Dermatologic Aspects of Behcet Disease Clinical Presentation
- Author: Amira M Elbendary, MBBCh, MSc; Chief Editor: William D James, MD more...
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:
Decreased or elevated temperature
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.
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.
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, 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.
Diagnostic criteria from the Behçet syndrome research committee of Japan (1987 revision) 
Major features are as follows:
Recurrent aphthous ulceration of the oral mucous membrane
Skin lesions - Erythema nodosum –like lesions, subcutaneous thrombophlebitis, folliculitis (acneiform lesions), cutaneous hypersensitivity
Eye lesions - Iridocyclitis, chorioretinitis, retinouveitis, definite history of chorioretinitis or retinouveitis
Minor features are as follows:
Arthritis without deformity and ankylosis
Gastrointestinal lesions characterized by ileocecal ulcers
Central nervous system symptoms
Diagnosis is as follows:
Complete - Four major features
Incomplete - (1) 3 major features, (2) 2 major and 2 minor features, or (3) typical ocular symptom and 1 major or 2 minor features
Possible - (1) 2 major features or (2) 1 major and 2 minor features
International criteria for the classification of Behçet disease (1990) 
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:
Recurrent genital ulceration - Recurrent genital aphthous ulceration or scarring, especially males, observed by a physician or reliably reported by a patient
Eye lesions - (1) Anterior uveitis, posterior uveitis, and cells in vitreous upon slit-lamp examination or (2) retinal vasculitis observed by physician (ophthalmologist)
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
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 
A score of 4 or more from the following point system indicates a Behçet disease diagnosis:
Ocular lesions: 2 points
Genital aphthosis: 2 points
Oral aphthosis: 2 points
Skin lesions: 1 point
Neurological manifestations: 1 point
Vascular manifestations: 1 point
Positive pathergy test: 1 point
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%. 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.
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. 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.
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.
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. 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. See the image below.
Papulopustular eruptions are observed in 30-90% of cases. 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.
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. See the image below.
Erythema multiforme–like lesions are a reported cutaneous manifestation.
Extragenital ulcers are rare but are reported to occur in axillary, inframammary, and interdigital areas of the feet.
Lesions resembling Sweet syndrome are seen in about 4% of cases of Behçet disease. 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. Surgical interventions in these Behçet disease patients may result in severe and nonspecific inflammatory reactions. 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. They were noted in 75% of patients in a study that included 33 patients with Behçet disease. and in 40% of Iranian patients in a study that included 128 Behçet disease patients.
Uncommon skin manifestations may include perniolike lesions, neutrophilic eccrine hidradenitis, ulcus cruris, and Kaposi sarcoma.
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 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. Childhood-onset Behçet uveitis is more common in males.
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.
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.
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.
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).
Arterial involvement occurs in about 2-17% of patients with Behçet disease.
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.
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. Coronary artery vasculitis may cause acute myocardial infarction, but this is rare.
See the images below.
Venous involvement is noted in about 40% of patients. Superficial and deep venous systems are affected.
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. Recurrent superficial and deep venous thrombosis in the lower extremities may be complicated by postthrombophlebitic syndrome. 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.
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.
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.
Cardiac and pulmonary inflammatory masses have been reported and may mimic metastatic disease.
The clinical spectrum of gastrointestinal effects 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. 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.
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. 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.
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. 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. Finally, it includes spinal cord involvement presenting by sensory, motor, or sphincter dysfunction. Pseudotumoral brain lesions have been noted.
Nonparenchymal affection includes intracranial and extracranial aneurysms and cerebral venous thrombosis. It carries a better prognosis than that of parenchymal affection.
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.
This affects a minority of patients, about 2%. 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.
Estrogen and progesterone exert an immunomodulatory effect on pregnant women with Behçet disease, typically making the disease activity regress during pregnancy. 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.
Exacerbations mostly occur in the form of recurrent oral and genital ulcer.
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.
Fetal complications can include intrauterine growth restriction and miscarriage, reportedly mostly related to impaired function of vascular endothelial cells.
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.
Close follow-up is necessary to monitor the health of the mother and baby.
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. The disease may start as early as the neonatal period, and this usually occurs in children of mothers with active Behçet disease during pregnancy. 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.
Recurrent mouth ulcers are the first manifestation of the disease in 87-98% of cases, 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 and usually affect the vulva. In males, the scrotum, penis, and perianal region are affected. Deep ulcers may leave scars on after healing.
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.
Ocular involvement affects 60% of children with Behçet disease. The predominant ocular disease in children is panuveitis. Anterior uveitis frequently occurs before age 1- years. Retinal vasculitis and retinitis more readily affect older adolescents (16-20 y) but have a better prognosis than that in adults.
Neurological involvement includes headaches, which are common. Cerebral venous thrombosis and paralysis of cranial nerve VI, which may cause diplopia, are reported frequently. Behavioral disorders and problems learning in school are reported complications.
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.
HLA-B51 or its B101 allele is significantly associated with Behçet disease in Japan, Korea, Turkey, and France and with ocular manifestations in Britain. Although HLA-B51 transgenic mice do not develop any manifestations of Behçet disease, their neutrophils show excessive function.
Other independent associations in the major histocompatibility complex class I region include HLA-B57, B27, B15, and A26. They were found to be risk factors in Behçet disease patients, while HLA-A03 and B49 were found to be protective for Behçet disease.
The MICA allele is a polymorphic MHC class I–related A gene (MICA) family.
The MICA6 allele has recently been shown to be significantly associated with Behçet disease (74%), compared with controls (45.6%) in Japan.
The relationship between MICA6 and Behçet disease was confirmed in France. The MICA6 allele is thought to be in linkage disequilibrium with HLA-B51; consequently, the search for genes related to Behçet disease continues. A recent study of 23 Japanese patients showed that the MICA6 allele had no significant association with Behçet disease, but it showed a strong association with HLA-B51; therefore, the association between MICA6 and Behçet disease may be a secondary phenomenon related to HLA-B51.
MEFV gene mutations, seen in persons with Mediterranean fever, are increased in persons with Behçet disease. This mutation has been associated with vascular Behçet disease.[64, 65]
Levels of tumor necrosis factor-alpha (TNF-alpha) have been reported to be significantly elevated in Behçet disease patients; thus, reports of TNF-alpha blockers having therapeutic benefits have been reported. Park et al analyzed TNF-alpha haplotypes in the promoter response element that affect the binding affinity of certain transcription factors. Their study showed that TNF-alpha -1031*C, -863*A, -857*C, and -308*G alleles were significantly associated with Behçet disease. TNF-alpha haplotypes in the promoter response elements may be useful in identifying those more susceptible to Behçet disease.
Single nucleotide polymorphism (SNP) of the gene encoding protein tyrosine phosphatase type 22 (PTPN22 620W) has been strongly genetically linked to human autoimmune diseases; however, an inverse relationship exists between Behçet disease and this gene.
ERAP1 is a gene that encodes an endoplasmic reticulum amino peptidase, which acts on amino acid terminals in peptides that are then involved in HLA class I molecules, affecting their length for optimum major histocompatibility complex (MHC)–I binding.
ERAP1 isoforms may affect some HLA molecules’ properties. Epistatic interaction was found between HLA-B 51 and ERAP1, which is believed to play a pathogenic role through HLA-B 51.
Other genes were found to have a role in the pathogenesis of the disease through defects in sensing and processing of signals that are related to regulation of innate and adaptive immunity. Different ethnicities showed association between IL10, IL23R, STAT4, CCR1, UBAC2, GIMAP2/GIMAP4, KLRC4 and rare variants in TLR4, NOD2, and MEFV genes in Behçet disease patients. In spondyloarthritides, an association with ERAP1, MEVF, IL10, and IL23R is established, which is also found in Behçet disease, suggesting a shared inflammatory pathway between both diseases.
In a study that included 305 Korean patients with Behçet disease, polymorphism in gene CD11a/DC18 was found to be significantly low, whereas CD11c/CD18 was found high, suggesting its role in the pathogenesis of Behçet disease.
Human β-defensins are antimicrobial peptides encoded by the β-defensin family of multiple copy genes. These peptides were found to be associated with many inflammatory diseases. These encoding genes were found to be significantly high in Behçet disease patients in a case control study that included 27 Iraqi patients.
Viral and bacterial infection
Investigations of the etiology of Behçet disease have focused on herpes simplex virus infection, streptococcal infection, Helicobacter pylori, and autoimmunity or cross-reactivity between microbial and oral mucosal antigens.
Behçet suggested the herpes simplex virus as a causative agent in his first report. Polymerase chain reaction studies have remarkably improved the diagnostic significance of viral infections, especially herpes simplex virus. Herpes simplex virus DNA has been detected in saliva, genital ulcers, and intestinal ulcers of patients with Behçet disease. Behçet disease–like symptoms have been induced in an Institute for Cancer Research mouse after inoculation of herpes simplex virus into its earlobe.
Acquired hypersensitivity to streptococcal antigens plays an important role in the etiopathology of Behçet disease. Streptococcal antigens were found to induce hyperreactivity on skin testing and may cause exacerbation of the disease.
Salivary colonization with Streptococcus mutans was found in high rates in a study that included 106 Turkish patients with Behçet disease. Marked improvement was noticed in Behçet disease patients who received benzathine penicillin with colchicine compared with patients who received colchicine only as a treatment.
The multiplicity of etiologic factors may have a common denominator in the 65-kd microbial heat shock protein (HSP), which shows significant homology with the human 60-kd mitochondrial HSP. Indeed, the uncommon serotypes of Streptococcus sanguis found in Behçet disease cross-react with the 65-kd HSP, which also shares antigenicity with an oral mucosal antigen.
No significant difference was noted in the prevalence of H pylori seropositivity between Behçet disease patients and a healthy population. However, cytotoxin-associated gene A antibodies were found to be significantly higher in Behçet disease patients. Treatment directed at Helicobacter showed significant improvement in the course of the disease, which suggests the role of host response to H pylori in the pathogenesis of the Behçet disease.
Autoimmunity or cross-reactivity between microbial and oral mucosal antigens
T-cell epitope mapping has identified 4 peptides derived from the sequence of the 65-kd HSP that specifically stimulates T-cell receptor (TCR+) lymphocytes from patients with Behçet disease.
These peptides (111-125, 154-172, 219-233, and 311-325) show significant homology with the corresponding peptides (136-150, 179-197, 244-258, 336-351) derived from the human 60-kd HSP.
B-cell epitopes within mycobacterial HSP65 or human HSP60 overlap with the T-cell epitopes, and both immunoglobulin G and immunoglobulin A antibodies have been identified.
Among the 4 T- and B-cell epitopes, peptide 336-351 of the 60-kd HSP is significantly associated with Behçet disease in Britain, Japan, and Turkey. HSP60/65 was also found to be significantly increased in the epidermal cells of Behçet disease skin lesions, and antibody levels to HSP65 were significantly elevated in the cerebrospinal fluid from patients with neurological manifestations of Behçet disease.
An experimental model of Behçet disease uveitis was established in rats, in which subcutaneous immunization with peptide 336-351 and adjuvants elicited uveitis in approximately 80% of Lewis rats. Furthermore, a mucosal model of induction of uveitis was developed in rats by oral or nasal administration of peptide 336-351 without an adjuvant, and this is consistent with the oral onset of ulceration in more than 90% of patients with Behçet disease.
Chemotaxis, phagocytosis, superoxide, and lysosomal enzyme production are increased in patients with Beh ç et disease.
CD4+ cells that produce interleukin (IL)–17 have a major role in autoimmune diseases. Th17 together with IL-21 and IL-22 control inflammation and immunity on mucosal surfaces. In Behçet disease, high levels were detected in patients with recurrent aphthous ulcers, as well as increased activation of the Notch pathway in association with it, which make drugs targeting IL-17 and its mediators promising candidates for therapy. Notch blockade has shown inhibition in Th17 response, as it is involved in Th17 lymphocyte differentiation.
Decreased levels of IL-37 expression and increased IL-6, IL-1b, and tumor necrosis factor-alpha were found in the serum of active Behçet disease patients.
An increased level of Th1 lymphocytes was found in serum, skin T cells, and cerebrospinal fluid of patients with Behçet disease. They produce IL 2, IL-6, IL-8, IL-12, IL-18, interferon-gamma, and tumor necrosis factor (TNF)–alpha. This increased level of Th1 cells and its cytokines result in an abnormal immune response; in addition, a complex interaction between neutrophils, T cells, and antigen-presenting cells induces a hyperactivity of neutrophils, which results in increased neutrophil chemotaxis, phagocytosis, and myeloperoxidase expression.
The concentration of the Th2 cytokine IL-6 is also increased in the serum of patients with Behçet disease, especially in the active stage, as was also found with IL-10 upon stimulation of the peripheral blood mononuclear cell.
The activated T cells and neutrophils show a resistance to apoptosis, which is mediated through CD95 and NF-kappaB. This may aggravate the inflammatory stage of Behçet disease. The activated neutrophils remain in the serum of Behçet disease patients during the remission stage.
Stimulation with S sanguis (KTH-1) of T-cell lines generated from patients with Behçet disease suggests that Th1-type mRNA is induced (IL-2 and IFN).
The intracellular adhesion molecule 1 was enhanced in human dermal microvascular endothelial cells after treatment with serum from patients with Behçet disease, and this may have induced increased adhesion of T cells to the endothelial cells.
IL-23 p19 mRNA has been detected in erythema nodosum-like lesions of Behçet's disease. This finding suggests that anti–IL-23 therapy may be an option for treatment.
Plasma levels of vascular endothelial growth factor, a proinflammatory cytokine, is significantly higher in persons with active Behçet disease.
Neopterin is produced by human monocytes and macrophages in response to interferon-gamma (IFN-gamma) released from activated T cells; thus, it serves as a marker for cellular immune activation. Kose et al showed that serum levels of neopterin were significantly higher in active and inactive Behçet disease patients than in controls. Those with active disease had higher levels than those with inactive disease.
Polymorphisms in toll-like receptor 4 have been associated with Behçet disease.
Activated phagocytes, monocytes, and vascular endothelial cells express calprotectin (MRP8/MRP14,) which induces an inflammatory response and thrombogenicity in microvascular endothelial cells. Calprotectin was found to be increased in the serum of Behçet disease patients, but this was not found to correlate with disease activity.
Endothelial and vascular dysfunctions
Vascular changes leading to vasculitis and thrombosis are important pathological features of Behçet disease.
High levels of IL-8, E- selectin, and matrix metalloproteinases levels have been found in Behçet disease patients. Angiostatin is a 38-kd fragment of plasminogen. It is an inhibitor of angiogenesis and was found to be significantly high in Behçet disease patients. Patients with uveitis, arthritis, and deep venous thrombosis show significant elevations in angiostatin levels and decreased angiogenesis.
A number of molecules that contribute to endothelial cell dysfunction are found to be elevated in patients with Behçet disease, including vascular endothelial growth factor (VEGF), nitric oxide, and immunoglobulin M (IgM) antiendothelial antibodies. As a result of endothelial dysfunction, blood flow decreases. In addition, this activation induces vascular inflammation. These factors may precipitate thrombosis.
Neutrophil migration to the target tissues contributes to endothelial cell damage.
Immunoglobulins to carboxy-terminal subunit of Sip1 (Sip1 C-ter) levels have been found to be elevated in 41% of Behçet disease patients and in 45% of patients with primary vasculitis.
Endothelial cell–dependent vasodilator function was significantly impaired in patients with Behçet disease, which can be demonstrated by high-resolution ultrasound imaging.
Thrombophilic factors, including thrombin, fibrinolytic inhibitors, plasminogen activator inhibitor-1, and thrombin activatable fibrinolysis inhibitor, were found in high levels in patients with Behçet disease.
Thrombomodulin is a receptor on vascular endothelial cells, which, when down-regulated, leads to a procoagulation state. High levels of thrombomodulin are mostly observed in persons with skin pathergy reactions.
Decreased levels of antithrombotic factors, including fibrinolysis and activated protein C, are noted.
However, thrombophilia in Behçet disease patients does not seem to be the major factor in the tendency to thrombosis ; instead, the vascular damage as a result of inflammation and endothelial dysfunction are proposed as the major driver for thrombosis.
Vascular wall abnormalities
Inflammation of vasa vasorum in the arterial wall results in medial fragmentation. Histologically, medial thickening and elastic fiber splitting is noted. These factors play a role in wall weakness and aneurysm formation.
Decreased arterial distensibility was also noted in patients with Behçet disease.
Flow-mediated dilatation and endothelial-mediated dilatation were found to be impaired in Behçet disease patients, even in patients with remission. In addition, intimal thickness of carotid arteries was found to be greater in Behçet disease patients.
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