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    Characteristics predicting tuberculosis risk under tumor necrosis factor-? inhibitors: Report from a large multicenter cohort with high background prevalence
    (Journal of Rheumatology, 2016) Kisacik B.; Pamuk O.N.; Onat A.M.; Erer S.B.; Hatemi G.; Ozguler Y.; Pehlivan Y.; Kilic L.; Ertenli I.; Can M.; Direskeneli H.; Keser G.; Oksel F.; Dalkilic E.; Yilmaz S.; Pay S.; Balkarli A.; Cobankara V.; Cetin G.Y.; Sayarlioglu M.; Cefle A.; Yazici A.; Avci A.B.; Terzioglu E.; Ozbek S.; Akar S.; Gul A.
    Objective. Screening strategies for latent tuberculosis (TB) before starting tumor necrosis factor (TNF)- inhibitors have decreased the prevalence of TB among patients who are treated with these agents. However, despite vigilant screening, TB continues to be an important problem, especially in parts of the world with a high background TB prevalence. The aim of this study was to determine the factors related to TB among a large multicenter cohort of patients who were treated with anti-TNF. Methods. Fifteen rheumatology centers participated in this study. Among the 10,434 patients who were treated with anti-TNF between September 2002 and September 2012, 73 (0.69%) had developed TB. We described the demographic features and disease characteristics of these 73 patients and compared them to 7695 patients who were treated with anti-TNF, did not develop TB, and had complete data available. Results. Among the 73 patients diagnosed with TB (39 men, 34 women, mean age 43.6 ± 13 yrs), the most frequent diagnoses were ankylosing spondylitis (n = 38) and rheumatoid arthritis (n = 25). More than half of the patients had extrapulmonary TB (39/73, 53%). Six patients died (8.2%). In the logistic regression model, types of anti-TNF drugs [infliximab (IFX), OR 3.4, 95% CI 1.88-6.10, p = 0.001] and insufficient and irregular isoniazid use (< 9 mos; OR 3.15, 95% CI 1.43-6.9, p = 0.004) were independent predictors of TB development. Conclusion. Our results suggest that TB is an important complication of anti-TNF therapies in Turkey. TB chemoprophylaxis less than 9 months and the use of IFX therapy were independent risk factors for TB development. Copyright © 2016 The Journal of Rheumatology. All rights reserved.
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    Identification of susceptibility loci in IL6, RPS9/LILRB3, and an intergenic locus on chromosome 21q22 in takayasu arteritis in a genome-wide association study
    (John Wiley and Sons Inc., 2015) Renauer P.A.; Saruhan-Direskeneli G.; Coit P.; Adler A.; Aksu K.; Keser G.; Alibaz-Oner F.; Aydin S.Z.; Kamali S.; Inanc M.; Carette S.; Cuthbertson D.; Hoffman G.S.; Akar S.; Onen F.; Akkoc N.; Khalidi N.A.; Koening C.; Karadag O.; Kiraz S.; Langford C.A.; Maksimowicz-Mckinnon K.; McAlear C.A.; Ozbalkan Z.; Ates A.; Karaaslan Y.; Duzgun N.; Monach P.A.; Ozer H.T.E.; Erken E.; Ozturk M.A.; Yazici A.; Cefle A.; Onat A.M.; Kisacik B.; Pagnoux C.; Kasifoglu T.; Seyahi E.; Fresko I.; Seo P.; Sreih A.G.; Warrington K.J.; Ytterberg S.R.; Cobankara V.; Cunninghame-Graham D.S.; Vyse T.J.; Pamuk O.N.; Ercan Tunc S.; Dalkilic E.; Bicakcigil M.; Yentur S.P.; Wren J.D.; Merkel P.A.; Direskeneli H.; Sawalha A.H.
    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. © 2015, American College of Rheumatology.
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    Incidence of cyclophosphamide-induced urotoxicity and protective effect of mesna in rheumatic diseases
    (Journal of Rheumatology, 2015) Yilmaz N.; Emmungil H.; Gucenmez S.; Ozen G.; Yildiz F.; Balkarli A.; Kimyon G.; Coskun B.N.; Dogan I.; Pamuk O.N.; Yasar S.; Cetin G.Y.; Yazici A.; Esmen S.E.; Cagatay Y.; Yilmaz S.; Cefle A.; Sayarlioglu M.; Kasifoglu T.; Karadag O.; Pehlivan Y.; Dalkilic E.; Kisacik B.; Cobankara V.; Erken E.; Direskeneli H.; Aksu K.; Yavuz S.
    Objective. To assess bladder toxicity of cyclophosphamide (CYC) and uroprotective effect of mesna in rheumatic diseases. Methods. Data of 1018 patients (725 women/293 men) treated with CYC were evaluated in this retrospective study. All of the following information was obtained: the cumulative CYC dose, route of CYC administration, duration of therapy, concomitant mesna usage, and hemorrhagic cystitis. Cox proportional hazard model was used for statistics. Results. We identified 17 patients (1.67%) with hemorrhagic cystitis and 2 patients (0.19%) with bladder cancer in 4224 patient-years. The median time for diagnosis to hemorrhagic cystitis was 10 months (4-48) and bladder cancer was 8 years (6-10.9). There were 583 patients (57.2%) who received mesna with intravenous CYC therapy. We observed similar incidence rate for hemorrhagic cystitis in both patient groups concomitantly treated with or without mesna [9/583 (1.5%) vs 8/425 (1.8%) respectively, p = 0.08]. Cumulative CYC dose (HR for 10-g increments 1.24, p < 0.001) was associated with hemorrhagic cystitis. Conclusion. Cumulative dose was the only risk factor for hemorrhagic cystitis in patients treated with CYC. No proof was obtained for the uroprotective effect of mesna in our cohort. © 2015 All rights reserved.