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ID PMID Title PublicationDate abstract
26103626 CXCL8 and CCL20 Enhance Osteoclastogenesis via Modulation of Cytokine Production by Human 2015 Generalized osteoporosis is common in patients with inflammatory diseases, possibly because of circulating inflammatory factors that affect osteoblast and osteoclast formation and activity. Serum levels of the inflammatory factors CXCL8 and CCL20 are elevated in rheumatoid arthritis, but whether these factors affect bone metabolism is unknown. We hypothesized that CXCL8 and CCL20 decrease osteoblast proliferation and differentiation, and enhance osteoblast-mediated osteoclast formation and activity. Human primary osteoblasts were cultured with or without CXCL8 (2-200 pg/ml) or CCL20 (5-500 pg/ml) for 14 days. Osteoblast proliferation and gene expression of matrix proteins and cytokines were analyzed. Osteoclast precursors were cultured with CXCL8 (200 pg/ml) and CCL20 (500 pg/ml), or with conditioned medium (CM) from CXCL8 and CCL20-treated osteoblasts with or without IL-6 inhibitor. After 3 weeks osteoclast formation and activity were determined. CXCL8 (200 pg/ml) and CCL20 (500 pg/ml) enhanced mRNA expression of KI67 (2.5-2.7-fold), ALP (1.6-1.7-fold), and IL-6 protein production (1.3-1.6-fold) by osteoblasts. CXCL8-CM enhanced the number of osteoclasts with 3-5 nuclei (1.7-fold), and with >5 nuclei (3-fold). CCL20-CM enhanced the number of osteoclasts with 3-5 nuclei (1.3-fold), and with >5 nuclei (2.8-fold). IL-6 inhibition reduced the stimulatory effect of CXCL8-CM and CCL20-CM on formation of osteoclasts. In conclusion, CXCL8 and CCL20 did not decrease osteoblast proliferation or gene expression of matrix proteins. CXCL8 and CCL20 did not directly affect osteoclastogenesis. However, CXCL8 and CCL20 enhanced osteoblast-mediated osteoclastogenesis, partly via IL-6 production, suggesting that CXCL8 and CCL20 may contribute to osteoporosis in rheumatoid arthritis by affecting bone cell communication.
25812537 Epigenetics of osteoarticular diseases: recent developments. 2015 Aug A variety of osteoarticular conditions possess an underlying genetic aetiology. Large-scale genome-wide association studies have identified several genetic loci associated with osteoarticular conditions, but were unable to fully account for their estimated heritability. Epigenetic modifications including DNA methylation, histone modification, nucleosome positioning, and microRNA expression may help account for this incomplete heritability. This articles reviews insights from epigenetic studies in osteoarticular diseases, focusing on osteoarthritis, but also examines recent advances in rheumatoid arthritis, osteoporosis, systemic lupus erythematosus (SLE), ankylosing spondylitis, and sarcoma. Genome-wide methylation studies are permitting identification of novel candidate genes and molecular pathways, and the pathogenic mechanisms with altered methylation status are beginning to be elucidated. These findings are gradually translating into improved understanding of disease pathogenesis and clinical applications. Functional studies in osteoarthritis, rheumatoid arthritis, and SLE are now identifying downstream molecular alterations that may confer disease susceptibility. Epigenetic markers are being validated as prognostic and therapeutic disease biomarkers in sarcoma, and clinical trials of hypomethylating agents as treatments for sarcoma are being conducted. In concert with advances in throughput and cost-efficiency of available technologies, future epigenetic research will enable greater characterisation and treatment for both common and rare osteoarticular diseases.
26255191 The amount of citrullinated proteins in synovial tissue is related to serum anti-cyclic ci 2016 Jan The objective of this study was to determine the relationship between citrullinated proteins in synovial tissue with peripheral anti-citrullinated peptides autoantibodies (ACPA) and peptidylarginine deiminase (PADI) PADI2, PADI3, and PADI4 messenger RNA (mRNA) expressions in synovial tissue and fibroblast-like synoviocytes in rheumatoid arthritis (RA) patients. Eleven RA and 12 osteoarthritis (OA) patients who underwent knee replacement surgery were studied. We detected citrullinated proteins in synovial tissue homogenates by western blot and serum ACPA by ELISA to anti-cyclic citrullinated peptide (anti-CCP) antibodies, and PADI2, PADI3, and PADI4 mRNA expressions in synovial tissue and in fibroblast-like synoviocytes. Patients with high amount of citrullinated proteins in synovial tissue (3 out of 7) have high levels of anti-CCP in serum. However, in the remaining 4 patients, the amount of synovial citrullinated proteins was minimal and their sera showed low levels of anti-CCP antibodies. Furthermore, we observed an increase in PADI2 mRNA expression in RA synovial tissue compared with OA patients (p = 0.02). We detected PADI3 mRNA in the synovial tissue of RA patients, but not in the tissue of OA patients. Even though fibroblast-type synoviocytes in RA are not the main source of PADs in the synovial tissue, they express PADI2 mRNA moderately, PADI4 mRNA weakly, while there is no detectable expression of PADI3 mRNA. In conclusion, we found a variety of citrullinated proteins in the synovial tissue of RA patients and the amount of such proteins is related to serum concentration of anti-CCP antibodies. We identified the presence of PADI3 mRNA expression in synovial tissue and PADI2 and PADI4 mRNA expressions in fibroblast-like synoviocytes from patients with RA.
27909722 Expression of soluble programmed death-1 protein in peripheral blood regulatory T cells an 2017 Jan The present study aimed to investigate the role of the soluble programmed death‑1 (sPD-1) protein, which is released by peripheral blood regulatory T cells (Treg) during the progression of rheumatoid arthritis (RA). From October 2012 to May 2014, 82 RA patients (RA group) and 90 healthy volunteers (healthy controls; HC) were recruited. Cluster of differentiation (CD)4, CD25 and forkhead/winged helix transcription factor p3 (Foxp3) and expression of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and Foxp3 were detected by flow cytometry. Expression of sPD‑1 in Treg was detected by western blot analysis. Immunosuppressive activity of CD4+CD25‑ Treg was measured via thiazolyl blue in an MTT assay. ELISA was used to detect interleukin‑10 (IL‑10), transforming growth factor beta (TGF-β), interleukin-4 (IL-4), interferon‑γ (IFN-γ) and nuclear factor of activated T cells (NF‑AT). It was observed that in peripheral blood, CD4+CD25-FOXP3+/CD4+ levels were reduced in the RA group (P<0.001), and sPD‑1 levels were markedly higher (P<0.001), compared with the HC group. Additionally, it was observed that relative sPD‑1 protein expression in the small interfering RNA (siRNA)-sPD-1 treated group was reduced compared with the untreated and scrambled siRNA groups (all P<0.0001). The mean fluorescence intensity of CTLA-4 and Foxp3 decreased markedly upon transfection with siRNA-sPD-1 (P<0.001). Compared with the normal CD4+CD25‑ T group, optical density (OD)540 values, IFN-γ/IL-4 concentration ratio and NF‑AT activity in siRNA untreated and scramble groups reduced significantly (all P<0.001). OD540 value, IFN-γ/IL-4 concentration ratio and NF‑AT activity in the siRNA‑sPD‑1 group were significantly upregulated (all P<0.001). Therefore, sPD-1 may suppress the level of CD4+CD25‑ Tregs in the peripheral blood of RA patients, and may be involved in a variety of immune processes mediated by CD4+CD25‑ Tregs.
27438209 Methotrexate and etanercept-induced primary cutaneous CD4 positive small/medium-sized pleo 2016 May Immunosuppressive drugs and biological agents may represent a potential risk of lymphoma development in patients with rheumatoid arthritis. But most cases are diffuse, large B-cell lymphomas. Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma, a provisional entity in the 2005 WHO-EORTC classification of cutaneous lymphomas, is only described in a limited number of reports. To our knowledge, our case is a rare instance of primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma, after associated treatment with methotrexate and etanercept, in a patient with moderate rheumatoid arthritis who had undergone an orchidectomy incorrectly.
25417811 Malondialdehyde-acetaldehyde adducts and anti-malondialdehyde-acetaldehyde antibodies in r 2015 Mar OBJECTIVE: Malondialdehyde-acetaldehyde (MAA) adducts are a product of oxidative stress associated with tolerance loss in several disease states. This study was undertaken to investigate the presence of MAA adducts and circulating anti-MAA antibodies in patients with rheumatoid arthritis (RA). METHODS: Synovial tissue from patients with RA and patients with osteoarthritis (OA) were examined for the presence of MAA-modified and citrullinated proteins. Anti-MAA antibody isotypes were measured in RA patients (n = 1,720) and healthy controls (n = 80) by enzyme-linked immunosorbent assay. Antigen-specific anti-citrullinated protein antibodies (ACPAs) were measured in RA patients using a multiplex antigen array. Anti-MAA isotype concentrations were compared in a subset of RA patients (n = 80) and matched healthy controls (n = 80). Associations of anti-MAA antibody isotypes with disease characteristics, including ACPA positivity, were examined in all RA patients. RESULTS: Expression of MAA adducts was increased in RA synovial tissue compared to OA synovial tissue, and colocalization with citrullinated proteins was found. Increased levels of anti-MAA antibody isotypes were observed in RA patients compared to controls (P < 0.001). Among RA patients, anti-MAA antibody isotypes were associated with seropositivity for ACPAs and rheumatoid factor (P < 0.001) in addition to select measures of disease activity. Higher anti-MAA antibody concentrations were associated with a greater number of positive antigen-specific ACPA analytes (expressed at high titer) (P < 0.001) and a higher ACPA score (P < 0.001), independent of other covariates. CONCLUSION: MAA adduct formation is increased in RA and appears to result in robust antibody responses that are strongly associated with ACPAs. These results support speculation that MAA formation may be a cofactor that drives tolerance loss, resulting in the autoimmune responses characteristic of RA.
26984006 Predicting the 10-year risk of hip and major osteoporotic fracture in rheumatoid arthritis 2016 Dec OBJECTIVES: FRAX incorporates rheumatoid arthritis (RA) as a dichotomous predictor for predicting the 10-year risk of hip and major osteoporotic fracture (MOF). However, fracture risk may deviate with disease severity, duration or treatment. Aims were to validate, and if needed to update, UK FRAX for patients with RA and to compare predictive performance with the general population (GP). METHODS: Cohort study within UK Clinical Practice Research Datalink (CPRD) (RA: n=11 582, GP: n=38 755), also linked to hospital admissions for hip fracture (CPRD-Hospital Episode Statistics, HES) (RA: n=7221, GP: n=24 227). Predictive performance of UK FRAX without bone mineral density was assessed by discrimination and calibration. Updating methods included recalibration and extension. Differences in predictive performance were assessed by the C-statistic and Net Reclassification Improvement (NRI) using the UK National Osteoporosis Guideline Group intervention thresholds. RESULTS: UK FRAX significantly overestimated fracture risk in patients with RA, both for MOF (mean predicted vs observed 10-year risk: 13.3% vs 8.4%) and hip fracture (CPRD: 5.5% vs 3.1%, CPRD-HES: 5.5% vs 4.1%). Calibration was good for hip fracture in the GP (CPRD-HES: 2.7% vs 2.4%). Discrimination was good for hip fracture (RA: 0.78, GP: 0.83) and moderate for MOF (RA: 0.69, GP: 0.71). Extension of the recalibrated UK FRAX using CPRD-HES with duration of RA disease, glucocorticoids (>7.5 mg/day) and secondary osteoporosis did not improve the NRI (0.01, 95% CI -0.04 to 0.05) or C-statistic (0.78). CONCLUSIONS: UK FRAX overestimated fracture risk in RA, but performed well for hip fracture in the GP after linkage to hospitalisations. Extension of the recalibrated UK FRAX did not improve predictive performance.
26886438 Direct Comparative Effectiveness Among 3 Anti-Tumor Necrosis Factor Biologics in a Real-Li 2016 Mar OBJECTIVE: This study aimed to compare the clinical response at 36 months and evaluate the adverse events in a cohort of patients with rheumatoid arthritis treated with etanercept, infliximab, or adalimumab. METHODS: An observational retrospective cohort study was performed. Patients older than 18 years with active rheumatoid arthritis, for which the physician had initiated a treatment scheme with etanercept, infliximab, or adalimumab, were included in the study. The follow-up was conducted through at least trimestral evaluations during the course of 36 months. Outcomes evaluated included Disease Activity Score 28, level of disease activity, Health Assessment Questionnaire, and degree of disability. RESULTS: Three hundred seven subjects were included in the cohort (108 adalimumab, 107 infliximab, and 92 etanercept). The median Disease Activity Score 28 at the onset was 4.1 and 2.39 at month 36. There were no differences among the 3 medications (P = 0.51). The remission rate was of 7.4 per 100 people per month (95% confidence interval [CI], 6.6-8.3) without differences between groups. The initial Health Assessment Questionnaire median was 1.75 and 0.25 at 36 months. No differences per medicine were found (P = 0.54). The most common adverse effect was dermatitis. Eighteen cases of serious adverse effects occurred, including 11 cases of serious infectious events. The adverse events rates were as follows: infliximab, 24 per 100 people per year (95% CI, 19-29); adalimumab, 22 per 100 people per year (95% CI, 18-27); and etanercept, 12 per 100 people per year (95% CI, 8-16). CONCLUSIONS: Etanercept, infliximab, and adalimumab are 3 effective therapeutic anti-tumor necrosis factor alternatives to reduce the level of severity and the degree of disability generated by rheumatoid arthritis. Etanercept presented a rate of adverse events lower than those for infliximab and adalimumab.
25672371 Measuring decreased serum IgG sialylation: a novel clinical biomarker of lupus. 2015 Aug INTRODUCTION: The aim of this work was to develop a simple assay to distinguish between patients with rheumatoid arthritis (RA) and patients with systemic lupus erythematosus (SLE) by measuring the serum sialylated IgG (SAIgG). METHODS: Using a newly established SNA-based ELISA method, we compared the sialylation of immunoglobulin G (IgG) from a healthy control group (n = 41), RA patients (n = 30), SLE patients (n = 45), patients with neuropsychiatric SLE (NPSLE) (n = 30) and patients with juvenile idiopathic arthritis (JIA) (n = 32). RESULTS: The average SAIgG level in healthy control individuals, RA patients, JIA patients, SLE patients and NPSLE patients was 0.64 ± 0.17, 0.82 ± 0.33, 0.69 ± 0.23, 0.12 ± 0.02 and 0.03 ± 0.01 mg/ml, respectively. The ratio of sialylated IgG to total IgG was significantly decreased in the SLE group (1.88 ± 0.32%) compared with the healthy population (4.64 ± 0.90%). CONCLUSION: In summary, while the mean serum SAIgG level of RA and JIA patients was similar to that of the healthy population, there was a significant decrease in the serum SAIgG of both SLE groups tested, whereby the level of the NPSLE population group was the lowest.
27980014 Stiffness Is the Cardinal Symptom of Inflammatory Musculoskeletal Diseases, Yet Still Vari 2017 Dec OBJECTIVE: The objectives of the Outcome Measures in Rheumatology (OMERACT) Stiffness special interest group (SIG) are to characterize stiffness as an outcome in rheumatic disease and to identify and validate a stiffness patient-reported outcome (PRO) in rheumatology. METHODS: At OMERACT 2016, international groups presented and discussed results of several concurrent research projects on stiffness: a literature review of rheumatoid arthritis (RA) stiffness PRO measures, a qualitative investigation into the RA and polymyalgia rheumatica patient perspective of stiffness, data-driven stiffness conceptual model development, development and testing of an RA stiffness PRO measure, and a quantitative work testing stiffness items in patients with RA and psoriatic arthritis. RESULTS: The literature review identified 52 individual stiffness PRO measures assessing morning or early morning stiffness severity/intensity or duration. Items were heterogeneous, had little or inconsistent psychometric property evidence, and did not appear to have been developed according to the PRO development guidelines. A poor match between current stiffness PRO and the conceptual model identifying the RA patient experience of stiffness was identified, highlighting a major flaw in PRO selection according to the OMERACT filter 2.0. CONCLUSION: Discussions within the Stiffness SIG highlighted the importance of further research on stiffness and defined a research agenda.
26020659 [Maternal and fetal outcome in Mexican women with rheumatoid arthritis]. 2015 OBJECTIVE: To report our experience in maternal-fetal outcome in women with RA in a national medical referral center. METHODS: A retrospective analysis of the records of pregnant women with rheumatoid arthritis attending at a Pregnancy and Autoimmune Rheumatic Diseases Clinic was performed. Maternal-fetal outcomes such as disease activity, preclampsia/eclampsia, rate of live births, abortions, stillbirths, preterm birth, weeks of gestation, birth weight, congenital malformations and use of anti-rheumatic drugs were studied. RESULTS: We included 73 pregnancies in 72 patients. Disease activity was documented in 47.2% of patients during pregnancy and/or postpartum and 87.7% of patients received some antirheumatic drug. Preclampsia developed in 8.2% of cases. The live birth rate was 98.6%, with preterm delivery in 15.9% and low weight at term in 17.6% of cases. Cesarean section was performed in 77.1% of cases. The disease activity was not associated with a higher percentage of maternal-fetal complications. CONCLUSIONS: Our study showed that most patients do not experience significant activity of RA during pregnancy, fetal outcome is satisfactory and disease activity did not appear to influence significantly the obstetric outcome.
24792332 The in vitro addition of methotrexate and/or methylprednisolone determines peripheral redu 2015 Jan The aim of our study was to evaluate methotrexate (MTX) and methylprednisolone (MP) effect on peripheral Th17 and Treg subsets in patients with rheumatoid arthritis (RA). We enrolled 15 patients (10 early RA and 5 long-standing disease) with active RA and 10 age-matched healthy donors as controls. Frequencies of Th17 and Treg were quantified using flow cytometry before and after in vitro addition of MTX, MP or both drugs. Our results showed a reduction in the overall Th17 population followed by an increase in Th17 IL-10(+) and Treg, after in vitro treatment of PBMCs with the drugs in patients with early RA. Long-standing disease patients showed a less evident increase in Treg cells and less enhancement of IL-10 Th17 cells. We suggest that the treatment with MTX and MP could ameliorate RA disease activity by normalizing the distribution/imbalance of Th17/Treg and indicate a new regulatory role of IL-17(+) cells in RA patients.
27353155 [A man with skin lesions of his face]. 2016 A 69-year-old man with rheumatoid arthritis developed a discoid rash on his face years after the initiation of treatment with adalimumab. Serological tests were positive for antinuclear antibodies (ANA) and autoantibodies against Sjögren's syndrome-related antigen A (SSA). We diagnosed him with 'lupus-like syndrome'. After discontinuation of the adalimumab therapy and the use of topical corticosteroids, his symptoms resolved quickly.
25944979 Mast cell and autoimmune diseases. 2015 Mast cells are important in innate immune system. They have been appreciated as potent contributors to allergic reaction. However, increasing evidence implicates the important role of mast cells in autoimmune disease like rheumatoid arthritis and multiple sclerosis. Here we review the current stage of knowledge about mast cells in autoimmune diseases.
25592093 Cardiovascular autonomic neuropathy in rheumatoid arthritis assessed by cardiovascular aut 2015 Sep OBJECTIVE: In this study, we aimed to evaluate cardiovascular autonomic neuropathy (CAN) in RA patients by cardiovascular autonomic function tests. Because CAN was reported of patients with automimmune rheumatic diseases those may in sudden death or myocardial infarction. METHODS: A total of 44 patients with RA and 44 age- and sex-matched healthy volunteers participated in this cross-sectional study. Assessment of CAN was performed using cardiovascular reflex tests. These five tests were: 1) beat-to-beat heart rate variation during deep breathing; 2) heart rate response to standing up; 3) heart rate response to the Valsalva maneuver; 4) blood pressure response to standing up; and 5) blood pressure response to sustained handgrip. RESULTS: The mean age was 43.15 (SD, 12.18) years (range, 23-68 years) in the RA group, and 38 were women. In beat-to-beat heart rate variation during deep breathing, expiration-to-inspiration ratio was abnormal in 3 cases with RA (6.8%) but in 1 (2.3%) control subject (p=0.3), and maximum minus minimum heart rate was abnormal in 8 patients (18.2%) and in 3 (6.8%) control subjects (p=0.1). 2) In heart rate response to standing up, all patients and controls had normal results. Valsalva ratio was abnormal in 7 RA patients (15.9%) and in 7 control subjects (15.9%). Blood pressure response to standing up was normal in RA patients but abnormal in 1 (2.3%) control subject (p=0.4). Blood pressure response to sustained handgrip was abnormal in 5 RA patients (11.4%) and 2 (4.6%) control subjects (p=0.2). CONCLUSION: Our study failed to show any statistically significant difference between cardiovascular autonomic function tests in RA patients with control subjects by our test done.
25195983 The long-term effects of anti-TNF-α agents on patients with chronic viral hepatitis C and 2015 Jan AIM: To evaluate the long-term effects of anti-tumor necrosis factor-alpha (TNF-α) therapy on patients with chronic hepatitis B and C infections. METHODS: Rheumatoid arthritis, ankylosing spondylitis and Crohn's disease patients administered anti-TNF-α therapy for at least 36 months were retrospectively reviewed for hepatitis B or C serology, liver function tests, viral load, genotype and liver biopsy results, if performed. Nine relevant cases receiving anti-TNF-α were evaluated: six patients had chronic hepatitis C, one had chronic dual hepatitis B and C and two had chronic hepatitis B infection. RESULTS: The patient with dual infection exhibited virologic breakthrough for hepatitis C and required treatment. Two patients with occult hepatitis B infection developed hepatitis B surface antigen (HBsAg) reversion and low-level viremia at the end of the study. CONCLUSION: Long-term use of anti-TNF-α treatments may result in viral replication that requires anti-viral therapy. Before determining the safety of anti-TNF drugs in the treatment of autoimmune diseases in patients with hepatitis C infection, studies with large homogeneous patient groups must be performed, and the exact group of hepatitis C virus infected patients for whom anti-TNF treatment would be deemed safe should be identified. Prior to anti-TNF-α treatment, it seems logical to screen all patients for HBsAg and anti-HB core immunoglobulin G status, especially in endemic regions. These patients must be followed periodically by means of alanine aminotransferase, HBsAg and hepatitis B virus DNA to identify HBsAg reversion and active viral replication that might require anti-viral prophylaxis or treatment.
25873634 Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis. 2016 Jan BACKGROUND: The aim of the Dose Reduction or Discontinuation of Etanercept in Methotrexate-Treated Rheumatoid Arthritis Patients Who Have Achieved a Stable Low Disease Activity-State study was to investigate the effect of etanercept (ETN) dose maintenance, reduction or withdrawal on patients with rheumatoid arthritis (RA) who had already achieved stable low disease activity (LDA) on ETN 50 mg+methotrexate (MTX). METHODS: Patients with RA (n=91) and stable LDA with ETN 50 mg once weekly (QW)+MTX were included. After 8 weeks with unchanged treatment, 73 patients were randomised in a double-blind design to ETN 50 mg QW+MTX (ETN50), ETN 25 mg QW+MTX (ETN25) or placebo QW+MTX (PBO) for 48 weeks. Patients who flared were declared failures and treated with open-label ETN50 until week 48. The primary outcome was the proportion of patients on ETN50 versus PBO who were non-failures after 48 weeks. RESULTS: The proportion of non-failure patients was significantly lower with ETN50 (52%; p=0.007) and ETN25 (44%; p=0.044) versus PBO (13%). Median time to failure was significantly shorter with PBO (6 weeks) compared with ETN50 (48 weeks; p=0.001) and ETN25 (36 weeks; p<0.001). The majority of patients who flared regained LDA with open-label ETN50 quickly. Adverse events were consistent with the known side effect profiles of these medications. CONCLUSIONS: In patients with established RA who have achieved stable LDA on ETN50+MTX, continuing both is superior to PBO+MTX. Reduced dose ETN was also more effective than PBO in maintaining a favourable response, suggesting that a maintenance strategy with reduced dose ETN may be possible in a number of patients with established RA. TRIAL REGISTRATION NUMBER: NCT00858780.
26286434 New data and an old puzzle: the negative association between schizophrenia and rheumatoid 2015 Oct BACKGROUND: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. METHODS: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. RESULTS: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090). CONCLUSIONS: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.
26236992 Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces i 2015 Sep Myostatin (also known as growth and differentiation factor 8) is a secreted member of the transforming growth factor-β (TGF-β) family that is mainly expressed in skeletal muscle, which is also its primary target tissue. Deletion of the myostatin gene (Mstn) in mice leads to muscle hypertrophy, and animal studies support the concept that myostatin is a negative regulator of muscle growth and regeneration. However, myostatin deficiency also increases bone formation, mainly through loading-associated effects on bone. Here we report a previously unknown direct role for myostatin in osteoclastogenesis and in the progressive loss of articular bone in rheumatoid arthritis (RA). We demonstrate that myostatin is highly expressed in the synovial tissues of RA subjects and of human tumor necrosis factor (TNF)-α transgenic (hTNFtg) mice, a model for human RA. Myostatin strongly accelerates receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclast formation in vitro through transcription factor SMAD2-dependent regulation of nuclear factor of activated T-cells (NFATC1). Myostatin deficiency or antibody-mediated inhibition leads to an amelioration of arthritis severity in hTNFtg mice, chiefly reflected by less bone destruction. Consistent with these effects in hTNFtg mice, the lack of myostatin leads to increased grip strength and less bone erosion in the K/BxN serum-induced arthritis model in mice. The results strongly suggest that myostatin is a potent therapeutic target for interfering with osteoclast formation and joint destruction in RA.
25541434 Cytokines pre-determined by genetic factors are involved in pathogenesis of Rheumatoid art 2015 Oct Rheumatoid arthritis (RA) is associated with the presence of autoreactive CD4 T cells that produce pro-inflammatory cytokines. The role of genetic factors in the predilection to develop RA is strongly supported by the increased presence of certain HLA class II molecules in patients. The HLA class II genes are highly polymorphic and are critical for generating an immune response to clear infections. Production of Th1 and Th17 response by the CD4 T cells helps to clear infections. HLA-DQ8 is a promiscuous binder and presents many peptides generating immune response and producing a Th17 response. DRB1∗0401 is associated with the production of both IL-17 and IFN-γ. Thus both DR4 and DQ8 can clear infections by producing TH1/Th17 cytokines, but their presence increases the risk of developing RA. Using transgenic mice expressing human HLA genes, we have shown that HLA polymorphism determines the cytokine profile. DRB1∗04 molecules modulate the DQ8-restricted response and determine the outcome of arthritis in mice carrying DR4/DQ8 haplotype. Thus, interaction between DQ and DR molecules determines the cytokine milieu and propensity of the HLA haplotype to predispose to autoimmunity.