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.

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.

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)).

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.

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 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.

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.

Ethnicity may be a reason for lipid changes and high Lp(a) levels in rheumatoid arthritis.

There are so many studies that suggest the changes in lipid profiles and lipoprotein (a) [Lp(a)] are associated with early atherosclerosis in rheumatoid arthritis (RA). But there are some opposite studies also. Because of marked ethnicity differences in the distribution of Lp(a), we aimed to investigate the associations of Lp(a) levels and lipid changes in Turkish RA patients. There were 30 women and 20 men, a total of 50 patients with RA (mean age 47.6 +/- 13.2 years), included and 21 healthy women and 14 healthy men (mean age 45.7 +/- 14.5 years) were recruited as a control (C) group. Serum Lp(a), total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) levels were analysed for each group. Analysis of six different studies was performed. In the RA and C groups, mean serum Lp(a) levels were 39.7 +/- 64.4 and 10.5 +/- 13.4 mg/dl, respectively (P=0.001). Mean TC levels were 189.2 +/- 142.5 and 174.0 +/- 29.3 mg/dl (P=0.294), mean TG levels were 121.4 +/- 65.4 and 106.5 +/- 80.0 mg/dl (P=0.030), mean HDL-C levels were 44.5 +/- 10.0 and 47.7 +/- 4.8 mg/dl (P=0.014) and mean LDL-C levels were 94.3 +/- 35.3 and 102.0 +/- 24.6 mg/dl (P=0.98), respectively. Analysis of the six studies showed Lp(a) level was higher and HDL level was lower in RA patients than in healthy controls. Patients with RA may have altered lipid profiles from one country to another one. Especially in Turkey, higher serum Lp(a), lower HDL-C and higher TG levels may be found in RA patients instead of some findings of other countries showing different results. Ethnicity may be a reason for these findings.

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.

Wegener's granulomatosis: clinical and laboratory results of a university hospital study of 20 patients from Turkey.

The aim of this study was to evaluate the clinical and laboratory features, the treatment approaches, and the long-term outcome of patients with Wegener's granulomatosis (WG) who were followed up in our hospital. The hospital files of the patients with the diagnosis of WG who were followed up between the years 1985 and 2003 in Hacettepe University Hospital were retrospectively evaluated. Male/female ratio was 12:8. The mean age was 39 years (range 20-65 years). Constitutional symptoms and upper and lower airway involvement were seen in 95% of all patients. Renal and musculoskeletal symptoms were seen in 90 and 80% of the patients, respectively. Five patients were treated with oral monotherapy (three with methylprednisolone and two with cyclophosphamide). Three patients were given a combination of orally administered cyclophosphamide and methylprednisolone. Ten patients were treated with pulse cyclophosphamide and methylprednisolone combination together with oral alternate-day methylprednisolone therapy. The remaining two resistant patients were treated with pulse cyclophosphamide, methylprednisolone, and intravenous immunoglobulin combination together with oral alternate-day methylprednisolone. Four patients died because of the disease activity. Intravenous pulse therapies with oral, alternate-day methylprednisolone were well tolerated. Sixteen patients experienced long-term remission after immunosuppressive treatment. Eleven patients have been asymptomatic for more than 12 months. In five patients, residual symptoms persisted: constitutional symptoms and renal and respiratory tract symptoms in varying combinations. The demographic and laboratory findings in this trial were similar with those of the previous results. Alternate-day glucocorticoids plus cyctotoxic drugs may be beneficial in patients with WG.

Intensified, intermittent, low-dose intravenous cyclophosphamide together with oral alternate-day steroid therapy in lupus nephritis (long-term outcome).

The objective of this study is to evaluate the efficacy, toxicity, and long-term outcome of low-dose IV cyclophosphamid therapy with repeated frequent intervals in combination with oral and IV methylprednisolone in patients with SLE nephritis. In this study, 113 patients diagnosed as having SLE and glomerulonephritis were assessed in between 1993 and 2002, with a median follow-up of 44.1+/-41.2 months. The patients were treated with 500 mg IV cyclophosphamide and 1 g IV methylprednisolone together with 60 mg/alternate-day oral methylprednisolone in a given schedule. The clinical and laboratory data were evaluated. There were significant improvements in the clinical and the laboratory parameters. Six patients died shortly after being hospitalized due to the disease activity itself. Eight patients were excluded from the study because of low compliance. The renal functions of the patients remained stable throughout the therapy; only 16/99 patients needed one or two additional pulses. Temporary leukopenia developed in 18/99 patients and diminished with the suspension or prolongation of the IV cyclophosphamide administration. Gastrointestinal side effects, which needed extra medication, developed in 20 patients. Hematuria was observed in 6/99 patients. Menstrual abnormalities were seen in 7/99 patients. No serious infections due to immunosuppression were observed with the given regimen. Hypertension was observed in 13 patients (minimum of 140/90 mmHg, maximum of 190/110 mmHg) and controlled with angiotensine-converting enzyme inhibitors. Mild central obesity was observed in 15 of the patients. Leimyosarcoma was observed in one patient who died during the follow-up period. Therapy starting with the weekly low-dose IV cyclophosphamide to induce remission together with IV and oral steroids, followed by prolonged intervals with the same doses for 2 years, appears to be useful in preserving renal function without major side effects in patients with lupus nephritis, in comparison to other studies.

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.

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.

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 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.

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.