Dermatologic Aspects of Behcet Disease 

Updated: May 13, 2019
Author: Amira M Elbendary, MBBCh, MSc; Chief Editor: William D James, MD 

Overview

Background

Behçet disease (BD) was named in 1937 after the Turkish dermatologist Hulusi Behçet, who described the triple-symptom complex of recurrent oral aphthous ulcers, genital ulcers, and uveitis,[1] but it is likely that Behçet disease was already described years earlier by Hippocrates, who described a disease with aphthous ulcers and defluxion around genital area, associated with warty ophthalmic conditions.[2]

Behçet disease is a complex, multisystemic disease that includes involvement of the mucocutaneous, ocular, cardiovascular, renal, gastrointestinal, pulmonary, urologic, and central nervous systems, as well as the joints, blood vessels, and lungs.

Pathophysiology

The cause of Behçet disease is not known; however, immunogenetics, immune regulation, vascular abnormalities (including arterial and venous abnormalities, affecting small, medium, and large vessels), or bacterial and viral infection may have a role in its development.

Etiology

Immunogenetics[3]

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.

In a study of 57 Egyptian patients with Behçet disease, it was found that Behçet disease was associated with HLA-A*24 and HLA-B*42 and highly associated with HLA-A*68 and B*15 and B*51, while HLA-A*03 and B*52 were protective against Behçet disease.[4] HLA-B*51 and HLA-A*68 were associated with blinding eye disease and could be a poor prognostic factor for eye involvement. HLA-B*51 was protective from neurological and vascular involvement.

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.[5]

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.[6]

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.[7, 8]

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.[9]

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.[10]

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.[11]

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.[12] 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.[13]

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.[14]

An allele of the IL-10 gene locus (rs 1800872 A) was found in significantly high levels in Behçet disease patients compared with the control group, suggesting this allele could contribute to the genetic susceptibility for Behçet disease through expression and regulation of IL-10, levels of which were also found to be significantly high in Behçet disease patients.[15]

In one study, miRNA 155 expression was found to be significantly decreased with increased Behçet disease activity score. This may be used as a biomarker for Behçet disease remission when its level increases.[16]

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.

Herpes virus

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.[17]

Streptococcal infection

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.[18]

Salivary colonization with Streptococcus mutans was found in high rates in a study that included 106 Turkish patients with Behçet disease.[19] Marked improvement was noticed in Behçet disease patients who received benzathine penicillin with colchicine compared with patients who received colchicine only as a treatment.[20]

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.

Studies have demonstrated higher colonization of Streptococcus species at ulcer sites than in healthy controls and in patients with recurrent aphthous stomatitis.[21, 22] However, no specific microorganism has been proven to be a causative agent for Behçet disease.[23]

H pylori

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.[24]

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.

Immunological abnormalities

Chemotaxis, phagocytosis, superoxide, and lysosomal enzyme production are increased in patients with Beh ç et disease.[25]

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.[26] 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.[27] Notch blockade has shown inhibition in Th17 response, as it is involved in Th17 lymphocyte differentiation.[28]

IL-26, a proinflammatory cytokine, was found to stimulate CD4+ T cells and monocytes, promoting the generation of Th17 mediators (IL-17A and IL-23). IL-26 was found in high levels in the serum, bronchoalveolar lavage fluid, and cerebrospinal fluid of Behçet disease patients, which suggests a role for IL-26 and its generation of Th17.[29]

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.[30]

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.[31] 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.[32]

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.[33]

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.[34]

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.[35]

Plasma levels of vascular endothelial growth factor, a proinflammatory cytokine, is significantly higher in persons with active Behçet disease.[36]

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.[37]

Polymorphisms in toll-like receptor 4 have been associated with Behçet disease.[38]

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.[39]

Endothelial and vascular dysfunctions

Vascular changes leading to vasculitis and thrombosis are important pathological features of Behçet disease.

Abnormal angiogenesis

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.[40]

Endothelial dysfunction

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.[41]

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.[42]

Endothelial cell–dependent vasodilator function was significantly impaired in patients with Behçet disease, which can be demonstrated by high-resolution ultrasound imaging.

Hypercoagulable state

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.[43]

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.[44]

Decreased levels of antithrombotic factors, including fibrinolysis and activated protein C, are noted.[45]

Additional factors include decreased deformability of red blood cells[46] and increased platelet activity.[47]

However, thrombophilia in Behçet disease patients does not seem to be the major factor in the tendency to thrombosis[43] ; 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.[48]

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.[49]

The role of hormones

A meta-analysis of 14 studies that assessed 637 Behçet disease patients and 520 healthy controls found significant higher levels of circulating adiponectin and leptin and lower levels of visfatin in Behçet disease patients when compared with the healthy controls, suggesting that adipokines could have an important role in the pathogenesis of Behçet disease.[50]

In one study, 9 of 18 Behçet disease patients reported a correlation between menstruation and flares of the disease.[51] The most common manifestations that were correlated with menstruation were oral ulcers (89%), followed by arthralgia (56%), genital ulcers (44%), lethargy (44%), skin lesions (11%) and headaches (11%).

Epidemiology

Frequency

United States

Behçet disease is not common in the United States. The American Southwest has a prevalence of 8.9-10.6 cases per 100,000 population, with ethnic proportions of 49.2% Hispanic American, 31.7% European-American, 14.3% Native American, and 1.7% derived from Silk Road populations.[52]

International

A wide geographic variation is noted in the frequency of Behçet disease, with high prevalence in Mediterranean area compared with the United States and Northern Europe. Studies have shown that immigrants from areas with high prevalence rate of Behçet disease remain at high risk of developing Behçet disease.[53] Behçet disease is most prevalent (and more virulent) in the Mediterranean region, Middle East, and Far East, with an estimated prevalence of 1 case per 10,000 persons.

The prevalence reported in different countries is as follows[53] :

  • Turkey: 20-420 cases per 100,000 population

  • Iran: 16-68 cases per 100,000 population

  • Israel: 15-120 cases per 100,000 population

  • Iraq: 17 cases per 100,000 population

  • Egypt: 7.6 cases per 100,000 population

  • Spain: 7.5 cases per 100,000 population

  • Japan: 7-13.5 cases per 100,000 population

  • Martinique: 7 cases per 100,000 population

  • France: 7.1 cases per 100,000 population

  • Italy: 3.8-16 cases per 100,000 population

  • Northern Europe: 0.5-5 cases per 100,000 population

  • Korea: 26.7 cases per 100,000 population[54]

Sex

Men are affected more often, and with more severe disease, than women in some Mediterranean areas. In Iran, for example, the male-to-female ratio was 24:1 among 1712 patients. In Turkey, the ratio was 16:1 among 427 patients.

Age

Onset can occur at any age, but is it most common during the third decade of life.[55] Behçet disease rarely occurs in individuals older than 50 years or during childhood.[56] Genetic anticipation was reported in Behçet disease, in which the onset of the disease becomes earlier with successive generations.[57]

Mortality/Morbidity

Chronic morbidity is typical; the leading cause is ophthalmic involvement, which can result in blindness. The effects of the disease may be cumulative, especially with neurologic, vascular, and ocular involvement.

The mortality rate is low, but death can occur from neurologic involvement, vascular disease, bowel perforation, cardiopulmonary disease, or as a complication of immunosuppressive therapy.[58]

A 2014 study has shown that sub-Saharan African patients with Behçet disease had three times higher mortality compared with North African and European patients, with the 15-year mortality rate reaching 20%, compared with mortality rates of about 5-10% reported in other countries.[59]

Clinical expression of the disease also shows geographic variation. Sub-Saharan African patients show higher CNS and cardiovascular involvement compared with Behçet disease patients in North Africa and Europe.

Gastrointestinal manifestations and neurological involvement was found to occur at higher rates in American patients compared with Turkish patients.[59]

Higher rates of folliculitis were found in patients of Iraqi/Iranian origin, and ocular complications were found to be at higher incidence in patients of Arabic origin in a study done on 66 Jewish patients.[59]

In a Japanese nationwide registry that included 6627 Behçet disease patients, a 60/40 female predominance was noted, with a median age of 39 years.[60] Genital ulceration was more common in females, while ocular involvement was more common in males. Arthritis, ocular lesions, and vascular lesions were observed more in elderly patients, whereas epididymitis and oral ulceration were observed more in younger patients.

Prognosis

The clinical course of Behçet disease is variable, even in the early stages, making determinations of the long-term prognosis difficult.

Men appear to have a poorer prognosis.

The disease usually runs a protracted course, with attacks generally lasting for several weeks and recurring more frequently early in the disease.

Mucocutaneous and arthritic involvement usually occur early.

Chronic morbidity is usual; the leading cause is ophthalmic involvement, which can result in blindness. The effects of the disease may be cumulative, especially for neurologic, vascular, and ocular involvement.

Mortality is low, but patients may die from neurologic involvement, vascular disease, bowel perforation, cardiopulmonary disease, or as a complication of immunosuppressive therapy.

The risk of cancer was evaluated in a large cohort study including 1,314 patients with Behçet disease. Non-Hodgkin lymphoma, hematologic malignancies, and female breast cancer were the most frequent malignancies observed. The cancer risk was found to be highest within the first year of follow up.[61]  In a Korean cohort, newly diagnosed cancer was noted in 3.19% of Behçet disease patients during routine follow up, with a high incidence of leukemia, lymphoma, oral cavity and pharyngeal cancer, prostate cancer, and thyroid cancer.[62]

Vascular involvement is one of the major causes of morbidity and mortality in Behçet disease, especially in males from the Middle East and Eastern Mediterranean.[63] An association between cerebral sinus venous thrombosis and pulmonary artery involvement,[63] intracardiac thrombosis and pulmonary artery involvement,[64] Budd-Chiari syndrome, and inferior vena cava syndrome[65] were reported. Lower extremity vein thrombosis often accompanies these combinations and often occurs prior to the other vascular involvements.[66]

Patient Education

For patient education resources, see the Teeth and Mouth Center, as well as Canker Sores.

 

Presentation

History

Signs and symptoms of Behçet disease, which may be recurrent, may precede the onset of the mucosal membrane ulcerations by 6 months to 5 years.

Prior to the onset of Behçet disease, patients may experience a variety of symptoms, such as the following:

  • Malaise

  • Anorexia

  • Weight loss

  • Generalized weakness

  • Headache

  • Perspiration

  • Decreased or elevated temperature

  • Lymphadenopathy

  • Pain of the substernal and temporal regions

A history of repeated sore throats, tonsillitis, myalgias, and migratory erythralgias without overt arthritis is common.

A diagnosis of Behçet disease is based on clinical criteria because of the absence of a pathognomonic laboratory test. The period between the appearance of an initial symptom and a major or minor secondary manifestation can be up to a decade in many cases.

The number of different criteria or classification systems that have been introduced over the past 25 years reflects the failure of any single one to meet clinical demands. The revised 1987 criteria of the Japanese group (Mizushima) have been widely applied.[67]

The diagnostic criteria of the International Study Group for Behçet Disease have been applied to establish a firmer diagnosis. They are the most widely used criteria.[68]

The major limitation of these criteria is the fact that recurrent oral ulceration is the characteristic symptom for the diagnosis of Behçet disease. For example, patients with uveitis and genital ulcers, without oral aphthosis, would not be considered to have Behçet disease, although this is, in fact, a far-advanced form of the disease.

International Criteria for Behçet Disease (ICBD) have been proposed by a collaborative study of 27 countries and includes a wide variety of symptoms,[69] putting in consideration that pathergy testing and oral ulcers are not mandatory for the diagnosis of Behçet disease, but a sum of a wide variety of symptoms should be considered, which increases its sensitivity.[69]

Diagnostic criteria from the Behçet syndrome research committee of Japan (1987 revision)[67]

Major features are as follows:

  • 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

  • Genital ulcer

Minor features are as follows:

  • Arthritis without deformity and ankylosis

  • Gastrointestinal lesions characterized by ileocecal ulcers

  • Epididymitis

  • Vascular lesions

  • 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)[68]

Recurrent oral ulceration

Minor aphthous or major aphthous or herpetiform ulceration is observed by a physician or reported reliably by a patient, and it recurs at least 3 times in one 12-month period, plus 2 of the following:

  • 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[69]

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

Physical Examination

Oral ulcers

Oral aphthae that occur in patients with Behçet disease are indistinguishable from common aphthae (canker sores). They are one of the most frequent symptoms occurring in Behçet disease, with a frequency of about 97-100%.[70] Aphthae may be more extensive, more painful, more frequent, and evolve quickly from a pinpoint flat ulcer to a large sore. Lesions can be shallow or deep (2-30 mm in diameter) and usually have a central, yellowish, necrotic base and a punched-out, clean margin. They can appear singly or in crops, are located anywhere in the oral cavity, persist for 1-2 weeks, and subside without leaving scars.

The most common sites are the tongue, lips, buccal mucosa, and gingiva; the tonsils, palate, and pharynx are less common sites. The interval between recurrences ranges from weeks to months.

Oral ulcers can be classified into 3 types: minor, major, and herpetiform.

Minor ulcers are 1-5 small, moderately painful ulcers persisting for 4-14 days (see the image below).

Minor aphthous ulcer. Minor aphthous ulcer.

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).

Major aphthous ulcer. Major aphthous ulcer.

Herpetiform ulcers are a recurrent crop of as many as 1000 small and painful ulcers (see the image below).

Herpetiform oral ulcer. Herpetiform oral ulcer.

In patients with recurrent aphthous ulcers, minor trauma such as eating foods with a rough texture, brushing teeth, and chewing gum may trigger the development of a new aphthous lesion.[71]

Genital manifestations

Genital ulcers resemble their oral counterparts but may cause greater scarring. They have been found in 56.7-97% of cases, but their appearance is mostly a secondary symptom that accompanies oral ulcers. In males, the ulcers usually occur on the scrotum (see the image below), penis, and groin.

A characteristic genital ulcer on scrotum. A characteristic genital ulcer on scrotum.

In females, they occur on the vulva (see the image below), vagina, groin, and cervix.

A single ulcer on vulva. A single ulcer on vulva.

The lesions start as a papule or pustules and evolve into painful ulcers. The ulcers have sharp, punched-out borders, with surrounding edema. Healing usually occurs within 2-4 weeks.[72] It was reported that ulcers smaller than 1 cm in diameter can cause scarring in about 49% of patients, while larger ulcers healed with scar in about 89% of cases. About 60% of ulcers in women located on the labia majora and inguinal region showed scar formation after healing.[73]

Ulcers have also been found in the urethral orifice and perianal area. Epididymitis may arise and is a minor diagnostic criterion for the disease according to the Behçet Disease Research Committee of Japan. An additional genital symptom is orchiepididymitis, observed in 10.8% of men.

Cutaneous manifestations

A variety of skin lesions may appear in patients with Behçet disease (58.6-97%).

Erythema nodosum–like lesions are noted in about half the patients with Behçet disease, more commonly in females. They present as erythematous painful nodules, usually located on the pretibial surface of the lower limbs, but they may occur on the arms and thighs.[74] Healing occurs with hyperpigmentation in about 6 weeks. Unlike erythema nodosum occurring with other diseases, lesions associated with Behçet disease often ulcerate, owing to the underlying medium-vessel vasculitis.[75] See the image below.

A retrospective study in Tunisia that included 213 Behçet disease patients revealed that patients with erythema nodosum–like lesions or neurological manifestations are prone to develop cardiac and vascular complications.[76]

Erythema nodosum–like lesions on skin. Erythema nodosum–like lesions on skin.

Papulopustular eruptions are observed in 30-90% of cases.[56] The acneiform lesions are composed of papules, pustules, and noninflammatory comedones. They are polymorphic in nature. Unlike acne vulgaris, the acneiform lesions are found commonly on the chest, back, and shoulders and less commonly on the face. See the images below.

Acneiform lesions in a Behçet disease patient. Cou Acneiform lesions in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
Acneiform lesions in a patient with Behçet disease Acneiform lesions in a patient with Behçet disease (an inflamed nodule and noninflammatory comedones). Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.

The mean age of development of these lesions is about 30 years. The international study group diagnostic criteria consider that postadolescent patients who develop acneiform lesions with no history of intake of systemic steroids are presenting a sign of Behçet disease. Most pustules are sterile, but coagulase-negative staphylococci and Prevotella species have been isolated from individual lesions. Papulopustular lesions are commonly associated with the presence of arthritis.[77] See the image below.

Papulopustular eruptions. Papulopustular eruptions.

Erythema multiforme–like lesions are a reported cutaneous manifestation.

Thrombophlebitis is noted commonly in males.[74] See the images below.

Superficial thrombophlebitis in a Behçet disease p Superficial thrombophlebitis in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
Postphlebitic limb in a Behçet disease patient. Co Postphlebitic limb in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.

Extragenital ulcers are rare but are reported to occur in axillary, inframammary, and interdigital areas of the feet.[78] Cutaneous ulcers affect approximately 3% of Behçet disease patients and are usually recurrent.[78] Necrotic ulcerations of fingers and toes with underlying necrotizing vasculitis have been reported.[79]

Other cutaneous lesions include subungual infarcts, palpable purpura, and erythema multiforme–like lesions. The presence of HLA-b51 and other signs of Behçet disease help establish the diagnosis.[80]

Lesions resembling Sweet syndrome are seen in about 4% of cases of Behçet disease.[74] See the image below.

Sweet syndrome–like lesion. Sweet syndrome–like lesion.

Bullous necrotizing vasculitis and pyoderma gangrenosum are reported.

Pathergy is nonspecific skin inflammatory reactivity that is observed to occur following any scratches or intradermal saline injection. The puncture site becomes inflamed and develops a small sterile pustule from hyperactivity of the skin to any intracutaneous insult. The pustular reaction of the skin is thought to denote increased neutrophil chemotaxis.

Higher positivity (84-98%) is found in Mediterranean areas and the Middle East than in the Far East (40-70%), with Western countries having significantly lower positivity than the other regions.[81] Surgical interventions in these Behçet disease patients may result in severe and nonspecific inflammatory reactions.[82] See the image below.

Typical positive pathergy reaction at injection si Typical positive pathergy reaction at injection site.

Abnormalities in nail fold capillaries can be seen using nail fold capillaroscopy in Behçet disease patients, mainly capillary dilatations and microhemorrhages.[83] They were noted in 75% of patients in a study that included 33 patients with Behçet disease.[84] and in 40% of Iranian patients in a study that included 128 Behçet disease patients.[85]

Uncommon skin manifestations may include perniolike lesions, neutrophilic eccrine hidradenitis, ulcus cruris, and Kaposi sarcoma.[86]

Lesions often occur in combination (eg, erythema nodosum–like lesions and papulopustular eruptions). Follicle-based pustules or acne lesions are not considered specific lesions of Behçet disease.

Ocular manifestations

Ocular involvement is the major cause of morbidity and the most dreaded complication because it occasionally progresses rapidly to blindness. It is reported in 47-65% of patients with Behçet disease, with more aggressive forms and high rates of blindness reported in Turkey compared with the American patients, in whom blindness is a rare complication of uveitis.[87] Childhood-onset Behçet uveitis is more common in males.[88]

Anterior uveitis presents mainly with photophobia and may progress to hypopyon.

Posterior uveitis (retinal vasculitis) is reported. Involvement of the retina may be severe, with papilledema, retinal exudates, and hemorrhages, and it may lead to blindness if therapy is delayed.

Panuveitis may occur. Involvement of the entire uveal tract was found to be the most common ocular lesion in a study that included 880 Turkish patients.[89]

Iridocyclitis, chorioretinitis, scleritis, keratitis, and optic neuritis are also reported ocular manifestations.

Retinal vein thrombosis can occur and lead to sudden blindness.

Ocular surface lesions in the form of dry eye syndrome, conjunctival lesions, and corneal ulceration have all been reported as ocular manifestations in Behçet disease patients.[90]

See the image below.

Ocular involvement showing posterior uveitis. Ocular involvement showing posterior uveitis.

Saadoun et al found that cerebral venous thrombosis (CVT) was present in 7.8% of a large cohort of patients with Behçet disease. The main complication of CVT was severe visual loss from optic atrophy. Papilledema and concurrent prothrombotic risk factors were independently associated with the occurrence of sequelae; peripheral venous thrombosis and concurrent prothrombotic risk factors were associated with relapse of thrombosis. Anticoagulant therapy proved safe and effective in up to 90% of patients.[91]

Vascular involvement

Vascular involvement is a common complication in Behçet disease, affecting about 40% of patients and making the prognosis for Behçet disease worse. It affects mainly young men.

Vascular involvement includes both the venous and arterial systems, affecting all sizes of vessels (large, medium, and small).[92]

Arterial system

Arterial involvement occurs in about 2-17% of patients with Behçet disease.[92]

Aneurysm is the most serious arterial complication. It affects large vessels, including the aorta (thoracic and abdominal) and pulmonary, femoral, iliac, and peripheral arteries. Rupture of a pulmonary artery aneurysm may present with hemoptysis and can be fatal, making the early diagnosis and treatment of vascular complications vital.

Arterial stenosis may manifest clinically as medial thickening, along with perivascular round cell infiltration found histologically. Depending on the site, different clinical presentations occur. Hypertension can originate from renal artery stenosis. Femoral artery stenosis and intermittent claudication cause avascular necrosis of the femoral head.

Arterial occlusion may be caused by thrombosis or progression of stenosis. Pulseless disease can result from subclavian artery occlusion. Atherosclerosis is not increased in Behçet disease.[93]

Arteritis may occur. Pulmonary vasculitis can produce dyspnea, chest pain, cough, or hemoptysis. Aortitis is a rare serious complication. Aortic regurgitation has been reported as a result of aortitis that causes sinus of Valsalva dilatation. Patients with Behçet disease undergoing valve replacement were reported to have complications from valve detachment compared with other patients.[94] Coronary artery vasculitis may cause acute myocardial infarction, but this is rare.[93]

See the images below.

Radial artery aneurysm with its effect distally on Radial artery aneurysm with its effect distally on index finger in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.
CT angiogram showing pulmonary artery aneurysm in CT angiogram showing pulmonary artery aneurysm in a Behçet disease patient. Courtesy of Mohanad Elfishawi, MD, Rheumatology Department, Cairo University.

Venous system

Venous involvement is noted in about 40% of patients. Superficial and deep venous systems are affected.[92]

Superficial and deep veins of the lower limbs are the most frequently affected. Involvement of large vessels, including the superior vena cava, inferior vena cava, deep femoral vein, subclavian vein, cerebral veins, and pulmonary veins, accounts for one third of venous thrombosis in Behçet disease patients. Budd-Chiari syndrome, is a very serious complication that increases the mortality rate 9 times.[92] Recurrent superficial and deep venous thrombosis in the lower extremities may be complicated by postthrombophlebitic syndrome.[95] Although thrombosis is a common complication in Behçet disease, the strong adherence of the thrombus to the vessel makes the frequency of thromboembolism in these patients very low.[56]

Chronic venous disease in Behçet patients is more common in men, frequently bilateral disease, with earlier age of onset of thrombosis. A severe disease course is common, and 51% of Behçet disease patients develop severe postthrombotic syndrome, while 32% develop venous claudication. These complications occur in 8% and 12%, respectively, in patients with venous disease who do not have Behçet disease.[96]

Cardiac involvement

Cardiac complications occur in about 6% of patients with Behçet disease. Involvement of all layers of the heart is noted. It includes pericarditis, increased thickness of epicardial fat, myocardial lesions including myocarditis, myocardial fibrosis and infarction, and endocardial involvement including aortic and mitral regurgitation and intracardiac thrombosis.[92]

Cardiac and pulmonary inflammatory masses have been reported and may mimic metastatic disease.[97]

Gastrointestinal involvement

The clinical spectrum of gastrointestinal effects[98] is enormously varied and occurs in more than 10% of patients with Behçet disease. Gastrointestinal involvement is noted in one third of Behçet disease patients in Japan, whereas it is less frequent in the Mediterranean area.[56] Anorexia, vomiting, dyspepsia, diarrhea, abdominal distention, and abdominal pain all may occur. Terminal ileum and ileocecal regions were reported to be frequently complicated by deep penetrating ulcers, ischemic infarctions, and thrombosis; these symptoms may mimic those of inflammatory bowel disease.[99]

Joint manifestations

More than half the patients develop signs or symptoms of synovitis, arthritis (asymmetrical, nonerosive, and nondeforming), and/or arthralgia during the course of the disease.[100] The most frequent minor feature in childhood-onset Behçet disease is reported to be arthritis, occurring in 11 of 40 patients. Multiple-joint involvement is common. Clinical features have been reported as pain, tenderness, swelling, limitation of joint movement, warmth, and morning stiffness.

Neurologic manifestations

The rate of neurologic involvement in persons with Behçet disease varies from 3.2-49% according to the reports of different populations. It is more frequent in men aged 20-40 years.[101] Neurological involvement can be parenchymal and nonparenchymal.

Parenchymal involvement includes brain stem involvement manifesting as cranial neuropathy, ophthalmoparesis, and cerebellar or pyramidal dysfunction. It also includes cerebral hemisphere involvement manifesting as hemiparesis, hemisensory loss, seizures, encephalopathy, dysphasia, psychosis, and cognitive dysfunction.[101] Finally, it includes spinal cord involvement presenting by sensory, motor, or sphincter dysfunction. Pseudotumoral brain lesions have been noted.[102]

Nonparenchymal affection includes intracranial and extracranial aneurysms and cerebral venous thrombosis. It carries a better prognosis than that of parenchymal affection.[101]

Neurologic involvement is one of the most serious complications, leading to severe disability and a high fatality rate. Neurologic manifestations usually occur within 5 years of disease onset. Severe headache is the most frequent initial neurological symptom.

Carpal tunnel syndrome can occur in Behçet disease patients as a result of inflammation of tendons, connective tissue, and vessels. It is reported in about 0.8% of patients with Behçet disease.[103]

Neuropsychiatric involvement

This affects a minority of patients, about 2%.[104] Symptoms such as hypersomnia, bipolar disorder, and acute psychosis have been reported, and some reports relate it to exacerbation of the disease. It may occur as a result of the associated neuroinflammatory process that occurs during disease activity.

A study showed that about 59% of patients with Behçet disease experience poor sleep quality often related to the depression, anxiety, painful genital ulcers, and arthritis present in Behçet disease patients.[105]

Pregnancy-associated manifestations

Estrogen and progesterone exert an immunomodulatory effect on pregnant women with Behçet disease, typically making the disease activity regress during pregnancy.[106] However, a paradoxical disease flare was reported in about 8% of pregnant patients with Behçet disease in one study, occurring mainly in the first trimester.[107]

Exacerbations mostly occur in the form of recurrent oral and genital ulcer.[108]

Hypercoagulability in pregnancy may increase the vascular complications, mainly the thrombotic complications. Budd-Chiari syndrome and cerebral venous thrombosis have been reported in pregnant women with Behçet disease.[109]

Fetal complications can include intrauterine growth restriction and miscarriage, reportedly mostly related to impaired function of vascular endothelial cells.[110]

The rate of cesarean delivery and medical termination of pregnancy was found to be higher in pregnant women with Behçet disease compared with other pregnant patients.[110]

Close follow-up is necessary to monitor the health of the mother and baby.

Childhood disease

Childhood Behçet disease is not uncommon; it accounts 3.3-26% of patients with Behçet disease. A large cohort study in Iran included 6500 patients and showed that 5.1% of patients had disease onset at age ten 10 years and 25.3% at age 11-20 years.[111] The disease may start as early as the neonatal period, and this usually occurs in children of mothers with active Behçet disease during pregnancy.[112] The neonatal form presents mainly with mucocutaneous manifestations that regress in the first months of life but may have a more prolonged course (>1 y).

Childhood Behçet disease differs in presentation, with girls having more genital ulcers and boys experiencing more eye and neurological complications.[113]

A family history of Behçet disease is noted in 9-30%[114] and 42% in a Turkish study.[115]

Recurrent mouth ulcers are the first manifestation of the disease in 87-98% of cases,[114] with an average age of onset of 7.4 years. They present mainly on the lips, cheeks, tongue, and lips. They should be investigated to eliminate other causes of recurrent mouth ulcers.

Genital ulcers are the second most common sign after mouth ulcers (60-83% of patients). They often appear after puberty, more frequently among girls[114] and usually affect the vulva. In males, the scrotum, penis, and perianal region are affected. Deep ulcers may leave scars on after healing.[116]

Skin lesions are noted in about 92% of patients, starting on average at age 13 years. Pseudofolliculitis (40-60%) and erythema nodosum (40%) are the most frequently seen cutaneous manifestations. Necrotic pseudofolliculitis occurs mainly in males.[114]

Ocular involvement affects 60% of children with Behçet disease.[114] The predominant ocular disease in children is panuveitis.[117] Anterior uveitis frequently occurs before age 1- years.[115] Retinal vasculitis and retinitis more readily affect older adolescents (16-20 y) but have a better prognosis than that in adults.[117]

Neurological involvement includes headaches, which are common. Cerebral venous thrombosis[118] and paralysis of cranial nerve VI, which may cause diplopia, are reported frequently. Behavioral disorders and problems learning in school are reported complications.[119]

Other organ manifestations

Cases with renal involvement, such as mild asymptomatic glomerulonephritis, have also been reported. Mediastinal lymphadenopathy, pleural effusions, and pericardial effusions may be observed.[120]

 

DDx

Diagnostic Considerations

Crohn disease has overlapping features with Behçet disease, namely gastrointestinal, cutaneous, articular, ocular, and cardiac manifestations.[121] The combination of arterial aneurysms and venous thrombosis should raise the suspicion of a diagnosis of Behçet disease. Finding a single or a few, large, discrete, and round or oval ulcerations in the ileocecal area also suggests Behçet disease. In Crohn disease, longitudinal ulcers (defined as ≥4-5 cm) in a discontinuous distribution, cobblestone appearance, and/or small aphthous ulcerations arranged in a longitudinal fashion are usually found. Histologic findings also help in distinguishing both entities.

Differential Diagnoses

 

Workup

Laboratory Studies

Mild anemia and leukocytosis are observed in some patients with chronic disease.

The erythrocyte sedimentation rate, C-reactive protein value, and other acute phase reactants may be elevated during the active stage of Behçet disease, but they do not correlate well with the clinical activity.

An increase in alpha-2 globulins is often observed. Serum immunoglobulin levels, especially immunoglobulin A, may be elevated.

Circulating immune complexes are often present.

Rheumatoid factor and antinuclear antibodies are absent.

Antineutrophil cytoplasmic antibody and antiphospholipid antibody test results are usually negative.

Human leukocyte antigen (HLA) typing can be performed as patients with the HLA-B51 allele have a significantly higher risk of developing Behçet disease.

Lumbar puncture for cerebrospinal fluid analysis can be performed when neuro-Behçet syndrome is suspected. In cases of parenchymal neuro-Behçet syndrome, the spinal fluid demonstrates elevated protein levels and a neutrophilic pleocytosis, which may later show transition to a lymphocytic predominance.

Positive pathergy test

The testing methodology varies in different institutions. However, the most common method is using a 20- to 26-g needle and performing 4-6 intradermal punctures in the flexor region of the forearm at an angle of 45º and reading the site at 48 hours.[122] The reaction is considered positive if an erythematous papule forms, sometimes topped with a sterile pustule greater than 2 mm in diameter. In smaller lesions and suspicious cases, histopathologic examination can help. An inflammatory infiltrate with predominant perivascular mononuclear cells and mast cells are typical findings. Neutrophilic vasculitis may be present.[122]

Imaging Studies

Echocardiography is important to exclude the presence of cardiac thrombi, which carry high morbidity and mortality if not diagnosed early. Right atrial and ventricular thrombi respond well to aggressive anti-inflammatory therapy.

In a study of 63 Behçet disease patients with cardiac involvement, the most common findings noted were prolapsed valves with aneurismal changes, echo-free spaces within the annulus, and vegetationlike lesions. The second most common form of involvement was aortic lesions in the form of aortic aneurysm or dilatation, or aortic pseudoaneurysm. Other findings included pulmonary aneurysm, coronary arterial pseudoaneurysm, and pericardial effusion.[123]

Magnetic resonance imaging (MRI) is the criterion standard for the diagnosis of neuro-Behçet disease. The MRI findings are dependent on the part affected: whether it is parenchymal or nonparenchymal.

Histologic Findings

The etiology and pathogenesis of Behçet disease remain obscure, although many reviews describe a lymphocytic vasculitis.

Vasculitis is thought to affect vessels of all sizes; the various skin lesions are thought to be secondary to small vessel vasculitis.

The histopathology is variable, dependent upon the type of lesion. Pathergic lesions are characterized by a heavy neutrophilic infiltrate without fibrin within the vessel walls. Folliculitis, acneiform lesions, and dermal abscesses have been described in Behçet disease.

The erythema nodosum–like lesions show a perivascular lymphocytic infiltrate of lymphocytes in the deep dermis and septa with a lymphocytic vasculitis but lack the histiocytic granulomas of typical erythema nodosum.

The aphthous ulcers have a nonspecific pathology with a variable infiltrate of lymphocytes, macrophages, and neutrophils at the base of the ulcer.

T-cell subsets with a preponderance of helper-inducer cells over T suppressor-cytotoxic cells have been observed in lesions.

Electron microscopic observations

Examination of erythema nodosum–like lesions shows microvascular changes and lymphocyte-mediated fat cell lysis. Additionally, small dermal blood vessels embolized by thrombi are observed at the sites of the needle prick reaction (pathergy) and at the erythema nodosum–like lesions.

The early changes in fat cells may be caused by vascular changes brought about by the specific degeneration of endothelial cells and vascular stenosis associated with the delayed-type hypersensitivity reaction.

Other Tests

Capsule endoscopy was evaluated in a case control study that included 19 patients with intestinal Behçet disease   and may have diagnostic value in patients with intestinal involvement.[124]

Bone scintigraphy for Behçet disease patients presenting with nonspecific arthralgia without significant signs was found to be of value in assessing joint involvement and specifying the sites of involvement.[125]

 

Treatment

Medical Care

Behçet disease is a multisystem disease, and treatment requires collaboration between different specialities to prevent irreversible organ damage.

The European League Against Rheumatism (EULAR) has developed recommendations for managing patients with Behçet disease, based on best-evidence–based trials in the literature and expert opinion from physicians experienced in managing Behçet disease.[126]

Oral and genital ulcers

The patient should dissolve the contents of a 250-mg tetracycline capsule in 5 mL of water or flavored liquid and hold the solution in his or her mouth for approximately 2 minutes before swallowing. This is repeated 4 times daily.

Topical corticosteroids are effective for oral or genital ulcerations if they are applied during the prodromal stage of ulceration.

Other useful drugs include lidocaine gel (2%), sucralfate suspension, and 5% amlexanox.

Twice-daily usage of topical 0.2% hyaluronic acid gel improved inflammation and healing periods and reduced oral ulcers.[127]

Intralesional glucocorticoids may be used for major aphthous ulcers. Triamcinolone 5-10 mg/mL may be used.

Insufficient response may require systemic treatment. Colchicine could be used in such cases, and resistant cases may require systemic glucocorticoids. In resistant cases, azathioprine, thalidomide, and tumor necrosis factor (TNF)–alpha antagonists (infliximab or etanercept) are reported to be effective. Infliximab and etanercept have steroid-sparing effects and have decreased the frequency of attacks in patients with Behçet disease.[128]

A patient with Behçet disease presenting with oral ulcers resistant to prednisone, azathioprine, colchicine, dapsone, and cyclosporin responded well to lenalidomide.[129]

A case of Behçet disease resistant to prednisone, cyclosporin, azathioprine, infliximab with methotrexate, and colchicine has been successfully treated with anakinra.[130]

There are no specific recommendations from EULAR regarding oral and genital ulcers, except for considering local corticosteroid therapy as a first-line treatment.

Acneiform lesions could be managed similarly to acne vulgaris.

In a single patient previously diagnosed with Behçet syndrome with recurrent oral aphthous ulcers, quadruple therapy (proton pump inhibitor, bismuth, tetracycline, and metronidazole), for histologically positive H pylori determined by upper gastrointestinal endoscopy, reduced the development of new ulcers and the frequency of recurrent attacks for less than 1 month. Breath testing for H pylori was negative in the first month after discontinuation of therapy.[131]

Erythema nodosum–like lesions are reported to respond well to colchicine, and that is what EULAR recommends. In cases with a delayed response, glucocorticoids and other immunosuppressive treatments may be used to prevent the progression into ulceration

Ocular involvement

The goal of treatment in cases of ocular involvement is to suppress the inflammation and prevent recurrent attacks that eventually result in irreversible damage and visual loss.

EULAR recommendations for any Behçet disease patient with eye involvement that includes the posterior segment should include azathioprine and systemic glucocorticoids. In refractory cases, EULAR recommended the use of infliximab in combination with azathioprine or systemic glucocorticoids or interferon-alfa with or without glucocorticoids.

Intravenous methylprednisolone (1 g/day) for 3 days may be used as initial therapy in sight-threatening conditions.[132]

FK506 (tacrolimus) has been particularly noteworthy. The Japanese FK506 study group reported that FK506 was effective in treating refractory uveitis in a dosage-dependent manner.[133] Adverse effects were renal impairment (28.3%), neurologic symptoms (20.8%), gastrointestinal symptoms (18.9%), and hyperglycemia (13.2%). The study group also noted the need for further clinical investigations on FK506 before more widespread application.

A patient with Behçet disease with ocular involvement, dependant on corticosteroids and refractory to azathioprine, showed improvement with the addition of pentoxifylline.[134]

Case reports describe treatment of patients with recalcitrant disease or those in whom conventional immunosuppressive agents have failed.[135, 136, 137, 138, 139] Pediatric case responding to infliximab has been reported.[140] Infliximab has resulted in responses after etanercept failed.[141] Infliximab infusions of 5-10 mg/kg have been used with variable dosing schedules. Infliximab infusions, at a starting dose of 5 mg/kg, have been beneficial in Behçet disease patients with ocular involvement who were unresponsive to standard immunosuppressive therapy.[142]

Tuberculosis was a reported adverse effect of infliximab infusion in one Behçet disease patient.[136]

Several patients not responding to infliximab have been treated with adalimumab.[143]

Observational studies revealed that interferon-alfa and monoclonal anti–TNA-α antibodies had beneficial results for refractory uveitis.[144]

Vascular involvement

Based on the fact that vein thrombosis in Behçet disease results mainly from inflammation in the vessel wall, EULAR recommends immunosuppressive drugs such as corticosteroids, azathioprine, cyclosporine, or cyclophosphamide in the management of acute deep venous thrombosis.

As the thrombus is adherent to the vessel wall, the use of anticoagulation is controversial and is not recommended.

Meta-analysis of case-control studies showed that deep venous thrombosis recurrence rate was significantly decreased with immunosuppressives compared with anticoagulants.[144]

Thrombosis of the superior vena cava or Budd-Chiari syndrome may require a potent immunosuppressive agent such as monthly pulses of cyclophosphamide.

Arterial aneurysms are treated with immunosuppressives followed by surgery to prevent recurrence. Surgery carries a very high risk in cases of pulmonary aneurysms, and treatment with potent immunosuppressives such as high doses of glucocorticoids or monthly pulses cyclophosphamide was found to yield better outcomes.

Cardiac involvement

Pericarditis has been treated with immunosuppressive agents and aspirin.[145] Myocardial involvement has been treated with high doses of prednisone with aspirin. Cardiac inflammatory masses and thrombi may also require immunosuppressive drugs together with anticoagulant therapy. Great caution should be used when administering antithrombotic therapy, owing to the risk of bleeding from asymptomatic pulmonary aneurysms.[146, 147]

Gastrointestinal involvement

Deep penetrating ulcers are treated first with immunosuppressive drugs unless emergency surgery is indicated. Azathioprine as maintenance therapy has been reported to decrease recurrence rates. In refractory cases, TNF-alpha antagonists and thalidomide have been reported to be effective.

Neurological involvement

EULAR recommendations for patients with parenchymal involvement include corticosteroids, azathioprine, cyclophosphamide, methotrexate, TNF-alpha antagonists, and interferon-alfa. In cases of dural thrombosis, corticosteroids are recommended.

Cyclosporine is best avoided, owing to its neurotoxic effects. Meta-analysis of case-control studies showed an increased risk of developing nervous system involvement with ciclosporin-A.[144]

Joint involvement

The use of nonsteroidal anti-inflammatory agents yields satisfactory results. Colchicine is beneficial. Intramuscular corticosteroid depot injections have not shown satisfactory results.

Tumor necrosis factor-alpha inhibitors in severe and refractory disease

The outcomes of tumor necrosis factor-alpha inhibitor use in Behçet disease was evaluated in a multicenter study that evaluated the outcome of infliximab (62%) and adalimumab (30%) in 124 Behçet disease patients. A response was achieved in 90.4% in patients with severe/refractory mucocutaneous ulcers and ocular, gastrointestinal, central nervous system, and cardiovascular manifestations. The lowest achieved remission rate was observed in patients with cardiovascular manifestations (66.7%). No significant difference was noted when these agents were used as monotherapy or when combined with conventional immunosuppressive therapy.[148]

Life-threatening pneumonia was reported in a Behçet disease patient with myelodysplastic syndrome following infliximab therapy,[149] whereas another case of chronic progressive neuro–Behçet disease was reported to improve with infliximab.[150]

The second Japanese consensus of intestinal Behçet disease in 2014 suggested that TNF-α inhibitors such as infliximab and adalimumab should be considered as standard therapy for intestinal Behçet disease.[151]

Surgical Care

Surgical therapy becomes necessary in serious conditions, including the following:

  • Gastrointestinal perforation

  • Enterocutaneous fistula formation

  • Spontaneous arterial aneurysm formation

  • Thrombotic obstruction in large-caliber vessels

  • Cardiac involvement

Proper timing for surgical treatment is important. Delayed wound healing or inflammation at operative sites may be related to pathergy.

Consultations

Consultation with the following specialists may be necessary:

  • Dermatologist - For evaluation of mucocutaneous lesions (ie, oral ulcer, genital ulcer, skin lesions)

  • Ophthalmologist - For evaluation of eye involvement

  • Rheumatologist or orthopedic surgeon - For evaluation of joint involvement

  • Neurologist or psychiatrist - For evaluation of CNS involvement

  • Internal medicine specialist - For evaluation of gastrointestinal, pulmonary, renal, or endocrine involvement

  • General surgeon - For evaluation of gastrointestinal involvement

  • Chest surgeon or cardiologist - For evaluation of cardiovascular involvement

  • Ear, nose, and throat specialist or dentist - For evaluation of oral cavity

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Corticosteroids have been used for all of the various clinical manifestations of Behçet disease. Anti-inflammatory and immunosuppressive agents are used to treat mucocutaneous lesions and arthritis associated with this disease.

Corticosteroids

Class Summary

These agents modify the body's immune response to diverse stimuli and therefore have anti-inflammatory properties. In addition, they cause profound and varied metabolic effects. Corticosteroids are immunosuppressive and affect the replication, movement, and activity of virtually all cells involved with inflammation.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Prednisone is an immunosuppressant used for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Hydrocortisone (Solu-Cortef)

Hydrocortisone decreases inflammation by suppressing migration of PMN leukocytes and reversing increased capillary permeability.

Methylprednisolone (Medrol, Medrol Dosepak, Depo Medrol, Solu-Medrol)

Methylprednisolone exerts anti-inflammatory effects by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Methylprednisolone sodium succinate (Solu-Medrol) is highly soluble and has a rapid effect by intramuscular and intravenous routes. Depo Medrol is available as intramuscular, intra-articular, and intralesional injections.

Nonsteroidal anti-inflammatory drugs

Class Summary

Although most NSAIDs are used primarily for their anti-inflammatory effects, they are effective analgesics and used to treat mild to moderate pain.

Ibuprofen (Ibuprin, Advil, Motrin)

Ibuprofen is the drug of choice for mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Antibiotics

Class Summary

These agents may be immunomodulatory.

Tetracycline (Sumycin)

Tetracycline inhibits bacterial protein synthesis by binding with 30S and, possibly, 50S ribosomal subunit(s). It has anti-inflammatory activity.

Antiulcer agents

Class Summary

These agents are used for topical treatment for aphthae.

Amlexanox (Aphthasol)

Amlexanox is a topical mucosal anti-inflammatory agent paste at 5% concentration. The exact mechanism of action remains unknown. Begin treatment as soon as the patient notices symptoms.

Sucralfate (Carafate, Sulcrate)

Sucralfate forms a viscous adhesive substance that protects the GI lining against pepsin, peptic acid, and bile salts. Use it for short-term management of ulcers.

Immunosuppressive agents

Class Summary

These agents are indicated for autoimmune diseases.

Azathioprine (Imuran)

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease proliferation of immune cells, which results in lower autoimmune activity.

Chlorambucil (Leukeran)

Chlorambucil alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription.

Tacrolimus (Prograf, Tacrine, FK506)

Tacrolimus suppresses humoral immunity (T lymphocyte) activity.

Cyclosporine (Sandimmune, Neoral)

Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for a variety of organs. For children and adults, base dosing on ideal body weight.

Cyclophosphamide (Cytoxan)

Cyclophosphamide is an alkylating agent that prevents cell division by cross-linking DNA strands and thus interfering with DNA replication. It has potent immunosuppressive activity. Cyclophosphamide is a prodrug that must be metabolized by the liver into active metabolites.

Cyclophosphamide has serious adverse effects, including bladder cancer, hemorrhagic cystitis, acute myeloid leukemia, and permanent infertility.

Closely monitor the CBC count with differential and platelets, BUN, and serum creatinine for signs and symptoms of hemorrhagic cystitis; also monitor liver function test results.

Colchicine (Colcrys, Mitigare)

Colchicine prevents activation, degranulation, and migration of neutrophils. It is contraindicated in patients with renal and hepatic impairment. Aplastic anemia and myelosuppression (eg, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia) have been reported in patients receiving therapeutic doses.

Immunomodulators

Class Summary

Immunomodulators are anti-inflammatory agents that modulate the immune system through a variety of mechanisms.

Thalidomide (Thalomid)

Thalidomide is an immunomodulatory agent that may suppress excessive production of TNF-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration.

Infliximab (Remicade)

Infliximab neutralizes cytokine TNF-alpha and inhibits its binding to the TNF-alpha receptor. Mix in 250 mL normal saline for infusion over 2 hours. It must be used with a low protein-binding filter (≥ 1.2 µm). It has been used off label for treating BD.

Etanercept (Enbrel)

Etanercept is a soluble p75 TNF receptor fusion protein (sTNFR-Ig). It inhibits TNF binding to cell surface receptors, which, in turn, decreases inflammatory and immune responses. It is off-label use for Behçet disease.

Adalimumab (Humira)

Adalimumab is a recombinant human anti-TNF-α IgG1 monoclonal antibody. It specifically binds to TNF-α and blocks its interaction with p55 and p75 cell surface TNF receptors and, accordingly, decreases the inflammatory and immune response. It is off-label use for Behçet disease.