Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study.

Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 × 10-5) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.

An investigation of thiol/disulfide homeostasis in patients with Behçet's disease.

INTRODUCTION: Behçet's disease (BD) is a relapsing systemic inflammatory disorder. The diagnosis of BD is primarily based on clinical findings. Current biomarkers are not yet sufficient to diagnose and cannot anticipate the course of the disease and response to treatment. The aim of this study was to evaluate the relationship between the thiol-disulfide balance and disease activity and organ involvement in BD. MATERIAL AND METHODS: A hundred fifty patients with BD and 100 age- and gender-matched healthy controls were included in the study. Disease activity was assessed with the BD Current Activity form score. Serum levels of native thiol (NT), total thiol (TT), and disulfide were measured and the disulfide/native thiol, disulfide/total thiol and native thiol/total thiol levels were calculated for the patient and control groups. RESULTS: Native thiol, total thiol, native thiol/total thiol values of the BD patients were significantly lower than those of the control group. The disulfide/native thiol, disulfide/total thiol values of BD patients were higher compared to the control group and the disulfide value of the BD group was slightly higher compared to the control group. No correlation was determined between thiol levels and disease activity and organ involvement in BD. CONCLUSIONS: In patients with Behcet's disease, the thiol-disulfide homeostasis balance shifted towards disulfide formation due to thiol oxidation. It may be used as a novel marker in BD because it is easy, practical, fully automated and relatively inexpensive.

Serum calprotectin and ischemia modified albumin levels as markers of disease activity in Behçet's disease.

INTRODUCTION: Behçet's disease (BD) is a complex multisystemic inflammatory disorder which is characterized by recurrent attacks of acute inflammation. As there is no universally recognized pathognomonic laboratory marker of BD, its diagnosis is still based on clinical findings. AIM: To evaluate the role of calprotectin and ischemia modified albumin (IMA) as biomarkers in the assessment of disease activity of BD. MATERIAL AND METHODS: A total of 93 patients with BD and 62 age- and gender-matched healthy controls were included in the study. Disease activity was assessed with the BD Current Activity Form (BDCAF) score. Serum levels of calprotectin, high-sensitivity C-reactive protein (hsCRP) and IMA were measured in the patient and control groups. RESULTS: Serum levels of calprotectin, IMA and hsCRP in patients with BD were higher than those of the healthy control group (p < 0.001 for all). No correlations between calprotectin and IMA, hsCRP, erythrocyte sedimentation rate, CRP, or BDCAF score were found. CONCLUSIONS: As the calprotectin level are increased in BD patients, it could be a candidate biomarker which plays a role in BD pathogenesis.

Follow-Up of Treatment Response With Dynamic Doppler Ultrasound in Raynaud Phenomenon.

OBJECTIVE: The purpose of this study was to investigate the role of flow parameters obtained with dynamic Doppler ultrasound in the objective follow-up of treatment response in patients with Raynaud phenomenon (RP). SUBJECTS AND METHODS: The study included 33 patients with newly diagnosed primary RP, 31 with secondary RP, and 26 healthy participants (control subjects). Both groups of patients with RP underwent sonography before and after treatment. The control group underwent sonography once. Baseline digital arterial diameter and flow volume were measured at room temperature. After cold provocation, diameter and flow volume were measured again, and flow starting time and flow normalizing time were recorded. Data were measured as mean (± SD) values. RESULTS: Baseline diameter did not significantly increase in either group after treatment (p > 0.05) (primary RP pretreatment, 0.79 ± 0.17 mm; posttreatment, 0.82 ± 0.19 mm; secondary RP pretreatment, 0.66 ± 0.13 mm; posttreatment, 0.68 ± 0.14 mm). Baseline flow volume increased significantly in both groups (p < 0.01) (primary RP pretreatment, 3.08 ± 2.96 mL/min; posttreatment, 3.91 ± 3.39 mL/min; secondary RP pretreatment, 2.14 ± 1.94 mL/min; posttreatment, 2.80 ± 2.15 mL/min). Cold provocation diameter increased significantly in both groups after treatment (p < 0.01) (primary RP pretreatment, 0.63 ± 0.15 mm; posttreatment, 0.70 ± 0.16 mm; secondary RP pretreatment, 0.56 ± 0.15 mm; posttreatment, 0.63 ± 0.13 mm). Cold provocation flow volume increased significantly in both groups after treatment (p < 0.01) (primary RP pretreatment, 1.18 ± 1.26 mL/min; posttreatment, 2.17 ± 2.16 mL/min; secondary RP pretreatment, 1.07 ± 1.40 mL/min; posttreatment, 1.46 ± 1.67 mL/min). After treatment, there was no statistically significant increase in flow starting time in patients with primary RP (p > 0.05), but there was a significant increase in patients with secondary RP (p < 0.05) (primary RP pretreatment, 1.15 ± 2.27 minutes; posttreatment, 0.61 ± 1.41 minutes; secondary RP pretreatment, 3.13 ± 4.81 minutes; posttreatment, 1.58 ± 2.36 minutes). After treatment, flow volume normalizing time improved significantly in both groups (p < 0.01) (primary RP pretreatment, 7.24 ± 7.60 minutes; posttreatment, 3.84 ± 3.39 minutes; secondary RP pretreatment, 9.58 ± 8.49 minutes; posttreatment, 4.32 ± 3.56 minutes). Among patients with primary RP, the posttreatment flow starting time was similar to that in the control group. Despite improvements, all remaining parameters differed in the treatment group compared with the control group. CONCLUSION: Doppler ultrasound can be used effectively to monitor RP treatment. Blood flow volume can be measured without cold provocation to facilitate follow-up care of patients with RP.

Rectal Adenocarcinoma As An Uncommon Cause of Immunoglobulin A Vasculitis (Henoch-Schönlein Purpura).

Immunoglobulin A vasculitis (Henoch-Schönlein purpura) is an immunoglobulin A-mediated vasculitis of unknown cause, which is characterized by non-thrombocytopenic purpura, arthralgia, abdominal pain, and glomerulonephritis. It most commonly occurs in children, and usually follows a benign course. It can also affect adults and is probably related to malignancy. In this article, we report a case of rectal adenocarcinoma in an immunoglobulin A vasculitis with renal involvement.

Identification of Susceptibility Loci in IL6, RPS9/LILRB3, and an Intergenic Locus on Chromosome 21q22 in Takayasu Arteritis in a Genome-Wide Association Study.

OBJECTIVE: Takayasu arteritis is a rare large vessel vasculitis with incompletely understood etiology. This study was undertaken to perform the first unbiased genome-wide association analysis of Takayasu arteritis. METHODS: Two independent cohorts of patients with Takayasu arteritis from Turkey and North America were included in our study. The Turkish cohort consisted of 559 patients and 489 controls, and the North American cohort consisted of 134 patients and 1,047 controls of European ancestry. Genotyping was performed using the Omni1-Quad and Omni2.5 genotyping arrays. Genotyping data were subjected to rigorous quality control measures and subsequently analyzed to discover genetic susceptibility loci for Takayasu arteritis. RESULTS: We identified genetic susceptibility loci for Takayasu arteritis with a genome-wide level of significance in IL6 (rs2069837) (odds ratio [OR] 2.07, P = 6.70 × 10(-9)), RPS9/LILRB3 (rs11666543) (OR 1.65, P = 2.34 × 10(-8)), and an intergenic locus on chromosome 21q22 (rs2836878) (OR 1.79, P = 3.62 × 10(-10)). The genetic susceptibility locus in RPS9/LILRB3 lies within the leukocyte receptor complex gene cluster on chromosome 19q13.4, and the disease risk variant in this locus correlates with reduced expression of multiple genes including the inhibitory leukocyte immunoglobulin-like receptor gene LILRB3 (P = 2.29 × 10(-8)). In addition, we identified candidate susceptibility genes with suggestive levels of association (P < 1 × 10(-5)) with Takayasu arteritis, including PCSK5, LILRA3, PPM1G/NRBP1, and PTK2B. CONCLUSION: Our findings indicate novel genetic susceptibility loci for Takayasu arteritis and uncover potentially important aspects of the pathophysiology of this form of vasculitis.

Fatigue in rheumatic diseases.

Fatigue is a common and important problem in many diseases including rheumatologic illnesses, and it has a negative impact on health-related quality of life. Fatigue is described as having an impact on multiple aspects of a patient's life. There is a need for knowledge about causes of and treatments for fatigue to ensure that patient outcomes are improved. There are several effective treatment strategies available for fatigue including pharmacological and non-pharmacological therapies. We aim to provide an overview of fatigue in rheumatologic disorders and some recommendations on its optimal management.

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)).

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.

PDCD1 polymorphisms are not associated with Takayasu's arteritis in Turkey.

OBJECTIVES: Takayasu's arteritis (TA) is a chronic arterial inflammation of unknown etiology involving mainly the aorta and its major branches. Based on the associations of programmed death-1 (PD-1) protein encoding gene (PDCD1) with connective tissue diseases and vasculitides, PDCD1 polymorphisms are studied for susceptibility to TA in this study. METHODS: The study group is made up of TA patients (n=229) fulfilling the 1990 ACR classification criteria and compared to 193 healthy controls (HC). PD-1.3, PD-1.5 and PD-1.6 single nucleotide polymorphisms of PDCD1 gene are genotyped by polymerase chain reaction and restriction analysis (PCR-RFLP). RESULTS: The distribution of PD-1.5 polymorphism in TA patients and HC revealed a similar presence of TT genotype in patients and controls (13.3% vs. 11.4%). PD-1.3 and PD-1.6 were less polymorphic and did not differ between the groups. Rare AA genotype of PD-1.3 (1.4% vs. 1.0%) and AG genotype of PD-1.6 was again similarly (22.4% vs. 19.2%) present in TA and HC. CONCLUSIONS: PD-1.3, 1.5 and 1.6 polymorphisms of PDCD1 gene, which were shown to be associated with various autoimmune disorders and vasculitides, are not associated with a susceptibility to TA in Turkish population.

Recent insights into the relationship between inflammatory liver diseases and atherosclerosis.

Atherosclerosis is a dynamic process in the human body. Many studies have evaluated atherosclerosis and its relationship with other systems in the body. Our perception of its pathogenesis is evolving with the introduction of new players in the game. It is no longer possible to consider the atherosclerosis as an independent process, unaffected by the liver and its function. Although several tasks performed by the liver, such as lipid metabolism, have been implicated in the pathogenesis of atherosclerosis, the role of other disorders of the liver (autoimmune diseases, viral hepatitis, and cirrhosis) are not fully understood. In this review, the most commonly encountered inflammatory liver diseases and their effects on atherosclerosis are discussed.

Autoimmune liver disease in patients with systemic lupus erythematosus: a retrospective analysis of 147 cases.

OBJECTIVE: We aimed to investigate the characteristics of autoimmune liver disease (AILD) developed in patients with systemic lupus erythematosus (SLE), including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and the AIH/PBC overlap syndrome. We also evaluated the accuracy of diagnostic criteria and scoring systems for AILD in SLE. METHODS: A retrospective analysis of patients attending the rheumatology and gastroenterology clinics in Ankara, Turkey, between 1999 and 2010. SLE patients with elevated liver enzymes were investigated for liver diseases. RESULTS: A total of 147 SLE patients were identified and 36 of them had liver enzyme abnormalities. AILD was diagnosed in 4.7% of all SLE patients, in 19.4% of those with elevated liver enzymes. Of patients with liver enzyme abnormalities, 72.3% fulfilled the criteria for AIH proposed by the International Autoimmune Hepatitis Group (IAIHG), whereas 66.7% had AIH by using the simplified criteria. Yet, only 13.8% of these patients had liver biopsy findings consistent with AIH. Patients with AILD were treated with conventional therapy including ursodeoxycholic acid, prednisolone, azathioprine or combinations of these. Treatment failure and subsequent advanced liver disease developed in one patient. CONCLUSIONS: AILD may occur during the course of SLE. Due to biochemical similarities between AIH and SLE, AIH could be considered very probable by using both IAIHG scoring system and simplified criteria. For definitive diagnosis of AIH, liver biopsy should be performed in all SLE patients with chronic enzyme abnormalities. The response to therapy is favorable in these patients, and early diagnosis is important for preventing advanced liver disease.

An update on the relationships between rheumatoid arthritis and atherosclerosis.

Rheumatoid arthritis is a chronic inflammatory disease. Cardiovascular events are the most important cause of mortality and morbidity in patients with rheumatoid arthritis. Beyond the traditional cardiovascular risk factors, chronic systemic inflammation has been shown to be a crucial factor in atherosclerosis development and progression from endothelial dysfunction to plaque rupture and thrombosis. Many studies have shown that atherosclerosis is not a passive event like accumulation of lipids in the vessel walls; by contrast, it represents an active inflammation of the vessels. Inflammatory cells such as macrophages, monocytes and T cells play important roles in the development of both rheumatoid arthritis and atherosclerosis. In this article we analyse the relationships between rheumatoid arthritis and atherosclerosis.

Atherogenic lipoprotein phenotype and LDL size and subclasses in drug-naïve patients with early rheumatoid arthritis.

OBJECTIVE: Subjects with rheumatoid arthritis (RA) have increased cardiovascular risk and may show atherogenic forms of dyslipidemia. The present study investigated whether patients with early RA, beyond alterations in plasma lipids, also show lower LDL size and altered LDL subclass distribution. DESIGN AND METHODS: We identified 25 subjects with RA (47+/-8 years, body mass index (BMI) 25+/-4kg/m(2)) by the American College of Rheumatology diagnostic criteria, with a disease durations <1 year and no prior treatment against it. In patients and 22 healthy subjects matched for age and BMI (controls) we measured plasma lipids and LDL size and subclasses by gradient gel electrophoresis. RESULTS: As compared to controls RA patients had higher plasma triglycerides (1.8+/-0.5 vs. 1.0+/-0.5mmol/L, p<0.0001) and lower HDL-cholesterol concentrations (1.2+/-0.2 vs. 1.4+/-0.2mmol/L, p=0.0027), while total- and LDL-cholesterol concentrations were similar. LDL particle size was lower in RA patients than controls (264+/-7 vs. 281+/-9A, p<0.0001), due to less LDL-I (31+/-6 vs. 38+/-7%, p=0.0004) and LDL-IIA (14+/-3 vs. 16+/-3%, p=0.0182), and more LDL-IIIB (7+/-1 vs. 5+/-1%), -IVA (11+/-2 vs. 8+/-2%) and -IVB particles (12+/-2 vs. 9+/-2%,) (p<0.0001 for all). Further, about 1/3 of patients showed the complete "atherogenic-lipoprotein-phenotype" (e.g. the concomitant presence of high triglycerides, low HDL-cholesterol and elevated small, dense LDL). CONCLUSIONS: Beyond plasma lipids, increased levels of small, dense LDL seems to be common in drug-naïve patients with early RA. Yet, whether these findings affect the atherogenic process and the clinical endpoints in these subjects remains to be determined by future prospective studies.

Skewed X-chromosome inactivation in scleroderma.

Scleroderma is a female-prevalent autoimmune disease of unclear etiology. Two fundamental gender differences, skewed X-chromosome inactivation (XCI) and pregnancy-related microchimerism, have been implicated in scleroderma. We investigated the XCI patterns of female scleroderma patients and the parental origin of the inactive X chromosome in those patients having skewed XCI patterns (>80%). In addition, we investigated whether a correlation exists between XCI patterns and microchimerism in a well-characterized cohort. About 195 female scleroderma patients and 160 female controls were analyzed for the androgen receptor locus to assess XCI patterns in the DNA extracted from peripheral blood cells. Skewed XCI was observed in 67 (44.9%) of 149 informative patients and in 10 of 124 healthy controls (8.0%) [odds ratio (OR) = 9.3 (95% confidence interval (CI) 4.3-20.6, P < 0.0001)]. Extremely skewed XCI (>90%) was present in 44 of 149 patients (29.5%) but only in 3 of 124 controls (2.4%; OR = 16.9; 95% CI 4.8-70.4, P < 0.0001). Parental origin of the inactive X chromosome was investigated for ten patients for whom maternal DNA was informative, and the inactive X chromosome was of maternal origin in eight patients and of paternal origin in two patients. Skewed XCI mosaicism could be considered as an important risk factor in scleroderma.