Inflammatory Arthritis Research Articles

Targeting p38 MAPK signaling pathway and neutrophil extracellular traps: An important anti-inflammatory mechanism of Huangqin Qingre Chubi Capsule in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common chronic autoimmune disease. Neutrophils release and their extracellular traps (NETs) tend to result in synovial inflammation and cartilage damage. Huangqin Qingre Chubi Capsule (HQC) is an important herbal formulation for RA treatment and has been used for many years. This study applied an interdisciplinary and integrated strategy combining clinical data, integrative bioinformatics, molecular modeling, and both in vitro and in vivo experiments to elucidate the efficacy and potential anti-inflammatory mechanisms of HQC for RA. Retrospective clinical data mining demonstrated that patients with RA treated with HQC exhibited recovery of immuno-inflammatory markers and self-perception. By applying network pharmacological analysis, molecular docking, molecular dynamics simulation, and cellular thermal shift assays, we determined that HQC can directly bind to MAPK14 and target p38 MAPK signaling pathway and NETs formation. Treatment of an adjuvant-induced arthritis rat model combining damp-heat patterns using HQC demonstrated it's effectiveness in reducing the severity of inflammatory arthritis in a dose-dependent manner and downregulated phosphorylation of p38 MAPK and NETs release. In vitro co-culture system mimicking inflammatory microenvironment of RA in vivo revealed that crosstalk between neutrophils (PMNs) and fibroblast-like synoviocytes (FLSs) was manifested by activation of p38 MAPK signaling pathway, release of NETs, and amplification of inflammation, which was blocked by HQC. Mechanistic validation using the p38 MAPK agonist diprovocim demonstrated that HQC inhibited NET formation by modulating the p38 MAPK pathway (mainly by inhibiting its phosphorylation) to exert anti-inflammatory effects. In conclusion, our interdisciplinary and integrated study demonstrated that HQC can target the p38 MAPK signaling pathway to inhibit NET formation and inflammatory response, thereby blocking the crosstalk between PMNs and FLSs to ameliorating RA.

Fishroesomes show intrinsic anti-inflammatory bioactivity and ability as celecoxib carriers in vivo.

According to the World Health Organization (WHO), chronic inflammatory-related diseases represent the greatest threat to human health. Indeed, failure in the resolution of inflammation leads to serious pathological conditions, such as cardiovascular diseases, arthritis, cancer, diabetes, autoimmune diseases, and neurodegenerative disorders that are often associated with extremely high human suffering and societal and economic burdens. Despite the number and efficacy of available therapeutic agents have been increased, the serious side effects associated with some of them often create a very high risk/benefit ratio for patients. Therefore, herein, a drug delivery system was engineered to overcome important drawbacks of conventional therapies and to have a synergistic action with the incorporated drug. Indeed, it will have an added beneficial role in controlling inflammation. For that, sardine (Sardina pilchardus) roe was used as the lipidic source to produce bioactive liposomes, namely fishroesomes. These spherical vesicles with ≈326nm in size and a significant negative surface charge (≈-31mV) were able to encapsulate and control the release of the anti-inflammatory drug celecoxib. Moreover, fishroesomes were cytocompatible for different cell types (chondrocytes and macrophages), at concentrations in which they present anti-inflammatory properties. Importantly, fishroesomes were more effective in reducing pro-inflammatory mediators than the free drug. We also demonstrated that a single intra-articular injection of the fishroesomes encapsulating or not celecoxib in an experimental rat model of inflammatory arthritis was safe and more effective in controlling the pain and reducing the synovial inflammation compared to the free drug. Notably, as the celecoxib concentration in the sardine roe-derived liposomes was less than half of the amount of free drug, this study demonstrates the value of fishroesomes in counteracting inflammation. Therefore, the developed formulations may be considered a promising therapeutic option for inflammatory conditions.

Diagnostic performance of optical spectral transmission compared to magnetic resonance imaging in patients with inflammatory arthritis

BackgroundOptical spectral transmission (OST) is a modern diagnostic method capable of quantifying inflammation in the finger and wrist joints of arthritis patients by assessing the blood-specific absorption of light transmitted through a tissue. The diagnostic performance of this modality has not been adequately examined and data regarding OST associations with magnetic resonance imaging (MRI) are limited. Aim of this study was therefore to investigate the performance of OST in assessing joint inflammation as compared to MRI in patients with inflammatory arthritis (IA).MethodsData from patients who underwent MRI and OST for suspected IA were analyzed. For comparison, a historical healthy control (HC) group with OST was also accounted. MRI findings were quantified using the Rheumatoid Arthritis MRI Score (RAMRIS). Diagnostic accuracy of OST was evaluated using Receiver Operating Characteristics (ROC), while correlation analyses were conducted to explore relationships between OST and MRI, as well as disease activity markers.ResultsOverall, 71 patients with known rheumatic diseases (n = 1,542 wrist and finger joints) and 114 HC (n = 2,508 joints) subjects were included. 51 patients showed inflammatory signs on MRI (MRI+). These also showed significantly higher OST scores (16.41 ± 5.53) than subjects without MRI inflammation (MRI-) (11.52 ± 5.03) or HC (10.78 ± 4.19) (all; p < 0.001). OST showed significant correlations with RAMRIS-synovitis and tenosynovitis scores in the MRI + group (rho = 0.541, p < 0.001; rho = 0.341, p = 0.01, respectively). Significant correlations were observed between OST and clinical parameters for disease activity. Using MRI as a reference, the best diagnostic value of OST was observed at the wrist level in the MRI + group, by an AUC of 0.833 (95%CI 0.700-0.966).ConclusionOST showed an excellent performance compared to MRI and correlated significantly with RAMRIS scores and clinical parameters in IA patients, also differentiating IA from HC.

Effectiveness and safety of radionuclide synovectomy with Yttrium-90 hydroxyapatite in patients with inflammatory arthritis: a longitudinal study.

Yttrium-90 plays a significant role in managing drug-resistant inflammatory arthritis through radionuclide synovectomy, where the radioisotope is injected into the affected joint to alleviate pain and inflammation by targeting the synovial tissue. This study aims to evaluate the effectiveness and safety of Yttrium-90 hydroxyapatite radionuclide synovectomy in improving joint functionality, as judged by physicians, in patients with inflammatory arthritis who had not responded to conventional treatments. Patients with inflammatory arthritis were recruited from the orthopedics department and referred to the nuclear medicine department for evaluation. A three-phase bone scan was conducted to identify eligible patients, who then received intra-articular injections of Yttrium-90 hydroxyapatite along with triamcinolone. After 48 h, patients underwent PET-CT imaging, followed by two follow-ups at 2 and 6 months to assess improvements in joint functionality and monitor for adverse reactions. Fifteen patients underwent radionuclide synovectomy. Significant improvements were observed between baseline and 2 months in joint restriction (P = 0.001), pain severity (P = 0.037), visual analog scale (VAS) (P = 0.004), and swelling (P = 0.002). At 6 months, further improvements were noted in joint restriction (P = 0.002), pain severity (P = 0.019), VAS (P = 0.013), and swelling (P = 0.023). However, no significant changes occurred between the 2- and 6-month follow-ups. One patient experienced radiation-induced skin necrosis, which resolved with conservative treatment, and another had self-limited skin rashes. Yttrium-90 hydroxyapatite radionuclide synovectomy proved to be an effective and safe treatment for improving joint functionality in patients with drug-resistant inflammatory arthritis of the knee for up to 6 months.

A holistic approach is needed for women with an inflammatory arthritis in the different phases around pregnancy; the results of the CAPRI study

IntroductionWomen with inflammatory arthritis (IA) face significant challenges throughout preconception, pregnancy, and postpartum phases, including concerns about disease management and medication safety. The Reproductive Rheumatology care pathway at Erasmus University Medical Center integrates specialized care from rheumatologists and specialized nurses to address both medical, nursing, practical and emotional needs during these phases. This study evaluates patient satisfaction, identifies unmet needs, and explores opportunities for enhancing support within this integrated care model.MethodsThis was a cross-sectional study. We designed a customized questionnaire for women 18 years and older who were treated following the Reproductive Rheumatology care pathway and had given birth between 2019 and 2021. These women were invited to fill in the questionnaire. The survey assessed satisfaction with care, challenges experienced, and information needs across preconception, pregnancy, and postpartum phases. Descriptive statistics and paired t-tests were used for data analysis.ResultsParticipants reported high satisfaction with care, rating rheumatologists an average of 8.8/10 and specialized nurses 9.2/10. While 78.9% experienced no major issues, some faced problems such as managing disease flares and difficulties around conception. Information needs varied by phase: preconception needs focused on medication safety and fertility, while pregnancy and postpartum concerns included disease management and emotional support. Specialized nurses were pivotal in offering personalized care and practical advice.ConclusionThe integrated Reproductive Rheumatology care pathway effectively supports women with IA through their reproductive journey. Despite high satisfaction, improvements could be made in personalized care and addressing challenges related to confidence and help acceptance. Future research should investigate the long-term impact of such care pathways on reproductive outcomes and patient well-being.

Genome-wide aggregated trans- effects analysis identifies genes encoding immune checkpoints as core genes for rheumatoid arthritis.

The sparse effector "omnigenic" hypothesis postulates that the polygenic effects of common SNPs on a typical complex trait are mediated by trans- effects that coalesce on expression of a relatively sparse set of core genes. The objective of this study was to identify core genes for rheumatoid arthritis by testing for association of rheumatoid arthritis with genome-wide aggregated trans- effects (GATE) scores for expression of each gene as transcript in whole blood or as circulating protein levels. GATE scores were calculated for 5400 cases and 453705 non-cases of primary rheumatoid arthritis in UK Biobank participants of European ancestry. Testing for association with GATE scores identified 16 putative core genes for rheumatoid arthritis outside the HLA region, of which six - TP53BP1, PDCD1, TNFRSF14, LAIR1, LILRA4, and IDO1 - were supported by Mendelian randomization analysis based on the marginal likelihood of the causal effect parameter. Five of these 16 genes were validated by a reported association of rheumatoid arthritis with SNPs within 200 kb of the transcription site, 8 by association of the measured protein level with rheumatoid arthritis in UK Biobank, 10 by experimental perturbation in mouse models of inflammatory arthritis, and two - CTLA4 and PDCD1 - by evidence that drugs targeting the gene cause or ameliorate inflammatory arthritis in humans. 14 of these 16 genes are in pathways affecting immunity or inflammation and six - CD5, CTLA4, TIGIT, LAIR1, TNFRSF14, PDCD1 - encode receptors that have been characterized as immune checkpoints exploited by cancer cells to escape the immune response. These results highlight the key role of immune checkpoints in rheumatoid arthritis and identify possible therapeutic targets.

Epigenetic trajectory predicts development of clinical rheumatoid arthritis in ACPA+ individuals: Targeting Immune Responses for Prevention of Rheumatoid Arthritis (TIP-RA).

The presence of autoantibodies to citrullinated protein antigens (ACPAs) in the absence of clinically-apparent inflammatory arthritis (IA) identifies individuals at-risk for developing future clinical rheumatoid arthritis (RA). However, it is unclear why some ACPA+ individuals convert to clinical RA while others do not. We explored the possibility in the Targeting Immune Responses for Prevention of Rheumatoid Arthritis (TIP-RA) study that epigenetic remodeling is part of the trajectory from an at-risk state to clinical disease and identifies novel biomarkers associated with conversion to clinical RA. ACPA- Controls, ACPA+ At-Risk, and Early RA individuals were followed for up to 5 years, including obtaining blood samples annually and at RA diagnosis. Peripheral blood mononuclear cells (PBMCs) were separated into CD19+ B cells, memory CD4+ T cells, and naive CD4+ T cells using antibodies and magnetic beads. Genome-wide methylation within each cell lineage was assayed using the Illumina MethylationEPIC v1.0 beadchip. ACPA+ At-Risk participants who did or did not develop RA were designated Pre-RA or Non-converters, respectively. Differentially methylated loci (DML) were selected using the Limma software package. Using the Caret package, we constructed machine learning models in test and validation cohorts and identified the most predictive loci of clinical RA conversion. Cross-sectional differential methylation analysis at baseline revealed DMLs that distinguish the Pre-RA methylome from ACPA+ Non-converters, the latter which closely resembled ACPA- Controls. Genes overlapping these DMLs correspond to aberrant NOTCH signaling and DNA repair pathways in B cells. Longitudinal analysis showed that ACPA- Control and ACPA+ Non-converter methylomes are relatively constant. In contrast, the Pre-RA methylome remodeled along a dynamic RA methylome trajectory characterized by epigenetic changes in active regulatory elements. Clinical conversion to RA, defined based on diagnosis, marked an epigenetic inflection point for cell cycle pathways in B cells and adaptive immunity pathways in naive T cells. Machine learning revealed individual loci associated with RA conversion. This model significantly outperformed autoantibodies plus acute phase reactants as predictors of RA conversion. DNA methylation is a dynamic process in ACPA+ individuals at-risk for developing RA that eventually transition to clinical disease. In contrast, non-converters and controls have stable methylomes. The accumulation of epigenetic marks over time prior to conversion to clinical RA conforms to pathways that are associated with immunity and can be used to identify potential pathogenic pathways for therapeutic targeting and/or use as prognostic biomarkers.

Advances in the use of nanotechnology for treating gout.

Gout is a commonly occurring form of inflammatory arthritis caused by persistently elevated levels of uric acid. Its incidence rate rises with the increases of living standards and poor dietary habits, which has a considerable impact on the quality of life of the patients. Although there is a wide assortment of drugs available for the management of gout, the effectiveness and security of these drugs are limited by their poor chemical stability and insufficient targeting. Therefore, development of effective nanomedicine systems to overcome these problems and treat gout becomes a high priority. This review provides a detailed introduction research progress on developing advanced nanomedicines using polymers, hydrogel, nanocapsules, lipids, bionic vesicles, inorganic artificial organelles and electronically controlled conveyor systems carriers to improve gout therapy.

Ginsenoside compound K decreases presentation of citrullinated peptides by regulating autophagy-induced autoantigen activation.

Citrullinated vimentin (cVIM) triggers the immune response and is the primary autoantigen of rheumatoid arthritis (RA). Ginsenoside compound K (CK), which exerts significant anti-inflammatory effects, was the objective of this study. We aimed to investigate the role and mechanism of CK in regulating presentation of citrullinated peptides. In RA fibroblast-like synoviocytes (RA-FLS), the expression of autoantigen cVIM, antigen presentation-related molecules, autophagy-related proteins, and autophagic flux were investigated. The effect of CK on the antigen presentation capability of FLS was also examined under conditions of autophagy induction and inhibition. Finally, Wistar rats were immunized with cVIM to evaluate the therapeutic effect of CK in an RA model. In RA-FLS, CK mitigated the expression of cVIM, autophagy-associated proteins, and antigen presentation-related molecules. This regulatory effect was associated with autophagy. cVIM-immunized rats exhibited more severe arthritis and higher levels of anti-CCP antibodies than those with adjuvant- and vimentin (VIM)-induced arthritis. CK significantly alleviated arthritis inflammation in cVIM-immunized rats. CK alleviates cVIM-induced arthritis symptoms, with the regulation of autophagy presenting a key cellular event involved in cVIM generation and RA-FLS antigen-presenting ability.

Imaging tests as predictors of progression to rheumatoid arthritis in clinically suspect arthralgia: A systematic review & meta-analysis.

To determine and compare the diagnostic accuracy of imaging tests for the prediction of RA progression in people with inflammatory joint pain or CSA. We searched MEDLINE, Embase and Web of Science from 1987 to March 2024. Studies evaluating any imaging tests in participants with inflammatory joint pain or CSA, without clinical synovitis were eligible. Reference standards included RA classification criteria, methotrexate initiation or development of inflammatory arthritis (IA). Two authors independently extracted data and assessed validity according to QUADAS-2. We estimated summary sensitivities and specificities for each imaging characteristic and fitted bivariate and hierarchical SROC models for meta-analysis where possible. We found 39 eligible studies including 42 cohorts, of which 12 evaluated MRI (n = 2,782; 19% with RA/IA), 26 evaluated ultrasound (US)(n = 6,805; 25% with RA/IA) and 10 evaluated other imaging tests (n = 3,362; 20% with RA/IA). Summary sensitivity and specificity for US Power Doppler ≥1 in at least one joint were 37% (95%CI 18%-60%) and 90% (95%CI 82%-94%), respectively (7 studies). Summary sensitivity and specificity for MRI synovitis in at least one joint were 45% (95%CI 29%-62%) and 84% (95%CI 66%-94%), respectively (4 studies). Lack of consensus regarding positive threshold definitions limited meta-analysis for other imaging features. Evidence for MRI or US in predicting RA/IA in people with CSA is heterogeneous and of variable quality. Further studies with larger sample sizes, longer follow-up times and uniform imaging test scoring, are warranted to determine whether imaging characteristics, in combination with clinical information, can predict RA in this population. PROSPERO: https://www.crd.york.ac.uk/prospero CRD42024501243.

Clinical features of inflammatory arthritis in daily practice-China's perspective.

This study aimed to analyze and compare the proportion of patients with different types of inflammatory arthritis and investigate the clinical characteristics, including symptoms and signs, medication choices, and disease activity, in the daily clinical practice of China. Patients with inflammatory arthritis were recruited from 16 Grade-A tertiary hospitals between August 2021 and April 2022. The medical profiles, encompassing sociodemographic characteristics, clinical and laboratory date, were collected. This study included 2,693 patients with arthritis, with rheumatoid arthritis (RA) accounting for the highest proportion (50.50%). Significant differences were observed in terms of age,gender, body mass index (BMI), disease duration, smoking and family history among patients with different types of inflammatory arthritis. Physical activity and cold exposure were identified as the main predisposing factors for RA, psoriatic arthritis (PsA), osteoarthritis (OA), and ankylosing spondylitis (AS), while alcohol consumption was the most common inducing factor for gout. Hypertension and hyperlipidemia were the primary concomitant diseases in RA, OA, and AS, whereas hyperuricemia and hypertension were mainly associated with gout, psoriasis and diabetes were the most common comorbidities in PsA. Peripheral joints were predominantly affected in PsA, RA, OA, and gout, while axial joints were mainly affected in AS. Methotrexate and leflunomide were the main therapeutic drugs for RA, while biologics were commonly prescribed for PsA and AS. OA and gout patients mainly utilized nonsteroidal anti-inflammatory drugs (NSAIDs). Patients with different types of inflammatory arthritis exhibited varying predisposing factors, joint inflammation, concomitant diseases, and medication choices, highlighting the importance of individualized approaches in the clinic. Key Points • 2,693 patients classified and diagnosed with inflammatory arthritis were recruited in this study from 16 Grade-A tertiary hospitals in China between August 2021 and April 2022. • This study analyzed and compared the proportion of patients with different types of arthritis in routine clinical practice in China. • Joint inflammation, comorbidities, and medication choices were assessed among patients with the most common types of arthritis in this study. • This study also provided some epidemiologically relevant information about inflammatory arthritis patients in China.

Joint fluid multi-omics improves diagnostic confidence during evaluation of children with presumed septic arthritis

BackgroundAn accurate diagnosis of septic versus reactive or autoimmune arthritis remains clinically challenging. A multi-omics strategy comprising metagenomic and proteomic technologies were undertaken for children diagnosed with presumed septic arthritis to advance clinical diagnoses and care for affected individuals.MethodsTwelve children with suspected septic arthritis were prospectively enrolled to compare standard of care tests with a rapid multi-omics approach. The multi-omics combined bacterial 16S rRNA metagenomics, single cell transcriptomics, and proteomics on knee joint fluid specimens. The diagnostic value of the multi-omics was ascertained relative to standard of care culture and PCR-negative results.ResultsTen children with suspected primary septic arthritis and two with acute hematogenous osteomyelitis (AHO) diagnoses were assessed. Joint fluid bacterial cultures were positive for 6/12 (50%) patients, consistent with elevated inflammatory markers (IL-4, IL-6, IL-17A, TNF-a, etc.). Metagenomic bacterial sequencing results were 100% concordant with the culture results. Six patients were culture- and PCR-negative. Multiomics analyses of the 6 culture negative patients established that 2/6 culture-negative children had inflammatory arthritis with potential Juvenile idiopathic arthritis (JIA) and 1 had post-Streptococcal Reactive Arthritis. The children without any bacteremia had autoantibodies (IgGs) in the joint-fluid targeting several nuclear antigens (i.e., dsDNA, histones, Jo-1, scl-70, Ro/SS-A, SmDs, CENP-A along with non-nuclear antigens i.e. Albumin, Collagens, Myosin, Laminin, etc. Single cell transcriptomics confirmed an abundance of CD4+ follicular helper T (Tfh), CD8 + T cells and B cells in the autoantibody positive subjects. The combination of 16S DNA sequencing (p = 0.006), cytokine assays (p = 0.009) and autoantibody profiling (p = 0.02) were significantly distinct between those children with and without infections. This improved the diagnostic confidence for 9 of 12 (75%) children, key for treatment decisions.ConclusionsThe multiomics approach rapidly identified children with bacterial or autoimmune inflammatory conditions, improving diagnostic and treatment strategies for those with presumptive septic arthritis.

Sleep disorders in rheumatoid arthritis, axial spondyloarthritis and psoriatic arthritis.

Sleep disorders are relatively common among patients with inflammatory arthritis (IA) and have a substantial impact on their quality of life. Although patients frequently recognize poor sleep as an important component of their disease, dyssomnias remain often underdiagnosed and untreated in routine clinical practice. This narrative review examines the prevalence, mechanism, risk factors and management of dyssomnias in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA). Relevant articles were retrieved from PUBMED, Scopus and DOAJ. The pathomechanism of sleep disorders in IA is multifactorial and partially differs in RA, axSpA and PsA, however, comparative studies are lacking. Various factors affecting sleep quality, including disease activity, pain, mood disorders, fatigue and female gender, have been examined, but their interplay complicates establishing clear causal relationships. The bidirectional link between sleep quality and rheumatic disease activity highlights the complexity of this issue and demonstrates the importance of holistic management of rheumatic patients. Both pharmacological (e.g., hypnotics, NSAIDs, antidepressants, cannabidiol) and non-pharmacological (e.g., psychotherapy, physical activity) interventions for improving sleep were analyzed. Additionally, questionnaires currently used for assessing sleep were discussed. This review aims to provide a comprehensive overview of sleep disorders across the three most common types of IA, emphasizing the need to develop reliable and patient-friendly tools for everyday clinical practice and further comparative research.

Do individuals with inflammatory arthritis receive minimally adequate treatment for incident depression and anxiety: A population-based study

ObjectivesDescribe patterns of pharmacotherapy and psychological treatment and evaluate receipt of minimally adequate treatment for incident depression and anxiety in individuals with inflammatory arthritis (IA).MethodsWe used population-based linked administrative health databases from British Columbia, Canada to evaluate pharmacotherapy and psychological treatments for incident depression and/or anxiety among individuals with IA and without IA (‘IA-free controls’). We defined minimally adequate pharmacotherapy as antidepressant prescriptions filled with ≥ 84 days’ supply and adequate psychological treatment as ≥ 4 counselling/psychotherapy services. Multivariable logistic regression models were used to evaluate the odds of individuals with IA receiving minimally adequate pharmacotherapy and/or psychological treatment compared to IA-free controls.Results6,951 (mean age 54.8 ± 18.3 years; 65.5% female) individuals with IA had incident depression and 3,701 (mean age 52.9 ± 16.8 years; 74.3% female) had incident anxiety. Minimally adequate pharmacotherapy and psychological treatment for depression was respectively observed in 50.5% and 19.6% of those with IA, proportions similar to IA-free controls (pharmacotherapy: aOR 1.10, 95% CI 1.00 to 1.21; psychological: aOR 1.07, 95% CI 0.94 to 1.21). Results were similar regarding anxiety treatment. Individuals with IA had a significantly greater likelihood of dispensing ≥ 1 benzodiazepine (anxiety: IA 45.0%, IA-free controls 39.0%, p-value < 0.001) and ≥ 1 tricyclic antidepressant prescription (anxiety: IA 12.8%, IA-free controls 7.8%, p-value < 0.001). Significantly higher average days’ supply of benzodiazepines was observed for IA (anxiety: IA 123.7 days, controls 112.4 days, p-value = 0.003).ConclusionsA substantial proportion of individuals with IA were not receiving adequate mental health treatment for depression and anxiety, a finding similar for IA-free controls. The undertreatment of mental disorders for people with IA has well-known negative implications for the provision of effective rheumatology care. It remains fundamental to expand publicly funded health care to include mental health services in an effort to address unmet counselling needs.

Fibroblasts in rheumatoid arthritis: novel roles in joint inflammation and beyond.

High-throughput technologies in human and animal studies have revealed novel molecular and cellular pathways involved in tissue inflammation of rheumatoid arthritis (RA). Fibroblasts have been in the forefront of research for several decades. Subpopulations with specific phenotypic and functional properties have been characterized both in mouse models and human disease. Data supporting the active involvement of fibroblasts in immune responses and tissue remodeling processes, as well as their central role in promoting clinical relapses and contributing to treatment resistance, have clearly reshaped their role in disease evolution. The lung is an important non-synovial component of RA both from a clinical and an immunopathogenic aspect. Interstitial lung disease (ILD) is a significant contributor to disease burden affecting morbidity and mortality. Although our knowledge of ILD has progressed, significant gaps in both basic and clinical science remain, posing hurdles to efficient diagnosis, prediction of disease course and its effective treatment. The specific role and contribution of fibroblasts to this process has not been clearly defined. The focus of this review is on fibroblasts and their contribution to RA and RA-ILD, presenting data on genetics and immune responses associated with RA-ILD in humans and animal models.

Dual neutralization of TGF-β and IL-21 regulates Th17/Treg balance by suppressing inflammatory signalling in the splenic lymphocytes of Staphylococcus aureus infection-induced septic arthritic mice.

Septic arthritis (SA) caused by Staphylococcus aureus is a severe inflammatory joint disease, characterized by synovitis accompanied with cartilage destruction and bone erosion. The available antibiotic treatment alone is insufficient to resolve the inflammation that leads to high rates of morbidity and mortality. Among the CD4+ T helper lymphocytes, the Th17 and Tregs are key regulators of immune homeostasis. A high Th17 could lead to autoimmunity, whereas an increase in Tregs indicates immunosuppression. Depending on the external cytokine milieu, naïve CD4+ T cells transform into either Th17 or Treg cell lineage. TGF-β in the presence of IL-21 produces Th17 cells and drives the inflammatory cascade of reactions. We studied the effects of in vivo neutralization of TGF-β and IL-21 in septic arthritic mice to control arthritic inflammation, which has not been studied before. The arthritic index showed maximum severity in the SA group which substantially reduced in the Ab-treated groups. Flow cytometric analyses of peripheral blood collected from mice at 9DPI revealed the highest Th17/Treg ratio in the SA group but least in the combined-antibody-treated group. TGF-β1 and IL-21 cytokine production from serum, spleen, and synovial tissue homogenates was significantly reduced in the dual Ab-treated group than in the untreated SA group. From the Western blot analyses obtained from splenic lymphocytes at 9 DPI, we elucidated the possible underlying mechanism of interplay in downstream signalling involving the interaction between different STAT proteins and SOCS, NF-κB, RANKL, mTOR, iNOS, and COX-2 in regulating inflammation and osteoclastogenesis. On endogenous blockade with TGF-β and IL-21, the Th17/Treg ratio and resultant arthritic inflammation in SA were found to be reduced. Therefore, maintaining the Th17/Treg balance is critical to eradicate infection as well as suppress excessive inflammation and neutralization of TGF-β and IL-21 could provide a novel therapeutic strategy to treat staphylococcal SA.

Inflammatory disease microbiomes share a functional pathogenicity predicted by C-reactive protein.

We examine disease-specific and cross-disease functions of the human gut microbiome by colonizing germ-free mice, at risk for inflammatory arthritis, colitis, or neuroinflammation, with over 100 human fecal microbiomes from subjects with rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, ulcerative colitis, Crohn's disease, or colorectal cancer. We find common inflammatory phenotypes driven by microbiomes from individuals with intestinal inflammation or inflammatory arthritis, as well as distinct functions specific to microbiomes from multiple sclerosis patients. Inflammatory disease in mice colonized with human microbiomes correlated with systemic inflammation, measured by C-reactive protein, in the human donors. These cross-disease patterns of human microbiome pathogenicity mirror features of the inflammatory diseases, including therapeutic targets and the presence or absence of systemic inflammation, suggesting shared and disease-specific mechanisms by which the microbiome is shaped and drives pathogenic inflammatory responses.

MtSTAT3 suppresses rheumatoid arthritis by regulating Th17 and synovial fibroblast inflammatory cell death with IL-17-mediated autophagy dysfunction

Th17 cells are activated by STAT3 factors in the nucleus, and these factors are correlated with the pathologic progression of rheumatoid arthritis (RA). Recent studies have demonstrated the presence of STAT3 in mitochondria, but its function is unclear. We investigated the novel role of mitochondrial STAT3 (mitoSTAT3) in Th17 cells and fibroblast-like synoviocytes (FLSs) and analyzed the correlation of mitoSTAT3 with RA. We used a collagen-induced arthritis (CIA) mouse model to determine the effect of mitochondrial STAT3. We observed changes in the RA mouse model via the use of a mitochondrial STAT3-inducing vector and inhibitor. We observed the accumulation of abnormal autophagosomes, increased inflammatory cell death signaling, and decreased mitoSTAT3 activity in FLSs from both patients with RA and patients with IL-17-treated FLSs. We first discovered that IL-17 increased the accumulation of abnormal autophagosomes and the expression of inflammatory cell death factors in synovial fibroblasts and decreased mitoSTAT3 activation. In a mouse model of CIA, arthritis and joint inflammation were decreased by injection vectors that induced mitoSTAT3 overexpression. The abnormal accumulation of autophagosomes and the expression of inflammatory cell death factors were also decreased in these mice. In mouse and human immune cells, ZnSO4, an inducer of mitochondrial STAT3, decreases the production of reactive oxygen species, the IL-17 concentration, and differentiation into Th17 cells. However, mitoSTAT3 blockade accelerated the development of arthritis, inflammatory cell death, and abnormal autophagosome/autophagolysosome formation. Therefore, this study suggests a novel inhibitory mechanism of RA using mitoSTAT3 via the regulation of autophagy, Th17 differentiation, and inflammatory cell death.

Targeting TRPC channels for control of arthritis-induced bone erosion.

Arthritis leads to bone erosion due to an imbalance between osteoclast and osteoblast function. Our prior investigations revealed that the Ca2+-selective ion channel, Orai1, is critical for osteoclast maturation. Here, we show that the small-molecule ELP-004 preferentially inhibits transient receptor potential canonical (TRPC) channels. While ELP-004 minimally affected physiological RANKL-induced osteoclast maturation in murine bone marrow- and spleen-derived myeloid cells (BMSMCs) and human PBMC-derived cells, it potently interfered with osteoclast maturation driven by TNFα or LTB4. The contribution of TRPC channels to osteoclastogenesis was examined using BMSMCs derived from TRPC4-/- or TRPC(1-7)-/- mice, again revealing preferential interference with osteoclastogenesis driven by proinflammatory cytokines. ELP-004 also reduced bone erosion in a mouse model of rheumatoid arthritis. These investigations reveal TRPC channels as critical mediators of inflammatory bone erosion and provide insight into the major target of ELP-004, a drug currently in preclinical testing as a therapeutic for inflammatory arthritis.

A new twist on superantigen-activated autoimmune disease.

Superantigen-induced (Sag-induced) autoimmunity has been proposed as a mechanism for many human disorders, without a clear understanding of the potential triggers. In this issue of the JCI, McCarthy and colleagues used the SKG mouse model of rheumatoid arthritis to characterize the role of Sag activity in inflammatory arthritis by profiling arthritogenic naive CD4+ T cells. Within the diseased joints, they found a marked enrichment of T cell receptor-variable β (TCR-Vβ) subsets that were reactive to the endogenously encoded mouse mammary tumor virus (MMTV) Sag. Arthritis was improved using reverse transcriptase inhibitors. Moreover, depletion of MMTV Sag-activated TCR-Vβ subsets affected the ability of transferred activated CD4+ T cells to induce disease in mice with severe combined immunodeficiency (SCID). Further virological studies should determine whether endogenous or exogenous MMTV is necessary or sufficient to trigger inflammatory arthritis in the SKG model.