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ID PMID Title PublicationDate abstract
34494955 High CD14+ peripheral monocytes expression of ALX/FPR2 and BLT1 in low disease activity an 2022 May OBJECTIVES: Specialised pro-resolving mediator (SPM) can dampen the acute inflammation through ERV1, ALX/FPR2 and BLT1 cell receptors and it is conceivable that their expression is dysregulated during chronic inflammation. The aim of this study was to evaluate the expression of ERV1, ALX/FPR2 and BLT1 on peripheral blood (PB) cells from rheumatoid arthritis (RA) patients. METHODS: At baseline, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), clinimetric indexes (28-joint disease activity score (DAS28) and clinical disease activity index (CDAI)), and PB samples were collected from 33 RA patients. Based on DAS28, patients were divided into high-moderate (H-Mo/RA, DAS28≥3.2) and low-remission (L-Rem/RA, DAS28<3.2) disease activity group. Cell membrane expression of ERV1, ALX/FPR2 and BLT1 on CD3pos, CD19pos, CD14pos cells and granulocytes was assessed by multi-parametric flow-cytometry analysis. Nine healthy controls (HC) were also studied. RESULTS: Sixteen H-Mo/RA and 17 L-Rem/RA patients were identified. The percentage of BLT1posCD14pos cells was significantly higher in L-Rem/RA (47.17%) than in H-Mo/RA (14.27%) group (p=0.005). Likewise, the percentage ALX/FPR2pos CD14pos cells was significantly higher in L-Rem/RA (33.02%) than in H-Mo/RA (8.77%; p=0.04) patients. An inverse correlation between BLT1posCD14pos cell percentage and DAS28 (r=-0.42; p=0.01), CDAI (r=-0.51; p=0.003), ESR (r=-0.39; p=0.025) and CRP (r=-0.40; p=0.02), ALX/FPR2posCD14pos cell percentage and CRP (r=-0.39; p=0.02) were found, while SPM-receptors mean fluorescence intensity (MFI) was not different between HC and L-Rem/RA patients. CONCLUSIONS: ALX/FPR2 and BLT1 receptors expression mirrors RA disease activity arising as potential biomarkers of inflammatory regulation.
35498132 C3-Epimer of 25-Hydroxyvitamin D3 as a Superior Marker for Predicting the Severity of Chro 2022 OBJECTIVE: 25-hydroxyvitamin D3 (25[OH]D3) is involved in oxidative stress regulation by upregulating the expression of antioxidant genes except for mineral homeostasis physiological role. C3-epimer of 25(OH)D3 (C3-epi-25[OH]D3) is a form of vitamin D metabolite with low bioaffinity in vivo, but little is known about the relationship between C3-epi-25(OH)D3 and diseases. This study was aimed at investigating the relationship between C3-epi-25(OH)D3 and the severity of chronic kidney disease (CKD) in patients with rheumatoid arthritis (RA). METHOD: A total of 318 RA inpatients were enrolled and divided into mild (n = 247), moderate (n = 46), and severe (n = 25) CKD groups according to the CKD prognosis criterion of the Kidney Disease Improving Global Outcomes guidelines. Serum levels of 25(OH)D2, 25(OH)D3, C3-epi-25(OH)D3, and free 25(OH)D (F25[OH]D) were measured, and the value of 25(OH)D was calculated. The relationship and changing trend of the indexes based on CKD severity were analyzed. RESULTS: The serum levels of 25(OH)D, 25(OH)D3, and F25(OH)D showed a decreasing trend (z = -2.781--3.996, P < 0.01) in RA patients with CKD progression from mild to severe, while C3-epi-25(OH)D3 showed an increasing trend (z = 6.741, P < 0.001) and 25(OH)D2 showed no significant difference among the groups (z = 0.976, P = 0.329). Only levels of C3-epi-25(OH)D3 presented significant differences between adjacent CKD severity groups in RA patients (mild to moderate: z = 3.963, Padj < 0.001; moderate to severe: z = 3.269, Padj = 0.002). Multiple logistic regression analysis showed that 25(OH)D3 and C3-epi-25(OH)D3 were significant predictors for CKD progression in RA patients, and C3-epi-25(OH)D3 had a better predictive advantage (moderate vs. mild: OR = 4.79, P < 0.001; severe vs. mild: OR = 17.85, P < 0.001). CONCLUSIONS: To the best of our knowledge, this is the first study to reveal that C3-epi-25(OH)D3 is a dominant predictor of CKD severity in RA patients. Further studies are needed to explore the relationship between C3-epi-25(OH)D3 and other diseases.
34927393 Extramucosal Formation and Prognostic Value of Secretory Antibodies in Rheumatoid Arthriti 2022 May OBJECTIVE: To investigate levels and possible extramucosal formation of secretory Ig, including anti-citrullinated protein antibodies (ACPAs), in rheumatoid arthritis (RA). METHODS: Three patient groups were studied: 1) ACPA-positive patients with musculoskeletal pain without clinical arthritis, 2) patients with recent-onset RA, and 3) patients with established RA. In baseline serum samples (groups 1 and 2) and paired synovial fluid samples (group 3), we analyzed total secretory IgA, total secretory IgM, free secretory component (SC), and SC-containing ACPA. Extramucosal formation of SC-containing ACPA was investigated by preincubating RA sera and affinity-purified ACPA with recombinant free SC. RESULTS: Compared to healthy controls, serum levels of total secretory IgA and total secretory IgM were increased both in patients with early RA and at-risk patients (P < 0.05). Patients with early RA with elevated total secretory Ig had significantly higher disease activity during the 3-year follow-up period compared to those without increased levels. At-risk patients who developed arthritis during follow-up (39 of 82) had higher baseline total secretory IgA levels compared to those who did not (P = 0.041). In established RA, total secretory IgA and total secretory IgM levels were higher in serum than in synovial fluid (P < 0.0001), but SC-containing ACPAs adjusted for total secretory Ig concentration were higher in synovial fluid (P < 0.0001). Preincubation with recombinant free SC yielded increased SC-containing ACPA reactivity in sera as well as in affinity-purified IgA and IgM ACPA preparations. CONCLUSION: Circulating secretory Ig are elevated before and at RA onset. In the presence of free SC, secretory Ig may form outside the mucosa, and SC-containing ACPAs are enriched in RA joints. These findings shed important new light on the mucosal connection in RA development.
35138463 Preliminary MRI-based investigation of characteristics and prognosis of knee bone marrow e 2022 Jun INTRODUCTION: Bone marrow edema (BME) is one of the main imaging characteristics of juvenile idiopathic arthritis (JIA) in children and rheumatoid arthritis (RA) in adult. Previous studies have shown that BME occurred in approximately 64% of adults with RA and was a key predictor of poor prognosis. But BME with JIA has not been of great concern. Therefore, we evaluated the prevalence, characteristics, and prognosis of knee joint BME in children with JIA. METHODS: In this retrospective study, we included children with JIA and knee joint involvement from January 2017 to December 2019. BME was evaluated according to the Juvenile Arthritis MRI Scoring system. Clinical characteristics were compared between the BME group and the non-BME group. The characteristics and prognosis of the BME were observed. RESULTS: A total of 128 children with 136 knee joint MRI data were identified, with 37 knee joints (27.2%) having BME. BME has positive correlation with synovial hypertrophy (Rs = 0.562, p = 0.019). There were significant differences in age (p = 0.010) and disease duration (p = 0.013) between the BME and non-BME groups. BME was found to be more common in older children and the patients with long duration of disease. Locations with BME were the lateral tibial plateau (17/37, 45.9%), the lateral weight-bearing femur (16/37, 43.2%), the medial tibial plateau and the medial femoral condyle (both with 15/37, 40.5%), and the medial weight-bearing femur (12/37, 32.4%). The lateral femoral condyle and both the lateral and medial sides of the patella were rarely involved. Of the 15 BME joints with the MRI follow-up data (interval 6.5 ± 3.0 months), the lesions disappeared or improved within 12 months after the treatments in 13 (86.7%) joints. CONCLUSIONS: The prevalence of knee BME in JIA was 27.2%. There was positive correlation between BME and synovial hypertrophy. Older children and children with long disease duration had a higher risk for BME, which was commonly a late presentation and more likely involved the weight-bearing surfaces of the joint. The overall prognosis was satisfactory after the standard treatments. Key Points • To the best of our knowledge, this paper is the first one to investigate the MRI manifestation in JIA focus on knee BME sign.
35135832 Distinct impact of DMARD combination and monotherapy in immunogenicity of an inactivated S 2022 May OBJECTIVES: To evaluate the distinct impact of disease modifying antirheumatic drugs (DMARD) combination and monotherapy in immune response to an inactivated SARS-CoV-2 vaccine in patients with rheumatoid arthritis (RA). METHODS: This phase 4 prospective study analysed seroconversion (SC) of anti-SARS-CoV-2 immunoglobulin G (IgG) and neutralising antibodies (NAb) induced by the inactivated vaccine (CoronaVac) in patients with RA in comparison to controls (CG). Disease activity and treatment were also assessed. Only participants with baseline negative IgG/NAb were included. RESULTS: Patients with RA (N=260) and CG (N=104) had comparable median ages (59 years (50-65 years) vs 58 years (49.8-64 years), p=0.483). Patients with RA had moderate but lower SC (61.8% vs 94.2%, p<0.001) and NAb positivity (45% vs 78.6%, p<0.001) in comparison to CG after full vaccination. Baseline disease activity did not influence immunogenicity (p>0.05). After multivariate analyses, factors independently related to reduced SC were: older age (OR=0.79 (0.70-0.89) for each 5-year interval, p<0.001), methotrexate (OR=0.54 (0.29-0.98), p=0.044), abatacept (OR=0.37 (0.19-0.73), p=0.004) and number of DMARD (OR=0.55 (0.33-0.90), p=0.018). Regarding NAb, age (OR=0.87 (0.78-0.96) for each 5-year interval, p=0.007) and prednisone >7.5 mg/day (OR=0.38 (0.19-0.74), p=0.004) were negatively related to the presence of NAb. Further comparison of SC/NAb positivity among RA treatment subgroups and CG revealed that methotrexate/tofacitinib/abatacept/tocilizumab use, in monotherapy or in combination, resulted in lower responses (p<0.05), while tumour necrosis factor inhibitor and other conventional synthetic DMARD interfered solely when combined with other therapies. CONCLUSIONS: Patients with RA under DMARD have a moderate immunogenicity to CoronaVac. We identified that nearly all DMARD combinations have a deleterious effect in immunogenicity, whereas a more restricted number of drugs (methotrexate/tofacitinib/abatacept/tocilizumab) also hampered this response as monotherapy. These findings reinforce the need of a broader approach, not limited to specific drugs, to improve vaccine response for this population. TRIAL REGISTRATION DETAILS: NCT04754698.
35216458 Hypoxia-Inducible Factor-2 Alpha Regulates the Migration of Fibroblast-like Synoviocytes v 2022 Feb 20 This study aimed to examine the role of CD70, which is highly expressed on fibroblast-like synoviocytes (FLS), in rheumatoid arthritis (RA) patients. FLS isolated from RA (n = 14) and osteoarthritis (OA, n = 4) patients were stimulated with recombinant interleukin-17 (IL-17; 5 ng/mL) and tumor necrosis factor alpha (TNF-α; 5 ng/mL) for 24 h. Expression of CD70, CD27/soluble CD27 (sCD27), and hypoxia-inducible factor-2 alpha (HIF-2α) was analyzed by RT-qPCR, flow cytometry, and ELISA assays, respectively. Reactive oxygen species (ROS) expression and cell migration were also examined. The HIF-2α inhibitor PT-2385 and CD70 inhibitor BU69 were used to specifically suppress these pathways. Stimulation with IL-17 and TNF-α significantly induced CD70 expression in RA FLS. Although the synovial fluids from patients with RA contained high levels of sCD27, surface expression of CD27, a ligand of CD70, was rarely detected in RA FLS. Cytokine-induced CD70 expression was significantly decreased following antioxidant treatment. Following HIF-2α inhibition, RA FLS had decreased expression of CD70 and ROS levels. Migration of RA FLS was also inhibited by inhibition of CD70 or HIF-2α. The surface expression of CD70 is regulated by HIF-2α and ROS levels and is a key contributor to cytokine-enhanced migration in RA FLS.
35080151 Antibodies to Cartilage Oligomeric Matrix Protein Are Pathogenic in Mice and May Be Clinic 2022 Jun OBJECTIVE: Cartilage oligomeric matrix protein (COMP) is an autoantigen in rheumatoid arthritis (RA) and experimental models of arthritis. This study was undertaken to investigate the structure, function, and relevance of anti-COMP antibodies. METHODS: We investigated the pathogenicity of monoclonal anti-COMP antibodies in mice using passive transfer experiments, and we explored the interaction of anti-COMP antibodies with cartilage using immunohistochemical staining. The interaction of the monoclonal antibody 15A11 in complex with its specific COMP epitope P6 was determined by x-ray crystallography. An enzyme-linked immunosorbent assay and a surface plasma resonance technique were used to study the modulation of calcium ion binding to 15A11. The clinical relevance and value of serum IgG specific to the COMP P6 epitope and its citrullinated variants were evaluated in a large Swedish cohort of RA patients. RESULTS: The murine monoclonal anti-COMP antibody 15A11 induced arthritis in naive mice. The crystal structure of the 15A11-P6 complex explained how the antibody could bind to COMP, which can be modulated by calcium ions. Moreover, serum IgG specific to the COMP P6 peptide and its citrullinated variants was detectable at significantly higher levels in RA patients compared to healthy controls and correlated with a higher disease activity score. CONCLUSION: Our findings provide the structural basis for binding a pathogenic anti-COMP antibody to cartilage. The recognized epitope can be citrullinated, and levels of antibodies to this epitope are elevated in RA patients and correlate with higher disease activity, implicating a pathogenic role of anti-COMP antibodies in a subset of RA patients.
33864023 An IgD-Fc-Ig fusion protein restrains the activation of T and B cells by inhibiting IgD-Ig 2022 Feb Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovitis and the destruction of small joints. Emerging evidence shows that immunoglobulin D (IgD) stimulation induces T-cell activation, which may contribute to diseases pathogenesis in RA. In this study, we investigated the downstream signaling pathways by which IgD activated T cells as well as the possible role of IgD in the T-B interaction. Peripheral blood mononuclear cells were isolated from peripheral blood of healthy controls and RA patients. We demonstrated that IgD activated T cells through IgD receptor (IgDR)-lymphocyte-specific protein tyrosine kinase (Lck)-zeta-associated protein 70 (ZAP70)/phosphatidylinositol 3-kinase (PI3K)/nuclear factor kappa-B (NF-κB) signaling pathways; IgD-induced CD4(+) T cells promoted the proliferation of CD19(+) B cells in RA patients. A novel fusion protein IgD-Fc-Ig (composed of human IgD-Fc domain and IgG(1) Fc domain, which specifically blocked the IgD-IgDR binding) inhibited the coexpression of IgDR and phosphorylated Lck (p-Lck) and the expression levels of p-Lck, p-ZAP70, p-PI3K on CD4(+) T cells, and decreased NF-κB nuclear translocation in Jurkat cells. Meanwhile, IgD-Fc-Ig downregulated the expression levels of CD40L on CD4(+) T cells as well as CD40, CD86 on CD19(+) B cells in RA patients and healthy controls. It also decreased the expression levels of CD40L on CD4(+) T cells and CD40 on CD19(+) B cells from spleens of collagen-induced arthritis (CIA) mice and reduced IL-17A level in mouse serum. Moreover, administration of IgD-Fc-Ig (1.625-13 mg/kg, iv, twice a week for 4 weeks) in CIA mice dose-dependently decreased the protein expression levels of CD40, CD40L, and IgD in spleens. IgD-Fc-Ig restrains T-cell activation through inhibiting IgD-IgDR-Lck-ZAP70-PI3K-NF-κB signaling, thus inhibiting B-cell activation. Our data provide experimental evidences for application of IgD-Fc-Ig as a highly selective T cell-targeting treatment for RA.
34170283 A pharmacist-managed virtual consult service for patients with rheumatologic conditions re 2022 Jan 1 PURPOSE: To describe a pharmacist-managed virtual consult service practice model for rheumatology patients and evaluate its initial impact on compliance with institutional critical care guidelines for biologic response modifiers (BRMs). SUMMARY: Pharmacologic care of patients with rheumatologic conditions often revolves around the use of BRMs. While these drugs are generally well tolerated, nearly all of them carry risks for serious adverse events. The severity of these possible problems necessitates a thorough initial and ongoing clinical workup. Based on results of a needs assessment, a virtual consult service was introduced at the University of Illinois Hospital and Health Sciences System (UI Health) in August 2018 to integrate clinical, specialty pharmacy, and therapeutic infusion services for proactive medication and safety management of patients with rheumatologic conditions requiring treatment with BRMs. The consult service was managed by an embedded clinical pharmacist and a postgraduate year 1 specialty pharmacy resident, who evaluated each request for therapy appropriateness prior to submission for insurance approval. CONCLUSION: Forty-one percent of the pharmacy benefit consult orders required a pharmacist intervention prior to referral to the specialty pharmacy. All consults (100%) adhered to the safety management guidelines for BRMs after review by the pharmacist. The pharmacist-managed virtual consult service is a novel practice model in specialty pharmacy that permits pharmacists to manage multiple patients simultaneously, virtually, and with optimal impact on medication selection and management at or before the point of prescribing.
33492028 Long-Term Retention Rate of Golimumab in Patients With Rheumatoid Arthritis, Psoriatic Art 2022 Jan 1 METHODS: We conducted a single-center, medical records review study of all patients with RA, PsA, and SpA on GLM treatment attending a large rheumatology department from 2010 to 2017. Times from start to end of GLM treatment were collected, as well as sociodemographic, clinical, and safety variables. Golimumab retention rate was estimated by the Kaplan-Meier method, and comparison across diseases was analyzed with the Mantel-Haenszel statistic (log-rank test). Cox proportional hazards regression models were used to identify factors associated with GLM discontinuation. RESULTS: In the study period, a total of 212 patients (61 RA, 48 PsA, 103 SpA) were prescribed GLM. Retention rates were 72% in the first year, 61% in the second, 56% in the third, and 38% at 5 years. Differences were statistically significant across diseases (median times to GLM discontinuation were 50.2, 46.0, and 38.7 months for RA, SpA, and PsA, respectively) and according to the number of previous biologic therapies (55.2 months in biologic-naive patients vs 14.0 months in patients with ≥2 previous biologics; p < 0.001). The use of concomitant conventional synthetic disease-modifying antirheumatic drugs was associated with a lower probability of discontinuation (hazards ratio [HR], 0.57; 95% confidence interval [CI], 0.33-0.97). Female sex (HR, 1.84; 95% CI, 1.07-3.17) and having used 2 biologics before GLM (HR, 2.99; 95% CI, 1.76-5.06) were associated with increased discontinuation rates. Twenty-three patients (10.9%) had at least 1 serious adverse event. CONCLUSIONS: In a real-life setting, GLM shows appropriate long-term safety-effectiveness ratio.
33853472 Anti-carbamylated protein antibodies positivity and disease activity in Hispanic patients 2022 Feb 28 OBJECTIVES: We aimed to determine the prevalence of anti-carbamylated protein (anti-CarP) antibodies in Mexican Hispanics with established rheumatoid arthritis (RA) and to assess their relationship with disease activity. METHODS: A cohort study was conducted in 278 patients with established RA during an 18-month follow-up. We measured IgG/IgM/IgA rheumatoid factor (RF), IgG anticitrullinated protein antibodies (ACPA) and IgG/IgM/IgA anti-CarP antibodies using enzyme-linked immunosorbent assay (ELISA). For disease activity, we performed the 28-joint disease activity score with erythrocyte sedimentation rate (DAS28-ESR). Repeated measures one-way ANOVA was used to test the association between anti-CarP IgG antibody status and longitudinal DAS28-ESR scores. Patients were evaluated at baseline and at 6, 12, and 18 months during follow-up. RESULTS: Anti-CarP IgG antibodies were positive in 47.8% of patients and, accounting for all isotypes, in 9.5% of patients with negative RF and ACPA. Triple antibody positivity was present in 42.6% of patients in our sample. Anti-CarP IgG antibody positivity did not show statistically significant differences in mean DAS28-ESR when compared to anti-CarP IgG antibody negative patients at baseline, 6, 12 or 18 months. CONCLUSION: Anti-CarP IgG antibodies are not associated to a higher disease activity in Hispanic patients with established RA. Our findings suggest that the clinical value of measuring anti-CarP antibodies in RA diminishes over time.
35468805 HLA-DRB1 haplotypes predict cardiovascular mortality in inflammatory polyarthritis indepen 2022 Apr 25 BACKGROUND: Haplotypes defined by amino acids at HLA-DRB1 positions 11, 71 and 74 associated with susceptibility to rheumatoid arthritis (RA) are associated with radiological outcome, anti-TNF response and all cause-mortality in RA. RA is associated with cardiovascular (CV) morbidity and mortality, but the increased prevalence of risk factors of CV disease in RA only partially explains this association. The aim of this study was to investigate whether amino acids at positions 11, 71 and 74 of HLA-DRB1 are associated with cardiovascular (CV) mortality in inflammatory polyarthritis (IP). METHODS: The Norfolk Arthritis Register (NOAR) is an incidence register of IP: recruitment 1990-2007, final follow-up 2011. Two thousand five hundred fourteen patients had available genetic and mortality data. Amino acids at positions 11, 71 and 74 of HLA-DRB1 were determined. Univariate Cox proportional hazard models were applied to assess the association of genetic markers and both all-cause mortality and cardiovascular mortality. RESULTS: Among 2514 participants, 643 (25.6%) died during the study, and 343 (53.3%) of these deaths were attributed to CV causes. One thousand six hundred fifty (65.6%) participants were female, 709 (32.3%) were anti-CCP-positive and the median age of participants was 54. HLA-DRB1 haplotypes associated with susceptibility to rheumatoid arthritis (RA) consistently show the same magnitude and direction of association for overall and CV mortality in IP. For example, the SEA-haplotype, associated with the lowest susceptibility to RA, and the best radiographic outcome, was found to be associated with decreased CV mortality (HR 0.67, 95% CI 0.47, 0.91, p=0.023). Mediation analysis revealed associations were independent of anti-CCP status. CONCLUSIONS: HLA-DRB1 haplotypes associated with susceptibility to RA also predispose to increased risk of CV mortality in IP, independent of known CV risk factors. Associations were independent of anti-CCP status, which suggests in the future, genetic factors will add to the prediction of risk of cardiovascular mortality beyond serological markers.
35628458 TNF-α Induces Mitophagy in Rheumatoid Arthritis Synovial Fibroblasts, and Mitophagy Inhib 2022 May 18 Mitophagy is a selective form of autophagy that removes damaged mitochondria. Increasing evidence indicates that dysregulated mitophagy is implicated in numerous autoimmune diseases, but the role of mitophagy in rheumatoid arthritis (RA) has not yet been reported. The aim of the present study was to determine the roles of mitophagy in patient-derived RA synovial fibroblasts (RASFs) and in the collagen antibody-induced arthritis mouse model. We measured the mitophagy marker PTEN-induced putative kinase 1 (PINK1) in RASFs treated with tumor necrosis factor-α (TNF-α) using Western blotting and immunofluorescence. Arthritis was induced in PINK1(-/-) mice by intraperitoneal injection of an anti-type II collagen antibody cocktail and lipopolysaccharide. RA severity was assessed by histopathology. PINK1 expression and damaged mitochondria increased in TNF-α treated RASFs via increased intracellular levels of reactive oxygen species. PINK1 knockdown RASFs decreased cellular migration and invasion functions. In addition, PINK1(-/-) mice with arthritis exhibited markedly reduced swelling and inflammation relative to wild-type mice with arthritis. Taken together, these findings suggest that regulation of PINK1 expression in RA could represent a potential therapeutic and diagnostic target for RA.
35354913 Identification of novel rheumatoid arthritis-associated MiRNA-204-5p from plasma exosomes. 2022 Mar Rheumatoid arthritis (RA) is an autoimmune disease characterized by infiltration of immune cells in the synovium. However, the crosstalk of immune cells and synovial fibroblasts is still largely unknown. Here, global miRNA screening in plasma exosomes was carried out with a custom microarray (RA patients vs. healthy controls = 9:9). A total of 14 exosomal miRNAs were abnormally expressed in the RA patients. Then, downregulated expression of exosomal miR-204-5p was confirmed in both the replication (RA patients vs. healthy controls = 30:30) and validation groups (RA patients vs. healthy controls = 56:60). Similar to the findings obtained in humans, a decreased abundance of exosomal miR-204-5p was observed in mice with collagen-induced arthritis (CIA). Furthermore, Spearman correlation analysis indicated that plasma exosomal miR-204-5p expression was inversely correlated with disease parameters of RA patients, such as rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein. In vitro, our data showed that human T lymphocytes released exosomes containing large amounts of miR-204-5p, which can be transferred into synovial fibroblasts, inhibiting cell proliferation. Overexpression of miR-204-5p in synovial fibroblasts suppressed synovial fibroblast activation by targeting genes related to cell proliferation and invasion. In vivo assays found that administration of lentiviruses expressing miR-204-5p markedly alleviated the disease progression of the mice with CIA. Collectively, this study identified a novel RA-associated plasma exosomal miRNA-204-5p that mediates the communication between immune cells and synovial fibroblasts and can be used as a potential biomarker for RA diagnosis and treatment.
35489682 Integrated proteome and malonylome analyses reveal the neutrophil extracellular trap forma 2022 Jun 30 Rheumatoid arthritis (RA) is an autoimmune inflammatory disease of unknown etiology in which the posttranslational modifications (PTMs) of proteins play an important role. PTMs, such as those involved in the formation of neutrophil extracellular traps (NETs), have been well studied. The excessive formation and release of NETs can mediate inflammation and joint destruction in RA. It has been gradually recognized that lysine malonylation (Kmal) can regulate some biological processes in some prokaryotes and eukaryotes. However, less is known about the role of Kmal in RA. We therefore performed proteome and malonylome analyses to explore the proteomic characteristics of the peripheral blood mononuclear cells from 36 RA patients and 82 healthy subjects. In total, 938 differentially expressed proteins (DEPs) and 42 differentially malonylated proteins (DMPs) with 55 Kmal sites were detected through a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based analysis. Functional analysis showed that two DEPs with four malonylated sites and one DMP with a malonylated site were identified in the neutrophil extracellular trap formation (NETosis) pathway. Altogether, this study not only describes the characteristics of the malonylome in RA for the first time, but it also reveals that malonylation may be involved in the NETosis pathway. SIGNIFICANCE: This is the first report that reveals the proteomic features of Kmal in RA through a LC-MS/MS-based method. In this study, we found that several key DMPs were associated with the NETosis pathway, which contributes to the development of RA. The present results provide an informative dataset for the future exploration of Kmal in RA.
35112275 Protective effect of methyl gallate on murine antigen-induced arthritis by inhibiting infl 2022 Feb Methyl gallate (MG) is a plant-derived phenolic compound known to present remarkable anti-inflammatory effect in different experimental models, such as paw oedema, pleurisy, zymosan-induced arthritis and colitis. Herein we investigated the effect of MG in the mice model of antigen-induced arthritis (AIA), a model with complex inflammatory response, driven primally by immune process and that cause bone and cartilage erosion similarly found in rheumatoid arthritis. Arthritis was induced by intra-articular injection of albumin methylated from bovine serum (mBSA) in C57BL/6 male mice previously immunized. The dose-response analysis of MG (0.7-70 mg/kg; p.o) showed that maximum inhibition was reached with the dose of 7 mg/kg on paw oedema and cell infiltration induced by AIA at 7 h. Treatment with MG (7 mg/kg; p.o) or with the positive control, dexamethasone (Dexa, 10 mg/kg, ip) reduced AIA oedema formation, leukocyte infiltration, release of extracellular DNA and cytokine production 7 and 24 h (acute response). Mice treated daily with MG for 7 days showed no significant weight loss or liver and kidney toxicity contrary to dexamethasone that induced some degree of toxicity. Prolonged treatment with MG inhibited the late inflammatory response (28 days) reducing oedema formation, cell infiltration, synovial hyperplasia, pannus formation and cartilage degradation as observed in histopathological analyses. Ultimately, MG reduced bone resorption as evidenced by a decrease in tartrate-resistant acid phosphate (TRAP)-positive cells number in femur histology. Altogether, we demonstrate that MG ameliorates the inflammatory reaction driven primarily by the immune process, suggesting a potential therapeutic application in arthritis treatment.
34595805 Prevalence and clinical correlates of antinuclear antibody in patients with gastroparesis. 2022 May BACKGROUND: Autoimmunity may play a role in the pathogenesis of gastroparesis in a subset of patients. Antinuclear antibody (ANA) testing is often used to screen for autoimmune disorders. AIMS: 1) Determine prevalence of a positive ANA in patients with gastroparesis; 2) Describe characteristics of idiopathic gastroparesis patients with positive ANA. METHODS: Patients were assessed with gastric emptying scintigraphy (GES), symptom assessment via Patient Assessment of Upper GI Symptoms [PAGI-SYM], and blood tests-ANA, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP). RESULTS: Positive ANA was seen in 148 of 893 (17%) patients with gastroparesis, being similar in idiopathic (16% of 536 patients), T1DM (16% of 162), T2DM (18% of 147), and postfundoplication (19% of 48 patients) gastroparesis. Among 536 patients with idiopathic gastroparesis, ANA titer 1:40-1:80 was seen in 33 (6%) patients, 1:160-1:320 in 36 (7%) patients, and ≥1:640 in 17 (3%) patients. Increasing ANA titer was associated with female gender (p = 0.05), Hispanic ethnicity (p = 0.02), comorbid rheumatoid arthritis (p = 0.02), systemic sclerosis (p = 0.004), and elevated ESR (p = 0.007). ANA positivity was associated with lower total GCSI (p = 0.007) and lower nausea/vomiting subscale (p = 0.0005), but not related to gastric emptying. CONCLUSIONS: The prevalence of a positive ANA in patients with gastroparesis was high at ~17% and did not differ significantly based on etiology. In idiopathic patients, ANA positivity was associated with rheumatoid arthritis, systemic sclerosis, and elevated ESR. ANA-positive gastroparesis represents a subset who often have other autoimmune symptoms or disorders, but less severe nausea and vomiting.
35410513 Dose-dependent effects of oleuropein administration on regulatory T-cells in patients with 2022 Jan INTRODUCTION: Rheumatoid arthritis (RA) is an autoimmune disease that is identified with chronic inflammation and progressive destruction of the joints. The defective activity of regulatory T cells (Tregs) plays a crucial role in RA development. Oleuropein (OLEU) is the most common polyphenolic compound in olive leaf extracts with numerous pharmacological activities. In this study, the potential effects of OLEU in shifting CD4(+) T cells toward Tregs are evaluated in patients with RA. METHODS: 32 healthy controls (HC) and 45 RA patients were included in two groups. The immunoturbidometric technique was used to measure serum levels of c-reactive protein (CRP) and rheumatoid factor (RF). Isolated CD4(+) T cells from peripheral blood mononuclear cells (PBMCs) of HC and RA patients were cultured with appropriate concentrations of OLEU. The cytotoxicity effects of OLEU were determined using the MTT assay at 24, 48, and 72 h. The percentage of CD4(+)CD25 + FoxP3 regulatory T lymphocytes (Tregs) and the expressions of IL-10 and TGF-β were evaluated by flow cytometry and immunoassay techniques after treatment of cells with different concentrations of OLEU for 24 h. The serum levels of RF and CRP in patients with RA were 11.8 ± 5.32 IU/ml and 6.36 ± 5.82 mg/l, respectively. RESULTS: OLEU had a dose-dependent effect on the CD4(+) T cells via increasing the frequency of CD4(+)CD25 + FoxP3 Tregs (p = 0.0001). Moreover, it induced the production of IL-10 (p = 0.0001) and TGF-β (p < 0.01) in both HC and RA patients. CONCLUSION: The findings of this study suggest that OLEU may have immunomodulatory effects by inducing Tregs, and it might help in developing a novel nutrition strategy for management of autoimmune diseases such as RA.
35356884 [The expression of semaphorins in synovial tissue of knee joint in patients with rheumatoi 2022 Feb Objective To investigate the expression level of semaphorin 3C (SEMA3C) and semaphorin 3F (SEMA3F) in synovial tissue of patients with rheumatoid arthritis (RA), and to analyze its correlation with clinical inflammatory markers and its clinical application value. Methods Knee joint synovial tissue specimens of 8 patients with RA and 8 patients with osteoarthritis (OA) were studied. The expression and distribution of SEMA3C, SEMA3F and tyrosine hydrogenase (TH) in synovial tissues were detected by immunohistochemistry. The mRNA and protein expression levels of SEMA3C and SEMA3F in synovial tissue were detected by real-time quantitative PCR and Western blot respectively. The correlations of SEMA3C and SEMA3F expression levels with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (ACPA), platelet count (PLT), plateletcrit (PCT), mean platelet volume (MPV), and platelet distribution width (PDW) were analyzed by Pearson method. Results Compared with those in synovial tissue of patients with OA, the distribution of SEMA3C and SEMA3F in synovial tissue of patients with RA was more extensive, while the expression of TH decreased. SEMA3C and SEMA3F mRNA and protein expressions in synovial tissue of patients with RA increased. Protein expression level of SEMA3C was negatively correlated with MPV and positively correlated with RF; protein expression level of SEMA3F was positively correlated with ESR and negatively correlated with PDW. Conclusion SEMA3C and SEMA3F are highly expressed in synovial tissue of patients with RA and correlated with the clinical inflammatory markers, which is expected to provide reference for the clinical evaluation of disease progression.
33336615 Overall survival and post-spontaneous regression relapse-free survival of patients with ly 2022 Jan 5 OBJECTIVES: To clarify factors affecting 5-year survival rates and relapse rates after spontaneous regression (SR) of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA). METHODS: This retrospective longitudinal study comprised 232 patients with RA diagnosed with LPDs between January 2000 and March 2017 at eight hospitals in Japan. The Kaplan-Meier method was used to analyze survival and the Cox proportional hazard model was applied to identify predictive factors. RESULTS: Among all patients, 1-, 2- and 5-year overall survival rates were 89.5%, 86.1%, and 78.2%, respectively. Multivariable analysis revealed four 5-year survival risk factors assessed at diagnosis: age above 70 years (p = .002), deep lymphadenopathy and/or more than one extranodal lesion (p = .008), Eastern Cooperative Oncology Group/Zubrod performance status of 2-4 (p = .004), and classic Hodgkin lymphoma (CHL) histology (p = .047). Among 143 patients who achieved SR, 2- and 5-year relapse rates were 14.2% and 24.9%, respectively. CHL histology (p = .003) and serum soluble interleukin-2 receptor levels exceeding 2000 IU/L (p = .014) were associated with post-SR relapse-free survival. Blood lymphocyte counts were significantly lower at relapse than at 3-6 months prior (p < .001). CONCLUSION: Assessment of the above risk factors and routine inspection of blood lymphocyte counts could aid in the care management of LPDs in RA.