Lack of association between carotid intima-media wall thickness and carotid plaques and markers of endothelial cell activation in rheumatoid arthritis patients undergoing anti-TNF therapy

Introduction: To determine the relationship between biomarkers of endothelial cell activation, and carotid artery intima-media wall thickness (IMT) and plaques, two surrogate markers of atherosclerosis, in a series of rheumatoid arthritis (RA) patients undergoing anti-TNF therapy. Methods: 29 consecutive Spanish patients who fulfilled the 1987 American College of Rheumatology classification criteria for RA, had no history of cardiovascular (CV) disease, and had at least one year of follow-up after disease diagnosis were selected. All patients were undergoing anti-TNF-infliximab therapy because of severe disease refractory to conventional disease modifying antirheumatic drugs. Carotid ultrasonography was performed to determine IMT and carotid plaques. Levels of sICAM-3, sICAM-1, sVCAM-1, sPselectin and sE-selectin were assessed by ELISA immediately before an infusion of infliximab. Results: The median disease duration was 14 years. Despite infliximab, no patient experienced a disease remission (DAS28: median 4.17). Only a marginally significant correlation between sVCAM-1 and carotid IMT was observed when both total correlation using Spearman correlation coefficient (p= 0.08) or partial correlation adjusting for sex, age at the time of study, disease duration, rheumatoid factor, and classic CV risk factors was performed (p= 0.09). Also, no association between presence of carotid plaques and levels of biomarkers of endothelial cell activation was observed. Conclusion: In long-standing RA patients without CV disease undergoing anti-TNF therapy no association between levels of soluble markers of endothelial cell activation and carotid ultrasonography abnormalities was observed. Further studies are needed to establish the best tools to be used in the assessment of CV risk of RA.Acknowledgements. This study was supported by two grants from "Fondo de Investigaciones Sanitarias" PI06-0024 and PS09/00748 and by RETICS Program, RD08/0075 (RIER) from "Instituto de Salud Carlos III" (ISCIII

Audiovestibular manifestations in patients with ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown origin affecting up to 1% of the population. Little is known about audiovestibular impairment in patients with AS, especially the presence of cochleovestibular dysfunction in these patients. To investigate audiovestibular manifestations in AS, we studied a series of 50 consecutive patients who fulfilled the modified New York diagnostic criteria for AS and 44 matched controls. Individuals with history of cardiovascular disease, cerebrovascular complications, peripheral artery disease, renal insufficiency, syphilis, Meniere and other vestibular syndromes, infections involving the inner ear, barotrauma, or in treatment with ototoxic drugs were excluded. Most patients with AS were men (80%). The mean age at the time of study was 52.5 years, and mean age at the onset of symptoms was 34.4 years. Twenty-nine (58%) patients showed abnormal hearing loss in the audiogram compared to only 8 (18%) controls (p < 0.001). Values of audiometric tests (pure-tone average and speech reception threshold) yielded significant differences between patients and controls (p < 0.001). It is noteworthy that the audiogram shape disclosed a predominant pattern of high-frequency sensorineural hearing loss in AS patients (50%) compared to controls (18%) (p = 0.002). Also, AS patients exhibited abnormal vestibular tests more commonly than controls. AS patients had an increased frequency of head-shaking nystagmus (20%) compared to controls (0%) (p < 0.001). Moreover, patients (26%) showed a significantly increased frequency of abnormal caloric test compared to controls (0%) (p < 0.001). Finally, a significantly increased frequency of abnormal clinical test of sensory integration and balance with a predominant vestibular loss pattern was observed in patients (36%) compared to controls (5%) (p < 0.001). In conclusion, the current study demonstrates strong evidence for inner ear compromise in patients with AS

Lack of association between TLR4 rs4986790 polymorphism and risk of cardiovascular disease in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased cardiovascular (CV) mortality. Toll-like receptor-4 (TLR4) activates the innate immune response via NF-kB pathway and mitogen-activated protein kinase signaling, leading to expression of proinflammatory cytokines and chemokines. The G allele of TLR4 rs4986790 (+896A > G, Asp299Gly) gene polymorphism has been implicated in reduction of risk of atherosclerosis. In this study, 1481 RA patients fulfilling the 1987 American College of Rheumatology (ACR) criteria were genotyped for the rs4986790 TLR4 variant to determine the influence of this variant in the risk of CV events in these patients. Also, HLA-DRB1 status was determined using molecular based methods. Moreover, potential influence of rs4986790 variant in the development of subclinical atherosclerosis was assessed in a subgroup of RA patients with no history of CV events by the measurement of surrogate markers of subclinical atherosclerosis. No statistically significant differences in allele or genotype frequencies for the rs4986790 variant between RA patients who experienced CV events or not were found. Likewise, no significant association between this gene variant and any of the surrogate markers of subclinical atherosclerosis was found. In summary, results in our study do not support the hypothesis that the rs4986790 (+896A > G, Asp299Gly) TLR4 variant may influence predisposition for subclinical atherosclerosis and clinically evident CV disease in RA patients

CARD8 rs2043211 (p.C10X) polymorphism is not associated with disease susceptibility or cardiovascular events in Spanish rheumatoid arthritis patients

Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis, which is the main cause of increased cardiovascular (CV) morbidity and mortality in RA patients. CARD8 is a constituent of inflammasome, which regulates interleukin 1-beta production, and has been associated with a worse disease course in early RA. One thousand six hundred twenty-one patients fulfilling the 1987 ACR classification criteria for RA and 1300 matched controls, were genotyped for the CARD8 rs2043211 (30T > A, p.C10X) single-nucleotide polymorphism (SNP) using predesigned TaqMan SNP genotyping assay. The genotyping success rate in our study was greater than 94%. We assessed CARD8 rs2043211 gene polymorphism results in 1530 Spanish RA patients in whom information on CV disease and CV risk factors was available at the time of the study. Also, a subgroup of patients with no history of CV events (n = 276) was assessed for the potential influence of the rs2043211 variant in the development of subclinical atherosclerosis, by measurement of carotid intima-media thickness (IMT) and presence of carotid plaques. No statistically significant differences in allele or genotype frequencies for the rs2043211 CARD8 gene variant between patients with RA and controls were seen. Similarly, CARD8 rs2043211 (30T > A, p.C10X) SNP did not influence the development of CV events or the risk of CV events throughout the time. Likewise, no significant association between this gene variant and carotid IMT or the presence of plaques was found. In summary, our results do not support a role of the CARD8 rs2043211 gene variant in susceptibility to RA or in the development of CV disease in patients with RA

Systemic lupus erythematosus in northwestern Spain: a 20-year epidemiologic study

To further investigate the epidemiology of systemic lupus erythematosus (SLE) in southern Europe, we assessed the incidence, prevalence, clinical spectrum of the disease, flares, and survival of patients diagnosed with SLE in the Lugo region of northwestern Spain. Between January 1987 and December 2006, 150 Lugo residents were diagnosed as having SLE according to the 1982 American College of Rheumatology criteria for the classification of SLE. Women outnumbered men (127 [84.7%] vs. 23 [15.3%]). The mean age at the time of disease diagnosis was 46.1 ± 19.6 years. The mean follow-up from the time of disease diagnosis was 7.8 ± 4.5 years. The age- and sex-adjusted annual incidence rate over the 20-year study period was 3.6 (95% confidence interval [CI], 3.0-4.2) per 100,000 population aged 15 years and older. The overall annual incidence rate over the 20-year study period in women (5.9/100,000 population aged ≥15 yr; 95% CI, 4.9-7.0) was higher than in men (1.1/100,000 population aged ≥15 yr; 95% CI, 0.7-1.7) (p < 0.001). By December 31, 2006, the overall age-adjusted SLE prevalence in the Lugo region for patients who fulfilled at least 4 of 1982 American College of Rheumatology criteria was 17.5 per 100,000 population aged 15 years and older (95% CI, 12.6-24.1). Prevalence in women (29.2/100,000 population aged ≥15 yr; 95% CI, 20.0-40.7) was higher than in men (5.8/100,000 population aged ≥15 yr; 95% CI, 2.0-12.0). The most frequent clinical manifestation was arthritis. As reported in population-based studies on SLE patients of European descent, renal disease was observed in only 27.3% of the patients. The rate of flares was 0.084/year. A younger age and the presence of nephritis at the time of disease diagnosis were associated with the development of flares during the follow-up of Lugo patients. Compared with the general population the probability of survival in patients with SLE was significantly reduced (p = 0.04). In conclusion, the present study establishes a baseline estimate of the incidence and clinical spectrum of SLE in northwestern Spain. According to our results, the incidence of SLE in northwestern Spain is slightly higher than that reported in most European regions. Patients with SLE from northwestern Spain have a later average age onset and a lower frequency of nephritis than in the African-American population. However, our data show a reduced probability of survival in Spanish patients with SLE

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.European Union FEDER Funds and “Fondo de Investigación Sanitaria” (Grants PI06/0024, PS09/00748, and PI12/00060) from “Instituto de Salud Carlos III” (ISCIII, Health Ministry, Spain). It was also partially supported by RETICS Programs RD12/0009/0013 and RD12/0009/0004 (RIER) from “Instituto de Salud Carlos III” (ISCIII, Health Ministry, Spain) and in part by grants from the European IMI BTCure Program.Peer reviewe

Evidence of association of the NLRP1 gene with giant cell arteritis

Recent studies have focused attention on the involvement of NLRP1 to confer susceptibility for extended autoimmune/inflammatory disorders, being considered a common risk factor in autoimmunity. NLRP1 provides a scaffold for the assembly of the inflammasome that activates caspases 1 and 5, required for processing and activation of the proinflammatory cytokines interleukin 1β (IL-1β), IL-18 and IL-33 and promoting inflammation

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

A genome-wide association study suggests the HLA Class II region as the major susceptibility locus for IgA vasculitis.

The genetic component of Immunoglobulin-A (IgA) vasculitis is still far to be elucidated. To increase the current knowledge on the genetic component of this vasculitis we performed the first genome-wide association study (GWAS) on this condition. 308 IgA vasculitis patients and 1,018 healthy controls from Spain were genotyped by Illumina HumanCore BeadChips. Imputation of GWAS data was performed using the 1000 Genomes Project Phase III dataset as reference panel. After quality control filters and GWAS imputation, 285 patients and 1,006 controls remained in the datasets and were included in further analysis. Additionally, the human leukocyte antigen (HLA) region was comprehensively studied by imputing classical alleles and polymorphic amino acid positions. A linkage disequilibrium block of polymorphisms located in the HLA class II region surpassed the genome-wide level of significance (OR = 0.56, 95% CI = 0.46-0.68). Although no polymorphic amino acid positions were associated at the genome-wide level of significance, P-values of potential relevance were observed for the positions 13 and 11 of HLA-DRB1 (P = 6.67E-05, P = 1.88E-05, respectively). Outside the HLA, potential associations were detected, but none of them were close to the statistical significance. In conclusion, our study suggests that IgA vasculitis is an archetypal HLA class II disease

Study of association of CD40-CD154 gene polymorphisms with disease susceptibility and cardiovascular risk in Spanish rheumatoid arthritis patients

Objective: rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased cardiovascular (CV) mortality. Since CD40-CD154 binding has direct consequences on inflammation process initiation, we aimed to replicate previous findings related to disease susceptibility in Spanish RA population. Furthermore, as the major complication in RA disease patients is the development of CV events due to accelerated atherosclerosis, and elevated levels of CD40L/CD154 are present in patients with acute myocardial infarction, we assessed the potential association of CD40 and CD154/CD40L gene variants with CV risk in Spanish RA patients. Methods: one thousand five hundred and seventy-five patients fulfilling the 1987 ACR classification criteria for RA and 1600 matched controls were genotyped for the CD40 rs1883832, rs4810485 and rs1535045 and CD154 rs3092952 and rs3092920 gene polymorphisms, using predesigned TaqMan single nucleotide polymorphism genotyping assays. Afterwards, we investigated the influence of CD40-CD154 gene variants in the development of CV events. Also, in a subgroup of 273 patients without history of CV events, we assessed the influence of these polymorphisms in the risk of subclinical atherosclerosis determined by carotid ultrasonography. Results: nominally significant differences in the allele frequencies for the rs1883832 CD40 gene polymorphism between RA patients and controls were found (p = 0.038). Although we did not observe a significant association of CD40-CD154 gene variants with the development of CV events, an ANCOVA model adjusted for sex, age at the time of the ultrasonography assessment, follow-up time, traditional CV risk factors and anti-cyclic citrullinated peptide antibodies disclosed a significant association (p = 0.0047) between CD40 rs1535045 polymorphism and carotid intima media thickness, a surrogate marker of atherosclerosis. Conclusion: data from our pilot study indicate a potential association of rs1883832 CD40 gene polymorphism with susceptibility to RA. Also, the CD40 rs1535045 gene variant may influence development of subclinical atherosclerosis in RA patients