Fernanda Genre

Exacerbation of type II collagen–induced arthritis in apolipoprotein E–deficient mice in association with the expansion of Th1 and Th17 cells

OBJECTIVE To explore the bidirectional relationship between the development of rheumatoid arthritis (RA) and atherosclerosis using bovine type II collagen (CII)-immunized B10.RIII apoE(-/-) mice, a murine model of spontaneous atherosclerosis and collagen-induced arthritis (CIA). METHODS Male B10.RIII apoE(-/-) mice and wild-type controls were immunized with 150 μg of CII emulsified in Freunds complete adjuvant (CFA). The clinical, radiologic, and histopathologic severity of CIA, the levels of circulating IgG1 and IgG2a anti-CII antibodies, the expression of proinflammatory and antiinflammatory cytokines in the joints, and the percentages of Th1, Th17, and Treg lymphocytes in the draining lymph nodes were evaluated during CIA induction. In addition, the size of atherosclerotic lesions was assessed in these mice 8 weeks after CIA induction. RESULTS B10.RIII apoE(-/-) mice that were immunized with CII and CFA developed an exacerbated CIA that was accompanied by increased joint expression of multiple proinflammatory cytokines and by the expansion in the draining lymph nodes of Th1 and Th17 cells. In contrast, the size of vascular lesions in B10.RIII apoE(-/-) mice was not affected by the development of CIA. CONCLUSION Our findings indicate that a deficiency in apolipoprotein E and/or its consequences in cholesterol metabolism act as accelerating factors in autoimmunity by promoting Th1 and Th17 inflammatory responses.

Cardiovascular risk assessment in patients with rheumatoid arthritis: The relevance of clinical, genetic and serological markers

Cardiovascular disease (CV) is the most common cause of premature mortality in patients with rheumatoid arthritis (RA). This is the result of an accelerated atherosclerotic process. Adequate CV risk stratification has special relevance in RA to identify patients at risk of CV disease. However, current CV risk screening and management strategies underestimate the actual CV risk in RA. Consequently, the search for additional tools that may help to identify those patients at high CV risk has become a key objective in the last years. In this regard, non-invasive surrogates, such as carotid ultrasonography, have been found to be excellent predictors of future CV events. In addition, several studies have revealed the relevance of a genetic component in the development of CV disease in RA patients. Besides an association with HLA-DRB1* shared epitope alleles other gene polymorphisms located inside and outside the HLA seem to influence the risk of cardiovascular disease in RA. Moreover, serum levels of some metabolic syndrome-related biomarkers, adipokines such as adiponectin and biomarkers of endothelial cell activation and inflammation such as Osteoprotegerin and Asymmetric dimethylarginine have recently been found useful for the prediction of CV disease in these patients. An update of the current knowledge on these potential markers, especially focused on new genetic and serological biomarkers is shown in this review.

Independent Relationship of Osteoprotegerin Concentrations with Endothelial Activation and Carotid Atherosclerosis in Patients with Severe Rheumatoid Arthritis

Objective. Osteoprotegerin (OPG) may contribute to the link between systemic inflammation and increased cardiovascular risk. We investigated the relationship of OPG concentrations with endothelial activation and carotid atherosclerosis in rheumatoid arthritis (RA). Methods. OPG concentrations and those of endothelial activation molecules were measured by using ELISA in 34 patients who were treated with infliximab (IFX), both immediately before and after an IFX infusion. Carotid intima-media thickness (CIMT) and plaque were determined by ultrasound in 27 of the study participants. Results. Median (interquartile range) OPG concentrations decreased from 4.8 pmol/l (2.8–6.5) to 4.4 pmol/l (2.9–6.1; p = 0.04) upon IFX infusion. Baseline OPG concentrations were inversely associated with those of total and low-density lipoprotein (LDL) cholesterol (partial R = −0.50, p = 0.004, and R = −0.48, p = 0.007, respectively). Prior to IFX administration, OPG concentrations were associated with those of intercellular adhesion molecule (ICAM)-1 (partial R = 0.34, p = 0.05), CIMT (partial R = 0.51 to 0.52, p < 0.009), and plaque (OR = 1.52, 95% CI 1.01–2.29 to OR = 1.61, 95% CI 1.03–2.51; p < 0.04), independent of conventional risk factors and C-reactive protein concentrations or disease activity. Except for the OPG concentrations-plaque association (p = 0.09), these relationships remained significant subsequent to IFX administration (p < 0.05). Reductions in OPG levels related to those in vascular cell adhesion molecule (VCAM)-1 concentrations (partial R = 0.35, p = 0.04) and had borderline significance (p = 0.09) with those in ICAM-1 (partial R = 0.29) concentrations. Conclusion. OPG concentrations are independently associated with endothelial activation and carotid atherosclerosis in RA. Reductions in OPG concentrations upon IFX administration are associated with decreased endothelial activation. OPG may be involved in increased cardiovascular disease risk and may improve its stratification in patients with RA.

The ZC3HC1 rs11556924 polymorphism is associated with increased carotid intima-media thickness in patients with rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is a complex polygenic disease associated with chronic inflammation, accelerated atherosclerosis and increased cardiovascular (CV) mortality. A recent meta-analysis has described the ZC3HC1 rs11556924 polymorphism as one of the most important signals associated with coronary artery disease (CAD) in non-rheumatic Caucasian individuals. In this study we evaluated the potential association of this gene polymorphism with subclinical atherosclerosis assessed by the evaluation of carotid intima-media thickness (cIMT) in RA patients.MethodsThis study included 502 RA patients from Northern Spain. The ZC3HC1 rs11556924 polymorphism was genotyped with TaqMan single-nucleotide polymorphism (SNP) genotyping assays (C__31283062_10) in a 7900HT real-time polymerase chain reaction (PCR) system. cIMT was also assessed in these patients by carotid ultrasonography (US) technology.ResultsRA patients carrying the TT genotype had significantly higher cIMT values than those homozygous for the CC genotype (mean ± standard deviation (SD): 0.76 ± 0.18 mm and mean ± SD: 0.71 ± 0.16 mm respectively; P = 0.03) even after adjusting the results for sex, age at the time of US study, follow-up time and traditional CV risk factors (P = 0.04) evidencing that the effect conferred by ZC3HC1 rs11556924 polymorphism is independent of the traditional CV risk factors.ConclusionOur results indicate that ZC3HC1 rs11556924 polymorphism is associated with subclinical atherosclerosis in RA.

Osteoprotegerin Concentrations Relate Independently to Established Cardiovascular Disease in Rheumatoid Arthritis

Objective. We determined whether osteoprotegerin (OPG) concentrations are associated with established cardiovascular disease (CVD) among patients with rheumatoid arthritis (RA). Methods. OPG concentrations were measured by ELISA in 151 patients with RA (54 with CVD) and 62 age-matched control subjects without CVD. Established CVD was composed of documented ischemic heart disease, cerebrovascular disease, and peripheral artery disease. Results. In patients with RA, age, body mass index (BMI), rheumatoid factor (RF) positivity, anticyclic citrullinated peptide (anti-CCP) antibody positivity, and joint erosion status were associated with OPG concentrations [partial R (p) = 0.175 (0.03), −0.277 (0.0009), 0.323 (< 0.0001), 0.217 (0.008), and 0.159 (0.05), respectively]. Median (interquartile range) OPG concentrations increased from 6.38 (3.46–9.31) to 7.07 (5.04–10.65) and 8.64 (6.00–11.52) ng/ml in controls and patients with RA who had CVD and those who did not, respectively (p = 0.0002). Upon adjustment for age, sex, traditional risk factors, and BMI in mixed regression models, OPG concentrations remained lower in controls compared to patients with RA without CVD (p = 0.05) and in the latter compared to those with CVD (p = 0.03); the association of OPG concentrations with CVD among patients with RA also persisted after additional adjustment for RF and anti-CCP antibody positivity, and erosion status (p = 0.04). Conclusion. OPG concentrations are associated with disease severity and CVD prevalence in patients with RA. Whether consideration of OPG concentrations can improve CVD risk stratification in RA merits future longitudinal investigation.

Adipokines, Biomarkers of Endothelial Activation, and Metabolic Syndrome in Patients with Ankylosing Spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease associated with accelerated atherosclerosis and increased risk of cardiovascular (CV) disease. AS patients also display a high prevalence of features clustered under the name of metabolic syndrome (MeS). Anti-TNF-α therapy was found to be effective to treat AS patients by suppressing inflammation and also improving endothelial function. Previously, it was demonstrated that a short infusion of anti-TNF-α monoclonal antibodyinfliximab induced a rapid and dramatic reduction in serum insulin levels and insulin resistance along with a rapid improvement of insulin sensitivity in nondiabetic AS patients. The role of adipokines, MeS-related biomarkers and biomarkers of endothelial cell activation and inflammation seem to be relevant in different chronic inflammatory diseases. However, its implication in AS has not been fully established. Therefore, in this review we summarize the recent advances in the study of the involvement of these molecules in CV disease or MeS in AS. The assessment of adipokines and biomarkers of endothelial cell activation and MeS may be of potential relevance in the stratification of the CV risk of patients with AS.

Lack of Association between ABO, PPAP2B, ADAMST7, PIK3CG, and EDNRA and Carotid Intima-Media Thickness, Carotid Plaques, and Cardiovascular Disease in Patients with Rheumatoid Arthritis

Introduction. Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. Recent studies have identified the ABO rs579459, PPAP2B rs17114036, and ADAMTS7 rs3825807 polymorphisms as genetic variants associated with coronary artery disease and the PIK3CG rs17398575 and EDNRA rs1878406 polymorphisms as the most significant signals related to the presence of carotid plaque in nonrheumatic Caucasian individuals. Accordingly, we evaluated the potential relationship between these 5 polymorphisms and subclinical atherosclerosis (assessed by carotid intima-media thickness (cIMT) and presence/absence of carotid plaques) and CV disease in RA. Material and Methods. 2140 Spanish RA patients were genotyped for the 5 polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 620 of these patients by carotid ultrasonography technology. Results. No statistically significant differences were found when each polymorphism was assessed according to cIMT values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV disease after adjusting for potential confounders. Conclusion. Our results do not confirm association between ABO rs579459, PPAP2B rs17114036, ADAMTS7 rs3825807, PIK3CG rs17398575, and EDNRA rs1878406 and subclinical atherosclerosis and CV disease in RA.

Brief Report: Association of HLA–DRB1*01 With IgA Vasculitis (Henoch‐Schönlein)

Objective: Henoch-Schönlein purpura (HSP) is the most common vasculitis in children but it is not exceptional in adults. Increased familial occurrence supports a genetic predisposition for HSP. In this context, an association with the human leukocyte antigen-HLA-DRB1*01 phenotype has been suggested in Caucasian individuals with HSP. However, data on the potential association of HSP with HLA-DRB1*01 were based on small case series. To further investigate this issue, we performed HLA-DRB1 genotyping of the largest series of HSP patients ever assessed for genetic studies in Caucasians. Methods: 342 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al classification criteria, and 303 sex and ethnically matched controls were assessed. HLA-DRB1 alleles were determined using a PCR-Sequence-Specific-Oligonucleotide Probe (PCR-SSOP) method. Results: A statistically significant increase of HLA-DRB1*01 in HSP patients when compared with controls was found (43% vs 7%, respectively; p<0.001; odds ratio-OR=2.03 [1.43-2.87]). It was due to the increased frequency of HLA-DRB1*0103 phenotype in HSP (14% vs 2%; p<0.001; OR=8.27 [3.46-23.9]). These results remained statistically significant after adjusting for Bonferroni correction. In contrast, a statistically significant decreased frequency of the HLA-DRB1*0301 phenotype was observed in patients compared to controls (5.6% vs 18.1%, respectively; p<0.001, OR=0.26 [0.14-0.47]), even after adjustment for Bonferroni correction. No HLA-DRB1 association with specific features of the disease was found. Conclusion: Our study confirms an association of HSP with HLA-DRB1*01 in Caucasians. Also, a protective effect against the development of HSP appears to exist in Caucasians carrying the HLA-DRB1*03 phenotype. This article is protected by copyright. All rights reserved.IgA vasculitis (Henoch‐Schönlein) (IgAV), formerly called Henoch‐Schönlein purpura, is the most common vasculitis in children, but it is not rare in adults. Increased familial occurrence supports a genetic predisposition to IgAV. In this context, an association with the HLA–DRB1*01 phenotype has been suggested in Caucasian individuals with IgAV. However, data on the potential association of IgAV with HLA–DRB1*01 were based on small case series. We undertook this study to further investigate this potential association by performing HLA–DRB1 genotyping in the largest series of IgAV patients ever assessed for genetic studies in Caucasians.

Association of HLA-B*41:02 with Henoch-Schönlein Purpura (IgA Vasculitis) in Spanish individuals irrespective of the HLA-DRB1 status

IntroductionA study was conducted to determine whether the human leukocyte antigen (HLA) B alleles are implicated in the susceptibility to Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies.MethodsThe study population was composed of 349 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria, and 335 sex and ethnically matched controls. HLA-B phenotypes were determined by sequencing-based typing (SBT) and analyzed by chi-square or Fisher exact test.ResultsA statistically significant increase of HLA-B*41:02 allele in HSP patients when compared with controls was found (8.3% versus 1.5% respectively; P = 0.0001; OR (odds ratio) =5.76 [2.15-19.3]). These results remained statistically significant after adjusting for Bonferroni correction (P = 0.0028). An internal validation also confirmed the susceptibility effect on HSP associated with HLA-B*41:02 (OR = 5.70 [1.98-16.44]). Since a former study described an association between HLA-DRB1*01:03 and HSP susceptibility, we also evaluated the implication of HLA-B*41:02 independently of HLA-DRB1*01:03. Interestingly, the association remained statistically significant (P = 0.0004, OR = 4.97 [1.8-16.9]). No HLA-B association with specific HSP clinical features was found.ConclusionsOur study indicates that HLA-B*41:02 is associated with the susceptibility to HSP in Spanish patients irrespective of HLA-DRB1 status.

Antitumour necrosis factor-α therapy modulates angiopoietin-2 serum levels in non-diabetic ankylosing spondylitis patients

Ankylosing spondylitis (AS) has been associated with increased cardiovascular (CV) mortality1 ,2 and accelerated atherosclerosis.3 Traditional CV risk factors and inflammation contribute to increased CV morbidity in AS.2 Antitumour necrosis factor (anti-TNF)-α therapy has been found to be effective in patients with AS and other spondyloarthropathies.4 We have observed that non-diabetic AS patients treated with infliximab experienced a dramatic reduction in serum insulin levels and improvement of insulin sensitivity after administration of this drug.5 It is plausible to think that TNF-α blockade may account for some other biological changes that slow the progression of atherosclerosis in AS. Therefore, it may be important to establish potential changes in biomarkers of endothelial cell activation following the administration of anti-TNF-α drugs in AS patients. Angiopoietin-2 (Angpt-2) is a marker of endothelial cell activation, involved in angiogenesis, which makes the endothelium responsive to inflammatory cytokines.6 Angpt-2 levels have been found increased in rheumatoid arthritis (RA) patients with CV disease (CVD) when compared with those without CVD.6 However, to our knowledge, there are no studies assessing Angpt-2 …