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)).

Health-related quality of life and its associations with mood condition in familial Mediterranean fever patients.

The aim of the present study was to investigate the health-related quality of life (HRQOL) and mood conditions in familial Mediterranean fever (FMF) patients. Ninety FMF patients (F/M 60/30, median age 29) and 67 control subjects (F/M 46/21, median age 30) were included in this study. HRQOL was assessed with short form-36 (SF-36) and mood conditions were assessed with hospital anxiety depression scale (HADS). FMF patients had significantly lower mean scores on SF-36 physical components compared to the control group. However, mental components were comparable between groups. FMF patients were significantly more likely to have depression and anxiety compared to the control group [30 (33%) vs. 8 (12%), respectively, χ (2) = 9.58, OR (95% CI) = 3.7 (1.5-8.7), p < 0.01 for depression and 48 (53%) and 11 (16%), respectively, χ (2) = 22.31, OR (95% CI) = 5.8 (2.7-12.5), p < 0.001 for anxiety]. When frequency of anxious subjects was adjusted for the presence of concomitant depressive status as a confounding factor, the difference between the groups remained statistically significant [χ (2) = 11.86, OR (95% CI) = 5.4 (2.1-13.7), p < 0.01]. However, the difference of depression status between groups was not statistically significant when adjusted for the presence of concomitant anxiety status [χ (2) = 0.08, OR (95% CI) = 1.3 (0.5-3.8), p = 0.78] and FMF was found to be independently associated with only anxiety [OR (95% CI) = 7.1 (2.3-20.3)]. In addition, pure anxious FMF subgroup had significantly lower scores of mental health and mental component summary when compared to normal mood subgroup. In conclusion, FMF might adversely affect HRQOL. Depression and anxiety are more frequent in FMF patients than healthy subjects.

Vascular endothelial growth factor and carotid intima-media thickness in patients with Behçet's disease.

There is morphologic evidence of subclinical atherosclerosis in Behçet's disease (BD) patients obtained by high-resolution B-mode ultrasonography (US). Vascular endothelial growth factor (VEGF) is a potent angiogenetic factor and a marker for endothelial dysfunction. VEGF could contribute to the pathological events in BD. VEGF could also be an important factor in the progression of atherosclerosis. In this study, we investigated whether there is correlation between intima-media thickness (IMT) of the carotid arteries and serum VEGF levels in BD patients and healthy controls. Twenty-one patients with BD (male/female: 15/6, mean age: 35.8 +/- 8.6 years) were individually matched to control subjects on the basis of age (within 3 years) and sex. Carotid IMT of the subjects was measured by high-resolution B-mode US. Mean IMT values of common carotid arteries were 0.86 +/- 0.18 mm for patients with BD, and 0.57 +/- 0.14 mm for healthy controls (p < 0.001). Mean VEGF levels were 130.41 +/- 58.28 pg/ml for patients with BD and 82.69 +/- 25.03 pg/ml for healthy controls (p < 0.001). There was no correlation between VEGF levels in the control group and in the BD group, but there was a significant correlation between VEGF levels and mean carotid IMT in the whole group (r = 0.317, p < 0.05). In conclusion, elevation of VEGF appears as a feature of the inflammatory reaction during the course of BD, not a direct determinant of subclinical atherosclerosis. On the other hand, the significant correlation between carotid IMT and serum VEGF levels in the whole group suggests that association between VEGF levels and carotid IMT warrants further investigation with larger sample sizes.

Development of calciphylaxis after long-term steroid and methotroxate use in a patient with rheumatoid arthritis.

Calciphylaxis may be considered a small vessel vasculopathy which is generaly associated with end-stage renal disease and hyperparathyroidism. The precise pathogenesis of the disease is not known. It needs sensitizers and challengers to occur. Steroids and immunosuppressive drugs including methotrexate are among those challenger agents. Calciphylaxis in collagen vascular diseases is rare. Only one case in rheumatoid arthritis was recently reported. Here we describe a case of calciphylaxis associated with active rheumatoid arthritis. This patient had active disease despite treatment of steroids and methotrexate for a long time. She died shortly after the diagnosis of calciphylaxis due to sepsis.

Takayasu's arteritis: results of a university hospital of 45 patients in Turkey.

BACKGROUND: Takayasu's arteritis (TA) is a rare disease which appears to be most common in East Asia. However, the disease has been reported to be worldwide. The clinical features of the disease can show variations in different geographical areas. The aim of this study is to evaluate clinical, laboratory and radiological features and the outcome of patients with TA in our hospital. METHODS: The hospital files of patients who were followed with the diagnosis of TA between the years 1973 and 2003 in Hacettepe University Hospital were retrospectively evaluated. RESULTS: Male/female ratio was 5/40, and the mean age was 34 years (18-59). Constitutional symptoms were present in 71% of the patients. Claudication and pallor of the extremity, decreased extremity pulsations, arterial hypertension, and arterial bruits were present in 44%, 56%, 58%, and 27% of the patients, respectively. Aortic valvular insufficiency, abdominal aortic aneurism, and cardiomegaly were present in four, one, and four patients, respectively. The initial complaint of six patients was cerebrovascular events. The distribution of the patients according to the angiographic findings was as follows, 56% Type I, 18% Type II, 22% Type III, and 4% Type IV arteritis. The need for vascular surgical interventions were significantly less common in patients who were treated with immunosuppressives plus alternate dose steroids (6%) compared to patients who were treated only with antiaggregant agents (33%). CONCLUSIONS: The demographic and angiographic findings of our patients were similar to previous observations from Japan and Italy, and disclose distinct clinical features in comparison to other Asian countries. Alternate-day glucocorticoids plus cytotoxic drugs may be beneficial and safe in patients with TA.

Angiotensin-converting enzyme gene polymorphism in Behçet's disease.

Endothelial cell activation and/or injury is a characteristic feature of Behçet's disease (BD). The local renin-angiotensin system (RAS) in the vessel wall plays a prominent role in the endothelial control of vascular tonus and contributes to inflammatory processes. Angiotensin-converting enzyme (ACE) is the regulatory component of the RAS. In this study, we investigated the distribution of different alleles of the ACE gene in patients with BD, and the influence of the I/D polymorphism on different clinical manifestations of the disease. A cohort of 90 patients with BD were evaluated for their ACE genotype (male/female: 49/41, mean age: 36.9+/-10.6 years, min/max: 16-66 years). The mean duration of symptoms was 9.5+/-6.9 years (min/max: 1-35 years). The control population was composed of 30 healthy subjects (male/female: 15/15, mean age: 31.2+/-7.1 years, min/max: 20-45). The distribution of DD, ID and II genotypes of the ACE gene was 22 (24.5%), 56 (62.2%) and 12 (13.3%) for patients with BD, and 9 (30%), 16 (53.3%) and 5 (16.7%) for healthy controls, respectively. There was no significant difference between the groups (p>0.05). Similarly, there was no significant association between the ACE gene polymorphism and ocular, neurologic or vascular involvement of BD. The ACE gene polymorphism does not seem to play a role in the pathogenesis of BD. Moreover, possession of either the D or the I allele does not have an impact on the development of ocular, neurologic or vascular manifestations of the disease.

Decreased protein Z concentrations complicating the hypercoagulable state of Behçet's disease.

Protein Z is a vitamin-K-dependent plasma protein that serves as a cofactor for the inhibition of factor Xa. Although the precise physiologic function of protein Z is still unknown, abnormal plasma protein Z concentrations have been associated with a number of thrombotic disease states. There is the evidence of universal activation of the hemostatic system in Behçet's disease (BD), which represents a hypercoagulable/prothrombotic state. Circulating protein Z levels in patients with BD were evaluated. Plasma protein Z concentrations were assayed in 24 patients with BD (male/female: 13/11, mean age 35.4 years) and in 24 healthy controls (males/females: 14/10, mean age 59.8 years). The disease duration was 10.6 years (range, 1-30 years). None of the subjects in either group had received anticoagulants within 3 weeks before the study, and none of them had liver dysfunction. Patients complicated with vascular disease were also excluded from the study. Mean plasma concentrations of protein Z were 141 ng/mL (range, 56.8-257) in healthy controls and 107.8 ng/mL (range, 21.2-202) in BD patients (p<0.05). There was a positive correlation between the disease duration and protein Z levels in the study group (p<0.05, r=0.448). Alterations of protein Z concentrations could complicate the pathobiology of the prothrombotic state of BD. Furthermore, the tendency of increment in the protein Z with the passage of time may reflect the diminution of the disease activity.

Enhanced depth imaging optical coherence tomography findings in Behçet disease.

PURPOSE: Investigation of subfoveal choroidal thickness in Behçet disease (BD) with enhanced depth imaging optical coherence tomography (EDI-OCT). METHODS: The study included 35 patients with posterior uveitis (PU) associated with BD, 35 patients with BD without ocular involvement, and 30 healthy controls. RESULTS: There were no significant differences between the groups in terms of age, gender, axial length, or spherical equivalent refractive error. The mean subfoveal choroidal thickness was thinner in eyes with PU than in eyes without PU and healthy controls (p = 0.026). CONCLUSION: EDI-OCT is a beneficial test for evaluating choroid morphology in BD. Thinning of the subfoveal choroidal tissue has been observed in patients with BD-associated PU.

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

INTRODUCTION: HLA-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 Behçet's disease and HLA-B*52 in Takayasu's 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. METHODS: TAK 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. RESULTS: We 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). CONCLUSIONS: In 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.

Morphologic evidence of subclinical atherosclerosis obtained by carotid ultrasonography in patients with Behcet's disease.

Subclinical atherosclerosis can be demonstrated by measuring the intima-media thickness (IMT) of the carotid arteries by high-resolution B-mode ultrasonography (US). Endothelial injury appears a key event in the atherogenesis. Endothelial cell activation and/or injury are the characteristic features of Behçet's disease (BD). In this study, we investigated morphologic evidence of subclinical atherosclerosis in the BD patients by using high-resolution B-mode US. Thirty-four patients with BD without arterial involvement (male/female 21/13; mean age 34.6+/-8.5 years) were individually matched to control subjects on the basis of age (within 2 years) and sex. Subjects with diabetes mellitus, hypertension, evidence of myocardial infarction or cerebrovascular disease, and patients on long-term steroids (i.e., >6 months) were excluded from the study. Mean IMT values of the right carotid arteries were 0.81+/-0.17 mm for patients with BD, and 0.54+/-0.13 mm for healthy controls (P<0.001). Mean IMT values of the left carotid arteries were 0.82+/-0.16 mm for patients with BD, and 0.55+/-0.12 mm for healthy controls (P<0.001). The overall prevalence of carotid atherosclerotic plaques was higher among the patients than the controls [prevalence of plaques were 17.6% (6/34) in BD patients and 0% in healthy controls, P<0.05]. In conclusion, our data indicate morphologic evidence of subclinical atherosclerosis in patients with BD.

Neutrophil CD64 expression in Behçet's disease.

OBJECTIVE: Hyperfunction of neutrophils is a characteristic finding in Behçet's disease (BD). Microbial agents have been proposed as causative agents in the disease flares. Fc gamma receptor 1 (CD64) is not normally expressed by neutrophils of healthy individuals, but is upregulated by these cells in response to microbial wall components and proinflammatory cytokines. The degree of polymorphonuclear leukocyte (PMN) CD64 expression is different in autoimmune diseases and systemic infectious diseases. We investigated PMN CD64 expression in patients with BD. METHODS: Thirty-seven patients with active BD (M/F: 18/19, mean age: 34.4 +/- 9.7 yrs), 35 patients with inactive BD (M/F: 11/24, mean age: 35.9 +/- 11.6 yrs), 27 patients with culture proven infections (M/F: 19/8, mean age: 54.4 +/- 15.2 yrs), 31 healthy controls (M/F: 14/17, mean age: 37.7 +/- 8.7 yrs), and 42 patients with active inflammatory disease (M/F: 13/29, mean age: 39.3 +/- 14.9 yrs) were enrolled in this study. Flow cytometry was used to assess the prevalence of CD64-bearing PMN in whole blood samples. RESULTS: The prevalence of CD64-bearing PMN was significantly higher in patients with infectious disease (77.1 +/- 18.4), inflammatory disease (37.1 +/- 27.5), and active BD (48.9 +/- 22.5) than in healthy controls (9.5 +/- 7.8) or patients with inactive BD (12.9 +/- 9.5). CD64 expression was similar in controls and patients with inactive BD. In the infectious disease group, expression of CD64 was significantly higher than in the active BD and active inflammatory disease groups, while there was no significant difference between the groups of patients with active BD and inflammatory disorders. CONCLUSION: Neutrophil CD64 expression increases during exacerbation of BD. This increase appears to be a non-specific inflammatory response and does not reflect PMN activation triggered by a living microorganism.