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ID PMID Title PublicationDate abstract
22899879 Anti-TNF-alpha-adalimumab therapy is associated with persistent improvement of endothelial 2012 To determine whether treatment with the anti-TNF-alpha blocker adalimumab yields persistent improvement of endothelial function and prevents from morphological progression of subclinical atherosclerosis in patients with rheumatoid arthritis (RA) refractory to conventional therapy, a series of 34 consecutive RA patients, attending hospital outpatient clinics and who were switched from disease modifying antirheumatic drug therapy to anti-TNF-alpha-adalimumab treatment because of severe disease, were assessed by ultrasonography techniques before the onset of adalimumab therapy (at day 0) and then at day 14 and at month 12. Values of flow-mediated endothelium-dependent vasodilatation at day 14 and at month 12 were significantly higher (mean ± standard deviation (SD): 6.1 ± 3.9%; median: 5.7% at day 14, and mean ± SD: 7.4 ± 2.8%; median: 6.9% at month 12) than those obtained at day 0 (mean: 4.5 ± 4.0%; median: 3.6%; P = 0.03 and P < 0.001, resp.). Endothelium-independent vasodilatation results did not significantly change compared with those obtained at day 0. No significant differences were observed when carotid artery intima-media wall thickness values obtained at month 12 (mean ± SD: 0.69 ± 0.21 mm) were compared with those found at day 0 (0.65 ± 0.16 mm) (P = 0.3). In conclusion, anti-TNF-alpha-adalimumab therapy has beneficial effects on the development of the subclinical atherosclerosis disease in RA.
21459939 Lymphotoxin-α 252 A>G polymorphism: a link between disease susceptibility and dyslipidemi 2011 Jul OBJECTIVE: Rheumatoid arthritis (RA) is associated with higher levels of inflammatory mediators and with a more atherogenic lipid profile. Dyslipidemia can be present years before arthritis develops. Lymphotoxin-α (LTA) is a cytokine that mediates proinflammatory responses while also participating in lipid homeostasis, and its transcriptional activity is in part genetically determined. We examined the role of the single-nucleotide polymorphism at position 252 of the LTA gene in the genetic background of RA and dyslipidemia. METHODS: The association between the LTA 252 A>G polymorphism and disease status was examined in a nested case-control study of 388 patients with RA and 269 unrelated healthy controls, all white. Demographics and disease features were assessed, fasting lipids measured, and the use of lipid-lowering agents evaluated. RESULTS: The LTA 252 A allele was more frequent in cases compared to controls (70.5% and 64.3%, respectively; p = 0.018, OR 1.325, 95% CI 1.049-1.675), as well as the A/A genotype (50.8% vs 43.5%; p = 0.025). The A/A genotype was independently associated with dyslipidemia in patients, but not in controls. Patients with RA who had the LTA 252 G/G genotype were younger at disease onset and had higher C-reactive protein (CRP) levels. CONCLUSION: We found the LTA 252 A allele to be associated with an increased risk for developing RA in whites. The LTA 252 A/A genotype translates to a phenotype more prone to dyslipidemia, and the G/G genotype to a phenotype with earlier onset of disease and higher levels of CRP, when RA does occur. These observations highlight a possible common genetic predisposition to RA and dyslipidemia.
22365994 Effects of kirenol on bovine type II collagen-induced rat lymphocytes in vivo and in vitro 2012 Jan OBJECTIVE: To investigate the effect of kirenol on bovine type II collagen (CII)-specific lymphocytes in vivo and in vitro, and explore the mechanism of kirenol-induced immunosuppression in antigen-specific lymphocytes. METHODS: Twenty-four Wistar rats were randomized into control group, collagen-induced arthritis (CIA) model group, kirenol group (2 mg/kg), and prednisolone group (2 mg/kg). After CII injection, the rats in the latter two groups received intragastric administration of kirenol and prednisolone for 30 days, and the spleens and draining lymph nodes of the rats were harvested to prepare single cell suspensions for measurement of the cytokine levels using ELISA. In the in vitro experiment, the lymphocytes from the control rats, with or without 20 µg/ml CII treatment in the presence of 0-80 µg/ml kirenol, were evaluated for cell proliferation and apoptosis using [(3)H]-thymidine incorporation and flow cytometry, respectively. RESULTS: Compared with those in CIA group, IFN-γ and TNF-α production was significantly reduced in splenocyte culture supernatant of kirenol group (P<0.05 and P<0.01, respectively), and the level of IL-10 and IL-4 was up-regulated (P<0.05 and P<0.01, respectively); IFN-γ and TNF-α secretion by the cultured lymph node cells (LNCs) significantly decreased (P<0.05 and P<0.001, respectively) and IL-10 and IL-4 production increased (P<0.05, P<0.001) in kirenol group. In the in vitro experiment, kirenol treatment caused obvious suppression of CII-induced LNC proliferation and dose-dependently induced antigen-specific apoptosis of the splenocytes and LNCs. CONCLUSION: Kirenol treatment reduces pro-inflammatory cytokine secretion, increases anti-inflammatory cytokine production, inhibits cell proliferation and induces apoptosis of CII-specific lymphocytes in vitro, suggesting the potential of kirenol as an immunosuppressant.
21279994 Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its ro 2011 Feb OBJECTIVE: MicroRNA (miRNA) are recognized as important regulators of a variety of fundamental biologic processes. Previously, we described increased expression of miR-155 and miR-146a in rheumatoid arthritis (RA) and showed a repressive effect of miR-155 on matrix metalloproteinase (MMP) expression in RA synovial fibroblasts (RASFs). The present study was undertaken to examine alterations in expression of miR-203 in RASFs and analyze its role in fibroblast activation. METHODS: Differentially expressed miRNA in RASFs versus osteoarthritis synovial fibroblasts (OASFs) were identified by real-time polymerase chain reaction (PCR)-based screening of 260 individual miRNA. Transfection of miR-203 precursor was used to analyze the function of miR-203 in RASFs. Levels of interleukin-6 (IL-6) and MMPs were measured by real-time PCR and enzyme-linked immunosorbent assay. RASFs were stimulated with IL-1β, tumor necrosis factor α (TNFα), lipopolysaccharide (LPS), and 5-azacytidine (5-azaC). Activity of IκB kinase 2 was inhibited with SC-514. RESULTS: Expression of miR-203 was higher in RASFs than in OASFs or fibroblasts from healthy donors. Levels of miR-203 did not change upon stimulation with IL-1β, TNFα, or LPS; however, DNA demethylation with 5-azaC increased the expression of miR-203. Enforced expression of miR-203 led to significantly increased levels of MMP-1 and IL-6. Induction of IL-6 by miR-203 overexpression was inhibited by blocking of the NF-κB pathway. Basal expression levels of IL-6 correlated with basal expression levels of miR-203. CONCLUSION: The current results demonstrate methylation-dependent regulation of miR-203 expression in RASFs. Importantly, they also show that elevated levels of miR-203 lead to increased secretion of MMP-1 and IL-6 via the NF-κB pathway and thereby contribute to the activated phenotype of synovial fibroblasts in RA.
21965649 Evidence for PTPN22 R620W polymorphism as the sole common risk variant for rheumatoid arth 2011 Nov OBJECTIVE: The PTPN22 rs2476601 genetic variant has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. Some reports suggest that this single-nucleotide polymorphism (SNP) may not be the only causal variant in the region of PTPN22. Our aim was to identify new independent RA-associated common gene variants in the PTPN22 region. METHODS: We analyzed Wellcome Trust Case-Control Consortium genome-wide association study data for associations in the 397.2 kb PTPN22 region and selected 9 associated SNP (with p < 5 × 10(-3)) for replication and dependence analysis. The replication cohorts comprised 2857 patients with RA and 2994 controls from Spain, Netherlands, and Norway. RESULTS: We found that 6 of the 9 selected SNP were associated in the Spanish cohort. Of these, 4 were also associated in the Dutch and Norwegian cohorts, and all 6 were associated with RA in the combined analysis. Conditional analyses showed that none of these associations was independent of rs2476601. CONCLUSION: The SNP rs2476601 located in the PTPN22 gene is the sole common genetic variant associated with RA in the 1p13.2 region, suggesting that neighbor genes of PTPN22 do not have a major influence in RA.
21285160 A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the effic 2011 May OBJECTIVE: To evaluate the efficacy, safety, and tolerability of oral SCIO-469, a p38 MAPK inhibitor that blocks tumor necrosis factor-α, interleukin-1ß, and cyclooxygenase-2 synthesis in patients with active rheumatoid arthritis (RA). METHODS: Patients were randomized to receive SCIO-469 at either 30 or 60 mg three times daily in an immediate-release (IR) formulation or at 100 mg once daily in an extended-release (ER) formulation, or placebo for 24 weeks. The primary endpoint was American College of Rheumatology (ACR)20 response at Week 12. Safety was monitored through Week 26. RESULTS: Overall, 302 patients were randomized: 76 to placebo, 75 to 30 mg IR, 73 to 60 mg IR, and 78 to 100 mg ER. There were no significant differences in ACR20 responses at Week 12 between SCIO-469 and placebo. Declines in C-reactive protein and erythrocyte sedimentation rate during early treatment did not persist to Week 12 and were not a consequence of decreased SCIO-469 plasma levels. The 60 mg IR regimen showed a dose-limiting toxicity manifested by elevations in alanine aminotransferase. Adverse events were common in all groups (79.7% and 86.7% through 13 and 26 weeks, respectively). Twenty-one patients reported 28 serious adverse events (SAE). SAE were more common with IR SCIO-469 than with placebo (7% vs 4%) but were not reported with ER SCIO-469. CONCLUSION: In all regimens tested, SCIO-469 showed no greater efficacy compared to placebo in patients with RA. The transient effect of SCIO-469 on acute-phase reactants suggests a complex role of p38 MAPK in inflammation.
20953815 Efficacy and tolerability of tocilizumab in rheumatoid arthritis patients seen in daily cl 2011 Apr Tocilizumab, a humanized monoclonal antibody to the interleukin 6 (IL-6) receptor, was approved for use as rheumatoid arthritis (RA) therapy in Japan in 2008, but its efficacy and tolerability in daily practice has not yet been reported. We report the results of a multicenter retrospective study on the efficacy and safety of tocilizumab involving all patients (n = 229) who were started on tocilizumab therapy at three rheumatology institutes in Japan from April 2008 through to March 2009. Tocilizumab was infused every 4 weeks at a dose of 8 mg/kg according to the drug labeling. Among the 229 patients, 55% concomitantly received methotrexate (MTX) and 63% had previously received anti-tumor necrosis factor (TNF) therapy. Average disease activity score (DAS) 28 of all 229 patients significantly decreased from 5.70 to 3.25 after 24 weeks of therapy. A European League Against Rheumatism (EULAR) good response and DAS28 remission was achieved in 57.4 and 40.7% of the patients, respectively, at 24 weeks. White blood cell counts significantly decreased and liver enzymes and total cholesterol slightly but significantly increased; however, liver enzyme levels did not increase in patients without MTX. Tocilizumab was discontinued in 47 cases (20.5%) due to lack of efficacy (5.2%), adverse events (11.4%), and other reasons (3.9%). The overall retention rate at 24 weeks was 79.5%. Based on these results, we conclude that tocilizumab therapy in daily rheumatology practice appears to be highly efficacious and well tolerated among active RA patients, including the anti-TNF therapy-refractory population. Tocilizumab infusion is therefore applicable not only as an alternative approach for anti-TNF therapy-resistant patients, but also as primary biologic therapy for active RA patients.
22416768 Metabolic syndrome prevalence is increased in rheumatoid arthritis patients and is associa 2012 May OBJECTIVES: To evaluate the prevalence of metabolic syndrome (MetS) in patients with rheumatoid arthritis (RA) vs. controls, and to verify possible associations of MetS with specific disease-related factors. METHODS: The subjects were 283 RA patients and 226 healthy controls, frequency matched by age and sex. MetS was defined according to National Cholesterol Education Program (NCEP) criteria. Disease activity was evaluated with the Disease Activity Score using 28 joints (DAS28). A standardized clinical evaluation was performed and cardiovascular risk factors were assessed. RESULTS: The criteria for MetS were met by 39.2% RA patients vs. 19.5% in the control group (p < 0.001). Increased waist circumference, elevated blood pressure (BP), and fasting glucose were more frequent in RA patients than controls (p < 0.001 for all associations). By multiple logistic regression analysis (adjusted for age, sex, and years at school), the risk of having MetS was significantly higher for RA patients than for controls [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.17-3.00, p = 0.009]. The DAS28 was significantly higher in RA patients with MetS than in those without MetS (3.59 ± 1.27 vs. 3.14 ± 1.53; p = 0.01). Disease duration, the presence of rheumatoid factor, and extra-articular manifestations were similar for patients with and without MetS. CONCLUSIONS: MetS frequency was higher in RA patients than in controls. Among RA patients, MetS was associated with disease activity. The higher prevalence of cardiovascular risk factors in RA suggests that inflammatory processes play a notable role in the development of cardiovascular disease (CVD), and indicates that tight control of systemic inflammatory activity and CVD modifiable risk factors should be recommended.
23165362 Disease activity in patients with long-lasting rheumatoid arthritis is associated with cha 2012 INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disease and it is known that lymphocytes play a major role in its pathogenesis. However, there have been no comprehensive studies on the changes in peripheral blood lymphocyte (PBL) subpopulations expressing different clusters of differentiation (CD) in patients with long-lasting RA. OBJECTIVES: The aim of our study was to measure the main subpopulations of PBL, expression of costimulatory marker CD28, and activation status of CD4+ T cells depending on clinical disease activity in long-lasting RA. PATIENTS AND METHODS: The study comprised 60 patients with RA and 19 healthy volunteers. Disease activity, the proportion and number of the main PBL subpopulations (T, B, natural killer [NK], and NK T cells [NKT]), the expression of costimulatory marker CD28, and the activation status of CD4+ T cells were evaluated on the same day. A multicolor flow cytometry with marked monoclonal antibodies was used for the assessment of lymphocyte subpopulations. RESULTS: The percentage of CD3+CD4+, NKT, CD4+CD28-, CD8+CD28-, CD4+CD69+, CD4+CD25+, and CD4+HLA-DR+ was significantly higher in RA compared with the control group. A higher proportion of CD4+CD28- was associated with more active disease, while an inverse correlation was observed for B cells. The proportion of CD4+CD28- was not associated with disease activity. The number of CD4+CD69+ cells in RA patients increased with increasing DAS28, while the number of CD4+HLA-DR+ T cells showed no such association. CONCLUSIONS: Our results have shown for the first time an association between the phenotype patterns of PBL T, B, and NKT and RA activity in patients with long-lasting disease, which reinforces the hypothesis that PBL play an important role in modifying or maintaining the disease activity.
21273108 Incidence of tuberculosis in patients with rheumatoid arthritis. A systematic literature r 2011 May OBJECTIVES: To determine the incidence and risk of tuberculosis in rheumatoid arthritis (RA) patients exposed or unexposed to TNFα antagonists, the impact of recommendations about managing latent tuberculosis, the time to diagnosis of active tuberculosis, and the proportion of extrapulmonary forms. METHODS: Systematic review of articles retrieved using Medline. From each article, we abstracted the incidence and risk of tuberculosis in RA patients exposed or unexposed to TNFα antagonists, the duration of TNFα antagonist exposure at the diagnosis of tuberculosis, and the distribution of the tuberculosis foci. RESULTS: We selected 14 articles. The risk of tuberculosis was increased 2- to 10-fold in RA patients unexposed to TNFα antagonists and 2- to 4-fold in those exposed to TNFα antagonists, compared to the general population. The incidence of tuberculosis in TNFα antagonist-treated patients varied across studies (9.3 to 449/100,000) according to the country, observation period, and TNFα antagonist used. The risk was greater with monoclonal antibodies than with the soluble receptor. Official recommendations have decreased the risk of tuberculosis in TNFα antagonist-treated patients. Over half the cases of active tuberculosis were diagnosed during the first treatment year. Among TNFα antagonist-treated patients with tuberculosis, 60% had extrapulmonary lesions. Disseminated tuberculosis was more common with monoclonal antibodies. CONCLUSIONS: The risk of tuberculosis is increased during TNFα antagonist therapy, and the increase is larger with the monoclonal antibodies than with the soluble receptor. Tuberculosis during TNFα antagonist therapy is a rare event that occurs early after treatment initiation. Extrapulmonary involvement is common and potentially severe. Therefore, clinicians should direct careful attention to the risk of tuberculosis associated with TNFα antagonist therapy.
21777779 Soft tissue pathology of the ankle. 2011 Jun Derangements of the soft tissues within the ankle joint are associated with a wide variety of pathophysiology, and typically can be classified as secondary to traumatic injury, rheumatic disease, or congenital lesions. Patients often present with persistent pain, swelling, and limitations on function, usually focused on the anterior aspect of the joint. Evaluation should be guided by a detailed history and physical examination, followed by clinical, laboratory, and imaging studies as indicated. The pathophysiology, diagnosis, and management of these conditions will be the focus of this article.
21427829 [Use of the flexible laryngeal mask in rheumatoid arthritis with the patient in lateral de 2011 Feb Rheumatoid arthritis is a chronic inflammatory disease leading to synovitis and joint deformities. The hands are often affected but in some cases there may be involvement of the temporomandibular, the atlantoaxial, and cricoarytenoid joints. For insertion of the mask, a patient may be placed in supine, lateral, or prone position with minimal complications. A 46-year-old woman with long-standing rheumatoid arthritis and mild atlantoaxial joint involvement was programed for removal of a large tumor from soft tissue near the right scapula. She was placed on her left side for surgery. After induction of anesthesia a flexible laryngeal mask was inserted without shifting her spinal column. At the end of the procedure, the mask was removed without complications and she orally assessed pain as 0. The flexible laryngeal mask can be used in patients with rheumatoid arthritis with little need to move the cervical spine. Insertion can take place in lateral decubitus position, thus avoiding movements that might worsen the patient's underlying disease.
21078715 Factors associated with radiographic progression in patients with rheumatoid arthritis who 2011 Feb OBJECTIVE: To identify factors associated with radiographic progression at 52 weeks in patients with rheumatoid arthritis (RA) after 12 weeks of methotrexate (MTX) therapy. METHODS: The study population consisted of patients from the MTX arm of the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO). Logistic regression analysis was used to identify clinical and laboratory assessments performed at Week 12 of MTX therapy that might be associated with Week 52 radiographic outcome (modified total Sharp score). Classification and regression tree (CART) modeling of the Week 12 assessments was used to determine the subgroups of patients with the best and worst radiographic outcomes. RESULTS: A total of 169 patients were analyzed: 116 patients in the best radiographic outcome group and 53 patients in the worst radiographic outcome group. Logistic regression analysis showed that Week 12 C-reactive protein (CRP) level, erythrocyte sedimentation rate, tender joint count, swollen joint count (SJC), and Health Assessment Questionnaire scores were significantly associated with radiographic progression at Week 52 (p < 0.05 for each assessment). CART modeling showed that patients with Week 12 CRP > 0.67 mg/dl and SJC > 1 and patients with Week 12 CRP ≤ 0.67 mg/dl and SJC > 10 were likely to show the worst radiographic progression at Week 52. The CART model had a sensitivity of 85%, specificity of 60%, and overall classification accuracy of 68%. CONCLUSION: In patients with RA, measures of CRP and SJC after 12 weeks of MTX therapy emerged as the factors most associated with radiographic progression at Week 52.
23233117 -174G/C interleukin-6 gene promoter polymorphism predicts therapeutic response to etanerce 2013 Jun To examine whether -174G/C interleukin-6 (IL-6) gene polymorphism, previously reported to correlate with IL-6 level, influences response to etanercept therapy in patients with rheumatoid arthritis. Seventy-seven patients with active RA were studied, at baseline and 6- and 12-month follow-up after etanercept therapy. Treatment response was estimated according to the European League Against Rheumatism response criteria. RA patients were genotyped for -174G/C IL-6 gene polymorphism by the PCR-RFLP method, and influence of genotype at this polymorphism to clinical response to etanercept was assessed. After 12 months of treatment, the percentage of responders (patients who had DAS28 improvement >1.2) was significantly increased in patients carrying the IL-6 -174G/G genotype (95.7 %) compared with those with the G/C (75.6 %) or CC (44.4 %) genotype (p = 0.006 by Chi-square test). No significant difference in the mean values of DAS28 improvement was observed between groups with different genotype. RA patients with an IL-6 -174GG genotype respond to etanercept better than patients with GC or CC genotype. This finding, if confirmed in future studies, suggests that the -174G/C IL-6 polymorphism may be a genetic marker of responsiveness to tumor necrosis factor-alpha (TNF-α) blockers in RA.
22653616 Association between serum thymosin β4 levels of rheumatoid arthritis patients and disease 2012 Aug The aim of this study was to evaluate whether thymosin β4 (Tβ4) levels are increased in the serum of rheumatoid arthritis (RA) patients, and if this increase is associated with RA disease activity and resistance to treatment. Blood samples from 40 patients with RA were collected at baseline and 6 months after starting treatment with disease-modifying antirheumatic drugs (DMARD) and/or tumor necrosis factor (TNF)-α blocker. Serum levels of Tβ4 were measured by ELISA. Tβ4 levels (mean ± standard deviation) in RA patients were significantly (approximately tenfold) higher than in healthy controls (577.4 ± 67.92 vs. 56.61 ± 5.72 ng/mL). Serum Tβ4 levels in patients with severe disease activity before therapy were slightly higher than in patients with moderate disease activity (662.4 ± 491.5 vs. 462.5 ± 305.3 ng/ml, P > 0.05). Tβ4 levels were significantly associated with disease activity according to the 28-joint Disease Activity Score. The mean Tβ4 level at baseline in the DMARD treatment group was significantly lower than in the DMARD + TNF-α blocker treatment group. Tβ4 levels were increased in the serum of patients with RA and were positively associated with disease activity. Levels of Tβ4 may also be relevant in determining or predicting resistance to RA treatment. Further studies are necessary to determine if Tβ4 is an appropriate therapeutic target for controlling inflammation associated with RA.
21110214 Amino-terminal pro-brain natriuretic peptide as a prognostic marker in patients with rheum 2011 Jan Rheumatoid arthritis (RA) is associated with increased cardiovascular (CV) morbidity and mortality, of which amino-terminal pro-brain natriuretic peptide (NT-proBNP) is a predictor. The objective of the study was to investigate associations between NT-proBNP and age, gender, markers of inflammation, disease activity, and kidney function in RA patients, without co-morbidities potentially influencing NT-proBNP concentration. The study group consisted of 90 patients with RA, without clinically relevant coronary heart disease, hypertension, diabetes, advanced chronic kidney disease. The comprehensive assessment of clinical and laboratory parameters of inflammation, disease activity, and kidney function was performed. Plasma samples were frozen for NT-proBNP analysis. Carotid intima media thickness (cIMT) was determined by high-resolution B-mode ultrasonography. The mean NT-proBNP concentrations were significantly higher in a group of RA patients with high disease activity (DAS28 > 5.1) and in a group of patients with subclinical atherosclerosis diagnosed by cIMT ≥ 0.6 mm. In all RA patients, NT-proBNP correlated positively with the age, C-reactive protein, erythrocyte sedimentation rate, cIMT, tricipital skin fold and negatively with hand-grip strength, hemoglobin, red blood cell count, albumin. In the group of women with RA, we found significant positive correlation between NT-proBNP and cystatin-C. Also, patients with NT-proBNP level ≥ 100 pg/ml had significantly higher cystatin-C than those with lower NT-proBNP. NT-proBNP level, in RA patients without co-morbidities potentially influencing this level, is correlated with age, disease activity markers of inflammation, and subclinical renal impairment. It means that risk of CV disorders is higher in older patients with more active RA.
21706348 The association between the PTPN22 C1858T polymorphism and rheumatoid arthritis: a meta-an 2012 Apr The aim of this study was to determine whether the protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. A meta-analysis was conducted on the PTPN22 C1858T polymorphism involving eighteen studies, which in total contained 20344 RA patients and 21828 controls. Meta-analysis revealed an association between the PTPN22 C1858T polymorphism T allele and RA in all subjects (odds ratio [OR] = 1.637, 95% confidence interval [CI] = 1.514-1.770, P < 0.001). After stratification by ethnicity, analysis indicated that the PTPN22 C1858T polymorphism T allele was significantly associated with RA in Europeans and Non-Europeans (OR = 1.587, 95% CI = 1.486-1.696, P < 0.001; OR = 1.748, 95% CI = 1.274-2.398, P < 0.001). Meta-analysis of the CT + TT genotype showed the same result patterns as that shown by the PTPN22 C1858T polymorphism T allele. Furthermore, a direct comparison between rheumatoid factor (RF)-positive and -negative subjects revealed a significant association with the T allele in RA patients with RF, but not in subjects without RF. In conclusion, this meta-analysis confirms that the PTPN22 C1858T polymorphism is associated with RA susceptibility in different ethnic groups, especially in Europeans, and the PTPN22 C1858T polymorphism T allele is significantly more prevalent in RF-positive patents than in RF-negative patients.
22433784 Development of macromolecular prodrug for rheumatoid arthritis. 2012 Sep Rheumatoid arthritis (RA) is a chronic autoimmune disease that is considered to be one of the major public health problems worldwide. The development of therapies that target tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and co-stimulatory pathways that regulate the immune system have revolutionized the care of patients with RA. Despite these advances, many patients continue to experience symptomatic and functional impairment. To address this issue, more recent therapies that have been developed are designed to target intracellular signaling pathways involved in immunoregulation. Though this approach has been encouraging, there have been major challenges with respect to off-target organ side effects and systemic toxicities related to the widespread distribution of these signaling pathways in multiple cell types and tissues. These limitations have led to an increasing interest in the development of strategies for the macromolecularization of anti-rheumatic drugs, which could target them to the inflamed joints. This approach enhances the efficacy of the therapeutic agent with respect to synovial inflammation, while markedly reducing non-target organ adverse side effects. In this manuscript, we provide a comprehensive overview of the rational design and optimization of macromolecular prodrugs for treatment of RA. The superior and the sustained efficacy of the prodrug may be partially attributed to their Extravasation through Leaky Vasculature and subsequent Inflammatory cell-mediated Sequestration (ELVIS) in the arthritic joints. This biologic process provides a plausible mechanism, by which macromolecular prodrugs preferentially target arthritic joints and illustrates the potential benefits of applying this therapeutic strategy to the treatment of other inflammatory diseases.
21434757 Effects of adalimumab therapy on disease activity and interferon-γ-mediated biochemical p 2011 May In patients with rheumatoid arthritis (RA), overwhelming inflammatory activity and immune activation are indicated by elevated concentrations of immune activation markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and neopterin. Furthermore, accelerated tryptophan (Trp) degradation by the enzyme indoleamine 2,3-dioxygenase (IDO) is detectable in blood samples of patients by an increased kynurenine (Kyn) to Trp ratio (Kyn/Trp). This study comprises 22 patients (20 women, 2 men) with long-standing, moderate to severe RA, who were treated with a monoclonal tumor necrosis factor (TNF)-antibody (Adalimumab 40 mg subcutaneously every other week) in addition to their concomitant, but inadequate anti-rheumatic therapies. Blood samples were collected before therapy and at week 12. ESR and CRP concentrations were measured within routine diagnostic. Serum concentrations of neopterin, Trp, and Kyn were determined by commercially available ELISA and by high performance liquid chromatography. Before therapy, disease activity as reflected by disease activity score 28 (DAS28) was significantly associated with concentrations of inflammation markers such as ESR (rs = 0.601, p < 0.01) and CRP (rs = 0.433, p < 0.05), but not with neopterin concentrations or Trp metabolic changes. Upon treatment, DAS28 improved significantly (median before therapy: 5.7 and after therapy: 3.1; p < 0.0001). During adalimumab treatment, only CRP decreased significantly (p < 0.05), while all other parameters investigated did not change significantly. Our results indicate that anti-TNF therapy does not influence neopterin concentrations or IDO activity in patients with RA, despite a highly significant improvement of patients' disease activity.
22277308 Mechanical and functional assessment of the wrist affected by rheumatoid arthritis: A fini 2012 Nov Understanding the pathomechanics involved in rheumatoid arthritis (RA) of the wrist provides valuable information, which will invariably allow various therapeutic possibilities to be explored. The computational modelling of this disease permits the appropriate simulation to be conducted seamlessly. A study that underpins the fundamental concept that produces the biomechanical changes in a rheumatoid wrist was thus conducted through the use of finite element method. The RA model was constructed from computed tomography datasets, taking into account three major characteristics: synovial proliferation, cartilage destruction and ligamentous laxity. As control, a healthy wrist joint model was developed in parallel and compared. Cartilage was modelled based on the shape of the articulation while the ligaments were modelled with linear spring elements. A load-controlled analysis was performed simulating physiological hand grip loading conditions. The results demonstrated that the diseased model produced abnormal wrist extension and stress distribution as compared to the healthy wrist model. Due to the weakening of the ligaments, destruction of the cartilage and lower bone density, the altered biomechanical stresses were particularly evident at the radioscaphoid and capitolunate articulations which correlate to clinical findings. These results demonstrate the robust finding of the developed RA wrist model, which accurately predicted the pathological process.