Neslihan Yilmaz

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.

TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus erythematosus in Turkey

A significant source of variability in the literature on systemic lupus erythematosus (SLE) susceptibility genes has been the inability to replicate genetic findings across different racial or ethnic groups. We investigated whether a single nucleotide polymorphism (SNP) of the STAT4 (rs7574865), PTPN22 (rs2476601), TRAF1/C5 (rs10818488), and C1q (rs292001) genes as well as the 27-bp VNTR polymorphism on intron 4 of eNOS, previously associated with SLE in other populations, are also associated with SLE risk in Turkey. A group of 158 SLE patients and 155 healthy controls were included in this study. A genetic association of the TRAF1/C5, C1q, and eNOS gene polymorphism, but not of STAT4 and PTPN22, was found to confer a degree of risk for SLE. These data highlight the importance of comparative studies in different populations to confirm the previously detected genetic associations.

A common SNP in the CD40 region is associated with systemic lupus erythematosus and correlates with altered CD40 expression: implications for the pathogenesis

Background In systemic lupus erythematosus (SLE) sustained CD40L expression by T cells and platelets activates a variety of cells via its receptor CD40 contributing to disease pathogenesis. Although CD40 has recently been identified in genome-wide association study as a novel rheumatoid arthritis susceptibility gene such an association has not been documented for SLE. Objective To investigate whether the rs4810485 CD40 single nucleotide polymorphism (SNP) is associated with increased risk for SLE and its impact on CD40 expression. Materials and methods The primary sample set consisted of 351 patients with SLE and 670 matched healthy controls of Greek origin. 158 patients with SLE and 155 controls from Turkey were used as a replication sample. Genotyping of rs4810485 was performed by restriction fragment length polymorphism and the Sequenom MassArray technology. The expression of CD40 mRNA and protein was assessed in unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells by quantitative real time PCR and flow cytometry, respectively. Results The minor allele T of CD40 rs4810485 SNP was significantly under-represented in Greek patients with SLE compared with healthy controls (OR=0.65, 95% CI 0.54 to 0.79). The association was replicated in the Turkish cohort (OR=0.57, 95% CI 0.41 to 0.80; meta-analysis of 509 patients with SLE and 825 healthy controls: OR=0.63, 95% CI 0.53 to 0.74, p = 2×10−8). In both cases and controls, the rs4810485 G/T and T/T genotypes were associated with significantly reduced CD40 mRNA and protein expression in peripheral blood CD14+ monocytes and CD19+ B cells compared with G/G genotype, both under basal conditions and following stimulation. Conclusions CD40 has been identified as a new susceptibility locus in Greek and Turkish patients with SLE. The rs4810485 minor allele T is under-represented in SLE and correlates with reduced CD40 expression in peripheral blood monocytes and B cells, with potential implications for the regulation of aberrant immune responses in the disease.

Comparison of QuantiFERON-TB Gold test and tuberculin skin test for the identification of latent Mycobacterium tuberculosis infection in lupus patients

The tuberculin skin test (TST) has low sensitivity for the diagnosis of tuberculosis (TB). QuantiFERON-TB Gold (QFT-G) is an IFN-gamma-release assay that measures the release of interferon-gamma after stimulation in vitro by Mycobacterium tuberculosis antigens using ELISA. The main advantage of this assay compared with TST is the lack of cross-reaction with Bacillus Calmette-Guérin (BCG) as well as most of non-tuberculous mycobacteria. The aim of our study is to compare QFT-G with TST for the detection of latent tuberculosis infection (LTBI) among patients with systemic lupus erythematosus (SLE). Methods: Seventy-eight patients with SLE and 49 healthy subjects (HCs) participated in the study. All patients and controls were interviewed for a history of TB then BCG vaccinations were recorded and chest X-rays were examined for a sign of TB infection. QTF-G and TST were performed on both patients and controls. QTF-G results were recorded as positive, negative or indeterminate. A positive TST for SLE was defined as ≥5 mm. Results: Seventy-six SLE patients (97.4%) had been BCG vaccinated. Similar to the HC (28.5%), 19 of 78 (24.3%) SLE patients had positive QTF-G. Two patients had an indeterminate result. The agreement between QTF-G and TST was 49/76 (64.4%) (κ = 0.33). There were fewer positive QFT-G test results than positive TST results (24.3% vs. 50%; p < 0.01). Twenty-two (28.9%) patients were TST(+)/QTF-G(−) while only 3(3.9%) patients were TST(−)/QTF-G(+). When the positive TST was defined as ≥10 mm indurations, which is the cut-off in screening for LTBI in Turkey, the agreement between two tests increased up to 58/76 (76.3%) with a κ value of 0.47. The mean TST measurements was higher in QTF-G positive patients (13.4 ± 8.8 mm) than the QTF-G negative patients (4 ± 5.3 mm) (p < 0.001). Discussion: In a TB-endemic and BCG vaccinated population, the QuantiFERON-TB Gold assay seemed to be a more accurate test for the detection of LTBI in SLE patients. Although 5 mm is usually accepted to be the standard cut-off for TST in immunocompromised patients such as SLE, the level of agreement between QTF-G and TST was better with a 10 mm cut-off in our population.

Two-year experience with mycophenolate mofetil in patients with scleroderma lung disease: a case series.

To assess the effect of mycophenolate mofetil (MMF) on pulmonary functions in patients with systemic sclerosis‐associated lung disease (SSc‐ILD) who experienced an inadequate response to first line cyclophosphamide (CYC) therapy. Twelve consecutive SSc‐ILD patients who received MMF due to inadequate response to CYC as a first line agent, were retrospectively reviewed. Over the course of 2 years, pulmonary function tests (PFT) and high‐resolution computed tomography (HRCT) scans were performed. Following initial baseline tests, PFTs were continued at a frequency of every 6 months and HRCT scans were performed every 12 months. After MMF treatment, values of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) improved in three (25%) and two (16.6%) patients, respectively. It is also noted that the evaluation of serial HCRT scans showed no change in 54.5% of patients. Our case series suggested that PFT and imaging scores seemed to be stabilized by MMF in SSc‐ILD patients who were inadequate responders to CYC.

Activity and damage in granulomatosis with polyangiitis

To retrospectively analyze disease activity and damage‐associated factors in granulomatosis with polyangiitis (GPA) in Turkey.

Dysexecutive syndrome: a specific pattern of cognitive impairment in systemic sclerosis.

Background and Purpose:Systemic sclerosis (SSc) is a connective-tissue disorder characterized by microvascular damage and tissue fibrosis. Although overt nervous system involvement is unusual in SSc, imaging studies have shown cerebral hypoperfusion. We evaluated cognitive functions in patients with SSc who had no history of neurological involvement, to seek cognitive impairment caused by the suggested cerebral hypoperfusion. Methods:We performed a comprehensive neuropsychological test battery on 31 patients with SSc and on 2 groups of age-adjusted, sex-adjusted, and education-adjusted controls: 15 patients with rheumatoid arthritis and 20 healthy volunteers. Results:The patients with SSc scored significantly worse on most of the measures of executive function than the 2 control groups (P<0.05). However, both patient groups did worse than the healthy controls on measures of attention and memory (P<0.005). Conclusions:Our results suggest that patients with SSc have a specific pattern of cognitive impairment: the dysexecutive syndrome. Attentional and memory problems, however, may arise from other confounders such as disease duration and chronic medication use. SSc may be a rare cause of vascular cognitive impairment.

Clinically silent Crohn’s disease in a patient with Takayasu’s Arteritis unresponsive to conventional therapies

Takayasu arteritis (TA) and Crohn’s disease (CD) are chronic inflammatory diseases with granulomatous nature. Here, we report a case of TA with a silent course of CD who was refractory to corticosteroid and immunosuppressive treatments and improved with adalimumab therapy.

AB0357 Pregnancy outcomes of rheumatic patients with pre/peri gestational leflunomide exposure

Background Leflunomide is a frequently used disease modifying drug in rheumatoid arthritis, psoriatic arthritis, vasculitis etc. Findings from animal studies have suggested that leflunomide may be a human teratogen and a wash out protocol is required for patients before planning pregnancy. Data about pregnancy in patients with leflunomide exposure is limited with case reports and case series. Objectives This study is aimed to evaluate the outcomes of pregnancies in patients with leflunomide exposure. Methods Hospital files between years of 2004-2012 were used for selecting patients who used leflunomide before or during pregnancy. In addition to demographic and clinical characteristics of patients, a study form consist of -drugs usedbefore pregnancy, elimination application, duration of pregnancy, drug use and pregnancy outcomes- is filled. Totally 33 patients (female /male: 24/9) were included into the study. Results In 12 of 33 patients (36.4%) no pregnancy occurred during more than 1 year follow up. Pregnancy took place in 16 (66.7%) of female and 5 (55.6%) of male patients’ wives while in others no pregnancy occurred Bloods levels of leflunomide were examined in 19 of 21 pregnancies. Leflunomide washout protocol with cholestyramine was applied in 15 patients. In 13 of female patients leflunomide was interrupted before pregnancy but in 3 patients it was stopped after detection of pregnancy. Results and the complications of pregnancies were shown in Table 1. Anti-Tumor necrosis factor (Anti-TNF) usage was positive in 4 of them – one of them had used during pregnancy. Majormalformations were not detected in any infants. Premature membrane rupture was observed in wife of a male patient. Conclusions Observation of none pregnancy in more than one third of patients during >1 year follow up, might reflect that rheumatic patients on leflunomide treatment had an increased reproductive problems. Wash out protocol and assessing blood drug level are used in most of patients before planning pregnancy. Althoughwe experienced no major malformations, the rate of complications such as premature rupture of membrane and low birth weight were higher. To give rise to more precise data, methods of contraception should be advised in patients receiving leflunomide. Disclosure of Interest None Declared

Role of Tyrosine Kinase Inhibition with Imatinib in an Encapsulating Peritoneal Sclerosis Rat Model

Background: Encapsulating peritoneal sclerosis (EPS) is characterized by neovascularization, increased inflammation, and interstitial fibrosis of the peritoneum. We investigated the effects of imatinib on the peritoneal membrane in an experimental EPS model. Methods: We separated 24 non-uremic Wistar rats into four groups: the control group which was injected with 2 mL isotonic saline intraperitoneally (IP) daily for 3 weeks, the CG group which was injected with chlorhexidine gluconate (CG) IP daily for 3 weeks, the resting group which was injected with CG IP between weeks 0–3 followed by a peritoneal rest period between weeks 3–6, and the CG + Imatinib mesylate group (CG + IMA) which received CG through weeks 0–3 followed by 50 mg/kg imatinib mesylate through weeks 3–6. At the end of the study, we performed a 1-h-peritoneal equilibration test and examined the peritoneal function and transforming growth factor-β1 (TGF-β1) in dialysate. Morphologic changes were evaluated by microscopy and immunohistochemistry. Results: An increased ultrafiltration, dialysate/plasma-creatinine-ratio, end-to-initial-dialysate-glucose-ratio, decreased active mesothelial cell ratio and inflammation, and a slightly decreased TGF-β1 of dialysate were found in the CG + IMA group compared to CG alone. Furthermore, the CG + IMA group had a lower concentration of active mesothelial cells than did the resting group. Ultrafiltration was improved in CG + IMA group compared to resting group, however, significant decrease in peritoneal thickness and inflammation were not found compared to those in resting group. Furthermore, there was no significant difference in fibrosis or TGF-β1-positivity on immunohistochemistry between the groups. Conclusions: Tyrosine kinase inhibition with imatinib may lead to a decrease in mesothelial cell activity and an increase in ultrafiltration. However, peritoneal fibrosis was unchanged by imatinib in EPS model.