To determine whether circulating osteopontin (OPN) levels in patients with ankylosing spondylitis (AS) undergoing TNF-α antagonist-infliximab-therapy are increased compared with controls and to ...establish whether disease activity, systemic inflammation, metabolic syndrome, adipokines and biomarkers of atherosclerosis are potential determinants of circulating OPN levels in these patients.
We assessed OPN serum concentrations in a series of 30 non-diabetic AS patients without cardiovascular disease undergoing TNF-α antagonist-infliximab therapy and 48 matched controls. OPN levels were measured immediately before and after an infliximab infusion, at time 0 and at time 120 minutes respectively. Correlations of OPN serum levels with clinical features, disease activity, systemic inflammation, metabolic syndrome and several biomarkers of atherosclerosis were assessed. Potential changes in OPN concentration following an infusion of anti-TNF-α monoclonal antibody-infliximab were also analysed.
At the time of the study AS patients undergoing anti-TNF-α therapy had low disease activity (mean BASDAI 2.94) and they showed similar OPN serum levels to healthy controls. No differences in OPN levels according to the specific clinical features of the disease were seen. Also, no correlation between OPN concentration and insulin resistance and adipokines was observed. However, a positive correlation between OPN and angiopoietin-2 (Angpt-2) serum levels was found (r=0.397; p=0.04). In addition, a single infliximab infusion led to a marginal statistically significant reduction in OPN levels (24112.19±14608.73 pg/ml at time 0 versus 21806.62±11390.83 pg/ml at time 120'; p=0.05).
OPN and Angpt-2 serum levels are correlated in non-diabetic AS patients undergoing TNF-α antagonist therapy.
Polymyalgia rheumatica (PMR) is often the presenting manifestation of giant cell arteritis (GCA). Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scan often ...discloses the presence of large vessel vasculitis (LVV) in PMR patients. We aimed to identify predictive factors of a positive PET/CT scan for LVV in patients classified as having isolated PMR according to well-established criteria.
A set of consecutive patients with PMR from a single hospital were assessed. All of them underwent PET/CT scan between January 2010 and February 2018 based on clinical considerations. Patients with PMR associated to other diseases, including those with cranial features of GCA, were excluded. The remaining patients were categorized in classic PMR (if fulfilled the 2012 EULAR/ACR classification criteria at disease diagnosis; n = 84) or atypical PMR (who did not fulfill these criteria; n = 16). Only information on patients with classic PMR was assessed.
The mean age of the 84 patients (51 women) with classic PMR was 71.4 ± 9.2 years. A PET/CT scan was positive in 51 (60.7%). Persistence of classic PMR symptoms was the most common reason to perform a PET/CT scan. Nevertheless, patients with positive PET/CT scan often had unusual symptoms. The best set of predictors of a positive PET/CT scan were bilateral diffuse lower limb pain (OR = 8.8, 95% CI: 1.7-46.3; p = 0.01), pelvic girdle pain (OR = 4.9, 95% CI: 1.50-16.53; p = 0.01) and inflammatory low back pain (OR = 4.7, 95% CI: 1.03-21.5; p = 0.04).
Inflammatory low back pain, pelvic girdle and diffuse lower limb pain are predictors of positive PET/CT scan for LVV in PMR.
The Fc gamma receptors have been shown to play important roles in the initiation and regulation of many immunological and inflammatory processes and to amplify and refine the immune response to an ...infection. We have investigated the hypothesis that polymorphism within the FCGR genetic locus is associated with giant cell arteritis (GCA). Biallelic polymorphisms in FCGR2A, FCGR3A, FCGR3B and FCGR2B were examined for association with biopsy-proven GCA (n = 85) and healthy ethnically matched controls (n = 132) in a well-characterised cohort from Lugo, Spain. Haplotype frequencies and linkage disequilibrium (D') were estimated across the FCGR locus and a model-free analysis performed to determine association with GCA. There was a significant association between FCGR2A-131RR homozygosity (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.12 to 3.77, P = 0.02, compared with all others) and carriage of FCGR3A-158F (OR 3.09, 95% CI 1.10 to 8.64, P = 0.03, compared with non-carriers) with susceptibility to GCA. FCGR haplotypes were examined to refine the extent of the association. The haplotype showing the strongest association with GCA susceptibility was the FCGR2A-FCGR3A 131R-158F haplotype (OR 2.84, P = 0.01 for homozygotes compared with all others). There was evidence of a multiplicative joint effect between homozygosity for FCGR2A-131R and HLA-DRB1*04 positivity, consistent with both of these two genetic factors contributing to the risk of disease. The risk of GCA in HLA-DRB1*04 positive individuals homozygous for the FCGR2A-131R allele is increased almost six-fold compared with those with other FCGR2A genotypes who are HLA-DRB1*04 negative. We have demonstrated that FCGR2A may contribute to the 'susceptibility' of GCA in this Spanish population. The increased association observed with a FCGR2A-FCGR3A haplotype suggests the presence of additional genetic polymorphisms in linkage disequilibrium with this haplotype that may contribute to disease susceptibility. These findings may ultimately provide new insights into disease pathogenesis.
Epidemiology of the vasculitides González-Gay, M A; García-Porrúa, C
Rheumatic diseases clinics of North America,
11/2001, Letnik:
27, Številka:
4
Journal Article
Recenzirano
In summary, systemic vasculitides constitute a heterogeneous group of overlapping diseases that are somewhat more common than previously considered. Although the causes of vasculitis are largely ...unknown, epidemiologic studies have implicated geographic, genetic, and environmental factors. Ethnicity, various genes such as those of the MHC, gender, and environmental factors seem to account for the different incidence rates of these syndromes. GCA is the most common vasculitis in elderly people from Western countries. Small-sized cutaneous vasculitides, particularly HSP in children and HV in adults, are also common diseases. Increased physician awareness and the routine use of ANCA tests may contribute to an increase in the recognition of conditions such as WG and MPA.
To investigate the potential implication of the STAT4 gene polymorphism rs7574865 in the predisposition to or the clinical expression of giant cell arteritis (GCA).
A total of 212 patients diagnosed ...with biopsy-proven GCA were studied. DNA from patients and controls matched by age, sex, and ethnicity was obtained from peripheral blood. Samples were genotyped for STAT4 rs7574865 polymorphism.
No statistically significant differences in the allele frequencies for the STAT4 rs7574865 polymorphism were observed between patients and controls. Although we observed an increased frequency of the T/T genotype in GCA patients (6.0%) compared to healthy controls (3.9%), this difference did not achieve statistical significance (OR 1.57, 95% CI 0.72-3.41). No statistically significant differences in allele or genotype frequencies were observed when patients were stratified according to the presence of typical disease features such as polymyalgia rheumatica, severe ischemic manifestations, and visual ischemic complications in the setting of this vasculitis.
Our results do not support a major role of the STAT4 rs7574865 gene polymorphism in susceptibility to or clinical manifestations of GCA.
To determine whether the interleukin (IL)6 -174 gene polymorphism may influence the development of subclinical atherosclerosis manifested by the presence of endothelial dysfunction in RA patients.
...311 patients (228 73.3% women; 243 78.1% rheumatoid factor positive) who fulfilled the 1987 ACR classification criteria for RA seen at the Rheumatology outpatient clinic of Hospital Xeral-Calde, Lugo between March 1996 and December 2006 and 226 matched controls were included in this study. Between March and December 2007, a subgroup of 98 patients randomly selected was assessed for the presence of endothelial dysfunction. Patients and controls were genotyped for a single biallelic (G/C) nucleotide polymorphism (rs1800795) in the promoter region at the position -174 of the IL6 gene using a TaqMan 5' allele discrimination assay.
No significant differences in the IL6 -174 allele or genotype frequency between RA patients and controls were found. However, RA patients homozygous for the IL6 -174 GG genotype had more severe endothelial dysfunction (flow-mediated endothelium-dependent vasodilatation-FMD%: 4.2 + or - 6.6) than those carrying the IL6 -174 GC (FMD%: 6.3 + or - 8.1) or IL6 -174 CC (FMD%: 6.0 + or - 3.3) genotypes. In this regard, significant differences were observed when FMD% values in RA patients carrying the IL6 -174 GG genotype were compared with that observed in those carrying the IL6 -174 GC and the IL6 -174 CC genotypes (FMD%: 6.3 + or - 4.6) (p=0.02).
Our results support a role of IL6 -174 gene polymorphism in the development of subclinical atherosclerosis in patients with RA.
Objective
To investigate the role of the HO‐1 gene as a novel functional candidate gene for rheumatoid arthritis (RA).
Methods
We performed a case–control study including 736 RA patients and 846 ...healthy controls of Spanish Caucasian origin. Two putative functional HO‐1 promoter polymorphisms, a (GT)n microsatellite and a −413 A/T single‐nucleotide polymorphism (SNP), were selected as genetic markers and genotyped using polymerase chain reaction–based methods. In addition, the intracellular expression of heme oxygenase 1 (HO‐1) was determined in healthy individuals with different (GT)n genotypes.
Results
The distribution of HO‐1 (GT)n short (S) alleles (≤25 GT repeats) and long (L) alleles (>25 GT repeats) revealed a significant protective effect of S (GT)n alleles (P = 0.019) (odds ratio OR 0.8, 95% confidence interval 95% CI 0.7–0.9) and the SS (GT)n genotype (P = 0.002) (OR 0.6, 95% CI 0.4–0.9). In contrast, the −413 HO‐1 promoter SNP did not yield any statistically significant deviation between RA patients and controls, considering either allele or genotype frequencies. The haplotype analysis showed a strong protective effect of the S/A haplotype (P = 7 × 10−7, corrected P Pcorr = 3 × 10−6) (OR 0.4, 95% CI 0.3–0.6), whereas the L/A haplotype showed the opposite tendency (P = 0.008, Pcorr = 0.03) (OR 1.2, 95% CI 1.0–1.4). In addition, we demonstrated that monocytes from individuals carrying the SS (GT)n genotype showed a significantly higher percentage of HO‐1 expression than did cells from LL homozygous individuals (P = 0.0003).
Conclusion
In this study, we identified the HO‐1 (GT)n microsatellite as a new genetic marker involved in RA genetics in our population.
Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide ...association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc. We selected 768 polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from Europe. Overall significance was calculated for replicated significant SNPs by meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097 controls). Six SNPs in regions not previously associated with SSc were selected for validation in another five independent cohorts, up to a total of 5270 SSc patients and 8326 controls. We found evidence for replication and overall genome-wide significance for one novel SSc genetic risk locus: CSK P-value = 5.04 × 10(-12), odds ratio (OR) = 1.20. Additionally, we found suggestive association in the loci PSD3 (P-value = 3.18 × 10(-7), OR = 1.36) and NFKB1 (P-value = 1.03 × 10(-6), OR = 1.14). Additionally, we strengthened the evidence for previously confirmed associations. This study significantly increases the number of known putative genetic risk factors for SSc, including the genes CSK, PSD3 and NFKB1, and further confirms six previously described ones.
PDF
