Zeynep Ozbalkan

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)).

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.

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.

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.

Frequency of Lymphadenopathy in Rheumatoid Arthritis and Systemic Lupus Erythematosus

This study aimed to assess the frequency of all palpable lymph nodes during active disease and remission in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Hospital records of 100 SLE patients, 100 RA patients, 100 spondyloarthropathy patients, and 150 osteoarthritis patients, treated in our rheumatology department, were evaluated retrospectively. Overall frequencies of enlarged lymph nodes in patients with active RA and SLE were 82% and 69%, respectively. Enlarged lymph nodes associated with RA were mostly located in the axillary region, and in SLE the nodes were smaller and lymphadenopathy was more generalized compared with RA. Palpable lymph nodes disappeared in the majority of patients during remission. Lymphadenopathy was significantly less frequent in patients treated with steroids before admission. Lymph node enlargement is an important physical finding associated with RA and SLE disease activity. Atypical locations and unusually large lymph nodes should raise clinical suspicion of another underlying disease.

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

Abstract 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.

The efficacy of oral cyclophosphamide plus prednisolone in early diffuse systemic sclerosis

Pharmacological treatment of diffuse systemic sclerosis (SSc) directed at the tissue fibrosis has generally been ineffective. Many immunosuppressive drugs have been tried as therapy for SSc, regardless of the disease subtype and/or stage. The aim of this study was to show the efficacy and the toxicity of oral cyclophosphamide and prednisolone therapy on the prevention of fibrosis-based tissue damage in the early stages of the diffuse SSc. Twenty-seven patients with early diffuse SSc were treated with oral cyclophosphamide (1–2 mg/kg/day) plus oral prednisolone (40 mg/every other day) between the years 1995 and 1998. The results regarding the efficacy and toxicity of cyclophosphamide were compared with those of 22 early SSc patients who had been treated with oral D-penicillamine between 1992 and 1995. All the patients were evaluated using clinical and laboratory parameters every 6 months for 2 years. There was a significant improvement on the skin score, maximal oral opening, flexion index, predicted forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO) in the cyclophosphamide group. The decrease in skin score in the cyclophosphamide group started earlier than in the D-penicillamine group. No life-threatening or irreversible adverse reaction was observed. This open study supports the use of oral cyclophosphamide plus prednisolone therapy to prevent fibrosis and its complications in the early stages of diffuse SSc.

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.

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

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.

Decreased Protein Z Concentrations Complicating the Hypercoagulable State of Behqet'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, abnornal 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 Behqets 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.