ABSTRACT
The endothelial glycocalyx (EG) is essential for proper function of the endothelium and for vascular integrity, but its role in premature atherogenesis in rheumatoid arthritis (RA) has not been studied yet. EG impairment can play a role in pathogenesis of vascular disease, and one of its characteristics is shedding of syndecan-1 from endothelial cells. Syndecan-1 shedding is mediated by matrix metalloproteinase-9 (MMP-9) and counteracted by tissue inhibitor of metalloproteinases (TIMP)-1. Cardiovascular disease risk in RA is reversible by disease modifying antirheumatic drugs (DMARDs), but the exact modes of action are still unclear. Therefore, we examined effects of DMARDs on syndecan-1, MMP-9 and TIMP-1 in RA patients, and searched for associations between these parameters and inflammatory activity. From the observational PSARA study, we examined 39 patients starting with methotrexate (MTX) monotherapy (in MTX naïve patients, n = 19) or tumor necrosis factor inhibitors (TNFi) in combination with MTX (in MTX non-responders, n = 20) due to active RA. Serum syndecan-1, MMP-9 and TIMP-1 were measured at baseline and after six weeks of treatment. Serum syndecan-1 (p = 0.008) and TIMP-1 (p<0.001) levels decreased after six weeks of anti-rheumatic treatment. Levels of MMP-9 also decreased, but the difference was not statistically significant. The improvement in syndecan-1 levels were independent of changes in inflammatory activity. There was no significant difference in changes in syndecan-1 levels from baseline to 6 weeks between the MTX and TNFi groups, however the change was significant within the MTX group. Six weeks of antirheumatic treatment was associated with reduction in serum levels of syndecan-1, which might reflect reduced syndecan-1 shedding from EG. Thus, it is possible that EG-preserving properties of DMARDs might contribute to their cardioprotective effects. These effects may be at least partly independent of their anti-inflammatory actions. Our findings do not support the notion that syndecan-1 shedding in RA is mediated mainly by increased MMP-9 or decreased TIMP-9 serum concentration.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/metabolism , Syndecan-1/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Female , Humans , Male , Matrix Metalloproteinase 9/metabolism , Methotrexate/therapeutic use , Middle Aged , Prospective Studies , Tissue Inhibitor of Metalloproteinase-1/metabolism , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: The complement system is involved in pathogenesis of cardiovascular disease, and might play a role in accelerated atherogenesis in spondylarthropathies (SpA). Hence, we examined complement activation in SpA, and its relationship to antirheumatic treatment, inflammatory and cardiovascular markers. METHODS: From PSARA, a prospective observational study, we examined 51 SpA patients (31 psoriatic arthritis (PsA), and 20 ankylosing spondylitis (AS)), starting tumor necrosis factor (TNF) inhibitor alone (n = 25), combined with methotrexate (MTX) (n = 10), or MTX monotherapy (n = 16). Complement activation was determined by the soluble terminal complement complex (sC5b-9), inflammation by erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and endothelial function by finger plethysmography (Endopat) at baseline, after 6 weeks and 6 months of treatment. RESULTS: SpA patients had sC5b-9 levels at (PsA) or above (AS) the upper limit of the estimated reference range. Median sC5b-9 levels decreased significantly from baseline to 6 weeks, with no significant difference between the AS and PsA group. Notably, a significant reduction in sC5b-9 was observed after administration of TNF inhibitor ± MTX, whereas no significant changes were observed in patients treated with MTX alone. Between 6 weeks and 6 months, sC5b-9 remained stable across all subgroups. Reduction in sC5b-9 was independently related to decreased ESR and CRP, and to increased high density cholesterol and total cholesterol. Reduction in sC5b-9 from baseline to 6 weeks was associated with improved EF in age and gender adjusted analyses. CONCLUSION: TNF-inhibition, but not MTX monotherapy, led to rapid and sustained reduction of complement activation in SpA. Thus, the observed decrease in cardiovascular morbidity in patients treated with TNF-inhibitors might be partly due to its beneficial effect on complement. TRIAL REGISTRATION: Clinical Trials (NCT00902005), retrospectively registered on the 14th of May 2009.
Subject(s)
Complement Activation/drug effects , Spondylarthropathies/immunology , Tumor Necrosis Factor Inhibitors/pharmacology , Adult , Complement Membrane Attack Complex/immunology , Female , Humans , Male , Methotrexate/administration & dosage , Methotrexate/pharmacology , Methotrexate/therapeutic use , Middle Aged , Spondylarthropathies/blood , Spondylarthropathies/drug therapy , Tumor Necrosis Factor Inhibitors/administration & dosage , Tumor Necrosis Factor Inhibitors/therapeutic useABSTRACT
Objectives: Studies assessing relative mortality risks across the spectrum of systemic inflammatory rheumatic diseases are largely missing. In this study, we wanted to estimate standard mortality ratios (SMRs) and causes of death in an ethnically homogeneous cohort covering all major CTDs and primary systemic vasculitides (PSVs). Methods: We prospectively followed all incident CTD and PSV cases included in the Norwegian CTD and vasculitis registry (NOSVAR) between 1999 and 2015. Fifteen controls for each patient matched for sex and age were randomly drawn from the Norwegian National Population Registry. Causes of death were obtained from the National Cause of Death Register, death certificates and hospital charts. Results: The cohort included 2140 patients (1534 with CTD, 606 with PSV). During a mean follow-up time of 9 years, 279 of the patients (13%) died, compared with 2864 of 32 086 (9%) controls (P < 0.001). Ten years after diagnosis, the lowest survival was 60% in dcSSc, 73% in anti-synthetase syndrome (ASS) and 75% in lcSSc. In the CTD group, the highest SMRs were observed in dcSSc (SMR 5.8) and ASS (SMR 4.1). In the PSV group, Takayasu arteritis (SMR 2.5) and ANCA-associated vasculitis (SMR 1.5) had the highest SMRs. Major causes of death were cardiovascular disease (CTD 27%, PSV 28%), neoplasms (CTD 25%, PSV 27%), chronic respiratory disease (CTD 20%, PSV10%) and infections (CTD 9%, PSV 16%). Conclusion: We observed premature deaths across the spectrum of CTDs and PSVs, with highest SMRs in dcSSc and ASS. The overall mortality was highest in the CTD group.
Subject(s)
Connective Tissue Diseases/mortality , Systemic Vasculitis/mortality , Adolescent , Adult , Age Factors , Aged , Cardiovascular Diseases/etiology , Cardiovascular Diseases/mortality , Case-Control Studies , Cause of Death , Connective Tissue Diseases/complications , Female , Humans , Male , Middle Aged , Norway/epidemiology , Opportunistic Infections/complications , Opportunistic Infections/mortality , Prospective Studies , Registries , Respiratory Tract Diseases/etiology , Respiratory Tract Diseases/mortality , Survival Rate , Systemic Vasculitis/complications , Young AdultABSTRACT
BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA. METHODS: We performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry. Correlation of SNP genotype and gene expression was investigated. Then we conducted targeted resequencing of a candidate locus, among a subset of 480 cases and 480 controls. SUM test was performed to evaluate the association of the identified rare functional variants. RESULTS: The CXCR4 locus on 2q22.1 was found to be significantly associated with JIA, peaking at SNP rs953387. However, this result is subjected to subpopulation stratification within the subjects of European ancestry. After adjusting for principal components, nominal significant association remained (p < 10(-4)). Because of its interesting known function in immune regulation, we carried out further analyses to assess its relationship with JIA. Expression of CXCR4 was correlated with CXCR4 rs953387 genotypes in lymphoblastoid cell lines (p = 0.014) and T-cells (p = 0.0054). In addition, rare non-synonymous and stop-gain sequence variants in CXCR4, putatively damaging for CXCR4 function, were significantly enriched in JIA cases (p = 0.015). CONCLUSION: Our results suggest the association of CXCR4 variants with JIA, implicating that this gene may be involved in the pathogenesis of autoimmune disease. However, because this locus is subjected to population stratification within the subjects of European ancestry, additional replication is still necessary for this locus to be considered a true risk locus for JIA. This cell-surface chemokine receptor has already been targeted in other diseases and may serve as a tractable therapeutic target for a specific subset of pediatric arthritis patients with additional replication and functional validation of the locus.
Subject(s)
Arthritis, Juvenile/genetics , Genetic Predisposition to Disease , Receptors, CXCR4/genetics , Adolescent , Amino Acid Sequence , Case-Control Studies , Child , Child, Preschool , Female , Genetic Loci , Genome-Wide Association Study , Genotyping Techniques , Humans , Male , Molecular Sequence Data , Polymorphism, Single Nucleotide , Principal Component Analysis , Sequence Analysis, DNA , White People/geneticsABSTRACT
Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.
Subject(s)
Autoimmune Diseases/congenital , Autoimmune Diseases/genetics , Adolescent , Age of Onset , Case-Control Studies , Child , Child, Preschool , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Polymorphism, Single Nucleotide , White People/geneticsABSTRACT
OBJECTIVES: Gonadotropin-releasing hormone (GnRH) and pituitary gonadotropins, which appear to be proinflammatory, undergo profound secretory changes during events associated with rheumatoid arthritis (RA) onset, flares, or improvement e.g. menopausal transition, postpartum, or pregnancy. Potential anti-inflammatory effects of GnRH-antagonists may be most pronounced in patients with high GnRH and gonadotropin levels. Therefore, we investigated the efficacy and safety of a GnRH-antagonist, cetrorelix, in RA patients with high gonadotropin levels. METHODS: We report intention-to-treat post hoc analyses among patients with high gonadotropin levels (N = 53), i.e. gonadotropin levels>median, from our proof-of-concept, double-blind AGRA-study (N = 99). Patients with active longstanding RA, randomized to subcutaneous cetrorelix (5mg days1-2; 3mg days 3-5) or placebo, were followed through day 15. Only predefined primary and secondary endpoints were analyzed. RESULTS: The primary endpoint, Disease Activity Score of 28-joint counts with C-reactive protein (DAS28-CRP), improved with cetrorelix compared with placebo by day 5 (-1.0 vs. -0.4, P = 0â010). By day 5, more patients on cetrorelix achieved at least a 20% improvement in the American College of Rheumatology scale (44% vs. 19%, P = 0.049), DAS28-CRP≤3.2 (24% vs. 0%, P = 0.012), and European League against Rheumatism 'Good-responses' (19% vs. 0%, P = 0.026). Tumor necrosis factor-α, interleukin-1ß, interleukin-10, and CRP decreased with cetrorelix (P = 0.045, P = 0.034, P = 0.020 and P = 0.042 respectively) compared with placebo by day 15. Adverse event rates were similar between groups. CONCLUSIONS: GnRH-antagonism produced rapid anti-inflammatory effects in RA patients with high gonadotropin levels. GnRH should be investigated further in RA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00667758.
Subject(s)
Anti-Infective Agents/administration & dosage , Arthritis, Rheumatoid , Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Gonadotropins/blood , Adult , Aged , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/drug therapy , C-Reactive Protein/metabolism , Cytokines/blood , Double-Blind Method , Female , Follow-Up Studies , Gonadotropin-Releasing Hormone/administration & dosage , Humans , Male , Middle Aged , PregnancyABSTRACT
Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.
Subject(s)
Autoimmune Diseases/genetics , Autoimmune Diseases/etiology , Child , Genome-Wide Association Study , Humans , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Risk FactorsABSTRACT
Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.
Subject(s)
Aminopeptidases/genetics , HLA-B27 Antigen/genetics , HLA-B40 Antigen/genetics , Spondylitis, Ankylosing/etiology , Case-Control Studies , Epistasis, Genetic , Genetic Predisposition to Disease , Humans , Major Histocompatibility Complex , Minor Histocompatibility Antigens , Polymorphism, Single NucleotideABSTRACT
Juvenile idiopathic arthritis (JIA) is a leading cause of childhood-onset disability. Although epistasis (gene-gene interaction) is frequently cited as an important component of heritability in complex diseases such as JIA, there is little compelling evidence that demonstrates such interaction. PTPN2, a vitamin D responsive gene, is a confirmed susceptibility gene in JIA, and PTPN2 has been suggested to interact with vitamin D pathway genes in type 1 diabetes. We therefore, tested for evidence of epistasis amongst PTPN2 and the vitamin D pathway genes GC, VDR, CYP24A1, CYP2R1, and DHCR7 in two independent JIA case-control samples (discovery and replication). In the discovery sample (318 cases, 556 controls), we identified evidence in support of epistasis across six gene-gene combinations (e.g., GC rs1155563 and PTPN2 rs2542151, ORint=0.45, p=0.00085). Replication was obtained for three of these combinations. That is, for GC and PTPN2, CYP2R1 and VDR, and VDR and PTPN2, similar epistasis was observed using the same SNPs or correlated proxies in an independent JIA case-control sample (1008 cases, 9287 controls). Using SNP data imputed across a 4 MB region spanning each gene, we obtained highly significant evidence for epistasis amongst all 6 gene-gene combinations identified in the discovery sample (p-values ranging from 5.6×10(-9) to 7.5×10(-7)). This is the first report of epistasis in JIA risk. Epistasis amongst PTPN2 and vitamin D pathway genes was both demonstrated and replicated.
Subject(s)
Arthritis, Juvenile/genetics , Epistasis, Genetic , Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics , Vitamin D/metabolism , Adolescent , Arthritis, Juvenile/metabolism , Child , Child, Preschool , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Humans , Infant , Infant, Newborn , Logistic Models , Male , Polymorphism, Single Nucleotide , Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism , Risk Factors , Vitamin D-Binding Protein/metabolismABSTRACT
BACKGROUND: Osteoporosis is a well-known extra articular manifestation in rheumatoid arthritis (RA). Biologic disease modifying anti rheumatic drugs (DMARDs) has been shown to be superior to synthetic DMARDs to reduce bone destruction including generalized bone loss in RA. Our aim was to study short- and long term changes in hip and spine bone mineral density (BMD) in early RA patients treated during the first decade with available biologic DMARDs. METHODS: RA patients diagnosed at an out-patient clinic between 1999 and 2001 were consecutively enrolled. Demographic, disease and treatment data were collected and BMD was assessed by dual energy X-ray absorptiometry at baseline and after 2, 5 and 10 years. RESULTS: The 92 included RA patients had a baseline mean age (SD) of 50.9 (13.3) years and symptom duration of 12.4 (6.7) months, 62.0% were women and 66.3% were RF positive. In the first 2 years ever use of biologic DMARDs was 18.5%, synthetic DMARDs 91.3% and prednisolone 62.0% whereas the figures for the subsequent 8 years were 62.6%, 89.2% and 51.4%, respectively. The annual rate of BMD loss in the first 2 years and the subsequent 8 years was at femoral neck -1.00% vs. -0.56%, at total hip -0.96% vs. -0.41% and at spine L1-4 -0.42% vs. 0.00%. CONCLUSIONS: Our study adds evidence that aggressive anti-inflammatory treatment including biologic DMARDs reduces the rate of bone loss in RA. Indicating that the burden of osteoporosis is reduced in RA patients treated in clinical practice in the new millennium.
Subject(s)
Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/drug therapy , Biological Products/therapeutic use , Bone Density/drug effects , Bone Resorption/diagnostic imaging , Bone Resorption/drug therapy , Absorptiometry, Photon/trends , Adult , Biological Products/pharmacology , Early Diagnosis , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , Risk Factors , Treatment OutcomeABSTRACT
The incidence of atherosclerosis is significantly increased in rheumatoid arthritis (RA). Infection is one factor that may be involved in the pathogenesis of both diseases. The cause of RA and atherosclerosis is unknown, and infection is one of the factors that may be involved in the pathogenesis of both diseases. The aims of this study were to identify bacteria in the aortic adventitia of patients with cardiovascular disease (CVD) in the presence and absence of RA, and to determine the effect of identified candidate pathogens on Toll-like receptor (TLR)-dependent signalling and the proinflammatory response. The aortic adventitia of 11 CVD patients with RA (RA+CVD) and 11 CVD patients without RA (CVD) were collected during coronary artery bypass graft surgery. Bacteria were detected in four samples from CVD patients and three samples from RA+CVD patients and identified by 16S rRNA gene sequencing. Methylobacterium oryzae was identified in all three RA+CVD samples, representing 44.1% of the bacterial flora. The effect of M. oryzae on TLR-dependent signalling was determined by transfection of HEK-293 cells. Although mild TLR2 signalling was observed, TLR4 was insensitive to M. oryzae. Human primary macrophages were infected with M. oryzae, and a TLDA qPCR array targeting 90 genes involved in inflammation and immune regulation was used to profile the transcriptional response. A significant proinflammatory response was observed, with many of the up-regulated genes encoding proinflammatory cytokines (IL-1α, IL-1ß, IL-6, TNF-α) and chemokines (CCR7, IL-8). The aortic adventitia of CVD patients contains a wide range of bacterial species, and the bacterial flora is significantly less diverse in RA+CVD than CVD patients. M. oryzae may stimulate an proinflammatory response that may aggravate and perpetuate the pathological processes underlying atherosclerosis in RA patients.
Subject(s)
Adventitia/microbiology , Arthritis, Rheumatoid/complications , Bacteria , Cardiovascular Diseases/complications , Cardiovascular Diseases/etiology , Adventitia/metabolism , Adventitia/pathology , Aged , Aorta/metabolism , Aorta/microbiology , Bacteria/classification , Bacteria/genetics , Cytokines/metabolism , Female , Humans , Inflammation Mediators/metabolism , Leukocyte L1 Antigen Complex/metabolism , Macrophages/metabolism , Male , Middle Aged , Mycobacterium/classification , Mycobacterium/genetics , Mycobacterium Infections/complications , Phylogeny , RNA, Bacterial , RNA, Ribosomal, 16S/genetics , Risk Factors , Signal Transduction , Toll-Like Receptors/metabolismABSTRACT
Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.
Subject(s)
Genetic Loci , Genetic Predisposition to Disease/genetics , Immune System Phenomena/genetics , Polymorphism, Single Nucleotide , Spondylitis, Ankylosing/genetics , Alleles , Case-Control Studies , DNA Mutational Analysis/methods , Genetic Loci/immunology , Genetic Predisposition to Disease/ethnology , Genome-Wide Association Study/methods , Genotype , Genotyping Techniques/methods , HLA-B27 Antigen/genetics , High-Throughput Nucleotide Sequencing , Humans , Risk Factors , Spondylitis, Ankylosing/ethnology , Spondylitis, Ankylosing/immunologyABSTRACT
OBJECTIVES: To examine the effect of methotrexate (MTX) with or without tumor necrosis factor alpha (TNF-α)-inhibitors on serum lipoprotein(a) (s-Lp(a)), and to explore a possible relationship between s-Lp(a) and endothelial function (EF) in terms of serum levels of adhesion molecules and reactive hyperaemic index (RHI) in patients with rheumatoid arthritis (RA). METHODS: Serum levels of Lp(a), endothelial adhesion molecules, RHI and inflammatory markers were studied in 64 RA patients, starting with either MTX (n=34) or MTX+TNF-α-inhibitor treatment (n=30) at baseline and after 6 weeks and 6 months. RESULTS: Compared to baseline values, s-Lp(a) was significantly reduced after 6 weeks (p=0.001) and 6 months (p=0.001) in RA patients treated with MTX, and after 6 weeks (p=0.001) in the MTX+TNF-α-inhibitor group. A non-significant reduction was found after 6 months (p=0.102) in the MTX+TNFα-inhibitor group. Serum E-selectin (s-E-selectin) was significantly reduced in both RA treatment groups at both control points. S-Lp(a) correlated positively with s-E-selectin at baseline (p=0.004), and change in s-E-selectin correlated with the change in s-Lp(a) during follow-up (p6weeks= 0.008, p 6months=0.009). No association was found between s-Lp(a) and the other adhesion molecules and RHI. CONCLUSIONS: MTX or MTX combined with a TNFα-inhibitor appears to significantly reduce Lp(a). This finding indicate that s-Lp(a) might be related to systemic inflammation, or that the examined drugs might reduce s-Lp(a) by other mechanisms. Anti-inflammatory treatment might be a novel therapeutic option to decrease s-Lp(a). The associations between s-E-selectin and s-Lp(a) suggest an interaction between these factors, or a common cause.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , E-Selectin/blood , Lipoprotein(a)/blood , Methotrexate/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab , Adult , Aged , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/physiopathology , Cohort Studies , Drug Therapy, Combination , E-Selectin/physiology , Etanercept , Female , Humans , Immunoglobulin G/therapeutic use , Infliximab , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/drug effects , Intercellular Adhesion Molecule-1/physiology , Lipoprotein(a)/physiology , Male , Middle Aged , Receptors, Tumor Necrosis Factor/therapeutic use , Vascular Cell Adhesion Molecule-1/blood , Vascular Cell Adhesion Molecule-1/physiologyABSTRACT
BACKGROUND: The aims were to evaluate the presence and extent of pentraxin 3 depositions in specimens from the outer layers of the aorta and from the internal thoracic artery of patients with coronary artery disease with and without rheumatoid arthritis and to search for relationships between pentraxin 3 and vascular inflammation. METHODS: Using histochemistry and immunohistochemistry, we examined biopsies from the aortic adventitia and from the internal thoracic artery (both with adjacent perivascular tissue), removed during coronary artery bypass grafting in 19 rheumatoid arthritis and 20 non-rheumatoid-arthritis patients, for presence/extent of pentraxin 3 depositions, inflammatory cell infiltrates, and fibrosis. RESULTS: In the aorta, pentraxin 3 deposition occurred in all specimens, mostly at sites with inflammatory cell infiltrates or fibrosis, and their extent was related to the extent of inflammatory cell infiltrates (rho=0.43, 95% confidence interval: 0.13-0.66, P=.007). The extent of pentraxin 3 and inflammatory cell infiltrates in the aorta was similar in rheumatoid arthritis and non-rheumatoid-arthritis patients, but rheumatoid arthritis patients had more fibrosis and a lower proportion of T-cells in inflammatory cell infiltrates. In the internal thoracic artery, pentraxin 3 occurred only in 36% patients, and inflammatory cell infiltrates and fibrosis occurred in none. CONCLUSIONS: Pentraxin 3 depositions in the outer aortic layers are common and are related to the local inflammation. On the other hand, they occur less frequently in the internal thoracic artery, i.e., a vessel highly resistant to atherosclerosis. Rheumatoid arthritis patients had more pronounced fibrosis in the aortic specimens and a different leukocytic response than non-rheumatoid-arthritis patients. In theory, pentraxin 3 might modulate the inflammatory process involved in the pathogenesis of cardiovascular disease and represent a target for new therapies.
Subject(s)
Aorta/metabolism , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/metabolism , C-Reactive Protein/metabolism , Coronary Artery Disease/complications , Coronary Artery Disease/metabolism , Serum Amyloid P-Component/metabolism , Adventitia/metabolism , Adventitia/pathology , Aged , Aorta/pathology , Arthritis, Rheumatoid/pathology , Biomarkers/metabolism , Case-Control Studies , Coronary Artery Disease/pathology , Female , Fibrosis , Humans , Immunohistochemistry , Inflammation/metabolism , Inflammation/pathology , Male , Middle Aged , T-Lymphocytes/pathologyABSTRACT
OBJECTIVE: To examine whether serum level of cartilage oligomeric matrix protein (S-COMP) is related to methotrexate (MTX) or to MTX and tumor necrosis factor-α (TNF-α) combination treatment for rheumatoid arthritis (RA); and to investigate whether S-COMP is related to cardiovascular risk factors including endothelial dysfunction and level of anticitrullinated protein antibodies (ACPA) in patients with RA. METHODS: Clinical and laboratory measures, including S-COMP and reactive hyperemic index (RHI), were examined in 55 consecutive patients with RA starting with either MTX (n = 34) or MTX and anti-TNF-α treatment (n = 21) at baseline, and after 6 weeks and 6 months. RESULTS: S-COMP was similar in the 2 treatment regimens during followup. We found a positive relationship between S-COMP at baseline and the use of disease-modifying antirheumatic drugs the last year preceding the study (p = 0.001), and a negative relation to current use of systemic glucocorticosteroids (p = 0.044). The nonsignificant change in S-COMP between baseline and the 6-month followup was positively and independently related to change in ACPA level (p = 0.009). There was no significant association between RHI and level of S-COMP at baseline. CONCLUSION: The cartilage turnover marker S-COMP did not change significantly after 6 months' treatment with MTX with or without a TNF-α inhibitor in patients with RA. The positive association between S-COMP and ACPA suggests that these factors might interact, and could both be contributors to an unknown link between inflammation and cartilage destruction in patients with RA. S-COMP was not related to endothelial function in patients with RA, or to other cardiovascular risk factors studied. Clinical Trials registration number NCT00902005.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Cardiovascular Diseases/blood , Cardiovascular Diseases/etiology , Endothelium, Vascular/drug effects , Extracellular Matrix Proteins/blood , Glycoproteins/blood , Methotrexate/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Aged , Cartilage Oligomeric Matrix Protein , Drug Therapy, Combination , Female , Glucocorticoids/therapeutic use , Humans , Hyperemia/blood , Hyperemia/drug therapy , Male , Matrilin Proteins , Middle Aged , Risk Factors , Treatment OutcomeABSTRACT
Treatments offered at the Maharishi Ayurveda Health Centre in Norway are based on Maharishi Vedic Medicine (MVM). MVM is a consciousness-based revival by Maharishi Mahesh Yogi, the founder of the Transcendental Meditation (TM) program of the ancient Ayurvedic medicine tradition in India. To extend from 6 to 24 months, a pilot study of the effects of the treatment program at the Health Centre on fibromyalgia. Retesting 2 years after a clinical trial. In this intention to treat study, 31 women with a diagnosis of fibromyalgia received an individually tailored program of (1) physiological purification therapy (Maharishi Panchakarma) and (2) Ayurvedic recommendations regarding daily routine and diet including a novel approach to food intolerance. Five subjects chose to learn TM for stress reduction, pain management and personal development. All were recommended Ayurvedic herbal products for follow-up treatment. A modified Fibromyalgia Impact Questionnaire (FIQ) that included seven dimensions. Scores at 24 months follow-up were compared with pre-treatment scores. At 24-months follow-up, there were significant reductions (26% to 44%) in six of the seven fibromyalgia dimensions: impairment of working ability, pain, tiredness, morning tiredness, stiffness and anxiety. The 7th, depression, decreased 32% (borderline significant). At 24 months, the four subjects who continued practising TM, had almost no symptoms and significantly lower FIQ change scores (-92% to 97%) than the non-meditators on all outcomes. This pilot study suggests that the treatments and health promotion programs offered at the Maharishi Ayurveda Health Centre in Norway lead to long-term reductions in symptoms of fibromyalgia, which is considered a treatment-resistant condition, and further studies are warranted.
Subject(s)
Fibromyalgia/therapy , Medicine, Ayurvedic , Meditation/methods , Phytotherapy , Activities of Daily Living , Adult , Aged , Fatigue/etiology , Fatigue/physiopathology , Fatigue/therapy , Female , Fibromyalgia/complications , Fibromyalgia/physiopathology , Humans , Middle Aged , Norway , Pain Management , Pain Measurement , Patient Satisfaction , Pilot Projects , Quality of Life , Surveys and Questionnaires , Treatment OutcomeABSTRACT
OBJECTIVES: Polymorphisms in genes related to the IFN pathway were investigated for susceptibility to rheumatic diseases and correlation with gene expression in thymus. METHODS: Forty-five polymorphisms were genotyped in Norwegian patients with RA (n = 518), JIA (n = 440), SLE (n = 154) and healthy controls (n = 756). Forty-two thymic samples were used for gene expression analysis. Six hundred and fifty SLE patients and 737 healthy controls from Spain were available for replication. RESULTS: We found a novel association between interferon regulatory factor 5 (IRF5), rs2004640 and JIA, in particular with the polyarthritis RF-negative patients [odds ratio (OR) = 1.60; 95% confidence interval (CI) 1.17, 2.20; P = 0.003]. Also, we confirmed the associations between rs2004640 and SLE (OR = 1.95; 95% CI 1.50, 2.53; P = 3.75 × 10(-7)), which was further strengthened in a meta-analysis (OR = 1.44; 95% CI 1.36, 1.52; P = 2.11 × 10(-37)). Suggestive evidence of association between rs2004640 and RA was found in the Norwegian discovery cohort (OR = 1.19; 95% CI 1.02, 1.40; P = 0.029) and strengthened in a meta-analysis (OR = 1.11; 95% CI 1.05, 1.18; P = 0.00028). Expression levels of exon 1B IRF5 transcripts were dependent on the presence of the rs2004640 T risk allele in thymic tissue, while exon 1A transcript levels correlated with IRF5 promoter CGGGG-indel variants. CONCLUSION: The IFN pathway gene, IRF5, is a common susceptibility factor for several rheumatic and autoimmune diseases, and risk variants are correlated with expression of alternative IRF5 transcripts in thymus implying a regulatory role.
Subject(s)
Interferon Regulatory Factors/genetics , Polymorphism, Single Nucleotide , Rheumatic Diseases/genetics , Thymus Gland/metabolism , Adolescent , Arthritis, Juvenile/genetics , Arthritis, Juvenile/metabolism , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/metabolism , Case-Control Studies , Child , Child, Preschool , Female , Gene Expression Regulation , Genetic Predisposition to Disease , Genotype , Humans , Infant , Infant, Newborn , Interferon Regulatory Factors/metabolism , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/metabolism , Male , Protein Isoforms/metabolism , Rheumatic Diseases/metabolism , Signal Transduction/geneticsABSTRACT
OBJECTIVES: The mechanism linking inflammation to atherosclerosis is unknown. We have previously demonstrated a high occurrence of inflammation in the aortic adventitia of patients with coronary artery disease (CAD), which was more pronounced in patients with inflammatory rheumatic diseases (IRDs), and which might be involved in the pathogenesis of cardiovascular disease. In theory, infections might play a role in the pathogenesis of vascular inflammation or atherosclerosis, or both. This study compared seropositivity and the burden of several common infections in patients with CAD, both with and without IRD, and in healthy controls (HCs). Moreover, we looked for relationships between the examined antibodies and inflammatory infiltrates in the aortic adventitia. METHODS: We examined sera for Chlamydophila pneumoniae, Mycoplasma pneumoniae, Helicobacter pylori, CMV, Streptococcus pyogenes, parvovirus B19, HBV and HCV with commercially available serological tests in 67 patients with IRD, 52 patients without IRD and 30 HCs. RESULTS: We observed neither any statistically significant differences in the examined antibodies between the groups nor a difference in the burden of infection. Except for a protective effect of mycoplasma immunoglobulin A (IgA), we did not find any other associations between the examined antibodies and the occurrence of aortic adventitial mononuclear cell infiltrates. CONCLUSION: Our study does not support the notion that chronic infections or infectious burden contribute to accelerated occurrence of CAD in IRD. Mycoplasma IgA was related to a lower occurrence of aortic adventitial inflammation.
Subject(s)
Bacterial Infections/complications , Coronary Artery Disease/microbiology , Rheumatic Diseases/complications , Virus Diseases/complications , Aged , Antibodies, Bacterial/blood , Antibodies, Viral/blood , Aorta/pathology , Bacterial Infections/immunology , Case-Control Studies , Connective Tissue/pathology , Coronary Artery Disease/pathology , Female , Humans , Immunoglobulin A/blood , Male , Middle Aged , Pneumonia, Mycoplasma/immunology , Virus Diseases/immunologyABSTRACT
BACKGROUND: The clinical relevance of observations of serum levels of osteoprotegerin (OPG) and receptor activator of nuclear factor -κB ligand (RANKL) in juvenile idiopathic arthritis (JIA) is not clear. To elucidate the potential role of OPG and RANKL in JIA we determined serum levels of OPG and RANKL in patients with early JIA compared to healthy children, and prospectively explored changes in relation to radiographic score, bone and lean mass, severity of the disease, and treatment. METHODS: Ninety children with early oligoarticular or polyarticular JIA (ages 6-18 years; mean disease duration 19.4 months) and 90 healthy children individually matched for age, sex, race, and county of residence, were examined at baseline and 2-year follow-up. OPG and RANKL were quantified by enzyme-immunoassay. Data were analyzed with the use of t-tests, ANOVA, and multiple regression analyses. RESULTS: Serum OPG was significantly lower in patients than controls at baseline, and there was a trend towards higher RANKL and a lower OPG/RANKL ratio. Patients with polyarthritis had significantly higher increments in RANKL from baseline to follow-up, compared to patients with oligoarthritis. RANKL was a significant negative predictor for increments in total body lean mass. Patients who were receiving corticosteroids (CS) or disease-modifying antirheumatic drugs (DMARDs) at follow-up had higher OPG/RANKL ratio compared with patients who did not receive this medication. CONCLUSIONS: The data supports that levels of OPG are lower in patients with JIA compared to healthy children, and higher levels of RANKL is associated with more serious disease. RANKL was a significant negative predictor of lean mass in patients with JIA. The OPG/RANKL ratio was higher in patients on DMARDs or CS treatment.