Nurşen Düzgün

Characteristics of vascular involvement in Behçet's disease.

Objective: Behçets disease (BD) is a multisystemic inflammatory disorder classified among the vasculitides, which can affect all types and sizes of blood vessels. Vascular involvement may be seen in 25–50% of BD patients. In this study, we examined the characteristics of vascular involvement in patients with BD. Methods: One hundred and eighty patients with BD were included in the study. The diagnosis of vascular involvement was made on clinical signs, by Doppler ultrasonography and/or angiography using computed tomographic or magnetic resonance techniques where appropriate. Detailed clinical characteristics were recorded for each patient. Results: Seventy‐one patients (39.4%) had vascular involvement. In patients with vascular lesions, the frequency of male sex was significantly higher than in patients without vascular lesions (89.8% vs. 63.3%, respectively; p<0.001). Of 71 BD patients with vascular involvement, 68 had venous lesions (95.8%). Three patients had arterial lesions without venous thrombosis. Eleven patients had arterial involvement with venous thrombosis. The most frequent type of vascular involvement was deep venous thrombosis in the lower extremities (n = 56, 78.9%). There was a significant association between deep venous thrombosis and superficial thrombophlebitis (r = 0.325, p<0.01). Twenty‐four patients (33.8%) had vena cava thrombosis and two had vena hepatica thrombosis. In patients with vascular involvement, the frequency of erythema nodosum was significantly higher (p = 0.001) and the frequency of ocular involvement was significantly lower (p<0.05) than in patients without vascular involvement. Conclusion: Our study illustrates the frequency and significance of vascular involvement in BD.

Identification of multiple genetic susceptibility loci in Takayasu arteritis

Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B*52. We genotyped ~200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r(2) < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10(-16)) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10(-9); and rs189754752, OR = 2.47, p = 4.22 × 10(-9)). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10(-12)). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10(-8)).

Identification of multiple independent susceptibility loci in the HLA region in Behçet's disease

Behçets disease is an inflammatory disease characterized by recurrent oral and genital ulcers and significant organ involvement. Localizing the genetic association between HLA-B*51 and Behçets disease and exploring additional susceptibility loci in the human leukocyte antigen (HLA) region are complicated by the strong linkage disequilibrium in this region. We genotyped 8,572 variants in the extended HLA locus and carried out imputation and meta-analysis of 24,834 variants in 2 independent Behçets disease cohorts from 2 ancestry groups. Genotyped SNPs were used to infer classical HLA alleles in the HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1 and HLA-DRB1 loci. Our data suggest that the robust HLA-B*51 association in Behçets disease is explained by a variant located between the HLA-B and MICA genes (rs116799036: odds ratio (OR) = 3.88, P = 9.42 × 10−50). Three additional independent genetic associations within PSORS1C1 (rs12525170: OR = 3.01, P = 3.01 × 10−26), upstream of HLA-F-AS1 (rs114854070: OR = 1.95, P = 7.84 × 10−14) and with HLA-Cw*1602 (OR = 5.38, P = 6.07 × 10−18) were also identified and replicated.

Plasma von Willebrand factor, tissue plasminogen activator, plasminogen activator inhibitor, and antithrombin III levels in Behçet's disease.

Sixty-three patients with Behçets disease (BD), 30 patients with recurrent oral ulcer and 30 healthy individuals as control group were included in the study. ISG criteria was used for the diagnosis of BD and patients were classified as active and inactive and evaluated accordingly. In the patient and control groups, von Willebrand factor (vWF), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI) levels were determined using ELISA method and antithrombin III (AT-III) by nephelometric methods. High levels of endothelial product, vWF in the active Behçet patient group (p < 0.005) supports endothelial destruction due to vasculitis related with BD. In the active patient group tPA levels were significantly lower (p < 0.05) than the inactive and control groups with higher levels of PAI (p < 0.05 and p < 0.01) respectively. In Behçet disease, besides the decrease in tPA synthesis, high PAI levels also can affect tPA decrease and lead to inhibition of fibrinolytic activity. In active Behçet group, levels of AT-III were low and no significant difference was observed in recurrent oral ulcer and control groups. This situation may arise from the excessive use of AT-III in active disease. In conclusion, high levels of vWF in Behçet patients is thought to arise from vasculitis and high levels of PAI from the accumulation of thrombocytes on the damaged surface of endothelium leading to a decrease in tPA levels and inhibition of fibrinolytic activity.

Cytokine inhibitors: soluble tumor necrosis factor receptor 1 and interleukin-1 receptor antagonist in Behçet’s disease

Serum levels of proinflammatory cytokines, interleukin-1 beta (IL-1β), tumor necrosis factor alpha, (TNF-α), and their inhibitors, IL-1 receptor antagonist (IL-1ra) and soluble TNF receptor 1 (sTNFR1), were determined by enzyme-linked immunosorbent assay in 104 patients with Behçet’s disease (65 active, 39 inactive) and 40 healthy controls. The levels of IL-1β and IL-1ra were significantly higher in both active and inactive patients than in control subjects (P<0.01 and P< 0.01, respectively). The concentrations of TNF-α and sTNFR1 were found to be higher in active patients than in controls (P< 0.01 and P< 0.001, respectively). There were no significant differences in the serum levels of these cytokines and their inhibitors between active and inactive patients. Significant increases in mean C-reactive protein level and erythrocyte sedimentation rate were found in patients with active vs inactive disease (P< 0.001 and P< 0.05, respectively). C-reactive protein values correlated with erythrocyte sedimentation rate but not with cytokines or their inhibitors. Our conclusion is that elevated serum TNF-α and sTNFR1 seem to be important inflammatory mediators in Behçet’s disease. The statistically significant increase in these levels may arise from the severity of inflammation in the tissue or organ involved.

A multicenter study of patients with adult-onset Still’s disease compared with systemic juvenile idiopathic arthritis

Adult-onset Still’s disease (AOSD) has often been regarded as the adult spectrum of systemic juvenile idiopathic arthritis (sJIA). The present study aims to compare the clinical and laboratory features, the disease course and the response to treatment in patients having AOSD with those having sJIA. Retrospective review of all available data that were filled out by adult and paediatric rheumatologists from six centers using a standard data extraction form was performed. A total of 95 patients with AOSD and 25 patients with sJIA were recruited for the study. The frequency of fever, rash, myalgia, weight loss and sore throat was higher in patients with AOSD. The pattern of joint involvement differed slightly. Laboratory findings were similar in both groups, except that liver dysfunction and neutrophilia were more common among adults. A multiphasic pattern dominated the childhood cases, whereas the most frequent course was a chronic one in adults. Corticosteroids and methotrexate were the most commonly employed therapy; however, chloroquine was another popular therapy in the adult group. We showed a difference in the rate of clinical and laboratory features between patients with AOSD and those with sJIA. AOSD and sJIA may still be the same disease, and children may simply be reacting differently as the result of the first encounter of the putative antigens with the immune system.

Serum homocysteine level is higher in Behçet’s disease with vascular involvement

ObjectiveBehçet’s disease (BD) is a multisystemic inflammatory disorder of unknown etiology that is sometimes associated with thrombosis. However, the mechanism of hypercoagulability is not known. In this study, we investigated whether hyperhomocysteinemia, being a well-known risk factor for thrombosis, is also a contributing risk factor to venous and arterial thromboses of BD.MethodsForty-five patients with BD and 40 healthy subjects were included in the study. Sixteen patients had vascular involvement. Serum homocysteine levels were determined by fluorescence polarization immunoassay.ResultsIn male patients, the frequency of vascular involvement was significantly higher than in females (46.7% vs 13.3%, P<0.05). Serum homocysteine levels were significantly higher in patients with BD than healthy controls (P<0.01), in patients with vascular involvement than those with mucocutaneous involvement (P<0.01) and healthy controls (P=0.001), and in male patients than in female patients (P<0.001). There was no significant difference in homocysteine levels between the BD patients with mucocutaneous involvement and healthy subjects. In multiple regression analysis, serum homocysteine level was independently associated with thrombosis (odds ratio 1.29, P<0.01), but male sex was not.ConclusionsThis preliminary study suggests that elevated serum homocysteine levels may play some role in the development of venous and arterial thromboses in BD.

Takayasu's arteritis is associated with HLA-B*52, but not with HLA-B*51, in Turkey

IntroductionHLA-B*51 and HLA-B*52 are two close human leukocyte antigen (HLA) allele groups with minor amino acid differences. However, they are associated with two different vasculitides (HLA-B*51 in Behçets disease and HLA-B*52 in Takayasus arteritis (TAK)) and with major clinical and immunological differences. In this study, we aimed to screen a large cohort of TAK patients from Turkey for the presence of HLA-B*51 and HLA-B*52 as susceptibility and severity factors.MethodsTAK patients (n = 330) followed at a total of 15 centers were included in the study. The mean age of the patients was 37.8 years, and 86% were women. DNA samples from the patients and healthy controls (HC; n = 210) were isolated, and the presence of HLA-B*51 or HLA-B*52 was screened for by using PCR with sequence-specific primers.ResultsWe found a significant association of HLA-B*52 with TAK (20.9% vs HC = 6.7%, P = 0.000, OR = 3.7, 95% CI = 2.02 to 6.77). The distribution of HLA-B*51 did not differ between TAK patients and HCs (22.7% vs 24.8%, OR = 0.9, 95% CI = 0.60 to 1.34). The presence of HLA-B*52 decreased in late-onset patients (> 40 years of age; 12.0%, P = 0.024, OR = 0.43, 95% CI = 0.20 to 0.91). Patients with angiographic type I disease with limited aortic involvement also had a lower presence of HLA-B*52 compared to those with all other disease subtypes (13.1% vs 26%, P = 0.005, OR = 0.43, 95% CI = 0.23 to 0.78).ConclusionsIn this study, the previously reported association of TAK with HLA-B*52 in other populations was confirmed in patients from Turkey. The functional relevance of HLA-B*52 in TAK pathogenesis needs to be explored further.

Association of HLA Class I and Class II Antigens with Rheumatic Fever in a Turkish Population

The distribution of class I and class II HLA antigens of 100 Turkish patients with rheumatic fever, 77 of whom had cardiac involvement, was examined. We compared the results with a control group of identical origin. The frequency of HLA A10 and HLA B35 antigens were found significantly higher in patients with rheumatic fever (p < 0.05, p < 0.01, respectively). The frequency of HLA A10 and HLA DRw11 in patients with cardiac involvement were significantly higher than in those without cardiac involvement (p < 0.05, p < 0.01, respectively). On the other hand, HLA Cw2 antigen frequency was found significantly higher in patients without cardiac involvement than in those with rheumatic heart disease (p < 0.05). We support the concept that rheumatic fever is an immunological reaction to group A, beta hemolytic streptococci in individuals who have genetic predisposition.

Elevated levels of soluble intercellular adhesion molecule-1 correlate with disease activity in Behçet's disease

The objective of this study was to measure soluble intercellular adhesion molecule-1 (sICAM-1) in patients with Behçets disease (BD) and to analyse the relationship of sICAM-1 levels with clinical and some laboratory measures of disease activity. Forty patients with BD fulfilling the International Study Group Criteria for the diagnosis of BD and 20 healthy controls were studied. Twenty patients had active, and 20 patients had inactive disease. Serum sICAM-1 was determined by a sandwich ELISA. The mean (±SD) sICAM-1 level was significantly higher in the whole BD group (297.3±86.6 ng/ml) than in the healthy controls (213±83.5 ng/ml; P< 0.05). The mean sICAM-1 levels in active and inactive BD patients were 315.7±76.3 ng/ml and 258.3±73.3 ng/ml, respectively. The mean sICAM-1 level in active patients was significantly higher than in inactive patients and healthy controls (P< 0.02 and P< 0.001, respectively). No statistically significant difference in mean sICAM-1 levels was found between inactive BD patients and healthy controls (P>0.05). There was no statistically significant difference between the mean sICAM-1 levels of active patients with (351.3±77.2 ng/ml) or without vascular lesions (292±68.8; P>0.05). In spite of a positive correlation between disease activity and both erythrocyte sedimentation rate and C-reactive protein (CRP; P< 0.01), we found no correlation between sICAM-1 and either of them (P>0.05). The elevated levels of sICAM-1 may be due to endothelial cell activation and/or damage or may be the result of inflammation. In either case it did not seem to be superior to more conventional measures of disease activity.