Behçet's disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]

Behçet’s disease is a chronic inflammatory condition caused by disturbances in the immune system. The immune system normally protects the body against infections through a controlled inflammatory reaction against the pathogen. In Behçet’s disease, the immune response becomes overactive and produces unpredictable outbreaks of exaggerated inflammation. This extra inflammation affects blood vessels, in particular, the smaller vessels. As a result, symptoms appear wherever the exaggerated inflammation response is produced. The inflammatory response can occur anywhere on the body where there is a blood supply.

Behcet disease was first discovered by Hippocrates in the 5th century. In 1937, Hulusi Behçet, Turkish dermatologist described Behçet’s disease that genital ulcerations, uveitis, and aphthous ulcers are it’s major presentations.

Neurologic disease of Behcet disease is classified into parenchymal or non-parenchymal. Parenchymal disease is due to lesions in the corticospinal tract, brainstem, periventricular white matter, spinal cord, and basal ganglia. Focal parenchymal lesions and complications of vascular thrombosis are the most common abnormalities. Progressive personality change, psychiatric disorders, and dementia may develop. Parenchymal disease may be divided into acuteand chronic progressive neuro-Behçet syndrome. Central nervous system lesions are detectable with MRI. In the chronic phase, lesions may be smaller or resolve, atrophy may be present, nonspecific white matter lesions may be present, and lesions usually do not enhance. Cerebrospinal fluid (CSF) may show increased protein and increased cells, and neutrophils may predominate. Non-parenchymal disease of Behcet disease include cerebral venous thrombosis, intracranial hypertension syndrome (pseudotumor cerebri), acute meningeal syndrome, and uncommonly stroke due to arterial thrombosis, dissection, or aneurysm. On average, a period of approximately five to six years elapsed between the onset of the earliest non-neurologic symptoms of Behçet syndrome and the appearance of neurologic symptoms or findings.

It is understood that Behçet disease is the result of vasculitis. It involves all sizes of blood vessels ( small, medium, and large). Arteries and veins are both involved in Behçet disease. Major mechanisms in pathogenesis of Behçet disease include environmental factors such as bacteria, viruses, and heat shock proteins (present in some bacteria and some of the bacterial HSPs share similaritis with human HSPs). Streptococcus sanguinis, streptococcus pyogenes, and mycobacterium tuberculosis produce HSPs that trigger anti HSP60 and anti HSP65 antibodies and then they target human HSPs and immune response such as uveitis in parenchymal neuro-Behçet disease, CD4+ T cells activation, secretion of cytokines and inflammation. Genes involved in the pathogenesis of Behçet disease include human leukocyte antigens, particularly HLA-B51.

The cause of Behçet disease has not been identified.

Behçet’s disease needs to be differentiated from other diseases that present with similar symptoms such as erythema nodosum and inflammatory bowel disease.

The prevalence of Behçet disease is approximately 0.12 to 7.5 per 100,000 individuals in the United States. Behçet disease commonly affects young adults 20 to 40 years of age. Males are more commonly affected by Behçet disease than females. Behçet disease usually affects individuals of the Turkish, Asian, and Middle Eastern populations. Middle Eastern and Asian individuals are more likely to develop Behçet disease due to the increased incidence of skin pathergy and HLA-B51 antigen. The male to female ratio ranges from approximately 11 to 1 to 2 to 1. The majority of Behçet disease cases are reported along the ancient silk road (from eastern Asia to the Mediterranean).

Common risk factors in the development of Behcet disease may be occupational, environmental, genetic, and viral. Behçet’s disease can affect people in any age, but the most common age is 20~30 years old. Behçet’s disease is more common in Middle East and Japan then in other race. It is rare in America. Researches demonstrate that the presence of the gene HLA–B51 is a risk factor for Behçet’s disease.

There is insufficient evidence to recommend routine screening for Behçet disease.

The symptoms of Behçet disease usually develop in the second to third decade of life, and start with symptoms such as uveitis, mouth sores, and skin lesions. Common complications of Behçet disease include neuro Behçet, vision loss, and aneurysm. Depending on the extent of the disease at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as good. The worst prognoses are associated with retinal vasculitis, leading to blindness; vascular aneurysm formation, with possible rupture; and neuro–Behçet syndrome, which may lead to dementia despite appropriate aggressive treatment.

Currently, there is not a specific test to confirm the diagnosis of Behçet’s disease. It is diagnosed clinically by specific patterns of symptoms and repeated outbreaks obtained by a thorough history of the patient’s symptoms (outlined below). Behçet’s disease is a diagnosis of exclusion, and other chronic inflammatory diseases should be evaluated for. The various inflammatory symptoms do not necessarily occur together, and they will vary in severity.

The hallmark of Behçet disease is recurrent aphthous ulcerations, genital ulcers, and uveitis. A positive history of joint pains and skin lesions are suggestive of Behçet disease. The most common symptoms of Behçet disease include mouth sores, uveitis, joint pain, and genital sores. Less common symptoms of Behçet disease include diarrhea, abdominal pain, headache, skin lesions-red nodules, acne, joint pains, and poor balance.

Patients with Behçet disease usually appear normal. Vital signs of patients with Behçet disease are usually normal. The presence of mouth sores, genital ulcers, and vision problems on physical examination are diagnostic of Behçet disease. Skin examination of patients with Behçet disease shows erythema nodosum lesions typically occur on the extremities, especially the lower legs, but they can also be observed on the face, neck, and buttocks. The lesions are painful and resolve spontaneously, although some may ulcerate or leave hyperpigmentation. A folliculitis like rash, resembling acne vulgaris, appears on the face, neck, chest, back, and hairline of patients. Some lesions become more pustular; 24-48 hours after a sterile needle prick, some patients develop erythema with a nodule or pustule at the prick site. Ophthalmoscopic exam may be abnormal with findings of retinal vasculitis, and vaso-occlusive lesions. Uveitis of anterior and posterior chambers diagnosed with slit-lamp examination. Erythematous throat with tonsillar swelling, and exudates. Ulcers 2-15 mm in diameter, with a necrotic center and surrounding red rim. A white or yellow pseudomembrane covers the surface of the ulcer. The ulcers are typically painful, nonscarring, and found on the lips, buccal mucosa, tongue, tonsils, and larynx. Most last 7-14 days and occur in crops. Hypopyon may be observed in the anterior chamber. Genitourinary examination of patients with Behçet disease will show ulcers on the scrotum and vulva, painful and heal with scarring. Genital ulcerations tend to be deeper and larger than the oral lesions. Females can have asymptomatic ulcers. Neuromuscular examination of patients with Behçet disease will show CNS involvement in 25% of the cases. Immune-mediated meningoencephalitis predominantly involves the brainstem. Meningitis, encephalitis, focal neurological deficits, and psychiatric symptoms can be present. Irreversible dementia can occur.

The laboratory tests used to diagnose Behçet’s disease are a pathergy test, a skin biopsy, and a lumbar puncture.

There are no ECG findings associated with Behçet’s disease.

There are no x-ray findings associated with Behçet disease.

Echocardiography is useful in patients with murmurs because it is useful for diagnosing the valve vegetations and ventricular thrombi, which may occur in Behçet disease. Vascular involvement can be seen in up to 40% of patients with Behçet disease (BS) with the lower-extremity vein thrombosis (LEVT) being the most common type where ultrasonography is needed.

There are no CT scan findings associated with Behçet disease. However, a CT scan may be helpful in the diagnosis of complications of Behçet disease including visualization of neurological lesions (helpful in patients with CNSinvolvement), and enlargement of ventricles or subarachnoid spaces.

There are no MRI findings associated with Behçet disease. MRI findings of the brain may be normal even in the presence of neurologic involvement. However, a MRI may be helpful in the diagnosis of complications of Behçet disease, which include enlargement of ventricles or subarachnoid spaces, and neurological lesions present in CNS involvement.

Endoscopy of the GI tract is useful for detecting gastrointestinal ulcerations in Behçet disease. A thorough eye examination and fluorescein angiography for evaluation of retinal vessels. Follow-up visits with an ophthalmologist should be scheduled at least every 6-12 months. Neuropsychologic testing may be useful with CNS involvement, revealing memory impairment or personality changes, and can be useful in monitoring neuropsychologic status.

There are no other diagnostic studies associated with Behçet disease.

Current treatment is aimed at easing the symptoms, reducing inflammation, and controlling the immune system. Anti-TNF therapy, such as infliximab, has shown promise in treating the uveitis associated with the disease. Another Anti-TNF agent, etanercept, may be useful in patients with mainly skin and mucosal symptoms. Interferon alfa-2a, azathioprine, colchicine, thalidomide, dapsone and rebamipide are among other agents that are used alternatives.

Surgery in Behcet’s disease is performed to treat severe complications such as gastrointestinal perforations or ocular inflammatory diseases.

There are no established measures for the primary prevention of Behçet disease.

There are no established measures for the secondary prevention of Behçet disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]Mahda Alihashemi M.D. [3]Dheeraj Makkar, M.D.[4]

Behcet disease was first discovered by Hippocrates in the 5th century. In 1937, Hulusi Behçet, Turkish dermatologist described behcet syndrome that genital ulcerations, uveitis, and aphthous ulcers are it’s major presentations.

• Behcet disease was first discovered by Hippocrates in the 5th century.^[1]
• In 1937, Hulusi Behçet, Turkish dermatologist described behcet syndrome that genital ulcerations, uveitis, and aphthous ulcers are it’s major presentations.^[2]

• Geographic origins: Behçet’s syndrome historically occurred in regions along the ancient Silk Road, which stretched from the Mediterranean through the Middle East to East Asia. This geographic distribution has shaped the understanding of its epidemiology

.

Prevalence patterns: The highest prevalence has been reported in Turkey (420 per 100,000 persons), with decreasing frequency toward Northern Europe and the United States. Migration studies also highlighted that immigrants from high-prevalence regions carry increased—but still lower than native—risks .

Recognition as a syndrome: Over the last 20 years, several discoveries have reshaped the understanding of Behçet’s disease. It has shifted from being considered a clinical curiosity to being classified as a primary systemic vasculitis affecting veins and arteries of all sizes. This change reflects the broader spectrum of signs and symptoms recognized and the prognostic implications for patients .

Early genetic insights: The first genetic association identified was with HLA-B*51, discovered decades ago. Later, genome-wide association studies and sequencing technologies revealed multiple additional genes, leading to new classification schemes and insights into immune dysregulation .

Evolution of classification criteria: Diagnostic and classification approaches have evolved—from the 1990 International Study Group (ISG) criteria, which required recurrent oral ulcers plus two additional findings, to the 2014 International Criteria for Behçet’s Disease (ICBD), which introduced a point-based system incorporating neurologic and vascular involvement. These refinements reflect recognition of the disease’s multisystemic nature .

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]

Neurologic disease of Behcet disease is classified into parenchymal or non-parenchymal. Parenchymal disease is due to lesions in the corticospinal tract, brainstem, periventricular white matter, spinal cord, and basal ganglia. Focal parenchymal lesions and complications of vascular thrombosis are the most common abnormalities. Progressive personality change, psychiatric disorders, and dementia may develop. Parenchymal disease may be divided into acute and chronic progressive neuro-Behçet syndrome. Central nervous system lesions are detectable with MRI. In the chronic phase, lesions may be smaller or resolve, atrophy may be present, nonspecific white matter lesions may be present, and lesions usually do not enhance. Cerebrospinal fluid (CSF) may show increased protein and increased cells, and neutrophils may predominate. Non-parenchymal disease of Behcet disease include cerebral venous thrombosis, intracranial hypertension syndrome (pseudotumor cerebri), acute meningeal syndrome, and uncommonly stroke due to arterial thrombosis, dissection, or aneurysm. On average, a period of approximately five to six years elapsed between the onset of the earliest non-neurologic symptoms of Behçet syndrome and the appearance of neurologic symptoms or findings.

• Neurologic disease of Behcet disease is classified into parenchymal or non-parenchymal.

• Parenchymal disease is due to lesions in the corticospinal tract, brainstem, periventricular white matter, spinal cord, and basal ganglia.
  • Brainstem disease (which may extend to the midbrain, basal ganglia, and diencephalon) including focal lesions or atrophy with signs and symptoms including ophthalmoparesis, cranial neuropathy, and cerebellar or pyramidal dysfunction are more characteristic of Behçet syndrome than multiple sclerosis.
  • Cerebral lesions are often multiple though may be single, are often subcortical, and are not particularly peri-ventricular, as in multiple sclerosis.
  • Spinal cord lesions (myelitis) may occur in isolation, but are more common in patients with other central nervous system lesions.
  • The clinical presentation of parenchymal disease is often subacute and manifestations may include headache, behavior changes, and deficits reflecting areas of parenchymal involvement.

• Focal parenchymal lesions and complications of vascular thrombosis are the most common abnormalities.
• Progressive personality change, psychiatric disorders, and dementia may develop.
• Unlike many other systemic vasculitic disorders, peripheral neuropathy is uncommon in Behçet syndrome.^[1][2][3]
• Parenchymal disease may be divided into acute and chronic progressive neuro-Behçet syndrome.
  • A meta-analysis reviewed 184 acute and 114 chronic progressive cases, and fever and higher cerebrospinal fluid cell counts were found more commonly in acute disease, and sphincter disturbances, ataxia, confusion, brain stem atrophy on magnetic resonance imaging (MRI), and cerebral changes on MRI were more common in chronic progressive disease.^[4]

• Central nervous system lesions are detectable with MRI.^[5][6]
• Acute and subacute lesions are hypointense or isointense on T1-weighted images; hyperintense on T2-weighted, FLAIR, and diffusion-weighted images; and commonly enhance with contrast.
• In the chronic phase, lesions may be smaller or resolve, atrophy may be present, nonspecific white matter lesions may be present, and lesions usually do not enhance.
• Cerebrospinal fluid (CSF) may show increased protein and increased cells, and neutrophils may predominate.^[7]
• Pathology reveals local perivenular lymphocytic cuffing, inflammatory cell infiltration, gliosis, necrosis, and neuronal loss. Although frank vasculitis is not always observed in parenchymal lesions, it is sometimes noted in larger cerebral vessels, including arteries or veins. Arteritis may lead to ischemic strokes, dissection, aneurysmal dilatation, and subarachnoid hemorrhage.

Non-parenchymal disease of Behcet disease include the following:

• Cerebral venous thrombosis, intracranial hypertension syndrome (pseudotumor cerebri), acute meningeal syndrome, and uncommonly stroke due to arterial thrombosis, dissection, or aneurysm.^[7]

• Central nervous system manifestations may result from arterial or venous thrombosis, including dural sinus thrombosis.^[8]
• Cerebral venous thrombosis may present with headache, papilledema, sixth nerve palsy, and an elevated CSF pressure.^[8][9][10]
• An association has been observed between dural sinus thrombosis and peripheral deep venous thrombosis.^[5]
• Thrombosis of the cerebral arteries may also be observed.^[5][8]
• One analysis of neurologic Behçet syndrome from Turkey, involving 26 children and 702 adults, found that dural venous sinus thrombosis was much more common in children than parenchymal neurologic involvement, although parenchymal disease was more frequent in adults.^[11]

• In one large series, the clinical features and outcomes of 200 patients with Behçet syndrome and neurologic involvement were reported.^[5]
• On an average, a period of approximately five to six years elapsed between the onset of the earliest non-neurologic symptoms of Behçet syndrome and the appearance of neurologic symptoms or findings.
• Nevertheless, neurologic findings may also appear concurrently (7.5 percent) or precede non-neurologic features (3 percent). Twenty percent of those with neurologic findings were asymptomatic.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2], Mahda Alihashemi M.D. [3] Dheeraj Makkar, M.D.[4]

It is understood that Behçet disease is the result of vasculitis. It involves all sizes of blood vessels ( small, medium, and large). Arteries and veins are both involved in Behçet disease. Major mechanisms in pathogenesis of Behçet disease include environmental factors such as bacteria, viruses, and heat shock proteins (present in some bacteria and some of the bacterial HSPs share similaritis with human HSPs). Streptococcus sanguinis, streptococcus pyogenes, and mycobacterium tuberculosis produce HSPs that trigger anti HSP60 and anti HSP65 antibodies and then they target human HSPs and immune response such as uveitis in parenchymal neuro-Behçet disease, CD4+ T cells activation, secretion of cytokines and inflammation. Genes involved in the pathogenesis of Behçet disease include human leukocyte antigens, particularly HLA-B51.

Pathophysiology of Behçet’s Syndrome

• Genetic Predisposition

Behçet’s syndrome develops in genetically predisposed hosts after exposure to environmental triggers.

The first genetic association was with HLA-B*51, particularly HLA-B*51:01, which increases disease risk nearly sixfold.

Genome-wide association studies (GWAS) have since revealed additional key genes:

ERAP1 (antigen processing, interacts with HLA-B*51).

IL23R–IL12RB2, STAT4, IL10 (T-cell polarization toward Th1 and Th17 responses).

KLRC4 (NK cell regulation).

CCR1–CCR3 (cell chemotaxis).

Other implicated genes include TNFAIP3 (A20 haploinsufficiency), MEFV (familial Mediterranean fever), and TLR4/NOD2/FUT2, linking Behçet’s to autoinflammatory syndromes.

Epigenetic changes, such as aberrant DNA methylation and histone modifications in immune cells, further amplify susceptibility .

• Environmental and Microbial Triggers

Proposed triggers include:

Microorganisms (e.g., Streptococcus species, HSV-1).

Dietary factors (histamine-releasing foods such as citrus, nuts, and cheese).

Poor oral hygiene and stress.

Studies show gut and salivary microbiome dysbiosis, leading to abnormal antigen repertoires that may drive immune responses .

• Immune Dysregulation

Adaptive immunity:

CD4+ T-helper lymphocytes differentiate into Th1 (producing TNF-α, IFN-γ) and Th17 (producing IL-17, IL-23) subsets.

There is diminished regulatory T-cell activity, further tipping the balance toward inflammation.

CD8+ T cells and natural killer (NK) cells also contribute to cytotoxicity.

Innate immunity:

Neutrophils are the main infiltrating cell type in lesions.

They generate excessive reactive oxygen species (ROS) and release neutrophil extracellular traps (NETs), promoting vascular inflammation and thrombosis.

Key inflammatory pathway:

The NF-κB pathway is upregulated in antigen-presenting cells, neutrophils, and T cells, amplifying proinflammatory cytokine production .

• Histopathology

Biopsies often show:

Leukocytoclastic vasculitis.

Neutrophilic or lymphocytic perivascular infiltrates.

Microvascular thrombi.

Neutrophilic dermal infiltrates.

• It is understood that Behçet disease is the result of vasculitis. It involves all sizes of blood vessels ( small, medium, and large). Arteries and veins are both involved in Behçet disease. Major mechanisms in pathogenesis of Behçet disease include:^[1]
  • Polygenic
  • Environmental factors such as bacteria, viruses, and heat shock proteins (present in some bacteria and some of the bacterial HSPs share similaritis with human HSPs).^[2]
    • Streptococcus sanguinis, streptococcus pyogenes, and mycobacterium tuberculosis produce HSPs that trigger anti HSP60 and anti HSP65 antibodies and then they target human HSPs and immune response such as uveitis in parenchymal neuro-Behçet disease.^[3]
  • CD4+ T cells activation, secretion of cytokines and inflammation.

• The development of Behçet disease is the result of multiple genetic mutations.
• Genes involved in the pathogenesis of Behçet disease include human leukocyte antigens, particularly HLA-B51.^[4]
• Familial cases of Behçet disease have higher rates of HLA-B51 in compare to sporadic cases.^[5]
• Genetic anticipation: earlier age of onset of disease in children of patients with Behçet disease.^[6]
• Some studies shows that major histocompatibility complex class I chain related gene A (MICA) A6 allele is related to Behçet disease. ^[7]
• Non-HLA genes also have roles in Behçet diesease. They include: ^[8]
  • Intercellular adhesion molecule (ICAM)-1 gene
  • Endothelial nitric oxide synthase gene^[9]
  • Tumor necrosis factor (TNF) genes^[10]
  • Vascular endothelial growth factor (VEGF) gene^[11]
  • Manganese superoxide dismutase gene^[12]
  • Cytochrome P450 gene^[13]
  • Interleukin (IL)-10 gene^[14]
  • IL-23 receptor gene^[15]
  • Missense mutations of the familial Mediterranean fever (MEFV) gene that encodes protein pyrin on the surface of neutrophils^[16]

• On gross pathology oral ulcers, genital ulcers, uveitis, and skin lesions are characteristic findings of Behçet disease.

• On microscopic histopathological analysis, neutrophilic and CD4+ T lymphocytes infiltrate and vasculitis are characteristic findings of Behçet disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]Dheeraj Makkar, M.D.[3]

The cause of Behçet disease has not been identified. To review risk factors for the development of Behçet disease, click here.

The cause of Behçet disease has not been identified. To review risk factors for the development of Behçet disease, click here. Behçet’s syndrome is a complex, multifactorial disorder in which both genetic predisposition and environmental triggers interact to produce immune dysregulation and widespread vascular inflammation.

• Genetic Factors

HLA-B*51: The first and strongest genetic association, particularly the HLA-B*51:01 subtype, confers about a sixfold higher risk of developing Behçet’s syndrome.

Other immune-related genes: Genome-wide association studies have identified additional susceptibility loci, including:

ERAP1 (involved in antigen processing and presentation).

IL23R–IL12RB2, STAT4, and IL10 (linked to polarization of Th1 and Th17 responses).

KLRC4 (regulation of natural killer cell activity).

CCR1–CCR3 (chemotaxis).

Autoinflammatory genes: Variants in TNFAIP3 (A20 haploinsufficiency) and MEFV (familial Mediterranean fever gene) suggest shared mechanisms with other monogenic inflammatory disorders.

Epigenetics: Studies have shown aberrant DNA methylation and abnormal histone activation marks in immune cells, further enhancing inflammatory responses .

• Environmental and Microbial Triggers

Microorganisms: Bacteria (e.g., Streptococcus species), viruses (e.g., HSV-1), and their byproducts have been implicated as potential initiating factors.

Dietary factors: Histamine-releasing foods such as citrus fruits, nuts, and cheese may precipitate flares.

Lifestyle and local factors: Poor oral hygiene and psychological stress have been proposed as contributing triggers.

Microbiome imbalance: Alterations in gut and salivary flora (dysbiosis) have been repeatedly observed, suggesting that microbial antigens may stimulate abnormal immune activation .

• Immune Dysregulation

Behçet’s syndrome displays both autoimmune and autoinflammatory features.

Adaptive immunity:

Hyperactive Th1 and Th17 responses lead to overproduction of proinflammatory cytokines such as TNF-α, IFN-γ, IL-17, and IL-23.

Regulatory T-cell activity is diminished, reducing immune tolerance.

Innate immunity:

Neutrophils are the predominant infiltrating cells, generating reactive oxygen species and releasing neutrophil extracellular traps (NETs), which contribute to vascular inflammation and thrombosis.

NF-κB pathway: Heightened signaling in antigen-presenting cells, T cells, and neutrophils amplifies the inflammatory cascade

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2]

Behçet’s disease needs to be differentiated from other diseases that present with similar symptoms such as erythema nodosum and inflammatory bowel disease.

• Erythema nodosum
• Inflammatory bowel disease
• Peptic ulcer
• Acute febrile neutrophilic dermatosis
• Lupus erythematosus
• Oral Candidiasis

Abbreviations: ANA: Antinuclear antibody, RF: Rheumatoid factor, Anti-CCp: Anti-cyclic citrullinated protein antibody, Anti U1RNP: Anti-U1 ribonucleoprotein antibodies , Anti Sm : Anti-Sm antibodies, Anti Ro: Anti Ro antibody also called anti-Sjögren’s-syndrome-related antigen A antibody, Anti-dsDNA: Anti-double stranded DNA.

Disease		Arthritis					Auto-antibodies							Raynaud phenomenon	Rash pattern	Distinguishing/specific features
		Polyarthritis	Tenderness	Edema	Deformity /Erosion	Pattern	ANA	RF	Anti-CCp	Anti U1RNP	Anti Sm	Anti Ro	Anti-dsDNA
Behçet’s disease		+/-	+/-	+/-	–	medium and large joints	–	–	–	–	–	–	–		Recurrent and usually painful mucocutaneous ulcers, acneiform lesions, papulo-vesiculo-pustular eruptions, superficial thrombophlebitis	Male dominancy
Systemic lupus erythematosus[1]		+	+	+	–	Small joints	↑	–	–	–	↑	↑	–	+	Malar rash and photosensitivity
Rheumatoid arthritis (RA)[2]		+	+	+	+	Small and large joints	–	↑↑	↑↑	–	–	–	–	+	Subcutaneous nodules	Erosive arthropathy
Rhupus[3]		+	+	+	+	Small and large joints	↑	↑	↑	↑	↑	–	↑	+	Malar rash and photosensitivity	Erosive arthropathy
Mixed connective tissue disease (MCTD)[4]		–	–	–	+	Small and large joints	–	↑↑	↑	–	–	–	–	+	Cutaneous eruptions, gottron’s papules, photodistributed erythema, poikiloderma, and calcinosis cutis	Overlapping features of SLE, systemic sclerosis (SSc), and polymyositis (PM) that lead to more than one diagnosis
Undifferentiated connective tissue disease (UCTD)[5]		+	–	–	–	Lower extremity	↑	↑	–	–	↑	–	–	+	Erythematous macules, patches, or papules with delicate scale	Multiple connective tissue diseases with no enough criteria for a single diagnosis
Systemic sclerosis (SSc)[6]		+/-	+	+	+/-	Lower extremity	↑↑	–	–	–	↑	–	↑	+	Hyperkeratosis, edema, and erythema	Sclerodactyly, Telangiectasias, Calcinosis, Malignant hypertension, acute renal failure
Sjögren’s syndrome[7]		+/-	+/-	–	–	Lower extremity, axiallary creases	↑	–	–	–	↑	↑	–	–	Xerosis, scaly skin, annular erythema	Keratoconjunctivitis sicca
Vasculitis	Giant cell[8]	–	+	+	–	Distal extremity	–	–	–	–	–	–	–	–	Rare	Involvement of cranial branches of arteries, visual loss
	Takayasu[9]	–	+/-	+/-	–	Transient extremity	–	–	–	–	–	–	–		Erythema nodosum, pyoderma gangrenosum	Absent or weak peripheral pulse
	Poly-arteritis nodosa[10]	–	+/-	–	–	General and mild	–	–	–	–	–	–	–		Tender erythematous nodules, purpura, livedo reticularis, bullous or vesicular eruption	Testicular pain or tenderness and neuropathies
Kikuchi’s disease[11]		–	+/-	–	–	medium and large joints	↑/↓	–	–	–	–	–	–	–	Transient skin rashes, malar rash, erythematous macules, patches, papules, or plaques	May be associated with SLE
Serum sickness[12]		+	+	+/-	–	General	–	–	–	–	–	–	–	–	Pruritic rash, urticaria and/or serpiginous macular rash	Self-limited
Psoriatic arthritis[13]		–	–	–	–	Small and large joints	–	–	–	–	–	–	–	–	Psoriasis and onychodystrophy	Dactylitis (sausage digits)
Human parvovirus B19 infection[14]		+	+	–	–	Small joints	–	–	–	–	–	–	–	–	Erythematous rashes	Rare in adults, fifth’s disease in children

Behçet’s disease oral lesions must be differentiated from other mouth lesions such as oral candidiasis and aphthous ulcer

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]Mahda Alihashemi M.D. [3]

The prevalence of Behçet disease is approximately 0.12 to 7.5 per 100,000 individuals in the United States. Behçet disease commonly affects young adults 20 to 40 years of age. Males are more commonly affected by Behçet disease than females. Behçet disease usually affects individuals of the Turkish, Asian, and Middle Eastern populations. Middle Eastern and Asian individuals are more likely to develop Behçet disease due to the increased incidence of skin pathergy and HLA-B51 antigen. The male to female ratio ranges from approximately 11 to 1 to 2 to 1. The majority of Behçet disease cases are reported along the ancient silk road (from eastern Asia to the Mediterranean).

• The prevalence of Behçet disease is approximately 80 to 370 per 100,000 individuals in Turkey.^[1][2]
• The prevalence of Behçet disease is approximately 13.5 to 20 per 100,000 individuals in Iran, Japan, Korea, China and Saudi Arabia.^[1]
• The prevalence of Behçet disease is approximately 7.1 per 100,000 individuals in Paris, France.^[3]
• The prevalence of Behçet disease is approximately 2.4 per 100,000 individuals in European ancestry.^[3]
• The prevalence of Behçet disease is approximately 34.6 per 100,000 individuals in North African ancestry.^[3]
• The prevalence of Behçet disease is approximately 17.5 per 100,000 individuals in Asian ancestry.^[3]
• The prevalence of Behçet disease is approximately 0.12 to 7.5 per 100,000 individuals in the United States.^[4]

• Behçet disease commonly affects young adults 20 to 40 years of age.^[5]

• Behçet disease usually affects individuals of the Turkish, Asian, and Middle Eastern populations.
• Middle Eastern and Asian individuals are more likely to develop Behçet disease due to the increased incidence of skin pathergy and HLA-B51 antigen.

• Males are more commonly affected by Behçet disease than females. The male to female ratio ranges from approximately 11 to 1 to 2 to 1.

• The majority of Behçet disease cases are reported along the ancient silk road (from eastern Asia to the Mediterranean).^[1]
• Behçet disease is most common in Turkey.

• Occurs in less than 10 percent of patients with Behçet syndrome in most series.^[6][7][8]
• Males are more commonly affected by neurological Behçet disease than females.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2] Dheeraj Makkar, M.D.[3]

Common risk factors in the development of Behcet disease may be occupational, environmental, genetic, and viral. Behçet’s disease can affect people in any age, but the most common age is 20~30 years old. Behçet’s disease is more common in Middle East and Japan then in other race. It is rare in America. Researches demonstrate that the presence of the gene HLA–B51 is a risk factor for Behçet’s disease.

The underlying cause of Behçet’s disease is not clear. It is suggested that the following factors may be associated with the disease:

• Genetic predisposition: Researches demonstrate that the presence of the gene HLA–B51 is a risk factor for Behçet’s disease.^[1][2]
• Age: Behçet’s disease can affect people in any age, but the most common age is 20~30 years old.
• Gender: Behçet’s disease most commonly affects men than women.
• Race: Behçet’s disease is more common in Middle East and Japan then in other race. It is rare in America.^[3]

Risk Factors for Behçet’s Syndrome

• Geographic and Ethnic Factors

Historically most common along the ancient Silk Road.

Highest prevalence: Turkey (≈420 per 100,000).

Higher prevalence in Middle East, East Asia, and Mediterranean countries compared with Northern Europe or the U.S.

Immigrants from high-prevalence regions carry higher risk than natives in low-prevalence countries, though lower than in their country of origin .

• Genetic Risk Factors

HLA-B*51: strongest genetic association; carriers are ~6 times more likely to develop Behçet’s syndrome.

Additional associated genes:

ERAP1, IL23R–IL12RB2, STAT4, IL10 (immune regulation, T-cell polarization).

KLRC4 (NK-cell regulation), CCR1–CCR3 (chemotaxis).

TNFAIP3 (A20 haploinsufficiency), MEFV (familial Mediterranean fever gene).

Epigenetics: altered DNA methylation and histone activation in immune cells amplify susceptibility .

• Demographic Factors

Age:

Mean age at diagnosis ≈30 years.

Most patients present between 15–45 years.

Sex:

Overall incidence similar between men and women.

Men are more likely to have severe forms of the disease, with higher risk of ocular, vascular, and neurologic involvement.

Male sex is associated with increased mortality (hazard ratio 4.94) .

Family history: familial aggregation reported, especially in early-onset cases.

• Environmental and Lifestyle Triggers (not direct causes, but risk enhancers for onset/flares)

Microorganisms: Streptococcus species, HSV-1, bacterial/viral byproducts.

• Diet: histamine-releasing foods (citrus fruits, nuts, cheese).

Poor oral hygiene.

Psychological stress.

Dysbiosis: gut and salivary microbiome imbalance .

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2] Dheeraj Makkar, M.D.[3]

The symptoms of Behçet disease usually develop in the second to third decade of life, and start with symptoms such as uveitis, mouth sores, and skin lesions. Common complications of Behçet disease include neuro Behçet, vision loss, and aneurysm. Depending on the extent of the disease at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as good. The worst prognoses are associated with retinal vasculitis, leading to blindness; vascular aneurysm formation, with possible rupture; and neuro–Behçet syndrome, which may lead to dementia despite appropriate aggressive treatment.

.

• Behçet’s is a chronic, relapsing–remitting multisystem vasculitis.

• • Onset: Mean age at diagnosis ≈30 years, with most cases between 15–45 years.

• • Course:

• • • Disease activity generally wanes with advancing age.

• • • Clinical features often overlap and evolve over time (e.g., mucocutaneous → ocular, vascular, or neurologic involvement).

• • Sex differences: Incidence similar in men and women, but men tend to develop more severe disease.

• • Familial aggregation reported, particularly in early-onset cases

.

• The symptoms of Behçet disease usually develop in the second to third decade of life, and start with symptoms such as uveitis, mouth sores, and skin lesions.^[1]

• Ocular Complications

Uveitis in ~50% of patients.

Can lead to vision loss, historically in up to 25% over 10 years before widespread immunosuppressive therapy.

Now reduced to ~13% with modern treatments.

Risk factors: male sex, posterior segment involvement, frequent relapses .

• Vascular Complications

Behçet’s can affect both veins and arteries.

Venous: Superficial thrombophlebitis, deep-vein thrombosis (15–40%), Budd–Chiari syndrome, cerebral sinus thrombosis.

Arterial: Aneurysms (especially aorta, pulmonary arteries), stenosis, thrombosis.

Cardiac involvement: Valvulitis, myocarditis, coronary arteritis, intracardiac thrombosis, endomyocardial fibrosis.

Vascular Behçet’s is the leading cause of death, mainly due to arterial aneurysms and Budd–Chiari syndrome .

• Neurologic Complications

Occurs in <30% of patients, either:

Parenchymal (brainstem, mesodiencephalic junction) → headaches, hemiparesis, seizures.

Non-parenchymal (cerebral venous thrombosis).

Associated with progressive disability in relapsing cases.

• Gastrointestinal Complications

Ulcers throughout the GI tract, resembling inflammatory bowel disease.

Can lead to pain, bleeding, perforation, sometimes requiring surgery

• Common complications of Behçet disease include:^[2]
  • Neuro Behçet
  • Vision loss
  • Aneurysm

• Mortality rates:

~5% over 7.7 years and ~9.8% over 20 years of follow-up.

• Poor prognostic factors:

• • Male sex (hazard ratio 4.94).

• • Arterial involvement (HR 2.51).

• • High frequency of flares (HR 2.37).

• Disability risks:

• • Neurologic Behçet’s → 25–60% risk of severe disability or death within 7–10 years.

• • Ocular Behçet’s → risk of blindness historically 25%, now closer to 13%.

• • Despite systemic severity, many patients experience decline in activity with age, and treatment advances (e.g., biologics, TNF inhibitors) have improved survival and reduced complications

• Depending on the extent of the disease at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as good.^[3]
• The worst prognoses are associated with retinal vasculitis, leading to blindness; vascular aneurysm formation, with possible rupture; and neuro–Behçet syndrome, which may lead to dementia despite appropriate aggressive treatment.

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