Damage In Rheumatoid Arthritis Research Articles

Prediction model for bone erosion in rheumatoid arthritis based on musculoskeletal ultrasound and clinical risk factors.

Progressive bone erosion (BE) is a prominent manifestation of structural damage in rheumatoid arthritis (RA). This study aimed to construct and validate a BE prediction model (BEPM) for RA based on musculoskeletal ultrasound and clinical risk factors. A total of 312 RA patients without BE were consecutively collected and followed up for 2years, who were divided into BE group and non-bone erosion group, as confirmed by two radiology experts based on at least two imaging techniques. Relevant clinical information, such as anti-cyclic citrullinated peptide (ACCP) antibody and disease duration, was collected. Musculoskeletal ultrasound examinations were performed on all patients upon admission. Univariate and binary logistic regression analyses were conducted to identify risk factors for BE and to establish the prediction model. The calibration, diagnostic efficacy, and clinical effectiveness of BEPM were evaluated by calibration curve plots, receiver-operating characteristic curve, and decision curve analysis (DCA). Binary logistic regression analysis screened four variables, including synovial hyperplasia, synovial blood flow, ACCP + , and disease duration, into the prediction model. BEPM exhibited good diagnostic performance in both the training and validation groups, with area under the curve values of 0.949 (95% CI 0.924-0.973) and 0.965 (95% CI 0.935-0.996), respectively. Using 0.376 as the optical cutoff value for BE, the sensitivity, specificity, and Youden index of the model in the training group were 86.0%, 90.4%, and 76.4%, respectively. In the DCA curves, BEPM indicated overall good population benefit. BEPM demonstrates high diagnostic performance and clinical utility, and may be a useful clinical model for predicting BE in patients with RA. Key Points • Synovial hyperplasia, synovial blood flow, ACCP+ , and disease duration are independent risk factors for bone erosion in RA patients. • BEPM exhibits good diagnostic performance in both the training and validation groups. • Combining musculoskeletal ultrasound parameters with key clinical risk factors to construct a bone erosion model is feasible.

Routine radiographs of hands and feet do not have diagnostic or prognostic value in patients with clinically suspect arthralgia: a large longitudinal study

BackgroundConventional radiographs of hands and feet are used to depict structural damage in rheumatoid arthritis (RA). This is also commonly done in clinical practice in symptomatic patients at risk for...

Methotrexate promotes the release of granulocyte–macrophage colony-stimulating factor from rheumatoid arthritis fibroblast-like synoviocytes via autocrine interleukin-1 signaling

BackgroundActivated fibroblast-like synoviocytes (FLS) are drivers of synovitis and structural joint damage in rheumatoid arthritis (RA). Despite the use of disease-modifying drugs, only about 50% of RA patients reach remission in real-world settings. We used an unbiased approach to investigate the effects of standard-of-care methotrexate (MTX) and a Janus kinase inhibitor, tofacitinib (TOFA), on gene expression in RA-FLS, in order to identify untargeted disease mediators.MethodsPrimary RA-FLS were activated by stimulation with interleukin-1β (IL-1β) or platelet-derived growth factor + IL-1β in the presence or absence of MTX or TOFA, with or without additional inhibitors. Co-cultures of synovial cells were performed in direct and indirect systems. Cells were collected for RNA sequencing or qPCR, and supernatants were analyzed for protein concentrations.ResultsSix thousand three hundred fifty genes were differentially expressed, the majority being upregulated, in MTX-treated activated RA-FLS and 970 genes, the majority being downregulated, in TOFA-treated samples. Pathway analysis showed that MTX had largest effects on ‘Molecular mechanisms of cancer’ and TOFA on ‘Interferon signaling’. Targeted analysis of disease-associated genes revealed that MTX increased the expression of cell cycle-regulating genes but also of pro-inflammatory mediators like IL-1α (IL1A) and granulocyte–macrophage colony-stimulating factor, GM-CSF (CSF2). The MTX-promoted expression of CSF2 in activated RA-FLS peaked at 48 h, could be mediated via either NF-κB or AP-1 transcription factors, and was abrogated by IL-1 inhibitors (IRAK4 inhibitor and anakinra). In a co-culture setting, MTX-treatment of activated RA-FLS induced IL1B expression in macrophages.ConclusionsMTX treatment induces secretion of IL-1 from activated RA-FLS which by autocrine signaling augments their release of GM-CSF. This unexpected effect of MTX might contribute to the persistence of synovitis.

Xuetongsu ameliorates synovial inflammatory hyperplasia in rheumatoid arthritis by inhibiting JAK2/STAT3 and NF-κB signaling pathways

Ethnopharmacological relevanceSynovial inflammatory hyperplasia is the key pathological process that leads to further joint damage in rheumatoid arthritis (RA) progress. Kadsura heteroclita (Roxb) Craib, also called Xuetong in Chinese Tujia ethnomedicine, is utilized for its medicinal properties, including promoting blood circulation, dispelling “wind evil”, and relieving “damp evil”. It has been used in the treatment of arthralgia and RA, within Tujia ethnomedicinal practices. Xuetongsu (XTS), the main component of Xuetong, has been shown to inhibit the proliferation of RA fibroblast-like synovial cells (RAFLS) cells. However, the molecular mechanism of XTS in RA treatment requires further investigation. Aim of the studyTo observe the therapeutic effect of XTS on synovial inflammatory hyperplasia in rheumatoid arthritis, focusing on its underlying molecular mechanisms involving the janus kinase 2 (JAK2)/transducer/activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) signaling pathways. Materials and methodsProtein-protein interaction (PPI) and molecular docking were used to find the main targets of XTS treatment for RA. In lipopolysaccharide (LPS)-induced RAFLS and RAW264.7 cells in vitro models, the levels of inflammatory cytokines were analyzed using enzyme linked immunosorbent assay (ELISA), and the expression of JAK2, STAT3, and NF-κB signaling pathways, as well as cyclooxygenase-2 (COX-2), were analyzed through western blotting test. A hemolysis assay was used to certify the biosecurity of XTS. A model of adjuvant arthritis (AIA) was established in 40 male rats, and different doses of XTS were administered, followed by an automatic blood routine, ELISA assay, hematoxylin and eosin (H&E) staining, and radiological analysis of the effect of no XTS on blood cytokines, histological changes, and improvement of posterior paw bone destruction in AIA rats. The protein levels of inflammatory cytokines were analyzed by immunofluorescence, immunohistochemistry, or Western blot. Finally, H&E staining was used to detect the damage of XTS on the heart, liver, spleen, lung, and kidney of AIA rats. ResultsOur results demonstrate that XTS effectively inhibited LPS-induced inflammatory responses in RAFLS and RAW264.7 cells by modulating the JAK2/STAT3 and NF-κB signaling pathways. Moreover, XTS administration in the AIA rats model significantly ameliorated paw swelling. Histological analysis revealed that XTS also suppressed the inflammatory response in paw tissue by modulating the JAK2/STAT3 and NF-κB signaling pathways. Importantly, during the treatment, XTS exhibited excellent safety profiles, as it did not induce any abnormalities in blood routine parameters or cause organ damage in the rats. ConclusionsOur findings highlight XTS as a promising natural agent for inhibiting synovial hyperplasia in RA. XTS holds great potential as an unprecedented natural agent for developing novel therapeutic strategies to target synovial hyperplasia in RA.

Deep Learning Enables Automatic Detection of Joint Damage Progression in Rheumatoid Arthritis-Model Development and External Validation.

Although deep learning has demonstrated substantial potential in automatic quantification of joint damage in rheumatoid arthritis (RA), evidence for detecting longitudinal changes at an individual patient level is lacking. Here, we introduce and externally validate our automated RA scoring algorithm (AuRA), and demonstrate its utility for monitoring radiographic progression in a real-world setting. The algorithm, originally developed during the Rheumatoid Arthritis 2-Dialogue for Reverse Engineering Assessment and Methods (RA2-DREAM) challenge, was trained to predict expert-curated Sharp-van der Heijde total scores in hand and foot radiographs from two previous clinical studies (n = 367). We externally validated AuRA against data (n = 205) from Turku University Hospital and compared the performance against two top-performing RA2-DREAM solutions. Finally, for 54 patients, we extracted additional radiograph sets from another control visit to the clinic (average time interval of 4.6 years). In the external validation cohort, with a root-mean-square-error (RMSE) of 23.6, AuRA outperformed both top-performing RA2-DREAM algorithms (RMSEs 35.0 and 35.6). The improved performance was explained mostly by lower errors at higher expert-assessed scores. The longitudinal changes predicted by our algorithm were significantly correlated with changes in expert-assessed scores (Pearson's R = 0.74, p< 0.001). AuRA had the best external validation performance and demonstrated potential for detecting longitudinal changes in joint damage. Available in https://hub.docker.com/r/elolab/aura, our algorithm can easily be applied for automatic detection of radiographic progression in the future, reducing the need for laborious manual scoring.

Role and Therapeutic Potential for Targeting Fibroblast Growth Factor 10/FGFR1 in Relapsed Rheumatoid Arthritis.

Fibroblast-like synoviocytes (FLSs) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLSs in relapse and remission of RA remain unknown. Identifying FLS heterogeneity and their underlying pathogenic roles may lead to discovering novel disease-modifying antirheumatic drugs. Combining single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, we sequenced six matched synovial tissue samples from three patients with relapse RA and three patients in remission. We analyzed the differences in the transcriptomes of the FLS subsets between the relapse and remitted phases. We validated several key signaling pathways using quantitative real-time PCR(qPCR)and multiplex immunohistochemistry (mIHC). We further targeted the critical signals in vitro and in vivo using the collagen-induced arthritis (CIA) model in rats. Lining and sublining FLS subsets were identified using scRNA-seq. Differential analyses indicated that the fibroblast growth factor (FGF) pathway was highly activated in the lining FLSs from patients with relapse RA for which mIHC confirmed the increased expression of FGF10. Although the type I interferon pathway was also activated in the lining FLSs, in vitro stimulation experiment suggested that it was independent of the FGF10 pathway. FGF10 knockdown by small interfering RNA in FLSs significantly reduced the expression of receptor activator of NF-κB ligand. Moreover, recombinant FGF10 protein enhanced bone erosion in the primary human-derived pannus cell culture, whereas the FGF receptor (FGFR) 1 inhibitor attenuated this process. Finally, administering an FGFR1 inhibitor displayed a therapeutic effect in a CIA rat model. The FGF pathway is a critical signaling pathway in relapse RA. Targeted tissue-specific inhibition of FGF10/FGFR1 may provide new opportunities to treat patients with relapse RA.

ALKBH5-Mediated RNA m6 A Methylation Regulates the Migration, Invasion, and Proliferation of Rheumatoid Fibroblast-Like Synoviocytes.

Fibroblast-like synoviocytes (FLSs) are critical for promoting joint damage in rheumatoid arthritis (RA). N6 -methyladenosine (m6 A) modification plays key roles in various diseases, but its role in the pathogenesis of RA is largely unknown. Here, we investigate increased demethylase ALKBH5 promotion of proliferation, migration, and invasion of RA FLSs via regulating JARID2 expression. ALKBH5 expression in FLSs was evaluated using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. 5-ethynyl-2'-deoxyuridine, scratch wound healing, and transwell assays were implemented to determine the role of ALKBH5 on RA FLS proliferation, mobility, and migration. Then, m6 A sequencing combined with RNA sequencing was performed to identify the potential targets of ALKBH5. RNA immunoprecipitation and RNA pulldown were then used to validate the interaction between the protein and messenger RNA (mRNA). Collagen-induced arthritis (CIA) and delayed-type hypersensitivity arthritis (DTHA) models were further established to assess the therapeutic potency of ALKBH5 in vivo. We demonstrated that ALKBH5 expression was increased in FLSs and synovium from RA. Functionally, ALKBH5 knockdown inhibited the proliferation, migration, and invasion of RA FLSs, whereas overexpression of ALKBH5 displayed the opposite effect. Mechanistically, ALKBH5 mediated m6 A modification in the JARID2 mRNA and enhanced its mRNA stability in cooperation with IGF2BP3. Intriguingly, the severity of arthritis was attenuated in mice with DTHA and ALKBH5 knockout or rats with CIA and intra-articular injection of ALKBH5 short hairpin RNA. Our findings suggest that ALKBH5-mediated m6 A modification is crucial for synovial hyperplasia and invasion in RA. ALKBH5 might be a potential therapeutic target for RA and even for dysregulated fibroblasts in a wide range of diseases.

Effect of JAK inhibitors on the three forms of bone damage in autoimmune arthritis: joint erosion, periarticular osteopenia, and systemic bone loss

BackgroundThe types of bone damage in rheumatoid arthritis (RA) include joint erosion, periarticular osteoporosis, and systemic osteoporosis. Janus kinase (JAK) inhibitors ameliorate inflammation and joint erosion in RA, but their effect on the three types of bone loss have not been reportedly explored in depth. We aimed to clarify how JAK inhibitors influence the various types of bone loss in arthritis by modulating osteoclastic bone resorption and/or osteoblastic bone formation.MethodsCollagen-induced arthritis (CIA) mice were treated with a JAK inhibitor after the onset of arthritis. Micro-computed tomography (μCT) and histological analyses (bone morphometric analyses) on the erosive calcaneocuboid joint, periarticular bone (distal femur or proximal tibia), and vertebrae were performed. The effect of four different JAK inhibitors on osteoclastogenesis under various conditions was examined in vitro.ResultsThe JAK inhibitor ameliorated joint erosion, periarticular osteopenia and systemic bone loss. It reduced the osteoclast number in all the three types of bone damage. The JAK inhibitor enhanced osteoblastic bone formation in the calcaneus distal to inflammatory synovium in the calcaneocuboid joints, periarticular region of the tibia and vertebrae, but not the inflamed calcaneocuboid joint. All the JAK inhibitors suppressed osteoclastogenesis in vitro to a similar extent in the presence of osteoblastic cells. Most of the JAK inhibitors abrogated the suppressive effect of Th1 cells on osteoclastogenesis by inhibiting IFN-γ signaling in osteoclast precursor cells, while a JAK inhibitor did not affect this effect due to less ability to inhibit IFN-γ signaling.ConclusionsThe JAK inhibitor suppressed joint erosion mainly by inhibiting osteoclastogenesis, while it ameliorated periarticular osteopenia and systemic bone loss by both inhibiting osteoclastogenesis and promoting osteoblastogenesis. These results indicate that the effect of JAK inhibitors on osteoclastogenesis and osteoblastogenesis depends on the bone damage type and the affected bone area. In vitro studies suggest that while JAK inhibitors inhibit osteoclastic bone resorption, their effects on osteoclastogenesis in inflammatory environments vary depending on the cytokine milieu, JAK selectivity and cytokine signaling specificity. The findings reported here should contribute to the strategic use of antirheumatic drugs against structural damages in RA.

E72 Distribution of cells and extracellular matrix in the marginal synovium during the postnatal period

Abstract Introduction The marginal transitional zone of the joint is of fundamental importance in joint pathology. The normal marginal synovium takes part in articular cartilage repair (Adachi et al. 2012). The inflamed marginal synovium, in turn, promotes irreversible damage to the adjacent cartilage and bone (Hitchon &amp; El-Gabalawy, 2011). Early erosive damage in rheumatoid arthritis and osteophyte formation in osteoarthritis occurs primarily here (Allard et al. 1990). Objectives The morphology of the marginal synovium from birth till the 90th day was studied using the hip joints of Wistar rats. Methods The collection of joints was carried out on the first, seventh, 14th, 30th, 45th, 60th and 90th day (six rats in each group, 42 in total). Joints were fixed, decalcified and dehydrated. Histologic paraffine sections were stained with Mallory's trichrome and Hart's elastin staining, analyzed at the acetabular labrum by light microscopy (χ100), morphometrical and statistical (P &amp;lt; 0.05) methods with extrapolation to humans (Sengupta, 2013). The obtained data were presented as percentages. Results In the marginal synovium, cells and components of the extracellular matrix, which are typical for fibrous connective tissue, could be seen. The synovial lining cells are embedded in the modified basement membrane which includes collagen and elastic fibers. They form a three-dimensional reticulum in it and adjacent synovial subintima. Vessels of the microcirculatory bed are also widely represented in the marginal synovium. The overall quantity of collagen fibers increased gradually, exceeding on the 90th day (approximately corresponds to 18–19 human years) that of newborns by one and a half times (48.92 ± 3.39 vs 72.17 ± 7.77; P = 0.023). The number of arranged collagen fibers increased gradually, exceeding on the 90th day that of newborns almost twofold (37.25 ± 3.21 vs 60.08 ± 5.99; P = 0.008). The area of distribution of disarranged collagen fibers in newborns was almost four and a half times less than the overall quantity of collagen fibers (11.67 ± 1.03 vs 48.92 ± 3.39; P &amp;lt; 0.001) and did not change substantially throughout the experiment. The number of elastic fibers increased till the 30th day (0.63 ± 0.11 vs 18.3 ± 1.25; P &amp;lt; 0.001) and did not undergo significant changes later. In newborns, the area of distribution of ground substance was not considerably higher than the ratio of disarranged collagen fibers (10.42 ± 1.8 vs 11.67 ± 1.03; P = 0.562) and did not undergo substantial changes later. The distribution density of vessels increased till the 30th-45th day (4.5 ± 0.67 vs 7.5 ± 0.82 and 7.7 ± 0.54; P &amp;lt; 0.001; approximately corresponds to the 9th and 14th human years respectively), followed by a gradual decrease from the 60th day (7.05 ± 0.72; roughly corresponds to the 16th human years). The maximum number of cells was in newborns. Subsequently, it gradually decreased and was almost three times less on the 90th day than that of newborns (38.01 ± 3.06 vs 12.58 ± 1.53; P &amp;lt; 0.001). Conclusion The morphogenesis of the marginal synovium during the postnatal period is accompanied by a gradual decrease in the number of cells, an increase in the area occupied by elastic and arranged collagen fibers with a relatively constant distribution density of disarranged collagen fibers and ground substance together with an undulatory pattern in the distribution of vessels. These peculiarities emphasize the morphological uniqueness of the marginal transitional zone, which forms the innate nonspecific barrier between the joint capsule and the articular cartilage, and thereby provides the necessary anatomical and physiological integrity of the joint as a whole organ. Knowledge about the patterns of morphogenesis of the marginal synovium will help in the future to analyze the modeled pathological or boundary states in it. Ethics The study was approved by the ethics committee of the Zaporizhzhia State Medical University.

LED irradiation at 630nm alleviates collagen-induced arthritis in mice by inhibition of NF-κB-mediated MMPs production.

Matrix metallopreteinase (MMP), a family of matrix degrading enzyme, plays a significant role in persistent and irreversible joint damage in rheumatoid arthritis (RA). Photobiomodulatory therapy (PBMT) has become an emerging adjunct therapy for RA. However, the molecular mechanism of PBMT on RA remains unclear. The purpose of this study is to explore the effect of 630nm light emitting diode (LED) irradiation on RA and its underly molecular mechanism. Arthritis clinic scores, histology analysis and micro-CT results show that 630nm LED irradiation ameliorates collagen-induced arthritis (CIA) in mice with the reduction of the extents of paw swelling, inflammation and bone damage. 630nm LED irradiation significantly reduces MMP-3 and MMP-9 levels and inhibits p65 phosphorylation level in the paws of CIA mice. Moreover, 630nm LED irradiation significantly inhibits the mRNA and protein levels of MMP-3 and MMP-9 in TNF-α-treated MH7A cells, a human synovial cell line. Importantly, 630nm LED irradiation reduces TNF-α-induced the phosphorylated level of p65 but not alters STAT1, STAT3, Erk1/2, JNK and p38 phosphorylation levels. Immunofluorescence result showed that 630nm LED irradiation blocks p65 nuclear translocation in MH7A cells. In addition, other MMPs mRNA regulated by NF-κB were also significantly inhibited by LED irradiation in vivo and in vitro. These results indicates that 630nm LED irradiation reduces the MMPs levels to ameliorate the development of RA by inhibiting the phosphorylation of p65 selectively, suggesting that 630nm LED irradiation may be a beneficial adjunct therapy for RA.Graphical abstract.

Anaemia is associated with higher disease activity in axial spondyloarthritis but is not an independent predictor of spinal radiographic progression: data from the Swiss Clinical Quality Management Registry

ObjectiveAs anaemia represents a biomarker for increased radiographic damage in rheumatoid arthritis, we aimed to investigate whether it independently predicts spinal radiographic progression in axial spondyloarthritis (axSpA).MethodsAxSpA patients with available haemoglobin levels from the prospective Swiss Clinical Quality Management Registry were included for comparison of patients with and without anaemia. Spinal radiographic progression was assessed according to the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) in patients with ankylosing spondylitis (AS) if ≥ 2 sets of spinal radiographs were available every 2 years. The relationship between anaemia and progression (defined as an increase ≥ 2 mSASSS units in 2 years) was analysed with generalized estimating equation models after adjustment for the Ankylosing Spondylitis Disease Activity Score (ASDAS) and potential confounding, as well as after multiple imputations of missing values.ResultsA total of 212/2522 axSpA patients presented with anaemia (9%). Anaemic patients had higher clinical disease activity, higher acute phase reactants and more severe impairments in physical function, mobility and quality of life. In the subgroup of patients with AS (N = 433), a comparable mSASSS progression was found in anaemic and non-anaemic patients (OR 0.69, 95% CI 0.25 to 1.96, p = 0.49). Age, male sex, baseline radiographic damage and ASDAS were associated with enhanced progression. The results were confirmed in complete case analyses and with progression defined as the formation of ≥ 1 syndesmophyte in 2 years.ConclusionAlthough anaemia was associated with higher disease activity in axSpA, it did not additionally contribute to the prediction of spinal radiographic progression.Key Points• Anaemia is associated with higher disease activity and more severely impaired physical function, mobility and quality of life in axSpA.• Anaemia does not provide an additional value to ASDAS for prediction of spinal radiographic progression.

Distinct subsets of synovial fibroblasts control cartilage destruction in joint diseases.

Inflammation-induced bone destruction is the main cause of progressive joint damage in rheumatoid arthritis (RA) and osteoarthritis (OA). In addition, depending on the tissue microenvironment stimulators, the synovium transforms into a hyperplastic invasive tissue. The synovium includes two specific subsets of fibroblasts surrounding the joints: lining and sublining synovial fibroblasts (SFs). These SFs grow and interact with immune cells invading the bone and cartilage; specifically, SFs, which are the major mesenchymal cells in the joints, develop an aggressive phenotype, thereby producing cytokines and proteases involved in arthritis pathogeneses. Transcriptomic differences in the heterogeneity of SFs reflect the joint-specific origins of the SFs interacting with immune cells. To understand the subsets of SFs that lead to joint damage in arthritis, clarifying the distinct phenotypes and properties of SFs and understanding how they influence bone cells, such as osteoclasts and chondrocytes, is crucial. This review provides an overview of the advancements in the understanding of SF subsets and features, which may aid in identifying newer therapeutic targets.

Role of reactive oxygen species and mitochondrial damage in rheumatoid arthritis and targeted drugs.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation, pannus formation, and bone and cartilage damage. It has a high disability rate. The hypoxic microenvironment of RA joints can cause reactive oxygen species (ROS) accumulation and mitochondrial damage, which not only affect the metabolic processes of immune cells and pathological changes in fibroblastic synovial cells but also upregulate the expression of several inflammatory pathways, ultimately promoting inflammation. Additionally, ROS and mitochondrial damage are involved in angiogenesis and bone destruction, thereby accelerating RA progression. In this review, we highlighted the effects of ROS accumulation and mitochondrial damage on inflammatory response, angiogenesis, bone and cartilage damage in RA. Additionally, we summarized therapies that target ROS or mitochondria to relieve RA symptoms and discuss the gaps in research and existing controversies, hoping to provide new ideas for research in this area and insights for targeted drug development in RA.

Segmentasi Radiografi Tangan Pasien Artritis Rematoid dengan Pendekatan Branches Filtering

This research is for the possibility of automating the assessment of hand radiographic joint damage in rheumatoid arthritis. The objective of this research is to design a segmentation algorithm to obtain the area which is the joint space object. This study has collected 46 radiographic images of the hands. Image preprocessing is performed using adaptive thresholds and the concept of morphological gradient, then segmentation is performed using branches filtering approach. Analysis based on accuracy, sensitivity and specificity compared with manual segmentation by experts. The results of segmentation research preceded by preprocessing produce better images with an accuracy of 96.413%, a sensitivity of 72.121% and a specificity of 97.891% in the highest percentage.

The Association of uPA, uPAR, and suPAR System with Inflammation and Joint Damage in Rheumatoid Arthritis: suPAR as a Biomarker in the Light of a Personalized Medicine Perspective.

In recent years, the involvement of the soluble urokinase Plasminogen Activator Receptor (suPAR) in the pathophysiological modulation of Rheumatoid Arthritis (RA) has been documented, resulting in the activation of several intracellular inflammatory pathways. We investigated the correlation of urokinase Plasminogen Activator (uPA)/urokinase Plasminogen Activator Receptor (uPAR) expression and suPAR with inflammation and joint damage in RA, evaluating their potential role in a precision medicine context. Currently, suPAR has been shown to be a potential biomarker for the monitoring of Systemic Chronic Inflammation (SCI) and COVID-19. However, the effects due to suPAR interaction in immune cells are also involved in both RA onset and progression. To date, the literature data on suPAR in RA endorse its potential application as a biomarker of inflammation and subsequent joint damage. Available evidence about suPAR utility in the RA field is promising, and future research should further investigate its use in clinical practice, resulting in a big step forward for precision medicine. As it is elevated in different types of inflammation, suPAR could potentially work as an adjunctive tool for the screening of RA patients. In addition, a suPAR system has been shown to be involved in RA pathogenesis, so new data about the therapeutic response to Jak inhibitors can represent a possible way to develop further studies.

Secretory phosphoprotein 1 secreted by fibroblast-like synoviocytes promotes osteoclasts formation via PI3K/AKT signaling in collagen-induced arthritis

Synovial tissue hyperplasia is a major cause of bone damage in rheumatoid arthritis (RA). Over-proliferation and secretion of cytokines of fibroblast-like synoviocytes (FLSs) are key contributors to bone damage in the joint microenvironment. Therefore, inhibition of FLSs-mediated bone damage is of great significance in RA patients. The aim of this study was to investigate the molecular mechanisms by which FLSs-mediated bone damage in the joint microenvironment. The results of whole transcriptome sequencing showed that Spp1 gene expression was significantly upregulated in collagen-induced arthritis FLSs compared to Normal FLSs. KEGG enrichment analysis revealed up-regulated Spp1 gene expression, associated with PI3K/AKT signaling. Animal and cellular experiments were designed to validate and explore the results of sequencing. Briefly, the data demonstrated secretory phosphoprotein 1 (SPP1) (encoded by Spp1 gene) secreted by FLSs promotes osteoclasts differentiation in vivo and in vitro and exacerbates articular bone damage in collagen-induced arthritis mice. Interestingly, SPP1 secreted by FLSs does not affect its own proliferation and apoptosis. The results of co-culture of FLSs with bone marrow-derived monocytes indicated the level of SPP1 secreted by FLSs positively correlates with the frequency of p-PI3K+PI3K+ osteoclasts, whereas not with the frequency of p-AKT+AKT+ osteoclasts. This may suggest that SPP1 secreted by FLSs acts directly on PI3K while indirectly on AKT. Together, the results revealed SPP1 secreted by FLSs promotes osteoclasts formation via PI3K/AKT signaling in collagen-induced arthritis. Regulation of Spp1 gene expression in FLSs may be a potential approach to treat RA bone damage in the joint microenvironment.

A Crowdsourcing Approach to Develop Machine Learning Models to Quantify Radiographic Joint Damage in Rheumatoid Arthritis

An automated, accurate method is needed for unbiased assessment quantifying accrual of joint space narrowing and erosions on radiographic images of the hands and wrists, and feet for clinical trials, monitoring of joint damage over time, assisting rheumatologists with treatment decisions. Such a method has the potential to be directly integrated into electronic health records. To design and implement an international crowdsourcing competition to catalyze the development of machine learning methods to quantify radiographic damage in rheumatoid arthritis (RA). This diagnostic/prognostic study describes the Rheumatoid Arthritis 2-Dialogue for Reverse Engineering Assessment and Methods (RA2-DREAM Challenge), which used existing radiographic images and expert-curated Sharp-van der Heijde (SvH) scores from 2 clinical studies (674 radiographic sets from 562 patients) for training (367 sets), leaderboard (119 sets), and final evaluation (188 sets). Challenge participants were tasked with developing methods to automatically quantify overall damage (subchallenge 1), joint space narrowing (subchallenge 2), and erosions (subchallenge 3). The challenge was finished on June 30, 2020. Scores derived from submitted algorithms were compared with the expert-curated SvH scores, and a baseline model was created for benchmark comparison. Performances were ranked using weighted root mean square error (RMSE). The performance and reproductivity of each algorithm was assessed using Bayes factor from bootstrapped data, and further evaluated with a postchallenge independent validation data set. The RA2-DREAM Challenge received a total of 173 submissions from 26 participants or teams in 7 countries for the leaderboard round, and 13 submissions were included in the final evaluation. The weighted RMSEs metric showed that the winning algorithms produced scores that were very close to the expert-curated SvH scores. Top teams included Team Shirin for subchallenge 1 (weighted RMSE, 0.44), HYL-YFG (Hongyang Li and Yuanfang Guan) subchallenge 2 (weighted RMSE, 0.38), and Gold Therapy for subchallenge 3 (weighted RMSE, 0.43). Bootstrapping/Bayes factor approach and the postchallenge independent validation confirmed the reproducibility and the estimation concordance indices between final evaluation and postchallenge independent validation data set were 0.71 for subchallenge 1, 0.78 for subchallenge 2, and 0.82 for subchallenge 3. The RA2-DREAM Challenge resulted in the development of algorithms that provide feasible, quick, and accurate methods to quantify joint damage in RA. Ultimately, these methods could help research studies on RA joint damage and may be integrated into electronic health records to help clinicians serve patients better by providing timely, reliable, and quantitative information for making treatment decisions to prevent further damage.

Increased eEF2K Promotes Glycolysis and Aggressive Behaviors of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis.

ObjectiveAggressive phenotype and abnormal glycolytic metabolism of fibroblast-like synoviocytes (FLSs) are essential to joint inflammation and damage in rheumatoid arthritis (RA). Eukaryotic elongation factor-2 kinase (eEF2K) is a negative regulator of protein synthesis and has been shown to play an important role in regulating various cellular processes and promoting glycolysis in tumor cells. However, the role of eEF2K in regulating the pathogenic FLS behaviors is unknown.MethodsA specific inhibitor of eEF2K, NH125, and siRNA were used to evaluate the role of eEF2K on RA FLSs in vitro. Collagen-induced arthritis (CIA) mice were used to evaluate the in vivo effect of eEF2K. Cell migration, invasion of RA FLSs were assessed by transwell or wound healing assays. Relative changes of cytokines were analyzed by quantitative real-time PCR, western blot and ELISA.ResultsHerein, we found an increased expression of eEF2K in synovial tissues and FLSs of RA patients. eEF2K knockdown by siRNA or treatment with NH125, an inhibitor of eEF2K, significantly reduced inflammation, migration/invasion, glucose uptake and lactate productions. eEF2K knockdown suppressed TNF-α-induced activation of NF-κB and AKT pathways in RA FLSs. Lactate reversed the inhibitory effect of eEF2K knockdown on inflammation and migration of RA FLSs. Moreover, lactate was also involved in eEF2K-mediated activation of NF-κB and AKT. NH125 treatment attenuated the severity of arthritis in collagen-induced arthritis mice.ConclusioneEF2K inhibition suppressed glycolysis and aggressive behaviors of RA FLS, which indicated that targeting eEF2K may be a new strategy for the treatment of RA.

Right ventriculoarterial coupling as a marker of subclinical myocardial damage in rheumatoid arthritis

Abstract Funding Acknowledgements Type of funding sources: None. Background The lung involvement in autoimmune diseases has been described previously. Currently the incidence of pulmonary hypertension in patients with rheumatoid arthritis (RA) ranges from 1-25%. Right ventriculoarterial coupling (RVAC) is altered early before presenting right ventricular dysfunction and pulmonary hypertension, its measurement in patients with RA has been barely studied. Objectives To determine if there is a difference in RVAC in patients with RA. Analyze if there are differences in patients with normal vs abnormal right RVAC. To investigate if there is an association in patients with RA to present abnormal RVAC. Methods A single-center, analytical, cross-sectional, observational study was performed. Patients with diagnosis of RA were included according to the ACR / EULAR 2010 classification criteria, without any other comorbidity. An ACUSON SC2000 echocardiogram was used. Patients were compared with healthy controls matched by age and gender. The clinical, laboratory and echocardiographic variables were contrasted. Among the echocardiographic variables, the left ventricular ejection fraction, the left ventricular volume index, the left atrial volume index, right ventricular diastolic area, right ventricular fractional area change (RV FAC), right atrial volume, pulmonary artery systolic pressure (PASP), right ventricular free wall longitudinal strain (RVFWLS) and right atrial global longitudinal strain (RAGLS). The RVAC was determined with the RVFWLS / PSAP ratio. A RVAC less than 0.8 was classified as abnormal. The quantitative variables were contrasted with Student"s t-test or Mann-Whitney"s u test, according to the normality of the variables; qualitative variables were compared with x2. The association with an abnormal RVAC was determined with univariate and multivariate analysis. Results Thirty-four patients were included in each group. Among the echocardiographic variables, it was found that patients with RA had a greater right ventricular diastolic area and the PASP; while the RV FAC, the RVFWLS and the RVAC were lower. 68% of the RA patients had an abnormal RVAC, and C-reactive protein (CRP) levels were higher in patients with an abnormal RVAC. In the multivariate analysis, we found that patients with RA and CRP levels were independently associated to an abnormal RVAC. Conclusion The right ventricular subclinical myocardial damage, determined by the RVAC, is present in patients with rheumatoid arthritis. CRP levels and rheumatoid arthritis were associated with an abnormal ventriculoarterial coupling. Abstract Table 1 Abstract Table 2

A Crowdsourcing Approach to Develop Machine Learning Models to Quantify Radiographic Joint Damage in Rheumatoid Arthritis

A Crowdsourcing Approach to Develop Machine Learning Models to Quantify Radiographic Joint Damage in Rheumatoid Arthritis