Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
ID | PMID | Title | PublicationDate | abstract |
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17878211 | Serum levels of sex steroid hormones and matrix metalloproteinases after intra-articular g | 2008 Mar | OBJECTIVES: To study metalloproteinase activity and sex steroid hormone production in serum after intra-articular glucocorticoid treatment for knee synovitis. METHODS: 18 female patients with rheumatoid arthritis and synovitis of the knee with need for intra-articular glucocorticoid treatment were included in this study. Serum samples of matrix metalloproteinases (MMP-1/TIMP complex and MMP-3), dehydroepiandrosterone sulphate, testosterone, oestradiol, steroid hormone binding globulin, follicle stimulating hormone and luteinising hormone were collected before injection with 20 mg triamcinolone hexacetonide, and 24 h, 48 h, 1 week and 2 weeks after injection, respectively. RESULTS: Serum levels of MMP-3 were significantly decreased, but MMP-1/TIMP complex was unaffected. Dehydroepiandrosterone sulphate, testosterone and oestradiol levels all decreased and tended to return to baseline levels during the observation period. Steroid hormone binding globulin, follicle stimulating hormone and luteinising hormone levels were unchanged. CONCLUSIONS: Intra-articular glucocorticoid treatment causes a temporary, but considerable suppression of sex steroid hormone secretion. The reduction of MMP-3 indicates an inhibition of the inflammatory, but probably also the cartilage destructive processes within the treated joint. | |
17304653 | Immune responses following administration of influenza and pneumococcal vaccines to patien | 2007 Feb | OBJECTIVE: This study compared the immunogenicity of influenza and pneumococcal vaccines in adult patients with rheumatoid arthritis (RA) receiving adalimumab or placebo. METHODS: In this double-blind, randomized, multicenter study, patients received adalimumab or placebo on Days 1, 15, and 29. Pneumococcal and influenza vaccines were administered on Day 8 (vaccine baseline). Vaccine response (> or = 2-fold titer increase from baseline in > or = 3 of 5 pneumococcal antigens and > or = 4-fold titer increase from baseline in > or = 2 of 3 influenza antigens) and protective antibody titers (> or = 1.6 microg/ml pneumococcal antibody concentration to > or = 3 of 5 antigens and > or = 1:40 influenza antibody titer to > or = 2 of 3 antigens) were analyzed 4 weeks' postvaccination. RESULTS: Following pneumococcal vaccination, percentages of patients achieving a vaccine response were similar in the adalimumab and placebo groups [37.4% and 40.4%, respectively; 95% CI (confidence interval) -16.2%, 10.3%]. Percentages of patients with protective antibody titers were similar in both treatment groups (adalimumab: 85.9%, placebo: 81.7%). Following influenza vaccination, percentages of patients achieving a vaccine response were lower with adalimumab than placebo (51.5% and 63.3%, respectively; 95% CI -25.2%, 1.6%)--a result explained by the subgroup of patients with preexisting protective antibody titers at baseline. For patients without protective antibody titers at baseline, response rates were similar in the 2 groups (adalimumab: 73.3%, placebo: 73.9%). Percentages of patients with protective antibody titers were similar in both treatment groups (adalimumab: 98%, placebo: 94.5%). CONCLUSION: Patients with RA treated with adalimumab can be effectively and safely immunized with pneumococcal and influenza vaccines. | |
17665443 | In vivo inhibition of angiogenesis by interleukin-13 gene therapy in a rat model of rheuma | 2007 Aug | OBJECTIVE: Interleukin-13 (IL-13) is a pleiotropic cytokine that can affect vessel formation, an important component of the rheumatoid arthritis (RA) synovial tissue pannus. The purpose of this study was to use a gene therapy approach to investigate the role of IL-13 in angiogenesis in vivo, using a rat adjuvant-induced arthritis model of RA. METHODS: Ankle joints of female rats were injected preventatively with an adenovirus vector containing human IL-13 (AxCAIL-13), a control vector with no insert (AxCANI), or phosphate buffered saline (PBS). Joints were harvested at the peak of arthritis, and histologic and biochemical features were evaluated. RESULTS: AxCAIL-13-treated joint homogenates had lower hemoglobin levels, suggesting reduced joint vascularity, and both endothelial cell migration and tube formation were significantly inhibited (P < 0.05). Similarly, AxCAIL-13 inhibited capillary sprouting in the rat aortic ring assay and vessel growth in the Matrigel plug in vivo assay. IL-13 gene delivery resulted in up-regulation and association of phosphorylated ERK-1/2 and protein kinase Calpha/betaII, suggesting a novel pathway in IL-13-mediated angiostasis. The angiostatic effect of AxCAIL-13 was associated with down-regulation of proangiogenic cytokines (IL-18, cytokine-induced neutrophil chemoattractant 1/CXCL1, lipopolysaccharide-induced CXC chemokine/CXCL5) and up-regulation of the angiogenesis inhibitor endostatin. The expression and activity of matrix metalloproteinases 2 and 9, which participate in angiogenesis, was impaired in response to IL-13 as compared with AxCANI and PBS treatment. CONCLUSION: Our findings support a role for IL-13 as an in vivo antiangiogenic factor and provide a rationale for its use in RA to control pathologic neovascularization. | |
17195360 | [Preliminary data concerning cross-reacting anticardiolipin antibodies as potential inhibi | 2006 May | In analyzed synovial fluids, suspected for endotoxin presence, the presence of endotoxin done was proved by LAL-test in 21 synovial fluids /42%/ and in 12 of 20 /60%/ the presence of endotoxin inhibiting substances /IS/ was proved. Because many parameters /like presence CIC, anti-LPS, KDO/ indicates that in the group of LAL-negative /IS/ - positive synovial fluids the presence of endotoxin is very possible, IS have been removed /by heating to 100 degrees C/ and after that the endotoxin activity was shown in about 27% of synovial fluids. Additional analysis of the Cohn fraction /prepared by ammonium sulfate precipitation/ confirmed the presence in the gamma and alpha and beta fractions a weak IS activity /in a dose dependent manner. No IS activity, have been shown yet in the fraction of affinity purified aCl antibodies. | |
18785317 | Functional improvement after patients with rheumatoid arthritis start a new disease modify | 2008 Oct | OBJECTIVE: We examined the relationships of rheumatoid arthritis (RA), disease duration (DD), number of previous disease modifying antirheumatic drugs (DMARD), and frequency of DMARD changes, with regard to changes in function in patients with RA evaluated by modified Health Assessment Questionnaire (mHAQ) after the start of a new DMARD. METHODS: In total, 889 patients with active RA from the CORRONA database [patients had mHAQ>or=0.5 and/or Disease Activity Score 28-joint count (DAS28)>or=1.6] started a new DMARD (baseline) and had at least one followup visit 6-12 mo later. Change in mHAQ from baseline to followup visit was modeled using univariate/multivariate linear regression analysis. Due to colinearity, separate multivariate regression models were performed including/excluding the predictors disease duration, number of prior DMARD, and frequency of DMARD changes. RESULTS: Baseline age, mHAQ, erythrocyte sedimentation rate (ESR), DAS28, and number of prior DMARD differed across DD groups. The univariate linear regression model showed that higher baseline values of mHAQ, DAS28, swollen joint count (SJC), tender joint count (TJC), Clinical Disease Activity Index (CDAI), ESR, physician global assessment, prednisone use, and subsequent addition/discontinuation of DMARD were associated with improvement of the mHAQ at followup (p=0.05). Multivariate linear regression models showed that mHAQ improvement was associated with shorter DD, higher baseline mHAQ, addition of subsequent DMARD, and the DMARD frequency index (no. previous DMARD/yrs of DD) (p<0.05). Number of DMARD patients used previously was not associated with change of mHAQ in either model. CONCLUSION: Our study demonstrates that in clinical rheumatologic practices, more frequent changes in DMARD are associated with greater improvement in function (by mHAQ). It does not support the idea that number of previous DMARD used predicts response. Indirectly, these data support the concept that DMARD should be changed if optimal responses are not achieved within a specified time. | |
17599743 | Angiopoietin 1 directly induces destruction of the rheumatoid joint by cooperative, but in | 2007 Jul | OBJECTIVE: To determine whether angiopoietin 1 (Ang-1) potentiates overgrowth of the synovium and joint degradation in rheumatoid arthritis (RA), and to clarify the cell-signaling mechanisms of Ang-1 in the rheumatoid joint. METHODS: Expression of Ang-1, TIE-2 (a receptor for Ang-1), and matrix metalloproteinase 3 (MMP-3) was studied by immunohistochemistry. Activation of the ERK/MAPK and phosphatidylinositol (PI) 3-kinase/Akt pathways and of NF-kappaB was determined by Western blotting and an NF-kappaB p65 DNA binding activity assay, respectively. Induction of apoptosis was evaluated by nuclear staining, cell viability assay, and Western blotting of caspases. Synovial cell migration was evaluated by actin polymerization, Western blotting of Rho family proteins, and affinity purification with Rhotekin-Rho and p21-activated kinase 1. Matrix degradation was examined by induction of proMMP-3 secretion from synovial cells followed by in vitro cartilaginous matrix degradation assay. RESULTS: Ang-1 stimulated the ERK/MAPK and PI 3-kinase/Akt pathways in a cooperative but independent manner, which enhanced rheumatoid synovium overgrowth and joint destruction. In addition, Ang-1 activated NF-kappaB via Akt to promote cell growth, but also inhibited cell apoptosis via ERK and Akt. Ang-1 directly potentiated the extension of synovial cells in an ERK- and Akt-dependent manner by up-regulating Rho family proteins, which attenuated Rac signaling and led to membrane ruffling. Ang-1 induced proMMP-3 secretion from synovial cells, which resulted in direct degradation of the cartilaginous matrix. CONCLUSION: Ang-1 stimulates the ERK/MAPK and PI 3-kinase/Akt pathways cooperatively, but in a manner independent of each other, to directly potentiate synovium overgrowth and joint destruction in RA. In addition to inflammatory cytokines, Ang-1/TIE-2 signaling appears to be an independent factor that contributes to the destruction of the rheumatoid joint. | |
17610321 | Effect of a collective educational program for patients with rheumatoid arthritis: a prosp | 2007 Aug | OBJECTIVE: To evaluate the effect on health and functional status of an 8-week group-education program for rheumatoid arthritis (RA) in addition to usual medical care. METHODS: All consecutive inpatients and outpatients with RA (ACR criteria) were asked to participate in this randomized, prospective, controlled trial. The educational intervention consisted of 8 weekly ambulatory sessions, each lasting 6 hours. Followup was undertaken after 1 year. The primary criterion for judging effectiveness was the Health Assessment Questionnaire (HAQ) score; secondary criteria consisted of coping, medical knowledge, patient global satisfaction, and quality of life scores before the intervention and after 1 year. RESULTS: We asked 1242 inpatients and outpatients to participate in the study: 208 (16.75%) agreed (104 in each group). At baseline, there was no statistically significant difference between the 2 groups. After 1 year, no statistically significant difference was observed between the 2 groups in change in HAQ score: -0.04 +/- 0.46 (education group) vs -0.06 +/- 0.47 (control group) (p = 0.79). Statistically significant differences were found in 3 domains: patient coping (-1.22 +/- 5.55 vs -0.22 +/- 3.81; p = 0.03), knowledge (3.42 +/- 4.73 vs 0.73 +/- 3.78; p < 0.0001), and satisfaction (10.07 +/- 11.70 vs 5.72 +/- 13.77; p = 0.02), all of which were better for the group attending the education sessions. CONCLUSION: Despite improvements in patient coping, knowledge, and satisfaction, the education program was not found to be effective at 1 year. There may have been methodological problems relating to the sensitivity of questionnaires and patient selection, and tailored educational interventions should be considered. | |
17846044 | Responsiveness of patient reported outcomes including fatigue, sleep quality, activity lim | 2008 Feb | OBJECTIVE: To evaluate the responsiveness of patient reported outcomes (PROs), including fatigue, sleep, activity limitation, and quality of life, in patients with rheumatoid arthritis (RA). METHODS: Data were considered from a randomised controlled trial comparing abatacept (n = 258) with placebo (n = 133) on a background of DMARD treatment in RA patients who were inadequate responders to anti-TNF therapy (ATTAIN study). PROs assessed included SF-36, activity limitation, fatigue, and sleep. For each outcome the treatment difference, relative per cent improvement, standardised response mean (SRM), and relative efficiency for assessing an outcome's ability to detect a treatment effect relative to tender joint count (TJC) were calculated. A relative efficiency >1 suggests a measure that is more efficient than TJC in detecting treatment effect. RESULTS: Moderate to large SRMs (>or=0.6) were observed for the PRO measures. In particular, SRMs (95% confidence interval) were: physician global, 0.72 (0.51 to 0.94); HAQ, 0.63 (0.42 to 0.85); SF-36 physical component score, 0.62 (0.40 to 0.83); SF-36 bodily pain, 0.68 (0.46 to 0.90); and fatigue, 0.59 (0.38 to 0.81). Relative efficiencies for physician global (1.6), SF-36 bodily pain domain (1.4), pain intensity (1.4), HAQ (1.2), SF-36 physical component score (1.2), fatigue (1.1), and patient global assessment (1.04) were all more responsive than TJC. The SF-36 mental component score (0.3), swollen joint count (0.6), activity limitation (0.8), sleep (0.7), and C reactive protein (0.9) were less responsive. CONCLUSIONS: Using PROs for evaluating treatments for RA can detect improvements and will identify changes that are important to patients. In general, physical assessments are more responsive to an effective treatment than mental assessments. | |
18163417 | Clinical remission and/or minimal disease activity in patients receiving adalimumab treatm | 2008 Jan 15 | OBJECTIVE: To evaluate the effect of adalimumab treatment on clinical remission and/or minimal disease activity (MDA) in 6,610 patients with active rheumatoid arthritis (RA) who were enrolled in the Research in Active RA trial, a multinational, open-label, 12-week study with an optional extension period. METHODS: Clinical remission was defined as a Disease Activity Score in 28 joints (DAS28)<2.6, Simplified Disease Activity Index (SDAI) score | |
16631753 | Biology of vascular endothelial growth factors. | 2006 May 22 | Angiogenesis is the process by which new blood vessels are formed from existing vessels. The vascular endothelial growth factors (VEGFs) are considered as key molecules in the process of angiogenesis. The VEGF family currently includes VEGF-A, -B, -C, -D, -E, -F and placenta growth factor (PlGF), that bind in a distinct pattern to three structurally related receptor tyrosine kinases, denoted VEGF receptor-1, -2, and -3. VEGF-C and VEGF-D also play a crucial role in the process of lymphangiogenesis. Here, we review the biology of VEGFs and evaluate their role in pathological angiogenesis and lymphangiogenesis. | |
17133607 | A novel autoantigen to differentiate limited cutaneous systemic sclerosis from diffuse cut | 2006 Dec | OBJECTIVE: To investigate the presence and clinical significance of autoantibodies against the interferon-inducible gene IFI16 in systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and other autoimmune diseases. METHODS: Immunohistochemical analysis was used to evaluate the expression of IFI16 in skin biopsy specimens obtained from patients with SSc and patients with SLE. Levels of antibodies against IFI16 in sera from 82 patients with SSc and 100 patients with SLE were determined by enzyme-linked immunosorbent assay. Other autoimmune diseases such as primary Sjögren's syndrome (SS), rheumatoid arthritis (RA), chronic urticaria, and hepatitis C virus (HCV) infection were also examined. RESULTS: Expression of IFI16 was greatly increased and was ubiquitous in all layers of the epidermis and in the dermal inflammatory infiltrates of lesional skin from both patients with SLE and patients with SSc. Patients with SLE, those with primary SS, and those with SSc exhibited significantly higher anti-IFI16 IgG antibody levels compared with normal controls (for SLE, P < 0.002; for primary SS, P < 0.001; for SSc, P < 0.0005). Anti-IFI16 titers above the ninety-fifth percentile for control subjects were observed in 26% of the patients with SLE, 50% of those with primary SS, and 21% of those with SSc (28% of patients with limited cutaneous SSc [lcSSc] versus 4% of patients with diffuse cutaneous SSc [dcSSc]). In contrast, the prevalence of anti-IFI16 was 4% in patients with RA, 5% in those with chronic urticaria, and 13% in those with HCV infection. CONCLUSION: The results of this study provide evidence that an IFN-inducible gene, IFI16, may be involved in the pathophysiologic mechanisms of connective tissue disorders such as SSc. Moreover, a strict correlation with lcSSc was also demonstrated, thus providing a novel tool in the differential diagnosis of lcSSc from dcSSc. | |
18577308 | Retrospective claims data analysis of dosage adjustment patterns of TNF antagonists among | 2008 Aug | OBJECTIVE: To describe dosing patterns for tumor necrosis factor (TNF) antagonists in patients with rheumatoid arthritis from health care provider and payer point of interest. RESEARCH DESIGN AND METHODS: Using privately insured US claims data from 31 large employers covering 31 companies across the US, rheumatoid arthritis (RA) patients were identified and three cohorts were defined based on first TNF-antagonist treatment (adalimumab, etanercept, or infliximab) administered after January 1, 2003. Dosage-adjustment patterns were assessed during the following 12-month period. Changes in dosage (both increases and decreases) and maintenance of a stable dosage were evaluated. For the health care provider point of interest, a new algorithm was developed to assess treatment patterns with chronic injectable therapies that incorporated the potential inconsistency between days of supply and prescription-gap data, thus providing the actual use of TNF-antagonist treatment. For the payer, usage data addressed whether the TNF antagonist was used at a greater dosage than recommended. Differences in baseline characteristics and dosage change rates between cohorts were tested using Chi-Square tests for categorical variables and Wilcoxon tests for continuous variables. RESULTS: From the health care provider point of interest, 83.4% of adalimumab-treated patients (n = 205) initially received the recommended dosage, 10.2% received less, and 6.3% received more; 87.7% of etanercept-treated patients (n = 455) initially received the recommended dosage, 11.2% received less, and 1.1% received more; and 83.8% of infliximab-treated patients (n = 148) started with 2-4 vials (the recommended dosage is based on the weight of the patient, not total milligrams). All treatments had similar dosage decrease and discontinuation rates. Maintenance of stable dosage was lower for infliximab (20.9%) than adalimumab (37.1%) and etanercept (39.1%); both p < 0.01. The infliximab dosage-increase rate (35.1%) was greater than adalimumab (3.9%) and etanercept (0); both p < 0.01. From the payer point of interest, dosage-increase rate was greater for infliximab (28.3%) than adalimumab (8.7%) and etanercept (6.9%), both p < 0.01. CONCLUSIONS: Infliximab had greater dosage-increase rates than adalimumab and etanercept. Adalimumab and etanercept had similar dosage-increase rates. All treatments had similar dosage-decrease and discontinuation rates. Maintenance of stable dosage was lower for infliximab than for adalimumab and etanercept. The study has the usual limitation of claims data analysis in that clinical details might be insufficient to draw causal inference. | |
18311749 | Effects of postmenopausal hormone therapy on rheumatoid arthritis: the women's health init | 2008 Mar 15 | OBJECTIVE: To study the effects of postmenopausal hormone therapy (PHT) on the incidence and severity of rheumatoid arthritis (RA). METHODS: The Women's Health Initiative randomized controlled trials evaluated the effects of unopposed estrogen (E-alone) and estrogen plus progestin (E+P) compared with placebo on a diverse set of health outcomes over 7.1 and 5.6 years, respectively. RA cases were identified using historical and medication data. The hazard of developing RA was estimated using Cox proportional hazards regression models. Disease symptom severity was estimated using the Short Form 36 (SF-36) and self-reported joint pain scores at baseline and after 1 year. Mean changes in severity were compared using linear regression models. RESULTS: Of the 27,347 participants, 63 prevalent cases and 105 incident cases of RA were identified. A nonsignificant reduction in the risk of developing RA (hazard ratio 0.74; 95% confidence interval [95% CI] 0.51, 1.10) was noted with PHT use. PHT use led to improved SF-36 scores in unadjusted analyses (percent change 12.5%; 95% CI -24.45, -0.57) but not after adjustment for relevant covariates (P = 0.33). Nonsignificant improvements in joint pain scores were seen with PHT use (odds ratio [OR] 4.10; 95% CI 0.83, 20.20). PHT did not improve swelling (OR 1.27; 95% CI 0.08, 19.63) or prevent new joint pains (OR 0.72; 95% CI 0.11, 4.68) in RA participants. CONCLUSION: There were no statistically significant differences in the risk of developing RA or the severity of RA between the PHT and placebo groups. | |
17052183 | Phosphoinositide 3-kinase signalling and FoxO transcription factors in rheumatoid arthriti | 2006 Nov | Although the mechanisms leading to the induction of RA (rheumatoid arthritis) are poorly understood, improper activation, proliferation, survival and retention of neutrophils, macrophages, lymphocytes and other leucocytes contribute to perpetuation of inflammation and eventual joint destruction through activation of stromal fibroblast-like synoviocytes. Fundamental studies in developmental biology, cellular biology and immunology have established critical roles for PI3K (phosphoinositide 3-kinase) signal transduction pathways in cellular chemotactic responses, proliferation, apoptosis and survival. Despite profound alteration of these cellular processes in RA, involvement of PI3K signalling pathways in this chronic inflammatory disease, and their assessment as potential therapeutic targets, has until recently received scant attention. This review highlights recent advances in our understanding of PI3K signalling pathways, in particular regulation of FoxO (forkhead box O) transcription factors, and their relevance to RA. | |
19066175 | Definition of arthritis candidate risk genes by combining rat linkage-mapping results with | 2009 Dec | OBJECTIVE: To define genomic regions that link to rat arthritis and to determine the potential association with rheumatoid arthritis (RA) of the corresponding human genomic regions. METHODS: Advanced intercross lines (AIL) between arthritis susceptible DA rats and arthritis resistant PVG.1AV1 rats were injected with differently arthritogenic oils to achieve an experimental situation with substantial phenotypic variation in the rat study population. Genotyping of microsatellite markers was performed over genomic regions with documented impact on arthritis, located on rat chromosomes 4, 10 and 12. Linkage between genotypes and phenotypes were determined by R/quantitative trait loci (QTL). Potential association with RA of single nucleotide polymorphisms (SNPs) in homologous human chromosome regions was evaluated from public Wellcome Trust Case Control Consortium (WTCCC) data derived from 2000 cases and 3000 controls. RESULTS: A high frequency of arthritis (57%) was recorded in 422 rats injected with pristane. Maximum linkage to pristane-induced arthritis occurred less than 130 kb from the known genetic arthritis determinants Ncf1 and APLEC, demonstrating remarkable mapping precision. Five novel quantitative trait loci were mapped on rat chromosomes 4 and 10, with narrow confidence intervals. Some exerted sex-biased effects and some were linked to chronic arthritis. Human homologous genomic regions contain loci where multiple nearby SNPs associate nominally with RA (eg, at the genes encoding protein kinase Calpha and interleukin 17 receptor alpha). CONCLUSIONS: High-resolution mapping in AIL populations defines limited sets of candidate risk genes, some of which appear also to associate with RA and thus may give clues to evolutionarily conserved pathways that lead to arthritis. | |
17968334 | Mechanisms of Disease: angiogenesis in inflammatory diseases. | 2007 Nov | Angiogenesis, the development of new vessels, is an important process in health and disease. The perpetuation of neovascularization in inflammatory diseases, such as rheumatoid arthritis, spondyloarthropathies and some systemic autoimmune diseases, might facilitate the ingress of inflammatory cells into the synovium and, therefore, stimulate pannus formation. Disorders associated with perpetuated neovascularization are considered to be angiogenic inflammatory diseases. Several angiogenic mediators, including growth factors, cytokines, matrix metalloproteinases, matrix macromolecules, cell adhesion receptors, chemokines and chemokine receptors, have been implicated in the process of capillary formation. There is a regulatory network in inflamed tissues that is involved in the upregulation or downregulation of angiogenesis. Endogenous angiostatic factors downregulate neovascularization and might act as angiostatic agents. Furthermore, angiogenesis might be targeted by several specific approaches that could be therapeutically used to control inflammatory diseases. | |
16755991 | [Polymorphism of gene promotor region for MMP-2 in rheumatoid arthritis]. | 2006 Apr | INTRODUCTION: Matrix metalloproteinase (MMP) belonging to family of zinc-dependent endopeptidases participates in remodelling of extracellular matrix in many physiological and pathological processes including rheumatoid arthritis (RA). Rheumatoid arthritis is a chronic autoimmune inflammatory multi-systemic disease characterized, among others, by degradation of hyaline articular cartilage and escalated angiogenesis. As a matter of fact, these processes may by influenced by MMP. On the other hand, MMP can suppress inflammation by degrading biologically active molecules like cytokines, chemokines or growth factor receptors. Increased levels of MMP-2 (gelatinase A) are observed in serum and synovial fluid of patients with RA. Gene polymorphism for MMP-2 can affect susceptibility to development and/or severity of RA. METHOD: The aim of the study was to prove possible association of polymorphisms in gene promotor region for MMP-2 (-1575 G/A, -1306 C/T, -790 T/G, -735 C/T) with RA. We worked with 101 patients with RA who met reviewed diagnostic criteria of ACR (1987) for RA, and suffer from RA for at least 2 years. Control group consisted of 101 healthy volunteers of similar age and gender distribution. RESULTS: RA patients and control group did not differ in genotype distributions or frequencies of alleles of polymorphisms -1575A/G, -1306C/T and -735 C/T. Significant difference was observed between RA patients and control group in allelic frequencies of polymorphism -790 T/G MMP-2 (T allele -0.70 vs. 0.66, Pa = 0.013). Also, a tendency of GG genotype growth was noted in RA patients (Pg = 0.053). Significant difference in allelic frequencies was also observed between men with RA and men from control group (T allele -0.80 vs. 0.61, Pa = 0.025). Haplotype of GCGC polymorphisms -1575 G/A, -1306 C/T, 790 T/G, -735 C/T was more frequent in RA patients (Pcorr = 0.016; OR = 0.09; confidence interval 0.00-0.65), whereas GCTC haplotype was noted more frequently in control group (Pcorr = 0.017; OR = 1.8; confidence interval 1.17-2.70). CONCLUSION: The results indicate the association between polymorphisms in gene promotor region for MMP-2 and susceptibility to development of RA. | |
18328150 | Reduction of oxidative stress marker levels by anti-TNF-alpha antibody, infliximab, in pat | 2008 Jan | OBJECTIVE: The aim of this study was to evaluate the effects of anti-TNF-alpha antibody, infliximab, on oxidative stress markers representing DNA damage, lipid peroxidation, and glycoxidation. METHODS: Twenty-three RA patients underwent infliximab treatment and were analyzed for 30 weeks. Six patients who experienced side effects and one patient who had a reduced efficacy of infliximab were discontinued the infliximab treatment at 30-54 weeks. Sixteen patients were analyzed for 54 weeks. The levels of serum total, urinary total, and free pentosidine, which is an advanced glycation end-product (AGE), and of urinary 15-Isoprostane F2t and 8-hydroxy-deoxy guanosine (8-OHdG) were determined at baseline and at 14, 30, and 54 weeks after initial treatment with infliximab. RESULTS: Serum total, urinary total, and free pentosidine levels were reduced at 54 weeks after initial infliximab treatment. Urinary 15-Isoprostane F2t and 8-OHdG levels were also reduced at 14, 30, and 54 weeks. Urinary 8-OHdG levels in RA patients correlated with CRP and the Disease Activity Score of 28 joints. CONCLUSION: In RA patients, infliximab plays an essential role as an anti-oxidative agent against AGE formation, oxidative DNA damage and lipid peroxydation. | |
18160420 | Role of pathogenic auto-antibody production by Toll-like receptor 9 of B cells in active s | 2008 Feb | OBJECTIVES: Toll-like receptor 9 (TLR9) is a pattern-associated receptor functioning in innate immunity that may be involved in the recognition of self-antigens and the production of pathogenic auto-antibodies. Therefore, we examined the expression of TLR9 in systemic lupus erythematosus (SLE) to determine whether TLR9 is involved in the production of pathogenic auto-antibodies. METHODS: B cells were collected from patients with active SLE, and subjected to analysis of the TLR9 molecule using flow cytometry fluorescence activated cell sorting (FACS) and TLR9 mRNA by reverse-transcriptase polymerase chain reaction. SLE B cells were stimulated with CpG-ODN, and subsequent cytokine and anti-dsDNA antibody production was measured by enzyme-linked immunosorbent assay. RESULTS: The expression and mRNA level of TLR9 on B cells was up-regulated in SLE patients, and SLE disease activity index (SLEDAI) and CH50 were correlated with TLR9 expression on CD20+ B cells. Moreover, TLR9-CpG interaction enhanced the production of anti-dsDNA antibody and IL-10. CONCLUSIONS: The present study demonstrated that higher expression of TLR9 on peripheral blood B cells from patients with active SLE was significantly correlated with CH50 and SLEDAI to TLR9, and induced the production of anti-dsDNA antibody and IL-10 by TLR9-CpG ligation. These results suggest that an abnormality of innate immunity plays a crucial role in the pathology of SLE, and that blockade of CpG-TLR9 interaction may be a new therapeutic approach for SLE. | |
17978466 | Recent advances in immunopathophysiology of interleukin-6: an innovative therapeutic drug, | 2007 Nov | Interleukin (IL)-6 cDNA was originally cloned as a terminal B cell differentiation factor into antibody-producing plasma cells. This revealed that it is a multifunctional cytokine that acts on a variety of cells. From the clinical viewpoint, it is especially important that IL-6 acts on hepatocytes to induce acute-phase reactants, including C-reactive protein, serum amyloid A protein, and fibrinogen, and to decrease serum albumin levels. Very recently, this cytokine has been found to enhance the synthesis of a peptide called hepcidin in the liver which regulates iron recycling, resulting in anemia due to hypofferemia. It has also been shown that IL-6 is responsible for various clinical symptoms, including the appearance of autoantibodies, fatigue, anemia, anorexia, fever, and increases in the erythrocyte sedimentation rate, all of which develop in patients with various chronic autoimmune inflammatory diseases. In practice, blocking the IL-6 signaling pathway with a recombinant humanized anti-IL-6 receptor antibody, tocilizumab (TCZ), has dramatically improved all the signs and symptoms of these patients. A study in mice demonstrated that IL-6 promotes the development of a new type of T-helper cells called Th17 cells that impact the pathogenesis of autoimmune diseases. This suggests that TCZ is not only an antiinflammatory agent but also might affect basic autoimmunity. In this review, recent advances in the immunobiology of interleukin-6 related to immune-mediated diseases are discussed. |