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ID PMID Title PublicationDate abstract
29410669 Lactoferrin-Containing Immunocomplexes Drive the Conversion of Human Macrophages from M2- 2018 Macrophages are multifunctional cells that perform diverse roles in health and disease and considered the main source of inflammatory cytokines in affected joints of patients with rheumatoid arthritis (RA). M2 macrophages are well known as anti-inflammation and wound-healing cells; however, recent evidence suggests that they can also promote inflammation in RA, although the underlying mechanism remains to be clarified. Based upon our recent finding that lactoferrin (LTF)-containing IgG immunocomplex (LTF-IC), found elevated in RA sera, potent activators of human monocytes/macrophages, we herein demonstrate that LTF-IC was able to elicit immediate proinflammatory cytokine production by M2-polarized human macrophages through coligation with CD14/toll-like receptor (TLR) 4 and FcγRIIa (CD32a). The LTF-IC-treated M2 cells adopted surface maker expression profile similar to that of M1 phenotype and became functionally hyperactive to subsequent stimuli such as lipopolysaccharide, zymosan and IL-1β, which could provide a positive feedback signal to promote excessive inflammation in RA. They also acquired the ability to facilitate activation of Th17 cells that are known to play critical roles in RA pathology. We propose that IgG ICs containing TLR agonizing autoantigens are able to directly switch human macrophages from M2 into M1-like phenotype, thereby promoting excessive inflammation in autoimmune diseases such as RA.
29891135 11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and sy 2018 Aug OBJECTIVE: In rheumatoid arthritis, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is highly expressed at sites of inflammation, where it converts inactive glucocorticoids (GC) to their active counterparts. In conditions of GC excess it has been shown to be a critical regulator of muscle wasting and bone loss. Here we examine the contribution of 11β-HSD1 to the pathology of persistent chronic inflammatory disease. METHODS: To determine the contribution of 11β-HSD1 to joint inflammation, destruction and systemic bone loss associated with persistent inflammatory arthritis, we generated mice with global and mesenchymal specific 11β-HSD1 deletions in the TNF-transgenic (TNF-tg) model of chronic polyarthritis. Disease severity was determined by clinical scoring. Histology was assessed in formalin fixed sections and fluorescence-activated cell sorting (FACS) analysis of synovial tissue was performed. Local and systemic bone loss were measured by micro computed tomography (micro-CT). Measures of inflammation and bone metabolism were assessed in serum and in tibia mRNA. RESULTS: Global deletion of 11β-HSD1 drove an enhanced inflammatory phenotype, characterised by florid synovitis, joint destruction and systemic bone loss. This was associated with increased pannus invasion into subchondral bone, a marked polarisation towards pro-inflammatory M1 macrophages at sites of inflammation and increased osteoclast numbers. Targeted mesenchymal deletion of 11β-HSD1 failed to recapitulate this phenotype suggesting that 11β-HSD1 within leukocytes mediate its protective actions in vivo. CONCLUSIONS: We demonstrate a fundamental role for 11β-HSD1 in the suppression of synovitis, joint destruction, and systemic bone loss. Whilst a role for 11β-HSD1 inhibitors has been proposed for metabolic complications in inflammatory diseases, our study suggests that this approach would greatly exacerbate disease severity.
30558852 Effect of communicating personalized rheumatoid arthritis risk on concern for developing R 2019 May OBJECTIVE: To investigate the effect of providing comprehensive personalized risk information on concern for chronic disease development. METHODS: Unaffected first-degree relatives (FDRs) of rheumatoid arthritis (RA) patients (n = 238) were randomly allocated to: 1) disclosure of RA risk personalized to demographics, genetics, biomarkers, and behaviors using a web-based tool (PRE-RA arm, n = 78); 2) PRE-RA with interpretation by a health educator (PRE-RA Plus arm, n = 80); and 3) standard RA education (Comparison arm, n = 80). Concern for developing RA was assessed at baseline and immediately, 6 weeks, 6 months, and 12 months post-intervention. RESULTS: FDRs randomized to PRE-RA arms were less concerned about developing RA than the Comparison arm at all post-intervention assessments (p < 0.05). Among those concerned about RA risk at baseline, the PRE-RA (OR = 4.7, 95%CI 1.5-14.4) and PRE-RA Plus (OR = 5.2, 95%CI 1.6-17.3) arms were more likely to have reassurance 6 months post-intervention than the Comparison arm. CONCLUSION: A comprehensive tool provided reassurance to those at risk for developing a chronic disease, with or without interpretation from a health educator, compared to standard education. PRACTICE IMPLICATIONS: Individuals may be more likely to be reassured using a personalized chronic disease risk disclosure tool than a standard non-personalized approach.
30275262 Biologic and Glucocorticoid Use after Methotrexate Initiation in Patients with Rheumatoid 2019 Apr OBJECTIVE: Biologic therapies can improve disease control for patients with rheumatoid arthritis (RA) but may be both overused and underused. We aimed to identify predictors of greater use of biologic therapies and to identify factors associated with persistent glucocorticoid use. METHODS: Using national US Veteran's Affairs databases 2005-2016, we identified patients with RA receiving a first-ever prescription of methotrexate (MTX), requiring ≥ 6 months of baseline data. We evaluated predictors of biologic therapy initiation within 2 years of starting MTX and factors associated with baseline and persistent glucocorticoid use at 6-12 months using multivariable models. RESULTS: Among 17,415 patients starting MTX, 3263 patients received biologic therapy within 2 years (20.6% 2-yr incidence). In adjusted analyses, biologic use was substantially lower in older patients [e.g., aHR 0.20 (95% CI 0.16, 0.26) for patients ≥ 80 vs < 50] and patients with more comorbidities [aHR 0.79 (95% CI 0.72, 0.87) for Charlson score ≥ 3 vs < 3]. Patients with heart failure [aHR 0.68 (95% CI 0.54, 0.84)], cancer [aHR 0.78 (95% CI 0.66, 0.92)], or who were nonwhite [aHR 0.79 (95% CI 0.72, 0.87)] were also less likely to receive a biologic. In contrast, baseline and persistent glucocorticoid use was similar across age groups and more common in patients with greater comorbidity. CONCLUSION: Biologic therapy is initiated less frequently in patients with RA who are older, have more comorbidities, and who are nonwhite. While biologics may be avoided in older and sicker patients because of safety concerns, glucocorticoid use is similar regardless of age and is more frequent in patients with comorbidities, with implications for patient outcomes.
30735108 Increased expression of CD40/TRAF1 and activation of nuclear factor-κκB-dependent proinf 2018 Nov OBJECTIVE: Genetic studies have implicated both CD40 and tumour necrosis factor receptor-associated factor-1 (TRAF1) with rheumatoid arthritis (RA). CD40 signalling is known to be associated with TRAF1 expression, directly or indirectly; however, the detailed mechanisms of these interactions are not clear in RA, and in particular in fibroblast-like synoviocytes. This study aims to investigate this pathway and the role of nuclear factor-κB (NF-κB) in a mouse model of RA. METHOD: We utilized the collagen-induced arthritis (CIA) model in DBA/1 mice. CD40, TRAF1, and NF-κB p65 were quantitated by enzyme-linked immunosorbent assay and immunohistochemistry in serum and tissue, respectively. Real-time polymerase chain reaction was applied to measure NF-κB-related gene expression, including cytokines [tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6)] and adhesion molecules [intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1)]. RESULTS: The severity of arthritis by clinical and histological assessments peaked on day 35 and decreased thereafter. Serum levels of CD40, TRAF1, and NF-κB p65 paralleled this time-course. The tissue expression of the CD40, TRAF1, total NF-κB p65, and phospho-NF-κB p65 proteins, as well as NF-κB-related gene expression, including cytokines (TNFα, IL-6) and adhesion molecules (ICAM-1, VCAM-1), were markedly upregulated within 25-50 days after CIA. CONCLUSION: Our data identify a cellular/molecular mechanism of the CD40/TRAF1 signalling pathway involved in CIA: increased expression of CD40 and its adaptor TRAF1 proteins and activation of the NF-κB-dependent proinflammatory pathway. These correlations implicate possible mechanistic pathways in this model that may also operate in human RA and thus provide rationales for new therapeutic modalities.
29185969 Arterial wave reflection and subclinical atherosclerosis in rheumatoid arthritis. 2018 May OBJECTIVES: Atherosclerotic cardiovascular disease risk is increased in rheumatoid arthritis (RA). Wave reflection occurs at arterial branching points, which are particularly prone to atherosclerosis. We explored the relationship of wave reflection with atherosclerosis in RA. METHODS: One hundred and sixty three RA patients (110 white, 31 Asian, 17 black and 5 of mixed ancestry) without cardiovascular disease participated. Arterial stiffness, wave reflection, pressure pulsatility, plaque in the extracranial carotid artery tree and the mean of the left and right common carotid arteries intima-thickness were determined. Associations were identified in multivariable regression models. RESULTS: One SD increase in reflected wave pressure (OR (95% CI) = 2.54 (1.41-4.44), p=0.001), reflection magnitude (OR (95% CI) = 1.84 (1.17-2.89), p=0.008), central pulse pressure (OR (95% CI) = 1.89 (1.12-3.22), p=0.02) and peripheral pulse pressure (OR (95% CI) = 2.09 (1.23-3.57), p=0.007) were associated with plaque. The association of wave reflection with plaque was independent of arterial stiffness and pressure pulsatility, and was present in both hypertensive and normotensive RA patients. In receiver operator characteristic curve analysis, the optimal cutoff value for reflected wave pressure in predicting plaque presence was 25 mmHg with a sensitivity, specificity, positive predictive value and negative predictive value of 45.2%, 89.3%, 78.6% and 66.2%, respectively; a reflected wave pressure of >25 mmHg was associated with plaque in univariate and adjusted analysis (p<0.0001 for both). Arterial function was not independently related to carotid intima-media thickness. CONCLUSIONS: Consideration and therapeutic targeting of wave reflection may improve cardiovascular disease prevention in RA.
29931592 Sarilumab: A Review in Moderate to Severe Rheumatoid Arthritis. 2018 Jun Sarilumab (Kevzara(®)), a monoclonal antibody against the interleukin-6 (IL-6) receptor, is approved in various countries, including the USA, those of the EU, and Japan, as a subcutaneous treatment administered every 2 weeks for moderately to severely active rheumatoid arthritis (RA) in adults who have responded inadequately to, or are intolerant of, one or more DMARDs. In placebo-controlled trials, sarilumab improved the signs and symptoms of RA, as well as physical function and health-related quality-of-life (HR-QOL), when administered in combination with conventional synthetic DMARD (csDMARD) therapy in patients with an inadequate response to methotrexate or an inadequate response to, or intolerance of, at least one tumour necrosis factor (TNF) inhibitor; benefits were sustained over ≤ 3 years' therapy in an open-label extension. Sarilumab plus methotrexate inhibited the progression of structural damage in patients who had inadequately responded to methotrexate. As monotherapy in patients who were inappropriate for continued treatment with methotrexate, sarilumab was more effective than adalimumab in reducing the signs and symptoms of RA and improving physical function. The safety profile of sarilumab was consistent with the anticipated effects of IL-6 inhibition. In the minority of patients who tested positive for anti-drug antibodies (ADAs), ADAs did not impact efficacy or increase adverse reactions. Thus, sarilumab extends the available treatment options for adults with moderately to severely active RA who have responded inadequately to, or are intolerant of, at least one DMARD.
29320550 Longitudinal micro-CT as an outcome measure of interstitial lung disease in TNF-transgenic 2018 INTRODUCTION: Rheumatoid arthritis associated interstitial lung disease (RA-ILD) is a debilitating condition with poor survival prognosis. High resolution computed tomography (CT) is a common clinical tool to diagnose RA-ILD, and is increasingly being adopted in pre-clinical studies. However, murine models recapitulating RA-ILD are lacking, and CT outcomes for inflammatory lung disease have yet to be formally validated. To address this, we validate μCT outcomes for ILD in the tumor necrosis factor transgenic (TNF-Tg) mouse model of RA. METHODS: Cross sectional μCT was performed on cohorts of male TNF-Tg mice and their WT littermates at 3, 4, 5.5 and 12 months of age (n = 4-6). Lung μCT outcomes measures were determined by segmentation of the μCT datasets to generate Aerated and Tissue volumes. After each scan, lungs were obtained for histopathology and 3 sections stained with hematoxylin and eosin. Automated histomorphometry was performed to quantify the tissue area (nuclei, cytoplasm, and extracellular matrix) and aerated area (white space) within the tissue sections. Spearman's correlation coefficients were used to evaluate the extent of association between μCT imaging and histopathology endpoints. RESULTS: TNF-Tg mice had significantly greater tissue volume, total lung volume and mean intensity at all timepoints compared to age matched WT littermates. Histomorphometry also demonstrated a significant increase in tissue area at 3, 4, and 5.5 months of age in TNF-Tg mice. Lung tissue volume was correlated with lung tissue area (ρ = 0.81, p<0.0001), and normalize lung aerated volume was correlated with normalized lung air area (ρ = 0.73, p<0.0001). CONCLUSIONS: We have validated in vivo μCT as a quantitative biomarker of ILD in mice. Further, development of longitudinal measures is critical for dissecting pathologic progression of ILD, and μCT is a useful non-invasive method to study lung inflammation in the TNF-Tg mouse model.
30851515 Comparison of combination therapy with methotrexate and sinomenine or leflunomide for acti 2019 Apr BACKGROUND: A combination of conventional disease-modifying anti-rheumatic drugs improves the treatment of rheumatoid arthritis but with high side-effects. Methotrexate (MTX) combination therapy that with high therapeutic efficacy and low toxicity is in demand in many countries to replace the use of expensive biological agents. STUDY DESIGN: This study was an open-label, 24-week, parallel randomized controlled trial conducted between November 2015 and December 2017. METHODS: Patients were randomly assigned at a 3:2 ratio to receive MTX combined with sinomenine (SIN) at a dose of 120 mg twice daily, or leflunomide (LEF) at a dose of 20 mg once daily. Efficacy and safety were assessed at weeks 4, 12 and 24. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology (ACR)50 response and a European League Against Rheumatism (EULAR) good response at week 24. RESULTS: A total of 101/120 (84.2%) patients completed 24 weeks of observation. In the intention-to-treat (ITT) analysis, 65.3% of patients treated with MTX + SIN showed improved disease activity as determined by the ACR50 response at week 24 compared to 69.6% of patients treated with MTX + LEF. A similar insignificant pattern was found for the ACR20 and ACR70 responses, as well as the clinical disease activity index, EULAR response, and remission and low disease activity rates between these two treatment groups. The per-protocol analysis showed results consistent with those of the ITT analysis. Notably, significant reductions in gastrointestinal adverse reactions and liver toxicity were found in patients treated with MTX + SIN compared to patients treated with MTX + LEF (p < 0.05). CONCLUSION: Considering the balance of efficacy and toxicity, the current study provides evidence that MTX + SIN combination therapy is probably one of the choices for treating patients with active rheumatoid arthritis in addition to MTX + LEF combination therapy.
29768212 mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflam 2018 May 15 Accumulating evidence suggests that metabolic master regulators, including mTOR, regulate adaptive and innate immune responses. Resident mesenchymal tissue components are increasingly recognized as key effector cells in inflammation. Whether mTOR also controls the inflammatory response in fibroblasts is insufficiently studied. Here, we show that TNF signaling co-opts the mTOR pathway to shift synovial fibroblast (FLS) inflammation toward an IFN response. mTOR pathway activation is associated with decreased NF-κB-mediated gene expression (e.g., PTGS2, IL-6, and IL-8) but increased STAT1-dependent gene expression (e.g., CXCL11 and TNFSF13B). We further demonstrate how metabolic inputs, such as amino acids, impinge on TNF-mTORC1 signaling to differentially regulate pro-inflammatory signaling circuits. Our results define a critical role for mTOR in the regulation of the pro-inflammatory response in FLSs and unfold its pathogenic involvement in TNF-driven diseases, such as rheumatoid arthritis (RA).
29112062 Health-related quality of life of people with HIV: an assessment of patient related factor 2018 Jan 2 OBJECTIVES: The health-related quality of life (HRQOL) of people with HIV is lower than in the general population, but it is unknown how it compares with that of persons with other chronic medical conditions. We compared HRQOL in HIV with HRQOL in diabetes mellitus type 1, diabetes mellitus type 2 and rheumatoid arthritis (RA). In addition, we investigated factors associated with HRQOL in HIV. DESIGN: Cross-sectional study. METHODS: HRQOL was measured with the Medical Outcomes Study Short Form 36-item Health Survey in a nationwide sample of people with HIV in care in the Netherlands and on combination antiretroviral therapy for at least 6 months. We added data from studies in diabetes mellitus types 1 and 2, and RA. Logistic regression analysis was used to examine: the association between disease group and a poor HRQOL, and patient factors associated with poor HRQOL in HIV. RESULTS: The odds of a poor physical HRQOL in the HIV group were comparable with the odds in diabetes mellitus types 1 and 2, but lower than in RA patients. The odds of a poor mental HRQOL in HIV were higher than in the other groups. In HIV, a history of AIDS, longer duration of combination antiretroviral therapy and severe comorbidity were associated with a poor physical HRQOL. Sub-Saharan African descent and CD4 cell count of less than 350 cells/μl were associated with poor mental HRQOL. CONCLUSION: People with HIV were more likely to have a poor mental HRQOL than patients with other chronic conditions. Addressing mental health should be an integral part of outpatient HIV care.
30686934 Increased Expression of TLR10 in B Cell Subsets Correlates with Disease Activity in Rheuma 2018 Toll-like receptor (TLR) 10, mainly expressed on B cells, has emerged as a modulatory receptor in inflammation. Nonetheless, the clinical significance of TLR10 in rheumatoid arthritis (RA) remains unclear. In this study, we explored the expression of TLR10 in B cells and B cell subsets in RA subjects and healthy controls (HCs) and determined its relevance to disease activity and inflammatory biomarkers. TLR10 levels in B cells and B cell subsets (CD19(+)CD27(+), CD19(+)CD27(-), CD27(+)IgD(-), CD27(+)IgD(+), CD27(-)IgD(+), D27(-)IgD(-), CD19(+)CD5(+), and CD19(+)CD5(-)) and inflammatory biomarker concentrations in peripheral blood (PB) obtained from RA subjects and HCs were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. The correlations of TLR10 expression with disease activity and inflammatory biomarkers were then analysed. Similar levels of TLR10 in all CD19(+) B cells were observed in the RA subjects and HCs. Compared to that in the HCs, TLR10 was elevated significantly in the CD19(+)CD27(-)IgD(-) and CD19(+)CD5(+) subsets in the RA subjects. In addition, almost all subsets expressing TLR10 were increased with disease activity. The present study reveals that enhanced TLR10 in B cell subsets is positively correlated with disease activity in RA subjects.
29657147 Longterm Safety and Efficacy of Subcutaneous Abatacept in Patients with Rheumatoid Arthrit 2018 Aug OBJECTIVE: To assess 5-year safety, tolerability, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA). METHODS: The Abatacept Comparison of sub[QU]cutaneous versus intravenous in Inadequate Responders to methotrexatE (ACQUIRE) phase IIIb, randomized, double-dummy, multinational trial compared efficacy and safety of SC and intravenous (IV) ABA in patients with RA. In the initial 6-month double-blind (DB) period, patients received IV or SC ABA, plus MTX, and in the subsequent open-label longterm extension (LTE) period, all patients received SC ABA (125 mg/wk). The final 5-year safety, tolerability, and efficacy analyses are reported. RESULTS: Of 1385 patients who completed the DB period, 1372 entered LTE and 945 (68.8%) completed ≥ 5 years of treatment. During LTE, 97 (7.1%) patients discontinued treatment because of an adverse event (AE). Incidence rate (IR; event/100 patient-yrs of exposure; based on LTE data, 95% CI) for AE of interest were the following: serious AE 7.73 (6.96-8.58), infection 38.60 (36.24-41.12), serious infection 1.68 (1.35-2.07), malignancies 1.09 (0.84-1.42), and autoimmune disorders 1.33 (1.05-1.69), and were stable over time. No association between immunogenicity and either worsening of ABA safety or loss of efficacy was noted. Efficacy in the LTE was consistent with the DB period and was maintained to the end of the study. CONCLUSION: These 5-year data establish that SC ABA (125 mg/wk) has a consistent safety profile and durable efficacy for longterm treatment of patients with RA who had an inadequate response to MTX.
29954342 LPG: A four-group probabilistic approach to leveraging pleiotropy in genome-wide associati 2018 Jun 28 BACKGROUND: To date, genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants among a variety of traits/diseases, shedding light on the genetic architecture of complex disease. The polygenicity of complex diseases is a widely accepted phenomenon through which a vast number of risk variants, each with a modest individual effect, collectively contribute to the heritability of complex diseases. This imposes a major challenge on fully characterizing the genetic bases of complex diseases. An immediate implication of polygenicity is that a much larger sample size is required to detect individual risk variants with weak/moderate effects. Meanwhile, accumulating evidence suggests that different complex diseases can share genetic risk variants, a phenomenon known as pleiotropy. RESULTS: In this study, we propose a statistical framework for Leveraging Pleiotropic effects in large-scale GWAS data (LPG). LPG utilizes a variational Bayesian expectation-maximization (VBEM) algorithm, making it computationally efficient and scalable for genome-wide-scale analysis. To demonstrate the advantages of LPG over existing methods that do not leverage pleiotropy, we conducted extensive simulation studies and applied LPG to analyze two pairs of disorders (Crohn's disease and Type 1 diabetes, as well as rheumatoid arthritis and Type 1 diabetes). The results indicate that by levelaging pleiotropy, LPG can improve the power of prioritization of risk variants and the accuracy of risk prediction. CONCLUSIONS: Our methodology provides a novel and efficient tool to detect pleiotropy among GWAS data for multiple traits/diseases collected from different studies. The software is available at https://github.com/Shufeyangyi2015310117/LPG .
28950421 Phase III Randomized Study of SB5, an Adalimumab Biosimilar, Versus Reference Adalimumab i 2018 Jan OBJECTIVE: SB5 is a biosimilar agent for adalimumab (ADA). The aim of this study was to evaluate the efficacy, pharmacokinetics (PK), safety, and immunogenicity of SB5 in comparison with reference ADA in patients with rheumatoid arthritis (RA). METHODS: In this phase III, randomized, double-blind, parallel-group study, patients with moderately to severely active RA despite treatment with methotrexate were randomized 1:1 to receive SB5 or reference ADA at a dosage of 40 mg subcutaneously every other week. The primary efficacy end point was the response rate based on the American College of Rheumatology 20% improvement criteria (ACR20) at week 24 in the per-protocol set (completer analysis). Additional end points included efficacy, PK, safety, and immunogenicity assessments. RESULTS: Of the 544 patients randomized to receive a study drug, the full analysis set comprised 542 patients (269 in the SB5 group, 273 in the reference ADA group) and the per-protocol set comprised 476 patients (239 receiving SB5, 237 receiving reference ADA). The ACR20 response rate at week 24 in the per-protocol set was equivalent between those receiving SB5 and those receiving reference ADA (72.4% and 72.2%, respectively); the difference in the ACR20 response rate (0.1%, [95% confidence interval -7.83%, 8.13%]) was within the predefined equivalence margin (±15%). Similar results were seen in the full analysis set (missing data being considered a nonresponse). The SB5 and reference ADA treatment groups were comparable across other end points, including the ACR 50% and ACR 70% improvement response rates, Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate, PK data, incidence of treatment-emergent adverse events, and the antidrug antibody response. Subgroup analyses showed that the efficacy and safety of SB5 and reference ADA were comparable regardless of antidrug antibody status. CONCLUSION: The ACR20 response rate at week 24 was equivalent between patients treated with the biosimilar agent SB5 and those treated with reference ADA. SB5 and reference ADA were both well tolerated, with comparable safety profiles, in patients with RA.
29673963 No difference in cardiovascular risk of tocilizumab versus abatacept for rheumatoid arthri 2018 Dec OBJECTIVES: While tocilizumab may increase serum lipid levels, recent studies do not suggest a link between tocilizumab use and clinical cardiovascular risk in patients with rheumatoid arthritis (RA). METHODS: To compare cardiovascular safety of tocilizumab with abatacept, we conducted a cohort study using data from Medicare (2010-2013), IMS PharMetrics (2011-2014) and MarketScan (2011-6/2015). RA patients aged ≥18 years who newly started tocilizumab or abatacept entered the cohort on the day of their first use of tocilizumab or abatacept after a continuous enrollment period for ≥365 days. The primary outcome was a composite cardiovascular endpoint of hospitalization for myocardial infarction or stroke. To control for more than 60 confounders, tocilizumab starters were propensity score (PS)-matched to abatacept starters with a variable ratio of 1:3 within each database. A fixed-effects model combined database-specific hazard ratios (HR). RESULTS: We included 6237 tocilizumab starters PS-matched to 14,685 abatacept starters in all three databases. Mean age was 72 years in Medicare, 51 in PharMetrics and 53 in MarketScan. The incidence rate of the composite cardiovascular events per 100 person-years ranged from 0.37 (PharMetrics) to 1.64 (Medicare) in the tocilizumab group and from 0.59 (PharMetrics) to 1.69 (Medicare) in the abatacept group. The risk of the composite cardiovascular events was similar between the two groups across all three databases, with a combined HR of 0.82 (95% CI: 0.55-1.22) in tocilizumab versus abatacept starters. CONCLUSIONS: This multi-database cohort study found no difference in the risk of cardiovascular events in RA patients who newly started tocilizumab versus abatacept.
29543869 N-3 polyunsaturated fatty acids restore Th17 and Treg balance in collagen antibody-induced 2018 N-3 polyunsaturated fatty acids (PUFA) have anti-inflammatory effects and were considered useful for the treatment of rheumatoid arthritis (RA). Recently, several studies suggested that n-3 PUFAs attenuated arthritis in animal model and human, however the mechanism is still unclear. Interleukin 17 (IL-17) is a pro-inflammatory cytokine mainly produced by T helper 17 (Th17) cells which cause tissue inflammation and bone erosion leading to joint destruction. In contrast, regulatory T (Treg) cells down-regulate various immune responses by suppression of naïve T cells. The imbalance between Th17 cells and Tregs cell is important for the pathogenesis of RA. Here, we investigated whether n-3 PUFAs attenuate arthritis in collagen antibody-induced arthritis (CAIA) model. We used fat-1 transgenic mice expressing the Caenorhabditis elegans fat-1 gene encoding an n-3 fatty acid desaturase that converts n-6 to n-3 fatty acids, leading to abundant n-3 fatty acids without the need of a dietary n-3 supply. Clinical arthritis score was significantly attenuated in fat-1 mice compared to wild type (WT) mice on day 7 (1.6±1.8, p = 0.012) and day 9 (1.5±1.6, p = 0.003). Ankle thickness also decreased significantly in fat-1 mice compared to WT mice (1.82±0.11, p = 0.008). The pathologic finding showed that inflammatory cell infiltration and bone destruction were reduced in fat-1 mice compared to WT. The expression levels of IL-17 and related cytokines including IL-6 and IL-23 decreased in the spleen and ankle joint tissue of fat-1 mice compared to WT mice. Furthermore, Treg cells were expanded in the spleen of fat-1 mice and Treg cell differentiation was significantly higher in fat-1 mice than in wild type (p = 0.038). These data suggest that n-3 PUFAs could attenuate arthritis through increasing the expression of FoxP3 and the differentiation of Treg, while reducing IL-17 production. Therefore, dietary supplementation of n-3 PUFAs could have a therapeutic potential for the treatment of RA.
29433534 Identification of a novel autoantibody against self-vimentin specific in secondary Sjögre 2018 Feb 12 BACKGROUND: Sjögren's syndrome (SS) is a primary autoimmune disease (pSS) or secondarily associated with other autoimmune diseases (sSS). The mechanisms underlying immune dysregulation in this syndrome remain unknown, and clinically it is difficult to diagnose owing to a lack of specific biomarkers. METHODS: We extracted immunoglobulins (Igs) from the sera of patients with sSS associated with rheumatoid arthritis (RA) and used them to screen a phage display library of peptides with random sequences. RESULTS: Our results show that an sSS-specific peptide, designated 3S-P, was recognized by sera of 68.2% (60 of 88) patients with sSS, 66.2% of patients with RA-sSS, and 76.5% of patients with systemic lupus erythematosus (SLE)-sSS. The anti-3S-P antibody was scarcely found in patients with pSS (1.8%), RA (1.3%), SLE (4.2%), ankylosing spondylitis (0%), and gout (3.3%), as well as in healthy donors (2%). The 3S-P-binding Igs (antibodies) were used to identify antigens from salivary glands and synovial tissues from patients with sSS. A putative target autoantigen expressed in the synovium and salivary gland recognized by anti-3S-P antibody was identified as self-vimentin. CONCLUSIONS: This novel autoantibody is highly specific in the diagnosis of sSS, and the underlying molecular mechanism of the disease might be epitope spreading involved with vimentin.
29533969 Fraxinellone Attenuates Rheumatoid Inflammation in Mice. 2018 Mar 13 This study aimed to evaluate the therapeutic effect of fraxinellone on inflammatory arthritis and identify the underlying mechanisms. Fraxinellone (7.5 mg/kg) or a vehicle control was injected into mice with collagen-induced arthritis (CIA). The severity of arthritis was evaluated clinically and histologically. The differentiation of CD4⁺ T cells and CD19⁺ B cells was investigated in the presence of fraxinellone. Osteoclastogenesis after fraxinellone treatment was evaluated by staining with tartrate-resistant acid phosphatase (TRAP) and by measuring the mRNA levels of osteoclastogenesis-related genes. Fraxinellone attenuated the clinical and histologic features of inflammatory arthritis in CIA mice. Fraxinellone suppressed the production of interleukin-17 and the expression of RAR-related orphan receptor γ t and phospho-signal transducer and activator of transcription 3 in CD4⁺ T cells. CD19⁺ B cells showed lower expression of activation-induced cytidine deaminase and B lymphocyte-induced maturation protein-1 after treatment with fraxinellone. The formation of TRAP-positive cells and the expression of osteoclastogenesis-related markers were reduced in the presence of fraxinellone. Inhibition of interleukin-17 and osteoclastogenesis was also observed in experiments using human peripheral mononuclear cells. Fraxinellone alleviated synovial inflammation and osteoclastogenesis in mice. The therapeutic effect of fraxinellone was associated with the inhibition of cellular differentiation and activation. The data suggests that fraxinellone could be a novel treatment for inflammatory arthritis, including rheumatoid arthritis.
29374669 Trends and determinants of length of stay and hospital reimbursement following knee and hi 2018 Jan 27 OBJECTIVES: To measure changes in length of stay following total knee and hip replacement (TKR and THR) between 1997 and 2014 and estimate the impact on hospital reimbursement, all else being equal. Further, to assess the degree to which observed trends can be explained by improved efficiency or changes in patient profiles. DESIGN: Cross-sectional study using routinely collected data. SETTING: National Health Service primary care records from 1995 to 2014 in the Clinical Practice Research Datalink were linked to hospital inpatient data from 1997 to 2014 in Hospital Episode Statistics Admitted Patient Care. PARTICIPANTS: Study participants had a diagnosis of osteoarthritis or rheumatoid arthritis. INTERVENTIONS: Primary TKR, primary THR, revision TKR and revision THR. PRIMARY OUTCOME MEASURES: Length of stay and hospital reimbursement. RESULTS: 10 260 primary TKR, 10 961 primary THR, 505 revision TKR and 633 revision THR were included. Expected length of stay fell from 16.0 days (95% CI 14.9 to 17.2) in 1997 to 5.4 (5.2 to 5.6) in 2014 for primary TKR and from 14.4 (13.7 to 15.0) to 5.6 (5.4 to 5.8) for primary THR, leading to savings of £1537 and £1412, respectively. Length of stay fell from 29.8 (17.5 to 50.5) to 11.0 (8.3 to 14.6) for revision TKR and from 18.3 (11.6 to 28.9) to 12.5 (9.3 to 16.8) for revision THR, but no significant reduction in reimbursement was estimated. The estimated effect of year of surgery remained similar when patient characteristics were included. CONCLUSIONS: Length of stay for joint replacement fell substantially from 1997 to 2014. These reductions have translated into substantial savings. While patient characteristics affect length of stay and reimbursement, patient profiles have remained broadly stable over time. The observed reductions appear to be mostly explained by improved efficiency.