity. Unfortunately, researchers have so far been unable to generalize results across geographic populations.

The study of heat shock proteins (HSPs) has provided some insight into possible mechanisms that contribute to the development of Behçet disease. Through discovery that human HSP-60 and HSP-65 share greater than 50% homology with mycobacterial HSP, enhanced T-cell response has been elicited with exposure to both bacterial and human homogenates in Behçet disease patients compared with controls in United Kingdom, Japanese, and Turkish populations.

HSP-65, found in high concentrations in oral ulcers and active skin lesions in patients with Behçet disease, has also been demonstrated to stimulate production of antibodies that exhibit cross-reactivity with streptococcal species present in the mouth.[7, 8, 9] Feng et al suggested that HSP-A6 levels may be useful in differentiating intestinal Behçet disease from Crohn disease: in their study, serum HSP-A6 expression was significantly elevated in intestinal Behçet disease (0.72 ± 0.39 ng/mL) compared with Crohn disease (0.50 ± 0.24 ng/mL, P = 0.000) and healthy controls (0.38 ± 0.37 ng/mL).[10] The clinical relevance of enzyme-linked immunosorbent assay (ELISA) testing to measure HSPA6 is currently unknown.

Attempts at determining whether tissue antigens have a role in channeling the immune response have been unsuccessful. Elevated peripheral levels of gamma-delta T cells (γδ+ T cells) in patients with Behçet disease in response to exposure to mycobacterial HSPs compared with those in healthy subjects imply a role for their production.[11] Antigen-driven expansion of oligoclonal Vβ+ T-cell receptor (TCR)–specific cell lines in Behçet disease patients has been demonstrated.[12] However, generalization of these results is not applicable because of the high degree of interindividual variability in TCR expression.

T cells and neutrophils

Systemic involvement of multiple organs is observed in Behçet disease, rooted primarily in the development of vasculitic or vasculopathic lesions in the affected areas. These areas may demonstrate microscopic evidence of inflammatory tissue infiltration with both T cells and neutrophils.[13, 7, 14, 15]

Studies of T lymphocytes have suggested a T-helper type 1 (TH1)–predominant response. Both CD4+ and CD8+ lymphocytes demonstrate higher concentrations in peripheral blood, with characteristic and corresponding elevations of cytokines (interleukin [IL]–2] and interferon-γ [IFN-γ]). Serum levels of IL-12 have also been shown to be elevated in patients with Behçet disease, possibly helping drive the response. Decreased levels and impaired activity of natural killer cells were demonstrated in bronchoalveolar lavage specimens of Behçet disease patients with pulmonary manifestations.[16]

Because of the degree of neutrophilic infiltration demonstrated in characteristic Behçet disease lesions (eg, hypopyon, pustular lesions, and pathergy reactions), the activity and function of these cells has been explored extensively. Unfortunately, existing studies offer inconsistent results regarding cell adhesion and chemotactic behavior, superoxide production, and phagocytic properties.

Thus, the specific role of neutrophils in Behçet disease has been difficult to characterize. Some studies have found that cytokine release in Behçet disease may, by an unknown mechanism, place neutrophils in a static pre-excitatory “primed” state, eventually triggered into hyperactivity by environmental stimuli at a lower threshold than in individuals who do not have Behçet disease.[17, 18, 19, 20]

Genetics

Behçet disease is a sporadic disease, but a familial aggregation is well known.[21] Carriers of HLA-B51/HLA-B5 have an increased risk of developing Behçet disease compared with noncarriers.[22] HLA-B51 is the the strongest associated genetic factor and it has been shown to be more prevalent in Turkish, Middle Eastern, and Japanese populations, corresponding with a higher prevalence of Behçet disease in these populations.[23] However, HLA-B51 has not been shown to affect the severity of symptoms and is less prevalant in patients not from endemic areas.[24]

In addition, genome-wide association (GWA) studies have linked increased susceptibility to Behçet disease with polymorphisms in genes encoding for cytokines, activator factors, and chemokines.[23]  Specific single-nucleotide polymorphisms involving the following genes have been identified[25, 26] :

• Familial Mediterranean fever gene ( MEFV) mutation Met694Val
• TLR4 (involved in pathogen recognition and activation of innate immunity)
• ERAP1 (codes for a molecule that processes microbial proteins in white blood cells)
• CCR1-CCR3 (involved in recruitment of effector immune cells to sites of infection)
• STAT4 (involved in increased risk for autoimmune disease)
• KLRK1-KLRC4

The specific etiology of Behçet disease remains elusive but, as described in Pathophysiology, the interplay between infectious-agent exposure and genetic factors may have a role. An environmentally triggered hyperactive primed state of autoimmunity ensues, resulting in two types of vascular damage. The first is vasculitic lesions that may be widespread. Sequelae depend on the various organ systems affected.

Some of the pathologic changes are not vasculitis but due to thrombosis and/or clot formation caused by the development of a hypercoagulable state. The mechanism is still undetermined; however, studies have demonstrated excessive thrombin formation and the potential role of impaired fibrinolytic kinetics in the generation of the hypercoagulable/prothrombotic state. Pathologic activation of the procoagulant cascade via endothelial injury has also been demonstrated in patients with Behçet disease.[27, 28]

The prevalence of Behçet disease in the United States is reported as 0.12-0.33 case per 100,000 population.[29] However, data from the study of residents of Olmsted County, Minnesota over a 45-year period identified a prevalence of 5.2 cases per 100,000 population.[30]

The incidence and prevalence of Behçet disease are highest along the old Silk Road, extending from the Middle East to China.

Turkey has the highest prevalence of Behçet disease, with 420 cases per 100,000 population. The prevalence in Japan, Korea, China, Iran, and Saudi Arabia ranges from 13.5 to 22 cases per 100,000 population. The prevalence in North America and Europe is much less, with 1 case per 15,000-500,000 population.[29, 19]

The prevalence of Behçet disease is highest in Middle Eastern and Japanese populations.

The sex prevalence varies by country. In the Middle East, Behçet disease is more common among males, with male-to-female ratios of 3.8:1 (Israel), 5.3:1 (Egypt), and 3.4:1 (Turkey). In Germany, Japan, and Brazil, the disease is slightly more common in females. In the United States, Behçet disease is more common in females (5:1 female-to-male ratio).[19, 29, 31]

Males are more likely to develop severe presentations of Behçet disease. Pulmonary aneurysms, eye involvement, thrombophlebitis, and neurologic disease are all more common in males. However, females are more likely to develop erythema nodosum–like skin lesions.

Behçet disease is most common in persons aged 20-40 years. The mean age at onset is 25-30 years. Cases that develop before age 25 years are more likely to involve eye disease and active clinical disease.

Prognosis is related to the site and severity of involvement. Aneurysms are an especially feared complication. Thrombotic events and vasculitis may lead to ischemia distal to vascular lesions. Uncontrolled ophthalmologic involvement in the form of anterior and posterior uveitis can lead to vision loss. Neurologic involvement suggests progressive disease and can lead to permanent deficits or even death.

Mortality and morbidity data include the following:

• The mortality rate in a cohort of 817 patients in France was 5% at a median follow-up of 7.7 years ^[32]
• Coronary/pulmonary arterial aneurysm rupture in association with Behçet disease carries a high mortality rate
• Neurologic involvement has been associated with mortality rates up to 20% at 7-year follow-up in one Turkish study ^[33]
• Thrombosis may lead to death
• Central nervous system involvement can lead to permanent deficits or death
• Eye involvement can result in blindness

In a study comparing 298 pregnancies in 94 Behçet disease patients with 219 pregnancies in 95 healthy controls, women with Behçet disease delivered smaller babies (3214 versus 3351 g, respectively; P= 0.028) and had higher miscarriage rates. The authors suggest vasculitis of the placenta as a possible cause.[34]

In 1990, the International Study Group (ISG) for Behçet's Disease clarified criteria for the diagnosis of Behçet disease.[3] The ISG compared the clinical findings of 914 patients with a history of aphthous ulcers with those of controls. Initial criteria for diagnosis require the occurrence of at least three episodes of oral herpetiform or aphthous ulcerations within a 12-month period observed directly by a physician or reported by the patient. To confirm the diagnosis, at least two of the following must also be demonstrated:

• Recurrent painful genital ulcers that heal with scarring

• Ophthalmic lesions, including anterior or posterior uveitis, hypopyon, or retinal vasculitis

• Skin lesions, including erythema nodosum–like lesions, pseudofolliculitis, or papulopustular or acneiform lesions

• Positive results from pathergy skin testing, defined as the formation of a sterile erythematous papule 2 mm in diameter or larger that appears 48 hours following a skin prick with a sharp sterile needle (22-24 gauge [a dull needle may be used as a control])

See the Behcet's Syndrome International Study Group Criteria calculator.

Considering the above diagnostic criteria, case presentation often includes the following characteristics:

• Multiorgan system involvement, often beginning with mucocutaneous involvement and usually sparing the liver, kidneys, and heart

• Age of 25-35 years at onset

• Organ-specific manifestations characterized by exacerbations and a relapsing/remitting course

In 2014, the International Team for the Revision of the International Criteria for Behçet's Disease (ICBD) proposed a set of diagnostic criteria including vascular and neurologic involvement (see the table below). The ICBD has considerably higher sensitivity than the ISG criteria (94.8% versus 85.0%, respectively) but somewhat lower specificity (90.5% versus 96.0%, respectively).[35]

Table. International Criteria for Behçet's Disease (Open Table in a new window)

Patients with an ICBD score of 4 or higher are classified as having Behçet disease.[35]

Skin and mucous membrane manifestations

Painful oral lesions (aphthous or herpetiform) are one of the criteria for diagnosis and may be the first manifestation (70% of cases). See the image below.

Oral lesions are commonly found in keratinized areas of the oropharynx, often excluding the nonkeratinized surfaces of the dorsal tongue, gums, and hard palate. The lesions are usually not distinguishable from those due to other causes but often have a high recurrence rate (often more than five times per year, despite only three times per year specified in ISG criteria) and appear as multiple lesions or crops (often more than six simultaneous lesions at a given time).

Skin lesions often occur in the genital region of both sexes. In males, scrotal involvement is most characteristic; however, lesions can also develop on the penile shaft. In females, the labial area is most commonly involved, with lesions occasionally developing in the vagina and on the perineum. Genital ulcerations typically heal with scarring and are more painful in men. Development of ulcerations in women may correlate with menstruation.

Nodules that resemble erythema nodosum are more common in the lower extremities of females. They are tender, erythematous, and nodular and usually resolve after 2-3 weeks but often recur. Erythema nodosum may be an indicator of mild Behçet disease.

Acneiform papulopustular lesions are more common in men and are usually found on the trunk and extremities, although they may develop anywhere on the body.

Extragenital ulcerations that heal with scarring are rare and affect only 3% of patients.[36] These are very specific for Behçet disease. They can be found in the axillae, neck, breast, interdigital skin of the feet, and groin.

Positive pathergy test is more common in Turkish and Japanese populations, as well as patients with ophthalmic and neurologic manifestations.

Ocular lesions

Ocular presentations (anterior or posterior uveitis, hypopyon, retinal vasculitis, cystoid macular degeneration) represent the first manifestation of disease in 10-20% of patients with Behçet disease. In most cases, however, ocular involvement follows the oral and genital ulcers by 3-4 years.[19, 37]

Symptoms and signs commonly include blurred vision, periorbital pain, photophobia, scleral injection, and excessive lacrimation.

Men, particularly of Iranian and Japanese descent, tend to present with more severe eye involvement.

Highly recurrent posterior uveitis can lead to blindness.

Ocular involvement resulting in blindness commonly develops within the first 7 years. The prognosis is better for persons who develop symptoms later in the disease course.

Neurologic manifestations

Collectively, neurologic signs and symptoms tend to be an unusual late manifestation, 1-8 years after disease onset. They include the following:

• Memory tends to be affected in most cases, particularly affecting recall and learning. Orientation, arithmetic, and language are often unaffected.
• Symptoms are usually parenchymal in nature, predominantly with brainstem involvement. ^[33]
• Behavioral changes, primarily apathy or disinhibition, occur in 54% of patients.
• Seizures and bulbar signs with ophthalmoplegia are less common.

Other less common findings include the following:

• Infarctions due to vasculitis or thrombosis
• Meningoencephalitis
• Lymphocytic meningeal infiltration
• Demyelinization

Vasculopathy

Behçet disease can cause aneurysms in the pulmonary arterial tree that often prove to be fatal. Pulmonary artery aneurysmal involvement is associated with right-sided cardiac thromboses and can manifest as hemoptysis, cough, chest pain, or dyspnea.[16]

Vasculitis of the small and large vessels can cause a panoply of symptoms depending on location of the lesions.

Arterial disease predominantly affects males and only rarely occurs in women.[38]

Venous involvement (usually in the form of superficial thrombophlebitis) is more common than arterial involvement.[36] Superficial thrombophlebitis presents in a linear fashion with overlying erythema and is often confused with erythema nodosum. In males, formation of these linear areas of vasculopathy leads to sclerosis and stringlike thickening in the affected areas.

Symptoms correlate with the vessel involved and may be devastating. For example, extension of an inferior vena caval clot to the hepatic vein may be the mechanism of Budd-Chiari syndrome in Behçet disease.[38]

Arthritis

Arthritis and arthralgias occur in as many as 60% of patients and primarily affect the lower extremities, especially the knee. Ankles, wrists, and elbows can also be primarily involved.

The arthritis is nondeforming and asymmetric in nature and can assume a monoarticular, oligoarticular, or polyarticular pattern of involvement.

Symptoms relapse and remit and rarely become chronic.

Diffuse arthralgias are also common.

Gastrointestinal (GI)/genitourinary manifestations (GU)

GI involvement affects 3-16% of patients with Behçet disease.[39] Areas affected often include the esophagus and ileocecal area. Symptoms include abdominal pain, bloating, and GI bleeding. Complications often result from deep ulceration of intestinal sections.

GU involvement can include epididymitis, neurogenic bladder, and sterile urethritis. Neurogenic bladder can present with typical symptoms of urinary retention.

Renal manifestations

Renal manifestations may be underreported. One study found that 1-29% of patients with Behçet disease developed such manifestations.[40]

Associated amyloidosis may develop.

The first presentation is often nephritic-range proteinuria found incidentally. Crescenteric and proliferative glomerulonephritis, as well as IgA nephritis, have also been reported in some cases.[40, 41, 42]

Cardiac manifestations

Cardiac manifestations (5-17% of cases) include the following::

• Coronary vasculitis and thrombosis
• Pericarditis
• Myocarditis
• Endocarditis with granulomatous changes or fibrosis
• Regurgitation
• Diastolic dysfunction

Pulmonary manifestations

Lung involvement occurs in up to 18% of patients with Behçet disease. Pulmonary vasculitis, hypertension, and pleural effusions have been reported. Pulmonary aneurysms represent a dreaded complication of Behçet disease and may result in massive hemoptysis. The detection of a pulmonary aneurysm in the setting of a vasculitic illness is highly suggestive of Behçet disease.[43]

Oral ulcers

Recurrent oral ulcers are the first clinical manifestation of Behçet disease in 50-70% of cases and eventually develop in as many as 98% of patients. Ulcers are aphthous or herpetiform in nature and can occur in various keratinized areas of the oral cavity, including the gingiva, lips, tongue, buccal mucosa, hard palate, uvula, and posterior pharynx. White or yellowish pseudomembrane usually covers the surface of the ulcers.They can be very painful. Ulcers tend to develop in crops, which recur at various frequencies.

Ulcers are usually small and heal within 7-10 days with no scarring. However, can vary in size, and may last up to 3-5 weeks. Fusion of several small ulcers may produce a large ulcer (> 10 mm in diameter).  Large ulcers  heal with scarring, as do their genital counterparts.

Skin

Approximately 70% of patients have skin involvement. Behçet disease may produce a variety of skin lesions; the most common are erythema nodosum, acneiform lesions, thrombophlebitis, and cutaneous hypersensitivity.

Erythema nodosum occurs in more than two thirds of patients with Behçet disease and is more common in females. Lesions usually appear on the anterior surface of the legs but may also occur on the face, arms, and buttocks. These lesions are slightly raised, red nodules with subcutaneous induration and tenderness. They tend to involute in 10-14 days without ulceration. The concomitant present of ulcers, which are more characteristic of Behçet disease, may help limit the differential diagnosis in patients with erythema nodosum.

Pseudofolliculitis and acneiform lesions, found more commonly in males with Behçet disease, primarily affect the trunk and extremities. However, Acneiform lesions are seen in almost 60% of patients and may occur in patients who receive corticosteroid treatment; therefore, their presence is of questionable diagnostic usefulness.

A peculiar feature of Behçet disease is cutaneous hypersensitivity, which results in small pustules that form on skin after it has been scratched, shaved, or pricked with a needle.

Eyes

Ocular involvement is described in 75% of patients with Behçet disease. Findings may include the following:

• Anterior uveitis with and without hypopyon formation
• Posterior uveitis that may cause blindness
• Glaucoma
• Synechiae
• Retinal vasculitis
• Infarctions
• Hemorrhage
• Edematous appearance of the disc, with retinal detachment
• Leaky retinal vessels revealed by fluorescein angiography, leading to atrophy and fibrosis in some cases

The classic ocular finding of Behçet disease, iridocyclitis with hypopyon, is present in about one third of cases. Gonioscopy may reveal an occult hypopyon in many cases. One characteristic feature of the hypopyon in Behçet disease is that it may change position with head movement, and it may form and disappear rapidly without sequelae. Recurrent attacks may result in posterior synechiae, peripheral anterior synechiae, iris atrophy, and secondary glaucoma.

Retinal disease is the most serious complication of Behçet disease. The classic fundus finding is retinal vasculitis, which affects both arteries and veins in the posterior pole. Ophthalmoscopy shows venous engorgement, retinal hemorrhages, yellow-white exudates deep in the retina, white focal retinal infiltrates, retinal edema, and optic disc edema with hyperemia.

Severe vasculitis may lead to thrombosis of vessels and secondary ischemic retinal changes. Optic disc edema may be secondary to inflammation and may be seen during the acute phase in at least one fourth of cases.

Vitreous cellular infiltration almost always is present during the acute phase.

Retinal neovascularization, secondary to either retinal vein occlusion or chronic inflammation, may result in retinal or vitreous hemorrhage.

Neovascular glaucoma occurs in as many as 6% of patients and often results in phthisis bulbi.

Repeated episodes of posterior segment inflammation cause sheathing of retinal vessels, chorioretinal scars, and retinal and optic nerve atrophy.

In a retrospective observational case series of 132 patients with Behçet-associated uveitis, the most common presentation was panuveitis, which occurred in 118 patients (89.4%). Bilateral episodes were observed in 100 patients (75.8%). At baseline, best-corrected visual acuity (BCVA) was 20/125 in both eyes.[44]

Other ocular manifestations at presentation included retinal vasculitis (61 eyes, 26.3%), occlusive vasculitis in (59 eyes, 25.4%), and macular edema (42 eyes, 18.1%). Anterior segment complications included glaucoma in 44 eyes (19%) and cataracts in 34 eyes (14.7%). Optic nerve atrophy was the most commonly observed posterior segment complication. BCVA was better than 20/50 at last follow-up in 131 eyes (56.5%).[44]

Panuveitis and posterior uveitis/retinitis occur more frequently in males than in females (28.9% vs 11.5% and 57.9% vs 36.1%, respectively; P < 0.05).

In a large retrospective study of Behçet disease, the mean age at onset of uveitis was 28.5 years in male patients and 30 years in female patients. Ocular involvement was bilateral in 78.1% of patients and unilateral in 21.9% of patients. Panuveitis was the most common form in both sexes. Fundus lesions and sight-threatening complications were more common in male than in female patients. At the beginning of follow-up, potential visual acuity was 0.1 or less in 30.9% of eyes in male patients and 24.2% of eyes in female patients. On Kaplan-Meier survival analysis estimated the risks of losing useful vision (P > 0.10) at 5 and 10 years in male patients and female patients, with results of 21% versus 10% and 30% versus 17%, respectively

Nervous System

Pyramidal tract lesions with spastic paralysis and dementia have been demonstrated in some patients with Behçet disease.[33] Neurologic signs may include the following:

• Mental status changes
• Seizures
• Clonus
• Positive Babinski sign
• Difficulty with speech and swallowing
• Emotional lability
• Acute deafness

Apathy or disinhibition is common. Difficulty with recall and learning has been demonstrated. Peripheral nerve involvement is rare.

Vascular system

Lower-extremity superficial thrombophlebitis often presents in a linear fashion with overlying erythema and tenderness. Palpation of sclerosed thrombophlebitis yields subcutaneous stringlike quality.

Deep venous thrombosis (DVT) develops in some cases and typically manifests as local tenderness or as disparity in limb girth.

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 due to 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.[45]

Arterial vasculitis may manifest as claudication symptoms.

Musculoskeletal system

The arthritis has predominance for the lower extremities, especially the knees, but may occur in any pattern. Joint involvement tends to be transient but recurrent.

Arthritis is usually not destructive or deforming. Joint-fluid content often reflects only inflammatory properties. Aseptic necrosis develops in rare cases.

Gastrointestinal system

Ulcerative lesions can cause abdominal pain, bloody diarrhea, and occasional intestinal perforation. GI lesions are indistinguishable from those associated with inflammatory bowel disease but commonly occur in the ileocecal region.

Genitourinary system

Genital ulcers occur in 80% of patients. They are painful punched-out lesions similar to those that occur in the mouth. In females, genital lesions commonly appear in the labial folds but can also be found in the vulva and vagina. In males, they usually occur on the scrotum but can also develop in the perianal region and penile shaft. Epididymitis manifests as scrotal tenderness.

Genital ulcers last longer than oral lesions, are deeper, and typically scar after healing.

Specific diagnostic tests for Behçet disease are lacking. Suggestive features of the disease can be obtained from laboratory evaluations, imaging studies, and histopathologic evaluation in the right clinical context. However, development of those features may take several months to years, leaving the diagnosis of Behçet disease rather suggestive in many cases. 

Imaging study findings are as follows:

• Sacroiliitis may be observed on a radiograph, magnetic resonance imaging (MRI) scan, or computed tomography (CT) scan
• Radiographs of peripheral joints may show soft-tissue swelling and/or effusions
• Brain CT scanning may identify areas of acute ischemia
• Brain MRI/magnetic resonance angiography (MRA) can identify cerebral vasculopathy and areas of acute/subacute ischemia (see the images below)
• Single-photon emission computed tomography (SPECT) has been used to identify areas of cerebral hypoperfusion.
• Angiography may be used to evaluate for aneurysms

In patients with neurologic manifestations, MRI is the imaging study of choice and often reveals iso-hypointense lesions in T1-weighted images and hyperintense lesions in T2-weighted images, mostly in the mesodiencephalic junction, cerebellar peduncles, and other parts of the brainstem.[47] See the images below.

 

In a study of lower-extremity vein thrombosis, patients with Behçet disease demonstrated the following findings on Doppler ultrasonography, compared with patients with thrombosis from other causes[48] :

• Significantly more bilateral involvement
• Less complete recanalization
• More frequent collateral formation
• Contiguous and symmetric pattern of venous involvement, affecting all deep and superficial veins of the lower extremities, with less affinity for crural veins

Fundus fluorescein angiography

Findings on fundus fluorescein angiography are as follows:

• Diffuse retinal vascular leakage and occlusion of retinal vessels
• Fluorescein leakage from retinal vessels may be seen before any clinical signs of vasculitis
• During acute inflammation, retinal vascular leakage is prominent, especially in the radial peripapillary area.
• Affected retinal and optic nerve vessels leak fluorescein profusely during early transit and their walls stain in late transit.
• Macular ischemia and cystoid macular edema may also be evident

Pathergy test

For the pathergy test, a sterile blunt needle is inserted into the skin of the forearm. The development of an inflammatory papule or pustule within 24-48 hours constitutes a positive result. This finding reflects an overactive immune response to minor injuries. Histologic studies of these lesions reveals mononuclear cell infiltrates and keratinocytes.

The pathergy test is helpful but is not sensitive or specific for the diagnosis of Behçet disease. Positive results tend to be more common in Mediterranean patients. 

Arthrocentesis and lumbar puncture may be used to rule out alternate causes of disease presentation, as they normally demonstrate nonspecific inflammatory findings.

Synovial fluid

Synovial fluid usually is cloudy with variable viscosity, and the white blood cell (WBC) counts are 300-36,000/µL (either noninflammatory or inflammatory). Polymorphonuclear leukocytes and protein elevations are the predominant findings, and glucose levels are near normal. Thus, because synovial fluid merely demonstrates general inflammation, examination serves only to rule out the presence of aseptic joint, crystal-induced arthropathy, or other alternative identifiable cause in patients with Behçet disease.

Cerebrospinal fluid

Analysis may indicate local inflammation with increased WBC counts, lymphocyte predominance, and elevated protein levels, as well as Ig levels and Ig index that reflect local production of Ig. Opening pressures are very high in some patients.

 

Although no specific histologic findings characterize Behçet disease, biopsy samples of affected tissue often reveal widespread vasculitis of the arteries and veins of any size. Thrombosis commonly develops in affected areas and must be distinguished from vasculitis as a precipitating cause for organ-specific symptoms. 

Other organ-system findings include the following:

• Skin -Skin biopsy results often reflect nondiagnostic findings but can be used to differentiate alternate disease entities. Erythema nodosum lesions with characteristic findings and occasional granulomas; folliculitis; leukocytoclastic vasculitis; dermal inflammation and perivascular infiltrates; fibrosis; and mucosal lesions, including aggregated intravascular conglomerates of neutrophils, endothelial cell swelling, fibrinoid necrosis, and a mixed perivascular infiltrate (see the image below)
• Eye - Cataracts, posterior and anterior uveitis, retinal vasculitis and thrombosis, cytoid macular degeneration, retinal detachment, and lymphocytic infiltrates in the iris (even during clinical remissions); in late stages, a proliferation of collagen fibers, thickening of the choroid, formation of cyclitic membrane, and sometimes hypotonia and phthisis bulbi are noted
• Brain - Infarctions due to vasculitis or thrombosis, meningoencephalitis, lymphocytic meningeal infiltration, or demyelinization
• Joint - Superficial inflammatory synovial infiltrates, mainly polymorphonuclear lymphocytes, and deposition of IgG in the synovium
• GI tract - Ulcerations from the buccal mucosa to the anus, intestinal perforation, peritonitis, infiltration with polymorphonuclear leukocytes and lymphocytes, hepatitis, cholecystitis, and pancreatitis
• Heart - Pericarditis, myocarditis, endocarditis, coronary arteritis, and myocardial fibrosis
• Lung - Serositis and vasculitis
• Kidneys - Glomerulonephritis

Laboratory findings

Laboratory findings are nonspecific and reflect the inflammatory state.

C-reactive protein levels, erythrocyte sedimentation rate (ESR), leukocyte count, complement components, and acute-phase reactants may all be elevated during an acute attack. Levels of IgA, IgG, alpha-2 globulin, IgM, and immune complexes are occasionally elevated.

In a study of 48 patients with Behçet disease and 47 healthy controls, serum levels of calprotectin were significantly elevated in the Behçet disease group. However, serum calprotectin levels did not correlate with scores on the Behçet Disease Current Activity Form or with measures of depression and anxiety or quality of life.[49]

None of these findings is specific for the diagnosis of Behçet disease, but such findings can corroborate active disease.

Antiphospholipid antibodies

These include lupus anticoagulant, dilute Russell viper venom test (DRVVT), and anticardiolipin antibodies. Although such antibodies are uncommon in Behçet disease, they are worth investigating to rule out alternate causes of thrombosis.

Up to one third of patients with Behçet disease who have thrombosis are found to have factor V Leiden–deficiency mutations. Therefore, antiphospholipid antibodies and other causes of hypercoagulability should be ruled out as contributing factors to thrombosis formation.

Antineutrophil cytoplasmic antibody

Occasionally, patients are found with positive test results for perinuclear antineutrophil cytoplasmic (p-ANCA) antibody. However, positive or negative results on this test do not change prognosis or therapy.

The goals of therapy in Behçet disease are to suppress inflammation and reduce the frequency and severity of recurrences. To be effective, treatment must be started early. The sites and extent of involvement and the severity of disease determine the choice of medication.

The treatment approach depends on the individual patient, severity of disease, and major organ involvement. The European League Against Rheumatism (EULAR) recommendations for the management of Behçet disease, which were developed in 2008 and updated in 2018, aid in the management of different aspects of Behçet disease.[50, 51] Recommendations related to the eye, skin/mucosa, and arthritic disease are mainly evidence based, but recommendations on vascular, neurologic, and gastrointestinal involvement are based largely on expert opinion and uncontrolled evidence from open trials and observational studies.[50, 51]

As disease activity subsides, taper medications to the lowest dose that effectively controls disease activity. Inpatient care is based on individual organ-system involvement. Individualize the transfer situation for each patient based on the specifics of organ-system involvement.

 

For oral and genital ulcerations, topical steroids or sucralfate solution are first-line therapy for mild isolated ulcerations. Colchicine has also been used to prevent mucocutaneous relapse.[52, 53] For severe mucocutaneous lesions, systemic corticosteroids, azathioprine, pentoxifylline, dapsone, interferon-alfa, colchicine, and thalidomide have demonstrated benefit. Apremilast is a second-line treatment for oral ulcers associated with Behςet disease.[54]

For ocular disease, azathioprine is widely accepted as the initial agent. For severe eye disease (significant drop in visual acuity, retinal vasculitis, or macular involvement), either cyclosporine or infliximab may be used in combination with azathioprine and corticosteroids.[55, 56, 50, 57] An expert panel has recommended considering infliximab and adalimumab as first-line immunomodulatory agents for the treatment of ocular manifestations.[58]

Interferon-alfa, alone or in combination with corticosteroids, can be a second choice in severe ocular Behçet disease.[59, 60] It is used primarily in Europe. A retrospective study of a large case series from Germany reported long-lasting remission and improved visual prognosis in patients with severe ocular Behçet disease treated with alpha interferon.[59]

For gastrointestinal lesions, treatment alternatives based on expert opinion are aminosalicylate (5-ASA) derivatives (eg, sulfasalazine or mesalamine), systemic corticosteroids, azathioprine, tumor necrosis factor–α (TNF-α) antagonists, and thalidomide.

Arthritis may respond to prednisone, local corticosteroid injections, nonsteroidal anti-inflammatory drugs (NSAIDs), and colchicine. Interferon-alfa, azathioprine, and TNF-α blockers may be tried in rare cases of patients with resistant, prolonged, and disabling attacks.

Cutaneous disease with erythema nodosum is a special circumstance and may be treated with colchicine or dapsone.

Central nervous system (CNS) disease is usually treated with systemic corticosteroids, interferon-alfa, azathioprine, cyclophosphamide,[61] methotrexate, and TNF-α antagonists.[47]

Treatment of major-vessel disease with thrombotic events is with systemic anticoagulation in addition to corticosteroids, azathioprine, cyclophosphamide, or cyclosporine. Pulmonary arterial aneurysms are treated with cyclophosphamide and corticosteroids.

TNF-α antagonists are increasingly used and have become standard treatment of Behçet disease that is inadequately controlled by standard immunosuppressive regimens.[62, 63] Infliximab has been most widely studied, but adalimumab has proved successful in cases refractory to both conventional therapy and infliximab.[64] Etanercept is the only TNF inhibitor with data from a short-term randomized controlled study demonstrating efficacy in suppressing most of the mucocutaneous manifestations of Behçet disease. [65]

In a multicenter study of the use of TNF-α antagonists (mainly infliximab and adalimumab) for treatment of severe and/or refractory Behçet's disease in 124 patients, clinical response rates with particular organ involvement were as follows[66] :

• Ocular - 96.3%
• Mucocutaneous - 88%
• Joint - 70%
• GI - 77.8%
• CNS - 92.3%
• Cardiovascular - 66.7%

Infliximab was reported to successfully treat a case of Behçet disease in pregnancy.[67]  Other therapies with data from case reports or small pilot studies include the following, among others:

• Rituximab ^{[68, 69]}
• Alemtuzumab ^[70]
• Golimumab ^[71]

An open-label multicenter study compared the efficacy of infliximab versus adalimumab as a first‐line treatment in 177 patients with refractory uveitis due to Behçet disease. After 1 year of therapy, both treatment groups showed improvement. However, the patients receiving adalimumab had significantly better outcomes in some parameters, including improvement in anterior chamber inflammation (92.31% versus 78.18% for infliximab; P = 0.06), improvement in vitritis (93.33% versus 78.95% for infliximab; P = 0.04), and best‐corrected visual acuity (mean ± SD 0.81 ± 0.26 versus 0.67 ± 0.34 for infliximab; P = 0.001).[72]  

Apremilast, an oral phosphodiesterase-4 inhibitor initially approved for the treatment of psoriasis and psoriatic arthritis, was approved for treatment of oral ulcers associated with Behςet disease in 2019.  In a phase III trial, patients taking apremilast had significantly fewer oral ulcers than individuals receiving a placebo (129.5 vs 222.1 respectively). However, 79% of those taking apremilast experienced adverse events, which included diarrhea, nausea, headache, upper respiratory tract infection, and viral upper respiratory tract infection. Although improvements were also observed in overall disease activity and patient-reported outcomes, the trial was not designed to determine whether apremilast would improve mucocutaneous manifestations other than oral ulcers.[73]

The role of anti–interleukin-17 in Behçet disease is not known. However, two small retrospective studies suggest improvement in mucocutaneous and articular symptoms with secukinumab.[74, 75]

 

GI presentations that require surgical intervention include the following:

• Intestinal stenosis
• Lesions unresponsive to medical therapy
• Fistula formation
• Perforation
• Severe bleeding

Surgery may also be considered in the following circumstances:

• Pulmonary aneurysms and areas that incur ischemic damage due to vasculitis or thrombosis may require resection
• Ventricular aneurysms, coronary thrombosis, and endocardial fibrosis are occasionally amenable to surgery
• Glaucoma, cataracts, and retinal detachment occasionally warrant surgical intervention
• Neurosurgery may be required to correct some CNS aneurysms and clots

Consultations with the following specialists based on clinical need:

• Rheumatologist
• Urologist for genital and urologic lesions
• Neurologist for CNS involvement
• Ophthalmologist for ocular disease
• Gastroenterologist for intestinal disease
• Dermatologist for possible help with recurrent skin lesions
• Surgeon, when indicated
• Nephrologist for proteinuria or hematuria
• Pulmonologist or cardiologist in rare cases of intracardiac or pulmonary thrombosis and aneurysms

No general dietary recommendations exist for Behçet disease. Patients with severe bowel involvement are advised to follow the same GI recommendations given to patients with inflammatory bowel disease. These patients often require total parenteral nutrition.

Activity is suggested as tolerated and may be limited owing to systemic symptoms or arthritis.

The drugs used to treat Behçet disease are generally immunosuppressive. Because the cause of Behçet disease is unknown, therapy is directed at diminishing symptoms by suppressing the immune system. These medications may increase the risk of infection due to the nonspecific nature of immunosuppression. Symptomatic therapy is directed at specific symptoms (eg, oral ulcers, arthritis).

Class Summary

These agents may be used orally or parenterally for systemic symptoms, topically for ulcers or ocular involvement, or intra-articularly for arthritis.

Methylprednisolone (Solu-Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Administered intravenously in severe cases.

Prednisone (Deltasone, Sterapred, Orasone)

Decreases release of inflammatory mediators, neutrophil migration, monocyte and T-cell function.

Dexamethasone (Decadron)

Has many pharmacologic benefits but significant adverse effects. Stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, and inhibits prostaglandin and proinflammatory cytokines (eg, TNF-alpha, IL-6, IL-2, and IFN-gamma). The inhibition of chemotactic factors and factors that increase capillary permeability inhibits recruitment of inflammatory cells into affected areas. Suppresses lymphocyte proliferation through direct cytolysis and inhibits mitosis. Breaks down granulocyte aggregates, and improves pulmonary microcirculation.

Adverse effects of all glucocorticoids include hyperglycemia, hypertension, weight loss, GI bleeding or perforation synthesis, cerebral palsy, adrenal suppression, and death. Most of the adverse effects of corticosteroids are dose-dependent or duration-dependent.

Readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites are excreted via the kidneys. Lacks salt-retaining property of hydrocortisone.

Patients can be switched from an IV to PO regimen in a 1:1 ratio.

Class Summary

These agents decrease the immune response that causes signs and symptoms of Behçet disease.

Azathioprine (Imuran)

Purine analog that inhibits DNA synthesis. The 50-mg tablets are metabolized to 6-mercaptopurine in the liver and RBCs.

Cyclophosphamide (Cytoxan, Neosar)

Potent alkylating agent that inhibits various cellular functions. Alkylation of DNA results in cross-linking, impaired DNA synthesis, and cell death.

Chlorambucil (Leukeran)

Potent alkylating agent that inhibits various cellular functions. Alkylation of DNA results in cross-linking, impaired DNA synthesis, and cell death. Onset of action is slower than cyclophosphamide.

Class Summary

These agents affect the immune system in various ways, thus decreasing the autoimmune symptoms characteristic of Behçet disease. Immunomodulators do not, however, cause the generalized immunosuppression characteristic of immunosuppressive drugs.

Colchicine

Inhibits cellular microtubule formation and may cause a transient leukopenia, followed by leukocytosis. Use in autoimmune disease primarily is empiric, and mechanism of action in decreasing inflammation is not clear, nor is it truly an immunomodulating agent.

Sulfasalazine (Azulfidine)

A conjugate of 2 drugs—sulfapyridine and 5-aminosalicylic acid—originally developed for the treatment of rheumatoid arthritis. Useful for the treatment of inflammatory bowel disease, spondyloarthropathies, rheumatoid arthritis, and Behçet disease. Enteric coated pills may decrease GI adverse effects.

Dapsone (Avlosulfon)

May be useful for erythema nodosum and genital ulcers. Not approved for this use but approved for the treatment of dermatitis herpetiformis and leprosy.

Levamisole (Ergamisol)

Used for patients with Behçet disease to treat genital and aphthous ulcers. An immunomodulator approved for the treatment of colon cancer. Restores immune function and stimulates T-cell activation and proliferation and monocyte function. Stimulates neutrophil chemotaxis, adhesion, and mobility.

Cyclosporine (Sandimmune, Neoral)

Used for uveitis. Originally used in transplant patients, and its use has been expanded to various autoimmune diseases. Inhibits cellular activation, most prominently T lymphocytes, at an early phase via calcineurin inhibition without being cytotoxic.

Tacrolimus (Prograf)

Immunomodulator produced by the bacteria Streptomyces tsukubaensis. Mechanisms of action similar to cyclosporine. Primarily used in transplants but used in Behçet disease to treat uveitis.

Thalidomide (Thalomid)

Used for aphthous ulcerations and may be effective in erythema nodosum lesions. An immunomodulatory agent whose mode of action is not fully known. May suppress TNF-alpha. Down-regulates some adhesion molecules.

Infliximab (Remicade)

A monoclonal antibody directed at TNF.  Neutralizes cytokine TNF-alpha and inhibits it from binding to TNF-alpha receptor. Infliximab has been used successfully in treating CNS vasculitis, colonic ulcerations, esophageal ulcerations, panuveitis, mucocutaneous ulcers, and polyarthritis. Doses of 3, 5, or 10 mg/kg were dispensed. Infusions were given 1-4 times in a 2-mo period, with or without regular maintenance doses thereafter. Remission was achieved in all patients, with follow-up ranging from 2 mo to 2 y. No significant side effects were noted during or after the infusions. Results were usually seen within the first 24 h of the infusion. These infusions were given as adjuvants to systemic immunosuppressant therapy.

In addition, an anecdotal report from Estrach et al documents the treatment of a 38-year-old woman with severe iritis, arthritis, and ulcers that failed to respond to other immunomodulators. She was treated with etanercept, without improvement. She was then switched to infliximab. Infusions of 3 mg/kg were given at 0 and 2 weeks and then at intervals of 8 weeks for treatment of rheumatoid arthritis, together with methotrexate 7.5 mg PO once a week. According to the author, a remarkable response occurred soon after the first infusion, with marked improvement in arthralgia, resolution of urogenital ulceration and erythema nodosum, and reduction of fatigue. She remained healthy 1 yr later and continued with this therapy during remission.

Etanercept (Enbrel)

Soluble p75 TNF receptor fusion protein (sTNFR-Ig). Inhibits TNF binding to cell surface receptors, which, in turn, decreases inflammatory and immune responses.

A 4-week double-blind placebo-controlled study of the use of etanercept in patients with Behçet disease was completed after a 4-week washout of systemic immunosuppressants. Patients with mucocutaneous lesions and arthritis were treated with etanercept 25 mg SC twice a week.

Good results were seen after the first week and were maintained throughout the study. Patients treated with etanercept had a 40% chance of remaining ulcer-free vs 5% with placebo. Another study used etanercept at the same dose for 6 months in patients with ocular involvement receiving systemic immunosuppressants. The benefits gleaned from use of etanercept were not sustained after 6-mo posttreatment follow-up.

Apremilast (Otezla)

Oral small molecule inhibitor of phosphodiesterase-4 specific for cyclic adenosine monophosphate (cAMP), resulting in increased intracellular cAMP levels. Indicated for oral ulcers associated with Behςet disease