Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 35350778 | RA Fibroblast-Like Synoviocytes Derived Extracellular Vesicles Promote Angiogenesis by miR | 2022 | Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory in joints. Invasive pannus is a characteristic pathological feature of RA. RA fibroblast-like synoviocytes (FLSs) are showed tumor-like biological characters that facilitate pannus generation. Importantly, it has been documented that extracellular vesicle (EVs) derived microRNAs have a vital role of angiogenesis in various immune inflammatory diseases. However, whether RA FLSs derived EVs can facilitate angiogenesis and the underlying mechanism is undefined. Herein, we aim to investigate the key role of RA FLSs derived EVs on angiogenesis in endothelial cells (ECs). We indicate that RA FLSs derived EVs promote ECs angiogenesis by enhancing migration and tube formation of ECs in vitro. Also, we confirm that RA FLSs derived EVs can significantly facilitate ECs angiogenesis with a matrigel angiogenesis mice model. In terms of the mechanisms, both RNAs and proteins in EVs play roles in promoting ECs angiogenesis, but the RNA parts are more fundamental in this process. By combining microRNA sequencing and qPCR results, miR-1972 is identified to facilitate ECs angiogenesis. The blockage of miR-1972 significantly abrogated the angiogenesis stimulative ability of RA FLSs derived EVs in ECs, while the overexpression of miR-1972 reversed the effect in ECs. Specifically, the p53 level is decreased, and the phosphorylated mTOR is upregulated in miR-1972 overexpressed ECs, indicating that miR-1972 expedites angiogenesis through p53/mTOR pathway. Collectively, RA FLSs derived EVs can promote ECs angiogenesis via miR-1972 targeted p53/mTOR signaling, targeting on RA FLSs derived EVs or miR-1972 provides a promising strategy for the treatment of patients with RA. | |
| 34918591 | Current evidence on the use of the adalimumab biosimilar SB5 (Imraldi(TM)): a multidiscipl | 2022 Feb | INTRODUCTION: This review provides an overview of data from trials and real-world studies available for SB5 (Imraldi(TM)) across three main therapeutic areas: rheumatology, gastroenterology, and dermatology. AREAS COVERED: A literature search for publications on data for SB5 efficacy/effectiveness, safety, and immunogenicity was undertaken. EXPERT OPINION: Evidence derived from clinical studies suggest that the biosimilar SB5 is a safe and effective alternative to reference adalimumab. Considering that patients suffering from immune-mediated inflammatory diseases such as inflammatory arthritis, inflammatory bowel disease and psoriasis often require long-term biologic treatment, biosimilar medicines (such as SB5) can reduce healthcare costs while increasing access to effective treatments. | |
| 35153284 | Use of Online Information in Musculoskeletal Conditions: An Analysis of Google Trends Data | 2022 Apr 1 | BACKGROUND/OBJECTIVE: We aimed to investigate the yearly online public interest for gout, low back pain, neck pain, osteoarthritis, and rheumatoid arthritis, the most popular topics searched for these conditions, and the association between the change in their interest over time and the sociodemographic index of the search location. METHODS: We conducted online searches in Google Trends for the aforementioned conditions between 2004 and 2020. The search volumes for each condition (relative to all searches conducted in the period) and the top and rising related queries and topics were downloaded and summarized. RESULTS: There was a rise in the online interest for musculoskeletal conditions between 2008 and 2020, with low back pain (annual percent change, 7.4; 95% confidence interval [CI], 7.1-7.7) and neck pain (annual percent change, 7.2; 95% CI, 6.9-7.5) presenting the highest increases. There was a negative, statistically significant, but small association between change in online interest and the country's sociodemographic index for low back pain (-0.007; 95% CI, -0.011 to-0.003), neck pain (-0.005; 95% CI, 0.009 to -0.001), and rheumatoid arthritis (-0.009; 95% CI, -0.017 to -0.001) between 2013 and 2020. The interest for the cause and symptoms of the selected conditions increased over time, except for gout. The proportion of queries and topics related to treatment of all conditions decreased over time. CONCLUSIONS: The worldwide interest in musculoskeletal conditions increased between 2008 and 2020. The public seems more interested in understanding what musculoskeletal conditions are and less interested in which treatment options are available. The results can guide the development of educational campaigns for musculoskeletal conditions. | |
| 35193873 | Two-week methotrexate discontinuation in patients with rheumatoid arthritis vaccinated wit | 2022 Jun | OBJECTIVE: To evaluate the effect on immunogenicity and safety of 2-week methotrexate (MTX) discontinuation after each dose of the Sinovac-CoronaVac vaccine versus MTX maintenance in patients with rheumatoid arthritis (RA). METHODS: This was a single-centre, prospective, randomised, investigator-blinded, intervention study (NCT04754698, CoronavRheum) including adult patients with RA (stable Clinical Disease Activity Index (CDAI) ≤10, prednisone ≤7.5 mg/day) randomised (1:1) to withdraw MTX (MTX-hold) for 2 weeks after each vaccine dose or maintain MTX (MTX-maintain), evaluated at day 0 (D0), D28 and D69. Coprimary outcomes were anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC) and neutralising antibody (NAb) positivity at D69. Secondary outcomes were geometric mean titres (GMT) and flare rates. For immunogenicity analyses, we excluded patients with baseline positive IgG/NAb, and for safety reasons those who flared at D28 (CDAI >10) and did not withdraw MTX twice. RESULTS: Randomisation included 138 patients with 9 exclusions (5 COVID-19, 4 protocol violations). Safety evaluation included 60 patients in the MTX-hold and 69 patients in the MTX-maintain group. Further exclusions included 27 patients (13 (21.7%) vs 14 (20.3%), p=0.848) with positive baseline IgG/NAb and 10 patients (21.3%) in MTX-hold with CDAI >10 at D28. At D69, the MTX-hold group (n=37) had a higher rate of SC than the MTX-maintain group (n=55) (29 (78.4%) vs 30 (54.5%), p=0.019), with parallel augmentation in GMT (34.2 (25.2-46.4) vs 16.8 (11.9-23.6), p=0.006). No differences were observed for NAb positivity (23 (62.2%) vs 27 (49.1%), p=0.217). At D28 flare, the rates were comparable in both groups (CDAI, p=0.122; Disease Activity Score in 28 joints with C reactive protein, p=0.576), whereas CDAI >10 was more frequent in MTX-hold at D69 (p=0.024). CONCLUSION: We provided novel data that 2-week MTX withdrawal after each dose of the Sinovac-CoronaVac vaccine improves anti-SARS-CoV-2 IgG response. The increased flare rates after the second MTX withdrawal may be attributed to the short-term interval between vaccine doses. This strategy requires close surveillance and shared decision making due to the possibility of flares. | |
| 35298288 | The Role of Different Circulating T Follicular Helper Cell Markers in Rheumatoid Arthritis | 2022 Mar | Rheumatoid arthritis (RA) is a chronic incurable inflammatory autoimmune disease. T follicular helper (Tfh) cells expressing different markers play critical roles in the development of RA. However, their specific mechanisms of action and association with RA clinical parameters are not clear. We therefore performed a cohort study to investigate the effects of different Tfh cell markers on RA pathogenesis. We retrospectively reviewed clinical data from 30 patients diagnosed with RA and 30 healthy controls (HCs) who visited our hospital. Based on X-ray findings, the patients were divided into a joint bone erosion group (n = 17) and a non-erosive joint bone group (n = 13). Using flow cytometry, we determined the frequencies of five peripheral blood CD4(+) Tfh cell types characterized by different markers, and examined these cell types for correlations with clinical parameters. RA patients exhibited higher frequencies of CD4(+)CXCR5(+), CD4(+)CXCR5(+)ICOS(+), CD4(+)CXCR5(+)OX40(+), and CD4(+)CXCR5(+)CD40L(+) Tfh cells than HCs. CD4(+)CXCR5(+), CD4(+)CXCR5(+)CD40L(+), and CD4(+)CXCR5(+)OX40(+) Tfh cell frequencies positively correlated with disease activity score-28 with erythrocyte sedimentation rate (DAS28-ESR), while those of CD4(+)CXCR5(+) and CD4(+)CXCR5(+)CD40L(+) Tfh cells were related to rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies. In RA patients without joint bone erosion, CD4(+)CXCR5(+)CD40L(+) Tfh cell frequencies were positively correlated with both RF and DAS28-ESR. Serum anti-CCP antibody levels and CD4(+)CXCR5(+)ICOS(+) Tfh cell frequencies were also positively correlated. Circulating CD4(+)CXCR5(+)CD40L(+) Tfh cells appear to play critical roles in RA pathogenesis, and restricting CD4(+)CXCR5(+)CD40L(+) Tfh cells may be a therapeutic strategy for controlling RA. | |
| 35032583 | Thermal and wine processing enhanced Clematidis Radix et Rhizoma ameliorate collagen Ⅱ i | 2022 Apr 24 | ETHNOPHARMACOLOGICAL RELEVANCE: Clematidis Radix et Rhizoma, a kind of traditional Chinese medicine, is derived from Clematis chinensis Osbeck, Clematis hexapetala Pall. and Clematis manshurica Rupr. This herb shows great effects on expelling wind and dispelling dampness in ancient and it has anti-inflammatory and analgesic activity in modern clinical application. AIM OF THE STUDY: This experiment aimed to research anti-rheumatoid arthritis effect of crude and wine processed RC based on glycolysis metabolism to provide new ideas treating RA. MATERIALS AND METHODS: Network pharmacology was applied to preliminarily forecast the potential pathways of common targets of RC and RA. RAW264.7 macrophages were induced by LPS, NO production, glucose uptake, lactate production, ROS and MMP were detected as instructions in vitro. ELISA was used to measure the content of HK2, PKM2 and LDHA involving in glycolysis process. Gut microbiota was analyzed by 16S rRNA gene amplicon sequencing in CIA rats. RESULTS: Crude and wine processed RC had good anti-inflammatory effect by reducing NO in RAW264.7 macrophages and ameliorating inflammatory infiltration and cartilage surface erosion in CIA rats. Whether in LPS-induced macrophages or CIA rats, crude and wine processed RC could inhibit glycolysis by down-regulating the expression of PKM2, causing less glucose uptake and lactic acid, which lead to less ROS and higher MMP to normal. PI3K-AKT and HIF-1α pathways were deduced to possibly play a crucial part in controlling glycolysis metabolism by network pharmacology analysis. Besides, it was displayed that Firmicutes and Bacteroidetes were prominent gut microbiota in CIA rats feces. CC-H and PZ-H groups could both increase the relative abundance of Firmicutes and decrease Bacteroidetes. These microbiota also played a role in RA pathological process via involving in energy metabolism, carbohydrate metabolism and immune system. CONCLUSION: Crude and wine processed RC have a good influence in ameliorating rheumatoid arthritis by inhibiting glycolysis and modulating gut microbiota together. | |
| 35370215 | Specneuzhenide Ameliorate Complete Freund Adjuvant Induced Arthritis in Rats: Involvement | 2022 | Rheumatoid arthritis (RA) is growing autoimmune and inflammatory disease that occur due to self-destruction of immune response inducing joint deformity and bone erosion. During the arthritis inducing the swelling, pain and inflammation in around the joint and other body organs due to injury of tendons and ligaments. Specneuzhenide (SZ) already proved antioxidant and anti-inflammatory effect against the various diseases. In this experimental study, we scrutinized the anti-arthritic effect of SZ against the complete freund adjuvant (CFA) induced arthritic in rats. Subcutaneously injection of CFA was injected into the subplantar region of the left hind paw for induction the arthritis and rats were divided into different groups and rats received the oral administration of SZ (5, 10 and 15 mg/kg) for 28 days. The body weight, paw swelling arthritic score mRNA expression and biochemical parameters were determined at regular time interval. CFA induced arthritic rats treated with SZ significantly (p < 0.001) enhanced the body weight and decreased the paw swelling, arthritic index and organ (spleen and thymus) index, respectively. SZ treated rats significantly (p < 0.001) decreased the hepatic parameter such as SGPT, SGOT and ALP, anti-CII IgG levels (IgG1 and IgG2A) and inflammatory parameters (COX-2 and PGE(2)). SZ treated rats significantly (p < 0.001) suppressed the level of MDA and increased the level of GSH, SOD and CAT. SZ treated rats suppressed the inflammatory cytokines such as TNF-α, Il-1β, IL-2, IL-6, IL-16, IL-17 and increased the level of IL-10, TGF-β. SZ treated rats significantly (p < 0.001) suppressed the mRNA expression of Nrf2, HO-1 and NF-κB. On the basis of result, we can say that specneuzhenide protective effect against CFA induced arthritis in rats via alteration of HO-1/Nrf-2 pathway. | |
| 35408888 | Gut Mucosal Microbiome Is Perturbed in Rheumatoid Arthritis Mice and Partly Restored after | 2022 Mar 24 | Rheumatoid arthritis (RA), an autoimmune disease, is characterized by chronic joint inflammation and pain. We previously found that the deletion of T-cell death-associated gene 8 (TDAG8) significantly reduces disease severity and pain in RA mice. Whether it is by modulating gut microbiota remains unclear. In this study, 64 intestinal samples of feces, cecal content, and cecal mucus from the complete Freund's adjuvant-induced arthritis mouse models were compared. The α- and β-diversity indices of the microbiome were significantly lower in RA mice. Cecal mucus showed a higher ratio of Firmicutes to Bacteroidetes in RA than healthy mice, suggesting the ratio could serve as an RA indicator. Four core genera, Eubacterium_Ventriosum, Alloprevotella, Rikenella, and Treponema, were reduced in content in both feces and mucus RA samples, and could serve microbial markers representing RA progression. TDAG8 deficiency decreased the abundance of proinflammation-related Eubacterium_Xylanophilum, Clostridia, Ruminococcus, Paraprevotella, and Rikenellaceae, which reduced local mucosal inflammation to relieve RA disease severity and pain. The pharmacological block of the TDAG8 function by a salicylanilide derivative partly restored the RA microbiome to a healthy composition. These findings provide a further understanding of specific bacteria interactions with host gut mucus in the RA model. The modulation by TDAG8 on particular bacteria can facilitate microbiota-based therapy. | |
| 34624452 | Saponins from Nigella glandulifera seeds attenuate collagen-induced rheumatoid arthritis i | 2022 Jan 30 | ETHNOPHARMACOLOGICAL RELEVANCE: Nigella glandulifera Freyn et Sint. (N. glandulifera) seeds are widely used in traditional Uyghur medicine for a variety of immuno-inflammatory diseases. The total saponins from N. glandulifera seeds (TSNGS) have been shown to have analgesic, antioxidant, and anti-inflammatory effects that can alleviate joint pain and swelling. AIM OF THE STUDY: Rheumatoid arthritis (RA) is a chronic and progressive, debilitating autoimmune disease for which current treatments are not sufficiently effective and result in unsatisfactory side effects. This study aimed to mechanistically investigate the therapeutic effects of TSNGS on RA. MATERIALS AND METHODS: Qualitative analysis of TSNGS was performed using ultra-high-performance liquid chromatography-Q-Orbitrap-high-resolution mass spectrometry. Rats with collagen-induced arthritis (CIA), IL-1β-induced HFLS-RAs, and VEGF-induced HUVECs were analyzed to determine the efficacy and mechanism of TSNGS on RA. RESULTS: Twenty-one compounds were identified in TSNGS. TSNGS (10, 50, or 250 mg/kg) reduced the severity of arthritis, indicated by a lower arthritis score, reduced paw swelling, and body weight in rats with CIA. TSNGS ameliorated histopathological changes involving inflammatory infiltration, bone degeneration, and angiogenesis in knee and ankle joints. TSNGS improved the immuno-inflammatory response by restoring the levels of the cytokines IFN-γ, TNF-α, IL-1β, IL-6, IL-17A, IL-4, and IL-10, and increasing the number of CD4(+)CD25(+) Tregs in the peripheral circulation and Foxp3 levels in knee joints in rats with CIA. Furthermore, TSNGS increased the OPG/RANKL ratio and downregulated p-p65 in serum and joint synovia. Inhibition of angiogenesis by TSNGS was associated with recovery of the angiogenesis-related Ang/Tie-2 signaling pathway. CONCLUSIONS: It was established that TSNGS provides a therapeutic effect on RA by alleviating synovitis, bone degeneration, and angiogenesis via the OPG/RANKL/NF-κB and Ang/Tie-2 pathways and may be used for the treatment of RA. | |
| 34125371 | Punicalagin ameliorates collagen-induced arthritis by downregulating M1 macrophage and pyr | 2022 Mar | Rheumatoid arthritis (RA) is a chronic inflammatory disease that eventually leads to disability. Inflammatory cell infiltration, severe joint breaking and systemic bone loss are the main clinical symptoms. In this study, we established a collagen-induced arthritis (CIA) model and found a large number of M1 macrophages and pyroptosis, which are important sources of proinflammatory cytokines. Punicalagin (PUN) is an active substance extracted from pomegranate peel. We found that it inhibited joint inflammation, cartilage damage and systemic bone destruction in CIA mice. PUN effectively alleviated the high expression of inflammatory cytokines in synovial tissue in vivo. PUN treatment shifted macrophages from the M1 phenotype to the M2 phenotype after stimulation with lipopolysaccharide (LPS) and interferon (IFN)-γ. The expression of inducible nitric oxide synthase (iNOS) and other proinflammatory cytokines released by M1 macrophages was decreased in the PUN treatment group. However, simultaneously, the expression of markers of anti-inflammatory M2 macrophages, such as arginase (Arg)-1 and interleukin (IL)-10, was increased. In addition, PUN treatment attenuated pyroptosis by downregulating the expression of NLRP3 and caspase-1, thereby preventing inflammatory cell death resulting from the release of IL-1β and IL-18. Mechanistically, PUN inhibited the activation of receptor activators of the nuclear factor-κB (NF-κB) signaling pathway, which contributes to M1 polarization and pyroptosis of macrophages. We concluded that PUN ameliorated pathological inflammation by inhibiting M1 phenotype polarization and pyroptosis and has great potential as a therapeutic treatment for human RA. | |
| 34695477 | Toxic mechanisms of cigarette smoke and heat-not-burn tobacco vapor inhalation on rheumato | 2022 Feb 25 | Tobacco combustion exposure worsens rheumatoid arthritis (RA). Non-combustible tobacco devices, as heat-not-burn tobacco (HNBT), are emerging as harm reduction to smokers by releasing nicotine and lower combustible tobacco products. Nevertheless, HNBT toxicity remains unclear. Hence, here we investigated the impacts of the tobacco combustible product (cigarette smoke; CS) or HNBT vapor exposures on antigen-induced arthritis (AIA) in C57BL/6 mice. Animals were exposed to airflow, HNBT vapor, or CS during 1 h/twice a day, under the Health Canada Intense (HCI) smoking regime, between days 14 to 20 after the first immunization. At day 21, 16 h after the last exposures, mice were i.a. challenged and the AIA effects were evaluated 24 h later. CS- or HNBT-exposed mice presented equivalent blood nicotine levels. CS exposure worsened articular symptoms, pulmonary inflammation, and expression of lung metallothioneins. Nevertheless, CS or HNBT exposures reduced lymphoid organs' cellularity, splenocyte proliferation and IL-2 secretion. Additional in vitro CS or HNBT exposures confirmed the harmful effects on splenocytes, which were partially mediated by the activation of nicotine/α7nAchR pathway. Associated, data demonstrate the toxic mechanisms of CS or HNBT inhalation at HCI regime on RA, and highlight that further investigations are fundamental to assure the toxicity of emerging tobacco products on the immune system during specific challenges. | |
| 35545340 | Effect of miR-124a on collagen-induced arthritis in mice and the underlying mechanisms. | 2022 Apr 28 | OBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune disease. MicroRNA has been shown to play an important role in RA. MicroRNA-124a (miR-124a) has anti-proliferative and anti-inflammatory effects in RA fibroblast synovial cells. This study aims to explore the effects of miR-124a overexpression on arthritis in collagen-induced arthritis (CIA) mice and the underlying mechanisms. METHODS: Bovine type II collagen and complete Ferris adjuvant were used to induce CIA model from DBA/1 mice. Twenty-eight days after initial immunization (D28), CIA mice were randomly divided into a model group, a miR-124a treatment group, and a negative control (NC) group. Physiological saline, miR-124a agomir, and miR-124a agomir NC were injected into the skin at the tail root of mice every 3 days for 4 times, respectively. The degree of joint swelling and arthritis index of mice were recorded accordingly. Sixty-three days after initial immunization (D63), the mice were sacrificed to obtain the synovial tissue of ankle joint. HE staining was used to observe the proliferation of synovial cell, infiltration of inflammatory cell, pannus, and bone erosion of synovial tissues; TUNEL staining was used to detect cell apoptosis; qRT-PCR was used to detect the mRNA expression of miR-124a, phosphatidylinositol-3-kinase catalytic subunit alpha (PIK3CA) and its downstream genes Bcl-2 and Bax. Immunohistochemistry was used to detect the protein expression of PIK3CA, Bcl-2, and Bax protein in synovial tissues of each group. RESULTS: Different degrees of swelling presented in the paws of DBA/1 mice at D28, which indicated the CIA model was constructed successfully. Forty-eight days after initial immunization (D48), the paws of mice in the miR-124a treatment group were only slightly red and swollen, while the paws of mice in the model group and the NC group were obviously red and swollen. The arthritis index of mice in the miR-124a treatment group were decreased significantly compared to the NC group at D51, D53, D59, and D62 (51, 53, 59, 62 days after initial immunization) (all P<0.05). Sixty-three days after initial immunization (D63), HE staining indicated that the scores of synovial cell proliferation, inflammatory cell infiltration, synovial pannus, and bone erosion were significantly reduced in the miR-124a treatment group (P<0.05 or P<0.01), while cell apoptosis was increased in the miR-124a treatment group compared with the model group and NC group (P<0.01 or P<0.001). Besides, the expression of miR-124a and Bax in the synovial tissue in miR-124a treatment group was significantly higher than those in the model group and NC group (P<0.01 or P<0.001), while the expressions of PIK3CA and Bcl-2 were decreased (P<0.05 or P<0.01 or P<0.001), and the ratio of Bcl-2 to Bax was significantly decreased (P<0.01 or P<0.001). CONCLUSIONS: Overexpression of miR-124a can reduce arthritis in CIA mice bacause it could promote synovial cell apoptosis and inhibit synovial cell proliferation via targeting PIK3CA and regulating its downstream pathways. | |
| 35148177 | Intestinal butyrate-metabolizing species contribute to autoantibody production and bone er | 2022 Feb 11 | The imbalance between pathogenic and beneficial species of the intestinal microbiome and metabolism in rheumatoid arthritis (RA) remains unclarified. Here, using shotgun-based metagenome sequencing for a treatment-naïve patient cohort and a "quasi-paired cohort" method, we observed a deficiency of butyrate-producing species and an overwhelming number of butyrate consumers in RA patients. These outcomes mainly occurred in patients with positive ACPA, with a mean AUC of 0.94. This panel was also validated in established RA with an AUC of 0.986 in those with joint deformity. In addition, we showed that butyrate promoted T(regs), while suppressing T(convs) and osteoclasts, due to potentiation of the reduction in HDAC expression and down-regulation of proinflammatory cytokine genes. Dietary butyrate supplementation conferred anti-inflammatory benefits in a mouse model by rebalancing T(FH) cells and T(regs), as well as reducing antibody production. These findings reveal the critical role of butyrate-metabolizing species and suggest the potential of butyrate-based therapies for RA patients. | |
| 35515003 | Accurate Machine Learning Model to Diagnose Chronic Autoimmune Diseases Utilizing Informat | 2022 | Heterogeneity and limited comprehension of chronic autoimmune disease pathophysiology cause accurate diagnosis a challenging process. With the increasing resources of single-cell sequencing data, a reasonable way could be found to address this issue. In our study, with the use of large-scale public single-cell RNA sequencing (scRNA-seq) data, analysis of dataset integration (3.1 × 10(5) PBMCs from fifteen SLE patients and eight healthy donors) and cellular cross talking (3.8 × 10(5) PBMCs from twenty-eight SLE patients and eight healthy donors) were performed to identify the most crucial information characterizing SLE. Our findings revealed that the interactions among the PBMC subpopulations of SLE patients may be weakened under the inflammatory microenvironment, which could result in abnormal emergences or variations in signaling patterns within PBMCs. In particular, the alterations of B cells and monocytes may be the most significant findings. Utilizing this powerful information, an efficient mathematical model of unbiased random forest machine learning was established to distinguish SLE patients from healthy donors via not only scRNA-seq data but also bulk RNA-seq data. Surprisingly, our mathematical model could also accurately identify patients with rheumatoid arthritis and multiple sclerosis, not just SLE, via bulk RNA-seq data (derived from 688 samples). Since the variations in PBMCs should predate the clinical manifestations of these diseases, our machine learning model may be feasible to develop into an efficient tool for accurate diagnosis of chronic autoimmune diseases. | |
| 34993729 | Effect of JAK inhibitors on high- and low-density lipoprotein in patients with rheumatoid | 2022 Mar | OBJECTIVES: Janus kinase (JAK) inhibitors are a new class of medication for treatment of rheumatoid arthritis (RA), and such inhibitors alter levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in RA patients. However, the extent of such changes has not been systematically reviewed. METHOD: A systematic review and network meta-analysis was performed on randomized trials in RA patients in response to JAKi identified from Pubmed, Medline, Embase, and Cochrane Controlled Trials Register. The primary outcome was mean change of HDL-C and LDL-C from baseline. Mean treatment differences and the rank of the effect of various JAKi on HDL-C and LDL-C were estimated. RESULTS: Based on data from 18 unique studies involving five approved JAK inhibitors and 6697 RA patients (JAKi = 3341, placebo = 3356), such inhibitors led to a mean increase of 8.11 mg/dl (95% CI 6.65-9.58, I(2) = 82%) in HDL levels from baseline, and a mean increase of 11.37 mg/dl (95% CI 7.84-14.91, I(2) = 88%) in LDL levels from baseline. Cardiovascular disease risk did not differ significantly between patients who received JAK inhibitors or those who received placebo or active agents. CONCLUSIONS: Our analysis suggests that, at their recommended doses, all five JAK inhibitors lead to an increase in HDL and LDL levels in RA patients. Further long-term research is required to extend these results and understand whether changes in lipid levels in RA patients can affect cardiovascular risk. Key Points • This is the first systematic review and NMA examining the effect of all five clinically approved JAK inhibitors on lipid levels in RA patients. • Recommended doses of JAK inhibitors used for the treatment of RA patients can induce a significant increase in HDL and LDL levels. • Indirect pairwise comparisons suggest that only upadacitinib and peficitinib have significantly different ability to induce LDL change in RA patients. | |
| 35136158 | Adiponectin is negatively associated with disease activity and Sharp score in treatment-na | 2022 Feb 8 | The association and potential role of the protein hormone adiponectin in autoimmune diseases causing musculoskeletal disorders, including rheumatoid arthritis (RA), are controversial. Conflicting results may arise from the influences of confounding factors linked to genetic backgrounds, disease stage, disease-modifying anti-rheumatic drugs and patients' metabolic characteristics. Here, we examined serum level of adiponectin and its relationship with disease activity score 28 with erythrocytes sedimentation rate (DAS28[ESR]) and Sharp score in a treatment-naïve Han Chinese RA population. This cross-sectional study enrolled 125 RA patients. Serum level of total adiponectin was assessed by enzyme-linked immunosorbent assay (ELISA). Other important clinical and laboratory parameters were collected from the hospital database. DAS28(ESR) was calculated according to the equation previously published. Sharp score was evaluated based on hands radiographs by an independent radiologist. The correlation between serum adiponectin level and DAS28(ESR) or the Sharp score was investigated by univariate and multivariable linear regression analyses, respectively. Multiple imputation by chained equations was used to account for missing data. Univariate analyses showed a significant positive correlation between DAS28(ESR) and age or C-reactive protein (CRP) (both p = 0.003), while serum adiponectin level was negatively correlated with DAS28(ESR) (p = 0.015). The negative correlation between adiponectin level and DAS28(ESR) remained true in multivariable analyses adjusted for confounders. In addition, the univariate analyses revealed positive correlations of Sharp score to disease duration (p < 0.001), CRP (p = 0.023) and ESR (p < 0.001). In the multivariable model adjusted for confounders, adiponectin was negatively correlated with Sharp score (p = 0.013). In this single-institution cross-sectional study, serum adiponectin level in treatment-naive RA patients is negatively correlated with DAS28(ESR) and the Sharp score after adjustment for prominent identified confounders. Serum adiponectin may be potentially useful for assessing disease activity and radiographic progression of RA. | |
| 35304204 | Per-/polyfluoroalkyl substance concentrations in human serum and their associations with i | 2022 Jul | Per-/polyfluoroalkyl substances (PFASs) are ubiquitous in the environment and have been proved to be immunotoxic to humans. However, it remains unclear whether exposure to PFASs affects the risk of rheumatoid arthritis (RA). In this study, nine PFASs were determined in human serum collected from 280 health populations and 294 RA patients in a cohort enrolled between 2018 and 2020 in Hangzhou, China, and were examined their correlations with immune marker levels. Perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) were the predominant PFASs in human serum, with median (mean) concentrations of 5.4 (7.6), 2.8 (3.5), and 1.9 (2.5) ng/mL, respectively. Serum PFOA and 6:2 Cl-PFESA concentrations were positively correlated with anti-cyclic citrullinated peptide antibody (ACPA) (β(PFOA) = 0.59, 95% confidence interval (CI): 0.37, 0.81; β(6:2 Cl-PFESA) = 0.48, 95% CI: 0.29, 0.66), immunoglobulin G (β(PFOA) = 0.25, 95% CI: 0.21, 0.29; β(6:2 Cl-PFESA) = 0.16, 95% CI: 0.12, 0.19) as well as rheumatoid factors (RF) (β(PFOA) = 0.57, 95% CI: 0.34, 0.80; β(6:2 Cl-PFESA) = 0.54, 95% CI: 0.36, 0.72). The correlations between serum PFOS levels and RF (β = 0.52, 95% CI: 0.28, 0.77), ACPA (β = 0.48, 95% CI: 0.23, 0.73), as well as immunoglobulin M (β = -0.24, 95% CI: 0.64, 0.15) respectively were statistically stronger. We also found PFOA concentrations in serum were associated with the level of C-reactive protein (β = 0.52, 95% CI: 0.40, 0.65). To our knowledge, this is the first study reporting significant associations between several PFASs and change of specific immune marker levels, suggesting that PFAS exposure may increase the risk of RA in adults. | |
| 35457251 | 1,5-Disubstituted Acylated 2-Amino-4,5-dihydroimidazoles as a New Class of Retinoic Acid R | 2022 Apr 17 | A growing body of evidence suggests a pathogenic role for pro-inflammatory T helper 17 cells (Th17) in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type I diabetes, and psoriasis-diseases for which no curative treatment is currently available. The nuclear retinoic acid receptor-related orphan receptors alpha and gamma (RORα/γ), in particular the truncated isoform RORγt that is specifically expressed in the thymus, play a critical role in the activation of a pro-inflammatory Th17 response, and RORγ inverse agonists have shown promise as negative regulators of Th17 for the treatment of autoimmune diseases. Our study underscores the screening of a large combinatorial library of 1,5-disubstituted acylated 2-amino-4,5-dihydroimidazoles using a demonstrated synthetic and screening approach and the utility of the positional scanning libraries strategy for the rapid identification of a novel class of ROR inhibitors. We identified compound 1295-273 with the highest activity against RORγ (3.3 µM IC(50)) in this series, and almost a two-fold selectivity towards this receptor isoform, with 5.3 and 5.8 µM IC(50) against RORα and RORβ cells, respectively. | |
| 35132350 | The ROS/GRK2/HIF-1α/NLRP3 Pathway Mediates Pyroptosis of Fibroblast-Like Synoviocytes and | 2022 | Hypoxia is an important factor in the development of synovitis in rheumatoid arthritis (RA). The previous study of the research group found that monomeric derivatives of paeoniflorin (MDP) can alleviate joint inflammation in adjuvant-induced arthritis (AA) rats by inhibiting macrophage pyroptosis. This study revealed increased levels of hypoxia-inducible factor- (HIF-) 1α and N-terminal p30 fragment of GSDMD (GSDMD-N) in fibroblast-like synoviocytes (FLS) of RA patients and AA rats, while MDP significantly inhibited their expression. Subsequently, FLS were exposed to a hypoxic environment or treated with cobalt ion in vitro. Western blot and immunofluorescence analysis showed increased expression of G protein-coupled receptor kinase 2 (GRK2), HIF-1α, nucleotide-binding oligomerization segment-like receptor family 3 (NLRP3), ASC, caspase-1, cleaved-caspase-1, and GSDMD-N. Electron microscopy revealed FLS pyroptosis after exposure in hypoxia. Next, corresponding shRNAs were transferred into FLS to knock down hypoxia-inducible factor- (HIF-) 1α, and in turn, NLRP3 and western blot results confirmed the same. The enhanced level of GSDMD was reversed under hypoxia by inhibiting NLRP3 expression. Knockdown and overexpression of GRK2 in FLS revealed GRK2 to be a positive regulator of HIF-1α. Levels of GRK2 and HIF-1α were inhibited by eliminating excess reactive oxygen species (ROS). Furthermore, MDP reduced FLS pyroptosis through targeted inhibition of GRK2 phosphorylation. According to these findings, hypoxia induces FLS pyroptosis through the ROS/GRK2/HIF-1α/NLRP3 pathway, while MDP regulates this pathway to reduce FLS pyroptosis. | |
| 34923432 | New insights into the taxonomy of autoimmune diseases based on polyautoimmunity. | 2022 Jan | OBJECTIVE: The clinical coexistence of two or more autoimmune diseases (ADs) fulfilling classification criteria is termed "overt polyautoimmunity" (PolyA), whereas the presence of autoantibodies unrelated to an index AD, without clinical criteria fulfillment, is known as "latent PolyA". We aimed to explore a new taxonomy of ADs based on PolyA. METHODS: In a cross-sectional study of 292 subjects, we evaluated the presence of PolyA in 146, 45, 29, 17, and 17 patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), autoimmune thyroid disease (AITD) and systemic sclerosis (SSc), respectively, and 38 healthy controls. Clinical assessment, autoantibody profile (by autoantigen array chip), lymphocytes immunophenotype and cytokine profile (by flow cytometry) were evaluated simultaneously. A mixed cluster methodology was used to classify ADs. RESULTS: Latent PolyA was more frequent than overt PolyA, ranging from 69.9% in RA to 100% in SSc. Nevertheless, both latent and overt PolyA clustered together. Over-expressed IgG autoantibodies were found to be hallmarks for the identification of index ADs. The combination of autoantibodies allowed high accuracy in the classification of ADs. Three well-defined clusters based on PolyA were observed with distinctive clinical and immunological phenotypes. CONCLUSIONS: This proof-of-concept study indicates that ADs can be classified according to PolyA. PolyA should be considered in all studies dealing with ADs, including epidemiological, genetic, and clinical trials. |