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.

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.

OBJECTIVES: To explore the therapeutic mechanism of puerarin for alleviating synovitis in rats with collagen-induced arthritis (CIA). METHODS: In a SD rat model of CIA, we tested the effects of daily gavage of puerarin at low, moderate and high doses (10, 30, and 100 mg/kg, respectively) for 3 weeks, with tripterygium glycosides (GTW, 10 mg/kg) as the positive control, on swelling in the hind limb joints regions evaluated by arthritis index scoring. Mass fraction of the liver of the rats was calculated, and pathologies in joint synovial membrane were observed with HE staining. The expressions of transforming growth factor β‑activated kinase-1 (TAK1), Toll-like receptor 4 (TLR4), and nuclear factor kappa-Bp65 (NF‑κB p65) at the mRNA and protein levels in the synovial tissues were detected using Real-time PCR and Western blotting. RESULTS: Compared with those in the model group, the rats in GTW group and high-dose puerarin group showed significantly reduced mass fraction of the liver. Treatment with GTW and puerarin at the 3 doses all significantly alleviated plantar swelling, lowered arthritis index scores, and improved synovitis in CIA rats (P<0.05), and the effects of puerarin showed an obvious dose dependence. Both GTW and puerarin treatments significantly lowered TAK1, TLR4, and NF‑κB p65 mRNA and protein expressions in the synovium of CIA rats. CONCLUSIONS Puerarin alleviates synovium damages in CIA rats possibly by suppressing the TLR4/NF‑κB signaling pathway via downregulating TAK1 expression.
Animals ; Toll-Like Receptor 4/metabolism* ; Rats, Sprague-Dawley ; Rats ; MAP Kinase Kinase Kinases/metabolism* ; Signal Transduction/drug effects* ; Arthritis, Rheumatoid/drug therapy* ; NF-kappa B/metabolism* ; Isoflavones/therapeutic use* ; Male ; Arthritis, Experimental/drug therapy* ; Transcription Factor RelA/metabolism* ; Synovial Membrane/metabolism*

OBJECTIVES: To analyze the molecular mechanism of Xixian Pills for treatment of rheumatoid arthritis (RA). METHODS: Forty-eight rats were randomized into 6 groups (n=8), including a normal control group, a collagen-induced arthritis (CIA) model group, 3 Xixian Pills treatment (200, 400 and 800 mg/kg) groups, and a Tripterygium glycosides tablet (TGT) treatment group. In the latter 4 groups, the rats were treated with daily gavage of Xixian Pills or TGT 2 weeks after CIA modeling for 3 consecutive weeks. The differentially expressed proteins in high-dose Xixian Pills group and the model group compared with the normal control group were screened based on the tandem mass spectrometry tag (TMT) technology, and the core targets and signaling pathways were analyzed. The immune cell infiltration and gene expression data were analyzed using ggplot2 and tidyverse packages, and the correlation coefficients between the core targets and the immune cells were calculated. RESULTS: The CIA rats showed significantly increased serum levels of TNF-α and IL-6 and lowered serum IL-10 level. Treatments with high- and medium-dose Xixian Pills and TGT all significantly reduced serum TNF‑α and IL-6 and increased IL-10 levels in CIA rats. Proteomic analysis identified 160 differential proteins between the model group and high-dose Xixian Pills group, and the core targets included CCL5, STAT1, GZMB and IL7R. The areas under the ROC curve of CCL5 and STAT1 were both greater than 0.9. Immunohistochemical and immunofluorescence staining revealed increased levels of CCL5 and STAT1 in the ankle joints of CIA rats, which were significantly decreased after treatment with Xixian Pills. CONCLUSIONS Treatment with Xixian Pills offers protection of the joints in CIA rats possibly by inhibiting joint inflammation via regulating protein expressions of CCL5 and STAT1.
Animals ; Drugs, Chinese Herbal/pharmacology* ; Rats ; Arthritis, Rheumatoid/metabolism* ; Proteomics ; Tripterygium/chemistry* ; Arthritis, Experimental/metabolism* ; Tumor Necrosis Factor-alpha/blood* ; Interleukin-10/blood* ; Interleukin-6/blood* ; Male ; Rats, Sprague-Dawley ; Signal Transduction

Tricellulin, a key tricellular tight junction (TJ) protein, is essential for maintaining the barrier integrity of acinar epithelia against macromolecular passage in salivary glands. This study aims to explore the role and regulatory mechanism of tricellulin in the development of salivary gland hypofunction in Sjögren's syndrome (SS). Employing a multifaceted approach involving patient biopsies, non-obese diabetic (NOD) mice as a SS model, salivary gland acinar cell-specific tricellulin conditional knockout (Tric^CKO) mice, and IFN-γ-stimulated salivary gland epithelial cells, we investigated the role of tricellulin in SS-related hyposalivation. Our data revealed diminished levels of tricellulin in salivary glands of SS patients. Similarly, NOD mice displayed a reduction in tricellulin expression from the onset of the disease, concomitant with hyposecretion and an increase in salivary albumin content. Consistent with these findings, Tric^CKO mice exhibited both hyposecretion and leakage of macromolecular tracers when compared to control animals. Mechanistically, the JAK/STAT1/miR-145 axis was identified as mediating the IFN-γ-induced downregulation of tricellulin. Treatment with AT1001, a TJ sealer, ameliorated epithelial barrier dysfunction, restored tricellulin expression, and consequently alleviated hyposalivation in NOD mice. Importantly, treatment with miR-145 antagomir to specifically recover the expression of tricellulin in NOD mice significantly alleviated hyposalivation and macromolecular leakage. Collectively, we identified that tricellulin deficiency in salivary glands contributed to hyposalivation in SS. Our findings highlight tricellulin as a potential therapeutic target for hyposecretion, particularly in the context of reinforcing epithelial barrier function through preventing leakage of macromolecules in salivary glands.
Sjogren's Syndrome/complications* ; Animals ; Xerostomia/etiology* ; Mice ; Mice, Inbred NOD ; MARVEL Domain Containing 2 Protein/metabolism* ; Humans ; Mice, Knockout ; Disease Models, Animal ; Interferon-gamma ; Salivary Glands/metabolism* ; Tight Junctions/metabolism* ; MicroRNAs/metabolism* ; Female

OBJECTIVE: Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects the small joints of the whole body and degrades the patients' quality of life. Zhengqing Fengtongning (ZF) is a traditional Chinese medicine preparation used to treat RA. ZF may cause liver injury. In this study, we aimed to develop a prediction model for abnormal liver function caused by ZF. METHODS: This retrospective study collected data from multiple centers from January 2018 to April 2023. Abnormal liver function was set as the target variable according to the alanine transaminase (ALT) level. Features were screened through univariate analysis and sequential forward selection for modeling. Ten machine learning and deep learning models were compared to find the model that most effectively predicted liver function from the available data. RESULTS: This study included 1,913 eligible patients. The LightGBM model exhibited the best performance (accuracy = 0.96) out of the 10 learning models. The predictive metrics of the LightGBM model were as follows: precision = 0.99, recall rate = 0.97, F1_score = 0.98, area under the curve (AUC) = 0.98, sensitivity = 0.97 and specificity = 0.85 for predicting ALT < 40 U/L; precision = 0.60, recall rate = 0.83, F1_score = 0.70, AUC = 0.98, sensitivity = 0.83 and specificity = 0.97 for predicting 40 ≤ ALT < 80 U/L; and precision = 0.83, recall rate = 0.63, F1_score = 0.71, AUC = 0.97, sensitivity = 0.63 and specificity = 1.00 for predicting ALT ≥ 80 U/L. ZF-induced abnormal liver function was found to be associated with high total cholesterol and triglyceride levels, the combination of TNF-α inhibitors, JAK inhibitors, methotrexate + nonsteroidal anti-inflammatory drugs, leflunomide, smoking, older age, and females in middle-age (45-65 years old). CONCLUSION This study developed a model for predicting ZF-induced abnormal liver function, which may help improve the safety of integrated administration of ZF and Western medicine. Please cite this article as: Yu Z, Kou F, Gao Y, Lyu CM, Gao F, Wei H. A machine learning model for predicting abnormal liver function induced by a Chinese herbal medicine preparation (Zhengqing Fengtongning) in patients with rheumatoid arthritis based on real-world study. J Integr Med. 2025; 23(1): 25-35.
Humans ; Arthritis, Rheumatoid/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Female ; Middle Aged ; Male ; Retrospective Studies ; Machine Learning ; Adult ; Aged ; Liver/physiopathology* ; Alanine Transaminase/blood*

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*

Sjögren's syndrome (SS) is an autoimmune disease characterized primarily by oral and periocular dryness. Astragalus-Salvia (AS) and Ophiopogon-Dendrobium (OD) represent two frequently utilized herb pairs in SS treatment. While the combination of AS-OD herb pairs demonstrates clinical efficacy in alleviating SS symptoms, its underlying mechanism remains unclear. This investigation sought to assess the therapeutic effects and elucidate the potential mechanisms of AS-OD in non-obese diabetic (NOD)/Ltj mice with SS. The study utilized NOD/Ltj mice as SS models, administering AS-OD treatment for 10 weeks at doses of 113.1, 226.2, and 339.3 mg·d^-1·20 g^-1. Results demonstrated that AS-OD improved SS symptoms, evidenced by enhanced salivary flow rate, decreased anti-SSA/Ro and anti-SSB/La antibody levels, increased swimming duration, and reduced lactate (LA) and blood urea nitrogen (BUN) levels in NOD/Ltj mice. AS-OD reduced lymphocyte infiltration, enhanced Aquaporin-5 (AQP5) expression in the submandibular gland, decreased inflammatory cytokine levels in the submandibular gland, and reduced the T helper type 17/regulatory T lymphocyte (Th17/Treg) cell ratio in the spleen. Transcriptomic and proteomic analyses indicated AS-OD's involvement in regulating phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and Janus kinase 3/signal transducer and activator of transcription 3 (JAK1/STAT3) pathways, with inhibitory effects validated in both NOD/Ltj mice submandibular gland and A-253 cells. Furthermore, AS-OD enhanced cell viability and reduced A-253 cell apoptosis through the PI3K/AKT pathway. In A-253 cells, AS-OD reduced inflammatory cytokine levels, CXC chemokine ligand 9/10 (CXCL9/10), and T-cell chemotaxis by inhibiting the JAK1/STAT3 pathway. AS-OD mitigates SS by suppressing inflammation and immune responses through the PI3K/AKT and JAK1/STAT3 pathways.
Animals ; STAT3 Transcription Factor/genetics* ; Sjogren's Syndrome/immunology* ; Mice, Inbred NOD ; Proto-Oncogene Proteins c-akt/genetics* ; Phosphatidylinositol 3-Kinases/genetics* ; Mice ; Drugs, Chinese Herbal/administration & dosage* ; Signal Transduction/drug effects* ; Janus Kinase 1/genetics* ; Humans ; Female ; Astragalus Plant/chemistry* ; Male

OBJECTIVE: To report the clinical experience of using Ilizarov wrist joint distraction technique in the treatment of a case of rheumatoid arthritis of the wrist. METHODS: In January 2019, a 49-year-old female patient with rheumatoid arthritis of the left wrist, complicated by ulnar impaction syndrome, was admitted for treatment. Preoperatively, the active range of motion of the left wrist was as follows: extension 0°-flexion 0°, pronation 65°-supination 35°, and grip strength of 4.0 kg. The visual analogue scale (VAS) score was 9, and the Cooney wrist function score was 15, indicating poor function. As conservative treatment failed to achieve symptom relief, Ilizarov wrist joint distraction surgery was performed. Postoperatively, joint distraction was applied at 2 mm increments on postoperative days 2 and 7, in 4 separate sessions. RESULTS: Postoperative X-ray film examination at 7 days revealed a distraction of 3.6 mm in the affected wrist joint compared to the contralateral side. The external fixator was removed 2.5 months postoperatively. At 22 months postoperatively, X-ray film and MRI examinations revealed that the joint space of the left wrist had returned to near-normal, with significant reduction in joint effusion and synovial proliferation. The active range of motion of the left wrist improved to extension 15°- flexion 30°, pronation 90°-supination 90°, with a grip strength of 18.0 kg. The wrist pain VAS score decreased to 0, and the Cooney wrist function score improved to 90, indicating excellent function. At 50 months postoperatively, follow-up X-ray film, MRI, and functional assessments showed the results similar to those at 22 months. CONCLUSION Ilizarov wrist joint distraction may be a viable treatment option for rheumatoid arthritis of the wrist.
Humans ; Female ; Middle Aged ; Wrist Joint/physiopathology* ; Arthritis, Rheumatoid/physiopathology* ; Range of Motion, Articular ; Ilizarov Technique ; Treatment Outcome ; Osteogenesis, Distraction/methods*