BACKGROUND

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammatory arthritis and extra-articular involvement. Comorbidities are highly prevalent in patients with RA, in particular cardiovascular disease (CVD), which is responsible for over 50% of premature deaths. This study aimed to describe cardiovascular diseases and their risk factors among patients with rheumatoid arthritis in the Philippine General Hospital (PGH).

To describe cardiovascular (CV) diseases and their risk factors among patients with rheumatoid arthritis.

A retrospective descriptive cross-sectional study was done in the University of the Philippines – Philippine General Hospital (UP-PGH) inpatient and outpatient services. The study included patients 18 years old and above diagnosed with RA and fulfills the 1987 American College of Rheumatology or 2010 American College of Rheumatology-European League Against Rheumatism (ACR/EULAR) classification criteria with no overlap features with other autoimmune connective tissue diseases and with complete records of the information required for the study from January 2019-December 2022. The primary outcomes of interest were the prevalence of CV diseases and CV risk factors. Descriptive statistics were used to summarize the data.

There were 123 patients in the study, 93.4% outpatients, and 95.1% females, with a mean age and disease duration of 51.3 and 9.8 years, respectively. Disease activity was moderate in 35% and high in 9.7%, based on disease activity score (DAS 28) or clinical disease activity index (CDAI) scores. Methotrexate (54%) was the most commonly used conventional synthetic disease-modifying antirheumatic drug (csDMARD). Glucocorticoid use was observed in 51.2%. None of the patients were receiving a biologic DMARD. There were 24 (19.5%) patients with CV diseases, namely myocardial infarction, heart failure, and stroke. There were 87 (70%) patients with at least one CV risk factor and 62 (50.4%) with multiple risk factors. The risk factors identified were: dyslipidemia (43.1%), hypertension (40.7%), elevated body mass index (35.7%), and diabetes mellitus (15.4%). There were f ive deaths in the hospitalized patients (4%), one due to a myocardial infarction.

The majority (70%) in our cohort had at least one CV risk factor, 19.5% had an identified CV disease, and one died from a myocardial infarction. Dyslipidemia was the most common CV risk factor. The high proportion of patients with CV disease and CV risk factors highlights the need to add the screening and management of CV diseases and risk factors as a priority among patients with rheumatoid arthritis.

Andrographolide sulfonate (AS) is a sulfonated derivative of andrographolide extracted from Andrographis paniculata (Burm.f.) Nees, and has been approved for several decades in China. The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis. Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling, improved body weights, and attenuated pathological changes in joints of rats with adjuvant-induced arthritis. Additionally, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in the serum and ankle joints were reduced. Bioinformatics analysis, along with the spleen index and measurements of IL-17 and IL-10 levels, suggested a potential relationship between AS and Th17 cells under arthritic conditions. In vitro, AS was shown to block Th17 cell differentiation, as evidenced by the reduced percentages of CD4⁺ IL-17A⁺ T cells and decreased expression levels of RORγt, IL-17A, IL-17F, IL-21, and IL-22, without affecting the cell viability and apoptosis. This effect was attributed to the limited glycolysis, as indicated by metabolomics analysis, reduced glucose uptake, and pH measurements. Further investigation revealed that AS might bind to hexokinase2 (HK2) to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or pyruvate kinase M2 (PKM2), and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation. Furthermore, AS impaired the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signals in vivo and in vitro, which was abolished by the addition of lactate. In conclusion, AS significantly improved adjuvant-induced arthritis (AIA) in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
Animals ; Th17 Cells/immunology* ; Diterpenes/pharmacology* ; Arthritis, Rheumatoid/metabolism* ; Proto-Oncogene Proteins c-akt/immunology* ; Glycolysis/drug effects* ; Cell Differentiation/drug effects* ; Phosphatidylinositol 3-Kinases/genetics* ; Rats ; Male ; Rats, Sprague-Dawley ; Humans ; Andrographis paniculata/chemistry* ; Arthritis, Experimental/drug therapy* ; Interleukin-17/immunology* ; Signal Transduction/drug effects*

Arthritis, encompassing osteoarthritis (OA), rheumatoid arthritis (RA), and gouty arthritis (GA), is a prevalent inflammatory disease that significantly impacts quality of life. Natural products (NPs), derived from animals, plants, marine organisms, and microorganisms, have demonstrated beneficial effects in arthritis treatment both domestically and internationally. These natural compounds offer advantages in drug discovery due to their skeletal diversity, structural complexity, and multi-effect, multi-target, and low-toxicity properties compared to conventional small-molecule medicines. However, unclear mechanisms have hindered the development and clinical application of NPs. This review summarizes recent experimental studies from the past decade on natural medicine for arthritis treatment, emphasizing key NPs with therapeutic effects on OA, RA, and GA. It examines the effects and molecular mechanisms of NPs acting on different cells to treat arthritis. Furthermore, this review provides insights into the future prospects of NP research in this field, which is crucial for advancing NP-based arthritis treatments.
Humans ; Biological Products/therapeutic use* ; Animals ; Arthritis, Rheumatoid/drug therapy* ; Arthritis, Gouty/drug therapy* ; Arthritis/drug therapy* ; Osteoarthritis/drug therapy*

Introduction: Autoimmune polyendocrine syndrome (APS) type 4 is a clustering of at least 2 or more organ-specific autoimmune diseases in a single patient, which do not fall into other categories of APS, in combination with at least one more endocrine or non-endocrine organs. The multitude of autoimmune comorbidities and their associated treatment may contribute to osteoporosis and fracture. Case Description: A 35-year-old female with bilateral distal femoral pathologic fracture from an inch fall underwent bilateral, minimally invasive plate osteosynthesis. Pathologic fracture from secondary osteoporosis resulted from rheumatoid arthritis, chronic steroid use from rheumatoid arthritis (prednisone 10 mg for 24 months), premature ovarian failure since 20 years old without hormone replacement therapy, and possible Turner syndrome. She had persistently elevated thyroid-stimulating hormone in spite of high levothyroxine (4.25 μg/kg/day) dose; hence, gastric malabsorption from possible atrophic gastritis was likewise considered. Benefits and risks associated with treatment were reviewed to manage the patient holistically. Conclusion APS is a rare complex syndrome which may lead to various complications. Presence of hypogonadism, rheumatoid arthritis, and chronic steroid use further predisposes the development of secondary osteoporosis. Early screening and treatment of osteoporosis would have decreased the risk of development of fracture.
Fractures, Spontaneous ; Primary Ovarian Insufficiency ; Arthritis, Rheumatoid

Rheumatoid arthritis (RA) is an autoimmune disease characterized by complex pathogenesis, with its development closely linked to immune dysregulation. Regulatory T cells (Tregs), as specialized immunomodulatory cells, play a pivotal role in negatively regulating immune responses and maintaining autoimmune tolerance. In recent years, extensive research has focused on the relationship between Tregs and RA pathogenesis, with the functional role of CD8⁺ Tregs as a critical area of investigation. This review summarizes the alterations in CD8⁺ Tregs during RA progression and their potential mechanisms of action. By elucidating the diversity of CD8⁺ Treg subsets and their intricate roles in modulating immune responses, this analysis provides novel insights and therapeutic strategies for RA diagnosis and treatment.
Arthritis, Rheumatoid/pathology* ; Humans ; T-Lymphocytes, Regulatory/immunology* ; CD8-Positive T-Lymphocytes/immunology* ; Animals

Objective To explore the expression of coagulation indexes in rheumatoid arthritis (RA) and dry syndrome (pSS) and their relationships with inflammation and immune function. Methods A total of 61 patients with RA who were hospitalized in the Department of Rheumatology of Anhui Provincial Hospital of Traditional Chinese Medicine from March 12 to September 9, 2024 were selected as the RA group. And 61 patients with pSS who were hospitalized in the Department of Rheumatology of the same hospital September 4, 2023, to August 17, 2024, were selected as the pSS group. 61 healthy individuals who underwent routine medical checkups at the Physical Examination Center of Anhui Provincial Hospital of Traditional Chinese Medicine during the same period were included as the control group. Baseline clinical indexes before treatment were collected from patients in each group, including prothrombin time(PT), international normalized ratio(INR), thrombia time(TT), fibrinogen(FBG), activated partial thromboplastin time(APTT), fibrin (ogen) degradation products(FDP) and D-Dimer(D-D). Results The expression levels of PT, FBG, TT, FDP, and D-D in the RA group, the pSS group, and the normal group were significantly different. The expression levels of PT, FBG, FDP, and D-D in the RA group were all higher than those in the pSS group and the control group, respectively. And the expression level of TT in the pSS group was lower than that in control group. ROC curve analysis showed that the AUC of PT was 0.638, the AUC of FBG was 0.899, the AUC of FDP was 0.866, and the AUC of D-D was 0.919 in the RA group compared with the normal group. And the AUC of coagulation indexes for joint diagnosis of RA was higher than that of the indexes detected individually. pSS group had an AUC of PT of 0.618 compared with that of the normal group. The AUC of TT was 0.645, and the AUC of coagulation indexes for the joint diagnosis of pSS was higher than the AUC of each index detected separately. Association rule analysis showed that elevated D-D in RA patients had a significant correlation with elevated hs-CRP, CCP and RF, and elevated FBG had a significant correlation with elevated hs-CRP, ESR, RF and CCP. Elevated D-D in pSS patients had a correlation with elevated hs-CRP and anti-SSA, and elevated INR has correlation with elevated hs-CRP, anti-SSA and anti-SSB. Correlation analysis showed that PT, INR, FBG, FDP, and D-D were positively correlated with CRP and ESR, and TT was negatively correlated with CRP and ESR in the RA group. FBG, FDP, and D-D were positively correlated with CRP and ESR in the pSS group. Moreover, coagulation indexes were positively correlated with immune indexes in RA group and pSS group which were all significant. The results of multiple linear regression analysis showed that FBG was a positive correlate of hs-CRP and ESR in RA patients. For PSS patients, FBG and FDP were positive correlates of hs-CRP. APTT and FBG were positive correlates of ESR. Conclusion Compared with pSS, coagulation indexes (especially PT, FBG, FDP and D-D) are more informative for the early diagnosis of RA and the judgment of the degree of the disease, and can be used as an important predictor for the confirmation of the diagnosis of RA.
Humans ; Female ; Male ; Arthritis, Rheumatoid/diagnosis* ; Middle Aged ; Fibrin Fibrinogen Degradation Products/analysis* ; Blood Coagulation ; Adult ; Fibrinogen/metabolism* ; Partial Thromboplastin Time ; Prothrombin Time ; Aged ; Inflammation/immunology* ; ROC Curve

OBJECTIVE: To elucidate the role and underlying mechanism of ubiquitin-specific protease 35 (USP35) in ferroptosis of rheumatoid arthritis-fibroblast like synoviocytes (RA-FLS), thereby enhancing our comprehension of the pathogenesis of RA and identifying potential therapeutic targets for its treatment. METHODS: (1) RA-FLS were cultured in vitro and transduced with lentiviral vectors to establish stable cell lines: A USP35-knockdown line (short hairpin ribonucleic acid of USP35, shUSP35) and its control (negtive control of short hairpin ribonucleic acid, shNC), as well as a overexpression of USP35 line (USP35 OE) and its control (Vector). To investigate the role of USP35 in ferroptosis regulation, a ferroptosis model was induced in RA-FLS by treatment with 1 μmol/L Erastin. The cells were divided into six groups: shNC, shNC + Erastin, shUSP35 + Erastin, Vector, Vector + Erastin, and USP35 OE + Erastin. (2) Cell viability was detected using the cell counting kit-8 (CCK-8). (3) Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione/glutathione disulfide (GSH/GSSG) ratios, and Ferrous ion (Fe²⁺) levels were measured using specific assay kits to evaluate oxidative stress, lipid peroxidation, and glutathione redox status in the cells. (4) Protein expression levels of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) were detected using Western blotting to investigate their potential involvement in USP35-mediated ferroptosis regulation. RESULTS: (1) Compared with the shNC +Erastin group, the cell viability of the shUSP35+Erastin group was significantly decreased (P < 0.001), while it was notably increased in the USP35 OE+Erastin group compared with the Vector+Erastin group (P < 0.001). These findings indicated that USP35 could alleviate the inhibitory effect of Erastin on RA-FLS cell viability. (2) In comparison to the shNC+Erastin group, the levels of ROS (P < 0.001), MDA (P < 0.05), and Fe²⁺ (P < 0.001) were significantly elevated, and the GSH/GSSG ratio was increased (P < 0.05) in the shUSP35+Erastin group. Conversely, the levels of ROS (P < 0.001), MDA (P < 0.05), and Fe²⁺ (P < 0.05) were significantly decreased, and the GSH/GSSG ratio was decreased (P < 0.05) in the USP35 OE+Erastin group compared with the Vector+Erastin group. These results suggested that USP35 could inhibit Erastin-induced oxidative stress and lipid peroxidation in RA-FLS. (3) In Erastin-induced RA-FLS, the expression of USP35 was positively correlated with the protein levels of SLC7A11 and GPX4, indicating a potential mechanism by which USP35 regulated ferroptosis in these cells. CONCLUSION USP35 inhibits ferroptosis in RA-FLS, potentially through the increased expression of SLC7A11 and GPX4.
Ferroptosis ; Humans ; Arthritis, Rheumatoid/metabolism* ; Synoviocytes/pathology* ; Reactive Oxygen Species/metabolism* ; Ubiquitin-Specific Proteases/metabolism* ; Fibroblasts/pathology* ; Cell Survival ; Piperazines/pharmacology* ; Endopeptidases/metabolism* ; Cells, Cultured ; Cell Line ; Amino Acid Transport System y+

OBJECTIVE: To explore the mechanism of action of asperosaponin VI (AVI) in the treatment of rheumatoid arthritis (RA) and validate it in ex vivo experiments using network pharmacology and molecular docking methods. METHODS: The predicted targets of AVI were obtained from PharmMaper, UniProt and SwissTarget Prediction platforms, the disease targets were collected from Online Mendelian Inheritance in Man, Therapeutic Target Database and GeneCards databases, the intersection targets of AVI and RA were obtained from Venny 2.1.0, and the protein-protein interaction (PPI) network was obtained from STRING database, which was analyzed by Cytoscape software and screened to obtain the core targets. Cytoscape software was used to analyze PPI network and screen the core targets. Based on the Database for Annotation, Visualization and Integrated Discovery database, Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed, and Cytoscape software was used to construct the "Disease-Pathway-Target-Drug" network, which was finally verified by molecular docking and animal experiments. RESULTS: Network pharmacological studies showed that AVI was able to modulate 289 targets, with 102 targets for the potential treatment of RA, with the core pathway being the AKT/PI3K signaling pathway, and the core targets being the epidermal growth factor receptor (EGFR) and matrix metalloproteinase 9 (MMP9). Molecular docking results showed that AVI could produce strong binding with both of the 2 core targets. In vitro cellular experiments showed that AVI reduced nitric oxide, prostaglandin E₂, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1 β levels (P<0.05) and inhibited cyclooxygenase-2, nitric oxide synthase, EGFR, MMP9, phosphorylated phosphoinositide 3-kinase (p-PI3K), and phosphorylated serine-threonine kinase (p-AKT) proteins (P<0.05). The results of in vivo studies showed that AVI improved RA score and foot swelling thickness and decreased TNF-α, IL-6, p-PI3K and p-AKT levels in RA rats (P<0.05). CONCLUSION AVI exerts anti-inflammatory and anti-RA effects which might be related to the EGFR/MMP9/AKT/PI3K pathway.
Saponins/chemistry* ; ErbB Receptors/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Signal Transduction/drug effects* ; Molecular Docking Simulation ; Animals ; Arthritis, Rheumatoid/drug therapy* ; Proto-Oncogene Proteins c-akt/metabolism* ; Matrix Metalloproteinase 9/metabolism* ; Protein Interaction Maps/drug effects* ; Humans ; Network Pharmacology ; Male ; Rats

OBJECTIVE: To explore the efficacy and safety of Juan Bi Pill (JBP) in treatment of active rheumatoid arthritis (RA). METHODS: From February 2017 to May 2018, 115 participants from 4 centers were randomly divided into JBP group (57 cases) and placebo group (58 cases) in a 1:1 ratio using a random number table method. Participants received a dose of JBP (4 g, twice a day, orally) combined with methotrexate (MTX, 10 mg per week) or placebo (4 g, twice a day, orally) combined with MTX for 12 weeks. Participants were required with follow-up visits at 24 and 48 weeks, attending 7 assessment visits. Participants were undergo disease activity assessment 7 times (at baseline and 2, 4, 8, 12, 24, 48 weeks) and safety assessments 6 times (at baseline and 4, 8, 12, 24, 48 weeks). The primary endpoint was 28-joint Disease Activity Score (DAS28-ESR and DAS28-CRP). The secondary endpoints included American College of Rheumatology (ACR) criteria for 20% and 50% improvement (ACR20/50), Health Assessment Questionnaire Disability Index (HAQ-DI), clinical disease activity index (CDAI), visual analog scale (VAS), Short Form-36 (SF-36) score, Medial Outcomes Study (MOS) sleep scale score, serum erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tender joint count, swollen joint count, and morning stiffness. The adverse reactions were observed during the treatment. RESULTS: After 12 weeks of treatment, DAS28-ESR and DAS28-CRP scores in both groups were lower than before treatment (both P<0.01), while the remission rate of DAS28-ESR and DAS28-CRP and low disease activity of JBP group were higher than those in the placebo group (both P<0.01). JBP demonstrated better efficacy on ACR20 and ACR50 compliance rate at 12 and 48 weeks comparing to placebo (all P<0.05). The CDAI and HAQ-DI score, pain VAS and global VAS change of RA patients and physicians, the serum ESR and CRP levels, and the number of tenderness and swelling joints were lower than before treatment at 4, 8, 12, 24, 48 weeks in both groups (P<0.05 or P<0.01), while the reduction of above indices in the JBP group was more obvious than those in the placebo group at 12 weeks (ESR and CRP, both P<0.05) or at 12 and 48 weeks (all P<0.01). There was no difference in adverse reactions between the 2 groups during treatment (P=0.75). CONCLUSION JBP combined with MTX could effectively reduce disease activity in patients with RA in active stage, reduce the symptoms of arthritis, and improve the quality of life, while ensuring safety, reliability, and fewer adverse effects. (Trial Registration: ClinicalTrials.gov, No. NCT02885597).
Humans ; Arthritis, Rheumatoid/drug therapy* ; Methotrexate/adverse effects* ; Female ; Double-Blind Method ; Male ; Middle Aged ; Treatment Outcome ; Drugs, Chinese Herbal/adverse effects* ; Drug Therapy, Combination ; Adult ; Antirheumatic Agents/adverse effects* ; Aged

The prevalence of rheumatoid arthritis (RA) has sharply increased in recent years, posing a serious threat to human health. RA is characterized as a chronic, multisystem disease with morning stiffness and symmetric small joint pain. However, its fundamental processes are poorly understood. With the advancements in molecular biology techniques, a growing body of research indicates that numerous non-coding RNAs (ncRNAs) are essential for the pathogenesis of RA. These ncRNAs not only contribute to the onset of RA but also play a role in the pathological processes of RA development, including synovial immune inflammation and bone destruction. Chinese medicine (single compounds, single herbs, and compound formulae, as well as non-drug therapies such as acupuncture and moxibustion), offer significant benefits for treating RA. This study examined the role of 3 different ncRNA types (circular RNA, long ncRNA, and microRNA) as biomarkers in RA diagnosis, as well as their regulatory roles in rheumatoid arthritis fibroblast-like synoviocytes functions such as inflammatory response, proliferation, cell cycle, apoptosis, and invasion. Additionally, the study explored the mechanisms by which Chinese medicine regulates these ncRNAs, with the goal of offering innovative strategies for RA treatment.
Arthritis, Rheumatoid/pathology* ; Humans ; RNA, Untranslated/metabolism* ; Medicine, Chinese Traditional ; Synoviocytes/metabolism* ; RNA, Circular ; Biomarkers/metabolism* ; Apoptosis/genetics*