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ID PMID Title PublicationDate abstract
31564625 Prolactin and autoimmunity: The hormone as an inflammatory cytokine. 2019 Dec Nowadays, more than 80 autoimmune disorders are recognized, in which an aberrant immune response against different organs and tissues plays a crucial role. Hormonal homeostasis has great influence in achieving competent and healthy immune system function. Prolactin has a bioactive function acting as a hormone and a cytokine. It influences the immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Hyperprolactinemia has been detected in many patients with different autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, multiple sclerosis, autoimmune thyroid disease, systemic sclerosis, among others, and its believed to play a crucial role in disease pathogenesis. A direct correlation between prolactin levels and disease activity was not clear. Genetic factors may have a role in humans as in animal models. Dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, the authors attempt to provide a critical overview on the role of prolactin in the immune system, exploring its contribution to the development of autoimmune diseases.
31457011 Ripoptocide - A Spark for Inflammation. 2019 The clinical success of biologics that inhibit TNF (Tumor Necrosis Factor) in inflammatory bowel diseases (IBD), psoriasis and rheumatoid arthritis (RA) has clearly established a pathogenic role for this cytokine in these inflammatory disorders. TNF binding to its receptors activates NFκB and MAPK signaling, inducing the expression of downstream pro-inflammatory genes. This is thought to be the primary mechanism by which TNF elicits inflammation. TNF is also a well-known trigger of caspase-dependent apoptosis or caspase-independent necroptosis. Whether cell death has any role in TNF-mediated inflammation has been less clear. Emerging data from animal models now suggest that cellular demise caused by TNF may indeed provoke inflammation. The default response of most cells to TNF stimulation is survival, rather than death, due to the presence of two sequential cell death checkpoints. The early checkpoint is transcription-independent involving the non-degradative ubiquitination of RIPK1 to prevent RIPK1 from becoming a death-signaling molecule. The later checkpoint requires the induction of pro-survival genes by NFκB-mediated transcription. When the early checkpoint is disrupted, RIPK1 initiates cell death and we suggest the term ripoptocide to describe this manner of death (encompassing both apoptosis and necroptosis). The sensitivity of a cell to ripoptocide is determined by the balance between regulatory molecules that enforce and those that disassemble the early checkpoint. As there is evidence suggesting that ripoptocide is inflammatory, individuals may develop inflammation due to ripoptocide brought about by genetic, epigenetic or post-translational alteration of these checkpoint regulators. For these individuals, drugs that reinforce the early checkpoint and inhibit ripoptocide could be useful in ameliorating inflammation.
31422864 Long-term outcome of cemented total hip arthroplasty with the Charnley-type femoral stem m 2019 Nov BACKGROUND: Total hip arthroplasty is a successful treatment for hip diseases including osteoarthritis, osteonecrosis of the femoral head, and rheumatoid arthritis. Various designs of cemented femoral stems made of stainless steel and titanium alloy have been used. Among them, Charnley-type femoral stems made of stainless steel have often been reported to have good long-term outcome. However, the long-term outcome of the Charnley-type femoral stem made of Ti alloy is yet to be reported. We conducted a retrospective study to assess the long-term outcome of cemented primary total hip arthroplasty with the Charnley-type femoral stem made of Ti alloy. METHODS: Between October 1988 and February 1997, 341 cemented primary total hip arthroplasties with the Charnley-type femoral stem made of Ti alloy were consecutively performed in our hospital. Among these, 164 patients (211 hips) who underwent this procedure were followed up for more than 12 years, and the surgical hips were analysed clinically and radiologically. The mean follow-up period was 20.6 years. Kaplan-Meier survival analyses were performed to assess femoral component survival. Factors affecting stem revision for aseptic loosening were also investigated using log-rank tests. RESULTS: In the functional assessment, the preoperative Japanese Orthopaedic Association score significantly improved from 47.2 points preoperatively to 79.0 points at the final follow-up. Eventually, 33 femoral stems were revised, of which 12 were revised for aseptic loosening. In the Kaplan-Meier survival analysis, the 20-year survival rates with stem revision for aseptic loosening and radiological stem loosening at the end points were 95.9% and 97.1%, respectively. Original diagnosis (non-osteoarthritis) was the only significant factor for aseptic loosening of the femoral stem. CONCLUSIONS: Cemented primary total hip arthroplasty with the Charnley-type femoral stem made of Ti alloy showed excellent outcomes for more than 20 years.
31369701 Novel functions of inactive rhomboid proteins in immunity and disease. 2019 Oct iRhoms are related to a family of intramembrane serine proteinases called rhomboids but lack proteolytic activity. In mammals, there are two iRhoms, iRhom1 and iRhom2, which have similar domain structures and overlapping specificities as well as distinctive functions. These catalytically inactive rhomboids are essential regulators for the maturation and trafficking of the disintegrin metalloprotease ADAM17 from the endoplasmic reticulum to the cell surface, and are required for the cleavage and release of a variety of membrane-associated proteins, including the IL-6 receptor, l-selectin, TNF, and EGFR ligands. iRhom2-dependent regulation of ADAM17 function has been recently implicated in the development and progression of several autoimmune diseases including rheumatoid arthritis, lupus nephritis, as well as hemophilic arthropathy. In this review, we discuss our current understanding of iRhom biology, their implications in autoimmune pathologies, and their potential as therapeutic targets.
31302100 Circulating cell-free DNA fragment analysis by microchip electrophoresis and its relations 2019 Oct Circulating cell-free DNA (cfDNA) has been directly related to cancer, diabetes, stroke, systemic lupus erythematosus, trauma, rheumatoid arthritis, inflammation, infection, and myocardial infarction (MI). In this study, plasma cfDNA was extracted from the plasma of cardiac disease patients and the cfDNA fragment distribution as well as the relationships between cfDNA concentration and deoxyribonuclease I (DNase I) activity enzyme implicated in double-stranded DNA processing were examined. Results revealed that the cfDNA concentrations in patients with MI and cardiac angina were significantly higher than that in healthy control subjects. Microchip electrophoresis of plasma cfDNA revealed a single fragment (150-200 bp) in some healthy control subjects and three fragments (150-200 bp, 300-400 bp, and 500-600 bp) in all cardiac patient samples. Moreover, a cfDNA ratio of 150-200 bp/500-600 bp was significantly more prevalent in MI patients than in patients with other cardiac diseases (chest pain, cardiac angina, atrial fibrillation and cardiac failure). In addition, a positive correlation between DNase I activity and cfDNA concentration was observed. These results suggest that the plasma cfDNA in cardiac disease patients may originate from apoptosis and that the 150-200 bp/500-600 bp ratio for cfDNA may be a novel diagnostic indicator for MI.
31155366 Anti-inflammatory Therapies for Cardiovascular Disease: Signaling Pathways and Mechanisms. 2019 Sep Cardiovascular diseases (CVD) are the clinical manifestation of atherosclerosis, a chronic inflammatory disease promoted by several risk factors such as dyslipidemia, type 2 diabetes mellitus, hypertension, and smoking. Acute CVD events are the result of an unresolved inflammatory chronic state that promotes the rupture of unstable plaque lesions. Of note, the existing intensive therapies modify risk factors but do not prevent life-threatening recurrent ischemic events in high-risk patients, who have a residual inflammatory risk displayed by increased C-reactive protein (CRP) levels. Better understanding of the role of innate and adaptive immunity in plaque development and rupture has led to intensive investigation of anti-inflammatory strategies for CVD. Some of them are being tested in specific clinical trials and use lower doses of existing medications originally developed for other inflammatory diseases such as rheumatoid arthritis and psoriasis, which have high CVD risk. Other investigations are retrospective and meta-analyses of existing clinical trials that evaluate the incidence of CVD in these inflammatory diseases. Others are based on preclinical testing such as vaccines. In this article, we summarize the main anti-inflammatory strategies and associated molecular mechanisms that are being evaluated in preclinical or clinical CVD studies.
31142199 Online Decision Aids for Knee Osteoarthritis and Low Back Pain: An Environmental Scan and 2019 May Background. Musculoskeletal conditions are leading causes of disability. Management options are plentiful, but the current evidence base suggests many are ineffective or unproven. Online decision aids can help support patients make informed health care choices. However, there are little data on the quality of online decision aids for common musculoskeletal conditions such as knee or low back pain. Purpose. To identify all publicly available online decision aids for knee osteoarthritis and low back pain and evaluate them against the International Patient Decision Aids Standards Inventory (IPDASi). Data Sources. Google Australia. Study selection. Two reviewers independently screened websites for inclusion and assessed the quality of included online decision aids between April and May 2018. Included online decision aids were free, provided information about knee osteoarthritis or low back pain, and written in English. Online decision aids that required payment, targeted health professionals, addressed rheumatoid arthritis, or addressed a screening decision were excluded. Data Extraction. IPDASi Version 4. Data Synthesis. Twenty-five online decision aids were identified: 15 knee osteoarthritis and 10 low back pain. Only 3 online decision aids (12%) provided a "wait-and-see" option. Nineteen (75%) met IPDASi criteria to be considered a decision aid and 3 (12%) met IPDASi criteria to state that the online decision aid was unbiased. Limitations. Dynamic nature of Google searches may not be replicable easily. Conclusions. Few good-quality online decision aids are available for people with knee osteoarthritis or low back pain. Most online decision aids failed to explicitly provide a wait-and-see option, suggesting a bias toward intervention. These online decision aids would benefit from explicitly highlighting a wait-and-see option to support informed choice.
31028959 Agonist-induced activation of the S1P receptor 2 constitutes a novel osteoanabolic therapy 2019 Aug BACKGROUND AND PURPOSE: Osteoporosis is a worldwide epidemic but pharmacological agents to stimulate new bone formation are scarce. We have shown that increasing tissue levels of sphingosine-1-phosphate (S1P) by blocking its degradation by the S1P lyase has pronounced osteoanabolic effect in mouse osteoporosis models by stimulating osteoblast differentiation through the S1P receptor 2 (S1P2). However, S1P lyase inhibitors have side effects complicating potential clinical use. Here, we tested whether direct S1P2 engagement by the S1P2 agonist CYM5520 exerted osteoanabolic potential in estrogen deficiency-induced osteopenia in mice. We compared its efficacy to LX2931, a novel S1P lyase inhibitor currently tested in rheumatoid arthritis. EXPERIMENTAL APPROACH: CYM5520, LX2931 or vehicle were administered to ovariectomized mice for 6 weeks beginning 5 weeks after ovariectomy, Bone mass, cellular composition and mechanical strength were assessed by microCT, histomorphometry and three point bending tests. Plasma markers of bone metabolism were analyzed by ELISA. KEY RESULTS: Therapeutic treatment with CYM5520 and LX2931 clearly increased long bone and vertebral bone mass to impressive 3-5 fold over vehicle in osteopenic ovariectomized mice. As expected, lymphopenia was a side effect of LX2931, whereas none occurred with CYM5520. Consistent with an osteoanabolic effect, CYM5520 increased osteoblast number, osteoid surface and alkaline phosphatase area 2-3 fold over vehicle. Plasma concentrations of the osteoanabolic marker procollagen I C-terminal propeptide were also elevated by CYM5520 and LX2931. LX2931 but not yet CYM5520 increased cortical thickness and mechanical strength without affecting mineral density. CONCLUSION AND IMPLICATIONS: Treatment with a pharmacological S1P2 agonist corrected ovariectomy-induced osteopenia in mice by inducing new bone formation thus constituting a novel osteoanabolic approach to osteoporosis.
31019572 New-onset cutaneous sarcoidosis under tocilizumab treatment for giant cell arteritis: a qu 2019 BACKGROUND: New-onset sarcoidosis has been previously described in three case reports in patients affected by rheumatoid arthritis treated with tocilizumab (TCZ). The existence of a cause-effect mechanism between the biological treatment and the onset of the illness is still being debated. PATIENT CONCERNS: A 74-year-old woman was diagnosed with giant cell arteritis (GCA). The first-line treatment with glucocorticoids; and the second-line with methotrexate and low-dose glucocorticoids were stopped due to multiple pathological vertebral fractures and insufficient biological and clinical response. The cytotoxic agent, cyclophosphamide, was then introduced and in turn stopped, because of gastrointestinal side effects. Thereafter a treatment with TCZ was begun. The patient experienced good clinical response; however, 8 months later she developed painful hyper-pigmented reddish cutaneous micronodular lesions localized to the abdomen and thorax. A cutaneous biopsy was performed, and histological analysis showed noncaseating epithelioid granulomas in the hypodermis. The diagnosis of cutaneous sarcoidosis was made. INTERVENTIONS: Topical corticosteroids were administered and, as requested by the patient, TCZ was discontinued with slow but complete resolution of the skin lesions. After TCZ discontinuation however, the GCA flared and the patient's symptoms and biological abnormalities reappeared. Thus, after a 6-month suspension, TCZ was re-administered. At 2 months later the skin lesions compatible with cutaneous sarcoidosis reappeared. Topical corticosteroids were once again prescribed and as suggested by the patient the TCZ posology was reduced. The patient's symptoms disappeared, and the cutaneous lesions resolved. LESSONS: The time elapsed from TCZ treatment start and the onset of cutaneous sarcoidosis, as well as its recurrence after TCZ suspension and rechallenge supported the diagnosis of a drug-induced reaction. To the best of our knowledge, this case report represents the first instance of cutaneous sarcoidosis most likely induced by TCZ in patients affected by GCA. In addition, our case emphasizes that although TCZ in monotherapy confirms to be an effective treatment for GCA, further immunological disorders could be unmasked, and the discussed side effect of the drug could be dose-dependent.
30841462 MicroRNA expression, targeting, release dynamics and early-warning biomarkers in acute car 2019 Mar Tripterygium wilfordii Hook. F. is a plant used in traditional Chinese medicine to treat rheumatoid arthritis, lupus erythematosus, and psoriasis in China. However, its main active substance, triptolide, has toxic effects on the heart, liver, and kidneys, which limit its clinical application. Therefore, determining the mechanism of cardiotoxicity in triptolide and identifying effective early-warning biomarkers is beneficial for preventing irreversible myocardial injury. We observed changes in microRNAs and aryl hydrocarbon receptor (AhR) as potential biomarkers in triptolide-induced acute cardiotoxicity by using techniques such as polymerase chain reaction (PCR) assay. The results revealed that triptolide increased the heart/body ratio and caused myocardial fiber breakage, cardiomyocyte hypertrophy, increased cell gaps, and nuclear dissolution in treated male rats. Real-time PCR array detection revealed a more than 2-fold increase in the expression of 108 microRNA genes in the hearts of the male rats; this not only regulated the signaling pathways of ErbB, FOXO, AMPK, Hippo, HIF-1α, mTOR, and PI3K-Akt but also participated in biological processes such as cell adhesion, cell cycling, action potential, locomotory behavior, apoptosis, and DNA binding. Moreover, triptolide reduced the circulatory and cardiac levels of AhR protein as a target of these microRNAs and the messenger RNA expression of its downstream gene CYP1 A1. However, decreases in myocardial lactate dehydrogenase, creatine kinase MB, catalase, and glutathione peroxidase activity and an increase in circulating cardiac troponin I were observed only in male rats. Moreover, plasma microRNAs exhibited dynamic change. These results revealed that circulating microRNAs and AhR protein are potentially early-warning biomarkers for triptolide-induced cardiotoxicity.
30769901 IL33/ST2 Axis in Diabetic Kidney Disease: A Literature Review. 2019 Feb 14 Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family, playing a role in inflammatory, infectious and autoimmune diseases and expressed in the cellular nucleus in several tissues. High levels of IL-33 are expressed in epithelial barrier tissues and endothelial barriers. ST2 is a receptor for IL-33, expressed selectively on a subset of Th2 cells, mediating some of their functions. The IL-33/ST2 axis plays an important role in several acute and chronic inflammatory diseases, including asthma and rheumatoid arthritis. Different disorders are related to the activity of IL-33, ST2, or their axis, including cardiovascular disease or renal disturbances. Therefore, in the present work, a literature review was conducted, covering the period from 1 January 2000 to 30 November 2018, in PubMed, ScienceDirect, and Google Scholar database, to assess the involvement of the IL-33/ST2 axis in diabetic kidney disease. 6 articles directly dealing with the argument were identified, highlighting a clear link between IL-33/ST2 axis and diabetic kidney disease or related nephropathy. Overall, the involvement of ST2 seems to be more predictive than IL-33, especially in investigating the deterioration of kidney function; however, both compounds are pivotal in the field of renal diseases. Future studies are required to confirm the scientific evidences on larger and more heterogeneous cohorts.
30603602 Interstitial Lung Disease in patients with Polymyalgia Rheumatica: A case series. 2019 INTRODUCTION: Severe morning stiffness with painful involvement of the girdles are often referred by patients with Interstitial Lung Disease (ILD), but the association between ILD and Polymyalgia Rheumatica (PMR) is rarely reported. The purpose of the work is to describe a series of patients classified as having PMR with ILD. MATERIAL AND METHODS: We retrospectively enrolled patients with a diagnosis of PMR referred to our center during the previous year for respiratory symptoms. Data concerning clinical and serological manifestations suggesting Connective Tissue Disease (CTD), High-Resolution Chest Tomography (HRCT), and Pulmonary Function Tests (PFTs) were systematically collected in order to verify the diagnosis. RESULTS: Fifteen out of seventeen PMR patients had ILD. Ten patients had a confirmed diagnosis of PMR, while in five patients a CTD was discovered. Seven patients showed a severe restrictive pattern at PFTs requiring oxygen supplementation (five with PMR and two with CTD). In thirteen patients pulmonary symptoms started before or together with muscular symptoms. Regarding HRCT patterns, patients showed a Nonspecific Interstitial Pneumonia in nine cases, Usual Interstitial Pneumonia (UIP) and possible UIP in two and three cases, and a single case of Organizing Pneumonia and Combined Pulmonary Fibrosis and Emphysema Syndrome. CONCLUSIONS: Lung involvement should be evaluated in PMR patients, especially if asthenia is poorly responsive to low doses of steroids. In these cases, the diagnosis should be re-evaluated in depth, looking for a seronegative Rheumatoid Arthritis, a clinically amyopathic myositis or Interstitial Pneumonia with Autoimmune features.
32476936 Diffuse alveolar hemorrhage: how relevant is etiology? 2019 BACKGROUND: Diffuse Alveolar Hemorrhage (DAH) is a rare and potentially life-threatening clinical syndrome whose early recognition is essential. OBJECTIVES: Characterization of patients with DAH and comparison of presentation and evolution of the disease according to etiology. METHODS: We retrospectively reviewed the clinical records of patients admitted to our hospital over a 7-year period with DAH. Criteria for DAH (1+2): 1 - hemoptysis and/or pulmonary infiltrates and/or anemia (DAH triad); 2 - hemorrhagic bronchoalveolar lavage (BAL) or siderophagic alveolitis. DAH was grouped in immune and nonimmune and the course of disease was compared. RESULTS: We included 24 patients admitted with DAH, of which 11 had an immune cause: p-ANCA vasculitis (n=7), Systemic Lupus Erythematosus (n=2), c-ANCA vasculitis (n=1), Rheumatoid Arthritis (n=1) and 13 had a nonimmune cause: heart disease (n=6), amiodarone toxicity (n=2), clotting disorder (n=2), cannabis toxicity (n=1), S. aureus infection (n=1) and idiopathic (n=1). Patients with nonimmune DAH were significantly older than those with immune DAH (67.9±18.1 vs 56.6±18.8 years, p=0.042). DAH triad was observed in 54% of all patients, hemoptysis in 67%, anemia in 79%, and pulmonary infiltrates in all cases. Patients with immune DAH had more frequently pulmonary-renal syndrome (p<0.001), kidney failure (p=0.048), shock (p=0.049) and needed more frequently admition in ICU (p=0.039) and blood transfusion (p=0.043). Hospital length of stay was superior in immune group (29.5±20.0 vs 19.5±14.3 days, p=0.047). In-hospital mortality was exclusive to immune DAH (12.5%). CONCLUSIONS: Patients with DAH due to immune causes were significantly younger, had more severe presentations of the disease and worst outcomes.
30522105 Taxifolin Inhibits Receptor Activator of NF-κB Ligand-Induced Osteoclastogenesis of Human 2019 It has been reported that taxifolin inhibit osteoclastogenesis in RAW264.7 cells. In our research, the inhibition effects of taxifolin on the osteoclastogenesis of human bone marrow-derived macrophages (BMMs) induced by receptor activator of NF-κB ligand (RANKL) as well as the protection effects in lipopolysaccharide-induced bone lysis mouse model have been demonstrated. In vitro, taxifolin inhibited RANKL-induced osteoclast differentiation of human BMMs without cytotoxicity. Moreover, taxifolin significantly suppressed RANKL-induced gene expression, including tartrate-resistant acid phosphatase, matrix metalloproteinase-9 nuclear factor of activated T cells 1 and cathepsin K, and F-actin ring formation. Further studies showed that taxifolin inhibit osteoclastogenesis via the suppression of the NF-κB signaling pathway. In vivo, taxifolin prevented bone loss in mouse calvarial osteolysis model. In conclusion, the results suggested that taxifolin has a therapeutic potential for osteoclastogenesis-related diseases such as osteoporosis, osteolysis, and rheumatoid arthritis.
30506106 DUSP6 Inhibitor (E/Z)-BCI Hydrochloride Attenuates Lipopolysaccharide-Induced Inflammatory 2019 Apr Macrophages play a fundamental role in human chronic diseases such as rheumatoid arthritis, atherosclerosis, and cancer. In the present study, we demonstrated that dual-specificity phosphatase 6 (DUSP6) was upregulated by lipopolysaccharide (LPS) treatment of macrophages. (E/Z)-BCI hydrochloride (BCI) functions as a small molecule inhibitor of DUSP6, and BCI treatment inhibited DUSP6 expression in LPS-activated macrophages. BCI treatment inhibited LPS-triggered inflammatory cytokine production, including IL-1β and IL-6, but not TNF-α, and also affected macrophage polarization to an M1 phenotype. In addition, BCI treatment decreased reactive oxygen species (ROS) production and significantly elevated the levels of Nrf2. Interestingly, pharmacological inhibition of DUSP6 attenuated LPS-induced inflammatory responses was independent of extracellular signal-regulated kinase (ERK) signaling. Furthermore, BCI treatment inhibited phosphorylation of P65 and nuclear P65 expression in LPS-activated macrophages. These results demonstrated that pharmacological inhibition of DUSP6 attenuated LPS-induced inflammatory mediators and ROS production in macrophage cells via activating the Nrf2 signaling axis and inhibiting the NF-κB pathway. These anti-inflammatory effects indicated that BCI may be considered as a therapeutic agent for blocking inflammatory disorders.
30378146 Daidzin inhibits RANKL-induced osteoclastogenesis in vitro and prevents LPS-induced bone l 2019 Apr Osteoclasts are multinuclear giant cells responsible for bone resorption in bone loss diseases, including rheumatoid arthritis, periodontitis, and the aseptic loosening of orthopedic implants. Because of injurious side effects with currently available drugs, it is necessary to continue research novel bone-protective therapies. Daidzin, a naturally occurring isoflavone found in leguminous plants, has numerous beneficial pharmacologic effects, including anti-cancer, anti-cholesterol, and anti-angiocardiopathy, promoting osteoblasts differentiation, and even anti-osteoporosis. However, the effect of daidzin on the regulation of osteoclast activity has not yet been investigated. In this study, our study showed that daidzin significantly inhibited receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclast differentiation of bone marrow macrophages and the hydroxyapatite-resorbing activity of mature osteoclasts by inhibiting RANKL-induced NF-kB signaling pathway. In addition, daidzin could inhibit the expression of osteoclast marker genes, including nuclear factor of activated T cells cytoplasmic 1 (NFATc1), cellular oncogene fos (c-Fos), tartrate-resistant acid phosphatase (TRAP), and cathepsin K (CTSK). Consistent with in vitro results, daidzin inhibited lipopolysaccharide-induced bone loss by suppressing the osteoclast differentiation. Together our data demonstrated that daidzin inhibits RANKL-induced osteoclastogenesis through suppressing NF-ĸB signaling pathway and that daidzin is a promising agent in the treatment of osteolytic diseases.
30303512 A three-dimensional model to study human synovial pathology. 2019 Therapeutic agents that are used by patients with rheumatic and musculoskeletal diseases were originally developed and tested in animal models, and although retrospective studies show a limited predictive value, it could be explained by the fact that there are no good in vitro alternatives. In this study, we developed a 3-dimensional synovial membrane model made of either human primary synovial cell suspensions or a mix of primary fibroblast-like synoviocytes and CD14+ mononuclear cells. We analyzed the composition of the mature micromasses by immunohistochemical staining and flow cytometry and show that the outer surface forms a lining layer consisting out of fibroblast-like and macrophage-like cells, reflecting the in vivo naïve synovial membrane. To recreate the affected synovial membrane in rheumatoid arthritis (RA), the micromasses were exposed to the pro-inflammatory cytokine Tumor Necrosis Factor Alpha (TNF-α). This led to increased pro-inflammatory cytokine expression and production and to hyperplasia of the membrane. To recreate the synovial membrane in osteoarthritis (OA), the micromasses were exposed to Transforming Growth Factor Beta (TGF-β). This led to fibrosis-like changes of the membrane, including increased Alpha Smooth Muscle Actin and increased expression of fibrosis-related genes PLOD2 and COL1A1. Interestingly, the macrophages in the micromass showed phenotypic plasticity as prolonged TNF-α or TGF-β stimulation strongly reduced the occurrence of Cluster of Differentiation 163-positive M2-like macrophages. We showed the plasticity of the micromasses as a synovial model for studying RA and OA pathology and propose that the synovial lining micromass system can be a good alternative for testing drugs.
30120052 Eurycoma longifolia, a promising suppressor of RANKL-induced differentiation and activatio 2019 Apr BACKGROUND: Eurycoma longifolia (E. longifolia) has gained remarkable recognition due to its promising efficacy of stimulating bone formation in androgen-deficient osteoporosis. Numerous in vivo studies have explored the effects of E. longifolia on osteoporosis; however, the in vitro cellular mechanism was not discovered yet. OBJECTIVES: The present study was aimed to investigate the effect of E. longifolia on the proliferation, differentiation and maturation of osteoclasts and the translational mechanism of inhibition of osteoclastogenesis using RAW 264.7 cells as an in vitro osteoclastic model. MATERIALS AND METHODS: Having assessed cytotoxicity, the cell viability, cell proliferation rate and osteoclastic differentiation capacity of E. longifolia was investigated by evaluating the tartrate-resistant acid phosphatase (TRAP) activity in receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclasts. Taken together, the time-mannered expression of osteoclast-related protein biomarkers such as matrix metallopeptidase-9 (MMP-9), cathepsin-K, TRAP, nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), superoxide (free radicals) generation and superoxide dismutase activity were also measured to comprehend the mechanism of osteoclastogenesis. RESULTS: E. longifolia did not show significant effects on cytotoxicity and cell proliferation of RAW 264.7 cells; however, a significant inhibition of cells differentiation and maturation of osteoclasts was observed. Moreover, a significant down-regulation of RANKL-induced TRAP activity and expression of MMP-9, cathepsin-K, TRAP, NFATc1 and generation of superoxide and enhanced superoxide dismutase activity was observed in E. longifolia treated cell cultures. CONCLUSION: We anticipated that E. longifolia that enhances bone regeneration on the one hand and suppresses osteoclast's maturation on the other hand may have great therapeutic value in treating osteoporosis and other bone-erosive diseases such as rheumatoid arthritis and metastasis associated with bone loss.
30975163 Clinical features and characteristics of uveitis associated with juvenile idiopathic arthr 2019 Apr 11 BACKGROUND: Although there are many reports on Juvenile Idiopathic arthritis-associated uveitis (JIA-U) from various countries, especially from Europe and North America, there are few reports from Asia. Our aim was to investigate the epidemiology, characteristics and predictors of JIA-U in Japan. METHODS: Data were retrospectively collected on 726 patients with JIA from medical records as of April 2016 at 15 medical centers specialized in pediatric rheumatic diseases. Of these, patients with uveitis were further investigated for the specific characteristics of this manifestation. RESULTS: The prevalence of uveitis was 6.1% in the 726 JIA patients examined. Incidence of uveitis was significantly higher in patients with an earlier arthritis onset (2.6-vs.-5.8 years, P < 0.0001), oligoarthritis (16.1%-vs.-1.6%, P < 0.001), or anti-nuclear antibodies. On the contrary, it was significantly less common in patients with rheumatoid factor or anti-cyclic citrullinated peptide antibodies. A history of using methotrexate (MTX), infliximab or adalimumab was also associated with uveitis occurrence. The median age at uveitis diagnosis was 5 years, and the median time from arthritis onset to uveitis diagnosis was 2 years. The occurrence of anterior and bilateral uveitis was 79.3 and 53.7%, respectively. There were no symptoms at uveitis diagnosis in 58.5% of cases. Complications arising between the time of uveitis diagnosis and the last observation increased from 31.7 to 56.1%; in particular, cataract was increased 3-fold. While no patients lost their vision, 61.9% did not recover normal vision (≥ 1.0), and in many cases active uveitis persisted, especially in males. In addition to steroid eye drops (97.6%) and MTX (15.4%), biological agents were used for treating the uveitis in 41.5% of patients. CONCLUSIONS: The epidemiology, characteristics and predictors of JIA-U in Japan are described here for the first time. Although the prevalence of JIA-U in Japan is lower than in predominantly Caucasian cohorts, as reported from North America and Europe, the epidemiology, characteristics and predictors were found to be similar.
30915082 Diagnostic Utility of Separate Anti-Ro60 and Anti-Ro52/TRIM21 Antibody Detection in Autoim 2019 Anti-SS-A antibodies are often sought for in autoimmune diseases diagnosis. Two different target proteins have actually been identified: Ro52 and Ro60. Clinical and immunological associations seem different depending on anti-Ro52 or anti-Ro60 antibodies presence. However, due to a heterogeneous presentation in the literature, some immunology laboratories in France have stopped providing anti-Ro52 antibody findings. We report here a new hospital study designed to determine the diagnostic utility of the separate detection of anti-Ro52 and anti-Ro60 antibodies. We conducted a retrospective, observational study, including every adult patient with positive antinuclear antibodies (ANA) tested in our immunology laboratory, and associated with anti-Ro52 and/or anti-Ro60 antibodies, between 2011 and 2014. Out of 13032 sera tested for ANA, 399 adults had antibodies to Ro52 and/or Ro60; 81.7% were female, with a mean age of 54.5 ± 17.0 years. Anti-Ro52 antibodies were found in 75.7% of the patients and anti-Ro60 antibodies in 56.9%. Among them, 43.1% were classified in the Ro52 + Ro60- group, 32.6% in the Ro52 + Ro60 + group and 24.3% in the Ro52-Ro60+ group. In the Ro52-Ro60+ group, systemic lupus was the most frequent diagnosis (48.5%), with a possible association with antiphospholipid antibodies (anti-cardiolipin antibodies: OR 2.5 (CI95 [1.0-5.0], p = 0.05) and lupus anticoagulant {OR 3.6 (CI95 [1.10-10.0] p = 0.02)}. In the Ro52+Ro60+, primary Sjögren Syndrome was the most likely (OR 4.2 95% CI [2.1-8.3] p < 10(-4)), especially in patients Ro52+Ro60+La+. Patients with isolated anti-Ro52 had a wider variety of diseases associated, but among auto-immune diseases they were more prone to inflammatory myositis (OR 10.5 [1.4-81.7], p = 0.02) and inflammatory rheumatism (OR 4.6 [1.6-13.8], p = 0.006) in contrast to systemic lupus (OR 0.2 [0.1-0.3], p < 10(-4)) or primary Sjögren's syndrome (OR 0.1 [0.06-0.2], p < 10(-4)). We therefore suggest that, when anti-ENA antibodies are prescribed, it should include separate anti-Ro52 and anti-Ro60 antibodies determination. To go even further, we would like to suggest a change in ENA nomenclature to avoid confusion, abandoning the anti-SS-A label in favor of the anti-Ro52/TRIM21 or anti-Ro60 antibody for a clearer designation.