Dermatologic Aspects of Behcet Disease

Updated: Mar 01, 2018
  • Author: Amira M Elbendary, MBBCh, MSc; Chief Editor: William D James, MD  more...
  • Print
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.

Next:

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.

Previous
Next:

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.

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. [4]

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. [5]

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. [6, 7]

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. [8]

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. [9]

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. [10]

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. [11] 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. [12]

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. [13]

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. [14]

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. [15]

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. [16]

Salivary colonization with Streptococcus mutans was found in high rates in a study that included 106 Turkish patients with Behçet disease. [17] Marked improvement was noticed in Behçet disease patients who received benzathine penicillin with colchicine compared with patients who received colchicine only as a treatment. [18]

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.

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. [19]

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. [20]

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. [21] 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. [22] Notch blockade has shown inhibition in Th17 response, as it is involved in Th17 lymphocyte differentiation. [23]

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. [24]

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. [25]

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. [26] 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. [27]

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. [28]

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. [29]

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. [30]

Plasma levels of vascular endothelial growth factor, a proinflammatory cytokine, is significantly higher in persons with active Behçet disease. [31]

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. [32]

Polymorphisms in toll-like receptor 4 have been associated with Behçet disease. [33]

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. [34]

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. [35]

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. [36]

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. [37]

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. [38]

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. [39]

Decreased levels of antithrombotic factors, including fibrinolysis and activated protein C, are noted. [40]

Additional factors include decreased deformability of red blood cells [41] and increased platelet activity. [42]

However, thrombophilia in Behçet disease patients does not seem to be the major factor in the tendency to thrombosis [38] ; 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. [43]

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. [44]

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. [45]

Previous
Next:

Epidemiology

Frequency

United States

Behçet disease is not common in the United States, with a prevalence of 5 cases per 100,000 persons.

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. [46] 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 [46] :

  • 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

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. [47] Behçet disease rarely occurs in individuals older than 50 years or during childhood. [48] Genetic anticipation was reported in Behçet disease, in which the onset of the disease becomes earlier with successive generations. [49]

Previous
Next:

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. [50]

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. [51]

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. [51]

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. [51]

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. [52] 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.

Previous
Next:

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. [53]  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. [54]

Previous
Next:

Patient Education

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

Previous