Transcription Factor Analysis to Investigate Immunosenescence in Rheumatoid Arthritis Patients.

Rheumatoid arthritis (RA) is linked to various signs of advanced aging, such as premature immunosenescence which occurs due to decline in regenerative ability of T cells. RA T cells develop a unique aggressive inflammatory senescent phenotype with an imbalance of Th17/T regulatory (Treg) cell homeostasis and presence of CD28- T cells. The phenotypic analysis and characterization of T cell subsets become necessary to ascertain if any functional deficiencies exist within with the help of transcription factor (TF) analysis. These subset-specific TFs dictate the functional characteristics of T-cell populations, leading to the production of distinct effector cytokines and functions. Examining the expression, activity, regulation, and genetic sequence of TFs not only aids researchers in determining their importance in disease processes but also aids in immunological monitoring of patients enrolled in clinical trials, particularly in evaluating various T-cell subsets [Th17 (CD3+CD4+IL17+RORγt+) cells and T regulatory (Treg) (CD3+CD4+CD25+CD127-FOXP3+) cells], markers of T-cell aging [aged Th17 cells (CD3+CD4+IL17+RORγt+CD28-), and aged Treg cells (CD3+CD4+CD25+CD127-FOXP3+CD28-)]. In this context, we propose and outline the protocols for assessing the expression of TFs in aged Th17 and Treg cells, highlighting the crucial aspects of this cytometric approach.

Inflammatory stimulus-responsive polymersomes reprogramming glucose metabolism mitigates rheumatoid arthritis.

Inflammation-resident cells within arthritic sites undergo a metabolic shift towards glycolysis, which greatly aggravates rheumatoid arthritis (RA). Reprogramming glucose metabolism can suppress abnormal proliferation and activation of inflammation-related cells without affecting normal cells, holding potential for RA therapy. Single 2-deoxy-d-glucose (2-DG, glycolysis inhibitor) treatment often cause elevated ROS, which is detrimental to RA remission. The rational combination of glycolysis inhibition with anti-inflammatory intervention might cooperatively achieve favorable RA therapy. To improve drug bioavailability and exert synergetic effect, stable co-encapsulation of drugs in long circulation and timely drug release in inflamed milieu is highly desirable. Herein, we designed a stimulus-responsive hyaluronic acid-triglycerol monostearate polymersomes (HTDD) co-delivering 2-DG and dexamethasone (Dex) to arthritic sites. After intravenous injection, HTDD polymersomes facilitated prolonged circulation and preferential distribution in inflamed sites, where overexpressed matrix metalloproteinases and acidic pH triggered drug release. Results indicated 2-DG can inhibit the excessive cell proliferation and activation, and improve Dex bioavailability by reducing Dex efflux. Dex can suppress inflammatory signaling and prevent 2-DG-induced oxidative stress. Thus, the combinational strategy ultimately mitigated RA by inhibiting glycolysis and hindering inflammatory signaling. Our study demonstrated the great potential in RA therapy by reprogramming glucose metabolism in arthritic sites.

Uncovering the mechanisms of Zhubi decoction against rheumatoid arthritis through an integrated study of network pharmacology, metabolomics, and intestinal flora.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhubi Decoction (ZBD) is a modified formulation derived from the classic traditional Chinese medicine prescription "Er-Xian Decoction" documented in the esteemed "Clinical Manual of Chinese Medical Prescription". While the utilization of ZBD has exhibited promising clinical outcomes in treating rheumatoid arthritis (RA), the precise bioactive chemical constituents and the underlying mechanisms involved in its therapeutic efficacy remain to be comprehensively determined. AIM OF THE STUDY: This study aims to systematically examine ZBD's pharmacological effects and molecular mechanisms for RA alleviation. MATERIALS AND METHODS: Utilizing the collagen-induced arthritis (CIA) rat model, we comprehensively evaluated the anti-rheumatoid arthritis effects of ZBD in vivo through various indices, such as paw edema, arthritis index, ankle diameter, inflammatory cytokine levels, pathological conditions, and micro-CT analysis. The UPLC-MS/MS technique was utilized to analyze the compounds of ZBD. The potential therapeutic targets and signaling pathways of ZBD in the management of RA were predicted using network pharmacology. To analyze comprehensive metabolic profiles and identify underlying metabolic pathways, we conducted a serum-based widely targeted metabolomics analysis utilizing LC-MS technology. Key targets and predicted pathways were further validated using immunofluorescent staining, which integrated findings from serum metabolomics and network pharmacology analysis. Additionally, we analyzed the gut microbiota composition in rats employing 16 S rDNA sequencing and investigated the effects of ZBD on the microbiota of CIA rats through bioinformatics and statistical methods. RESULTS: ZBD exhibited remarkable efficacy in alleviating RA symptoms in CIA rats without notable side effects. This included reduced paw redness and swelling, minimized joint damage, improved the histopathology of cartilage and synovium, mitigated the inflammatory state, and lowered serum concentrations of cytokines TNF-α, IL-1ß and IL-6. Notably, the effectiveness of ZBD was comparable to MTX. Network pharmacology analysis revealed inflammation and immunity-related signaling pathways, such as PI3K/AKT, MAPK, IL-17, and TNF signaling pathways, as vital mediators in the effectual mechanisms of ZBD. Immunofluorescence analysis validated ZBD's ability to inhibit PI3K/AKT pathway proteins. Serum metabolomics studies revealed that ZBD modulates 170 differential metabolites, partially restored disrupted metabolic profiles in CIA rats. With a notable impact on amino acids and their metabolites, and lipids and lipid-like molecules. Integrated analysis of metabolomics and network pharmacology identified 6 pivotal metabolite pathways and 3 crucial targets: PTGS2, GSTP1, and ALDH2. Additionally, 16 S rDNA sequencing illuminated that ZBD mitigated gut microbiota dysbiosis in the CIA group, highlighting key genera such as Ligilactobacillus, Prevotella_9, unclassified_Bacilli, and unclassified_rumen_bacterium_JW32. Correlation analysis disclosed a significant link between 47 distinct metabolites and specific bacterial species. CONCLUSION: ZBD is a safe and efficacious TCM formulation, demonstrates efficacy in treating RA through its multi-component, multi-target, and multi-pathway mechanisms. The regulation of inflammation and immunity-related signaling pathways constitutes a crucial mechanism of ZBD's efficacy. Furthermore, ZBD modulates host metabolism and intestinal flora. The integrated analysis presents experimental evidence of ZBD for the management of RA.

Sporidiobolus pararoseus polysaccharides relieve rheumatoid arthritis by regulating arachidonic acid metabolism and bone remodeling signaling pathway.

Rheumatoid arthritis (RA) is an autoimmune-mediated disease with the highest disability rate. Sporidiobolus pararoseus polysaccharides (SPP) have been demonstrated to have anti-rheumatoid and microbiota-modulatory effects; however, the underlying mechanisms remain unclear. This study employed collagen-induced arthritis (CIA) mice to explore the metabolic and genetic pathways. The results revealed SPP intervention significantly reduced the serum levels of rheumatoid and pro-inflammatory complement factors. SPP promoted the transition of macrophages of CIA mice toward the M2 phenotype (F4/80+/CD206+) from an inflammatory phenotype (F4/80+/CD86+) using flow cytometry analysis. A total of 44 metabolites were upregulated, and 110 metabolites were significantly downregulated by SPP compared to those in RA group. The decreased metabolites, 12(S)-HPETE, prostaglandin H2, 15-HETE, hepoxilin B3, and 15-keto-prostaglandin F2a, were mostly enriched in arachidonic acid metabolism (enrichment = 11.4 %), which was highly correlated with the anti-rheumatic activity of SPP. Gene expression analysis revealed that SPP significantly regulated OPG/RANKL/TRAF6 signaling pathway, stimulating osteogenic remodeling. Furthermore, arachidonic acid metabolism was identified as the critical metabolic driver of RA phenotypes and osteoclast differentiation, potentially associated with SPP-reshaped intestinal microbiota (i.e., Rikenellaceae_RC9_gut_group, Bacteroides, and Parabacteroides). Collectively, this study utilized an integrated approach of metabolomics and gene expression analysis to investigate the regulatory role of SPP in RA progression.

Association of methotrexate polyglutamates concentration with methotrexate efficacy and safety in patients with rheumatoid arthritis treated with predefined dose: results from the MIRACLE trial.

OBJECTIVES: The usefulness of methotrexate-polyglutamates (MTX-PGs) concentration for management of rheumatoid arthritis has been debated. We aimed to clarify the association of MTX-PGs concentration with efficacy and safety in MTX-naïve patients initiating MTX in a prospective interventional clinical trial. METHODS: The MIRACLE trial enrolled 300 MTX-naïve patients. Oral MTX was initiated and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission according to the Simplified Disease Activity Index at week 24 were randomised to either the continued dose or reduced dose group and were started on subcutaneous adalimumab. We measured the concentrations of MTX-PGs in erythrocytes using liquid chromatography-tandem mass spectrometry and analysed the association of these concentrations with efficacy and safety. RESULTS: The mean concentration of total MTX-PGs increased with an increasing dose of MTX and continued to elevate for another 12 weeks after the dose was fixed. At week 24, the total MTX-PGs concentration was 110.5 (SD 43.8) nmol/L with MTX dose of 12.6 (3.0) mg/week (0.23 (0.07) mg/kg/week). During MTX monotherapy, the higher MTX-PGs concentration was an independent factor for lower disease activity; however, this association disappeared after adalimumab initiation in patients with continued MTX dose. Hepatotoxicity was related to the higher MTX-PGs concentration regardless of adalimumab use. The total MTX-PGs concentration was significantly elevated by lower estimated glomerular filtration rate, serum albumin and body mass index. CONCLUSIONS: The MIRACLE trial demonstrated that higher total MTX-PGs concentration in erythrocytes is related to the higher efficacy and lower safety of MTX. TRIAL REGISTRATION NUMBER: NCT03505008.

Peripheral blood immunophenotypic diversity in patients with rheumatoid arthritis and its impact on therapeutic responsiveness.

OBJECTIVE: Considering the diverse aetiologies and immunodysregulatory statuses observed in each patient with rheumatoid arthritis (RA), stratification based on peripheral blood immunophenotyping holds the potential to enhance therapeutic responses to molecular targeted therapies, biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). METHODS: Immunophenotype analysis was conducted on a cohort of over 500 b/tsDMARDs-naïve patients using flow cytometry. Patients with RA were stratified based on their immunophenotypes, and the treatment response to each targeted therapy was evaluated. Validation was performed using an additional cohort of 183 b/tsDMARDs-naïve patients with RA. RESULTS: Patients with RA were stratified into five clusters, two of which exhibited distinct RA phenotypes compared with controls, characterised by significant increases in CD4+ effector memory T cells re-expressing CD45RA. Notably, the effectiveness of different b/tsDMARDs varied across clusters. The group using promising b/tsDMARDs was labelled as 'expected' whereas the 'non-expected' group comprised those using others. The expected group outperformed the non-expected group with higher 26-week remission rates (39.9% vs 24.6%, p=0.0004) and low disease activity achievement (80.8% vs 60.2%, p<0.0001). Trajectory analysis showed the non-expected group's 26-week disease activity was influenced by Clinical Disease Activity Index at baseline unlike the expected group. Additionally, different molecular targeted therapies influenced the proportions of each immune cell subset variably. To validate, immunophenotyping was performed on a validation cohort. When 183 cases were grouped based on their b/tsDMARDs usage into expected/non-expected groups, the expected group had a higher remission rate (p=0.0021), further confirming the observed trend. CONCLUSION: Our findings offer valuable insights into the diversity of RA and potential therapeutic strategies grounded in the molecular underpinnings.

Rheumatoid arthritis in Latin America: pharmacotherapy and clinical challenges.

INTRODUCTION: Rheumatoid arthritis (RA) poses significant healthcare challenges in Latin America (LA) due to its high prevalence and unique healthcare dynamics. Despite global advancements, LA faces specific hurdles in effectively managing RA. AREAS COVERED: This review examines RA epidemiology, treatment strategies, and clinical challenges in LA. RA prevalence varies, with higher rates among indigenous populations. While conventional disease-modifying antirheumatic drugs (csDMARDs) are recommended as first-line therapy, access remains inconsistent. Biologics and targeted synthetic DMARDs are available, but biosimilars have limited accessibility, with drug prices varying significantly. Key barriers include supply interruptions, diagnosis delays, and high non-adherence rates driven by socioeconomic factors. A severe shortage of rheumatologists, particularly in rural areas, affects patient care. Cardiovascular events, comorbidities, and endemic infections further complicate RA management. EXPERT OPINION: Although RA care in LA has improved through better use of csDMARDs and advanced treatments, major challenges persist, such as a shortage of specialists, limited medical education, and fragmented healthcare systems. Expanding training programs, enhancing telemedicine, and ensuring drug supply continuity are essential. Strengthening clinical research, improving access to affordable treatments, and developing comprehensive, region-specific strategies are crucial to closing the gap between LA and more developed regions in RA care..

Biologic and targeted synthetic disease-modifying anti-rheumatic drugs improve body composition in rheumatoid arthritis patients more than conventional synthetic disease-modifying anti-rheumatic drugs: Results from the PRESENT study.

INTRODUCTION: The effects of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) and conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) on body composition and muscle function in rheumatoid arthritis (RA) patients requiring treatment enhancement were compared. METHODS: This multicenter, prospective, observational study (PRESENT Study) divided RA patients non-randomly into a csDMARD group (n = 100) and a b/tsDMARD group (n = 100). Changes in body composition and muscle function were examined in 80 patients in each group followed for 52 weeks. The percentages of new-onset and improved sarcopenia over 1 year were investigated. Patients in the b/tsDMARD group were divided into three groups by drug type: TNF inhibitors (n = 30), non-TNF inhibitors (n = 23), and JAK inhibitors (n = 27). RESULTS: Baseline median age and disease duration were 70.0 and 4.0 years, respectively. Changes in weight (24 and 52 weeks) and muscle mass (52 weeks) were significantly higher in the b/tsDMARD group (p = .035, p < .001, and p = .002, respectively). On multivariate logistic regression analysis, b/tsDMARD treatment (OR 3.21, p = .002), DAS28-ESR (OR 0.65 p = .011), and muscle mass (OR 0.90, p = .023) were independently associated with increased muscle mass at 52 weeks. The percentages of new-onset and improved sarcopenia were almost equal. There were no significant differences in the time-dependent changes (52 weeks) of clinical status, body composition, muscle function, and status of sarcopenia among TNF inhibitors, non-TNF inhibitors, and JAK inhibitors. CONCLUSIONS: Weight and muscle mass increased significantly more with b/tsDMARD than with csDMARD treatment. There were no differences in body composition changes by mode of action with b/tsDMARDs.

Serum selenium, selenoprotein P and glutathione peroxidase 3 in rheumatoid, psoriatic, juvenile idiopathic arthritis, and osteoarthritis.

INTRODUCTION: Selenoprotein P (SELENOP) controls selenium transport, and glutathione peroxidase 3 (GPx3) elicits antioxidant activity in blood. Inflammation associates with Se deficiency, but knowledge concerning selenoproteins in inflammatory rheumatic musculoskeletal diseases (iRMD) is limited. We compared three Se biomarkers in patients with rheumatoid (RA), psoriatic (PsA), and juvenile idiopathic arthritis (JIA) in comparison to osteoarthritis (OA) and healthy subjects, to improve the data base on selenoprotein expression in iRMD. METHODS: The cross-sectional study enrolled n=272 patients with RA (n=131), PsA (n=67), JIA (n=22) and OA (n=52). Serum Se was quantified by total reflection X-ray fluorescence, SELENOP by ELISA and GPx3 by an enzymatic test. Data from the EPIC trial served as reference. Impairment of daily life was assessed by the Functional Ability Questionnaire (FfbH). RESULTS: Serum SELENOP and Se concentrations correlated linearly in all groups and were below the average measured in EPIC. Se concentration was not different between the patient groups. Compared to controls, SELENOP levels were low in iRMD patients. GPx3 activity was particularly low in JIA and PsA. Seropositive but not seronegative RA patients displayed a disrupted interaction between GPx3 and Se or SELENOP. SELENOP associated with the functional status measured by the FfbH, most pronounced in OA (R=0.76, p<0.01). DISCUSSION: The data indicate selenoprotein deficiency in the majority of patients with iRMD, and a positive relation of SELENOP with functional status in OA. Since increased Se supply improves selenoprotein biosynthesis, a personalized correction of diagnosed deficiency merits consideration to improve Se transport and ameliorate disease burden.

Wutou Decoction attenuates rheumatoid arthritis in rats through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM), Wutou Decoction (WTD) has long been used to alleviate arthritis. Emerging studies have reported that WTD could improve the symptoms of rheumatoid arthritis (RA). However, the mechanism by which WTD is involved in the treatment of RA remains elusive, posing a challenge to the worldwide acceptance of WTD as an efficient RA therapy. AIM OF THE STUDY: This study investigated the antiarthritic efficacy of WTD in a collagen-induced arthritis (CIA) rat model and explored silent information regulator 1 (SIRT1)-mediated deacetylation of the high mobility group box 1 (HMGB1)/NF-κB pathway. MATERIALS AND METHODS: A rat CIA model was used to evaluate the antiarthritic activity of WTD. Clinical arthritis score assessment, left ankle thickness assessment, micro-CT, histopathological staining, immunofluorescence staining, and ELISA were conducted to elucidate the anti-inflammatory effects of WTD. The M1 macrophage polarization state, cell viability, and invasion were also determined to assess the effects of WTD on macrophage proliferation and invasion in vitro. Additionally, in vivo and in vitro HMGB1 nuclear translocation and NF-κB activation were analysed. Finally, deacetylase activity was assessed by Western blot, NAD+/NADH analysis, and co-immunoprecipitaion. RESULTS: WTD significantly alleviated arthritis in CIA rats and inhibited pathological changes in joint lesions while concurrently suppressing TNF-α, IL-6, and IL-1ß release. Mechanistically, WTD suppressed M1 infiltration in ankle tissues and their invasion in vitro. Furthermore, WTD downregulated HMGB1/p65 nuclear translocation and acetylation, which may be associated with SIRT1 upregulation. CONCLUSIONS: Overall, WTD potentially alleviates RA through SIRT1-mediated downregulation of HMGB1 and NF-κB acetylation.

2024 update of the recommendations of the French Society of Rheumatology for the diagnosis and management of patients with rheumatoid arthritis.

The French Society of Rheumatology recommendations for managing rheumatoid arthritis (RA) has been updated by a working group of 21 rheumatology experts, 4 young rheumatologists and 2 patient association representatives on the basis of the 2023 version of the European Alliance of Associations for Rheumatology (EULAR) recommendations and systematic literature reviews. Two additional topics were addressed: people at risk of RA development and RA-related interstitial lung disease (RA-ILD). Four general principles and 19 recommendations were issued. The general principles emphasize the importance of a shared decision between the rheumatologist and patient and the need for comprehensive management, both drug and non-drug, for people with RA or at risk of RA development. In terms of diagnosis, the recommendations stress the importance of clinical arthritis and in its absence, the risk factors for progression to RA. In terms of treatment, the recommendations incorporate recent data on the cardiovascular and neoplastic risk profile of Janus kinase inhibitors. With regard to RA-ILD, the recommendations highlight the importance of clinical screening and the need for high-resolution CT scan in the presence of pulmonary symptoms. RA-ILD management requires collaboration between rheumatologists and pulmonologists. The treatment strategy is based on controlling disease activity with methotrexate or targeted therapies (mainly abatacept or rituximab). The prescription for anti-fibrotic treatment should be discussed with a pulmonologist with expertise in RA-ILD.

Metabolic effects of quercetin on inflammatory and autoimmune responses in rheumatoid arthritis are mediated through the inhibition of JAK1/STAT3/HIF-1α signaling.

BACKGROUND: Rheumatoid arthritis, a chronic autoimmune disease, is characterized by synovial hyperplasia and cartilage erosion. Here, we investigated the potential mechanism of action of quercetin, the main component of flavonoids, in treating rheumatoid arthritis. OBJECT: To examine the anti-arthritic effects of quercetin and elucidate the specific mechanisms that differentiate its metabolic effects on autoimmune and inflammatory responses at the synovial cell level. METHODS: We created a collagen-induced arthritis (CIA) model in Wistar rats, which were administered quercetin (50 or 100 mg/kg) continuously for four weeks via stomach perfusion. The arthritis score, histopathological staining, radiological assessment, and serum biochemical parameters were used to study the impact of quercetin on disease improvement. Additionally, immunofluorescence was employed to detect JAK1/STAT3/HIF-1α expression in rat joints. Moreover, the effects of quercetin (20, 40, and 80 µmol/L) on the properties and behavior of synovial fibroblasts were evaluated in an in vitro MH7A cell model using flow cytometry, CCK8, and transwell assays. Further, the mRNA expression levels of inflammatory cytokines IL1ß, IL6, IL17, and TNFα were assessed by quantitative real-time PCR. Glucose, lactate, lactate dehydrogenase, pyruvate, pyruvate dehydrogenase, and adenosine triphosphate assay kits were employed to measure the metabolic effects of quercetin on synovial fibroblasts. Finally, immunoblotting was used to examine the impact of quercetin on the JAK1/STAT3/HIF-1α signaling pathway in synovial fibroblasts. RESULTS: In vivo experiments confirmed the favorable effects of quercetin in CIA rats, including an improved arthritis score and reduced ankle bone destruction, in addition to a decrease in the pro-inflammatory cytokines IL-1ß, IL-6, IL-17, and TNF-α in serum. Immunofluorescence verified that quercetin may ameliorate joint injury in rats with CIA by inhibiting JAK1/STAT3/HIF-1α signaling. Various in vitro experiments demonstrated that quercetin effectively inhibits IL-6-induced proliferation of MH7A cells and reduces their migratory and invasive behavior, while inducing apoptosis and reducing the expression of the pro-inflammatory cytokines IL1ß, IL6, IL17, and TNFα at the mRNA level. Quercetin caused inhibition of glucose, lactate, lactate dehydrogenase, pyruvate, and adenosine triphosphate and increased pyruvate dehydrogenase expression in MH7A cells. It was further confirmed that quercetin may inhibit energy metabolism and inflammatory factor secretion in MH7A cells through JAK1/STAT3/HIF-1α signaling. CONCLUSIONS: Quercetin's action on multiple target molecules and pathways makes it a promising treatment for cartilage injury in rheumatoid arthritis. By reducing joint inflammation, improving joint metabolic homeostasis, and decreasing immune system activation energy, quercetin inhibits the JAK1/STAT3/HIF-1α signaling pathway to improve disease status.

Visnagin alleviates rheumatoid arthritis via its potential inhibitory impact on malate dehydrogenase enzyme: in silico, in vitro, and in vivo studies.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder. The present study aimed to evaluate the in silico, in vitro, and in vivo inhibitory effect of visnagin on malate dehydrogenase activity and elucidate its inflammatory efficacy when combined with methotrexate in the RA rat model. The molecular docking, ADMET simulations, MDH activity, expression, and X-ray imaging were detected. Moreover, CRP, RF, (anti-CCP) antibody, (TNF-α), (IL-6), (IL-17), and (IL-10) were evaluated. The expression levels of MMP3 and FOXP3 genes and CD4, CD25, and CD127 protein levels were assessed. Histological assessment of ankle joints was evaluated. The results revealed that visnagin showed reversible competitive inhibition on MDH with inhibitory constant (Ki) equal to 141 mM with theoretical IC50 equal to 1202.7 mM, LD50 equal to 155.39 mg/kg, and LD25 equal to 77.69 mg/kg. In vivo studies indicated that visnagin exhibited anti-inflammatory effects through decreasing MDH1 activity and expression and induced proliferation of anti-inflammatory CD4+CD25+FOXP3 regulatory T cells with increasing the anti-inflammatory cytokine IL-10 levels. Moreover, visnagin reduced the levels of inflammatory cytokines and the immuno-markers. Our findings elucidate that visnagin exhibits an anti-inflammatory impact against RA through its ability to inhibit the MDH1 enzyme, improve methotrexate efficacy, and reduce oxidative stress.

Temporomandibular Joint Disorder and Anterior Scleritis as Initial Presentations of Undiagnosed Rheumatoid Arthritis.

Rheumatoid arthritis is an autoimmune inflammatory process that involves multiple organ systems. While symmetric joint swelling of the extremities are the most widely recognized symptoms, the disease can present in a myriad of different ways, of which scleritis and temporomandibular involvement are less recognized manifestations. While scleritis and temporomandibular disorder (TMD) may at times present in isolation, it is critical to consider their strong association with autoimmune disease as it allows for early diagnosis of inflammatory conditions and allow for the formulation of tailored treatment plans to halt their progression.

Incidence of cardiovascular events in a population-based Danish cohort with atopic dermatitis.

Background: The risk of cardiovascular disease in atopic dermatitis (AD) is not well established. Objectives: Our aims were to evaluate the incidence rate (IR) of venous thromboembolism (VTE) in patients with AD in a population-based cohort study and to assess atherosclerotic cardiovascular disease (ASCVD) risk factors and incidence of malignancies, major adverse cardiovascular events (MACE), and VTE in patients with AD and rheumatoid arthritis (RA) in a nested cohort analysis. Methods: Data from individuals age 12 years or older (nested cohort age ≥ 18 years) from January 1, 2000, to December 31, 2018, were extracted from the Danish National Patient Registry. Patients with AD were age- and sex-matched with 10 healthy controls. ASCVD risk factors included age 65 years or older and history of smoking, coronary artery disease, stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and malignancy. Results: The population-based cohort comprised 190,751 patients (17,341 patients with AD and 173,410 healthy controls). The IRs per 100 patient-years were comparable between the AD cohort and healthy controls for VTE (0.14 [95% CI = 0.12-0.16] vs 0.11 [95% CI = 0.11-0.12]), DVT (0.08 [95% CI = 0.06-0.09] vs 0.06 [95% CI = 0.06-0.07]), and PE (0.06 [95% CI = 0.05-0.08] vs 0.05 [95% CI = 0.05-0.05]). The IR for VTE was higher in the AD cohort age 65 years or older (0.71 [95% CI = 0.56-0.90]) than in the age-matched controls (0.50 [95% CI = 0.46-0.54]). ASCVD risk factors were more frequent in the patients with RA than in the patients with AD. The IRs for malignancies and MACE were higher with specific ASCVD risk factors. Conclusions: The IRs of cardiovascular events were comparable between the AD cohort and general population. The risk of VTE, malignancy, or MACE was higher with specific ASCVD risk factors, underscoring the need for patient monitoring.

A case report and review of rheumatoid arthritis co-occurring with tuberous sclerosis complex, a rare occurrence.

Rheumatoid arthritis (RA) is a common autoimmune disease. Tuberous sclerosis complex(TSC) is a rare autosomal dominant disorder. We report a case of RA with TSC. The patient was a 46-year-old woman with polyarthritis and cough symptoms, rheumatoid arthritis associated interstitial lung disease (RA-ILD) was initially considered, and after more than 3 months of anti-rheumatic treatment, the patient still had cough, and further examination revealed that the patient had lymphangioleiomyomatosis in the lungs, hepatic and renal angiomyolipomas, multiple subependymal nodules, Vertebral osteosclerotic nodules, as well as facial angiofibromas and periungual fibroma, RA was finally diagnosed with TSC, and everolimus 10mg qd was added to anti-rheumatic therapy for 1 month, and the patient's cough symptoms were relieved.

The gut homeostasis-immune system axis: novel insights into rheumatoid arthritis pathogenesis and treatment.

Rheumatoid arthritis is a widely prevalent autoimmune bone disease that imposes a significant burden on global healthcare systems due to its increasing incidence. In recent years, attention has focused on the interaction between gut homeostasis and the immune system, particularly in relation to bone health. Dysbiosis, which refers to an imbalance in the composition and function of the gut microbiota, has been shown to drive immune dysregulation through mechanisms such as the release of pro-inflammatory metabolites, increased gut permeability, and impaired regulatory T cell function. These factors collectively contribute to immune system imbalance, promoting the onset and progression of Rheumatoid arthritis. Dysbiosis induces both local and systemic inflammatory responses, activating key pro-inflammatory cytokines such as tumor necrosis factor-alpha, Interleukin-6, and Interleukin-17, which exacerbate joint inflammation and damage. Investigating the complex interactions between gut homeostasis and immune regulation in the context of Rheumatoid arthritis pathogenesis holds promise for identifying new therapeutic targets, revealing novel mechanisms of disease progression, and offering innovative strategies for clinical treatment.

Menopausal state and rheumatoid arthritis: a systematic review and meta-analysis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory condition primarily affecting the joints. The higher prevalence of RA among females, combined with the known effects of sex hormones on immune function, has led researchers to investigate the potential relationship between menopausal status and the risk, severity, or progression of RA. This systematic review and meta-analysis aimed to determine the association between menopause and rheumatoid arthritis. METHODS: In 2023, we conducted a comprehensive search across multiple databases, including Google Scholar, Scopus, PubMed/MEDLINE, Science Direct, Web of Science, EMBASE, Springer, and ProQuest. The search aimed to identify studies exploring the association between menopause and rheumatoid arthritis. RESULTS: Our analysis revealed that post-menopausal women had a higher risk of developing rheumatoid arthritis compared to pre-menopausal women, with an estimated odds ratio of 1.35 (95% CI: 1.04-1.67). Additionally, women who experienced early menopause (defined as onset before age 45) showed significantly higher odds of developing RA, with an odds ratio of 2.97 (95% CI: 1.73-4.22). CONCLUSION: These findings highlight the importance of considering menopausal status when assessing the risk of RA development in women. The results suggest that post-menopausal women, particularly those who experience early menopause, may be at higher risk for developing RA. Further research in this area could provide valuable insights into potential preventive measures and targeted interventions for high-risk individuals.

Low dose methotrexate impaired T cell transmigration through down-regulating CXCR4 expression in rheumatoid arthritis (RA).

BACKGROUND: CXC chemokine CXCL12 is involved in the pathological development of rheumatoid arthritis (RA) through abnormal migration of peripheral immune cells in the joint. Although low dose methotrexate (MTX) is clinically used to treat RA patients, CXCL12 signaling responses to MTX-mediated treatments is still not well understood. METHODS: In this study, we examined the expression of CXCR4 (cognatic receptor for CXCL12) in peripheral T cells from RA patients and arthritis mice models received from low dose MTX therapies. The effects of low dose MTX on CXCR4 were further determined via both in vitro CD3+ T cells and Cxcr4 conditional knockout (CKO) arthritis mice models. RESULTS: Our clinical data shows that low dose MTX treatment was clinically associated with down-regulated expression of chemokine receptor CXCR4 on patient peripheral T cells. In vitro, low dose MTX significantly decreased cell transmigration through down-regulated CXCR4's expression in CD3+ T cells. Consistently, CD3+ T cells treated with low dose MTX demonstrated an increased genomic hypermethylation across the promoter region of Cxcr4 gene. Furthermore, our preclinical studies showed that low dose MTX-mediated downregulation of CXCR4 significantly improved the pathological development in mouse arthritis models. Conditional disruption of the Cxcr4 gene in peripheral immune cells potentially alleviated inflammation of joints and lung tissue in the arthritis mice, though genetic modification itself overall did not change their clinical scores of arthritis, except for a significant improvement on day 45 in CXCR4 CKO arthritis mice models during the recovery phase. CONCLUSION: Our findings suggest that the effect of low dose MTX treatment could serve to eliminate inflammation in RA patients through impairment of immune cell transmigration mediated by CXCR4.

The potential role of fatigue in difficult-to-treat rheumatoid arthritis.

OBJECTIVES: A subset of patients with rheumatoid arthritis (RA) who remains symptomatic after failing to multiple drugs are deemed to have "difficult-to-treat RA" (D2T RA). Fatigue is a burdensome symptom for RA patients, hindering their improvement. Our purpose was to evaluate the role of fatigue in D2T RA. METHODS: This cross-sectional study included rheumatoid arthritis (RA) patients between 2018 and 2022, treated with biological agents or targeted synthetic disease-modifying antirheumatic drugs. D2T RA was defined attending EULAR criteria. Independent variable was fatigue (dimensions and impact) assessed by the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire and Numerical Rating Scales. Covariables: sociodemographic, clinical and treatment. To identify factors independently associated to D2T RA, multivariable logistic regression was run. RESULTS: The study included 145 patients and 38 (26.21%) developed D2T RA. D2T RA group were older, with more comorbidity and disability. D2T RA patients scored higher for global fatigue (p = 0.003), and almost for all their dimensions except for cognitive fatigue (p = 0.06) and fatigue coping (p = 0.07). Females with D2T RA showed more fatigue than those with non-D2T RA. In the adjusted models, all fatigue dimensions were associated with D2T RA: global fatigue RA (OR: 1.03; p = 0.007), physical (OR: 1.09; p = 0.008), living (OR: 1.09; p = 0.016), cognitive (OR: 1.1; p = 0.046) and emotional (OR: 1.18; p = 0.012). CONCLUSIONS: Despite the absence of an explicit mention of fatigue in the definition of D2T RA, it appears to be associated to this outcome. Fatigue should be evaluated in a multidimensional perspective, and gender-specific differences should be considered.