Fatma Alibaz-Oner

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)).

Advances in the diagnosis, assessment and outcome of Takayasu's arteritis.

Takayasu’s arteritis (TAK) is a rare, chronic large-vessel vasculitis (LVV) that predominantly affects aorta, its major branches, and the pulmonary arteries. Segmental stenosis, occlusion, dilatation, or aneurysm formation may occur in the vessel wall during the course of the disease. The vascular involvement can be shown with different imaging modalities to make the diagnosis of TAK. Conventional angiography, the gold standard method for initial diagnosis, seems to be replaced with the new imaging modalities such as magnetic resonance angiography (MRA) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in recent years. The data coming from the new studies support that MRA and FDG-PET are also promising for the assessment of disease activity. Prognosis is possibly getting better with lower mortality in recent years; however, it is difficult to assess the widely different vascular intervention rates among the clinical series. Leflunomide, TNF-α antagonists, and tocilizumab are new options in patients resistant to conventional therapies. There is a clear need to develop a validated set of outcome measures for use in clinical trials of TAK. The OMERACT Vasculitis Working Group has taken on this task and aims to develop a core set of outcomes for LVV.

Epigenome-wide scan identifies a treatment-responsive pattern of altered DNA methylation among cytoskeletal remodeling genes in monocytes and CD4+ T cells from patients with Behçet's disease.

The pathogenesis of Behçets disease (BD), an inflammatory disease with multisystem involvement, remains poorly understood. This study was undertaken to investigate whether there are DNA methylation abnormalities in BD that might contribute to the pathogenesis 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.

Update on Takayasu's arteritis

Takayasu arteritis (TAK) is a rare, chronic large-vessel vasculitis (LVV) that predominantly affects aorta, its major branches and the pulmonary arteries. Recent advances in the genetics, clinical course, prognosis, disease assessment with biomakers/imaging/new scoring systems and new treatment options in TAK are discussed in this review. New imaging modalities such as MRAngiography (MRA) and 18-FDG-PET seem to have replaced conventional angiography for the initial diagnosis in recent years. MRA and 18-FDG-PET are also promising for the assessment of disease activity. New tools for disease assessment such as Indian Takayasu Arteritis Score (ITAS2010) and colour-Doppler ultrasonography score (CDUS) aim to quantify disease activity better, however different imaging modalities, used in routine follow-up, are not sufficiently incorporated in these scoring systems. Prognosis is possibly getting better with lower mortality in recent years, however there are still widely different vascular intervention rates in clinical series. Leflunomide, TNF-α antagonists and tocilizumab are new options in patients resistant to conventional therapies.

Evaluation of oxidative stress, the activities of paraoxonase and arylesterase in patients with subclinical hypothyroidism.

Introduction In subclinical hypothyroidism (SH), serum lipid and lipoprotein concentrations are frequently changed. Compared with the healthy population, the levels of oxidized low-density lipoprotein cholesterol are higher, and the levels of high-density lipoprotein cholesterol are lower. In patients with SH, the mechanism of atherosclerosis may beattributed to the lipid abnormalities. There is evidence showing that oxidation plays an important role during the process of atherosclerosis. Inthis study, we evaluated the activity of paraoxonase (PON) and arylesterase (ARE) in patients with SH and investigated their relation with oxidative stress. Methods The study enrolled 25 patients with SH and 20 sex- and age-matched healthy controls. The patient group and the control group were compared in terms of the activity of PON and ARE and the oxidative stress index. Results Between 2 groups, no significant difference was found in terms of age, sex, serum levels of total cholesterol, low-density lipoprotein, and high-density lipoprotein. In the SH group, the activity of PON was significantly lower than that observed in the control group (P < 0.05). Arylesterase activity also was significantly lower in the group with SH, compared with the control group (P < 0.05). Oxidative stress index was found to be significantly higher in the patient group, compared with the healthy subjects (P < 0.01). Oxidative stress index showed a strong positive correlation with the levels of thyroid stimulating hormone in all cases (r = 0.60, P < 0.01). Conclusions The activity of PON and ARE were significantly decreased, and oxidative stress was increased in patients with SH. Lower activities of these 2 biomarkers indicate increased oxidative damage in SH. Atherosclerosis in SH can be attributed to increased oxidative stress.

Patients with Takayasu's arteritis having persistent acute-phase response usually have an increased major vessel uptake by 18F-FDG-PET/CT

Abstract Objectives. Although not uniformly accepted, an increased uptake by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in large vessels is accepted to be a sign of active disease in Takayasus arteritis (TAK). We aimed to investigate the value of 18F-FDG-PET/CT for clinical assessment in a subset of TAK patients having a persistent acute-phase response (APR) without any signs or symptoms of clinical disease activity. Method. We studied 14 patients (mean age: 38.6 ± 13.9 years, Female/Male: 11/3, and disease duration: 5.7 ± 5 years). Patients were clinically inactive (according to the definition of activity by Kerr et al.), while categorized as having “persistent” disease activity by physicians global assessment due only to APR. 18F-FDG uptake was graded using a four-point scale from grade 0 (no uptake present) to grade 3 (high grade: uptake higher than that of liver). Any uptake in major vessels with a grade ≥ 2 was accepted to be “active.” Results. Mean erythrocyte sedimentation rate was 50.8 ± 13.2 mm/hour and mean C-reactive protein level was 28.5 ± 22.1 mg/L. Active vasculitic lesions were observed by 18F-FDG-PET/CT in 9 of 14 (64.3%) patients. The median number of active vascular lesions was 2 (range: 1–5). A step-up treatment change was decided in 8 patients according to 18F-FDG-PET/CT results. Conclusion. We observed increased 18F-FDG uptake in the majority of TAK patients with an increased APR, but clinically silent disease. 18F-FDG-PET/CT showed the presence and localization of active inflammation in the aorta and its branches. Although specificity for observed lesions is not clear, 18F-FDG-PET/CT imaging may influence physicians assessment of clinical activity and treatment choices in TAK.

Activation of the JAK/STAT pathway in Behcet’s Disease

Th1/Th17-type T-cell responses are upregulated in Behcet’s disease (BD). However, signaling pathways associated with this aberrant immune response are not clarified. Whole-genome microarray profiling was performed with human U133 (Plus 2.0) chips using messenger RNA of isolated CD14+ monocytes and CD4+ T cells from peripheral blood mononucleated cell (PBMC) in patients with BD (n=9) and healthy controls (HCs) (n=9). Flow cytometric analysis of unstimulated (US) and stimulated (phytohaemagglutinin) signal transducer and activator of transcription (STAT3) and pSTAT3 expressions of PBMCs were also analyzed (BD and HC, both n=26). Janus family of kinase (JAK1) was observed to be upregulated in both CD14+ monocytes (1.95-fold) and CD4+ T lymphocytes (1.40-fold) of BD patients. Using canonical pathway enrichment analysis, JAK/STAT signaling was identified as activated in both CD14+ monocytes (P=9.55E−03) and in CD4+ lymphocytes (P=8.13E−04) in BD. Interferon signaling was also prominent among upregulated genes in CD14+ monocytes (P=5.62E−05). Glucocorticoid receptor signaling and interleukin (IL-6) signaling were among the most enriched pathways in differentially expressed genes in CD14+ monocytes (P=2.45E−09 and 1.00E−06, respectively). Basal US total STAT3 expression was significantly higher in BD (1.2 vs 3.45, P<0.05). The JAK1/STAT3 signaling pathway is activated in BD, possibly through the activation of Th1/Th17-type cytokines such as IL-2, interferon (IFN-γ), IL-6, IL-17 and IL-23.

Assessment of the New 2012 EULAR/ACR Clinical Classification Criteria for Polymyalgia Rheumatica: A Prospective Multicenter Study

Objective. To assess the performance of the new 2012 provisional European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) polymyalgia rheumatica (PMR) clinical classification criteria in discriminating PMR from other mimicking conditions compared with the previous 5 diagnostic criteria in a multicenter prospective study. Methods. Patients older than 50 years, presenting with new-onset bilateral shoulder pain with elevated acute-phase reactants (APR), were assessed for the fulfillment of the new and old classification/diagnostic criteria sets for PMR. At the end of the 1-year followup, 133 patients were diagnosed with PMR (expert opinion) and 142 with non-PMR conditions [69 rheumatoid arthritis (RA)]. Discriminating capacity, sensitivity, and specificity of the criteria sets were estimated. Results. Discriminating capacity of the new clinical criteria for PMR from non-PMR conditions and RA as estimated by area under the curve (AUC) were good with AUC of 0.736 and 0.781, respectively. The new criteria had a sensitivity of 89.5% and a specificity of 57.7% when tested against all non-PMR cases. When tested against all RA, seropositive RA, seronegative RA, and non-RA control patients, specificity changed to 66.7%, 100%, 20.7%, and 49.3%, respectively. Except for the Bird criteria, the 4 previous criteria had lower sensitivity and higher specificity (ranging from 83%–93%) compared with the new clinical criteria in discriminating PMR from all other controls. Conclusion. The new 2012 EULAR/ACR clinical classification criteria for PMR is highly sensitive; however, its ability to discriminate PMR from other inflammatory/noninflammatory shoulder conditions, especially from seronegative RA, is not adequate. Imaging and other modifications such as cutoff values for APR might increase the specificity of the criteria.

Response rate of initial conventional treatments, disease course, and related factors of patients with adult-onset Still's disease: Data from a large multicenter cohort.

BACKGROUND Adult-onset Stills disease (AOSD) is a rare condition, and treatment choices are frequently dependent on expert opinions. The objectives of the present study were to assess treatment modalities, disease course, and the factors influencing the outcome of patients with AOSD. METHODS A multicenter study was used to reach sufficient patient numbers. The diagnosis of AOSD was based on the Yamaguchi criteria. The data collected included patient age, gender, age at the time of diagnosis, delay time for the diagnosis, typical AOSD rash, arthralgia, arthritis, myalgia, sore throat, lymphadenopathy, hepatomegaly, splenomegaly, pleuritis, pericarditis, and other rare findings. The laboratory findings of the patients were also recorded. The drugs initiated after the establishment of a diagnosis and the induction of remission with the first treatment was recorded. Disease patterns and related factors were also investigated. A multivariate analysis was performed to assess the factors related to remission. RESULTS The initial data of 356 patients (210 females; 59%) from 19 centers were evaluated. The median age at onset was 32 (16-88) years, and the median follow-up time was 22 months (0-180). Fever (95.8%), arthralgia (94.9%), typical AOSD rash (66.9%), arthritis (64.6%), sore throat (63.5%), and myalgia (52.8%) were the most frequent clinical features. It was found that 254 of the 306 patients (83.0%) displayed remission with the initial treatment, including corticosteroids plus methotrexate with or without other disease-modifying antirheumatic drugs. The multivariate analysis revealed that the male sex, delayed diagnosis of more than 6 months, failure to achieve remission with initial treatment, and arthritis involving wrist/elbow joints were related to the chronic disease course. CONCLUSION Induction of remission with initial treatment was achieved in the majority of AOSD patients. Failure to achieve remission with initial treatment as well as a delayed diagnosis implicated a chronic disease course in AOSD.