Endothelial Progenitor Cells as a Potential Biomarker in Interstitial Lung Disease Associated with Rheumatoid Arthritis

Interstitial lung disease (ILD) increases morbidity and mortality in patients with rheumatoid arthritis (RA). Although the pathogenesis of ILD associated with RA (RA-ILD(+)) remains poorly defined, vascular tissue is crucial in lung physiology. In this context, endothelial progenitor cells (EPC) are involved in endothelial tissue repair. However, little is known about their implication in RA-ILD(+). Accordingly, we aimed to investigate the potential role of EPC related to endothelial damage in RA-ILD(+). EPC quantification in peripheral blood from 80 individuals (20 RA-ILD(+) patients, 25 RA-ILD(-) patients, 21 idiopathic pulmonary fibrosis (IPF) patients, and 14 healthy controls) was performed by flow cytometry. EPC were considered as CD34(+), CD45(low), CD309(+) and CD133(+). A significant increase in EPC frequency in RA-ILD(+) patients, as well as in RA-ILD(-) and IPF patients, was found when compared with controls (p < 0.001, p = 0.02 and p < 0.001, respectively). RA-ILD(+) patients exhibited a higher EPC frequency than the RA-ILD(-) ones (p = 0.003), but lower than IPF patients (p < 0.001). Our results suggest that EPC increase may represent a reparative compensatory mechanism in patients with RA-ILD(+). The degree of EPC frequency may help to identify the presence of ILD in RA patients and to discriminate RA-ILD(+) from IPF

HLA association with the susceptibility to anti-synthetase syndrome

Objective: To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). Methods: We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. Results: A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P = 1.56E–09, odds ratio–OR [95% confidence interval–CI] = 2.54 [1.84–3.50] and 21.4% versus 5.5%, P = 18.95E–18, OR [95% CI] = 4.73 [3.18–7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P = 0.0003, OR [95% CI] = 0.48 [0.31–0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P = 0.001, OR [95% CI] = 2.54 [1.39–4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. Conclusions: Our results support the association of the HLA complex with the susceptibility to ASSD

Protective role of the proprotein convertase subtilisin/kexin type 9 (PCSK9) RS2495477 polymorphism in patients with rheumatoid arthritis and subclinical atherosclerosis

Background: RA is associated with the development of cardiovascular (CV) disease and subclinical atherosclerosis1. The presence of carotid plaques assessed by ultrasonography studies is a surrogate marker for subclinical atherosclerosis2. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in homeostasis of cholesterol, a traditional CV risk factor related to RA and atherosclerosis1,3. PCSK9 polymorphisms can both increase and decrease the risk of CV disease in patients with atherosclerosis3. Moreover, PCSK9 levels have been also related with CV risk4. However, there is little information on PCSK9 in RA. Objectives: To assess the role of several PCSK9 polymorphisms in RA and subclinical atherosclerosis in RA as well as to determine if these ones may influence on PCSK9 mRNA and protein levels. Methods: PCSK9 rs2479409, rs11583680, rs2483205, rs2495477 and rs562556 polymorphisms were genotyped in 1,169 Spanish RA patients, who met the 1987 ACR and the 2010 ACR/EULAR criteria for RA5-6, and 528 healthy controls. Associations were estimated using odds ratios (OR) and 95% confidence intervals (CI). The potential association between PCSK9 polymorphisms in both RA and controls and the presence/absence of carotid plaques in RA was evaluated by logistic regression. PCSK9 mRNA expression and PCSK9 serum levels were determined by qPCR and ELISA, respectively. All results were adjusted by sex, age and traditional CV risk factors. Results: Significant differences in the allele frequencies of PCSK9 rs2495477 between RA patients and controls were found (minor allele: OR=0.55, 95% CI=0.34-0.89, p=0.01). A significant association between minor allele of rs2495477 and carotid plaques was also disclosed in RA patients (OR=0.72, 95% CI=0.56-0.92, p=0.01). PCSK9 levels were significantly decreased in RA patients carrying rs2495477 minor allele compared to controls (97.8 ? 104.9 vs 235.8 ? 93.5 ng/mL, p=0.001). None of the five PCSK9 polymorphisms influenced on its expression. Conclusion: Our study showed for the first time that PCSK9 rs2495477 confers protection against RA susceptibility and the development of subclinical atherosclerosis in RA patients. Furthermore, rs2495477 decreased PCSK9 serum levels in RA that may be crucial to control the disease

Protective Role of the Vitamin D Receptor Apai (rs7975232) Polymorphism Against Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis from Northern Spain

Pathophysiology and treatment of rheumatic disease

HLA-B*08 Identified as the Most Prominently Associated Major Histocompatibility Complex Locus for Anti-Carbamylated Protein Antibody-Positive/Anti-Cyclic Citrullinated Peptide-Negative Rheumatoid Arthritis

Objective. Previously, only the HLA-DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti-carbamylated protein antibody-positive (anti-CarP+) RA.Methods. Analyses were restricted to RA patients who were anti-cyclic citrullinated peptide antibody negative (anti-CCP), because the anti-CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti-CCP- RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for similar to 8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti-CarP status in RA patients was tested with logistic regression and combined with inverse-variance meta-analysis. Significance of the associations was assessed according to a study-specific threshold of P < 2.0 x 10(-5).Results. The HLA-B*08 allele and its correlated amino acid variant Asp-9 showed a significant association with anti-CarP+/anti-CCP- RA (P < 3.78 x 10(-7); I-2 = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti-CarP-/anti-CCP- RA patients, and anti-CCP- RA patients who were positive for other anti-citrullinated protein antibodies. Based on these findings, anti-CarP+/anti-CCP- RA patients could be separated from other antibody-defined subsets of RA patients in whom an association with the HLA-B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti-CarP+/anti-CCP- RA after accounting for the presence of the HLA-B*08 allele. Specifically, the reported association of HLA-DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium.Conclusion. These results identify HLA-B*08 carrying Asp-9 as the MHC locus showing the strongest association with anti-CarP+/anti-CCP- RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies.Pathophysiology and treatment of rheumatic disease

IL-17A GENE IMPLICATION IN SPANISH PATIENTS WITH RHEUMATOID ARTHRITIS

Pathophysiology and treatment of rheumatic disease

Lack of Association Between ZHX2, Lepr, Gckr and ASCL1 and Carotid Intima-Media Thickness, Carotid Plaques and Cardiovascular Disease in Patients with Rheumatoid Arthritis

Pathophysiology and treatment of rheumatic disease