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ID PMID Title PublicationDate abstract
30624775 Protein modeling, molecular network and molecular dynamics study of newly sequenced interl 2019 Aug Interleukin-18 (IL-18) belongs to the superfamily of IL-1 protein and exerts a pleiotropic pro-inflammatory effect on the body. Generally, this protein is significantly involved in immune defense during infection in cells, but sometimes its anomalous activities produce some inflammatory diseases like rheumatoid arthritis and Crohn's disease. In the present study, the IL-18 gene was isolated from mice and was subsequently cloned and sequenced. Further, the network analysis was carried out to explore the functional role of IL-18 protein in animals. The 3D protein structure of the IL-18 protein was generated and docked with appropriate 3-([3-cholamidopropyl]dimethylammonio)-1-propanesulfonate (CPS) ligand. Later the complex structure of the protein was subjected to molecular dynamics simulation (MDS) for 50 ns to determine the effect of ligand on protein. The network analysis explored the correlation of IL-18 protein with others proteins and their involvement in the different significant pathway to defend the cell from various diseases. As confirmed by MDS, the CPS:IL-18 complex was found to be highly stable. Our results further indicated that CPS ligand has the potential to act as a drug molecule, in future, for counteracting IL-18 activity. To date, no structural details were available for animal IL-18. Hence, the finding of this study will be useful in broadening the horizon towards a better understanding of the functional and structural aspects of IL-18 in animals.
31077735 Down-regulation of microRNA-98 promoted apoptosis of TNF-α stimulated human fibroblast-li 2019 Jul 20 In this study, we constructed a tumor necrosis factor α (TNF-α)-induced synovial cell inflammatory model using human synoviocytes (HS) cell line to explore the function of miR-98 in rheumatoid arthritis (RA). miR-98 mimics or miR-98 inhibitor were transfected into HS cells to up-regulate or down-regulate the expression of miR-98. The proliferation and apoptosis of HS cells were determined using CCK8 assay and flow cytometry, respectively. TargetScan website was utilized to predict the targets of miR-98. Luciferase assay was carried out to verify that IL-10 is a target of miR-98. Western blot was performed to analyze the expression of IL-10, apoptosis-related and NF-κB signaling pathway-related proteins. Our results demonstrated that the expression of miR-98 was up-regulated in HS cells stimulated by TNF-α. Down-regulation of miR-98 by inhibitor in TNF-α-stimulated HS cells dramatically inhibited cell proliferation and promoted cell apoptosis compared with the miR-98 inhibitor NC group. The protein expression of Bcl-2 was declined while the levels of Bax and Bim were increased by miR-98 inhibitor in TNF-α-stimulated HS cells. IL-10 was predicted and verified as a target of miR-98. qRT-PCR and western blot results revealed that the level of IL-10 was negatively regulated by miR-98. Finally, we identified that down-regulation of miR-98 reduced the expression level of p-p65 and p-IκBα in TNF-α-stimulated HS cells. In summary, our present study demonstrated that down-regulation of miR-98 inhibited the proliferation and promoted the apoptosis of TNF-α-stimulated HS partly by targeting IL-10 and regulating NF-κB signaling pathway, insinuating miR-98 as a candidate biomarker in RA.
31522762 Patterns of glucocorticoid prescribing and provider-level variation in a commercially insu 2020 Apr OBJECTIVE: Glucocorticoids are common in RA management despite an unfavorable, exposure-dependent risk profile impacted by patient and provider-level factors. Existing work describing glucocorticoid use in RA is not generalizable and does not adequately examine provider factors. We aim to describe how providers prescribe glucocorticoids to commercially insured, newly diagnosed RA patients in the United States. METHODS: This was a retrospective cohort study which used the national Optum© administrative database. We identified 9221 adults ages 18-65 with RA diagnosed 2010-2014. We assessed glucocorticoid dispensing 3 months pre-diagnosis through 12months post-diagnosis ("study period"), cumulatively stratified by calendar quarter and prescriber specialty (rheumatologist, primary care, other). We examined prescribing variation among individual rheumatologists by dividing quarterly distribution of per-patient dose and days' supply into quartiles. RESULTS: 6717 (72.8%) patients filled ≥1 glucocorticoid prescription during the study period. 2890 (31.3%) patients received ≥3 months' supply, with median (IQR) daily dose 10 (6.6) mg/day and days' supply 189 (143) days. 52.6% of patients received glucocorticoids 1-3 months post-diagnosis; 29.2% received glucocorticoids 10-12 months post-diagnosis. Among glucocorticoid users post-diagnosis, quarterly median daily dose and days' supply were consistently ≥10 mg/day and ≥30 days, respectively. Rheumatologists prescribed most glucocorticoids, with median per-quarter daily dose and days' supply 10 mg/day and 43-60 days. Individual rheumatologists' prescribing varied widely across all quarters. CONCLUSION: Among commercially insured incident RA patients, receipt of ≥10 mg/day prednisone equivalent for months is common, typically prescribed by rheumatologists, and persists a year post-diagnosis in 29.2% of patients. Glucocorticoid prescribing varies widely across rheumatologists. Further work is warranted to identify provider factors explaining variation in glucocorticoid prescribing, and assess how these affect health outcomes.
31683648 The Systemic Immune Response to Collagen-Induced Arthritis and the Impact of Bone Injury i 2019 Oct 31 Rheumatoid arthritis (RA) is a systemic disease that affects the osteoarticular system, associated with bone fragility and increased risk of fractures. Herein, we aimed to characterize the systemic impact of the rat collagen-induced arthritis (CIA) model and explore its combination with femoral bone defect (FD). The impact of CIA on endogenous mesenchymal stem/stromal cells (MSC) was also investigated. CIA induction led to enlarged, more proliferative, spleen and draining lymph nodes, with altered proportion of lymphoid populations. Upon FD, CIA animals increased the systemic myeloid cell proportions, and their expression of co-stimulatory molecules CD40 and CD86. Screening plasma cytokine/chemokine levels showed increased tumor necrosis factor-α (TNF-α), Interleukin (IL)-17, IL-4, IL-5, and IL-12 in CIA, and IL-2 and IL-6 increased in CIA and CIA+FD, while Fractalkine and Leptin were decreased in both groups. CIA-derived MSC showed lower metabolic activity and proliferation, and significantly increased osteogenic and chondrogenic differentiation markers. Exposure of control-MSC to TNF-α partially mimicked the CIA-MSC phenotype in vitro. In conclusion, inflammatory conditions of CIA led to alterations in systemic immune cell proportions, circulating mediators, and in endogenous MSC. CIA animals respond to FD, and the combined model can be used to study the mechanisms of bone repair in inflammatory conditions.
30809737 Elevated circulating T cell subsets and cytokines expression in patients with rheumatoid a 2019 Jul OBJECTIVE: This study aimed to assess the role of different subsets of circulating follicular helper T cells (Tfh), central memory (TCM), effector memory (TEM), Naïve T, chemokines, and cytokines in the pathogenesis of rheumatoid arthritis (RA). METHODS: Blood samples from RA patients (n = 44) and healthy controls (n = 37) were analyzed. The frequencies of circulating Tfh, TCM, TEM, and Naïve T cell subsets were enumerated, and the expression of co-stimulatory molecules, such as inducible co-stimulator (ICOS) and programmed death-1 (PD1), on these cells was evaluated by flow cytometry. The disease state in RA patients was assessed using the DAS28. Concentrations of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-cyclic citrullinated peptide (anti-CCP), and rheumatoid factor (RF) were measured. Cytokines and chemokines, such as IL-1β, TNF-α, IL-4, IL-6, IL-9, IL-17A, MCP-1, IL-10, IL-12p70, and IL-21, were measured by a cytometric beads array assay. RESULTS: The percentages of circulating PD1(+)ICOS(+) Tfh, PD1(+)ICOS(+) TEM, and PD1(+)ICOS(+) TCM of PBMCs from RA patients were higher than those in healthy controls. Furthermore, expression of circulating PD1(+)ICOS(+) Tfh, PD1(+)ICOS(+) TEM, and PD1(+)ICOS(+) TCM showed a positive correlation with DAS28. In addition, increased levels of IL-1β, IL-6, and MCP-1 were detected in the patients with RA compared to healthy controls. CONCLUSIONS: Elevated circulating T cell subsets and cytokines expression profile were observed in RA patients. IL-6, MCP-1, and IL-1β were significantly increased in RA, and PD1(+)ICOS(+) TEM, PD1(+)ICOS(+) TCM, and PD1(+)ICOS(+) Tfh cell subsets were positively correlated with disease activity DAS28. Therefore, PD1(+)ICOS(+) TEM, PD1(+)ICOS(+) TCM, and PD1(+)ICOS(+) Tfh cells might serve an important role in the progression of RA.
31107176 Technology-Enabled Outreach to Patients Taking High-Risk Medications Reduces a Quality Gap 2020 Feb Clinical laboratory quality improvement (QI) efforts can include population test utilization. The authors used a health care organization's Medical Data Warehouse (MDW) to characterize a gap in guideline-concordant laboratory testing recommended for safe use of antirheumatic agents, then tested the effectiveness of laboratory-led, technology-enabled outreach to patients at reducing this gap. Data linkages available through the Kaiser Permanente Colorado MDW and electronic health record were used to identify ambulatory adults taking antirheumatic agents who were due/overdue for alanine aminotransferase (ALT), aspartate aminotransferase (AST), complete blood count (CBC), or serum creatinine (SCr) testing. Outreach was implemented using an interactive voice response system to send patients text or phone call reminders. Interrupted time series analysis was used to estimate reminder effectiveness. Rates of guideline-concordant testing and testing timeliness in baseline vs. intervention periods were determined using generalized linear models for repeated measures. Results revealed a decrease in percentage of 3763 patients taking antirheumatic agents due/overdue for testing at any given time: baseline 24.3% vs. intervention 17.5% (P < 0.001). Among 3205 patients taking conventional antirheumatic agents, concordance for all ALT testing was baseline 52.8% vs. intervention 65.4% (P < 0.001) among patients chronically using these agents and baseline 20.6% vs. intervention 26.1% (P < 0.001) among patients newly starting these agents. The 95(th) percentiles for days to ALT testing were baseline 149 vs. intervention 117 among chronic users and baseline 134 vs. intervention 92 among new starts. AST, CBC, and SCr findings were similar. Technology-enabled outreach reminding patients to obtain laboratory testing improves health care system outcomes.
30985594 Turning Feed-forward and Feedback Processes on Patient-reported Data into Intelligent Acti 2019 May INTRODUCTION: The collection of patient-reported outcomes (PROs) in routine clinical practice provides opportunities to "feed-forward" the patient's perspective to his/her clinical team to inform planning and management. This data can also be aggregated to "feedback" population-level analytics that can inform treatment decision-making, predictive modeling, population-based care, and system-level quality improvement efforts. METHODS AIDING INTERPRETATION AND ACTING ON RESULTS: Three case studies demonstrate a number of system-level features which aid effective PRO interpretation: (1) feed-forward and feedback information flows; (2) score interpretation aids; (3) cascading measurement; (4) registry-enabled learning health care systems; and (5) the maturational development of information systems. DISCUSSION: The case studies describe the developmental span of feed-forward PRO programs-from simple to mature applications. The Concord Hospital (CH) Multiple Sclerosis Neurobehavioral Clinic exemplifies a simple application in which PRO data are used before and during clinic visits by patients and clinicians to inform care. The Dartmouth-Hitchcock (D-H) Spine Center exemplifies a mature program which utilizes population-level analytics to provide decision support by predicting outcomes for different treatment options. The Swedish Rheumatology Quality (SRQ) Registry epitomizes an exceptional application which has spread to multiple systems across an entire country. KEY POINTS: Feed-forward and feedback PRO information systems can better inform, involve, and support clinicians, patients and families, and allow health systems to monitor and improve system performance and population health outcomes. Ideal systems have the capability for multilevel analyses at patient, system, and population levels, and an information technology infrastructure that is linked to associated workflows and a supportive practice culture. As systems mature, they progress beyond the ability to describe and inform towards higher level capabilities including prediction and decision support. Finally, there is additional promise for the integration of patient-reported information that is adjusted (or weighted) by preferences and values to guide shared decision-making and inform individualized precision health care in the future.
31419081 Plasma α-L-fucosidase-1 in patients with Sjögren's syndrome and other rheumatic disorder 2019 Sep BACKGROUND: Human α-fucosidase (EC 3.2.1.51) is a hydrolase the importance of which has been increasing in the latest years. However, data about its plasma level in children with autoimmune disorders, particularly Sjögren's syndrome (SS), are lacking. In this study, the plasma activity of L-α-fucosidase-1 (α-L-FUCA-1) was assayed in hospitalized children and adults and its association with SS and other rheumatic disorders further evaluated. METHODS: In total 73 Hungarian hospitalized patients, 32 children (2.5-10 years) and 41 adults (32-68 years), were enrolled in the study and underwent plasma assay of α-L-FUCA1 activity. Linear regression, Durbin-Watson (DW), and Pearson tests were evaluated to investigate the relationship between α-L-FUCA-1 plasma levels and autoimmune manifestations. RESULTS: α-L-FUCA-1 correlated with SS both in children (2-sided t test, P = 0.0023) and in adults (2-sided t test, P = 0.00035). Linear regressions showed that in other rheumatic disorders, α-L-FUCA1 did not show any differential distribution related to the particular pathology (r = 0.2042, P = 0.1531, DW test = 2.2139 positive), while this trend was radically opposite for patients with SS (r = 0.1462, P = 0.0032, DW test = 1.3664, negative). CONCLUSIONS: Alterations in plasma level of α-L-FUCA-1 were significantly associated with SS. This preliminary result should encourage further research on α-L-FUCA-1 as a possible differential serological marker of SS.
31502681 Inducible nitric oxide synthase inhibitors: A comprehensive update. 2020 May Inducible nitric oxide synthase (iNOS), which is expressed in response to bacterial/proinflammatory stimuli, generates nitric oxide (NO) that provides cytoprotection. Overexpression of iNOS increases the levels of NO, and this increased NO level is implicated in pathophysiology of complex multifactorial diseases like Parkinson's disease, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Selective inhibition of iNOS is an effective approach in treatment of such complex diseases. l-Arginine, being a substrate for iNOS, is the natural lead to develop iNOS inhibitors. More than 200 research reports on development of nitric oxide synthase inhibitors by different research groups across the globe have appeared in literature so far. The first review on iNOS, in 2002, discussed the iNOS inhibitors under two classes that is, amino acid and non-amino acid derivatives. Other review articles discussing specific chemical classes of iNOS inhibitors also appeared during last decade. In the present review, all reports on both natural and synthetic iNOS inhibitors, published 2002 onwards, are studied, classified, and discussed to provide comprehensive information on iNOS inhibitors. The synthetic inhibitors are broadly classified into two categories that is, arginine and non-arginine analogs. The latter are further classified into amidines, five- or six-membered heterocyclics, fused cyclics, steroidal type, and chalcones analogs. Structures of the most/significantly potent compounds from each report are provided to know the functional groups important for incurring iNOS inhibitory activity and selectivity. This review is aimed to provide a comprehensive view to the medicinal chemists for rational designing of novel and potent iNOS inhibitors.
30777075 Baricitinib induces LDL-C and HDL-C increases in rheumatoid arthritis: a meta-analysis of 2019 Feb 18 BACKGROUND: Baricitinib, an oral-administrated selective inhibitor of the JAK1 and JAK2, is recently approved for rheumatoid arthritis (RA) treatment. With the aim to provide some insights on the clinical safety, the current study mainly focused on the effect of baricitinib on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular risk. METHODS: The net change scores [least squares mean (LSM) and mean change] of LDL-C and HDL-C levels from baseline with the comparison of baricitinib versus placebo were pooled, respectively. Risk rations (RR) of major cardiovascular events (MACEs) and differences of cardiovascular risk scores at the end of treatment across groups were compared. RESULTS: Six trials with randomized 3552 patients were finally included in summary analysis. Results showed that baricitinib significantly increased LDL-C levels, the net mean change was 13.15 mg/dl with 95% CI 8.89~17.42 (I(2) = 0) and the net LSM was 11.94 mg/dl with 95% CI 7.52~16.37 (I(2) = 84%). HDL-C also increased obviously with the net LSM change was 7.19 mg/dl (95% CI, 6.05~8.33, I(2) = 47%) and net mean change was 5.40 mg/dl (95% CI, 3.07~7.74, I(2) = 10%). Subgroup and meta-regression analysis demonstrated baricitinib induced LDL-C and HDL-C increases in a dose-response manner. However, both the pooled RRs of MACEs and differences of cardiovascular risk scores were not statistically significant across groups. CONCLUSION: This study confirmed that baricitinib induced a stable dose-response increase in LDL-C and HDL-C levels. Since the causality association between altered lipids and cardiovascular risk was not identified yet, this issue cannot be completely dismissed. Future research is needed to fully dissect the implications of these lipid changes.
31205958 Circulating CD3(+)HLA-DR(+) Extracellular Vesicles as a Marker for Th1/Tc1-Type Immune Res 2019 Extracellular vesicles (EVs) are known to contain unique proteins that reflect the cells of origins. Activated T cells are reported to secrete various EVs. To establish T cell subset-specific biomarkers, we performed proteomic analysis with Th1- and Th2-derived EVs and identified HLA-DR as a Th1-dominated EV membrane protein. We designed a measurement system for CD3(+)CD4(+), CD3(+)CD8(+), and CD3(+)HLA-DR(+) EVs to specifically determine EV subpopulations derived from CD4(+), CD8(+), and Th1-type T cells, respectively. In vitro analysis showed that CD3(+)CD4(+) EVs and CD3(+)CD8(+) EVs were selectively secreted from activated CD4(+) and CD8(+) T cells, respectively, and that CD3(+)HLA-DR(+) EVs were actively secreted from not only Th1 but also activated CD8(+) T (probably mostly Tc1) cells. To evaluate the clinical usefulness of these EVs, we measured the serum levels in patients with inflammatory diseases, including Epstein-Barr virus (EBV, n = 13) infection, atopic dermatitis (AD, n = 10), rheumatoid arthritis (RA, n = 20), and osteoarthritis (OA, n = 20) and compared the levels with those of healthy adults (n = 20). CD3 (+) CD4 (+) EVs were significantly higher in all of EBV infection, AD, RA, and OA while CD3(+)CD8(+) EVs were higher in EBV infection, lower in RA, and not different in AD and OA relative to the control. The levels of CD3(+)HLA-DR(+) EVs were markedly higher in EBV infection and significantly lower in AD. The results suggest that these EV subpopulations reflect in vivo activation status of total CD4(+), total CD8(+), and Th1/Tc1-type T cells, respectively, and may be helpful in T cell-related clinical settings, such as cancer immunotherapy and treatment of chronic infection, autoimmune diseases, and graft-versus-host disease.
31120380 Anti-Inflammatory Action of Blueberry Polyphenols in HIG-82 Rabbit Synoviocytes. 2019 Oct Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease resulting in joint destruction and disability in the adult population. The etiology of RA is not well understood and presently there is no known cure for this disease. The accumulation and proliferation of fibroblast-like synoviocytes may be involved in cartilage destruction. Both in vitro and in vivo studies support an anti-inflammatory role of dietary polyphenols, the bioactive constituents found in fruits and vegetables. The objective of this study was to investigate the anti-inflammatory role of blueberry polyphenols (BBPs) using rabbit synoviocytes stimulated with tumor necrosis factor alpha (TNFα). Rabbit synoviocytes (HIG-82) were treated with varying doses of BBPs and stimulated with TNFα. Stimulation of rabbit synoviocytes with the proinflammatory cytokine TNFα increased cell proliferation by ∼19% compared with the nonstimulated control. Cell proliferation was significantly decreased in a dose-dependent manner by the treatment with BBPs. Post-TNFα stimulation, cells treated with BBPs resulted in decreases in interleukin 1 beta and nuclear factor kappa B (NFκB) concentration. Reverse transcription-polymerase chain reaction analysis showed that matrix metalloproteinase 3 increased fivefold in the control TNFα-stimulated group, but was decreased by threefold in the blueberry treatment group. These results suggest that downregulation of proinflammatory cytokines and transcription factor NFκB by naturally occurring bioactives such as BBPs may be a potential therapeutic strategy for reducing inflammation associated with RA.
31023238 Methotrexate-associated lymphoproliferative disorder in the stomach and duodenum: a case r 2019 Apr 25 BACKGROUND: Methotrexate-associated lymphoproliferative disorder (MTX-LPD) can present as a benign lymphoid proliferation or a malignant lymphoma in patients taking MTX. Almost 50% of MTX-LPD cases show spontaneous remission after withdrawal of MTX treatment. Studies have suggested that the hyper-immune state of rheumatoid arthritis, the immunosuppressive state associated with MTX, and the carcinogenicity of the Epstein-Barr virus might contribute to MTX-LPD development. Although most cases of MTX-LPD occur at extranodal sites, few cases of MTX-LPD affecting the stomach and duodenum have been reported. To our knowledge, no other study has reported on the endoscopic observations of dramatic withdrawal and appearance of multiple digestive tract lesions in a short period of time. Herein, we report the clinical course and imaging findings of our case, which may be useful for understanding the pathological condition of MTX-LPD. CASE PRESENTATION: We describe the case of a 70-year-old woman with MTX-LPD of the stomach and duodenum. Disease regression was temporarily achieved after cessation of MTX treatment; however, it subsequently recurred, and complete response was only achieved after six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (R-CHOP) chemotherapy. CONCLUSIONS: The first-choice therapy for patients taking MTX who develop suspected MTX-LPD should be the withdrawal of MTX treatment. Even after remission is achieved, patients should be kept under careful observation, and if the disease recurs, chemotherapy should be commenced promptly.
31170097 Cervical Spine Deformity: Indications, Considerations, and Surgical Outcomes. 2019 Jun 15 Cervical spinal deformity (CSD) in adult patients is a relatively uncommon yet debilitating condition with diverse etiologies and clinical manifestations. Similar to thoracolumbar deformity, CSD can be broadly divided into scoliosis and kyphosis. Severe forms of CSD can lead to pain; neurologic deterioration, including myelopathy; and cervical spine-specific symptoms such as difficulty with horizontal gaze, dysphagia, and dyspnea. Recently, an increased interest is shown in systematically studying CSD with introduction of classification schemes and treatment algorithms. Both major and minor complications after surgical intervention have been analyzed and juxtaposed to patient-reported outcomes. An ongoing effort exists to better understand the relationship between cervical and thoracolumbar spinal alignment, most importantly in the sagittal plane.
31068444 HBEGF(+) macrophages in rheumatoid arthritis induce fibroblast invasiveness. 2019 May 8 Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF(+) inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor-dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF(+) inflammatory macrophages; however, in some cases, medication redirected them into a state that is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions.
31801802 All-Trans Retinoic Acid Inhibits Migration and Invasiveness of Rheumatoid Fibroblast-Like 2020 Feb Fibroblast-like synoviocytes (FLSs) are pivotal in inflammation and joint damage of rheumatoid arthritis (RA). They acquire an active and aggressive phenotype, displaying increased migration and invasiveness and contributing to perpetuate synovial inflammation and destruction of cartilage and bone. The main current therapies of RA are focused against inflammatory factors and immune cells; however, a significant percentage of patients do not successfully respond. Combined treatments with drugs that control inflammation and that reverse the pathogenic phenotype of FLS could improve the prognosis of these patients. An unexplored area includes the retinoic acid, the main biologic retinoid, which is a candidate drug for many diseases but has reached clinical use only for a few. Here, we explored the effect of all-trans retinoic acid (ATRA) on the aggressive phenotype of FLS from patients with RA. RA FLSs were treated with ATRA, tumor necrosis factor (TNF), or TNF+ATRA, and cell migration and invasion were analyzed. In addition, a microarray analysis of expression, followed by gene-set analysis and quantitative polymerase chain reaction validation, was performed. We showed that ATRA induced a notable decrease in FLS migration and invasion that was accompanied by complex changes in gene expression. At supraphysiological doses, many of these effects were overridden or reverted by the concomitant presence of TNF. In conclusion, these results have demonstrated the therapeutic potential of retinoic acid on RA FLS provided TNF could be counterbalanced, either with high ATRA doses or with TNF inhibitors. SIGNIFICANCE STATEMENT: All-trans retinoic acid (ATRA) reduced the rheumatoid arthritis (RA) fibroblast-like synoviocyte migration and invasiveness and down-regulated gene expression of cell motility and migration genes. At supraphysiological doses, some of these effects were reverted by tumor necrosis factor. Therefore, ATRA could be an RA drug candidate that would require high doses or combined treatment with anti-inflammatory drugs.
31755231 Inhibition of DNM1L and mitochondrial fission attenuates inflammatory response in fibrobla 2020 Jan Mitochondrial fission and fusion are important for mitochondrial function, and dynamin 1-like protein (DNM1L) is a key regulator of mitochondrial fission. We investigated the effect of mitochondrial fission on mitochondrial function and inflammation in fibroblast-like synoviocytes (FLSs) during rheumatoid arthritis (RA). DNM1L expression was determined in synovial tissues (STs) from RA and non-RA patients. FLSs were isolated from STs and treated with a DNM1L inhibitor (mdivi-1, mitochondrial division inhibitor 1) or transfected with DNM1L-specific siRNA. Mitochondrial morphology, DNM1L expression, cell viability, mitochondrial membrane potential, reactive oxygen species (ROS), apoptosis, inflammatory cytokine expression and autophagy were examined. The impact of mdivi-1 treatment on development and severity of collagen-induced arthritis (CIA) was determined in mice. Up-regulated DNM1L expression was associated with reduced mitochondrial length in STs from patients with RA and increased RA severity. Inhibition of DNM1L in FLSs triggered mitochondrial depolarization, mitochondrial elongation, decreased cell viability, production of ROS, IL-8 and COX-2, and increased apoptosis. DNM1L deficiency inhibited IL-1β-mediated AKT/IKK activation, NF-κBp65 nuclear translocation and LC3B-related autophagy, but enhanced NFKBIA expression. Treatment of CIA mice with mdivi-1 decreased disease severity by modulating inflammatory cytokine and ROS production. Our major results are that up-regulated DNM1L and mitochondrial fission promoted survival, LC3B-related autophagy and ROS production in FLSs, factors that lead to inflammation by regulating AKT/IKK/NFKBIA/NF-κB signalling. Thus, inhibition of DNM1L may be a new strategy for treatment of RA.
31836320 Anti-tumour necrosis factor-α therapy and recurrent or new primary cancers in patients wi 2020 Mar BACKGROUND: Safety of anti-tumour necrosis factor-α (TNFα) therapy in people with a history of cancer and with an immune-mediated disease is unknown. We aimed to assess the risk of recurrence of initial cancer or development of a new primary cancer after treatment with anti-TNFα therapy. METHODS: In this Danish, population-based cohort study we recruited adults (≥18 years) with inflammatory bowel disease (IBD), rheumatoid arthritis, or psoriasis and a primary cancer diagnosed between Jan 1, 1999 and Dec 31, 2016. Patients were recruited from the prospectively recorded Danish National Patient Registry and the Danish Cancer Registry. Participants were matched 1:10 between the treatment group who received anti-TNFα therapy and the control group (no anti-TNFα therapy) and we excluded individuals with a cancer diagnosed before their first anti-TNFα treatment (or before matching date for controls), individuals diagnosed with IBD, rheumatoid arthritis, or psoriasis after anti-TNFα initiation (or respective match date for controls), and individuals who received anti-TNFα with fewer than five matched controls. Using adjusted Cox proportional hazards regression, we estimated the primary outcome of development of recurrent or new primary cancer in patients who received anti-TNFα therapy compared with patients who did not receive this therapy, matched by sex, immune-mediated disease type, cancer type, and time from initial cancer diagnosis to first anti-TNFα registration. FINDINGS: Overall, 25 738 patients with immune-mediated disease and a history of cancer were identified. 434 patients who received anti-TNFα therapy after their initial cancer were matched to 4328 patients in the control group. During 18 752 person-years (median 5·6 years [IQR 2·8-7·9]) of follow up, 635 individuals developed recurrent or new primary cancer, 72 of whom had received anti-TNFα therapy and 563 of whom were in the control group. The median time between anti-TNFα treatment and recurrent or new primary cancer diagnosis was 2·8 years (IQR 1·7-5·4). The incidence of recurrent or new primary cancer development was 30·3 cases (95% CI 24·0-38·2) per 1000 person-years in the anti-TNFα treatment group and 34·4 cases (31·7-37·3) per 1000 person-years in the control group, yielding an adjusted hazard ratio of 0·82 (95% CI 0·61-1·11). INTERPRETATION: Use of anti-TNFα therapy was not associated with recurrent or new primary cancer development in patients with previous cancer. Timing of anti-TNFα therapy after an initial cancer diagnosis did not influence recurrent or new primary cancer development. This observation might guide clinical decision making among providers treating immune-mediated diseases with anti-TNFα medications. FUNDING: None.
30647172 The SPECTRA Collaboration OMERACT Working Group: Construct Validity of Joint Space Outcome 2019 Oct OBJECTIVE: We assessed construct validity of high-resolution peripheral quantitative computed tomography (HR-pQCT) joint space outcomes by comparison with radiographs in patients with rheumatoid arthritis. METHODS: In 43 patients, quantitative, volumetric, HR-pQCT measurements were compared with ordinal Sharp/van der Heijde scoring (SvdH) in the 2nd and 3rd metacarpophalangeal joints. RESULTS: Generalized estimating equations showed that joint space minimum, SD, and asymmetry by HR-pQCT were associated with SvdH scores (p < 0.05). There was a considerable range in HR-pQCT measurements at SvdH equal to 0. CONCLUSION: HR-pQCT demonstrated construct validity outcomes and provides improved 3-D visualization of joint space.
30649524 Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of su 2019 Jun 1 OBJECTIVES: This post hoc analysis of the TOZURA study programme evaluated the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) as monotherapy or with concomitant conventional synthetic DMARDs (csDMARDs) in patients with RA categorized by baseline glucocorticoid (GC) use. METHODS: TOZURA was a multinational, open-label, single-arm, common-framework study programme (11 protocols, 22 countries) in patients with moderate to severe RA in whom csDMARDs or biologic therapies had failed or who were MTX naïve. Patients received once-weekly TCZ-SC 162 mg for ⩾24 weeks as monotherapy or in combination with csDMARDs and/or oral GC use (⩽10 mg/day prednisone or equivalent), which was to be continued unchanged for 24 weeks. Treatment subgroups were defined by baseline GC use and analysed for efficacy and safety. RESULTS: Of 1804 patients who received TCZ-SC, 145 received monotherapy + GC, 208 received monotherapy without GC, 730 received combination therapy + GC and 721 received combination therapy without GC. The median GC dose in both GC subgroups was 5 mg/day. The proportion of patients who achieved clinical remission, defined as DAS in 28 joints using ESR <2.6, increased similarly from baseline to week 24 in all subgroups. Improvements in patient-reported outcomes were similar in all subgroups. Overall adverse event profiles were generally similar between subgroups, with some slight numerical differences between GC and non-GC subgroups. CONCLUSION: The incremental efficacy benefits of TCZ-SC as monotherapy and in combination with csDMARDs were similar between patients with and without previous and continued oral GC treatment, with generally similar safety profiles. TRIAL REGISTRATION: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT01941940, NCT01941095, NCT01951170, NCT01987479, NCT01988012, NCT01995201, NCT02001987, NCT02011334, NCT02031471, NCT02046603, NCT02046616.