Treatment Of RA Research Articles

Secreted PD-L1 alleviates inflammatory arthritis in mice through local and systemic AAV gene therapy

IntroductionRheumatoid arthritis (RA) primarily affects the joints but can also affect multiple organs and profoundly impacts patients’ ability to carry out daily activities, mental health, and life expectancy. Current treatments for RA are limited in terms of duration, efficacy, and adverse effects. PD-L1 is a checkpoint protein that plays important roles in immune regulation and has been implicated in the initiation and progression of multiple autoimmune diseases.MethodIn a previous study, we demonstrated that intra-articular injection with adeno-associated virus (AAV) vectors encoding wild type PD-L1 improved local inflammation in the joint in the collagen-induced arthritis (CIA) mouse model of RA. To further improve efficacy, we explored AAV-mediated delivery of the soluble PD-L1 (sPD-L1) to CIA mice.ResultAfter intra-articular injection of AAV6 vectors expressing the optimal isoform of sPD-L1 (shPD-L1), more potency was observed when compared to wild type PD-L1, with a lower dose of AAV6/shPD-L1 needed for arthritis improvement. To study the therapeutic effect of systemic expression of sPD-L1, we administered AAV8/shPD-L1 gene therapy in CIA mice via retro-orbital injection and found significant improvements in joint inflammation and paw swelling, exhibiting similar phenotypes to that in naïve mice. The levels of total immunoglobulin and anti-collagen specific antibodies were lower in AAV8/shPD-L1 treated CIA mice than those in controls. The levels of pro-inflammatory cytokines in blood were also significantly decreased in shPD-L1 treated mice. Additionally, T cell apoptosis rates in the spleen showed a 2-fold increase in treated mice. Finally, we investigated the therapeutic effect of AAV/shPD-L1 via intramuscular injection. After injection of AAV6/shPD-L1, decreased paw swelling, reduced joint inflammation, and lower levels of pro-inflammatory cytokines in blood were achieved. The therapeutic effect of shPD-L1 was dose dependent via intramuscular treatment with AAV vectors.ConclusionIn conclusion, the findings in this study suggest that intra-articular injection of AAV vectors encoding sPD-L1 results in greater therapeutic benefit on arthritis, and systemic AAV/sPD-L1 is able to block the development of inflammatory arthritis with inhibition of the systemic immune response, underlining the potential of gene therapy with systemic delivery of shPD-L1 via AAV vectors in RA.

2024 Update of the Japan College of Rheumatology Clinical Practice Guidelines for the Management of Rheumatoid Arthritis - secondary publication.

To update the Japan College of Rheumatology Clinical Practice Guidelines for the Management of Rheumatoid Arthritis (CPG for RA). The recommendations were developed based on the evidence published until the end of June 2022 using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). The steering committee, CPG panel, systematic review (SR) group, and SR support team were organised. The treatment goal and drug treatment algorithm required no modifications; however, the footnotes of the drug treatment algorithm were modified. SR of 21 new or updated recommendations for subcutaneous methotrexate (n=1), biological disease-modifying antirheumatic drugs (n=1), rituximab (n=5), Janus kinase inhibitors (n=6), biosimilars (n=2), older patients (n=4), and pregnancy and lactation (n=2) was conducted. The recommendations for comorbidities and surgery and rehabilitation remained unchanged from the 2020 CPG for RA. The 2024 CPG for RA, which provide recommendations that reflect the current healthcare environment for RA in Japan, can be used effectively as a tool for shared decision-making between rheumatologists and patients in the treatment of RA.

3-MA attenuates collagen-induced arthritis in vivo via anti-inflammatory effect and autophagy inhibition

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease which afflicts about nearly 1% of global population. RA results in synovitis and cartilage/bone damage, even disability which aggravates the health burden. Many drugs are used to relieve RA, such as glucocorticoids (GCs), non-steroidal anti-inflammatory drugs (NSAIDs), and disease-modifying anti-rheumatic drugs (DMARDs) in the clinical treatment. However, present clinical drugs have various disadvantages such as poor bioavailability and short biological half-life and drug resistance, or adverse effects. A recent study showed autophagy modulation may be a novel strategy in the treatment of RA. 3-Methylademine (3-MA), is the most widely used autophagy inhibitor, which blocks autophagy at the initiation and maturation stages. The aim of this study is to evaluate the effect of 3-MA in collagen-induced-arthritis (CIA) mice and further elucidate how 3-MA attenuated inflammation, and cartilage/bone damage in arthritis.MethodsAn in-vivo mouse collagen-induced arthritis model was applied to compare differences in ankle destruction among control mice and CIA mice treated with or without 3-MA. Bone and cartilage destruction degree was evaluated by histology and micro-computed tomography (µCT). Further in-vivo assays utilized mouse serum samples to investigate inflammatory levels, oxidative levels, and bone resorption cytokines. At last, an immunofluorescence assay was applied to detect the autophagy level among the three groups.ResultsThe in-vivo mouse collagen-induced arthritis model showed that CIA mice revealed apparent hind paw and ankle swelling which was aggravated gradually along with time, while 3-MA treatment attenuated swelling gradually. µCT and histological results showed typical lesions in CIA group while 3-MA treatment alleviated arthritis-related destruction. Serum assay showed that 3-MA significantly reduced inflammatory cytokines levels, suppressed oxidative levels and bone resorption cytokines. Immunofluorescence assay revealed 3-MA significantly inhibited the abnormal autophagy level in CIA mouse ankle.Conclusions3-MA protects bone destruction in CIA-induced mice arthritis by anti-inflammatory effect and autophagy inhibition.

Therapeutic Effect of a Near‐Infrared Responsive MTX‐Mn3O4@PDA Nano‐Delivery System on Rheumatoid Arthritis

AbstractRheumatoid arthritis (RA) is an autoimmune disease associated with chronic inflammatory processes. RA, which is typically associated with the accumulation of hyperactive immune cells (HICs), particularly M1 proinflammatory macrophages, is accompanied by elevated levels of reactive oxygen species (ROS) and decreased pH in the synovial membranes of the joints. In this work, a nano‐delivery system (MTX‐Mn3O4@PDA) is designed that can deliver photothermal materials, ROS scavengers, and synovial fibroblast inhibitors at the joint site for the treatment of RA. After injecting MTX‐Mn3O4@PDA into the inflamed site of RA, photothermal therapy is initiated by near‐infrared (NIR) laser irradiation, which resulted in the death of activated inflammatory cells at the lesion site. While polydopamine (PDA) slowly dissociates under stimulation by a low pH microenvironment. Subsequently, excess ROS interacts with the Mn3O4 nanozyme and the undissociated PDA nanozyme, promoting ROS clearance, while Methotrexate (MTX) inhibits the proliferation of synovial fibroblasts. Intra‐articular injection of MTX‐Mn3O4@PDA (7 mg kg−1) into collagen‐induced arthritis mice demonstrated efficacy in reducing toe swelling and significantly alleviating synovial inflammation, bone erosion, and cartilage degeneration. This nano‐delivery system has potential clinical applications for treating RA.

Inhibition of macrophage polarization and pyroptosis in collagen-induced arthritis through MSC-exo and ginsenoside Rh2

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, tissue damage, and fibrosis, significantly affecting the quality of life. While there are currently some effective treatments available, they often come with side effects. There is an urgent need to find new treatments that can further improve therapeutic outcomes and reduce side effects.MethodsOur study investigates the role of Mesenchymal Stem Cell exosomes (MSC-exo) combined with Ginsenoside Rh2 (Rh2) in the treatment of RA. We specifically focus on how this combined strategy influences macrophage polarization and pyroptosis. This research utilized a collagen-induced rat arthritis model.ResultsThe study findings reveal that the combination of MSC-exo combined with Rh2 can inhibit the polarization of M1 macrophages, increase the proportion of M2-like macrophages, and suppress M1-like macrophage pyroptosis via the NLRP3/Caspase11/GSDMD-N pathway. In the rat arthritis model, the combination of MSC-exo and Rh2 showed synergistic therapeutic effects.ConclusionThis research contributes to a deeper understanding of RA’s pathogenesis and presents new potential targeted therapeutic interventions. The combined application of MSC-exo and Rh2 offers promising insights for future innovative strategies in RA treatment, paving the way for more effective management of this autoimmune disease.

Piperine and piperine-loaded albumin nanoparticles ameliorate adjuvant-induced arthritis and reduce IL-17 in rats

AimRheumatoid arthritis (RA) is one of the most common chronic, inflammatory, autoimmune diseases affecting mainly the joints. Piperine (PIP), an alkaloid found in black pepper, has anti-inflammatory properties and its use in drug delivery systems such as nanoparticles might be a treatment for RA. This study aims to evaluate the possible anti-inflammatory and anti-arthritic effects of PIP and its use in albumin nanoparticles as a possible approach for the treatment of Adjuvant-induced arthritis (AIA) rats. MethodsPIP-loaded Bovine Serum Albumin nanoparticles (PIP-BSA NPs) were prepared using a desolvation method. AIA rats were given intraperitoneal injections of either 40 mg PIP or 131 mg PIP-BSA NPs every two days until day 28 when animals were sacrificed. Clinical score, histopathology, X-ray radiography, and serum levels of pro-inflammatory cytokines such as IL-1β, IL-17, and TNF-α were evaluated. ResultsPIP and PIP-BSA NPs significantly reduced clinical scores, and alleviated inflammation within the joints. PIP was superior to PIP-BSA NPs for the alleviation of fibrin deposition and periosteal reactions while bone inflammation and erosion were less severe in the case of PIP-BSA NPs. Besides, both of the treatments suppressed serum levels of IL-17 in AIA rats (p = 0.003 and p = 0.02; respectively). ConclusionsPIP and PIP-BSA NPs effectively alleviate the severity of AIA and suppress inflammation. Due to the superiority of PIP in improving fibrin deposition and periosteal reactions and the efficacy of PIP-BSA NPs in suppressing bone inflammation and erosion, their simultaneous use might be investigated.

Research progress in acupoint administration of new dosage forms of traditional Chinese medicine preparations for rheumatoid arthritis

The conventional acupoint therapy for rheumatoid arthritis often uses traditional Chinese medicine preparations in the dosage forms of powder, ointment, and paste. However, these dosage forms have obvious drawbacks, such as low transdermal absorption, strong skin irritation, and easy detachment. Creating a traditional Chinese medicine acupoint therapy characterized by high penetration, low toxicity, low irritation, and convenient administration is of great significance. With the development of new technology for modern traditional Chinese medicine preparations, modern dosage forms such as microemulsion, microparticle, hydrogel, and liposome are combined with acupoint administration, and the derived therapeutic methods include acupoint application, acupoint injection, microneedle, and nanoporous acupuncture needle. The combination of new dosage forms of traditional Chinese medicine preparations and acupoint administration has the advantages of high drug permeability, high retention, and the formation of drug acupoint storage. The accumulation of drugs in acupoints continuously amplifies the acupoint effect, achieving a synergistic effect of drug treatment and acupoint treatment(1+1>2). This article reviews the relevant research and improvement of new dosage forms of traditional Chinese medicine preparations combined with acupoint administration for the treatment of RA, providing new development ideas for the combination of traditional Chinese medicine acupoint therapy and modern new formulation technologies.

Jingfang Granules alleviates the lipid peroxidation induced ferroptosis in rheumatoid arthritis rats by regulating gut microbiota and metabolism of short chain fatty acids

BackgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation, bone and cartilage damage, musculoskeletal pain, swelling, and stiffness. Inflammation is one of the key factors that induce RA. Jingfang Granule (JFG) is a traditional Chinese medicine (TCM) with significant anti-inflammatory effects. Clinical studies have confirmed that JFG can be used to treat RA, but the mechanism is still vague. PurposeThis study was designed to evaluate the protective function and the mechanism of JFG on rats with RA. Study design and methodsComplete Freud's Adjuvant (CFA) was used to establish a rat RA model, and JFG or Diclofenac Sodium (Dic) was orally administered. Foot swelling and hematoxylin eosin (H&E) staining were used to test the therapeutic effect of JFG on RA treatment, while ELISA kits were used to detect serum cytokines. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and reactive oxygen species (ROS) were used to evaluate oxidative stress levels. The integration of label-free proteomics, fecal short chain fatty acid (SCFA) targeted metabolomics, peripheral blood SCFA, medium and long chain fatty acid targeted metabolomics, and 16S rDNA sequencing of gut microbiota were used to screen the mechanism. Western blot technology was used to validate the results of multiple omics studies. Serum D-Lactic acid, lipopolysaccharide specific IgA antibody (LPS IgA), diamine oxidase (DAO), and colon Claudin 5 and ZO-1 were used to evaluate the intestinal barrier. ResultsThe results confirmed that JFG effectively protected rats from RA injury, which was confirmed by improved foot swelling and synovial pathology. At the same time, JFG reduced the levels of TNF-α, IL-1β, and IL-6 in serum by inhibiting the NLRP3 inflammasome signaling pathway and TLR4/NF-κB signaling pathway in synovial tissue. Multiple omics studies indicated that JFG increased the abundance of gut microbiota and regulated the number of gut bacteria, thereby increased the levels of Acetic acid, Propionic acid, and Butyric acid in the gut and serum of RA rats, which activated AMPK to regulate fatty acid metabolism and fatty acid biosynthesis, thereby inhibited lipid oxidative stress induced ferroptosis to improve tissue damage caused by RA. Meanwhile, JFG improved the intestinal barrier by upregulating the expresses of Claudin 5 and ZO-1, which was confirmed by low concentrations of D-Lactic acid, LPS-SIgA and DAO in serum. ConclusionsThis study confirmed that JFG improved the disturbance of fatty acid metabolism by modulating gut microbiota and the production of fecal SCFAs to activate AMPK, and then inhibited ferroptosis caused by lipid oxidative stress in synovium tissue and prevented AR injury. This study proposes for the first time to investigate the mechanism of JFG treatment for RA from the perspective of the "Gut-joint" axis, and provides a promising approach for the treatment of RA.

The Ability of Indigenous Plants in Alleviating Rheumatoid Arthritis: A Comprehensive Review.

Rheumatoid Arthritis is a long-lasted, inflammatory, systemic autoimmune disease that predominantly manifests in people between the ages of 30 and 50 Rheumatoid arthritis is characterized by more than a half-hour of morning stiffness in the affected joints, fever, soreness, swelling, weight loss, tiredness, warm joints, and subcutaneous rheumatoid nodules. Hormonal, genetic, epigenetic, reproductive, and neuroendocrine risk factors, as well as comorbid host variables, are the categories of host-related risk factors associated with the evolution of RA. Additional risk variables that have been linked to RA include food, environmental variables, socioeconomic status, smoking, microbiome, infection agents, and other airborne exposures. The objective of RA therapies is to minimise joint deformity and destruction, minimise discomfort and inflammation in the joints, and maximise joint function.Growing data suggests that the course of Rheumatoid Arthritis is affected by the minimisation of disease activity caused by disease-modifying medications, and that patients may benefit from early antirheumatic medication delivery that modifies illness. While numerous herbs have been explored for their anti-inflammatory properties, it is important to note that not all herbs have been thoroughly researched. This review focuses on seventeen native plant species that have shown either promising or established anti-arthritic effects based on preclinical and clinical studies where available. The review highlights the biochemical and immunological attributes of these herbs, summarizing their therapeutic potential for RA management while also acknowledging the limitations and gaps in current research. This examination provides insights into the potential of these herbal treatments for RA and calls for further research to explore their efficacy and safety in greater depth.

Chromone components of Saposhnikovia divaricate attenuate rheumatoid arthritis development by inhibiting the inflammatory response

Ethnopharmacological relevanceSaposhnikovia divaricata (Turcz.) Schisck., a traditional Chinese medicine (TCM), has historically been utilized in the clinical treatment of RA. It was initially documented in the 'Shennong Ben Cao Jing' as a superior quality, with the text stating: 'The herb is widely renowned for its efficacy in alleviating whole-body discomfort, bone pain, malaise, and promoting long-lasting vitality. Chromones (CHR) were identified as the primary active components in Saposhnikovia divaricata. However, the specific molecular mechanisms by which CHR impacts RA remain incompletely understood. Aim of the studyTo explore the therapeutic efficacy of CHR, a class of compound derived from Saposhnikovia divaricata, in alleviating arthropathy and immune hyperactivity in a collagen-induced arthritis (CIA) mouse model. Material and methodsSurface plasmon resonance (SPR) molecular fishing and UHPLC-QTOF/MS technology were used to identify CHR in Saposhnikovia divaricata as an active ingredient for treating RA. A CIA mouse model was used to verify the anti-RA effect of CHR in vivo. The anti-RA efficacy of CHR in vivo was evaluated by body weight change, joint swelling, arthritis index, immune organ index, ankle joint disease, and immunoglobulin G (IgG) content. The mechanism of improving RA was further analyzed by a protein chip assay and verified by Western blotting. ResultsCHR treatment reduced swelling, arthritis index, and IgG, IgG1, IgG2a, and IgG2b levels in CIA mice. Protein microarray indicated that CHR mitigated CIA-induced joint inflammation by inhibiting immune cell activation, reducing the expression of inflammatory factors and chemokines, potentially by modulating the rheumatoid arthritis pathway involving tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), and chemokines. This hypothesis was supported by the upregulation of bone morphogenetic proteins 3 (BMP3) and phospho-Smad2 (p-Smad2) proteins, coupled with the downregulation of interleukin-6 (IL-6), interleukin-1β (IL-1β), TNF-α, and IL-17A proteins in the joints of CHR-treated mice. ConclusionCHR shows promise as a potential therapeutic agent for RA, exerting its effects through anti-inflammatory mechanisms.

The Mechanisms and Quality Markers of Anti-rheumatoid Arthritis of Traditional Chinese Medicine.

RA is a recurrent autoimmune disease that has significant adverse effects on the physical and mental health of patients. Traditional Chinese medicine has shown significant advantages in the prevention and treatment of RA. Numerous clinical and experimental studies have confirmed that traditional Chinese medicine components have clear therapeutic effects and minimal adverse reactions in treating RA. The research on traditional Chinese medicine for the prevention and treatment of RA has become a hot topic in the field of autoimmune diseases. The related references about the mechanisms and Q-markers of anti-RA of traditional Chinese medicine in this review were collected from Willy, SpringLink, Web of Science, Elsevier, PubMed, SciFinder, Scopus, ACS publications, Baidu Scholar, Google Scholar, and CNKI. The traditional Chinese medicine components such as terpenoids, flavonoids, and alkaloids have significant anti-RA effects, and their mechanisms are mainly to inhibit NF-κB signaling pathway, inhibit the proliferation of RA fibroblasts like synovial cells, and regulate Th1/Th2 cell balance, and so on. Predicting and studying the Q-markers of traditional Chinese medicine anti-RA by plant phylogeny and chemical componentss, traditional medicinal properties, pharmacokinetics, component measurability, correlation between composition and efficacy, and gut microbiota will provide scientific foundations for the research and further development of anti-RA traditional Chinese medicine. The active components of traditional Chinese medicine exhibited the characteristic of multiple mechanisms in the treatment of RA, such as terpenoids had anti-angiogenesis effects, flavonoids had anti-inflammatory and cartilage protective effects, and alkaloids had antiinflammatory and analgesic effects. The proposal of Q-markers for anti-RA provided new research ideas for promoting the development of new drugs for anti-RA and ensuring the safety and effectiveness of clinical medications.

Multicenter observational study on the efficacy of selective Janus Kinase-1 inhibitor upatacitinib in rheumatoid arthritis.

Upadacitinib (UPA) is a selective, reversible Janus kinase inhibitor (JAKi) approved for the treatment of RA. However, there is still no solid evidence on the long-term efficacy of UPA in treated patients. The purpose of this study was to determine the efficacy of UPA to obtain remission or low disease activity (LDA) in a series of UPA patients in patients with RA after 6 and 12 months of treatment in a real-world setting. A series of 111 consecutive patients treated with UPA in 23 rheumatology centers were enrolled. Personal history, treatment history and disease activity at baseline, after 6 and 12 months were recorded. Intention-to-treat (ITT) and per-protocol (PP) analyses assessed achievement of remission or LDA or defined as DAS28 <2.6 and ≤3.2, respectively. Logistic regression analysis examined the role of several independent factors on the reduction of disease activity after 6 months of treatment. Of the initial group of 111 subjects at baseline, 86 and 29 participants completed clinical assessments at 6 and 12 months. According to ITT analysis, the rates of remission and LDA were 18% and 18% at 6 months and 31.5% and 12.5% at 12 months, respectively. PP analysis showed higher rates of remission and LDA at 6 (23.3% and 19.8%) and 12 months (55.2% and 20.7%). Results of multivariate logistic regression analysis indicated that a low DAS28 score (P=0.045) was the only predictor of achieving remission at 6 months. None of the baseline factors predicted remission/LDA at 6 months. RA patients treated with UPA achieved a significant rate of disease remission or LDA in a real-world setting. The 6-month response was found to depend only on the baseline value of DAS28, while it was not influenced by other factors such as disease duration, line of treatment or concomitant therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or corticosteroids.

Causal associations of air pollution with rheumatoid arthritis: A transethnic Mendelian randomization study.

Rheumatoid arthritis is a common rheumatic disease, and its onset is closely related to genetic and environmental factors, however, the relationship between air pollution and RA is still hotly debated. Further investigation of the relationship between air pollution and rheumatoid arthritis is conducive to a comprehensive understanding of the risk factors of the disease, providing certain value for the clinical prevention and treatment of RA. We used a Two-Sample Mendelian Randomization approach, integrating the large-scale public genomewide association study, to assess the genetically predicted causal effect of air pollution (including: PM2.5, PM2.5-10, PM10, nitrogen dioxide, nitrogen oxides) on RA in European and European East Asian populations, respectively. Indicators related to air pollution (2,505 individuals to 423,796 individuals), including European and East Asian populations were obtained from the Integrative Epidemiology Unit open GWAS project. Published East Asian RA data were also obtained from the IEU open GWAS project (212,453 individuals), while large-scale publicly available European RA data were obtained from finngen R10 (13,621 cases and 262,844 controls). Inverse variance weighting was used as the primary analytical method, complemented by MR-egger, Weighed median, and Weighted mode results. Cochran Q tested for heterogeneity, and MR-Egger regression analyses were performed to test for multiplicity. leave-one-out analysis allowed for the robustness and reliability were assessed. No statistically significant effects of PM2.5, PM2.5-10, PM10, nitrogen dioxide, nitrogen oxides and RA were observed in either European or East Asian populations. Results from European data: PM2.5 (IVW OR: 0.71; 95% CI: 0.27-1.91; p = 0.498; number of SNPs: 5), PM2.5-10 (IVW OR: 1.20; 95% CI: 0.61-2.40; p = 0.596; number of SNPs: 15), PM10 (IVW OR: 1.69; 95% CI: 0.84-3.39; p = 0.142; number of SNPs: 9), nitrogen dioxide (IVW OR: 3.88; 95% CI: 0.19-77.77; p = 0.375; number of SNPs: 2), nitrogen oxides (IVW OR: 0.51; 95% CI: 0.16-1.67; p = 0.268; number of SNPs: 4). East Asian data results: PM2.5 (IVW OR: 1.16; 95% CI: 0.98-1.38; p = 0.086; number of SNPs: 4), PM2.5-10 (IVW OR: 1.14; 95% CI: 0.95-1.38; p = 0.166; number of SNPs: 2), PM10 (IVW OR: 0.95; 95% CI: 0.81-1.11; p = 0.503; number of SNPs: 3), nitrogen dioxide (IVW OR: 0.87; 95% CI: 0.76-1.00; p = 0.051; number of SNPs: 6), nitrogen oxides (IVW OR: 0.96; 95% CI: 0.82-1.14; p = 0.671; number of SNPs: 3). No signs of pleiotropy or heterogeneity were observed in the MR-Egger intercept, MR-PRESSO and Cochrane's Q (p>0.05). In addition, no outliers were found in the MR-PRESSO analysis. The results were further validated by leave-one-out tests, confirming the robustness of the findings. We performed transethnic MR analysis suggesting that there may not be a genetically predicted causal relationship between air pollution and RA.

Anti-arthritic studies of ethnomedicine Gaultheria trichophylla Royle extract and salicylate-rich fraction using complete Freud's adjuvant-induced rats: molecular docking and network pharmacology analysis.

Gaultheria trichophylla Royle is a traditional treatment for inflammatory conditions including arthritis. The objective was to evaluate the anti-arthritic activity of the extracts and salicylate-rich fractions through adjuvant-induced arthritis, histopathological analysis, radiological imaging, hematological, biochemical parameters along with using bioinformatic tools. In vivo anti-arthritic efficacy of the extract and SRF (at 100, 200, 300, and 150mg/kg doses) was assessed using healthy albino rats. Molecular docking of identified compounds along with network pharmacology analysis helped to determine the route of action of drug. Both the extract and SRF showed dose-dependent anti-arthritic activity by decreasing the joint diameter, increase in pain threshold and body weight compared with negative control group. Along with SRF (150mg/kg), EEGT (300 and 200mg/kg) shows significant (P < 0.01) anti-arthritic activity by lowering levels of WBC, platelets, serum C-reactive protein (CRP), and rheumatoid factor (RF) and raising levels of RBC and Hb. The modified biochemical measures (AST, ALT, ALP, and total protein level) further supported the anti-arthritic action. Histopathology and radiology study showed that EEGT (300 and 200mg/kg), SRF (150mg/kg) and diclofenac (10mg/kg) inhibited joint destruction. GCMS analysis showed the presence of methyl salicylate, sitosterol, calcifediol, and ergosta-5,22-dien-3-ol, acetate as important bioactive constituents. Moreover, as the significant node in the pharmacology network and docking against TNF-α, a classical therapeutic target in RA showed potential of G. trichophylla in treatment of RA. The results showed that G. trichophylla have effectively reduced the inflammation of the joints.

Is Baricitinib Effective and Safe for Patients with Difficult-to-Treat Rheumatoid Arthritis? Comparative Data with the Rheumatoid Arthritis Group of Rheumatoid Arthritis Not Difficult to Treat

Objective: This study investigates the efficacy and safety of baricitinib, an oral targeted synthetic disease-modifying antirheumatic drugs (DMARDs), in patients with difficult-to-treat rheumatoid arthritis (D2T RA) compared to those without, aiming to determine its potential as an alternative treatment for D2T RA. Subject and Methods: A total of 78 patients participated in this retrospective cohort study, with 33 meeting the D2T RA criteria and 45 in the non-D2T RA group. Various clinical and laboratory parameters, adverse events, and disease activity indices were assessed, alongside drug efficacy and survival rates. Results: Patients with D2T RA exhibited higher seronegativity, prior use of b-DMARDs and c-DMARDs, and longer disease duration. Both groups experienced reductions in VAS and DAS28 scores, as well as SDAI, CDAI, HAQ, CRP, and ESR levels at baseline and 3, 6, and 12 months post-baricitinib initiation, with sustained efficacy observed over 12 months. The most prevalent adverse event was infection (28.21%). Although initial drug survival rates were similar between groups, the non-D2T RA group demonstrated higher rates at 24 months (46.70% vs. 59.40%). Subgroup analyses showed comparable survival rates between D2T RA and non-D2T RA groups, whether treated with baricitinib alone or in combination with methotrexate or leflunomide. Conclusion: Despite potential treatment resistance, patients meeting the D2T RA criteria shared similar safety and efficacy profiles with those non-D2T RA. Baricitinib emerges as a promising treatment option for D2T RA patients, offering effectiveness and safety comparable to the non-D2T RA group.

Advances in Phytochemical-Based Nanocarrier Approaches for Rheumatoid Arthritis: Challenges and Scope for Future-generation Formulations

The study aims to investigate and assess the effectiveness of current novel techniques for the preparation of an efficient nanocarrier system in resolving the drawbacks associated with the delivery of herbal bioactives to treat rheumatoid arthritis. Systematic utilization of various search engines like Science Direct, Pubmed, Shodhganga, Google Scholar, and Google Patent databases based on various sets of key phrases has been performed. All the findings from these data have been studied and briefed based on their relevant and irrelevant information. The current study summarizes the existing research and development of new nano-formulations with a focus on herbal bioactive compounds for treating rheumatoid arthritis. Physicochemical properties of phytoconstituents, such as low aqueous solubility, low permeation coefficient, and chemical instability, poor bioavailability, short plasma half-life, and ultimately sub-therapeutic efficacy, limit their clinical translation despite their great potency. The utilization of Phytochemical-Based Nanocarrier Approaches for rheumatoid arthritis can be a milestone as a major population is affected by this disease worldwide. The intensive study recapitulates that novel drug delivery systems can provide new opportunities to efficiently deliver herbal bioactives with improved pharmacokinetic and pharmacodynamic properties. The exhaustive study concluded that transferosomes, ethosomes, transethosomes, niosomes, phytosomes, Solid Lipid Nanoparticles (SLN), Nano Lipid Carriers (NLC), bilosomes and hylurosomes are some of the efficient nanocarrier systems that may impart numerous benefits to the delivery of herbal bioactives for treatment of RA. These nanocarrier systems fabricated with phytoconstituents flaunt the evident promising benefits of improved aqueous solubility, low first-pass metabolism with upgraded bioavailability, sustained release action, resistance to enzymatic degradation etc. providing support in rheumatoid arthritis recovery. This review discusses that the upgradation of the pharmacological action and other relevant issues of herbal bioactives are possible by utilizing novel drug delivery systems, resulting in successful development of nano-loaded herbal bioactives. It also focuses on highlighting the pioneering progression in the field of herbal bioactives-loaded nanocarrier systems for rheumatoid arthritis both in vitro and in vivo along with their advanced preparation methods and applications and discussing the opportunities for further prospects. This compiled informative review will enlighten various researchers in the field of delivering herbal bioactives for rheumatoid arthritis.

Significant decrease of osteoporosis and osteoporotic fractures in rheumatoid arthritis within a period of 24 years: experiences of a single centre

ObjectivesRheumatoid arthritis (RA) is associated with an increased risk for osteoporosis and osteoporotic fractures. Since the treatment of RA has improved significantly in recent years, we can expect RA-associated osteoporosis...

Identification of critical genes and metabolic pathways in rheumatoid arthritis and osteoporosis toward drug repurposing

BackgroundRheumatoid arthritis (RA) and osteoporosis (OP) are considered to be complex diseases. In recent studies, a positive association between RA and OP has been reported triggering growing research interest. This study aims to investigate the drugs related to critical genes in RA and OP, using bioinformatics approaches, toward drug repurposing. MethodRA and OP genes were identified. The RA–OP PPI network was constructed and analyzed using the STRING and Cytoscape, respectively. Hub genes and modules were extracted and enriched Gene Ontology, through the WebGestalt and g:Profiler. The identification of the drugs related to critical genes using the DGIDB, and extracted the miRNAs using miRWalk and miRNet. ResultsBy network clustering, five significant modules were obtained that have important roles in the immune system. IL6, TNF, IL1B, STAT3, TGFB1, TP53, HIF1A, CCL2, IL10, and MMP9 were found as the top 10 hub genes in the RA-OP network. Hub genes were shown to have implications in inflammatory response, significant functions in cytokine receptor binding, and localized mostly in extracellular space. By investigating the drugs related to hub genes, 16 drugs were identified as repurposing candidate drugs. The 10 drugs included Hydroxychloroquine, Infliximab, Adalimumab, Etanercept, Certolizumab, Cyclosporine, Diacerein, Gevokizumab, Canakinumab, and Olokizumab proposed for OP. Also, six drugs including Pirfenidone, Pentoxifylline, Vadimezan, Rilonacept, Metelimumab, and Siltuximab have important roles in inflammatory control and were proposed for both RA and OP. ConclusionsThe results of the present study can provide novel insights into the pathogenesis and treatment of RA and OP.

A double-blind, placebo-controlled, randomized multiple dose phase 1b trial of a CDK4/6 inhibitor, TCK-276, in patients with active rheumatoid arthritis.

The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics, and efficacy (as an exploratory endpoint) of TCK-276, a novel CDK4/6 inhibitor, after multiple oral doses for 7 days in patients with active RA. This multicentre, randomized, placebo-controlled, dose-ascending, double-blind, phase 1b, multiple-dose study included 32 patients with active RA in 4 cohorts of 8 patients (6 active and 2 matching placebo), each receiving an oral dose of TCK-276 or matching placebo for 7 days (once daily). The doses of TCK-276 were 10, 25, 75, and 175 mg/day. Safety and pharmacokinetic endpoints, and exploratory disease activity parameters for RA were assessed. There were no deaths, serious adverse events, notable clinically meaningful laboratory findings (including hematological changes), clinically meaningful vital sign changes, or clinically meaningful electrocardiogram or cardiac telemetry changes. TCK-276 was rapidly absorbed and the half-life time ranged approximately from 6 to 12 hours. No obvious accumulation was observed, and the increase in TCK-276 exposure was dose proportional. At day 7, DAS28-CRP responses (EULAR good or moderate responses) were observed in 40%, 80%, and 66.7% at 25, 75, and 175 mg/day TCK-276, respectively, versus 12.5% in placebo; ACR20 responses were 33.3%, 60%, and 50% respectively, versus none in placebo. TCK-276 (≤175 mg) was well tolerated with no clinically meaningful safety signals in patients with active RA. Together with the preliminary efficacy (≥25 mg/day), these data warrant further study of TCK-276 for the treatment of active RA. ClinicalTrails.gov, NCT05437419.

Therapeutic Applications and Challenges of a Widely Used Antifolate Drug

Introduction and purpose: Methotrexate (MTX) is an antifolate metabolite that interferes with the synthesis and repair of DNA and with cell replication. It has anti-inflammatory and immunomodulatory properties and was first used in 1951 for the treatment of RA and psoriasis. Methotrexate (4-amino-10-methylfolic acid, MTX) is a popular disease-modifying drug for the treatment of rheumatoid arthritis, psoriasis and leukaemia. MTX is an antagonist of folic acid, primarily through inhibition of the proliferative effect. MTX and its metabolites are associated with many serious adverse effects, including gastrointestinal and hepatic toxicity, myelosuppression, stomatitis, etc. Taking methotrexate may contribute to a reduction in the quality of life for patients. Additionally, long-term use of methotrexate requires regular monitoring, which can be burdensome and stressful for patients. In this context, different approaches have been used to improve the therapeutic properties of MTX and to reduce its adverse effects. The long history of the drug has made it possible to assess its efficacy and to collect data on adverse events, including potentially life-threatening adverse events. This article aims to provide a literature-based overview of current knowledge about methotrexate in clinical practice. Materials and Methods: Review and summary of research studies available in open-source format on Google Scholar, PubMed. Conclusion: The result is a picture of methotrexate as a drug that is used for many conditions, but is associated with many side effects that can be a significant problem for patients and healthcare professionals.