Behcet Disease

Etiology

The exact etiological basis of Behçet disease remains unknown, although genetic and environmental factors appear to contribute. Moreover, the increased prevalence of Behçet disease along the Silk Road and its familial aggregation suggest a genetic component, although the disease does not follow a Mendelian inheritance pattern.[6][7][8] The most important genetic association is with HLA-B51 carriers, who have a higher risk of developing Behçet disease than those without HLA-B51.[9][10][11][12][13][14]

Results from a systematic review of 78 studies showed that HLA-B51 was associated with an increased risk of Behçet disease, with an odds ratio of 5.80.[9] HLA-B51 is a common genetic factor that is prevalent in Middle Eastern, Turkish, and Japanese populations, but is somewhat less common in Central Asia, Southern Europe, and Brazil, and less common in Northern Europe and North America.[15] Patients with Behçet disease and HLA-B51 positivity have more severe disease than patients without HLA-B51.[14] 

HLA-B51 is also associated with ocular disease in several ethnicities, including Turkish,[12] Japanese,[11] and Italian populations.[14] Associations between HLA-B51 and other organ involvement vary among ethnic groups. Results from a multiethnic systematic review and meta-analysis of 72 studies showed that HLA-B51 was associated with male sex (odds ratio, 1.14), ocular involvement (odds ratio, 1.13), genital ulcers (odds ratio, 1.07), and skin involvement (odds ratio, 1.10).[16]

Results from a study of patients in Türkiye showed that HLA-B51 was associated with a younger age at disease onset, genital ulcers, ocular disease, neurologic involvement, and vascular involvement but not with other disease manifestations (Table 1). Men had an earlier disease onset, more frequent ocular, neurologic, and vascular involvement, and fewer genital ulcers.[12] Results from a large nationwide survey in Japan showed that HLA-B51 was associated with a slightly older age at disease onset, male sex, ocular involvement, and a lower risk of genital ulcers.[11]

Among 241 Italian patients with Behçet disease, 62.7% had HLA-B51. The HLA-B51:01 and HLA-B51:08 subtypes occurred at substantially higher frequencies of 44.8% and 16.2%, respectively.[14] Greater disease severity and ocular involvement were associated with HLA-B51, particularly these subtypes. Results from a study identified other HLA alleles among Saudi patients with Behçet disease, including HLA-A26 and HLA-A31, in addition to HLA-B51.[17]

Behçet disease is sometimes described as a major histocompatibility complex class 1–opathy, in which HLA-B51 and the ERAP1 gene contribute to altered antigen presentation and multiorgan inflammation.[15] Epigenetic mechanisms have been increasingly implicated in the pathophysiology of Behçet disease. Aberrant DNA methylation affects genes that regulate cytoskeletal dynamics and cell adhesion, and activating histone marks are overrepresented in multiple immune cell types, including natural killer cells, monocytes, lymphocytes, and neutrophils. [18]

Table 1. Clinical and Demographic Characteristics According to HLA-B51 Status in Türkiye And Japan                                                                        

Genetic associations with Behçet disease vary according to geographic region and ethnicity. Several other HLA alleles have been associated with Behçet disease, including HLA-B15, HLA-B27, HLA-B57, and HLA-A26, while HLA-B49 and HLA-A03 are protective alleles.[8] Non-HLA genes associated with Behçet disease include IL23R, IL12RB2, IL10, IL1A, IL1B, STAT4, IL12A, and ERAP1.[8][7] Results from studies identified several additional genes, including the TNF gene, heat shock protein genes, and major histocompatibility complex class I chain-related genes, although their independent contributions to the development of Behçet disease remain uncertain.[19] Table 2, Table 3, and Table 4 describe the other genes associated with the disease. 

Table 2. Genes Associated With Behçet Disease: Cytokines and Chemokines                

CCR1, C-C motif chemokine receptor 1 gene; CCR3, C-C motif chemokine receptor 3 gene; CD4, cluster of differentiation 4; IL, interleukin; IL1A, interleukin 1α gene; IL1B, interleukin 1β gene; IL1RL1, interleukin 1 receptor-like 1 gene; IL2, interleukin 2 gene; IL4, interleukin 4 gene; IL10, interleukin 10 gene; IL12A, interleukin 12 subunit α gene; IL12RB2, interleukin 12 receptor subunitβ 2 gene; IL17F, interleukin 17F gene; IL18R1, interleukin 18 receptor 1 gene; IL18RAP, interleukin 18 receptor accessory protein gene; IL23A, interleukin 23 subunit α gene; IL23R, interleukin 23 receptor gene; IL27, interleukin 27 gene; IL37, interleukin 37 gene; p19, interleukin 23 p19 subunit; SLC9A4, solute carrier family 9 member A4 gene; TGF-β, transforming growth factor β; TGFB1, transforming growth factor β 1 gene; Th1, T helper 1; Th2, T helper 2; Th17, T helper 17; TNF, tumor necrosis factor gene; TNF-α, tumor necrosis factor

Table 3. Genes Associated With Behçet Disease: Transcription Factors and Signaling Pathways

A20, tumor necrosis factor α-induced protein 3; ADO, 2-aminoethanethiol dioxygenase gene; CD4, cluster of differentiation 4 gene; CEBPB, CCAAT enhancer binding protein β gene; EGR2, early growth response 2 gene; ERAP1, endoplasmic reticulum aminopeptidase 1 gene; GIMAP, GTPase of immunity-associated protein; GIMAP4, GTPase, IMAP family member 4 gene; IL-6, interleukin 6; IL-17, interleukin 17; IL-23, interleukin 23; IRF8, interferon regulatory factor 8 gene; NF-κB, nuclear factor κB; NOD2, nucleotide-binding oligomerization domain containing 2 gene; PTPN1, protein tyrosine phosphatase nonreceptor type 1 gene; REL, REL proto-oncogene, NF-κB subunit gene; RIPK2, receptor-interacting serine/threonine kinase 2 gene; STAT4, signal transducer and activator of transcription 4 gene; Th1, T helper 1; Th17, T helper 17; TNF, tumor necrosis factor; TNF-α, tumor necrosis factor α; TNFAIP3, tumor necrosis factor α-induced protein 3 gene; TNFRSF, tumor necrosis factor receptor superfamily; TNFSF, tumor necrosis factor superfamily; TNFSF15, tumor necrosis factor superfamily member 15 gene; Treg, regulatory T cell

Table 4. Genes Associated With Behçet Disease: Other Genes

ABO, ABO blood group system; CNTN5, contactin 5 gene; CPVL, carboxypeptidase vitellogenic-like gene; FUT, fucosyltransferase; FUT2, fucosyltransferase 2 gene; GAS6, growth arrest-specific 6 gene; JRKL, JRK-like gene; KIAA1529, former symbol for the coiled-coil domain containing 180 gene (CCDC180); KIR, killer cell immunoglobulin-like receptor; KIR2DL4, killer cell immunoglobulin-like receptor, 2 immunoglobulin domains and long cytoplasmic tail 4 gene; KIR3DL3, killer cell immunoglobulin-like receptor, 3 immunoglobulin domains and long cytoplasmic tail 3 gene; KLRC4, killer cell lectin-like receptor C4 gene; LACC1, laccase domain containing 1 gene; LOC100129342, uncharacterized locus 100129342; NK, natural killer; NOD2, nucleotide-binding oligomerization domain containing 2 gene; NOS3, nitric oxide synthase 3 gene; PROS1, protein S gene; TAM, Tyro3, Axl, and Mer receptor tyrosine kinase family; UBAC2, ubiquitin-associated domain containing 2 gene; UBASH3B, ubiquitin-associated and Src homology 3 domain containing B gene. The updated designation for KIAA1529 is CCDC180.

Several genes associated with Behçet disease overlap with those associated with ankylosing spondylitis (including IL23R and ERAP1); psoriatic arthritis (including IL23R); and Vogt-Koyanagi-Harada syndrome (including IL17F and IL23A). Increased copy numbers of the C3 gene were associated with ocular Behçet disease and Vogt-Koyanagi-Harada syndrome, whereas increased copy numbers of the C5 gene were associated only with ocular Behçet disease.[24] Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome; recurrent aphthous stomatitis; and Behçet disease share genetic susceptibility involving IL10, IL23R-IL12RB2, IL12A, CCR1, CCR3, STAT4, and FUT2.[25] Results from studies identified polymorphisms in genes associated with autoinflammatory syndromes among patients with Behçet disease, including MEFV, NOD2, PSTPIP1, and TNFRSF1A. Potential epistatic interactions may occur between HLA-B51 and the MEFV gene, and the NOD2 gene may have a protective effect.[10]

Exposure to infectious agents, particularly enhanced delayed hypersensitivity to Streptococcus sanguinis antigens, has been implicated in a pathological role.[4][26][27][28] Although other infectious agents, including Staphylococcus aureus organisms, herpes simplex virus type 1, and Prevotella species, have been suggested as potential contributors, their direct association with the development of Behçet disease has not been confirmed.[29] Current evidence suggests that exposure to an infectious or external agent initiates an autoinflammatory response in genetically predisposed individuals.

Altered bacterial peptide presentation by HLA-B51 produces an inflammatory response and supports classifying Behçet disease as a major histocompatibility complex class 1–opathy.[15] Dysbiosis of the gut and oral microbiota may also contribute to the etiology of Behçet disease by activating innate immunity and triggering an inflammatory response.[4][26][30][31] Other proposed environmental triggers include histamine-releasing foods, poor oral hygiene, and stress.[18]

Epidemiology

Behçet disease is more prevalent along the ancient Silk Road from the Middle East across Central Asia to East Asia, including Korea, Japan, and northeast China.[3] In this geographic area, patients with Behçet disease are more likely to carry the HLA-B51 allele. The highest prevalence is in the Middle East and the Far East. Turkey has the highest prevalence of Behçet disease, at 420 per 100,000 persons. The prevalence in other countries includes Iran at 80 per 100,000, Saudi Arabia at 20 per 100,000, Israel at 15.2 per 100,000, China at 14 per 100,000, Japan at 11.9 per 100,000, southern Italy at 15.9 per 100,000, northern Italy at 3.8 per 100,000, United Kingdom at 0.64 per 100,000, and the United States at 5.2 per 100,000.[4]

Behçet disease usually affects young adults aged 20 to 40 years and is also seen less frequently in children.[32][33] Both sexes are equally affected by the disease; a male predominance is observed in Arab populations, while female predominance is evident in Korea, China, the United States, and some northern European countries. The disease has a more severe course in males and younger populations.[34] Most cases are sporadic, although familial clusters are also reported.[35] Genetic anticipation, defined as earlier disease onset in successive generations, has also been documented.[36]

Pathophysiology

Behçet disease is an autoinflammatory vasculitis that involves arteries and veins of all sizes. In the 2012 Chapel Hill classification of vasculitides, Behçet disease is classified as variable vessel vasculitis.[37] Unlike lesions associated with other vasculitides, vasculitic lesions in Behçet disease lack necrotizing vasculitis or giant cell formation. Venular involvement and pulmonary arterial aneurysm formation are unique to Behçet disease.[38] Furthermore, patients with Behçet disease lack specific autoantibodies, unlike patients with other autoimmune disorders, such as systemic lupus erythematosus. Behçet disease is sometimes referred to as a major histocompatibility complex class I–opathy, in which human leukocyte antigen B51 (HLA-B51) and variants in the endoplasmic reticulum aminopeptidase 1 gene (ERAP1) alter antigen presentation and promote multiorgan inflammation.[15] 

Cell-mediated immunity plays a significant role in the pathogenesis of this disease. Antigen presentation by HLA-B51+ antigen-presenting cells activates CD8+ cytotoxic T cells, which produce various proinflammatory cytokines, including IL-17, IL-18, and granulocyte-macrophage colony-stimulating factor. The proinflammatory cytokines have diverse effects, including neutrophil recruitment and activation.[13]

Patients with active disease have higher levels of activated CD8+ T cells in the peripheral blood than healthy individuals or patients with inactive disease.[39] Aqueous humor from patients with ocular involvement contains increased numbers of CD8+ T cells, and CD8+ T cells are the predominant source of IL-17 in skin lesions associated with Behçet disease.[40][41] The predominance of CD8+ T cells in affected tissues suggests an important role for these cells in the organ-specific manifestations of Behçet disease.[13]

Type 1 helper T cell activation leads to increased circulating levels of T-lymphocytes, accounting for various symptoms of Behçet disease. Levels of proinflammatory cytokines, including IL-1, IL-8, IL-12, IL-17, IL-37, and tumor necrosis factor, are elevated in Behçet disease and are thought to contribute to its pathogenesis. Elevated cytokine levels may also indicate disease severity.

Lesions associated with Behçet disease exhibit macrophage activation, neutrophil chemotaxis, and phagocytosis. Mucocutaneous lesions, including oral aphthae, skin pustules, and erythema nodosum, are thought to result from neutrophil hyperactivation, leading to a neutrophilic vascular reaction that causes tissue injury.[42] Circulating immune complexes contribute to the characteristic neutrophilic vascular reaction. Antiendothelial cell antibodies and endothelial cell dysfunction are also thought to contribute to the pathogenesis of Behçet disease.[43] 

Neutrophils constitute the main infiltrating cell type in Behçet disease lesions. By producing excessive levels of reactive oxygen species and releasing neutrophil extracellular traps, neutrophils contribute to the development of a procoagulant state. Oxidation of proteins, particularly fibrinogen, by reactive oxygen species and neutrophil extracellular traps has been linked to prothrombotic risk.[18][44] In addition, results from studies indicate that the nuclear factor of kappa light chain enhancer of B cells (NF-κB) proinflammatory pathway plays a pivotal role in immune-response signaling in Behçet disease. NF-κB intracellular signaling is upregulated in antigen-presenting cells, neutrophils, and Th1 and Th17 cells.

Histopathology

The histopathologic hallmarks of Behçet disease are vasculitis and thrombosis. Although Behçet disease is usually considered a neutrophilic perivasculitis, its complex immunoinflammatory nature accounts for variable histopathologic findings. Biopsy findings from mucocutaneous lesions show lymphocytic infiltration with immunoglobulin and complement deposition, dermoepidermal junction degeneration, and necrosis.[44]

Vasculitic lesions may involve arterial and venous vessels of any size, with a marked neutrophilic infiltrate often accompanied by mononuclear cell infiltration, endothelial cell swelling, and fibrinoid necrosis.[44] Results from a histopathologic study of cutaneous vasculitis in Behçet disease found that lymphocytic vasculitis was more common than leukocytoclastic vasculitis (31% compared with 17% among patients with cutaneous lesions), and the investigators suggested that Behçet disease should be considered a vasculitis-associated disease rather than a neutrophilic dermatosis.[45] Synovial fluid findings in Behçet disease show neutrophil-predominant leukocyte counts ranging from 300 cells/mm³ to more than 30,000 cells/mm³.[46]

History and Physical

While mucocutaneous lesions are the hallmark of Behçet disease, the most severe manifestations are uveitis, large-vessel, and neurological involvement.

Aphthae

Although mucocutaneous lesions are the hallmark of Behçet disease, the most severe manifestations include uveitis and large-vessel and neurologic involvement. Oral ulcers occur in 97% to 99% of patients with Behçet disease and often represent the initial clinical feature. The ulcers are usually painful, recurrent, and multiple and may involve the soft palate, hard palate, buccal mucosa, tongue, gingiva, lips, and tonsils. More than 90% of oral ulcers heal without scarring. Genital lesions occur in more than 80% of patients with Behçet disease. Genital ulcers are also recurrent. In contrast to oral ulcers, more than 70% of genital ulcers heal with scarring. Genital ulcers occur on the scrotum in men and on the vulva or vagina in women.

Cutaneous Manifestations

Several cutaneous manifestations occur in Behçet disease. Erythema nodosum-like lesions commonly affect the lower extremities. Erythema nodosum lesions associated with Behçet disease have a greater vasculitic component than idiopathic erythema nodosum or erythema nodosum from other causes.[47]

Superficial thrombophlebitis appearing as nodular lesions may be associated with deep venous thrombosis. Acneiform or pseudofolliculitis lesions are common but are nonspecific and may be indistinguishable from ordinary acne.[48] Other described cutaneous manifestations include pyoderma gangrenosum-like lesions, pustular vasculitic lesions, cutaneous small-vessel vasculitis, and Sweet syndrome–like lesions. A positive pathergy reaction is characterized by the formation of erythematous papules or pustules 24 to 48 hours after needle insertion and is considered highly specific for Behçet disease.[49] Although a positive pathergy reaction occurs in 60% to 70% of patients in Türkiye and Japan, the reaction is rarely observed among patients with Behçet disease in Northern Europe or the United States.[50]

Ocular Manifestations

The eye is the most frequently affected major organ in Behçet disease. Ocular involvement occurs in approximately 50% of patients and is much more common among men and younger patients.[18] Eye involvement is usually not the presenting feature of Behçet disease but typically develops within the first few years after diagnosis and rarely develops later if absent earlier in the disease course.[51] 

Relapsing, chronic, bilateral uveitis involving both anterior and posterior uveal tracts is common. Anterior uveitis causes ocular redness and photophobia, while posterior uveitis causes vision loss. Hypopyon uveitis is less common but is very severe because it almost always accompanies severe retinal disease. Retinal vasculitis may cause blindness in affected patients. Conjunctivitis and isolated anterior uveitis are rare.

Musculoskeletal Manifestations

Inflammatory, nonerosive, nondeforming arthritis occurs in 50% of patients with Behçet disease and is more common among patients with acneiform lesions.[52] Joint involvement usually presents as symmetric or asymmetric oligoarthritis, although monoarthritis and polyarthritis may also occur. Peripheral joint involvement and spinal or sacroiliac involvement are uncommon, which helps distinguish Behçet disease from HLA-B27–associated erosive sacroiliitis. The knees are the most commonly involved joints, followed by the ankles, wrists, and elbows.[53]

Vascular Manifestations

Involvement of arterial and venous vessels of all sizes is a hallmark of Behçet disease and occurs in 25% of patients, with a higher frequency among men. The most common vascular manifestations are superficial thrombophlebitis and deep venous thrombosis of the lower extremities. Rare manifestations include Budd-Chiari syndrome and vena cava obstruction. Embolization of these thrombi is rare because the inflammatory thrombi adhere tightly to the diseased endothelium. Arterial vasculitis may involve an artery of any size and may cause an aneurysm or occlusion. Aortitis and vasculitis involving the carotid, femoral, and popliteal arteries may occur. Pulmonary artery aneurysm formation is unique to Behçet disease and is the leading cause of death among patients with the disease.[54] 

Neurological Manifestations

Central nervous system involvement occurs in 5% to 10% of patients with Behçet disease. Parenchymal involvement accounts for 75% to 90% of neurologic disease, most commonly affects the brainstem, and produces cerebellar, pyramidal, and sensory signs and symptoms. Cerebrospinal fluid findings are sterile but may include elevated protein levels, cell counts, or both.

Nonparenchymal involvement, characterized by dural sinus thrombosis, occurs in 10% to 25% of patients and causes headaches and papilledema. Simultaneous parenchymal and nonparenchymal involvement, isolated cerebellar involvement, and cranial and peripheral nerve involvement are rare.[55] Neurologic Behçet disease includes acute and chronic progressive forms that differ in clinical presentation, treatment, and prognosis. Acute forms more frequently present with fever and elevated cerebrospinal fluid cell counts, whereas chronic progressive forms usually manifest with ataxia, dementia, sphincter disturbances, and confusion, along with large and extensive lesions and isolated brainstem atrophy on MRI. HLA-B51 positivity is associated with a 3.6-fold increased risk of relapse and worse event-free survival.[44][56] 

Gastrointestinal Tract Manifestations

Mucosal ulcerations resembling orogenital aphthae may occur in the terminal ileum, cecum, colon, and esophagus. Extensive ulceration, especially in the ileocecal region, may cause perforation. Inflammatory bowel disease may present with similar gastrointestinal tract manifestations and extraintestinal features, including uveitis, erythema nodosum, oral ulcers, inflammatory arthritis, and pyoderma gangrenosum. Clinicians should exclude inflammatory bowel disease before confirming a diagnosis of Behçet disease.

Other Systemic Manifestations

Cardiac manifestations include pericarditis, myocarditis, endocarditis, coronary artery vasculitis, and coronary aneurysms. Renal involvement is rare and may include serum amyloid A amyloidosis and glomerulonephritis. Epididymitis may also occur.

Evaluation

The diagnosis of Behçet disease is clinical and can be difficult because no pathognomonic laboratory findings exist. Inflammatory bowel disease, systemic lupus erythematosus, reactive arthritis, and herpesvirus infections may present with features that mimic Behçet disease and should be excluded. Laboratory findings are usually nonspecific and may include anemia of chronic disease, leukocytosis, and elevated inflammatory markers.

Diagnostic testing should be directed toward the involved organ and may include radiography and arthrocentesis to evaluate arthritis; CT to assess bleeding, thrombosis, and ischemia; angiography to evaluate aneurysms; and lumbar puncture to evaluate for meningitis. These investigations help exclude alternative causes of the clinical presentation. Clinicians should perform a thorough ophthalmic examination at the initial presentation to evaluate for ocular involvement and biopsy cutaneous lesions when needed to confirm the diagnosis.

Although several classification criteria have been published, clinicians should use them cautiously when establishing a diagnosis. The International Criteria for Behçet Disease (ICBD) were published in 2014.[57] The ICBD criteria are point-based and assign 2 points each for oral aphthosis, genital aphthosis, and ocular lesions and 1 point each for skin manifestations, including pseudofolliculitis and skin aphthosis; neurologic manifestations; vascular manifestations, including phlebitis, large-vein thrombosis, aneurysm, and arterial thrombosis; and positive pathergy test results, when performed. A score of 4 points or more is required to classify Behçet disease.[57]

Results from the original validation study involving 27 countries showed that the ICBD criteria had a sensitivity of 94% to 95% and a specificity of 91% to 92%.[57] Results from a subsequent Bayesian inference analysis confirmed a sensitivity of 97.6% (95% credible interval, 96.9% to 98.2%) and a specificity of 90.8% (95% credible interval, 89.4% to 92.1%) using a cutoff of 4 points or more. Notably, a cutoff of 5 points or more produced the highest diagnostic consistency with the International Study Group criteria (κ = .999) while maintaining a high sensitivity (97.5%) and specificity (99.6%).[58]

Treatment / Management

The 2025 European Alliance of Associations for Rheumatology (EULAR) recommendations for the treatment of Behçet disease include 5 overarching principles and 12 recommendations organized by organ involvement. Key overarching principles emphasize recognition of the relapsing-remitting disease course, individualized treatment based on disease activity and prognostic risk factors, an interdisciplinary approach, patient education, and shared decision-making.[59] The overall goal is to control inflammation promptly to prevent relapses and irreversible organ damage.[60]

Mucocutaneous Manifestations

Isolated oral and genital aphthae:

• Topical triamcinolone acetonide cream may be applied 3 to 4 times daily until ulcer-related pain resolves.[61]
• Topical sucralfate at a concentration of 1 g/5 mL may be applied 4 times daily with topical corticosteroids or as an alternative treatment.[62]
• Topical anesthetics are generally less effective than topical corticosteroids or sucralfate but may provide temporary relief.
• Anti-inflammatory mouthwashes may also be used for recurrent oral manifestations.[60]
(A1)

 Prevention of recurrent oral and genital ulcers:

• Colchicine 1–2 mg/day, in divided doses, is a first-line drug.
  • Doses ranging from 1.2 to 1.8 mg can be used when 0.5 mg tablets are unavailable.[63]
  • This is more effective for genital ulcers than for ulcer ulcers.
  • The medication has a narrow therapeutic index, and cytopenias are a significant adverse effect.
• Apremilast is titrated by 10 mg daily over 6 days to attain a maintenance dose of 30 mg twice daily.[64]
  • Apremilast is approved by the United States Food and Drug Administration for the treatment of oral ulcers associated with Behçet disease and is currently considered a second-line treatment.[60]
  • Results from the phase 3 randomized controlled RELIEF trial showed that apremilast significantly reduced the number of oral ulcers and pain compared with placebo among patients with active oral ulcers refractory to at least one previous nonbiologic agent.[65]
  • Apremilast is more effective in oral ulcers.
  • Adverse effects include nausea, diarrhea, and headache.
(A1)

Multiple lesions or isolated oral aphthae or genital ulcers that are refractory to the therapy mentioned above:

• Prednisone may be prescribed at 15 mg/d, reduced to 10 mg/d after 1 week, and tapered to complete treatment within 2 to 3 weeks.
  • Low-dose prednisone, such as 5 mg/d, may be prescribed for a prolonged period in patients with recurrent oral aphthae.

Disease refractory to the treatments described above:

• Azathioprine:
  • The initial dose of azathioprine is 50 mg daily.
  • The daily dose may be increased by 50 mg every 4 weeks as tolerated.
  • The target dose is 2.5 mg/kg/day.
  • A complete blood count (CBC) should be obtained every 2 weeks initially until the maximum required dose is achieved and then every 6 to 12 weeks.
  • A lower dose should be prescribed for patients with renal impairment.
  • Genetic testing for thiopurine S-methyltransferase is advised before starting therapy. Thiopurine S-methyltransferase deficiency increases the risk of severe, potentially life-threatening bone marrow toxicity from conventional doses of azathioprine or mercaptopurine.[66]
  • Azathioprine may be combined with tumor necrosis factor α (TNF-α) inhibitors, including infliximab, adalimumab, and etanercept.[67]
• Interferon:
  • Interferon alfa-2a and interferon alfa-2b are generally administered at 3 to 6 million units 3 times weekly.[68][69]
(A1)

Cutaneous Manifestations Other Than Erythema Nodosum and Pyoderma Gangrenosum

• Mild disease:
  • Colchicine may be prescribed at 1 to 2 mg daily in divided doses.
• Lesions unresponsive to colchicine:
  • Prednisolone may be prescribed at a dose of up to 40 mg/d initially, followed by a maintenance dose of 5 to 10 mg/d.

Erythema Nodosum

• Initial treatment consists of oral prednisone at 40 to 60 mg daily combined with azathioprine.
  • The initial dose of azathioprine is 50 mg daily.
  • The daily azathioprine dose may be increased by 50 mg every 4 weeks as tolerated.
  • The target dose is 2.5 mg/kg/day.
  • A CBC should be obtained every 2 weeks initially until the maximum required dose is achieved and then every 6 to 12 weeks.
  • The initial prednisone dose is administered for 1 month and then tapered gradually over 3 to 4 months.

Pyoderma Gangrenosum

• Extensive debridement is discouraged.
• Sterile saline or a mild antiseptic for wound care
  •  Mild, localized pyoderma gangrenosum:
    • Treatment includes a high-potency or superpotent topical corticosteroid or topical tacrolimus at a concentration of 0.03% to 0.3%.[70]
  • More extensive or rapidly progressing pyoderma gangrenosum:
    • Systemic glucocorticoids
      • Oral prednisolone at 0.5 to 1.5 mg/kg/d or an equivalent medication, with a maximum dose of 60 mg/d.
      • Intravenous pulse therapy with methylprednisolone at 1 g/d for 1 to 5 days can be started initially for very aggressive or painful disease.[71]
      • Glucocorticoids should be tapered and discontinued within 4 to 10 weeks, with close monitoring for continued improvement and adverse effects.
    • Systemic cyclosporine
      • Cyclosporine is an alternative for patients who cannot tolerate glucocorticoids or whose disease is unresponsive to glucocorticoids.[72]
      • Treatment is initiated at 4 to 5 mg/kg and subsequently tapered as tolerated.
      • Treatment is limited to less than 1 year because of adverse effects, such as hypertension and renal toxicity.
(B2)

Arthritis

• Initial treatment:
  • Colchicine may be started at 1 to 2 mg/day in divided doses.[73]
  • Nonsteroidal anti-inflammatory drugs may provide symptomatic pain relief.
• Uncontrolled disease with colchicine:
  • Prednisone may be initiated at 10 mg/d.
  • Low-dose prednisone, such as 5 mg/d or lower, may be prescribed when prolonged treatment is required.
• Refractory or persistent arthritis:
  • Treatment options include azathioprine, TNF-α inhibitors, or both.
• Disease refractory to the therapy mentioned above:
  • Treatment options include interferon alfa or methotrexate.[74]
  • Apremilast is also for refractory disease.[75][76]
(A1)

Gastrointestinal Tract Disease

• Mild disease: 5-Aminosalicylic acid derivatives are recommended as first-line treatment for mild gastrointestinal tract involvement.[44][60]
• Moderate to severe disease:
  • Treatment consists of glucocorticoids combined with azathioprine.
  • Prednisone is initiated at 0.5 to 1 mg/kg/d.[77]
    • The initial dose is continued for at least 1 month or until symptoms resolve.
    • The prednisone dose is then reduced to 10 mg/d over 2 to 3 months.
  • Azathioprine is initiated concurrently with prednisone.
    • The initial dose of azathioprine is 50 mg daily.
    • The daily dose may be increased by 50 mg every 4 weeks as tolerated.
    • The target dose is 2.5 mg/kg/day.
    • A CBC should be obtained every 2 weeks initially until the maximum required dose is achieved and then every 6 to 12 weeks.
(B3)

Refractory disease:

• TNF-α inhibitors are used when the disease does not respond to glucocorticoids combined with azathioprine.[78]
• Infliximab and adalimumab have been used successfully.
(A1)

Renal Disease

Minimal or mild nephritis:

• No specific therapy is indicated

Secondary amyloidosis:

•  Colchicine 1 to 1.2 mg daily

Ocular Involvement

Anterior uveitis:

• Initial treatment includes topical corticosteroids and cycloplegic agents, such as cyclopentolate 1%.[44]
• Systemic immunosuppressants (mainly azathioprine) should be considered in patients with poor prognostic factors, including young age, male sex, and early disease onset.[44]
• Growing evidence supports the use of TNF-α inhibitors in preventing recurrences of anterior Behçet disease uveitis.[44]
• Unresponsive to initial therapy:
  • Prednisone at a starting dose of 40 mg and may be tapered to discontinuation over one month.[79]
(B3)

Posterior uveitis:

• Initial therapy:
  • Combination of glucocorticoids and systemic immunosuppressants (azathioprine or cyclosporine) or biologics (TNF-α inhibitors, particularly infliximab or adalimumab)[44]
    • Prednisone is started at 1 mg/kg per day for one month and is tapered as tolerated.
    • Methylprednisolone pulse therapy at 1 g/day for 3 days may be used empirically to preserve vision.
    • The initial dose of azathioprine is 50 mg daily and is increased every 4 weeks to a target dose of 2.5 mg/kg/day, as tolerated.
    • A CBC should be obtained every 2 weeks initially until the maximum required dose is achieved and then every 6 to 12 weeks.
• Severe or refractory disease:
  • Infliximab and adalimumab have been used successfully.[80]
  • The initial dose of infliximab is 5 mg/kg at weeks 0, 2, and 6 and every 8 weeks thereafter.
  • Adalimumab is administered as a loading dose of 80 mg, followed by 40 mg 1 week later and 40 mg every 2 weeks thereafter.[81]
(B2)

Vascular Disease

Large artery disease:

• Induction therapy consists of high-dose glucocorticoids and cyclophosphamide, or a TNF inhibitor (particularly infliximab).[60]
• Patients with pulmonary or aortic aneurysms should be treated with high-dose glucocorticoids and cyclophosphamide or TNF-α inhibitors.
• Glucocorticoids and azathioprine should be considered for small aneurysms, and azathioprine may be used to maintain remission.
• Interventional or surgical procedures should preferably be performed when the disease is inactive.
• Peripheral arterial aneurysms require a surgical procedure or stenting unless they are small, asymptomatic, and associated with a low risk of rupture.

Venous thrombosis:

• Treatment of venous thrombosis associated with Behçet disease primarily involves immunosuppressants, whereas the role of anticoagulants remains controversial.
• Immunosuppressants are the cornerstone of treatment because Behçet disease represents a model of inflammation-induced thrombosis.
• Treatment options include glucocorticoids, sometimes combined with conventional immunosuppressants such as cyclophosphamide or azathioprine, or biologic agents such as TNF-α inhibitors.
• Anticoagulants combined with immunosuppressants, preferably cyclophosphamide or a TNF-α inhibitor, are recommended for extensive thrombosis of larger veins, particularly the vena cava, and for cerebral venous sinus thrombosis or intracardiac thrombi.[44]
• Anticoagulation may be recommended on a case-by-case basis for patients with dural sinus thrombosis associated with Behçet disease.
• For refractory venous thrombosis, recommended options include TNF-α inhibitors with or without conventional disease-modifying antirheumatic drugs or interferon alfa in selected patients. Emerging evidence supports the use of alternative agents, such as baricitinib, for multirefractory disease.[44]

Neurologic Disease

Acute parenchymal neurologic Behçet disease:

• Treatment consists of high-dose glucocorticoids, typically oral prednisone at 1 mg/kg/d, with or without intravenous methylprednisolone pulse therapy at 500 to 1000 mg/d for 3 to 7 consecutive days. Glucocorticoid treatment is followed by a slow taper and combined with an immunosuppressive agent. Azathioprine is usually the first-line immunosuppressant for moderate disease.[44]
• In patients with severe, persistent, or relapsing involvement, TNF-α inhibitors or cyclophosphamide should be started as soon as possible.[82] 
• Case series support the use of a TNF inhibitor as first-line treatment for severe or refractory neurologic Behçet disease.
• The 2025 EULAR recommendations encourage early use of monoclonal antibodies against TNF-α in patients with organ or life-threatening manifestations.[59]
• Methotrexate can be considered for treating chronic progressive forms.
• Mycophenolate mofetil can be an option for patients with major organ involvement who cannot tolerate azathioprine or are receiving warfarin.
• Results from observational reports supported the use of tocilizumab, and individual case reports described successful treatment with secukinumab.
• Cyclosporine should be avoided, even in patients who no longer have active neurologic involvement, because of its potential neurotoxicity.
• Results from one study showed that central nervous system symptoms developed in 25.5% of patients with Behçet uveitis who received cyclosporine compared with 3.3% of patients who did not receive cyclosporine.[83][84]

Nonparenchymal Neurologic Disease With Cerebral Venous Sinus Thrombosis

• Treatment consists of immunosuppressants with or without anticoagulants, as described in the Vascular Disease section.

Differential Diagnosis

Behçet disease is a clinical diagnosis. However, other diseases can mimic clinical features seen in Behcet disease, all of which should be ruled out before confirming a diagnosis of Behcet disease.

• Inflammatory bowel disease: The diagnosis of Behçet disease is clinical, and clinicians should exclude disorders that can mimic its manifestations before confirming the diagnosis. In addition to gastrointestinal tract involvement, inflammatory bowel disease (IBD) and Behçet disease share several clinical features, including oral ulcers, uveitis, inflammatory arthritis, erythema nodosum, and pyoderma gangrenosum. Colon biopsy findings may not adequately differentiate these diseases. However, sacroiliitis and axial inflammatory arthritis can occur in IBD but are uncommon in Behçet disease. Posterior uveitis and panuveitis are rare in IBD. Vascular inflammation leading to aneurysms, venous thrombosis, central nervous system involvement, and positive pathergy test results are features of Behçet disease rather than IBD. In the absence of these additional extraintestinal manifestations, differentiating the 2 conditions may be challenging.
• Seronegative arthritis: Reactive arthritis is another major differential diagnosis because it can also cause peripheral inflammatory arthritis, ocular inflammation, and skin disease. Similar to IBD, posterior uveitis and panuveitis are rare in reactive arthritis, and vascular or central nervous system involvement is also rare. Sacroiliitis and axial involvement are common in reactive arthritis but uncommon in Behçet disease. Urethritis, lesions of the glans penis, and conjunctivitis are features of reactive arthritis that are uncommon in Behçet disease.
• Systemic lupus erythematosus (SLE): SLE can have a clinical presentation similar to that of Behçet disease and may affect many of the same organs. However, inflammatory thrombi are not usually seen in SLE. Disease-specific autoantibodies associated with SLE may help differentiate the 2 conditions.
• Herpetic infections: Oral and genital lesions can occur. When appropriate, clinicians should obtain a culture from an active lesion to exclude herpesvirus infection before diagnosing Behçet disease.
• Behçet-type disease has been reported in patients treated with IL-17 inhibitors.[85]

Additional differential diagnoses depend on the organs involved and include sarcoidosis, other systemic vasculitides, relapsing polychondritis, and multiple sclerosis.

Prognosis

No curative treatment exists for Behçet disease, which is associated with significant morbidity and mortality. Male sex and a younger age at disease onset are associated with a poorer prognosis and higher mortality. Major causes of death include rupture of pulmonary and peripheral aneurysms and neurologic or gastrointestinal tract involvement. Renal involvement, especially amyloidosis, also carries a poor prognosis. However, more than 60% of patients achieve remission after the initial years of greatest disease activity. In addition, most patients eventually experience fewer disease flares and reductions in morbidity and mortality.

Complications

Complications of Behçet disease include:

• In addition to increased mortality, Behçet disease is associated with several potential lifelong complications, most of which result from ocular or neurologic involvement. Patients with hypopyon uveitis or retinal involvement have a high risk of permanent vision loss or blindness.
• Rupture of a coronary or pulmonary artery aneurysm is another potentially fatal complication of Behçet disease.
• Central nervous system involvement can lead to significant morbidity, permanent deficits, and death.
• Placental vasculitis may also increase the risk of miscarriage in patients with Behçet disease.