Exploring the supplementary potential of all-trans retinoic acid with methotrexate in rheumatoid arthritis: modulation of synovial cell apoptosis and autophagy.

OBJECTIVES: The imbalance between apoptosis and proliferation in fibroblast-like synoviocytes (FLSs) plays a key role in the pathogenesis of rheumatoid arthritis (RA). This study aims to investigate the potential of all-trans retinoic acid (ATRA) as a supplementary therapeutic agent alongside methotrexate (MTX) for RA, by examining its ability to inhibit synovial cell proliferation and enhance apoptosis through the ROS-JNK signalling pathway. METHODS: The viability, apoptosis, and autophagy levels of human rheumatoid arthritis fibroblast-like synovial cells (HFLS-RA) were evaluated, while ROS generation was measured through the DCFH-DA fluorescence microplate assay. Western blotting was used to analyse the expression levels of JNK signalling pathway-related proteins. To assess therapeutic potential in vivo, a collagen-induced arthritis (CIA) model was established in Wistar rats. RESULTS: Small doses of MTX did not significantly affect the viability of HFLS-RAs or induce apoptosis. However, when ATRA was added to the treatment, the therapy markedly inhibited cell proliferation and induced apoptosis and excessive autophagy. Mechanistically, ATRA activated the ROS/JNK signalling pathway in HFLS-RAs. ROS scavengers and JNK inhibitors significantly attenuated ATRA-induced apoptosis and autophagy. In vivo, the combination therapy demonstrated a remarkable enhancement of the anti-arthritic efficacy in CIA rats. CONCLUSIONS: The ability of ATRA to inhibit proliferation in RA FLSs through autophagy and apoptosis underscores its potential as a supplementary therapeutic agent alongside MTX for RA, particularly when compared to the limited impact of MTX on these processes. This combined strategy holds promise for enhancing therapeutic outcomes and warrants further investigation in the management of RA.

Development of hyaluronic acid hydrogel containing prednisolone-encapsulated nonphospholipid liposomes for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) requires therapeutic approaches that alleviate symptoms and inhibit the progression of joint damage. Glucocorticoids (GCs) have been a cornerstone of RA treatment, yet their use is often limited by side effects. Recent advancements suggest that liposome-based delivery systems can improve GC biodistribution, minimizing toxicity. This study introduces an innovative tool for RA treatment using prednisone-encapsulated nonphospholipid liposomes (NPLs) in combination with a hyaluronic acid (HA) hydrogel. Our methodology involved incorporating prednisone (PR) with palmitic acid and cholesterol to formulate stable NPLs using a thin-film hydration technique. The synthesized PR-NPLs, characterized by a mean size of 150 nm, demonstrated uniform distribution and higher drug encapsulation in comparison with conventional phospholipid liposomes. In vitro assays revealed that PR-NPL markedly reduced inflammatory responses in macrophages. Additionally, we successfully incorporated PR-NPL into an HA hydrogel, employing a photoinitiated cross-linking process. This novel composite offered modulable PR release, governed by the degree of hydrogel cross-linking. The developed system presents a promising advancement in RA management, especially suited for intraarticular injections. It potentially enables targeted, controlled drug release with a reduced risk of side effects, signifying a significant improvement over existing RA therapies.

Abatacept retention and clinical effectiveness in patients with rheumatoid arthritis in a real-world setting in Taiwan.

AIM: To evaluate real-world abatacept retention and clinical outcomes in patients with rheumatoid arthritis in Taiwan. METHODS: This prospective, observational study enrolled patients with rheumatoid arthritis aged ≥20 years who received abatacept in real-world practice. The primary endpoint was the abatacept retention rate at 24 months. Patients were categorized into subgroups based on abatacept treatment status and previous biological disease-modifying antirheumatic drug (bDMARD) therapy. Risk factors affecting abatacept retention were determined by regression analysis. RESULTS: A total of 212 patients were enrolled. The overall abatacept retention rate at 24 months among all patients was 59.9% (95% confidence interval 53.0%-66.6%). Patients who were ongoing users of abatacept and bDMARD-naïve had the highest retention rate (76.3%); of these, 31.6% achieved low disease activity or remission after 2 years. Previous treatment with bDMARDs was associated with an increased risk of abatacept discontinuation (hazard ratio 1.99; p = .002). The most common reasons for abatacept discontinuation were drug switch (11.3%) and loss to follow-up (6.1%). Abatacept was well-tolerated with no new safety signals. CONCLUSION: The 24-month retention rate of abatacept was 59.9%; abatacept was associated with improved clinical outcomes and was well-tolerated in the real-world setting in Taiwan.

Graphene oxide quantum dots-loaded sinomenine hydrochloride nanocomplexes for effective treatment of rheumatoid arthritis via inducing macrophage repolarization and arresting abnormal proliferation of fibroblast-like synoviocytes.

The characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in developing a suitable therapeutic strategy for RA that targets the synovial macrophages and fibroblast-like synoviocytes (FLSs). In this study, we used graphene oxide quantum dots (GOQDs) for loading anti-arthritic sinomenine hydrochloride (SIN). By combining with hyaluronic acid (HA)-inserted hybrid membrane (RFM), we successfully constructed a new nanodrug system named HA@RFM@GP@SIN NPs for target therapy of inflammatory articular lesions. Mechanistic studies showed that this nanomedicine system was effective against RA by facilitating the transition of M1 to M2 macrophages and inhibiting the abnormal proliferation of FLSs in vitro. In vivo therapeutic potential investigation demonstrated its effects on macrophage polarization and synovial hyperplasia, ultimately preventing cartilage destruction and bone erosion in the preclinical models of adjuvant-induced arthritis and collagen-induced arthritis in rats. Metabolomics indicated that the anti-arthritic effects of HA@RFM@GP@SIN NPs were mainly associated with the regulation of steroid hormone biosynthesis, ovarian steroidogenesis, tryptophan metabolism, and tyrosine metabolism. More notably, transcriptomic analyses revealed that HA@RFM@GP@SIN NPs suppressed the cell cycle pathway while inducing the cell apoptosis pathway. Furthermore, protein validation revealed that HA@RFM@GP@SIN NPs disrupted the excessive growth of RAFLS by interfering with the PI3K/Akt/SGK/FoxO signaling cascade, resulting in a decline in cyclin B1 expression and the arrest of the G2 phase. Additionally, considering the favorable biocompatibility and biosafety, these multifunctional nanoparticles offer a promising therapeutic approach for patients with RA.

Cost of lost productivity in inflammatory arthritis and osteoarthritis in the year before and after diagnosis: An inception cohort study.

AIM: Existing studies on the cost of inflammatory arthritis (IA) and osteoarthritis (OA) are often cross-sectional and/or involve patients with various disease durations, thus not providing a comprehensive perspective on the cost of illness from the time of diagnosis. In this study, we therefore assessed the cost of lost productivity in an inception cohort of patients with IA and OA in the year before and after diagnosis. METHODS: Employment status, monthly income, days absent from work, and presenteeism were collected at diagnosis and 1 year later to estimate the annual costs of unemployment, absenteeism, and presenteeism using human capital approach. Non-parametric bootstrapping was performed to account for the uncertainty of the estimated costs. RESULTS: Compared to patients with OA (n = 64), patients with IA (n = 102, including 48 rheumatoid arthritis, 19 spondyloarthritis, 23 psoriatic arthritis, and 12 seronegative IA patients) were younger (mean age: 52.3 vs. 59.5 years) with a greater proportion receiving treatment (99.0% vs. 67.2%) and a greater decrease in presenteeism score (median: 15% vs 10%) 1 year after diagnosis. Annual costs of absenteeism and presenteeism were lower in patients with IA than those with OA both in the year before (USD566 vs. USD733 and USD8,472 vs. USD10,684, respectively) and after diagnosis (USD636 vs. USD1,035 and USD6,866 vs. USD9,362, respectively). CONCLUSION: Both IA and OA impose substantial cost of lost productivity in the year before and after diagnosis. The greater improvement in productivity seen in patients with IA suggests that treatment for IA improves work productivity.

Google Internet searches related to inflammatory arthritis: An observational study using Google Trends data.

OBJECTIVE: The Internet has transformed how patients access health information. We examined Google search engine data to understand which aspects of health are most often searched for in combination with inflammatory arthritis (IA). METHODS: Using Google Trends data (2011-2022) we determined the relative popularity of searches for 'patient symptoms' (pain, fatigue, stiffness, mood, work) and 'treat-to-target' (disease-modifying drugs, steroids, swelling, inflammation) health domains made with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (AxSpA) in the UK/USA. Google Trends normalises searches by popularity over time and region, generating 0-100 scale relative search volumes (RSV; 100 represents the time-point with most searches). Up to five search term combinations can be compared. RESULTS: In all IA forms, pain was the most popular patient symptom domain. UK/USA searches for pain gave mean RSVs of 58/79, 34/51, and 39/63 with RA, PsA, and AxSpA; mean UK/USA RSVs for other patient symptom domains ranged 2-7/2-8. Methotrexate was the most popular treat-to-target search term with RA/PsA in the UK (mean 28/21) and USA (mean 63/33). For AxSpA, inflammation was most popular (mean UK/USA 9/34). Searches for pain were substantially more popular than searches for methotrexate in RA and PsA, and inflammation in AxSpA. Searches increased over time. CONCLUSIONS: Pain is the most popular search term used with IA in Google searches in the UK/USA, supporting surveys/qualitative studies highlighting the importance of improving pain to patients with IA. Routine pain assessments should be embedded within treat-to-target strategies to ensure patient perspectives are considered.

Real-world comparative study of drug retention of Janus kinase inhibitors in patients with rheumatoid arthritis.

BACKGROUND: Janus kinase (JAK) inhibitors (JAKis) are effective therapeutic agents against rheumatoid arthritis (RA). However, patients having RA with particular risk factors may have a higher incidence of adverse effects (AEs), including major cardiovascular events (MACE) and infections. In this multicenter cohort study, we aimed to clarify the risk factors affecting the drug retention of JAKis in patients with RA. METHODS: We retrospectively evaluated patients with RA who received their first JAKi (tofacitinib, baricitinib, upadacitinib, or filgotinib) at our institute. The clinical outcomes, including AEs, were recorded, particularly MACE and serious infections. The drug retention rates were analyzed using the Kaplan-Meier method, and risk factors affecting drug retention rates were determined using a multivariable Cox regression hazards model. RESULTS: Overall 184 patients with RA receiving their first use of baricitinib (57.6%), tofacitinib (23.9%), upadacitinib (12.0%), or filgotinib (6.5%) were included in this study. Fifty-six (30.4%) patients discontinued JAKi treatment owing to ineffectiveness (9.2%) or AEs, including infections (21.2%). The overall drug retention rates were significantly lower in patients treated with pan-JAKi than in those treated with JAK1 inhibitors (p = 0.03). In the Cox regression model, the presence of baseline high RA disease activity, use of glucocorticoid and treatments with pan-JAKis were associated with reduced drug retention rates of JAKis (p < 0.001, p = 0.01 and 0.04, respectively). Pan-JAKi treated patients with high disease activity had significantly lower drug retention rates (p < 0.001). CONCLUSIONS: In a real-world setting, the drug retention rates of JAKis were reduced mainly by treatment discontinuation owing to AEs. Treatment with pan-JAKis and high baseline RA disease activity were identified as predictive factors for the discontinuation of JAKis. Lower drug retention rates were found in patients receiving pan-JAKis with high disease activity than in those without high disease activity.

Tofacitinib Regulates Endostatin via Effects on CD147 and Cathepsin S.

Angiogenesis is critical for rheumatoid arthritis (RA) progression. The effects of tofacitinib, a JAK-STAT inhibitor used for RA treatment, on angiogenesis in RA are unclear. We, therefore, evaluated the levels of angiogenic factors in two systems of a human co-culture of fibroblast (HT1080) and monocytic (U937) cell lines treated with tofacitinib and in serum samples from RA patients before and after six months of tofacitinib treatment. Tofacitinib reduced CD147 levels, matrix metalloproteinase-9 (MMP-9) activity, and angiogenic potential but increased endostatin levels and secreted proteasome 20S activity. In vitro, tofacitinib did not change CD147 mRNA but increased miR-146a-5p expression and reduced STAT3 phosphorylation. We recently showed that CD147 regulates the ability of MMP-9 and secreted proteasome 20S to cleave collagen XVIIIA into endostatin. We show here that tofacitinib-enhanced endostatin levels are mediated by CD147, as CD147-siRNA or an anti-CD147 antibody blocked proteasome 20S activity. The correlation between CD147 and different disease severity scores supported this role. Lastly, tofacitinib reduced endostatin' s degradation by inhibiting cathepsin S activity and recombinant cathepsin S reversed this in both systems. Thus, tofacitinib inhibits angiogenesis by reducing pro-angiogenic factors and enhancing the anti-angiogenic factor endostatin in a dual effect mediated partly through CD147 and partly through cathepsin S.

Selection and Mechanism Study of Q-Markers for Xanthocerais lignum Anti-Rheumatoid Arthritis Based on Serum Spectrum-Effect Correlation Analysis.

OBJECTIVE: To elucidate the chemical profile of Xanthocerais lignum's extracts of different polarities and their impact on rheumatoid arthritis (RA), we identified anti-RA markers and predicted their action mechanisms. METHODS: A collagen-induced arthritis rat model was established, and UPLC-Q-Exactive Orbitrap MS technology was employed to analyze and identify the chemical constituents within the alcohol extract of Xanthocerais lignum and its various extraction fractions, as well as their translocation into the bloodstream. Serum spectrum-effect correlation analysis was utilized to elucidate the pharmacodynamic material basis of Xanthocerais lignum against RA and to screen for Q-Markers. Finally, the potential anti-RA mechanisms of the Q-Markers were predicted through compound-target interaction data and validated using molecular docking techniques. RESULTS: We identified 71 compounds, with flavan-3-ols and flavanones as key components. Of these, 36 were detected in the bloodstream, including 17 original and 19 metabolized forms. Proanthocyanidin A2, dihydroquercetin, catechin, and epicatechin (plus glucuronides) showed potential anti-RA activity. These compounds, acting as Q-Markers, may modulate ERK, NF-κB, HIF-1α, and VEGF in the HIF-1 pathway. CONCLUSIONS: This research clarifies Xanthocerais lignum's pharmacodynamic material basis against RA, identifies 4 Q-Markers, and offers insights into their mechanisms, aiding quality assessment and lead compound development for RA treatment.

Therapeutic potential and recent progression of BTK inhibitors against rheumatoid arthritis.

Rheumatoid arthritis (RA) is a complex chronic inflammatory illness that affects the entire physiology of human body. It has become one of the top causes of disability worldwide. The development and progression of RA involves a complex interplay between an individual's genetic background and various environmental factors. In order to effectively manage RA, a multidisciplinary approach is required, as this disease is complicated and its pathophysiological mechanism is not fully understood yet. In majority of arthritis patients, the presence of abnormal B cells and autoantibodies, primarily anti-citrullinated peptide antibodies and rheumatoid factor affects the progression of RA. Therefore, drugs targeting B cells have now become a hot topic in the treatment of RA which is quite evident from the recent trends seen in the discovery of various B cell receptors (BCRs) targeting agents. Bruton's tyrosine kinase (BTK) is one of these recent targets which play a role in the upstream phase of BCR signalling. BTK is an important enzyme that regulates the survival, proliferation, activation and differentiation of B-lineage cells by preventing BCR activation, FC-receptor signalling and osteoclast development. Several BTK inhibitors have been found to be effective against RA during the in vitro and in vivo studies conducted using diverse animal models. This review focuses on BTK inhibition mechanism and its possible impact on immune-mediated disease, along with the types of RA currently being investigated, preclinical and clinical studies and future prospective.

DA-9601 has protective effects comparable to those of proton pump inhibitor and rebamipide against nonsteroidal anti-inflammatory drugs-induced upper and lower gastrointestinal bleeding in patients with rheumatoid arthritis: A nationwide study using Korean Health Insurance Review and Assessment Service database.

DA-9601 extracted from Artemisia asiatica contains a bioactive compound - eupatilin - that can protect against gastric mucosal damage through anti-inflammatory and anti-oxidative properties and is approved for treating acute and chronic gastritis in Korea, but their ability to protect gastrointestinal (GI) bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is unclear. We aimed to compare the protective effects of DA-9601 to those of proton pump inhibitors (PPI) and rebamipide against upper and lower GI bleeding in patients with rheumatoid arthritis (RA) undergoing long-term NSAIDs therapy using the Korean Health Insurance Review and Assessment database. In this nationwide retrospective cohort study, we evaluated patients with RA who concurrently received NSAIDs for >3 months with DA-9601, PPI, or rebamipide between January 2015 and December 2017. The index date was the date of NSAIDs initiation, and all patients were followed up until December 2020 to detect upper and lower GI bleeding. In total, 24,258 patients with RA were eligible, and 5468 (22.5%), 4417 (18.2%), and 14,373 (59.3%) received DA-9601, PPI, or rebamipide, respectively, on the index date. During follow-up, upper and lower GI bleeding occurred in 508 (2.1%) and 402 (1.6%) patients with RA, respectively. The incidence rate of upper and lower GI bleeding was 615/100,000 and 485/100,000 person-years, respectively. Among patients with RA receiving DA-9601, PPI, or rebamipide, the frequencies of NSAIDs-induced upper GI bleeding were 0.5%, 0.4%, and 1.2%, respectively. The frequencies of NSAIDs-induced lower GI bleeding were 0.4%, 0.4%, and 0.9%, respectively. The incidence of NSAIDs-induced upper GI bleeding in patients with RA receiving DA-9601, PPI, and rebamipide was 601/100,000, 705/100,000, and 596/100,000 person-years, respectively, while the incidence of NSAIDs-induced lower GI bleeding in the same groups was 449/100,000, 608/100,000, and 465/100,000 person-years, respectively. In the multivariate Cox regression analysis, no significant difference was observed in lower and upper GI bleeding hazards between patients with RA using DA-9601, PPI, and rebamipide. Our results suggest that DA-9601 may exhibit protection against NSAIDs-induced GI bleeding that is comparable to those of PPI and rebamipide in patients with RA.

In patients at high risk for RA, abatacept reduced inflammation and RA development at 6 mo.

SOURCE CITATION: Rech J, Tascilar K, Hagen M, et al. Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial. Lancet. 2024;403:850-859. 38364841.

Impact of MTHFR gene polymorphism on the outcome of methotrexate treatment in a sample of Iraqi rheumatoid arthritis patients.

Analyze the relationship between genetic variations in the MTHFR gene at SNPs (rs1801131 and rs1801133) and the therapy outcomes for Iraqi patients with rheumatoid arthritis (RA). The study was conducted on a cohort of 95 RA Iraqi patients. Based on their treatment response, the cohort was divided into two groups: the responder (47 patients) and the nonresponder (48 patients), identified after at least three months of methotrexate (MTX) treatment. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was employed to analyze the MTHFR variations, specifically at rs1801133 and rs1801131. Overall, rs1801131 followed both codominant and dominate models, in which in the codominant model, GG [OR (95% CI) 0.11 (0.022-0.553)] and TG [OR (95% CI) 0.106 (0.021-0.528)] predict responders compared to the TT genotype; meanwhile, for the dominate model, the presence of both GG and TG genotypes [OR (95% CI) 0.108 (0.023-0.507)] together predict responders compared to the TT genotype. The Ars1801133Grs1801131 haplotype was significantly associated with responders [OR (95% CI): 0.388 (0.208-0.723)], while the Grs1801133Trs1801131 haplotype was associated marginally with nonresponders [OR (95% CI) 1.980 (0.965-4.064)]. In the final multivariate analysis, GG/TGrs1801131 genotypes were independently related to responders after adjustment for patients, disease, and treatment characteristics, while TTrs1801131 genotypes were associated with nonresponders. The Iraqi RA patients showed genetic polymorphism in MTHFR gene rs1801131 with T carrier allele associated with nonresponders to MTX therapy. The rs1801131 followed both codominant and dominant models. The G-carried allele for rs1801131 showed an independent association with responder to MTX therapy after adjustment for patients, disease, and treatment characteristics.

Effects of IL-6, JAK, TNF inhibitors, and CTLA4-Ig on knee symptoms in patients with rheumatoid arthritis.

This study aims to identify factors influencing the alleviation of knee joint symptoms in patients with rheumatoid arthritis treated with biologic or target synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Among 2321 patients who started b/tsDMARDs between 2010 and 2023, we focused on 295 patients who had knee swelling or tenderness at the initiation of b/tsDMARDs and continued b/tsDMARDs at least 3 months, with recorded knee symptoms 6 months later. Symptom relief after 6 months was 78.2% for interleukin 6 (IL-6) inhibitors, 68.6% for Janus kinase (JAK) inhibitors, 65.8% for tumor necrosis factor (TNF) inhibitors, and 57.6% for cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig). The initial use of b/tsDMARDs and the use of IL-6 inhibitors in comparison to CTLA4-Ig emerged as a significant factor associated with the improvement of knee joint symptoms. Among 141 patients who underwent knee radiography at baseline and two years later, the deterioration in knee joint radiographs was 7.7% for IL-6 inhibitors, 6.3% for JAK inhibitors, 21.9% for TNF inhibitors, and 25.9% for CTLA4-Ig. The use of IL-6 inhibitors was a significant factor associated with the improvement of knee joint symptoms and the inhibition of joint destruction compared to CTLA4-Ig.

Risk factors for vertebral fracture in rheumatoid arthritis patients using biological disease-modifying anti-rheumatic drugs (cases over 5 years): An observational study.

While biological disease-modifying anti-rheumatic drugs (bDMARDs) are considered beneficial for preventing osteoporosis and bone fracture, it is unclear whether bone loss is involved in the development of vertebral fracture, and few reports have examined the factors related to vertebral fracture in rheumatoid arthritis (RA) patients using bDMARDs. This study aims to identify factors influencing vertebral fracture in RA patients treated with bDMARDs. We retrospectively examined the records of 129 RA patients treated with bDMARDs for over 5 years. The lumbar spine and femoral bone mineral density, Disease Activity Score-28-C-Reactive Protein (DAS28-CRP) value, Simplified Disease Activity Index (SDAI), and modified Health Assessment Questionnaire (mHAQ) score were evaluated. The frequency of new vertebral fracture during the study and their risk factors were investigated. A comparison between the fracture group and the nonfracture group was performed. Multivariate analysis was performed using logistic regression analysis to detect risk factors for new vertebral fracture. The number of patients with new vertebral fracture during follow-up was 15 (11.6%) of the 129 patients in the study. Age and mHAQ score were significantly higher and lumbar spine and femoral neck bone mineral density were significantly lower in the fracture group than the nonfracture group. The risk factors for new vertebral fracture during the disease course were older age and higher mHAQ score indicating no remission over the 5 years of follow-up. In this study, there was no significant difference in disease indices such as the DAS28-CRP value and the SDAI between the fracture and nonfracture groups, suggesting an effective control of RA with bDMARDs. However, age and the mHAQ score, an index of RA dysfunction, were significantly higher in the fracture group. These results suggest that improving functional impairment may be important to prevent vertebral fracture in patients using bDMARDs.

Deciphering the molecular landscape of rheumatoid arthritis offers new insights into the stratified treatment for the condition.

Background: For Rheumatoid Arthritis (RA), a long-term chronic illness, it is essential to identify and describe patient subtypes with comparable goal status and molecular biomarkers. This study aims to develop and validate a new subtyping scheme that integrates genome-scale transcriptomic profiles of RA peripheral blood genes, providing a fresh perspective for stratified treatments. Methods: We utilized independent microarray datasets of RA peripheral blood mononuclear cells (PBMCs). Up-regulated differentially expressed genes (DEGs) were subjected to functional enrichment analysis. Unsupervised cluster analysis was then employed to identify RA peripheral blood gene expression-driven subtypes. We defined three distinct clustering subtypes based on the identified 404 up-regulated DEGs. Results: Subtype A, named NE-driving, was enriched in pathways related to neutrophil activation and responses to bacteria. Subtype B, termed interferon-driving (IFN-driving), exhibited abundant B cells and showed increased expression of transcripts involved in IFN signaling and defense responses to viruses. In Subtype C, an enrichment of CD8+ T-cells was found, ultimately defining it as CD8+ T-cells-driving. The RA subtyping scheme was validated using the XGBoost machine learning algorithm. We also evaluated the therapeutic outcomes of biological disease-modifying anti-rheumatic drugs. Conclusions: The findings provide valuable insights for deep stratification, enabling the design of molecular diagnosis and serving as a reference for stratified therapy in RA patients in the future.

Mangiferin: A natural bioactive immunomodulating glucosylxanthone with potential against cancer and rheumatoid arthritis.

Mangiferin is a naturally occurring glucosylxanthone that has shown promising immunomodulatory effects. It is generally isolated from the leaves, peels, bark, and kernels of Mangifera indica Linn. Mangiferin is like a miraculous natural bioactive molecule that has an immunomodulatory function that makes it a potential therapeutic candidate for the treatment of rheumatoid arthritis (RA) and cancer. The anticancer activity of mangiferin acts by blocking NF-κB, as well as regulating the ß-catenin, EMT, MMP9, MMP2, LDH, ROS, and NO, and also by the activation of macrophages. It has no cytotoxic effect on grown chondrocytes and lowers matrix metalloproteinase levels. Additionally, it has a potent proapoptotic impact on synoviocytes. The precise molecular mechanism of action of mangiferin on RA and malignancies is still unknown. This comprehensive review elaborates on the immunomodulatory effect of mangiferin and its anticancer and anti-RA activity. This also explained the total synthesis of mangiferin and its in vitro and in vivo screening models.

Safety of TNF-α inhibitors: A real-world study based on the US FDA Adverse Event Reporting System Database.

As a common treatment for rheumatoid arthritis (RA), the adverse reactions of TNF-α inhibitors (TNFis) in practical application have garnered attention. This study aims to investigate the adverse drug events (ADEs) associated with TNFi in RA patients as reported in the FDA Adverse Event Reporting System, to offer insights for clinical use. Cases related to RA and primarily involving TNFi were extracted from the FDA Adverse Event Reporting System database and compared by gender stratification. Screening was conducted based on reporting odds ratio and information component to identify positive ADEs for different TNFis and evaluate common and unique ADEs among various TNFis. There are 4 common ADEs among TNFis, including pulmonary tuberculosis, infection, hypersensitivity, and herpes zoster, as described in the package inserts. However, each TNFi has unique positive ADEs. Adalimumab has 63 unique positive ADEs, including lower respiratory tract inflammation, systemic lupus erythematosus rash, vascular dementia, ovarian neoplasm, adhesion, sarcoma, coccidioidomycosis, etc. Golimumab has 6 unique positive ADEs, including pneumonia cryptococcal, device deployment issue, pneumonia bacterial, polyneuropathy, device malfunction, device issue, etc; certolizumab has 24 unique positive ADEs, including maternal exposure before pregnancy, premature rupture of membranes, exposure via breast milk, staphylococcal sepsis, erysipelas, low birth weight baby, herpes virus infection, premature delivery, etc; etanercept has 180 unique positive ADEs, including joint destruction, chondrolysis, finger deformity, ankle deformity, joint warmth, etc; infliximab has 60 unique positive ADEs, including Hodgkin's disease, metastatic neoplasm, non-Hodgkin's Lymphoma, etc. Although the aforementioned 5 TNFis share common ADEs such as herpes zoster, clinicians must exercise caution when selecting specific medications, especially for RA patients concurrently suffering from malignancies. The analysis indicates that infliximab is associated with 60 unique positive ADEs, including Hodgkin's disease, metastatic neoplasm, and non-Hodgkin's lymphoma; therefore, these patients should use infliximab with greater caution. Similarly, certolizumab should be used with increased caution in pregnant and postpartum women.