Person: DİRESKENELİ, RAFİ HANER
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DİRESKENELİ
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RAFİ HANER
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Publication Open Access Biologic treatments in Behcet's disease(AVES, 2021-11-22) ALİBAZ ÖNER, FATMA; Alibaz-Oner, Fatma; Direskeneli, HanerBehcet's disease (BD) significantly increases morbidity and mortality, especially in young men. While vascular involvement is the most frequent cause of mortality, ocular involvement, which can cause visual loss, is the most important cause of morbidity in BD. Immunosuppressive treatment is the mainstay for major organ involvement. However, despite optimal immunosuppressive treatment, relapses and disease-related damage develop in a subgroup of patients, especially among those with ocular or vascular involvement. With the recent understanding of the immuno-pathogenesis, biologic treatments targeting potential pathogenic cells, cytokines or pathways are better optimized in BD. Data from large series showed that tumor necrosis factor-alpha inhibitors and interferon-alpha are effective and safe treatment options for the treatment of refractory and major organ involvement, such as ocular, neurologic, vascular, and gastrointestinal. Anakinra and ustekinumab also seem to be promising agents for refractory mucocutaneous disease. IL-1 inhibitors and tocilizumab may be alternatives for the treatment of patients with refractory eye involvement. Still, randomized controlled trials of biologic agents, especially for the treatment of major organ involvement, are insufficient, and further prospective, long-term follow-up studies are needed to clarify the efficacy, safety, and optimal treatment duration of biologic agents in BD.Publication Metadata only Femoral vein wall thickness measurement: A new diagnostic tool for Behcet's disease(OXFORD UNIV PRESS, 2021) ALİBAZ ÖNER, FATMA; Alibaz-Oner, Fatma; Ergelen, Rabia; Yildiz, Yasin; Aldag, Mustafa; Yazici, Ayten; Cefle, Ayse; Koc, Ertan; Esen, Bahar Artim; Mumcu, Gonca; Ergun, Tulin; Direskeneli, HanerObjectives. Diagnosing Behcet's disease (BD) is a challenge, especially in countries with a low prevalence. Recently, venous wall thickness (VWT) in lower extremities has been shown to be increased in BD patients. In this study, we aimed to investigate the diagnostic performance of common femoral vein (CFV) thickness measurement in BD and whether it can be used as a diagnostic tool. Methods.. Patients with BD (n=152), ankylosing spondylitis (n=27), systemic vasculitides (n=23), venous insufficiency (n=29), antiphospholipid syndrome (APS; n=43), deep vein thrombosis due to non-inflammatory causes (n=25) and healthy controls (n=51) were included in the study. Bilateral CFV thickness was measured with ultrasonography by a radiologist blinded to cases. Results. Bilateral CFV thickness was significantly increased in BD compared with all control groups (P < 0.001 for all). The area under the receiver operating characteristic curve for bilateral CFV thicknesses in all comparator groups was >0.95 for the cut-off value (0.5 mm). This cut-off value also performed well against all control groups with sensitivity rates >90%. The specificity rate was also >80% in all comparator groups except APS (positive predictive value: 79.2-76.5%, negative predictive value: 92-91.8% for right and left CFV, respectively). Conclusion. Increased CFV thickness is a distinctive feature of BD and is rarely present in healthy and diseased controls, except APS. Our results suggest that CFV thickness measurement with ultrasonography, a non-invasive radiological modality, can be a diagnostic tool for BD with sensitivity and the specificity rates higher than 80% for the cut-off value >= 0.5mm.Publication Open Access Anti-MHC autoimmunity in Behcet's disease: T cell responses to an HLA-B-derived peptide cross-reactive with retinal-S antigen in patients with uveitis(BLACKWELL SCIENCE LTD, 2001-12-24) DİRESKENELİ, RAFİ HANER; Kurhan-Yavuz, S; Direskeneli, H; Bozkurt, N; Ozyazgan, Y; Bavbek, T; Kazokoglu, H; Eksioglu-Demiralp, E; Wildner, G; Diedrichs-Mohring, M; Akoglu, TImmune response to retinal autoantigens plays a central role in the pathogenesis of uveitis. A synthetic peptide (B27PD) from a common sequence of various HLA-B molecules associated with uveitis, such as HLA-B27 and 51, which shares amino acid homologies with a retinal-S antigen (S-Ag)-derived peptide (PDSAg), was shown to be immunogenic in human and experimental uveitis in the rat. In this study we investigated T cell responses to B27PD and PDSAg in patients with Behcet's disease and posterior uveitis (BD-posterior uveitis; n = 33) in comparison with non-Behcet anterior uveitis (AU, n = 14), Behcet's patients without uveitis (BD, n = 15) and healthy controls (HC, n = 32) in a 6-day proliferation assay. Patients with BD and posterior uveitis had significantly higher responses (stimulation index (SI) 2.8 +/- 1.3) than those with AU (SI 1.5 +/- 0.4), BD without uveitis (SI 1.1 +/- 0.4) and HC (SI 1.1 +/- 0.6) for B27PD (P < 0.0001). Responses to PDSAg were also higher in BD with posterior uveitis patients (SI 3.3 +/- 1.6) than AU (SI 1.5 +/- 0.4), BD without uveitis (SI 1.2 +/- 0.3) and HC (SI 1.1 +/- 0.6) (P < 0.0001). A significant correlation between the responses to PDSAg and B27PD (r = 0.56, P < 0.001) was observed. Elevated levels of IL-2 and tumour necrosis factor-alpha were also observed in culture supernatants obtained from peripheral blood mononuclear cells after stimulation with the peptides, but no correlation was found between the proliferative responses and cytokine levels. These results suggest that cellular immunity to cross-reactive HLA-B and S-Ag-derived peptides might play a role in the pathogenesis of posterior uveitis in BD.Publication Open Access Autoimmunity vs autoinflammation in Behcet's disease: do we oversimplify a complex disorder?(OXFORD UNIV PRESS, 2006-08-18) DİRESKENELİ, RAFİ HANER; Direskeneli, H.Behcet's disease (BD) is a systemic inflammatory disorder with a diverse spectrum of clinical manifestations including mucocutaneous, ocular, vascular, gastrointestinal, musculoskeletal and central nervous system involvement [1]. A complex genetic background leading to a pro-inflammatory, innate-immune-system-derived activation perpetuated by adaptive immune responses against enviromental and auto-antigens is accepted to be the hallmark of BD [2]. This review aims to make an in-depth critical analysis of current data for recent controversies on the role of innate immune system vs autoimmunity in BD [3-5].Publication Metadata only Behcet's disease in patients with chronic myelogenous leukemia: Possible role of interferon-alpha treatment in the occurrence of Behcet's symptoms(SPRINGER VERLAG, 1997) DİRESKENELİ, RAFİ HANER; BudakAlpdogan, T; Demircay, Z; Alpdogan, O; Direskeneli, H; Ergun, T; Bayik, M; Akoglu, TTwo patients with chronic myelogenous leukemia (CML) who developed characteristic features of Behcet's disease (ED) during alpha-interferon (IFN-alpha) treatment and another patient who had a diagnosis of ED preceding CML are presented. In the first two patients, features of ED appeared 6 months after the initiation of IFN-alpha treatment; they included recurrent oral aphthae, genital ulceration, arthritis, folliculitis, and a positive skin pathergy test. The third patient, however, had a diagnosis of Behcet's disease 4 years before diagnosis of Philadelphia-positive CML. We prospectively examined the skin pathergy reaction in a group of patients with CML, multiple myeloma, and hairy cell leukemia both before and after IFN-alpha treatment and found two additional patients with CML who developed a positive skin pathergy test following IFN-alpha treatment.Publication Open Access Pro-inflammatory cytokine and caspase-1 responses to pattern recognition receptor activation of neutrophils and dendritic cells in Behcet's disease(OXFORD UNIV PRESS, 2013-05-01) MUMCU, GONCA; Ture-Ozdemir, Filiz; Tulunay, Aysin; Elbasi, Mehmet Onur; Tatli, Imren; Maurer, Anne-Marie; Mumcu, Gonca; Direskeneli, Haner; Eksioglu-Demiralp, EmelObjective. Activated innate immunity is implicated in the pathogenesis of Behcet's disease (BD). To clarify the mechanisms of innate immune responses, we investigated inflammasome activation in dendritic cells (DCs) and neutrophils, following stimulation with two different pattern recognition receptors (PRRs) RIG-1-like (RLR) and NOD-like (NLR) in patients with BD. Methods. Sixteen active BD patients with mucocutaneous lesions and 17 healthy controls (HCs) were included in this study. DCs were generated from monocytes. DCs and isolated neutrophils were activated by RLR and NLR ligands. Caspase-1 activation and expression of p38 and RIP2 were determined by flow cytometry. Levels of IL-1 beta, IL-6, TNF-alpha, IFN-alpha and IL-18 in culture supernatants were measured by ELISA. Results. Activation of caspase-1 following intracellular PRR stimulation was found to be of similar levels in DCs and neutrophils of BD patients compared with HCs. However, activation of DCs from BD patients to NOD2 stimulus measured by the expression of RIP2 and p38 as well as IL-18 levels was found to be slightly defective (P < 0.05). In neutrophil cultures, IL-6 levels were lower in response to all stimuli in patients with BD compared with HCs (P < 0.01). Conclusion. Inflammasome formation following stimulation with NOD1/NOD2 and RIG measured by caspase-1 activation, cytokine levels and expression of RIP2 and p38 seems to be functionally normal in DCs and neutrophils of BD patients, although slightly defective responses in some pathways and cytokine levels were observed. These results may suggest that caspase-1-independent pathways such as toll-like receptors may be more prominent in BD pathogenesis.Publication Metadata only Thalidomide has both anti-inflammatory and regulatory effects in Behcet's disease(SPRINGER, 2008) DİRESKENELİ, RAFİ HANER; Direskeneli, H.; Ergun, T.; Yavuz, S.; Hamuryudan, V.; Eksioglu-Demiralp, E.Thalidomide is shown to be an effective treatment for mucocutaneous symptoms of Behcet's disease (BD). In this study, the effects of thalidomide on peripheral blood mononuclear cells were investigated ex vivo. In an open prospective study, ten patients were given 200 mg/day thalidomide for 12 weeks and cluster of differentiation 4 (CD4), CD8, CD11a, CD11b, CD16, CD18, CD28, CD44, CD45RO, CD45RA, CD56, CD120a and gamma delta+ T cells were analysed with flow cytometry at 0, 3, 7, 30 and 90 days. Two patients were excluded from the analysis for attacks of uveitis within the first 2 weeks. At day 7, tumour necrosis factor-alpha (TNF-alpha) receptor+ (CD120a; 12% vs 5%), CD8/CD11b+ (12% vs 6%) and CD16/CD56+ (16% vs 9%) cells decreased in BD patients compared to day 0. On the other hand, CD4+CD45RO+ T cells (24% vs 34%) at day 30 and gamma delta+ T cells (11% vs 21%) at day 90 increased after treatment. These results suggest that thalidomide tends to decrease TNF-alpha receptor levels, CD8/CD11b+ T cells and natural killer cells in early treatment and increases CD4+CD45RO+ memory T and gamma delta+ T cells later in BD.Publication Metadata only Oral health is a mediator for disease severity in patients with Behcet's disease: A multiple mediation analysis study(WILEY, 2019) AKSOY, AYSUN; Yay, Meral; Celik, Zulal; Aksoy, Aysun; Alibaz-Oner, Fatma; Inanc, Nevsun; Ergun, Tulin; Direskeneli, Haner; Mumcu, GoncaObjectivesThe aim of the study was to examine whether oral health as an infection focus could mediate disease course in patients with Behcet's disease (BD). MethodsIn the study, oral health of 194 BD patients was examined at baseline and follow-up periods. The reasons for last dental visits were recorded as tooth extraction or regular control visits/planned treatments at the end of follow-up period. The Behcet's disease severity score was calculated with higher scores indicating a more severe course. Mediation analysis was carried out to assess the effects of oral health on disease severity score at follow-up period in the study. ResultsDental and periodontal indices were found to be higher at follow-up visit compared to those of baseline (P<0.05). Disease severity score was found to be higher in males (5.32.4) compared to females (4.4 +/- 2.5) in the whole group (P=0.005). Moreover, patients having tooth extraction at their last dental visit and patients with dental caries had a more severe disease course (5.4 +/- 2.4; 5.5 +/- 2.5) compared to others (4.2 +/- 2.3; 4.4 +/- 2.4; P<0.0001). In multiple mediation analysis, disease severity score was a dependent variable and was directly mediated by male gender (B=-0.8822, P=0.0145) and indirectly mediated through the presence of dental caries (B=0.9509 P=0.0110) and need of tooth extraction (B=0.8758, P=0.0128). ConclusionBoth presence of dental caries and need of tooth extraction were observed to be effective mediators for a more severe disease course in BD. Therefore, better oral health should be aimed to eliminate microbial factors, which are a part of pathogenic processes.Publication Open Access Immune and inflammatory gene expressions are different in Behcet's disease compared to those in Familial Mediterranean Fever(AVES, 2017-01-11) DİRESKENELİ, RAFİ HANER; Ozdemir, Filiz Ture; Demiralp, Emel Eksioglu; Aydin, Sibel Z.; Atagunduz, Pamir; Ergun, Tulin; Direskeneli, HanerObjective: The immune classification of Behcet's disease (BD) is still controversial. In this study, we aimed to compare the immune/inflammatory gene expressions in BD with those in familial Mediterranean fever (FMF), an autoinflammatory disorder with innate immune activation. Material and Methods: CD4+ T cells and CD14+ monocytes were isolated from the peripheral blood mononuclear cells of Behcet's disease patients (n=10), FMF (n=6) patients, and healthy controls (n=4) with microbeads, and then, the mRNA was isolated. The expressions of 440 genes associated with immune and inflammatory responses were studied with a focused DNA microarray using a chemiluminescent tagging system. Changes above 1.5-fold and below 0.8-fold were accepted to be significant. Results: In BD patients, in the CD4+ T-lymphocyte subset, interleukin 18 receptor accessory protein (1.7-fold), IL-7 receptor (1.9-fold), and prokineticin 2 (2.5-fold) were all increased compared to those in FMF patients, whereas chemokine (C-X3-C motif) receptor-1 (CX3CR1) (0.7-fold) and endothelial cell growth factor-1 (0.6-fold) were decreased. In the CD14+ monocyte population, the V-fos FBJ murine osteosarcoma viral oncogene homolog (1.5-fold), Interleukin-8 (IL-8) (2.1-fold), and Tumor Necrosis Factor alpha (TNF-alpha) (1.8-fold) were all increased, whereas the chemokine (C-C motif) ligand 5 (CCL5) (0.6-fold), C-C chemokine receptor type 7 (0.6-fold), and CX3CR1 (0.7-fold) were decreased, again when compared to those in FMF. Compared to healthy controls in the CD4+ T-lymphocyte population, in both BD and FMF patients, pro-platelet basic protein and CD27 had elevated expression. In BD and FMF patients, 24 and 19 genes, respectively, were downregulated, with 15 overlapping genes between both disorders. In the CD14+ monocytes population, chemokine (C-C motif) receptor-1 (CCR1) was upregulated both in BD and FMF patients compared to that in the controls, whereas CCL5 was downregulated. Conclusion: Immune and inflammatory gene expressions seem to be variable in both the innate (CD14+) and adaptive (CD4+) immune responses in BD and FMF patients compared to those in controls, suggesting differences in immune regulation between the two disorders.Publication Open Access Oral ulcer activity in Behcet's disease: Poor medication adherence is an underestimated risk factor(AVES, 2017-06-12) ALİBAZ ÖNER, FATMA; Mumcu, Gonca; Alibaz-Oner, Fatma; Oner, Sibel Yilmaz; Ozen, Gulsen; Atagunduz, Pamir; Inanc, Nevsun; Koksal, Leyla; Ergun, Tulin; Direskeneli, HanerObjective: The aim of this study was to evaluate the relationship between oral ulcer activity and medication adherence according to gender in Behcet's disease (BD) patients. Material and Methods: The study group included 330 BD patients (F/M: 167/163, mean age: 38.5 +/- 10.5 years). Oral ulcer activity and medication adherence were evaluated in the previous month. Medication adherence was evaluated using the 8-item Morisky Medication Adherence Scale (MMAS-8) having a score range of 0 to 8 with high scores indicating better adherence. Low adherence was defined as < 6 points on MMAS-8. Results: Over half of the group had active oral ulcers (n= 219, 66.4%) within the month preceding the visit. The number of oral ulcers was significantly higher in female patients with low medication adherence (2.39 +/- 3.24) than in the rest of the female group (1.28 +/- 2.05; p= 0.023). Although a similar trend was also observed in male patients (2.14 +/- 3.3 vs. 1.81 +/- 2.31), a significant relationship was not observed (p= 0.89). The frequency of medication intake per day was lower in patients with high medication adherence than in the rest of the study group (p= 0.04). Conclusion: Low medication adherence is a hidden risk factor in the management of BD. Poor adherence was associated with oral ulcer activity in female BD patients.