Dual effects of testosterone in Behcet's disease: implications for a role in disease pathogenesis.

Behcet's disease (BD) exhibits more severe disease course and higher mortality among male patients. However, underlying mechanisms of gender differences in clinical manifestations and disease severity are unclear. The aim of this study was to determine whether testosterone (T) has any role on BD pathogenesis. We studied peripheral blood mononuclear cells (PBMC) and neutrophils of BD patients and controls. Functional assay of neutrophils, cytokine measurements of culture supernatants and gene expressions on both cells were analyzed before and after T incubation. Neutrophils were significantly activated after incubation with T in only BD patients. Incubation with T caused significantly elevated interleukin (IL)-12 and IL-2 in BD. Gene expression of IL-10 was significantly downregulated after incubation with T in BD, especially in male patients. The same difference was observed in IL-10 levels in culture supernatant after T. Baseline TLR4 expression was significantly higher in BD patients compared to healthy donors (HC). Toll-like receptor (TLR) 4 expression on PBMC was significantly elevated in female BD patients. ERAP1 expressions of all patients and controls were decreased under the T effect but it differed significantly between BD vs HC. Baseline IL23R expression was higher in BD males compared with females but the difference disappeared after T. When BD patients were analyzed separately, baseline C-C motif chemokine receptor1 (CCR1), STAT4, TLR4 and KLRC4 expressions were lower in males. Despite immunosuppressive behavior in healthy subjects, T causes neutrophil hyperactivation and TH1 type immune alterations in BD patients. Our results suggest that T may have a role in BD pathogenesis by altering the expression level of IL-10, TLR4, ERAP1, CCR1.

Role of fibrinolytic parameters and plasminogen activator inhibitor 1 (PAI-1) promoter polymorphism on premature atherosclerosis in SLE patients.

Premature atherosclerosis has been recognized as a major co-morbid condition in systemic lupus erythematosus (SLE). In this study, we aimed to investigate the effect of tPA (tissue plasminogen activator) and PAI-1 (plasminogen activator inhibitor) antigen concentrations and 4G/5G polymorphism of the PAI-1 gene on the development of atherosclerosis in SLE patients. One hundred and six SLE patients, 28 Takayasu arteritis (TA) patients and 98 healthy control subjects (HCs) were studied. PAI-1 and tPA antigen levels were measured by ELISA method. PAI-1 gene polymorphism was determined by using allele-specific PCR method. SLE patients had a significantly higher frequency (22.6%) of plaque (p = 0.01) and higher IMT (p=0.04) compared with HCs respectively. Only age at disease onset was associated with plaque formation in multivariate regression analysis (p = 0.001). Plasma tPA ag levels in SLE patients were significantly higher compared with HCs (p = 0.005) and PAI-1 ag levels were significantly higher compared with TA patients (p = 0.03). There were no significant differences between study groups in both genotype distribution and allele frequencies of PAI-1 gene, but SLE patients with 4G/4G genotype had higher IMT (p = 0.02) calcium scoring (p = 0.006) compared with 4G5G/5G5G genotypes. The present study suggests that measuring fibrinolytic parameters would have little additional benefit beyond traditional and novel risk factors in predicting coronary artery disease (CAD).

Takayasu's arteritis in Turkey - clinical and angiographic features of 248 patients.

OBJECTIVE: Takayasu's arteritis (TA) is a chronic, inflammatory vasculitis affecting the aorta and its major branches. Although it is more prevalent in Far-East Asia, the distribution of the disease is worldwide with different vascular involvement patterns and clinical manifestations. The objective of this study was to evaluate the demographic, clinical, angiographic and prognostic features of TA patients in Turkey. METHODS: Clinical and angiographic findings of 248 TA patients (228 female, 27 male) followed at 15 Rheumatology Centers were prospectively evaluated according to a predefined protocol. RESULTS: The mean age was 40.1 years (30.2 years at the clinical onset). Clinical manifestations included constitutional symptoms in 66%, absent or diminished pulses in 88%, bruits in 77%, extremity pain in 69%, claudication in 48%, hypertension in 43% and cerebrovascular accidents (CVA) in 18% of the patients. Renal artery stenosis, aortic regurgitation and pulmonary hypertension were present in 26%, 33% and 12%, respectively. According to the new angiographic classification, type V (50.8%) and Type I (32%) were the most frequent types of involvement. Corticosteroids were the main treatment in 93% of the patients alone (9%) or in combination with immunosuppressive agents (84%). Most frequently preferred immunosuppressive agents were methotrexate (63%), azathioprine (22%) and cyclophosphamide (13%). Remission was observed at least once in 94% of the patients and sustained remission in 71% during follow-up. CONCLUSION: The demographical, clinical and angiographic findings of TA patients in our series were similar to those reported from Japan, Brazil and Colombia. Combination therapies with immunosuppressive agents were the preferred choice of treatment in Turkey.

PTPN22 gene polymorphism in Takayasu's arteritis.

OBJECTIVE: Takayasu's arteritis (TA) is a chronic, rare granulomatous panarteritis of unknown aetiology involving mainly the aorta and its major branches. In this study, genetic susceptibility to TA has been investigated by screening the functional single nucleotide polymorphism (SNP) of PTPN22 gene encoding the lymphoid-specific protein tyrosine phosphatase. METHODS: Totally, 181 patients with TA and 177 healthy controls are genotyped by PCR-RFLP method for the SNP rs2476601 (A/G) of PTPN22 gene. Polymorphic region was amplified by PCR and digested with Xcm I enzyme. RESULTS: Detected frequencies of heterozygous genotype (AG) were 5.1% (9/177) in control group and 3.8% (7/181) in TA group (P = 0.61, odds ratio: 0.75, 95% CI: 0.3, 2.0). No association with angiographic type, vascular involvement or prognosis of TA was observed either. CONCLUSION: The distribution of PTPN22 polymorphism did not reveal any association with TA in Turkey.

Anti-Saccharomyces cerevisiae antibodies (ASCA) in spondyloarthropathies: a reassessment.

OBJECTIVES: Seronegative spondyloarthropathies, especially ankylosing spondylitis (AS), is shown to be associated with inflammatory bowel disease. Anti-Saccharomyces cerevisiae antibodies (ASCA) is a valid serological marker for Crohn's disease. Presence of ASCA is controversial in AS. In this study, we aimed to investigate the prevalence of ASCA in spondyloarthropathies and its relationship with disease activity and severity. METHODS: One hundred and seventy-five patients with AS, 47 patients with undifferentiated spondyloarthropathy (uSpA) and 103 healthy controls (HCs) were studied. All patients were questioned for demographic features and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores. Radiological damage is assessed by Bath Ankylosing Spondylitis Radiology Index (BASRI) and modified Stroke Ankylosing Spondylitis Spinal Score (mSASSS). ASCA levels were measured with standard ELISA kits. RESULTS: There was an overall increased prevalence of ASCA IgA in AS and uSpA compared with HCs (20.6 and 19.1% vs 5.8%, P = 0.0008 and P = 0.02, respectively). No association was observed between ASCA positivity and erythrocyte sedimentation rate, C-reactive protein levels and BASDAI scores. However, ASCA-positive patients had higher BASRI scores [median BASRI: 7 (2-12) vs 6 (2-12); P = 0.037]. Although not reaching significance, they also had reduced chest expansion and higher Bath Ankylosing Spondylitis Functional Index (BASFI) scores. ASCA-positive AS patients also required anti-tumour necrosis factor therapy more frequently (P = 0.006). CONCLUSIONS: ASCA IgA seems to be more prevalent in AS and uSpA. ASCA can also be a marker of radiological damage and a more severe course in AS.

PTPN22 gene polymorphism in Behçet's disease.

A functional single nucleotide polymorphism (SNP) of PTPN22 gene encoding the protein tyrosine phosphatase has been reported to be associated with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus and type I diabetes. PTPN22 R620W polymorphism has a wide variation of allelic frequencies among different populations. This polymorphism is investigated in Turkish patients with Behçet's disease (BD), a systemic vasculitis with immune activation. DNA samples from 134 patients with BD and 177 healthy controls are genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism method for the SNP (rs2476601, A/G) of PTPN22 gene. Polymorphic region was amplified by PCR and digested with XcmI enzyme. The frequency of heterozygous genotype (AG) was 5.1% (9/177) in control group, whereas polymorphic allele was not present in the whole BD group (P = 0.012, OR 0.65, 95% confidence interval 0.0-1.1). Both the lower prevalence in the general population and the absence in BD show the limited role of PTPN22 polymorphism in the pathogenesis of autoimmunity in Turkey.

Interleukin (IL)-12, IL-2, and IL-6 gene polymorphisms in Takayasu's arteritis from Turkey.

Takayasu's arteritis (TA) is a chronic arterial inflammation of unknown etiology involving mainly the aorta and its major branches. Genetic polymorphisms of cytokines are screened as susceptibility factors for TA in Turkey. A total of 94 patients with TA were investigated for the genetic polymorphisms of the interleukin genes IL12, IL2,and IL6 and were compared with 108 healthy control subjects using polymerase chain reaction-sequence-specific primer method. The frequencies of IL12B 1188 C allele (p = 0.03, OR = 1.7) and CC genotype (p = 0.007, OR = 3.7) were both higher in TA patients than in control subjects. TT genotype at IL2-330 (p = 0.006, OR = 2.4) and GG genotype at IL6-174 (p = 0.04, OR = 1.9) were more frequent in TA patients. Lower prevalence of GT genotype at IL2-330 (p = 0.005, OR = 0.4), CG genotype at IL6-174 (p = 0.001, OR = 0.4), and AG genotypes at IL6-598 (p = 0.01, OR = 0.4) were also detected. The polymorphism of IL-12 as well as IL-6 and IL-2 genes may contribute to susceptibility and pathogenesis of TA by altering cytokine production and inducing inflammation.