Expression of bcl-2 protein in active skin lesions of Behçet's disease

Abstract Background Expression of bcl‐2 protein has been shown to play an important role in the pathogenesis of some inflammatory as well as neoplastic disorders. In this study we have investigated the presence of bcl‐2 protein in active skin lesions of Behçet's disease and compared these results with normal skin samples of Behçet's disease (BD) patients and BD unrelated leukocytoclastic vasculitis. Methods Active skin lesions of 23 Behçet's disease patients, normal skin samples of seven Behçet's disease patients, and archival biopsy specimens of 23 cutaneous leukocytoclastic vasculitis were investigated for the presence of bcl‐2 protein by immunohistochemical methods. Results of staining were assessed semiquantitatively. Chi‐square tests were used for statistical analysis. Results Expression of bcl‐2 protein were demonstrated in 16 of 23 (69.5%) and 8 of 23 (34.7%) patients with Behçet's disease and leukocytoclastic vasculitis, respectively. There were statistically significant difference between two groups (x² = 4.27, P < 0.05). None of the normal skin samples of Behçet's disease patients showed bcl‐2 expression. Conclusion Expression of bcl‐2 protein may play a particular role in the development of skin lesions in Behçet's disease by causing prolonged survival of infiltrating lymphocytes.     

The significance of immunohistochemistry in the skin pathergy reaction of patients with Behçet''s syndrome

Background Behçet's syndrome is a chronic systemic immuno‐inflammatory disorder affecting multiple organs with generalized vasculitis of arteries and veins. Although the aetiology is still unknown, endothelial dysfunction is one of the most prominent features in Behçet's syndrome. The skin pathergy reaction (SPR) is a non‐specific hyperreactive lesion formation that is one of the major features and diagnostic criteria of the disease. It develops after 24–48 h at the site of the needle‐prick, especially in the exacerbation period, and it is very similar to the erythematous papules or pustules that appear spontaneously in patients with Behçet's syndrome. Therefore, an investigation into the formation of the SPR lesion may contribute to the pathophysiology of skin lesions of this unique disorder. Objective To evaluate the immunological features of SPR formation by assessing the immunohistochemical staining of cell adhesion molecules and endothelial growth factor markers such as E‐selectin, P‐selectin and endoglin (CD 105). Methods Patients with Behçet's syndrome showing positive (n = 15) or negative (n = 10) SPR and 15 age‐ and sex‐matched hospital‐based healthy control subjects from a similar ethnic background were included in this study. Patients were divided into active and inactive stage by clinical findings and acute‐phase reactant parameters including erythrocyte sedimentation rate (ESR) and neutrophil count. Punch biopsy specimens were obtained both from the lesion site on the forearms at 48 h and from normal skin approximately 5 cm adjacent to the SPR site. A biopsy was also obtained from the test application site in Behçet's syndrome patients with negative SPR and healthy volunteers. Biopsy specimens were then evaluated by immunohistochemical staining. Results Immunohistochemical examination demonstrated a mixed inflammatory cell infiltrate around the vessels and skin appendages that extended somewhat into the deep dermis. A positive segmental staining of E‐selectin and P‐selectin was noted in the endothelial cells of biopsies obtained from the patients with positive SPR. A positive segmental staining of CD 105 in the endothelial cells was also observed in the same group of patients. However, the immunostaining of the same markers was found to be negative in the biopsies obtained from normal skin of SPR‐positive patients, SPR‐negative patients and healthy control subjects. Both acute‐phase reactant levels were significantly higher in the active stage than in inactive patients or healthy controls. Conclusion Interaction of cellular adhesion molecules together with endothelial proliferation may play an important role in the formation of SPR lesions in patients with Behçet's syndrome. The involvement of the vascular endothelium in a large number of diseases including Behçet's syndrome supports the importance of vascular‐specific adhesion molecules for their aetiopathogenesis.     

Guidelines for the treatment of skin and mucosal lesions in Behçet's disease: A secondary publication

In the current study, we present guidelines for the diagnosis and treatment of the mucocutaneous lesions of Behçet's disease, which is a chronic inflammatory disease characterized by the involvement of various organs, including mucocutaneous, ocular, vascular, intestinal and central nervous system lesions. It is often identified in the Middle East Mediterranean to East Asia region. Skin manifestations include erythema nodosum, papulopustular lesions and thrombophlebitis, and mucosal manifestations include oral and genital ulcers. These mucocutaneous lesions are characteristically the first signs of Behçet's disease and are important to be recognized for the early diagnosis of the disease. Moreover, these manifestations also recur and persist over the long-term course of the disease. The management of mucocutaneous lesions is important to prevent recurrence. We developed consensus guidelines that provide recommendations for general practitioners and dermatologists and physicians on the management of the mucocutaneous lesions of Behçet's disease.     

Caspase-9 expression is increased in endothelial cells of active Behçet's disease patients

Background Behçet's disease is a multisystem disease of unknown etiology. Caspase‐9 is responsible for initiating the caspase activation cascade during apoptosis. The aim of this study was to examine caspase‐9 expression in both endothelial and perivascular infiltrates of patients with active Behçet's disease. Methods Fifteen patients with active Behçet's disease, attending the First Dermatology Department, Ankara Numune Hospital, Ankara, Turkey between June 2003 and December 2005, were included in the study. Oral biopsy specimens from nine healthy volunteers were taken as the healthy control group, and skin biopsies from 18 psoriasis patients were used as the inflammatory control group. The specimens were examined with caspase‐9 primary antibody. Statistical analyses were performed using SPSS 11.5. Results The mean caspase‐9‐positive endothelial cell counts were 7.17 ± 2.45 in active Behçet's disease, 4.81 ± 0.76 in healthy controls, and 4.35 ± 1.34 in inflammatory controls. The difference between Behçet's disease and healthy controls was statistically significant, with increased endothelial staining in active Behçet's disease (P = 0.049). The difference between Behçet's disease and inflammatory controls was also statistically significant; the rate of staining was higher in Behçet's disease (P = 0.006). The mean caspase‐9‐positive dermal perivascular cell counts were 5.15 ± 2.32 in Behçet's disease, 3.32 ± 0.82 in healthy controls, and 5.54 ± 4.95 in inflammatory controls. These values did not show any statistically significant difference (P = 0.407). Conclusion Endothelial cells are one of the key cells in Behçet's disease, and our findings support the role of endothelial cells in the etiopathogenesis of Behçet's disease.     

Formation of arcuate crusted lesions after non-ablative 1450-nm diode laser treatment equipped with a dynamic cooling device

Abstract

Behçet's disease (BD) is a chronic systemic inflammatory disorder of unknown etiology with variable clinical manifestations. HLA-B51 allele is the most strongly associated known genetic factor. The mucocutaneous lesions (oral aphthae, genital aphthae, skin lesions such as pseudofolliculitis) constitute the hallmark of the disease, but also gastrointestinal, vascular, central nervous systems, and others may be involved. We report a case of a young man affected with Behçet's disease who presented facial telangiectasias and striae rubra in the inner region of his arms and at the level of his hips, as uncommon minor superficial vascular manifestations of BD. To manage them we have subjected the patient to a cycle of Intense Pulsed Light (IPL) therapy. Our findings showed that the use of IPL is a safe and effective treatment for telangiectasias and striae rubra, also in the complex clinical condition of Behçet's disease. In fact, the treatments were well tolerated, no sign of scarring or hyper/hypopigmentation was reported and we obtained a significant improvement of the lesions in terms of color and size of them.     

The quantification and significance of mast cells in lesions of Behçet's disease

Mast cells in the upper dermis and mucosal subepithelial layer were counted in thirty consecutive light microscopy oil-immersion fields of the following: thirty-four skin and oral specimens from lesions in patients with active Behçet's disease, eight specimens of apparently uninvolved skin of the same patients, and 102 lesions of a variety of other skin diseases. The results revealed a significant increase in the number of mast cells in Behçet's lesions. Furthermore, the histamine content of five reactive lesions showed a two-fold increase compared with that in apparently uninvolved skin of patients with active Behçet's disease. It is suggested that mechanisms similar to cutaneous basophil hypersensitivity may be involved in the production of Behçet's lesions.     

Histopathologic Study of Cutaneous Lesions in Behçet's Syndrome

Light microscopic studies of 55 patients with complete and incomplete types of Behçet's syndrome were reviewed. We reported here 39 skin biopsies from 30 patients with cutaneous lesions of oral, and genital ulcers, folliculitis, erythema multiforme, and thrombophlebitis. Leukocytoclastic vasculitis was seen in 5 of 12 (42%) cases of oral ulcers and 2 of 7 (29%) of genital ones. Lymphocytic vasculitis was demonstrated in 3 of 12 (25%) cases of oral ulcers and 4 of 7 (57%) of genital ulcers. However, the vasculitis was observed only locally in the areas with moderate or severe inflammation. From the biopsy specimens of our cases with fully developed mucocutaneous lesions of Behçet's syndrome, it appears that the forms of vasculitis that are often emphasized in the literature are a phenomenon secondary to the intense inflammation seen in such cutaneous lesions.     

A comparison between the effects of low (1 µg) and standard dose (250 µg) ACTH stimulation tests on adrenal cortex functions with Behçet's disease

Introduction Behçet's disease is a rare, chronic disorder. The cause of Behçet's disease is unknown. It is believed to be caused by an autoimmune reaction. As in other chronic autoimmune diseases, Behçet's disease may show a subclinical adrenal failure and some changes in cortisol levels. We aimed to evaluate adrenal gland function in Behçet's disease patients. Material and method This study included 18 Behçet's disease patients and 15 healthy controls. Patient and control groups were administered i.v. 1 µg low dose test (LDT) and 250 µg standard dose test (SDT) adrenocorticotropic hormone (ACTH) stimulation test after 12 h of night fasting with an interval of 3‐days and cortisol responses in the 0th, 30th and 60th minutes were evaluated. Results There was no statistically significant difference between basal cortisol values of Behçet's disease and control groups. Cortisol values in the 60th minute in LDT were significantly lower in Behçet's disease group than in the control group. In the peak cortisol responses to LDT, a significant decrease was found in Behçet's disease group. Conclusion These findings suggest that hypothalamo‐pituitary adrenal axis is partially suppressed in Behçet's disease.     

Can specific vessel‐based papulopustular lesions of Behçet's disease be differentiated from nonspecific follicular‐based lesions clinically?

Background Although papulopustular lesions are one of the diagnostic criteria for Behçet's disease, controversy exists as to the nature of these lesions. Specific vessel‐based papulopustular lesions as well as nonspecific follicular lesions may be seen in patients with Behçet's disease. Some authors suggest that papulopustular lesions should be considered a positive criterion only if they exhibit a vessel‐based neutrophilic reaction. Objective To determine whether specific vessel‐based papulopustular lesions can be differentiated clinically from nonspecific follicular lesions in patients with Behçet's disease. Methods Twenty‐three papulopustular lesions in 20 patients with Behçet's disease were initially examined clinically by two dermatologists blind to each other's diagnosis. Biopsies taken from these lesions were examined by a pathologist unaware of the patient data. Results Leukocytoclastic vasculitis or perivascular infiltration was observed in 10 lesions, perifollicular and perivascular infiltration was noted in nine lesions, and perifollicular inflammation was seen in four biopsy specimens. Most of the lesions interpreted clinically as specific papulopustular lesions of Behçet's disease had predominantly perivascular infiltration or leukocytoclastic vasculitis; however, three papulopustular lesions evaluated by both observers as specific papulopustular lesions had only perifollicular inflammation, and one lesion diagnosed clinically as a nonspecific follicular eruption revealed perivascular neutrophilic reaction. Interobserver variance was noted in three papulopustular lesions. Conclusions Clinical examination may not be sufficient to predict the dermatopathologic pattern in all lesions. Papulopustular lesions with no specific clinical and histopathologic features may create problems in the diagnosis of Behçet's disease.     

JUVENILE BEHÇET'S DISEASE AMONG 1784 TURKISH BEHÇET'S PATIENTS

Background. Behçet's disease is a chronic, relapsing disease, about which information on its clinical course in juveniles is only available from small groups of patients. Materials and Methods. Patients suffering from Behçet's disease who had their first lesion at or before the age of 16 were evaluated in terms of: age at onset, mucocutaneous signs, and findings related to systemic involvement. Ninety-five patients, evaluated as having juvenile Behçet's disease (JBD), were detected among 1784 Turkish Behçet's patients. The mean age of these 95 patients (51 boys or men, 44 girls or women) who had JBD was 26.8 ± 7.1 years. Results. The difference between sexes in terms of age at onset, development period of second lesions, and systemic involvement was not found to be significant in JBD. Patients were divided into two groups, one showing severe disease (N = 27) and the other mild disease (N = 68). There was no significant difference between the two groups with respect to age, age at onset, and sex distribution. The interval between the development of the first and second lesions was shorter in the patient group with severe disease (P < 0.001) and the development of second lesion was most frequently seen in the first 5 years (P < 0.05). Systemic involvement developed also in a shorter time in the group with the severe disease (P < 0.01) and was most frequently encountered during the first 5 years (P < 0.05). Conversely, patients with the mild disease developed systemic involvement more frequently after 6 years or later. Conclusions. Severe Behçet's disease in children and juveniles shows no age or sex predilection, but leads to an earlier recurrence and more severe systemic signs than the mild form.     

Lack of association between leptin G2548A gene polymorphism and Behçet''s disease

Background Behçet's disease is a chronic, multisystem, inflammatory disease characterized by the predominance of T‐helper 1 cytokines. The disease is also characterized by infiltration of lymphocytes and neutrophils into the affected tissues. Because cytokines are involved in the regulation of lymphocyte and phagocyte functions, they may play an important role in the pathogenesis of Behçet's disease. Leptin, a member of the gp 130 family of cytokines, induces a strong T‐helper 1 response and is regarded as a proinflammatory inducer. Recent studies have shown that serum leptin concentration was increased in patients with Behçet's disease and correlated with disease activity. Objectives We aimed to investigate the role of G2548A polymorphism of leptin gene in patients with Behçet's disease and compare the results with healthy controls. Patients and methods A total of 93 subjects with Behçet's disease and 125 healthy controls were included in this study. Analyses of G‐2548A polymorphism of the LEP gene were performed using the PCR‐restriction fragment length polymorphism technique. The genotypes (GG, GA, and AA of leptin G2548A) and alleles (G and A of leptin 2548) were scored and the frequency was estimated. The frequencies of the alleles and genotypes in patients and controls were compared. We analysed the correlation between leptin gene polymorphism and the clinical features of BD. Results Both genotype and allele frequencies were not significantly different between controls and Behçet's disease patients [OR = 0.67, 95% CI (0.35–1.29), P = 0.197 and OR = 0.77, 95% CI (0.52–1.15), P = 0.184]. We did not find any significant relationship between leptin gene polymorphism and the clinical features of BD (P > 0.05). Conclusion In the present case‐control study, we found no evidence of an association between the G‐2548A variant of the leptin gene and BD among Turks. Further studies are needed to investigate serum leptin level to explain the mechanisms behind the lack of association between leptin G2548A gene polymorphism and BD.     

BEHÇET'S DISEASE: CLINICAL STUDY OF JORDANIAN PATIENTS

Background. Behçet's disease is a chronic, recurrent, inflammatory disorder characterized by the triad of oral and genital ulcers and ocular lesions. The etiology is unknown. This is the first report giving details of the clinical manifestations of Behçet's disease in Jordanian patients. Methods. Twenty patients with Behçet's disease were studied to determine the clinical pattern in the North of Jordan. The patients were seen in Princess Basma Teaching Hospital in North Jordan. They presented to various clinics and underwent full clinical examination. Data for each patient on all features of Behçet's disease were recorded on a standard form. A comparison was made between Behçet's disease in Jordan and other countries in the region. Results. Of the 20 patients, 14 were men and six women, giving a ratio of 2.3:1. Their ages ranged from 14 to 58 years. All had mouth ulcers, 65% genital ulcers, 65% ocular involvement, 55% joint involvement, 35% skin lesions, 20% vascular lesions, and 5% gastrointestinal involvement. The oral ulcers were the first manifestation of the disease process in 70% of our patients. Skin lesions, genital ulcers, and involvement of the central nervous system and the pulmonary system were less frequent in our study. Conclusions. Although it is difficult to obtain figures as to the incidence and prevalence of Behçet's disease in Jordan, the clinical manifestations, with a few exceptions, are similar to those in other countries in the region.     

Clinical Spectrum of Behçet's Disease

Behçet's disease is a chronic systemic inflammatory disease involving mucous membranes, skin, eyes, the gastrointestinal tract, joints, blood vessels, and the neurologic system. Behçet's disease occurs endemically in the Middle East and Mediterranean regions. It is also distributed in the Central and Far Eastern Asian countries including Korea, Japan, and China. With the volume of clinical information obtained from over 5,000 patients who visited the Behçet's Disease Specialty Clinic, Severance Hospital, Yonsei University College of Medicine, informative and educational viewpoints of Behçet's disease including dermatologic and other systemic manifestations were introduced.     

A case of pediatric Behçet's disease with intestinal involvement

We report a 6-year-old girl with recurrent oral aphthae, genital and perianal ulcers, and folliculitis-like erythema followed by intestinal symptoms. No ocular lesions were found. Her ailment was diagnosed as incomplete Behçet's disease with intestinal involvement. According to the literature, pediatric Behçet's disease is characterizesd by a low incidence of ocular lesions and a high incidence of intestinal involvement, as exhibited in this case. As intestinal lesions in pediatric Behçet's disease are often life-threatening, a barium enema must be given to exclude the possibility of intestinal involvement when pediatric patients with Behçet's disease complain of abdominal pain     

Case of neuro‐Behçet's disease successfully maintained a remission using infliximab for 2 years

Behçet's disease is a systemic inflammatory disorder with chronic remissions and relapses. Involvement of the central nervous system, called neuro‐Behçet's disease (NBD), is a serious complication. Although corticosteroids and immunosuppressive agents are used, there is no definite standard of treatment with long term‐effects for NBD. Here, we report a female case with NBD successfully treated by infliximab and corticosteroids for 2 years. Our report suggests treatment with infliximab may be effective for long‐term remission of NBD.     

Evaluation of clinical findings according to sex in 2313 Turkish patients with Behçet's disease

Background Behçet's disease is a multisystem disease featuring mucocutaneous, ocular, articular, vascular, intestinal, urogenital, and neurologic involvement and occurs with a high prevalence in the Mediterranean including Turkey. Higher incidence of severe clinical course and systemic involvement is observed in male patients. Objective To determine the influence of sex on the clinical course of Behçet’ s disease. Methods We retrospectively evaluated the clinical findings of 2313 Behçet patients followed up at the multidisciplinary Behçet's Disease Center at Ankara University. Results The male/female patient ratio was 1.03. Oral aphthae was seen in all patients. In male Behçet patients, the prevalence of mucocutaneous lesions and systemic manifestations was as follows: 85.6% genital aphthae, 45.5% erythema nodosum, 59.5% papulopustular lesions, 17.5% thrombophlebitis, 38.1% ocular involvement, 11.3% articular involvement, 11.7% vascular involvement, 3.3% neurologic involvement, 1.4% gastrointestinal involvement, and 1.8% pulmonary involvement. In female Behçet patients, the prevalence of manifestations were as follows: 91% genital aphthae, 49.8% erythema nodosum, 48.3% papulopustular lesions, 3.5% thrombophlebitis, 19.8% ocular involvement, 11.8% articular involvement, 2.1% vascular involvement, 1.3% neurologic involvement, 1.4% gastrointestinal involvement, and 0.03% pulmonary involvement. Conclusions Only genital aphthae and erythema nodosum were more frequent in females. On the other hand papulopustular eruptions, thrombophlebitis, ocular, neurologic, pulmonary and vascular involvement were more frequent in males. While female patients had the best prognosis, male patients had a worse overall prognosis than females.     

Association of class I HLA antigens with the clinical manifestations of Turkish patients with Behçet's disease

Summary Genetic factors appear to be important in the pathogenesis of Behçet's disease. Although it is known to be strongly associated with HLA‐B51, the association of HLA class I antigens with specific clinical findings of the disease has not been studied extensively and the few studies are conflicting. The aim of this study was to investigate the association of HLA class I alleles with the manifestations of Behçet's disease in Turkish patients. Eighty‐five patients with Behçet's disease were typed for HLA‐A, B, and C antigens with the serologic, standard microlymphocytotoxicity technique. Possible associations of the HLA complex with clinical findings of Behçet's disease were examined. Statistically significant findings are as follows (P < 0.05): increased HLA‐B51 and decreased HLA‐B35 frequency in patients with thrombophlebitis, increased HLA‐A29 and decreased HLA‐Bw6 frequency in patients with ocular involvement, decreased HLA‐Cw2 frequency in patients with erythema nodosum, and decreased HLA‐Cw7 frequency in patients with genital ulceration. Of particular note, the results of this study suggest that the presence of HLA‐B51 and the absence of HLA‐B35 can be regarded as laboratory risk factors of venous thrombosis in patients with Behçet's disease.     

Dapsone in Behçet's disease: a double-blind,placebo-controlled,cross-over study

The study was designed to investigate the effects of dapsone in the treatment of mucocutaneous manifestations of Behçet's disease and the possible prophylactic role of dapsone in a double blind/placebo controlled clinical trial. Twenty patients diagnosed according to the International Study Group criteria as Behçet's disease were included in the study. Patients were randomly allocated to receive either dapsone 100 mg daily or placebo for three months in a double‐blind manner. After three months, patients were crossed over and followed for a further three months. Patients were followed up in each visit by assessing the number, size, duration and frequency of oral and genital ulcers, other cutaneous manifestations, and systemic manifestations of the disease. A pathergy test was done on each visit. Laboratory investigations included hemoglobin concentration, white blood cell count, ESR, and C‐reactive protein. In dapsone‐treated patients, there were significant reductions in the oral and genital ulcer parameters as well as the incidence of other cutanous and systemic manifestations. In the placebo‐treated group, there were no significant changes in these parameters. The pathergy test result as well as those of other laboratory tests were all decreased in the dapsone‐treated group. Although this study was a small scale study, it shows that dapsone was effective in treatment of mucocutaneous manifestations of Behçet's disease and possibly in prophylaxis against systemic manifestations of the disease. This result should lead to a larger scale study with a longer duration of follow‐up.     

Colchicine in the treatment of the cutaneous manifestations of Behçet's disease

Five patients with Behçet's disease were satisfactorily treated with colchicine. Oral aphthosis, erythema nodosum-like lesions and genital erosions improved greatly within a month as did laboratory findings. We believe colchicine to be the first choice in the management of the cutaneous and ocular lesions of Behçet's disease.     

The clinical course of Behçet's disease in pregnancy: a retrospective analysis and review of the literature

Although Behçet's disease is mainly diagnosed during the reproductive periods of life, we know little about the influence of pregnancy on the clinical course of Behçet's disease. Therefore, we analyzed the relationship between Behçet's disease and pregnancy retrospectively, in order to detect any possible interaction between the two multisystemic processes, particularly in regard to the influence of pregnancy on the clinical course of Behçet's disease. We studied 44 pregnancies in 28 women with Behçet's disease. The diagnoses were made according to the criteria of the International Study Group for Behçet's disease. The patients were observed during pregnancy and puerperium periods at monthly intervals. The existence and incidence of symptoms were recorded during these periods. There was remission of Behçet's disease during 23 (52.3%) pregnancies, although the disease had been in a stage of exacerbation before pregnancy. The disease became exacerbated during 12 (27.3%) pregnancies, although it had been in a stage of remission before pregnancy. There were no changes in the clinical course of Behçet's disease in 9 (20.4%) pregnancies. The most frequent manifestations of the clinical exacerbation were increases in the intensity and severity of outbreaks of oral ulcers during pregnancy. Outbreaks of genital ulcers, eye inflammations, and arthritis were other signs of exacerbation. Other than spontaneous abortion in three patients, we did not observe maternal or fetal complications. Although Behçet's disease tends toward remission during pregnancy, the influence of pregnancy on its clinical course is quite variable between patients and even during different pregnancies in the same patient. On the basis of our and previous results, we speculate that pregnancy in general does not seem to markedly affect the natural course of Behçet's disease.