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ID PMID Title PublicationDate abstract
31028068 Investigation of the Potential Use of Sialic Acid as a Biomarker for Rheumatoid Arthritis. 2019 Mar BACKGROUND: Sialic acids are a diverse family of sugar units attached to the outermost ends of sugar chains, which were demonstrated to be related to many diseases. We hypothesized sialic acids could be used as biomarkers for diagnosis of rheumatoid arthritis (RA). METHODS: The serum level of the main sialic acids, N-acetyl-D-neuraminic acid (Neu5Ac) in 163 RA patients and 50 healthy individuals were detected by pre-column derivatization-high performance liquid chromatography method. And three biomarkers to diagnose RA in clinic, C-reactive protein (CRP), rheumatoid factor (RF), and cyclic citrullinated peptides (CCP) in serum of these subjects were analyzed using enzyme-linked immunosorbent assay (ELISA). The data was analyzed using the receiver operating characteristic (ROC) curve and the Youden index. RESULTS: We found the concentration of Neu5Ac in RA group was significantly higher than healthy group. There was a positive correlation between the concentration of Neu5Ac and the RA disease activity score (DAS). The sensitivity and specificity of Neu5Ac were significantly greater than CRP, RF, CCP. CONCLUSIONS: Higher serum levels of Neu5Ac were significantly associated with the presence as well as severity of RA. Neu5Ac may be a potential biomarker for prediction and severity of RA in clinical practice.
31573472 Is cholecalciferol a potential disease-modifying anti-rheumatic drug for the management of 2020 Mar Vitamin D is a pleiotropic molecule with a well-characterised immunomodulatory activity in vitro; however, its potential clinical application in autoimmune conditions has yet to be clarified. Several authors have investigated the use of vitamin D as a disease-modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis (RA), obtaining divergent conclusions. This systematic review summarises and critically analyses the findings of papers assessing the impact of vitamin D supplementation on pain relief, disease activity, functional status and flare rate. We conclude that the correction of hypovitaminosis D may have a beneficial effect on pain perception; moreover, the achievement of an adequate plasma vitamin D concentration obtained with high-dose regimens might evoke immunomodulatory activities of vitamin D and favourably impact on disease control. Nevertheless, the current evidence is still not strong enough to support the use of cholecalciferol as a DMARD in RA, and further studies are required to clarify this issue.
30426384 Reciprocal regulation of pro-inflammatory Annexin A2 and anti-inflammatory Annexin A1 in t 2019 Feb Annexin A2 has been implicated in several immune modulated diseases including Rheumatoid arthritis (RA) pannus formation. The most relied treatment option for RA pathogenesis is glucocorticoids. Glucocorticoids regulate the synthesis, phosphorylation and cellular deposition of Annexin A1. This annexin mediates the anti-inflammatory actions of glucocorticoids. These two first characterized members of annexin superfamily proteins acts reciprocally, one as an anti-inflammatory and the other proinflammatory in nature. The possibility of these molecules as soluble biomarkers and as an upstream regulator of major cytokine devastation at RA microenvironment has not been previously explored. Current study elucidates the reciprocal regulation of these two annexins in RA pathogenesis. These Annexin A2/A1 and downstream cytokines in RA serum were analysed by ELISA. Western blot, Immunocytochemistry, immunoprecipitation and Immunohistochemistry were adapted to analyse these molecules in tissue and synovial fibroblasts and also in different experimental conditions. Significant increase in the level of Annexin A2 was noticed in naïve RA patients compared to controls (14.582 ± 1.766 ng/ml vs. 7.37 ± 1.450 ng/ml; p ≤ 0.001). In remission cases significant low levels was detected. On the contrary, significant decrease in the level of Annexin A1 was noticed in naïve RA patients compared to healthy controls (12.322 ± 2.91 vs. 16.998 ± 4.298 ng/ml; p ≤ 0.001), wherein remission cases serum Annexin A1 was significantly high. The knockdown of proinflammatory Annexin A2 by siRNA/antibody treatment could mimic the glucocorticoid treatment as which induced cellular Annexin A1 and membrane translocation resulting in the terminal action. Current data elucidating the regulatory interplay between Annexin A2 and Annexin A1 in RA pathogenesis.
31249277 Validation of Rheumatoid Arthritis Quality of Life (RAQoL) Questionnaire into Portuguese L 2019 Jan BACKGROUND: Rheumatoid Arthritis (RA) is a chronic inflammatory disease with high impact on patients´ quality of life (QoL). The Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL) is a self-completed questionnaire designed to assess QoL in patients with RA. A Portuguese adaptation of the RAQoL was available but required formal validation. AIM: To validate the RAQoL into the Portuguese language. METHODS: Patients with diagnosis of RA were included. The Portuguese RAQoL was administered on two occasions, 14 days apart. Participants also completed the Nottingham Health Profile (NHP) and Health Assessment Questionnaire (HAQ) at Time 1. Internal consistency was assessed using Cronbach's alpha and reliability through Spearman's Correlation Coefficient. Construct validity was evaluated through Spearman's correlation analyses between RAQoL, NHP and HAQ. Known-group validity was tested comparing the RAQoL across different groups, considering self-perceived general health status, flare symptoms and RA severity through non-parametric tests. RESULTS: 178 RA patients (mean age 56.6, 82% female, mean disease duration 13.6 years) were included. The mean score of RAQoL was 11, with low rates of missing data (3.9%), floor (4.5%) and ceiling (2.2%) effects. Cronbach's α was 0.95 and test-retest reliability 0.92. RAQoL scores correlated moderately with scores on the NHP Physical Mobility (r=0.77), Emotional reactions (r=0.69), Pain (r=0.68) and Energy (r=0.65) section scores. RAQoL showed to be discriminative for groups according to self-perceived general health status, flare of arthritis and disease severity. CONCLUSION: The Portuguese version of the RAQoL is a valid, feasible and reliable questionnaire, suitable for use in clinical practice and research purposes.
30608608 The effect of rheumatoid arthritis on patient-reported outcomes following knee and hip rep 2019 Jun 1 OBJECTIVES: To compare outcomes of total knee replacement (TKR) and total hip replacement (THR) for individuals with RA and OA. METHODS: We performed a cohort study using routinely collected data. Oxford Knee Score, Oxford Hip Score, and EuroQol 5-dimension 3-level (EQ-5D-3L) questionnaires were collected before and 6 months after surgery. Multivariable regressions were used to estimate the association between diagnosis and post-operative scores after controlling for pre-operative scores and patient characteristics. RESULTS: Study cohorts included 2070 OA and 142 RA patients for TKR and 2030 OA and 98 RA patients for THR. Following TKR, the median Oxford Knee Score was 37 [interquartile range (IQR) 29-43] for OA and 36 (27-42) for RA while the median EQ-5D-3L was 0.76 (0.69-1.00) and 0.69 (0.52-0.85), respectively. After THR, the Oxford Hip Score was 42 (IQR 36-46) for OA and 39 (30-44) for RA while the EQ-5D-3L was 0.85 (0.69-1.00) and 0.69 (0.52-1.00), respectively. The estimated effect of RA, relative to OA, on post-operative scores was -0.05 (95% CI -1.57, 1.48) for the Oxford Knee Score, -0.09 (-0.13, -0.06) for the EQ-5D-3L following TKR, -1.35 (-2.93, -0.22) for the Oxford Hip Score, and -0.08 (-0.12, -0.03) for the EQ-5D-3L following THR. CONCLUSION: TKR and THR led to substantial improvements in joint-specific scores and overall quality of life. While diagnosis had no clinically meaningful effect on joint-specific outcomes, improvements in general quality of life were somewhat less for those with RA, which is likely due to the systemic and multijoint nature of rheumatoid disease.
30620285 Pain catastrophising worsens RAPID3 in all rheumatologic conditions. 2019 Jul OBJECTIVES: To assess RAPID3 in various rheumatologic conditions, and the impact of pain catastrophising on RAPID3. METHODS: A set of questionnaires, including RAPID3 (0-30) and pain catastrophising score (0-52), was given to all outpatients seen in a one-month period: 518 patients fulfilled the questionnaires, including 127 RA (42% taking biologics), and 135 SpA (58% taking biologics). RESULTS: Mean pain catastrophising was 18.5±12.5, and 19% of patients could be classified as catastrophisers (>30). Higher RAPID3 scores were observed in the 33 osteoarthritis of lower limbs (16.44±5.20), 10 fibromyalgia (15.52±5.53), 47 back-pain (14.88±5.17), 17 osteoarthritis of upper limbs (13.61±7.42), and 38 tendinopathies (12.85±4.38). Lower RAPID3 were observed in the 135 SpA (12.79±6.03), 127 RA (12.18±6.30), 27 miscellaneous disorders (9.83±6.28), 7 entrapment neuropathies (9.81±4.51), 19 systemic connective tissue disorders (8.26±7.04) and 58 osteoporosis (7.85±6.95). Much higher RAPID3 scores were observed in the 19% with high pain catastrophising scores, whatever the conditions, and lower scores in the 15% with disablement benefits. RAPID3 was not associated with age or disease duration, but strongly correlated with daily fatigue, poor sleep, and length of daily pain. CONCLUSIONS: Thanks to progress made in RA and SpA treatment, higher RAPID3 scores were mostly observed in other rheumatic conditions, but co-morbidities and pain catastrophising might contribute to floor effects when assessing rheumatic disorders with RAPID3, hindering the recognition of low disease activity in some RA of SpA patients.
30299248 Serum calprotectin as a marker of ultrasound-detected synovitis in early psoriatic and rhe 2019 May OBJECTIVES: We aimed to evaluate the correlation between serum calprotectin and clinical and ultrasonographic (US) variables in early-onset psoriatic arthritis (PsA) and controls with rheumatoid arthritis (RA). METHODS: In a retrospective cross-sectional study, including PsA and matched RA patients, 44 joint counts (TJC, SJC), calprotectin, ESR and CRP were measured. US of wrists and MCPs 1-5 was performed, with grey-scale (GS) and power Doppler (PD) scored 0-3 at each site, summed in a total score. The correlation between calprotectin, clinical and US variables was evaluated by Spearman's coefficient, the predictivity by calprotectin of US by regression. Secondary analyses separating polyarticular PsA and using different US definitions (GS>1, PD>1) were performed. RESULTS: 78 PsA and 78 RA were included (PsA male 32%; mean age 51.7 (13.5)). Calprotectin did not significantly differ in PsA and RA. In PsA, calprotectin correlated with GS score (ρ=0.340, p=0.008), PD score (ρ=0.292, p=0.023) and the presence of PD (ρ=0.263, p=0.042); in RA there were no significant correlations. In polyarticular PsA, a significant correlation between calprotectin and GS (ρ=0.369, p=0.019) and PD scores (ρ=0.363, p=0.021) was confirmed. In both PsA and RA, calprotectin and CRP significantly correlated, while SJC and TJC did not. In the regression analysis, calprotectin did not predict US variables in PsA. Similar results were achieved in RA. CONCLUSIONS: In early PsA, serum calprotectin correlates with US measures of disease activity. Our results provide preliminary evidence for the application of this biomarker in early PsA.
31729440 Structural insights into heme binding to IL-36α proinflammatory cytokine. 2019 Nov 15 Cytokines of the interleukin (IL)-1 family regulate immune and inflammatory responses. The recently discovered IL-36 family members are involved in psoriasis, rheumatoid arthritis, and pulmonary diseases. Here, we show that IL-36α interacts with heme thereby contributing to its regulation. Based on in-depth spectroscopic analyses, we describe two heme-binding sites in IL-36α that associate with heme in a pentacoordinated fashion. Solution NMR analysis reveals structural features of IL-36α and its complex with heme. Structural investigation of a truncated IL-36α supports the notion that the N-terminus is necessary for association with its cognate receptor. Consistent with our structural studies, IL-36-mediated signal transduction was negatively regulated by heme in synovial fibroblast-like synoviocytes from rheumatoid arthritis patients. Taken together, our results provide a structural framework for heme-binding proteins and add IL-1 cytokines to the group of potentially heme-regulated proteins.
31025930 Early and late responses in patients with rheumatoid arthritis who were conventional synth 2019 Nov OBJECTIVES: To evaluate early and late responses in biological-naïve patients with rheumatoid arthritis (RA) initiating tocilizumab and early tocilizumab non-responders who switched to rituximab. METHODS: In this open-label, non-randomised phase 3 study, RA patients with inadequate response to conventional synthetic DMARDs received tocilizumab 8 mg/kg intravenously at study begin and weeks 4, 8 and 12. After evaluation at week 16, early responders (Disease Activity Score based on 28 joints-erythrocyte sedimentation rate [DAS28-ESR] <2.6) completed the study; partial responders (DAS28-ESR decrease >1.2 or DAS28-ESR ≥2.6-≤3.2) were to continue tocilizumab through week 28; non-responders (DAS28-ESR decrease ≤1.2) switched to rituximab (1000 mg, weeks 16 and 18) with safety follow-up through week 66. RESULTS: Of 519 patients, 222 (42.8%) achieved early DAS28-ESR remission at week 16; 240 patients continued treatment, 213 (41.0%) received tocilizumab, and 27 (5.2%) switched to rituximab. At week 32 DAS28-ESR remission was achieved by 117/213 patients (54.9%) who continued tocilizumab and 4/27 patients (14.8%) who switched to rituximab; good EULAR response was achieved by 66.7% and 25.9% and CDAI remission by 19.2% and 14.8% of patients, respectively. Serious adverse events occurred through week 32 in 45/490 patients (9.2%) who received tocilizumab (serious infections, 2.7%) and through week 66 in 8/27 patients (29.6%) who switched to rituximab. CONCLUSIONS: Early response to tocilizumab was observed in 42.8% of patients. Half of early partial responders benefitted from continuing tocilizumab. Switching non-responders to rituximab seems feasible. No new safety signals were observed in patients treated with tocilizumab or switched to rituximab.
30620725 Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimm 2019 Mar 1 Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors, and loss of PTPN2 promotes T cell expansion and CD4- and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Tregs) plays a role in autoimmunity. Here we aimed to model human autoimmune-predisposing PTPN2 variants, the presence of which results in a partial loss of PTPN2 expression, in mouse models of RA. We identified that reduced expression of Ptpn2 enhanced the severity of autoimmune arthritis in the T cell-dependent SKG mouse model and demonstrated that this phenotype was mediated through a Treg-intrinsic mechanism. Mechanistically, we found that through dephosphorylation of STAT3, PTPN2 inhibits IL-6-driven pathogenic loss of FoxP3 after Tregs have acquired RORγt expression, at a stage when chromatin accessibility for STAT3-targeted IL-17-associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in mouse RORγt+ Tregs and that loss of function of PTPN2 in Tregs contributes to the association between PTPN2 and autoimmunity.
30639474 Calreticulin induced endothelial ICAM-1 up-regulation associated with tristetraprolin expr 2019 Mar The present study was undertaken to determine whether extracellular calreticulin (CRT) participates in the regulation of ICAM-1in rheumatoid arthritis (RA) and further explore the potential mechanism. Our results showed that ICAM-1 and VCAM-1 levels were positively correlated with CRT levels in RA serum and synovial fluid, respectively. In RA synovial tissue, increased co-expressions of CRT and ICAM-1 in vascular endothelium and perivascular areas and elevated co-location of CRT and VCAM-1 localized predominantly to lining layer were observed compared to those in OA. In in vitro HUVECs model, enhanced ICAM-1expression and increased phosphorylation levels of Akt and eNOS were detected in the presence of CRT. Increased phosphorylated eNOS was significantly inhibited by a PI3K inhibitor LY294002 and elevated ICAM-1expression was partially blocked by the inhibitors of both PI3K and eNOS (L-NAME). It has been certified that the RNA-binding protein TTP targets AU-rich elements in the ICAM-1 3'-UTR and suppresses ICAM-1 expression. Knocking down TTP in HUVECs led to an increased induction of ICAM-1 by CRT. We have currently known that activation of p38 downstream kinase MK-2 leads to phosphorylation and inactivation of human TTP. The block of p38 MAPK/MK-2 signaling led to decreased protein expression and mRNA stability of TTP and ICAM-1. Furthermore, L-NAME and/or LY294002 pre-treated HUVECs manifested decreased p38 and MK-2 phosphorylation, which was accompanied by reduced TTP and ICAM-1 protein expression as well as decreased mRNA stability. Our results suggested that CRT could promote ICAM-1 expression in endothelial cells through PI3K/Akt/eNOS/p38 MAPK signaling mediated TTP accumulation, probably in an inactive form, which may provide a possible proinflammatory mechanism of CRT in RA.
31694744 Soluble IL-6R promotes chondrogenic differentiation of mesenchymal stem cells to enhance t 2020 Jul OBJECTIVES: Although articular cartilage contributes to smooth joint motion, once damaged this functionality cannot be recovered. Activation of the IL-6/STAT3 signalling pathway contributes to chondrogenic differentiation of mesenchymal stem cells (MSCs), indicating a role for soluble IL-6R (sIL-6R) during chondrogenesis in vitro. The aim of this study is to develop a novel therapeutic tool for regenerative medicine of articular cartilage. METHODS: Human bone marrow-derived MSCs were pre-treated with sIL-6R to direct their differentiation into chondrocytes, then seeded on a poly-lactic-co-glycolic acid (PLGA) sheet to enhance the localised residence of MSCs. The material was implanted into knee joint spaces of antigen-induced arthritis (AIA) rats, an animal model of rheumatoid arthritis (RA). After 8 weeks, the effects of the implantation on articular cartilage repair were assessed by x-ray image and staining with safranin O (S-O), aggrecan and human leukocyte antigen (HLA). RESULTS: Swelling of knees in AIA rats, but not sham-treated rats, was observed. AIA rats implanted with PLGA and sIL-6R-treated MSCs showed similar knee joint imaging to sham rats using x-ray; however, those with PLGA alone, or with PLGA with MSCs, did not. Rats implanted with PLGA and sIL-6R-treated MSCs, but not PLGA alone or PLGA with MSCs, showed positive imaging by S-O staining as well as human aggrecan. HLA was not detected in the knees of any of the rats. CONCLUSIONS: PLGA and sIL-6R-treated MSCs help to repair articular cartilage with high efficacy. Thus, the application of this promising strategy to regenerative medicine for articular cartilage in patients with RA is anticipated.
30171335 Rheumatoid arthritis in remission : Decreased myostatin and increased serum levels of peri 2019 Jan BACKGROUND: Chronic inflammation of rheumatoid arthritis (RA) is associated with disturbances in muscle and bone metabolism. AIM: The purpose of this study was to investigate whether endocrine regulators of myogenesis and bone metabolism in patients with rheumatoid arthritis (RA) in remission differed from unaffected healthy controls. An additional point was whether these were associated with patients' health-related functioning or particular bodily functions of the International Classification of Functioning, Disability and Health (ICF). METHODS: Bone turnover and the markers for muscle, i.e. myostatin (MSTN), follistatin (FSTN), growth differentiation factor (GDF-15) and for bone, i.e. sclerostin (SOST), dickkopf 1 (Dkk1), periostin (PSTN) metabolism were determined in 24 female RA patients and matched healthy controls. The chair rising test (CRT), timed up and go test (TUG), 6 min walking test, maximum hand grip and back extensor strength tests were used to assess patients' health-related functions. Additionally, bone mineral density of the lumbar spine and the hip region was measured. RESULTS: For the bone turnover markers no differences were observed between patients and controls. In contrast, the markers MSTN and Dkk1 were significantly lower and FSTN and PSTN significantly higher in patients than controls. Patients performed worse in the CRT and TUG. Some correlations reflected associations between these endocrine factors and physical function. CONCLUSION: Anti-inflammatory therapy may be responsible for the positive effect on endocrine factors influencing myogenesis. Elevation of PSTN probably reflects the increased risk of fragility fractures in RA patients.
31194885 Exposure-Response Analyses of Upadacitinib Efficacy in Phase II Trials in Rheumatoid Arthr 2019 Dec The relationships between upadacitinib, an oral selective Janus kinase 1 inhibitor, plasma exposures, and its efficacy (assessed by the American College of Rheumatology 20%/50%/70% responses over time) in moderate-to-severe active rheumatoid arthritis (RA) were characterized using data from 574 patients, on background methotrexate and inadequate response to methotrexate or anti-TNF therapy, from two phase II trials conducted with twice-daily dosing of an immediate-release formulation. The developed time-continuous Markov models were used to simulate efficacy of once-daily (q.d.). regimens of upadacitinib extended-release incorporating sources of uncertainty. Upadacitinib plasma concentrations associated with 15 and 30 mg extended-release q.d. doses were predicted to achieve that plateau of response across RA subpopulations. Results from these analyses provided the rationale that supported selection and de-risked evaluation of upadacitinib extended-release doses for the first time in >4,000 patients in five large phase III trials.
31785770 Differential Expression of Renin-Angiotensin System-related Components in Patients with Rh 2020 Jan BACKGROUND: The purpose of this study was to demonstrate the role of renin-angiotensin system (RAS)-related components, vascular endothelial growth factor (VEGF) and atrial metalloproteinase-13 (MMP-13) in synovial tissue and synovial fluid from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). MATERIALS AND METHODS: Thirty-four patients with RA and 41 patients with OA were included in the study. Renin, angiotensin-converting enzyme (ACE), VEGF and MMP-13 protein levels in the synovial fluid were measured by enzyme-linked immunosorbent assay. Quantitative real-time polymerase chain reaction analysis, western blot analysis and immunohistochemistry were used to quantify renin, ACE, angiotensin type 1 and type 2 receptors, VEGF and MMP-13 in OA and RA. Additionally, the correlation was determined by Pearson's coefficient. RESULTS: In synovial fluid, expression levels of renin, ACE, VEGF and MMP-13 in patients with RA were significantly higher than those in patients with OA. In synovial tissue, the RAS components VEGF and MMP-13 were also elevated in patients with RA. The results of immunohistochemistry in synovial tissue also showed that the RAS components VEGF and MMP-13 were significantly increased in patients with RA. Notably, the Pearson coefficient demonstrated that the levels of the RAS components were positively correlated with the expression of VEGF and MMP-13 in OA and RA. CONCLUSIONS: The present results suggest that RAS-related components in RA and OA, including renin, ACE, angiotensin type 1 and type 2 receptors, are associated with increased expression of VEGF and play an important role in angiogenesis. Furthermore, there was a significant positive correlation between the expression of VEGF and MMP-13.
30797689 Clostridioides difficile-related toxic megacolon after Cryptococcus neoformans cellulitis: 2019 May A 76-year-old Japanese woman was admitted due to uncontrolled cellulitis of the right lower leg. She had deep vein thrombosis on the right limb. Moreover, she had a long history of rheumatoid arthritis treated with corticosteroids. Skin biopsy and lumbar puncture were performed to diagnose disseminated cryptococcosis. She was administered antifungal agents (liposomal amphotericin B and 5-fluorocytosine). On treatment day 14, debridement was performed, and cryptococcosis was controlled. However, she developed toxic megacolon due to Clostridioides difficile infection (CDI). On day 32, she was transferred to the intensive care unit due to severe acidosis and acute kidney injury secondary to CDI-related toxic megacolon. Vancomycin, metronidazole, and tigecycline were administered for treatment of CDI. After several weeks of intensive care, toxic megacolon was improved, but renal replacement therapy was discontinued according to the patient's will. On day 73, she died of renal failure. We experienced a complex of rare diseases, Cryptococcus neoformans cellulitis and Clostridioides difficile-related toxic megacolon. Both diseases were presumed to be the result of corticosteroid and methotrexate use. Hence, careful monitoring is required when treating immunocompromised hosts to reduce the risk of developing complications.
31863922 Gene delivery of TIPE2 attenuates collagen-induced arthritis by modulating inflammation. 2020 Feb Rheumatoid arthritis (RA) is an autoimmune disease that leads to severe disabilities through the induction of synovitis and subsequent cartilage and bone destruction. The development of a novel therapeutic strategy for suppressing inflammatory responses in RA will be of great benefit to patients. Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) is an important regulator of immune response in various diseases. However, the expression and function of TIPE2 in RA are still unclear. In the present study, the expression of TIPE2 during the development of collagen-induced arthritis (CIA) was determined. Lentivirus (LV) was utilized to deliver a TIPE2 overexpression system into the joints of CIA mice, and this was followed by pathological analysis, immune cell infiltration analysis, and inflammatory cytokine detection. TIPE2 was downregulated in CIA mice, which was inversely correlated with arthritis progression. The ectopic expression of TIPE2 from gene delivery prevented susceptibility and disease severity by inhibiting the infiltration of macrophages and myeloid-derived suppressor cells (MDSCs) in the joints of CIA mice. Furthermore, lower expression of proinflammatory cytokines was observed in LV-TIPE2-injected CIA mice, which was in part associated with the activation of STAT3 and NF-κB signaling pathways in the cartilage cells. These data support the suppressive function of TIPE2 in autoimmune diseases and identify the gene delivery of TIPE2 as an important therapeutic agent for the treatment of RA and perhaps other autoimmune diseases.
31505915 Incidence and predictors of new onset left ventricular diastolic dysfunction in asymptomat 2019 Sep 10 Rheumatoid arthritis (RA) is associated with higher risk of heart failure. Several studies report that left ventricular (LV) diastolic dysfunction (LVDD), a silent precursor of heart failure, is widely present in RA patients. Very little is known about the factors related to the development of LVDD in this disease. In this study we assessed the incidence and the predictors of new-onset LVDD in RA patients. Two-hundred-ninety-five adults with RA without overt cardiac disease were prospectively analyzed from March 2014 to March 2015 by Doppler echocardiography. Among the 295 subjects evaluated, 217 (73.6%) had normal LV diastolic function and represented the final study population. At 1-year follow-up, 53 of 217 patients (24%) developed LVDD, which was of degree I (mild dysfunction) in all of them. By multivariate logistic regression analysis, lower E/A ratio of transmitral flow (ratio between the peak velocity of early diastolic "E" wave and late diastolic "A" wave of transmitral flow) was independently associated with new-onset LVDD [OR 0.17 (CI 0.09-0.57)], together with older age and higher systolic blood pressure. In a clinical predictive model derived from multivariate analysis, the new-onset LVDD rate event ranged from 0% (patients without any factor) to 75% (patients in whom the three predictors coexisted). A significant portion of patients with RA without overt cardiac disease develop LVDD at 1-year follow-up. This condition can be predicted by a simple clinical model which could improve the clinical management and the prognostic stratification of patients with RA.
31415347 Hepatitis E infection in a patient with rheumatoid arthritis treated with leflunomide: A c 2019 Aug RATIONALE: Hepatitis E is an infectious disease due to inflammation of the liver caused by hepatitis E virus (HEV) and represents one of the most common causes of acute hepatitis and jaundice in the world. Although data of hepatitis E infection in patients with rheumatoid arthritis (RA) are accumulating, little is known on the course of HEV infection. We reported, for the 1st time, a case of patient with RA with hepatitis E that developed during leflunomide therapy in combination with low-dose steroids. PATIENT CONCERNS: We present a 39-year-old woman, affected by RA and treated with leflunomide, reported diffuse itching and persistent fatigue laboratory data revealed elevated liver enzyme levels. DIAGNOSIS: Positivity for anti-HEV IgM and IgG was observed. HEV-RNA of the genotype 3 was detected, indicating acute E hepatitis. INTERVENTIONS AND OUTCOMES: Leflunomide was stopped and restarted 5 months after the initial diagnosis at the same dosage, with a close clinical and laboratory follow-up. The virus was eradicated from the serum without chronic transformation. The patient is alive and well 7 months after the initial diagnosis. LESSONS: To our knowledge, this report is the 1st case of acute E hepatitis in a patient with RA developed during leflunomide therapy in combination with low-dose steroids. Moreover, geoepidemiology of infection is important, due to the fact that Abruzzo, a central region of Italy, has the highest HEV seroprevalence in general population, related to the zoonotic transmission of the infection from domestic and wild animals. Our case highlighted that immunosuppressive therapy, and in particular leflunomide, could be safely reintroduced after the resolution of the infection and the clearance of the virus. Further studies are needed to evaluate potential advantages in serologic testing for HEV infection as a part of the routine workup done to patients with rheumatic diseases and selected for immunosuppressive therapy.
31439354 Nonsteroidal anti-inflammatory drugs and cardiovascular risk - a matter of indication. 2020 Apr The term non-steroidal anti-inflammatory drugs (NSAIDs) covers a heterogeneous group of compounds that possess analgesic, antipyretic and anti-inflammatory properties. NSAIDs are recommended as first-line therapy in patients with ankylosing spondylitis (AS) and are also frequently used in rheumatoid arthritis (RA). However, adverse reactions are relatively common, including an increased risk for cardiovascular events which has remained a concern for both, patients and physicians, and the United States Food and Drug Administration (FDA) has recently expressed a straight forward warning in this regard. Recent data on the use of NSAIDs in inflammatory diseases are now challenging this hypothesis. In two large independent studies, it was not the high but the low intake of NSAIDs that was associated with mortality in AS patients. Analogous data exist for RA. This observation is obviously not consistent with a general increase of cardiovascular mortality due to NSAIDs. Here we discuss the important impact of indication (inflammatory vs. non-inflammatory diseases) on the cardiovascular effects of NSAIDs, including traditional NSAIDs (t-NSAIDS) and coxibs.