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ID PMID Title PublicationDate abstract
34601644 Interactive effect of sarcopenia and falls on vertebral osteoporotic fracture in patients 2021 Oct 3 Patients with rheumatoid arthritis (RA) had higher incidences of sarcopenia, falls, osteoporosis, and vertebral osteoporotic fractures (VOPF). Sarcopenia was associated with longer disease duration, higher disease activity, and more severe RA. The interactive effect of sarcopenia and falls was associated with a higher risk of VOPF in patients with RA. PURPOSE: Whether sarcopenia and falls are a risk factor for vertebral fracture in RA patients has not been demonstrated. This study aimed to explore the incidence of vertebral osteoporotic fracture (VOPF) and its relationship with sarcopenia and falls in RA patients. METHODS: A total of 474 RA patients and 156 controls were enrolled in this study. Anteroposterior and lateral X-ray examinations of the vertebral column (T4-L4) were used for the semiquantitative assessment of VOPF. Bone mineral density was measured by dual-energy X-ray absorptiometry. Skeletal muscle mass was measured by direct segmental multifrequency bioelectrical impedance analysis (DSM-BIA method). RESULTS: RA patients had an increased risk of sarcopenia (62.4% vs 9.0%, x(2) = 47.478, P < 0.001), falls (30.2% vs 3.2%), osteoporosis (OP) (33.5% vs 12.8%, x(2) = 134.276, P < 0.001), and VOPF (20.3% vs 3.8%, x(2) = 47.478, P < 0.001) than controls. Patients with sarcopenia were more likely to have VOPF than RA without sarcopenia (24.0% vs 14.0%, x(2) = 6.802, P = 0.009). RA with sarcopenia and prior falls had the highest incidences of VOPF (36.7%). Older age (OR = 1.056, P < 0.001, 95% CI 1.030-1.083), falls (OR = 2.043, P = 0.003, 95% CI 1.238-3.371), OP (OR = 1.819, P = 0.034, 95% CI 1.046-3.163), and usage of glucocorticoids (GCs) (OR = 1.862, P = 0.022, 95% CI 1.093-3.172) were risk factors for VOPF in RA patients, while a higher skeletal muscle index (SMI) was a protective factor (OR = 0.754, P = 0.038, 95% CI 0.578-0.984) for VOPF in RA patients. CONCLUSIONS: The interactive effect of sarcopenia and falls is associated with a higher risk of VOPF in patients with RA.
34505620 Establishment of a human three-dimensional chip-based chondro-synovial coculture joint mod 2021 Oct 26 Rheumatoid arthritis is characterised by a progressive, intermittent inflammation at the synovial membrane, which ultimately leads to the destruction of the synovial joint. The synovial membrane as the joint capsule's inner layer is lined with fibroblast-like synoviocytes that are the key player supporting persistent arthritis leading to bone erosion and cartilage destruction. While microfluidic models that model molecular aspects of bone erosion between bone-derived cells and synoviocytes have been established, RA's synovial-chondral axis has not yet been realised using a microfluidic 3D model based on human patient in vitro cultures. Consequently, we established a chip-based three-dimensional tissue coculture model that simulates the reciprocal cross talk between individual synovial and chondral organoids. When co-cultivated with synovial organoids, we could demonstrate that chondral organoids induce a higher degree of cartilage physiology and architecture and show differential cytokine response compared to their respective monocultures highlighting the importance of reciprocal tissue-level cross talk in the modelling of arthritic diseases.
33452937 Earlier chronotype in patients with rheumatoid arthritis. 2021 Jun OBJECTIVES: Rheumatoid arthritis (RA) patients show an earlier circadian rhythm (i.e. serum melatonin peaks earlier during the night, indicating an earlier timing of the internal circadian pacemaker). In the current study, we examined whether the chronotype, which is influenced by the circadian rhythm, is also earlier. In addition, we explored whether chronotype is related to disease activity and patient-reported outcomes. METHODS: The chronotype (Munich Chronotype Questionnaire) of patients with RA (n = 121; mean age 60 years, 73% female) was compared with that of subjects from the general population (norm group; n = 1695) with a one-sample t test. In addition, we investigated chronotype in relation to disease activity (Disease Activity Score; DAS), reported morning stiffness, fatigue (Checklist Individual Strength), and health-related quality of life (RAND-36). RESULTS: The chronotype of patients with RA was, on average, 23 min (95% CI, 15 to 31 min) earlier than that of the norm group (t(115) = - 5.901, p < 0.001, d = 0.55). Chronotype was not related to disease activity or patient-reported outcomes (p > 0.05). CONCLUSION: As expected, chronotype was earlier in RA patients. However, in this correlational study, chronotype was not related to disease activity or patient-reported outcomes. An experimental study is needed to examine whether delaying the circadian rhythm has a positive influence on these outcomes. This insight could improve our understanding of the pathophysiology of RA and contribute to exploring new treatment possibilities. Key Points • This is the first study examining chronotype in patients with rheumatoid arthritis, and how chronotype relates to disease activity and patient-reported outcomes. • We found an earlier chronotype in patients with rheumatoid arthritis than in subjects from the general population. • In this correlational study, chronotype was not related to disease activity or patient-reported outcomes. An experimental study is needed to examine whether delaying the circadian rhythm positively influences these outcomes.
34819172 Recommendations of the Brazilian Society of Rheumatology for the use of JAK inhibitors in 2021 Nov 24 Rheumatoid arthritis (RA) is a chronic and autoimmune systemic inflammatory disease that can cause irreversible joint deformities, with increased morbidity and mortality and a significant impact on the quality of life of the affected individual. The main objective of RA treatment is to achieve sustained clinical remission or low disease activity. However, up to 40% of patients do not respond to available treatments, including bDMARDs. New therapeutic targets for RA are emerging, such as Janus kinases (JAKs). These are essential for intracellular signaling (via JAK-STAT) in response to many cytokines involved in RA immunopathogenesis. JAK inhibitors (JAKi) have established themselves as a highly effective treatment, gaining increasing space in the therapeutic arsenal for the treatment of RA. The current recommendations aim to present a review of the main aspects related to the efficacy and safety of JAKis in RA patients, and to update the recommendations and treatment algorithm proposed by the Brazilian Society of Rheumatology in 2017.
33628011 Safety, Tolerability, and Pharmacokinetics of Ibuprofenamine Hydrochloride Spray (NSAIDs), 2021 BACKGROUND: Ibuprofenamine hydrochloride spray is novel transdermal nonsteroidal anti-inflammatory drugs (NSAIDs), under clinical development for the treatment of Rheumatoid Arthritis and Osteoarthritis as a novel transdermal drug. METHODS: A single and multiple ascending dose study investigated the safety, tolerability and pharmacokinetics of ibuprofenamine hydrochloride in healthy Chinese subjects. A total of 34 subjects (single-dose study: 34 subjects and multiple-dose study: 20 subjects) were involved in the trial. In the single-dose study, subjects were assigned to one of the four groups received 35, 70, 140, 280 mg. In the 70 mg and 140 mg treatment groups, subjects received one dose on the first day and twice a day from day 6 to 12. The starting dose was determined considering the no observed adverse effect level based on preclinical studies, and the dose escalations in subsequent cohorts were decided based on safety, tolerability, and pharmacokinetic data from previous dose cohorts. RESULTS: After a single dose, both ibuprofenamine and ibuprofen plasma exposure showed a more than dose-proportional increase across a dose range of 35-280 mg. After multiple dosing, both ibuprofenamine and ibuprofen steady-state exposure increased obviously more than dose-proportional manner across the evaluated dose range (twice a day for 7 days) resulted in obvious accumulation. Single or multiple doses of ibuprofenamine hydrochloride were generally well tolerated and no obvious skin irritation was observed. CONCLUSION: Ibuprofenamine hydrochloride exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for Rheumatoid Arthritis and Osteoarthritis.
34526997 Common Transcriptomic Effects of Abatacept and Other DMARDs on Rheumatoid Arthritis Synovi 2021 OBJECTIVES: Our goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab. METHODS: Synovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3(+), CD20(+), and CD68(+) cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR. RESULTS: Gene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders. CONCLUSION: We provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets.
32928608 Do RA associated HLA-DR molecules bind citrullinated peptides or peptides from PAD4 to hel 2021 Jan PURPOSE: Rheumatoid arthritis (RA) is associated with HLA-DRB1 genes encoding a five amino acid basic motive, the shared epitope SE). Each HLA-DRB1 genotype defines a genotype specific risk of developing RA. RA is preceded by the emergence of anti citrullinated protein antibodies (ACPAs). Citrullin is a neutral version of arginin, a basic amino acid, formed after post translational modification by Peptidyl Arginyl Deiminases (PADs). HLA-DRB1 genes associated with RA are also associated with ACPAs. Two models might explain this association. Here we tested both models for prediction of HLA-DRB1 genotypic risks of developing RA. METHODS: We calculated the likelihoods for the 2 HLA-DR molecules encoded by 12 common HLA-DRB1 genotypes to bind at least one randomly chosen peptide from PAD4 or fibrinogen(native or citrullinatd) and compared them with the 12 respective HLA-DRB1genotypic risks of developing RA. RESULTS: HLA-DRB1 Genotypic risks of developing RA correlate with likelihoods of binding PAD4 peptides, not citrullinated Fibrinogen peptides. Thus, the molecular basis for the association of HLA-DR and ACPA positive RA is most likely the capability for RA associated HLA-DR molecules to bind peptides(s) from PAD4.
34103083 Plasma metabolomic profiling in patients with rheumatoid arthritis identifies biochemical 2021 Jun 8 BACKGROUND: Rheumatoid arthritis (RA) is a chronic, autoimmune disorder characterized by joint inflammation and pain. In patients with RA, metabolomic approaches, i.e., high-throughput profiling of small-molecule metabolites, on plasma or serum has thus far enabled the discovery of biomarkers for clinical subgroups, risk factors, and predictors of treatment response. Despite these recent advancements, the identification of blood metabolites that reflect quantitative disease activity remains an important challenge in precision medicine for RA. Herein, we use global plasma metabolomic profiling analyses to detect metabolites associated with, and predictive of, quantitative disease activity in patients with RA. METHODS: Ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was performed on a discovery cohort consisting of 128 plasma samples from 64 RA patients and on a validation cohort of 12 samples from 12 patients. The resulting metabolomic profiles were analyzed with two different strategies to find metabolites associated with RA disease activity defined by the Disease Activity Score-28 using C-reactive protein (DAS28-CRP). More specifically, mixed-effects regression models were used to identify metabolites differentially abundant between two disease activity groups ("lower", DAS28-CRP ≤ 3.2; and "higher", DAS28-CRP > 3.2) and to identify metabolites significantly associated with DAS28-CRP scores. A generalized linear model (GLM) was then constructed for estimating DAS28-CRP using plasma metabolite abundances. Finally, for associating metabolites with CRP (an indicator of inflammation), metabolites differentially abundant between two patient groups ("low-CRP", CRP ≤ 3.0 mg/L; "high-CRP", CRP > 3.0 mg/L) were investigated. RESULTS: We identified 33 metabolites differentially abundant between the lower and higher disease activity groups (P < 0.05). Additionally, we identified 51 metabolites associated with DAS28-CRP (P < 0.05). A GLM based upon these 51 metabolites resulted in higher prediction accuracy (mean absolute error [MAE] ± SD: 1.51 ± 1.77) compared to a GLM without feature selection (MAE ± SD: 2.02 ± 2.21). The predictive value of this feature set was further demonstrated on a validation cohort of twelve plasma samples, wherein we observed a stronger correlation between predicted and actual DAS28-CRP (with feature selection: Spearman's ρ = 0.69, 95% CI: [0.18, 0.90]; without feature selection: Spearman's ρ = 0.18, 95% CI: [-0.44, 0.68]). Lastly, among all identified metabolites, the abundances of eight were significantly associated with the CRP patient groups while controlling for potential confounders (P < 0.05). CONCLUSIONS: We demonstrate for the first time the prediction of quantitative disease activity in RA using plasma metabolomes. The metabolites identified herein provide insight into circulating pro-/anti-inflammatory metabolic signatures that reflect disease activity and inflammatory status in RA patients.
35027248 Association between serum amyloid A and rheumatoid arthritis: A systematic review and meta 2022 Feb BACKGROUNDS: Consistent correlation of serum amyloid A (SAA) to rheumatoid arthritis (RA) is not completely established. The present study is to systematically summarize their relationship. METHODS: Publications up to may 2021 were examined using key terms in the PubMed, Cochrane Library, Embase and China national knowledge infrastructure (CNKI) databases. RESULTS: The total 33 studies, involving in 3524 RA cases and 3537 normal participants, were included. The pooled result indicated that the SAA level in the RA group was markedly higher than that in the control group [standardized mean difference (SMD) = 0.80, 95% CI (0.51, 1.08)]. By stratified analyses, the concentration of SAA was found to be gradually increased with the aggravation of RA. Additionally, the meta-analysis of correlation demonstrated that SAA levels were positively associated with the levels of disease activity score 28 (DAS28) [r = 0.55, 95% CI (0.15, 0.94)], erythrocyte sedimentation rate (ESR) [r = 0.65, 95% CI (0.53, 0.76)], C-reactive protein (CRP) [r = 0.92, 95% CI (0.57, 1.57)], rheumatoid factor (RF) [r = 0.24, 95% CI (0.09, 0.39)], interleukin 4 (IL-4) [r = 0.54, 95% CI (0.30, 0.78)], interleukin 6 (IL-6) [r = 0.46, 95% CI (0.27, 0.65)], interleukin 10 (IL-10) [r = 0.53, 95% CI (0.29, 0.77)], interleukin 17 (IL-17) [r = 0.52, 95% CI (0.27, 0.77)], and anti-cyclic citrullinated peptide antibody (A-CCP) [r = 0.32, 95% CI (0.15, 0.50)], but inversely linked with the levels of hemoglobin [r=-0.51, 95% CI (-0.84, -0.18)]. Furthermore, the allele of SAA 1.3 was actively related with increased risks of RA [OR=1.30, 95% CI (1.02, 1.65)] and of RA with amyloidosis [OR=2.06, 95% CI (1.63, 2.60)]. Besides, the genotype of SAA 1.3/1.3 was positively connected with the risks of RA [OR=1.56, 95% CI (1.00, 2.43)] and of RA with amyloidosis [OR=4.47, 95% CI (2.70, 7.41)]. CONCLUSIONS: High levels of SAA might be associated with elevated risk of RA, and the concentration of SAA might be gradually increased with the aggravation of RA. Moreover, high levels of SAA might play a vital role in RA by enhancing the levels of DAS28, ESR, CRP, RF, IL-4, IL-6, IL-10, IL-17 and A-CCP, or by attenuating hemoglobin levels. More importantly, the allele of SAA 1.3 and genotype of SAA 1.3/1.3 might be the risk factor of RA and of RA with amyloidosis.
33464392 Long-term effects on bone mineral density after four years of treatment with two intensive 2021 Jul In this study, no difference in bone loss was observed between patients with early RA initially treated with COmbinatietherapie Bij Reumatoide Artritis (COBRA) (including initially 60 mg/day prednisolone) and patients treated with COBRA-light (including initially 30 mg/day prednisolone) during 4-year observation. PURPOSE: To assess changes in bone mineral density (BMD) after 4 years in early rheumatoid arthritis (RA) patients initially treated with COBRA-light or COBRA therapy. METHODS: In a 1 year, open-label, randomised, non-inferiority trial, patients were assigned to COBRA-light (methotrexate 25 mg/week plus initially prednisolone 30 mg/day) or COBRA (methotrexate 7.5 mg/week, sulfasalazine 2 g/day plus initially prednisolone 60 mg/day) therapy. After 1 year, antirheumatic treatment was at the discretion of treating rheumatologists. BMD was measured at baseline and after 1, 2 and 4 years at hips and lumbar spine with dual-energy X-ray absorptiometry. BMD changes between treatment strategies on average over time were compared with GEE analysis. RESULTS: Data from 155 out of 162 patients could be analysed: 68% were female with a mean age of 52 (SD 13) years. Both COBRA-light and COBRA therapy showed declines in BMD at the total hip of -3.3% and -1.7%, respectively (p = 0.12), and the femoral neck, -3.7% and -3.0%, respectively (p = 0.95). At the lumbar spine, both treatment groups showed minor decline in BMD over 4 years: -0.5% and -1.0%, respectively (p = 0.10). CONCLUSION: In a treat-to-target design in early RA, over 4 years, no differences between groups were found in change in BMD at total hip, femoral neck and the lumbar spine. At the hip, bone loss was around 3% in both groups, while mild bone loss was observed at lumbar spine, both in patients starting prednisolone 60 and 30 mg/day. These data suggest that the well-known negative effects of prednisolone can be modulated by modern treatment of RA.
33727152 Antibody glycosylation in autoimmune diseases. 2021 May The glycosylation of the fragment crystallizable (Fc) region of immunoglobulins (Ig) is critical for the modulation of antibody effects on inflammation. Moreover, antibody glycosylation may induce pathologic modifications and ultimately contribute to the development of autoimmune diseases. Thanks to progress in the analysis of glycosylation, more data are available on IgG and its subclass structures in the context of autoimmune diseases. In this review, we focused on the impact of Ig glycosylation in autoimmunity, describing how it modulates the immune response and how glycome profiles can be used as biomarkers of disease activity. The analysis of antibody glycosylation demonstrated specific features in human autoimmune and chronic inflammatory conditions, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and autoimmune liver diseases, among others. Within the same disease, different patterns are associated with disease severity and treatment options. Future research may increase the information available on the distinct glycome profiles and expand their potential role as biomarkers and as targets for treatment, ultimately favoring an individualized approach.
34235789 Polymeric Aggregate-Embodied Hybrid Nitric-Oxide-Scavenging and Sequential Drug-Releasing 2021 Aug Selective depletion of overproduced nitric oxide (NO) with nanoscavengers is a promising approach for treating rheumatoid arthritis (RA), preventing both oxidative/nitrosative stress and the upregulation of immune cells. However, its practical applications are limited owing to the minimum time interval between intra-articular injections and unwanted off-target NO depletion. Herein, the rational design of an injectable in situ polymeric aggregate-embodied hybrid NO-scavenging and sequential drug-releasing (M-NO) gel platform for the combinatorial treatment of RA by incorporating a "clickable" NO-cleavable cross-linker (DA-NOCCL) is reported. This network is held together with polymeric aggregates to achieve a self-healing capability for visco-supplementation and on-demand dual drug (both hydrophilic and hydrophobic)-releasing properties, depending on the NO concentration. Moreover, consecutive NO-scavenging action reduces pro-inflammatory cytokine levels in lipopolysaccharides-stimulated macrophage cell lines in vitro. Finally, the intra-articularly injected M-NO gel with anti-inflammatory dexamethasone significantly alleviates the symptoms of RA, with negligible toxicity, in animal models. It is believed that this novel M-NO gel platform will provide a guideline for the combinatorial treatment of RA and various NO-related diseases.
34025065 Immune disorders and rheumatologic manifestations of viral hepatitis. 2021 May 14 Infection with hepatotropic viruses is not limited to the liver and can lead to the development of various immunological disorders (the formation of cryoglobulins, rheumatoid factor, antinuclear antibodies, autoantibodies specific for autoimmune hepatitis and primary biliary cholangitis, and others), which can manifest as glomerulonephritis, arthritis, uveitis, vasculitis (cryoglobulinemic vasculitis, polyarteritis nodosa, Henoch-Schonlein purpura, isolated cutaneous necrotizing vasculitis), and other rheumatologic disorders, and be a trigger for the subsequent development of autoimmune hepatitis and primary biliary cholangitis. A further study of the association between autoimmune liver diseases and hepatotropic virus infection would be useful to assess the results of treatment of these associated diseases with antiviral drugs. The relationship of these immune disorders and their manifestations with hepatotropic viruses is best studied for chronic hepatitis B and C. Only isolated cases of these associations are described for hepatitis A. These links are least studied, and are often controversial for hepatitis E, possibly due to their relatively rare diagnoses. Patients with uveitis, glomerulonephritis, arthritis, vasculitis, autoimmune liver diseases should be tested for biomarkers of viral hepatitis, and if present, these patients should be treated with antiviral drugs.
34177888 Cross-Tissue Transcriptomic Analysis Leveraging Machine Learning Approaches Identifies New 2021 There is an urgent need to identify biomarkers for diagnosis and disease activity monitoring in rheumatoid arthritis (RA). We leveraged publicly available microarray gene expression data in the NCBI GEO database for whole blood (N=1,885) and synovial (N=284) tissues from RA patients and healthy controls. We developed a robust machine learning feature selection pipeline with validation on five independent datasets culminating in 13 genes: TNFAIP6, S100A8, TNFSF10, DRAM1, LY96, QPCT, KYNU, ENTPD1, CLIC1, ATP6V0E1, HSP90AB1, NCL and CIRBP which define the RA score and demonstrate its clinical utility: the score tracks the disease activity DAS28 (p = 7e-9), distinguishes osteoarthritis (OA) from RA (OR 0.57, p = 8e-10) and polyJIA from healthy controls (OR 1.15, p = 2e-4) and monitors treatment effect in RA (p = 2e-4). Finally, the immunoblotting analysis of six proteins on an independent cohort confirmed two proteins, TNFAIP6/TSG6 and HSP90AB1/HSP90.
33608744 Methotrexate does not increase the risk of liver fibrosis in patients with rheumatoid arth 2021 Jun OBJECTIVES: Only limited data are available on the risk of liver fibrosis in patients with rheumatoid arthritis on long-term methotrexate treatment. To assess the risk of liver fibrosis in patients with rheumatoid arthritis treated with methotrexate, non-invasive, ultrasound-based elastography [acoustic radiation force impulse (ARFI) imaging] was applied. METHODS: In total, 119 patients were assessed using acoustic radiation force impulse (ARFI) imaging between July 2018 and April 2019. In a cross-sectional, single-centre study design, ARFI scores were compared between patient subgroups with (n = 65) and without (n = 54) methotrexate exposure. The main outcome variable was the mean fibrosis score as measured by the ARFI method. The mean shear wave velocity was calculated from 10 valid ARFI measurements for each patient. Inferential statistical analyses (between group) were performed using ANOVA for independent samples in the case of continuous outcome variables. RESULTS: Sixty-five patients with and fifty-four patients without MTX exposure were assessed using the ARFI elastography method. Participating patients on MTX medication (1.113 m/s) showed ARFI scores that were comparable to those of participants without MTX exposure (1.062 m/s); P = 0.228. The mean cumulative dose in the group of MTX-exposed patients was 3602 mg. CONCLUSION: The mean value of the repeated determination of liver density using ARFI imaging did not differ significantly between the MTX-exposed and MTX-naive patients with RA. No increased rate of liver fibrosis was found among RA patients treated with MTX.
33707464 Higher PGD(2) production by synovial mast cells from rheumatoid arthritis patients compare 2021 Mar 11 We previously reported that synovial mast cells (MCs) from patients with rheumatoid arthritis (RA) produced TNF-α in response to immune complexes via FcγRI and FcγRIIA. However, the specific functions of synovial MCs in RA remain unclear. This study aimed to elucidate those functions. Synovial tissues and fluid were obtained from RA and osteoarthritis (OA) patients undergoing joint replacement surgery. Synovium-derived, cultured MCs were generated by culturing dispersed synovial cells with stem cell factor. We performed microarray-based screening of mRNA and microRNA (miRNA), followed by quantitative RT-PCR-based verification. Synovial MCs from RA patients showed significantly higher prostaglandin systhetase (PTGS)1 and PTGS2 expression compared with OA patients' MCs, and they produced significantly more prostaglandin D(2) (PGD(2)) following aggregation of FcγRI. PGD(2) induced IL-8 production by human group 2 innate lymphoid cells, suggesting that PGD(2)-producing MCs induce neutrophil recruitment into the synovium of RA patients. PTGS2 mRNA expression in RA patients' MCs correlated inversely with miRNA-199a-3p expression, which down-regulated PTGS2. RA patients' synovial fluid contained significantly more PGD(2) compared with OA patients' fluid. Synovial MCs might regulate inflammation in RA through hyper-production of PGD(2) following FcRγ aggregation. Our findings indicate functional heterogeneity of human MCs among diseases.
34929309 Erteng Tongbi Decoction ameliorates collagen-induced arthritis in mice via modulating T ce 2022 Mar 25 ETHNOPHARMACOLOGICAL RELEVANCE: Herbs have been commonly used for the treatment of rheumatoid arthritis (RA). It has been verified that Erteng Tongbi Decoction has good therapeutic effects on RA, while, relatively few studies on the relationship between its components and anti-rheumatoid efficacy were carried out. AIM OF THE STUDY: To discuss the anti-RA effects of Erteng Tongbi Decoction on collagen-induced arthritis (CIA) in mice and the influence of T cell differentiation and cytokines balance. MATERIALS AND METHODS: Separate researches on the two traditional Chinese medicines of the Erteng Tongbi Decoction were conducted. First, a murine peritoneal macrophage model was established, and then the cytokines levels and macrophage maturity were measured to select the best extraction solvent. Furthermore, ethanol extracts were partitioned successively with four kinds of solvents, and the anti-inflammatory parts were selected by the same vitro model. Subsequently, mice were arbitrarily divided into control, CIA model, positive control, effective parts alone or in combination. After 20 days of oral administration, the weight, hind paw volume, rheumatism index value, and the pathological changes were checked to assess the obvious level of arthritis. Furthermore, the levels of IL-6, TNF-α, IL-10, and IL-17A in serum and the balance of Th17/Treg and Th1/Th2 cells in spleen and mesenteric lymph nodes (MLN) was detected. Finally, the major active constituents were identified. RESULTS: In vitro, the anti-inflammatory effects of ethanol extracts was much better than water extract. In addition, the effective parts of Celastrus orbiculatus Thunb. ethanol extract were petroleum ether parts and dichloromethane parts. The effective parts of Spatholobus suberectus Dunn. ethanol extracts was petroleum ether parts and ethyl acetate parts screened. In vivo, effective parts compatibility could inhibit the progression of inflammation by modulating T cell differentiation and cytokines balance. Constituent analysis revealed that effective parts contained sesquiterpenes alkaloids, phenolic acids, and flavanols. CONCLUSIONS: Erteng Tongbi Decoction could notably ameliorate CIA mice by modulating T cell differentiation and cytokines balance and support its application in folk medicine.
33879179 Gender- and age-related differences of statin use on incident dementia in patients with rh 2021 Apr 20 BACKGROUND: Some observational studies have found a significant association between the use of statin and a reduced risk of dementia. However, the results of these studies are unclear in patients with rheumatoid arthritis (RA). This study is to determine the association between the use of statins and the incidence of dementia according to sex and age-related differences in patients with RA. METHODS: We conducted a nationwide retrospective cohort study using the Taiwan Health Insurance Review and Assessment Service database (2003-2016). The primary outcome assessed was the risk of dementia by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Multiple Cox regression was used to estimate the adjusted hazard ratio of new-onset dementia. Subgroup analysis was also conducted. RESULTS: Among the 264,036 eligible patients with RA aged > 40 years, statin users were compared with non-statin users by propensity score matching at a ratio of 1:1 (25,764 in each group). However, no association was found between the use of statins and the risk of new-onset dementia (NOD) in patients with RA (HR: 1.01; 95% CI: 0.97-1.06). The subgroup analysis identified the use of statin as having a protective effect against developing NOD in male and older patients. CONCLUSION: No association was observed between the use of a statin and the risk of NOD in patients with RA, including patients of both genders and aged 40-60 years, but these parameters were affected by gender and age. The decreased risk of NOD in patients with RA was greater among older male patients. Use of a statin in older male (> 60 years) patients with RA may be needed in clinical practice to prevent dementia.
33769258 Interleukin-7: a potential factor supporting B-cell maturation in the rheumatoid arthritis 2021 Mar OBJECTIVES: The exact function of interleukin-7 (IL-7) in autoimmune diseases remains unclear although it is a recognised therapeutic target for cytokine blockade. Our objective was to investigate the regulation and downstream effect of IL-7 in diseased tissue from rheumatoid arthritis (RA) patients notably with respect to its function as bone turnover regulator and tissue architecture (TA) organiser. METHODS: Synovial tissues (fresh, frozen or xed) were obtained from our tissue bank and distributed between experiments for live cell cultures, histology, immunohistochemistry or gene expression array by qPCR. RESULTS: IL-7 expression in synoviocyte cultures was up-regulated by pro-in ammatory cytokines, notably IL-6. Gene expression pro ling segregated synovial biopsies based on the presence of B/plasma cells and ectopic TA. IL-7 gene expression was associated with that of several genes whose function was to support B-cell maturation in tissue with distinct B-cell aggregates (despite the lack of IL-7-Receptor expression on B-cells) as well as with ectopic germinal-like centres. IL-7 was associated with bone turnover regulation in biopsies with diffuse in ltration. A novel relationship between the IL-7 and IL-6 axis was also highlighted in human tissue. CONCLUSIONS: Overall, IL-7 may contribute to the maintenance of the pro-in ammatory cycle perpetuating in ammation in RA synovium. We therefore propose a novel role for IL-7 as an orchestrator of TA with an impact on B-cell maturation in relation with IL-6.
33556301 Alantolactone alleviates collagen-induced arthritis and inhibits Th17 cell differentiation 2021 Dec CONTEXT: Alantolactone, the bioactive component in Inula helenium L. (Asteraceae), exhibits multiple biological effects. OBJECTIVE: We aimed to determine the anti-inflammatory effect of alantolactone in a collagen-induced arthritis (CIA) mouse model and its immunomodulatory effects on Th17 differentiation. MATERIALS AND METHODS: A CIA mouse model was established with DBA/1 mice randomly divided into four groups (n = 6): healthy, vehicle and two alantolactone-treated groups (25 or 50 mg/kg), followed by oral administration of alantolactone to mice for 21 consecutive days after arthritis onset. The severity of CIA was evaluated by an arthritic scoring system and histopathological examination. Levels of cytokines and anti-CII antibodies as well as percentages of splenic Th17 and Th17 differentiation with or without alantolactone treatments (0.62, 1.2 or 2.5 μM) were detected with ELISA and flow cytometry, respectively. Western blot analysis was used to evaluate intracellular signalling in alantolactone-treated spleen cells. RESULTS: In CIA mice, alantolactone at 50 mg/kg attenuated RA symptoms, including high arthritis scores, infiltrating inflammatory cells, synovial hyperplasia, bone erosion and levels of the proinflammatory cytokines TNF-α, IL-6 and IL-17A, but not IL-10 in paw tissues. Alantolactone also reduced the number of splenic Th17 cells and the capability of naïve CD4(+) T cells to differentiate into the Th17 subset by downregulating STAT3/RORγt signalling by as early as 24 h of treatment. DISCUSSION AND CONCLUSIONS: Alantolactone possesses an anti-inflammatory effect that suppresses murine CIA by inhibiting Th17 cell differentiation, suggesting alantolactone is an adjunctive therapeutic candidate to treat rheumatoid arthritis.