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ID PMID Title PublicationDate abstract
30523152 Metabolic fingerprinting for diagnosis of fibromyalgia and other rheumatologic disorders. 2019 Feb 15 Diagnosis and treatment of fibromyalgia (FM) remains a challenge owing to the lack of reliable biomarkers. Our objective was to develop a rapid biomarker-based method for diagnosing FM by using vibrational spectroscopy to differentiate patients with FM from those with rheumatoid arthritis (RA), osteoarthritis (OA), or systemic lupus erythematosus (SLE) and to identify metabolites associated with these differences. Blood samples were collected from patients with a diagnosis of FM (n = 50), RA (n = 29), OA (n = 19), or SLE (n = 23). Bloodspot samples were prepared, and spectra collected with portable FT-IR and FT-Raman microspectroscopy and subjected to metabolomics analysis by ultra-HPLC (uHPLC), coupled to a photodiode array (PDA) and tandem MS/MS. Unique IR and Raman spectral signatures were identified by pattern recognition analysis and clustered all study participants into classes (FM, RA, and SLE) with no misclassifications (p < 0.05, and interclass distances > 2.5). Furthermore, the spectra correlated (r = 0.95 and 0.83 for IR and Raman, respectively) with FM pain severity measured with fibromyalgia impact questionnaire revised version (FIQR) assessments. Protein backbones and pyridine-carboxylic acids dominated this discrimination and might serve as biomarkers for syndromes such as FM. uHPLC-PDA-MS/MS provided insights into metabolites significantly differing among the disease groups, not only in molecular m/z (+) and m/z (-) values but also in UV-visible chromatograms. We conclude that vibrational spectroscopy may provide a reliable diagnostic test for differentiating FM from other disorders and for establishing serologic biomarkers of FM-associated pain.
30348492 Comorbidity profiles among patients with recurrent aphthous stomatitis: A case-control stu 2019 Mar BACKGROUND/PURPOSE: Recurrent aphthous stomatitis (RAS) is common and associated with certain comorbidities. The aim of this study was to investigate the prevalence of selected comorbidities in patients with RAUs and to compare the risks of comorbidity between the two cohorts of patients with or without RAUs based on the Taiwanese National Health Insurance Research Database. METHODS: This case-control study included patients with recurrent aphthous stomatitis (the RAS cohort) and patients without recurrent aphthous stomatitis using 1:1 matching for year of index date, age, sex, monthly income, geographical location, and urbanization level (the non-RAS cohort). We calculated the prevalence of 31 medical comorbidities based on a modified version of the Elixhauser comorbidity index within 1 year before and after the index date. Conditional logistic regression was conducted to compare the risks of each comorbidity between the two cohorts. RESULTS: Compared with the non-RAS cohort, the RAS cohort had a significantly higher prevalence of 16 comorbidities, with 2% or higher prevalence difference for hyperlipidemia (2.9%), headaches (6.9%), liver diseases (2.8%), and peptic ulcers (5.4%). The adjusted odds ratios were >1.5 for headaches (1.92), migraines (1.62), hypothyroidism (1.50), rheumatoid arthritis (1.92), ankylosing spondylitis (1.94), systemic lupus erythematosus (1.82), liver diseases (1.51), peptic ulcers (1.69), hepatitis (1.62), depression (1.76), and psychoses (1.50). CONCLUSION: Patients with recurrent aphthous stomatitis were associated with increased risk of specific comorbidities. Physicians should screen for these comorbidities for early detection and treatment.
31788092 High gene expression levels of VEGFA and CXCL8 in the peritumoral brain zone are associate 2019 Dec The present study aimed to identify differentially regulated genes between the peritumoral brain zone (PBZ) and tumor core (TC) of glioblastoma (GBM), to elucidate the underlying molecular mechanisms and provide a target for the treatment of tumors. The GSE13276 and GSE116520 datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) for the PBZ and TC were obtained using the GEO2R tool. The bioinformatics and evolutionary genomics online tool Venn was used to identify common DEGs between the two datasets. The Database for Annotation, Visualization, and Integrated Discovery online tool was used to analyze enriched pathways of the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The Search Tool for the Retrieval of Interacting Genes/Proteins online tool was used to construct a protein-protein interaction (PPI) network of DEGs. Hub genes were identified using Cytohubba, a plug-in for Cytoscape. The Gene Expression Profiling Interactive Analysis (GEPIA) database was utilized to perform survival analysis. In total, 75 DEGs, including 12 upregulated and 63 downregulated genes, were identified. In the GO term analysis, these DEGs were mainly enriched in 'regulation of angiogenesis' and 'central nervous system development'. Furthermore, in the KEGG pathway analysis, the DEGs were mainly enriched in 'bladder cancer' and 'endocytosis'. When filtering the results of the PPI network analysis using Cytohubba, a total of 10 hub genes, including proteolipid protein 1, myelin associated oligodendrocyte basic protein, contactin 2, myelin oligodendrocyte glycoprotein, myelin basic protein, myelin associated glycoprotein, SRY-box transcription factor 10, C-X-C motif chemokine ligand 8 (CXCL8), vascular endothelial growth factor A (VEGFA) and plasmolipin, were identified. These hub genes were further subjected to GO term and KEGG pathway analysis, and were revealed to be enriched in 'central nervous system development', 'bladder cancer' and 'rheumatoid arthritis'. These hub genes were used to perform survival analysis using the GEPIA database, and it was determined that VEGFA and CXCL8 were significantly associated with a reduction in the overall survival of patients with GBM. In conclusion, the results suggest that the recurrence of GBM is associated with high gene expression levels VEGFA and CXCL8, and the development of the central nervous system.
31701373 Potential molecular mechanisms underlying the effect of arsenic on angiogenesis. 2019 Nov Arsenic is a potent chemotherapeutic drug that is applied as a treatment for cancer; it exerts its functions through multiple pathways, including angiogenesis inhibition. As angiogenesis is a critical component of the progression of many diseases, arsenic is a feasible treatment option for patients with other angiogenic diseases, including rheumatoid arthritis and psoriasis, among others. However, arsenic is also a well-known carcinogen, demonstrating a pro-angiogenesis effect. This review will focus on the dual effects of arsenic on neovascularization and the relevant mechanisms underlying these effects, aiming to provide a rational understanding of arsenic treatment. In particular, we expect to provide a comprehensive overview of the current knowledge of the mechanisms by which arsenic influences angiogenesis.
31684196 Associations of Anti-Aquaporin 5 Autoantibodies with Serologic and Histopathological Featu 2019 Nov 3 Biomarkers to stratify the complex and heterogeneous phenotypes of Sjogren's syndrome (SS) are needed. We aimed to validate the prevalence of anti-aquaporin 5 (AQP5) IgG in a non-Korean cohort and to optimize the method to screen the anti-AQP5 IgG. The study cohort included 111 primary SS and 43 non-SS Sjögren's International Collaborative Clinical Alliance (SICCA) controls that were obtained from the Sjögren's International Collaborative Clinical Alliance registry, in addition to 35 systemic lupus erythematosus (SLE) and 35 rheumatoid arthritis (RA) phenotypes. Anti-AQP5 IgG was screened by cell-based immunofluorescence cytochemistry (CB-IFC) assay in the absence or presence of epitope peptides, as well as by ELISA using the epitope peptides as coated antigens. Anti-AQP5 IgG specific to an E1 epitope was best at discriminating between SS and non-SS, and the two different methods (CB-IFC and ELISA) presented comparable performance in diagnostic accuracy (0.690 vs. 0.707). Notably, the SLE and RA groups had substantially lower levels of anti-AQP5 IgG than the SS group. In addition, the presence of anti-AQP5_E1 IgG was associated with serologic and histopathological features of SS. In conclusion, a similar prevalence of anti-AQP5 IgG was confirmed in a non-Korean cohort. Screening anti-AQP5 autoantibodies may help to form subgroups of SS for targeted therapy.
31485375 The socioeconomic impact of Korean dental health insurance policy on the elderly: a nation 2019 Aug PURPOSE: The purpose of this retrospective study was to investigate the relationships of types of dental insurance coverage in Korea with sociodemographic characteristics and the prevalence of systemic and oral diseases, as well as to evaluate the socioeconomic impact of Korean dental insurance policies. METHODS: Sample cohort data from 2006 to 2015 were obtained from the National Health Insurance Service. Patients were divided into 2 groups. The exposed group comprised patients who received insurance benefits for complete dentures, removable partial dentures, and implant care, while the control group comprised patients who did not receive these benefits. The type of insurance coverage and the prevalence of systemic and oral diseases were compared between the 2 groups. RESULTS: Patients who received benefits in the form of complete dentures, removable partial dentures, and implants had similar sociodemographic characteristics in terms of sex, age, income quintile, and type of insurance coverage to the control group. The prevalence of hypertension, anemia, renal disease, rheumatoid arthritis, osteoporosis, asthma, and cerebral infarction was higher in the exposed group than in the control group (P<0.05). The prevalence of periodontal diseases and dental caries was also higher in the exposed group. CONCLUSIONS: Korean dental health insurance policy has been beneficial for the medical expenses of low-income and elderly people suffering from a cost burden due to systemic diseases. However, since there is a tendency to avoid invasive interventions in older patients due to the high risk of systemic diseases, insurance coverage of dentures may be more helpful from a socioeconomic perspective than coverage of dental implant treatments.
31172410 Adverse events in patients with ankylosing spondylitis treated with TNF inhibitors: a cros 2019 Aug Background Although TNF inhibitors are well established in ankylosing spondylitis treatment, the majority of studies on TNF inhibitors safety have been performed in rheumatoid arthritis patients. Meanwhile, it seems that TNF inhibitors in ankylosing spondylitis may present a better safety profile than we thought. Objective The aim of our study was to retrospectively investigate the occurrence of adverse events in ankylosing spondylitis patients treated with TNF inhibitors. Setting A single referral center in Poland. Methods Detailed medical history of ankylosing spondylitis patients was obtained during the interview with the patient and by reviewing electronic medical records. Patients treated with TNF inhibitors and patients without TNF inhibitors treatment were compared. Main outcome measure The incidence of adverse events during the 3 months period before the interview. Results A total of 150 patients, 103 in the treatment group and 47 in the control group, were included in the study. There were no differences in the incidence of adverse events, serious adverse events, infections and opportunistic infections between both groups. However, in the treatment group, noninfectious adverse events were significantly less frequent than in control group (RR 0.39, 95% CI 0.23-0.66), with abdominal pain as the most common noninfectious adverse event (RR 0.20, 95% CI 0.07-0.63). The differences in incidence rates of specific infections were not significant, except acute infectious diarrhea which also was less frequent in patients treated with TNF inhibitors (RR 0.17, 95% CI 0.03-0.85). The female gender was significantly associated with any adverse event occurrence (OR 2.36, 95% CI 1.15-4.83). Conclusion TNF inhibitors show a good safety profile in ankylosing spondylitis patients.
31114575 Immunopathogenesis of Pediatric Localized Scleroderma. 2019 Localized scleroderma (LS) is a complex disease characterized by a mixture of inflammation and fibrosis of the skin that, especially in the pediatric population, also affects extracutaneous tissues ranging from muscle to the central nervous system. Although developmental origins have been hypothesized, evidence points to LS as a systemic autoimmune disorder, as there is a strong correlation to family history of autoimmune disease, the presence of shared HLA types with rheumatoid arthritis, high frequency of auto-antibodies, and elevated circulating chemokines and cytokines associated with T-helper cell, IFNγ, and other inflammatory pathways. This inflammatory phenotype of the peripheral blood is reflected in the skin via microarray, RNA Sequencing and tissue staining. Research is underway to identify the key players in the pathogenesis of LS, but close approximation of inflammatory lymphocytic and macrophage infiltrate with collagen and fibroblasts deposition supports the notion that LS is a disease of inflammatory driven fibrosis. The immune system is dynamic and undergoes changes during childhood, and we speculate on how the unique features of the immune system in childhood could potentially contribute to some of the differences in LS between children and adults. Interestingly, the immune phenotype in pediatric LS resembles to some extent the healthy adult cellular phenotype, possibly supporting accelerated maturation of the immune system in LS. We discuss future directions in better understanding the pathophysiology of and how to better treat pediatric LS.
31081724 Association of Autoantibody to Rods and Rings with Hepatitis C Outcome and Viral Load. 2019 Jun Despite the current availability of more potent drugs, hepatitis C virus (HCV) infection is still treated with a combination of IFN-α and ribavirin in many countries. Interferon/ribavirin therapy can induce the appearance of autoantibodies to Rods and Rings (anti-RR), which have been associated to a poorer prognosis. The aim of this study was to investigate the prevalence of anti-RR antibodies before and after ribavirin therapy and to look for a possible association with HCV infection outcome. In this context, anti-RR antibodies were detected by IFI on HEp-2 cells in 142 patients under ribavirin therapy (G1: 74 patients with a positive posttreatment HCV-PCR and G2: 68 patients with a negative posttreatment HCV-PCR, matched in age and gender), 84 kidney transplant recipients (KTRs) under mycophenolate and 158 controls (30 with systemic lupus erythematosus, 37 with rheumatoid arthritis, and 91 healthy blood donors). No patient had anti-RR antibody before IFN-α/ribavirin therapy, while 27 (19%) developed the anti-RR pattern under treatment. The anti-RR antibody was absent in all KTRs and the 158 controls. The frequency of anti-RR antibody was significantly higher in G1 (27; 36.48%) than in G2 (0), p < 0.001. Moreover, and in G1, anti-RR antibody was more frequent in nonresponders (NR) patients (23, 56.1%) than in relapsers (REL) (4, 12.1%); p < 0.001, OR [95%CI] = 9.26 [2.75-31.18]. Moreover, anti-RR antibody titer was significantly higher in NR patients (3,200 [1,600-6,400]) comparatively to REL patients (800 [500-1,400]), p = 0.002. Likewise, log of viral load postribavirin therapy was significantly higher in anti-RR positive patients (6.24 ± 0.64) than in anti-RR negative (4.69 ± 1.06), p < 0.001. Based on these findings, ribavirin-induced anti-RR autoantibody seems to be associated with a more frequent nonresponse to IFN-α/ribavirin therapy with a significant higher HCV viral load.
30815894 Daphnetin attenuates LPS-induced osteolysis and RANKL mediated osteoclastogenesis through 2019 Aug Aseptic prosthetic loosening and periprosthetic infection resulting in inflammatory osteolysis is a leading complication of total joint arthroplasty (TJA). Excessive bone destruction around the bone and prosthesis interface plays a key role in the loosening prostheses leading to revision surgery. The bacterial endotoxins or implant-derived wear particles-induced inflammatory response is the major cause of the elevated osteoclast formation and activity. Thus, agents or compounds that can attenuate the inflammatory response and/or inhibit the elevated osteoclastogenesis and excessive bone resorption would provide a promising therapeutic avenue to prevent aseptic prosthetic loosening in TJA. Daphnetin (DAP), a natural coumarin derivative, is clinically used in Traditional Chinese Medicine for the treatment of rheumatoid arthritis due to its anti-inflammatory properties. In this study, we report for the first time that DAP could protect against lipopolysaccharide-induced inflammatory bone destruction in a murine calvarial osteolysis model in vivo. This protective effect of DAP can in part be attributed to its direct inhibitory effect on RANKL-induced osteoclast differentiation, fusion, and bone resorption in vitro. Biochemical analysis found that DAP inhibited the activation of the ERK and NFATc1 signaling cascades. Collectively, our findings suggest that DAP as a natural compound has potential for the treatment of inflammatory osteolysis.
30800683 Influences of Corydalis decumbens on the Activities of CYP450 Enzymes in Rats with a Cockt 2019 Corydalis decumbens, a Traditional Chinese Medicine, has been widely used for the alternative and/or complementary therapy of hypertension, arrhythmias rheumatoid arthritis, sciatica, stroke, hemiplegia, paraplegia, and vascular embolism. The aim of this study was to determinate the potential effects of Corydalis decumbens on the five cytochrome P450 (CYP) enzyme activities (CYP1A2, CYP3A4, CYP2C9, CYP2C19, and CYP2D6) by cocktail approach. To evaluate whether concurrent use of Corydalis decumbens interferes with the effect of several prescription drugs, saline (control group) or Corydalis decumbens (XTW group) were administrated via gavage for 7 successive days. A probe cocktail solution (phenacetin, omeprazole, metoprolol, tolbutamide, and midazolam) was given 24 h after the last dose of saline or Corydalis decumbens. A specific and sensitive UHPLC-MS/MS method was validated for the determination of five substrates and their metabolites in control group and XTW group. Our results indicated that Corydalis decumbens could have inductive effects of CYP2C19 and inhibit the activities of CYP1A2 and CYP3A4. However, Corydalis decumbens had no significant influence on CYP2C9 and CYP2D6. The herb-drug interaction should require more attention by careful monitoring and appropriate drug dosing adjustments to the concurrent use of western medications which were metabolized by CYP1A2, CYP2C19, and CYP3A4 in human-Corydalis decumbens, Cytochrome P450, Cocktail, Pharmacokinetics, herb-drug interactions.
30591286 Why Colchicine Should Be Considered for Secondary Prevention of Atherosclerosis: An Overvi 2019 Jan PURPOSE: Colchicine is a widely available, inexpensive drug with a range of antiinflammatory properties that may make it suitable for the secondary prevention of atherosclerosis. This review examines how past and contemporary approaches to antiinflammatory therapy for atherosclerosis have led to a better understanding of the nature of the disease and sets out the reasons why colchicine has the potential to become a cornerstone therapy in its management. METHODS: We performed a literature search using PubMed, the Cochrane library, and clinical trial registries to identify completed and ongoing clinical studies on colchicine in coronary artery disease, and a PubMed search to identify publications on the mechanism of action of colchicine relevant to atherosclerosis. FINDINGS: A large body of data confirms that inflammation plays a pivotal role in atherosclerosis. The translation of this extensive knowledge into improved clinical outcomes has until recently been elusive. Findings from statin trials support the possibility that targeting inflammation may be beneficial, but this evidence has been inconclusive. Direct inhibition of atherosclerotic inflammation is being explored in current clinical trials. Targeted inhibition of interleukin 1β with canakinumab provided the proof of principle that limiting inflammation can improve outcomes in atherosclerotic vascular disease, but long-term treatment with a monoclonal antibody is unlikely to have widespread uptake. Other approaches using agents with a wider set of targets are being explored. Findings from observational studies suggest that methotrexate may reduce cardiovascular risk in patients with rheumatoid arthritis, but CIRT (Cardiovascular Inflammation Reduction Trial) demonstrated that methotrexate provided no cardiovascular benefit in patients with atherosclerotic vascular disease. Recent demonstration that cholesterol crystals trigger the NLRP3 (nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3) inflammasome and the release of inflammatory cytokines that also drive uric acid crystal-induced inflammation indicates that the multiple actions of colchicine that make it effective in gout may be relevant to preventing inflammation and limiting inflammatory injury in atherosclerosis. The ongoing LoDoCo2 (Low Dose Colchicine2) and COLCOT (Colchicine Cardiovascular Outcomes Trial) trials and several other planned large-scale rigorous trials will determine the long-term tolerability and efficacy of low-dose colchicine for secondary prevention in patients with coronary disease. IMPLICATION: Colchicine holds promise as an important, accessible drug that could be successfully repurposed for the secondary prevention of atherosclerotic cardiovascular disease should its tolerability and cardiovascular benefits be confirmed in ongoing clinical trials.
30548260 Hesperetin suppresses RANKL-induced osteoclastogenesis and ameliorates lipopolysaccharide- 2019 Jul Destructive bone diseases caused by osteolysis are increasing in incidence. They are characterized by an excessive imbalance of osteoclast formation and activation. During osteolysis, the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways are triggered by receptor activator of NF-κB ligand (RANKL), inflammatory factors, and oxidative stress. Previous studies have indicated that the common flavanone glycoside compound hesperetin exhibits anti-inflammatory and antioxidant activity by inhibition of NF-κB and MAPK signaling pathways. However, the direct relationship between hesperetin and osteolysis remain unclear. In the present study, we investigated the effects of hesperetin on lipopolysaccharide (LPS)-induced osteoporosis and elucidated the related mechanisms. Hesperetin effectively suppressed RANKL-induced osteoclastogenesis, osteoclastic bone resorption, and F-actin ring formation in a dose-dependent manner. It also significantly suppressed the expression of osteoclast-specific markers including tartrate-resistant acid phosphatase, matrix metalloproteinase-9, cathepsin K, c-Fos, and nuclear factor of activated T-cells cytoplasmic 1. Furthermore, it inhibited osteoclastogenesis by inhibiting activation of NF-κB and MAPK signaling, scavenging reactive oxygen species, and activating the nuclear factor E2 p45-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway. Consistent with in vitro results, hesperetin effectively ameliorated LPS-induced bone loss, reduced osteoclast numbers, and decreased the RANKL/OPG ratio in vivo. As such, our results suggest that hesperetin may be a great candidate for developing a novel drug for destructive bone diseases such as periodontal disease, tumor bone metastasis, rheumatoid arthritis, and osteoporosis.
30502083 Gene microarray analysis of expression profiles in Suberoyllanilide hyroxamic acid-treated 2019 Jan 8 OBJECTIVE: The purpose of this study is to provide a further theoretical basis for the role of Suberoyllanilide hyroxamic acid (SAHA) affect on Dendritic cells (DCs). METHODS: We first downloaded the GSE74306 microarray data, which was about the effect of SAHA act on DCs, from the Gene Expression Omnibus database. Then we analyzed the differential expression genes (DEGs) between SAHA-treated DCs and SAHA-untreated DCs by limma package of R software; The Database for Annotation, Visualization and Integrated Discovery was used to analyze the Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for these DEGs. The protein protein interaction (PPI) network was constructed by using STRING database, Cytoscape 3.6.1 software was used to dispose the PPI network for visualization. Finally, we determine the Hub genes in the PPI network according by the degree centrality and betweenness centrality, which were calculated by the CentScaPe 2.2 plug-in of Cytoscape 3.6.1 software. RESULT: There were 551 DEGs between SAHA-treated DC cells and SAHA-untreated DC cells, including 357 upregulated genes and 194 downregulated genes. These DEGs genes were enriched in 115 Go terms (Biological Process, 51; Cellular Component, 35 and Molecular Function, 29) and a total of 16 pathways. Glutathione metabolic process, Glutathione metabolism pathway, Rheumatoid arthritis pathway and Systemic lupus erythematosus pathway were most significant function clusters. In the PPI network, Rad51, Src, and Eno2 were Hub genes. CONCLUSION: The biological function and KEGG pathway enriched by DEGs may reveal the molecular mechanism of SAHA acting on DC cells. Its Hub genes, Src, Rad51 and Eno2, were expected to be new targets for SAHA therapeutic effects. However, it still need to be confirmed by the next more rigorous molecular biological experiments research.
30498258 Intra-articular treatment options for knee osteoarthritis. 2019 Feb Intra-articular drug delivery has a number of advantages over systemic administration; however, for the past 20 years, intra-articular treatment options for the management of knee osteoarthritis (OA) have been limited to analgesics, glucocorticoids, hyaluronic acid (HA) and a small number of unproven alternative therapies. Although HA and glucocorticoids can provide clinically meaningful benefits to an appreciable number of patients, emerging evidence indicates that the apparent effectiveness of these treatments is largely a result of other factors, including the placebo effect. Biologic drugs that target inflammatory processes are used to manage rheumatoid arthritis, but have not translated well into use in OA. A lack of high-level evidence and methodological limitations hinder our understanding of so-called 'stem' cell therapies and, although the off-label administration of intra-articular cell therapies (such as platelet-rich plasma and bone marrow aspirate concentrate) is common, high-quality clinical data are needed before these treatments can be recommended. A number of promising intra-articular treatments are currently in clinical development in the United States, including small-molecule and biologic therapies, devices and gene therapies. Although the prospect of new, non-surgical treatments for OA is exciting, the benefits of new treatments must be carefully weighed against their costs and potential risks.
30339839 Reduced Terminal Complement Complex Formation in Mice Manifests in Low Bone Mass and Impai 2019 Jan The terminal complement complex (TCC) is formed on activation of the complement system, a crucial arm of innate immunity. TCC formation on cell membranes results in a transmembrane pore leading to cell lysis. In addition, sublytic TCC concentrations can modulate various cellular functions. TCC-induced effects may play a role in the pathomechanisms of inflammatory disorders of the bone, including rheumatoid arthritis and osteoarthritis. In this study, we investigated the effect of the TCC on bone turnover and repair. Mice deficient for complement component 6 (C6), an essential component for TCC assembly, and mice with a knockout of CD59, which is a negative regulator of TCC formation, were used in this study. The bone phenotype was analyzed in vivo, and bone cell behavior was analyzed ex vivo. In addition, the mice were subjected to a femur osteotomy. Under homeostatic conditions, C6-deficient mice displayed a reduced bone mass, mainly because of increased osteoclast activity. After femur fracture, the inflammatory response was altered and bone formation was disturbed, which negatively affected the healing outcome. By contrast, CD59-knockout mice only displayed minor skeletal alterations and uneventful bone healing, although the early inflammatory reaction to femur fracture was marginally enhanced. These results demonstrate that TCC-mediated effects regulate bone turnover and promote an adequate response to fracture, contributing to an uneventful healing outcome.
30146094 Attempting to remedy sub-optimal medication adherence in haemophilia: The rationale for re 2019 Jan Haemophilia is marked by joint bleeding (haemarthrosis) leading to cartilage damage (arthropathy). Lifelong prophylaxis-initiated after the first bleeding episode-leads to a dramatic decrease in arthropathy in haemophilia patients. However, adherence to continuous intravenous administrations of factor VIII (FVIII) or FIX products is challenging, and patients potentially suffer from breakthrough bleedings while on prophylaxis. Newer FVIII/FIX products with enhanced convenience attributes and/or easier infusion procedures are intended to improve adherence. However, pharmacokinetic data should be harmonised with information from individual attitudes and treatment needs, to tailor intravenous dosing and scheduling in patients who receive extended half-life products. Nor is there sound evidence as to how subcutaneous non-FVIII/FIX replacement approaches (concizumab; emicizumab; fitusiran) or single intravenous injections of adeno-associated viral vectors (when employing gene therapy) will revolutionize adherence in haemophilia. In rheumatoid arthritis, repeated ultrasound examination of a patient's major joints is a valuable tool to educate patients and parents to understand the disease and provide an objective framework for clinicians to acknowledge patient's adherence. Joint ultrasound examination in haemophilia significantly correlates with cartilage damage, effusion, and synovial hypertrophy evaluated by magnetic resonance imaging. Furthermore, in patients with haemophilia undergoing prophylaxis with an extended half-life product for a ≈ 2.8 year period, a significant continued improvement in joint health is detected at the physical examination. This provides the rationale for studies on repeated ultrasound examinations of joint status to attempt to remedy sub-optimal medication adherence and help identify which approach is most suited on which occasion and for which patient.
31765834 Linking genetic variation with epigenetic profiles in Sjögren's syndrome. 2020 Jan DNA methylation represents an important regulatory event governing gene expression that is dysregulated in Sjögren's syndrome (SjS) and a number of autoimmune/inflammatory diseases. As disease-associated single-nucleotide polymorphisms (SNPs) have relevance in controlling DNA methylation, 94 non-HLA SjS-SNPs were investigated, among them 57 (60.6%) with widespread effects on 197 individual DNA methylation quantitative trait loci (meQTL) were selected. Typically, these SNPs are intronic, possess an active promoter histone mark, and control cis-meQTLs located around transcription start sites. Interplay is independent of the physical distance between SNPs and meQTLs. Using epigenome-wide association study datasets, SjS-meQTLs were characterized (41 genes and 13 DNA methylation CpG motifs) and for the most part map to a pro-inflammatory cytokine pathway, which is important for the control of DNA methylation in autoimmune diseases. In conclusion, exploring meQTLs represents a valuable tool to predict and investigate downstream effects of genetic factors in complex diseases such as SjS.
31801074 Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjögren Syndrome-like Inf 2019 Dec 3 Human genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27Rα. In contrast to wild-type NOD mice, both NOD.Il27(-/-) and NOD.Il27ra(-/-) strains are completely resistant to T1D. IL-27 from myeloid cells and IL-27 signaling in T cells are critical for T1D development. IL-27 directly alters the balance of regulatory T cells (Tregs) and T helper 1 (Th1) cells in pancreatic islets, which in turn modulates the diabetogenic activity of CD8 T cells. IL-27 also directly enhances the effector function of CD8 T cells within pancreatic islets. In addition to T1D, IL-27 signaling in T cells is also required for lacrimal and salivary gland inflammation in NOD mice. Our study reveals that IL-27 contributes to autoimmunity in NOD mice through multiple mechanisms and provides substantial evidence to support its pathogenic role in human T1D.
30923955 Tolerability and safety of long-term rituximab treatment in systemic inflammatory and auto 2019 Jun Rituximab, an anti-CD20 monoclonal antibody causing selective B-cell depletion, is used for various systemic inflammatory and autoimmune diseases (SIADs). Long-term safety data on rituximab are limited. The objectives of this study were to evaluate the long-term safety and tolerability of rituximab treatment for SIADs. A retrospective, single-center observational study including all patients ≥ 16 years treated with rituximab for SIADs was performed. The electronic medical records were reviewed, and data concerning indication and duration of rituximab treatment, prior and concurrent immunosuppressive therapy, and adverse events such as infections requiring hospitalization, dysgammaglobulinemia and end organ damage, were collected. A total of 70 patients were included, with a median treatment duration of 54 months, ranging 30-138 months. The most common indications for rituximab treatment were granulomatosis with polyangiitis (22.9%), primary Sjögren's syndrome (20.0%) and systemic lupus erythematosus (14.3%). Infections and persistent dysgammaglobulinemia were the most common adverse events, occurring in 34.3% and 25.7%, respectively. A total of 64 infections were observed in 24 (34.3%) patients, including 1 case of fatal infection. Seventeen patients performed B-cell quantitation during the first 2 years following discontinuation, of which only four (19.0%) demonstrated B-cell reconstitution. End organ damage occurred in two patients, presenting as pyoderma gangrenosum and interstitial pneumonitis. No opportunistic infections were observed. Three patients died during the observational period, of which one was due to lethal infection. This study presents observational data with long treatment duration. It demonstrates that long-term rituximab treatment is relatively well tolerated, and that no cumulative side effects were observed.