Efficacy In Treatment Of Rheumatoid Arthritis Research Articles

Triptolide regulates neutrophil function through the Hippo signaling pathway to alleviate rheumatoid arthritis disease progression

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammatory changes in the joints, the etiology of which is unclear. It is now well established that regulated cell death (RCD) and migration of neutrophils play an important role in the pathogenesis of RA. Tripterygium wilfordii Hook.f (TwHF) is a total saponin extracted from the root of Tripterygium wilfordii Hook.f, a plant of the family Wesleyanaceae, which has strong anti-inflammatory and immunomodulatory effects and has been used as a basic drug in the clinical treatment of RA. Despite the good efficacy of TwHF treatment, the mechanism of action of TwHF remains unclear. Several studies have demonstrated that the drug tripterygium glycosides, in which TwHF is the main ingredient, has achieved excellent efficacy in the clinical treatment of RA. Investigations have also found that TwHF can affect cellular RCD, cell migration, cell proliferation, and the apoptosis-related Hippo signaling pathway. In this study, we first analyzed the RCD and migration differences of neutrophils in patients with RA through network pharmacology and transcriptome analysis. Subsequently, we used electron microscopy, immunofluorescence, and other methods to identify the RCD phenotype of neutrophils. In collagen-induced arthritis (CIA) model, we demonstrated that Triptolide (the main active ingredient in TwHF) could alleviate the progression of arthritis by reducing the bone destruction and the infiltration of neutrophils. Furthermore, in vitro experiments showed that Triptolide induced neutrophil apoptosis, inhibited the formation of neutrophil extracellular traps (NETs), and impeded the neutrophil migration process in a Hippo pathway-dependent manner. Taken together, these findings indicate that Triptolide has potential for treating RA and provide theoretical support for the clinical application of TwHF, as a traditional Chinese medicine, in RA.

Bitongqing Attenuates CIA Rats by Suppressing Macrophage Pyroptosis and Modulating the NLRP3/Caspase-1/GSDMD Pathway.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis and inflammatory cell infiltration. The traditional Chinese medicine prescription, Bitongqing (BTQ) exhibited significant efficacy in the clinical treatment of RA. However, the potential therapeutic mechanisms of BTQ in treating RA have not been fully investigated. This study aims to elucidate the effect of BTQ on collagen-induced arthritis (CIA) rat macrophage pyroptosis, providing a theoretical basis for treating RA. This research employed liquid chromatography-mass spectrometry (LC-MS) to identify the primary components of BTQ. The therapeutic effects of BTQ were evaluated in a rat model of CIA. In vivo experiments were conducted using pathohistological staining, immunofluorescence, micro-CT, and Western blotting. Next, Mouse leukemia cells of monocyte macrophage cells (RAW264.7) were induced to undergo pyroptosis using lipopolysaccharide (LPS) and adenosine triphosphate (ATP), and the impact of BTQ on RAW264.7 macrophages was assessed through cell viability, immunofluorescence analysis, lactate dehydrogenase (LDH) secretion measurement, and Western blotting. BTQ had a therapeutic effect on CIA rats, which was mainly manifested as a reduction in joint inflammation, foot swelling, bone erosion, and amelioration of pathological changes in these rats. Further studies revealed that BTQ inhibited the levels of cytokine production interleukin-18 (IL-18) and interleukin-1β (IL-1β), and likewise, it inhibited the expression of key proteins in the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) mediated pyroptosis in the synovial tissues of CIA rats. The results of in vitro experiments demonstrated that BTQ attenuated LDH secretion, decreased IL-18 and IL-1β cytokine production, and downregulated expression of key proteins involved in the NLRP3-mediated pyroptosis on RAW264.7 macrophages. The therapeutic potential of BTQ in CIA lies in its ability to inhibit NLRP3-mediated macrophage pyroptosis, thereby suggesting a promising strategy for the treatment of RA.

Jin-Gu-Lian Capsule Did Not Significantly Improve Clinical Value in Rheumatoid Arthritis Therapy: A Real-World Study.

To investigate the clinical value of adding Jin-gu-lian (JGL) capsules into rheumatoid arthritis (RA) treatment by examining its impact on disease activity and quality of life (QoL) through a real-world study (RWS). RWS was conducted to compare the inflammatory markers, including IgM-RF, ESR, and CRP, between RA patients treated with only Western medicine (reference group) and Western medicine plus JGL (study group) during one-year follow-up. The clinical data was acquired from the hospital information system (HIS). Telephone call-based follow-up on QoL (SF-36) and accompanying symptoms, including gastrointestinal complaints, attacks of pneumonia, herpes zoster, URTIs, UTIs, and LTBIs. Finally, the anti-rheumatic drugs given to both groups were also compared. RWS was further validated for its feasibility by performing studies with hydroxychloroquine (HCQ) treatment, which is a commonly used anti-rheumatic drug for RA with mild effect. The study group failed to show a significant effect on inflammatory markers, especially on the CRP levels, indicating no additional clinical value of supplementing with JGL. Similarly, at the endpoint, no significant differences between the two groups on QoL and related symptoms were observed. Our study suggests that the patients in the study group might need more anti-rheumatic drugs to fill the treatment insufficiency, and the application ratio of NSAIDs would be significantly higher than the reference group. By conducting this study on HCQ treatment, the positive aspects of controlling disease activity and reducing NSAIDs application were found, which demonstrates the utility of performing the RWS to evaluate the effect of JGL. Adding JGL did not significantly improve the clinical efficacy of RA treatment by this RWS. Folk herbal prescriptions such as JGL are suggested to underwent strict clinical trials before application.

Advances in the implications of the gut microbiota on the treatment efficacy of disease-modifying anti-rheumatic drugs in rheumatoid arthritis.

Alterations in the composition or function of the gut microbiota are associated with the etiology of human diseases. Drug-microbiota interactions can affect drug bioavailability, effectiveness, and toxicity through various routes. For instance, the direct effect of microbial enzymes on drugs can either boost or diminish their efficacy. Thus, considering its wide range of metabolic capabilities, the gut microbiota is a promising target for pharmacological modulation. Furthermore, drugs can alter the microbiota and the mechanisms by which they interact with their host. Individual variances in microbial profiles can also contribute to the different host responses to various drugs. However, the influence of interactions between the gut microbiota and drugs on treatment efficacy remains poorly elucidated. In this review, we will discuss the impact of microbiota dysbiosis in the pathogenesis of rheumatoid arthritis (RA), and we will attempt to elucidate the crosstalk between the gut microbiota and disease-modifying anti-rheumatic drugs (DMARDs), with an emphasis on how drug-microbiota interactions affect the treatment efficacy in RA. We speculate that improved knowledge of these critical interactions will facilitate the development of novel therapeutic options that use microbial markers for predicting or optimizing treatment outcomes.

A novel multi-biomarker combination predicting relapse from long-term remission after discontinuation of biological drugs in rheumatoid arthritis

Biological disease modifying anti-rheumatic drugs (bDMARDs) show dramatic treatment efficacy in rheumatoid arthritis (RA). Long-term use of bDMARDs, however, has disadvantages such as high costs and infection risk. Therefore, a methodology is needed to predict any future RA relapse. Herein, we report a novel multi-biomarker combination which predicts relapse after bDMARDs-withdrawal in patients in remission. Forty patients with RA in remission for more than 12 months were enrolled. bDMARDs were withdrawn and they were followed monthly for the next 24 months. Fourteen patients (35%) of 40 in the cohort remained in remission at 24 months, whereas 26 (65%) relapsed at various time-points. Serum samples obtained longitudinally from patients in remission were assessed for the relapse-prediction biomarkers and index from 73 cytokines by the exploratory multivariate ROC analysis. The relapse-prediction index calculated from the 5 cytokines, IL-34, CCL1, IL-1β, IL-2 and IL-19, strongly discriminated between patients who relapsed and those who stayed in remission. These findings could contribute to clinical decision-making as to the timing of when to discontinue bDMARDs in RA treatment.

Reshaping the Inflammatory Environment in Rheumatoid Arthritis Joints by Targeting Delivery of Berberine with Platelet‐Derived Extracellular Vesicles

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction. Herein, an inflamed joint‐targeting delivery platform is developed based on platelet‐derived extracellular vesicles (PEVs) that are naturally occurring nanoparticles released by platelets, loaded with berberine (BBR) for suppressing the progress of RA. It is found that PEVs could selectively target the inflamed arthritis site in RA mice. In addition, BBR‐loaded PEVs exert anti‐inflammatory effects by reshaping the inflammatory environment in affected joints. It is shown that intravenous injection of BBR‐loaded PEVs into RA mice can effectively reduce joint swelling and bone erosion and restore mobility compared with free drug therapy. This strategy can effectively enhance the efficacy of RA treatment with limited side effects.

Systems approach for classifying the response to biological therapies in patients with rheumatoid arthritis in clinical practice

IntroductionBiological therapies have greatly improved the treatment efficacy in rheumatoid arthritis (RA). However, in clinical practice a significant proportion of patients experience an inadequate response to treatment. The aim of this study is to classify responding and non-responding rheumatoid arthritis patients treated with biological therapies, based on clinical parameters and symptoms used in Western and Chinese medicine. MethodsCold and Heat symptoms assessed by a Chinese medicine (CM) questionnaire and Western clinical data were collected as baseline data, before initiating biological therapy. Categorical principal components analysis with forced classification (CATPCA-FC) approach was applied to the baseline data set to classify responders and non-responders. ResultsIn this study, 61 RA patients were characterized using a CM questionnaire and clinical measurements. The combination of baseline symptoms (‘preference for warm food’, ‘weak tendon severity’) and clinical parameters (positive rheumatoid factor/anti-cyclic citrullinated peptide antibody, C-reactive protein, creatinine) were able to differentiate responders from non-responders to biological therapies with a positive predictive value of 82.35% and a misclassification rate of 24.59%. Adding CM symptom variables in addition to clinical data did not improve the classification of responders, but it did show 8.3% improvement in classifying non-responders. ConclusionsNo significant differences were found between the three classification models. Adding CM symptoms to the clinical parameters in the combined model improved the classification of non-responders. Although this improvement is not significant in the current study, we consider it worthwhile to further investigate the potential of adding symptom variables for improving treatment efficacy.

High-Frame-Rate Power Doppler Ultrasound Is More Sensitive than Conventional Power Doppler in Detecting Rheumatic Vascularisation

Early recognition of joint inflammation will increase treatment efficacy in rheumatoid arthritis (RA). Yet, conventional power Doppler (PD) ultrasound might not be sufficiently sensitive to detect minor inflammation. We investigated the sensitivity of high-frame rate Doppler, combined with singular value decomposition technique, to suppress tissue signals, for microvascular flow in a flow phantom setup and in a proof-of-principle study in healthy controls and in RA patients with different disease activities. In the flow phantom, minimal detectable flow velocity was a factor 3 lower with high-frame-rate PD than with conventional PD ultrasound. In the proof-of-principle study we detected a positive PD signal in all volunteers, diseased or healthy, with high-frame-rate PD ultrasound. We saw a gradual increase in PD signal in RA patients depending on disease activity. In conclusion, high-frame rate Doppler is more sensitive in detecting vascularisation than conventional PD ultrasound.

Application of 1H NMR-based serum metabolomic studies for monitoring female patients with rheumatoid arthritis

Rheumatoid arthritis is a chronic autoimmune-based inflammatory disease that leads to progressive joint degeneration, disability, and an increased risk of cardiovascular complications, which is the main cause of mortality in this population of patients. Although several biomarkers are routinely used in the management of rheumatoid arthritis, there is a high demand for novel biomarkers to further improve the early diagnosis of rheumatoid arthritis, stratification of patients, and the prediction of a better response to a specific therapy.In this study, the metabolomics approach was used to provide relevant biomarkers to improve diagnostic accuracy, define prognosis and predict and monitor treatment efficacy. The results indicated that twelve metabolites were important for the discrimination of healthy control and rheumatoid arthritis. Notably, valine, isoleucine, lactate, alanine, creatinine, GPC APC and histidine relative levels were lower in rheumatoid arthritis, whereas 3-hydroxyisobutyrate, acetate, NAC, acetoacetate and acetone relative levels were higher. Simultaneously, the analysis of the concentration of metabolites in rheumatoid arthritis and 3 months after induction treatment revealed that L1, 3-hydroxyisobutyrate, lysine, L5, acetoacetate, creatine, GPC+APC, histidine and phenylalanine were elevated in RA, whereas leucine, acetate, betaine and formate were lower. Additionally, metabolomics tools were employed to discriminate between patients with different IL-17A genotypes.Metabolomics may provide relevant biomarkers to improve diagnostic accuracy, define prognosis and predict and monitor treatment efficacy in rheumatoid arthritis.

SAT0090 Depression Recovery Improves the Efficacy of Rheumatoid Arthritis Treatment

Backgroundthe prevalence of stress-related depressive and anxiety disorders in rheumatoid arthritis (RA) patients (pts) is very high. Their associations with disease activity and chronic pain confirmed in several studies related...

AB0346 Safety and efficacy of rheumatoid arthritis treatment with modified-release prednisone (mr-pdn), experience in “real life”.

BackgroundGlucocorticoids (GC) are commonly used for rheumatoid arthritis (RA) treatment with concerns about their side effects. A modified-release formulation of prednisone (MR-PDN) allows the release of the drug during the...

AB0519 Auto-antibody titers for monitoring rituximab therapy in rheumatoid arthritis

BackgroundMonitoring auto-antibody titers has been suggested as a means of assessing treatment efficacy in rheumatoid arthritis (RA) patients. Several studies evaluated the effect of anti-TNF antagonist treatment on auto-antibody titers...

Genome‐wide association study of genetic predictors of anti–tumor necrosis factor treatment efficacy in rheumatoid arthritis identifies associations with polymorphisms at seven loci

ObjectiveAnti–tumor necrosis factor (anti-TNF) agents are successful therapies in rheumatoid arthritis (RA); however, inadequate response occurs in 30–40% of patients treated. Knowledge of the genetic factors that influence response may facilitate personalized therapy. The purpose of this study was to identify genetic predictors of response to anti-TNF therapy in RA and to validate our findings in independent cohorts.MethodsData from genome-wide association (GWA) studies were available from the Wellcome Trust Case Control Consortium for 566 anti-TNF–treated RA patients. Multivariate linear regression analysis of changes in the Disease Activity Score in 28 joints at 6 months was conducted at each single-nucleotide polymorphism (SNP) using an additive model. Associated markers (P < 10−3) were genotyped in 2 independent replication cohorts (n = 379 and n = 341), and a combined analysis was performed.ResultsOf 171 successfully genotyped markers demonstrating association with treatment response in the GWA data, 7 were corroborated in the combined analysis. The strongest effect was at rs17301249, mapping to the EYA4 gene on chromosome 6: the minor allele conferred improved response to treatment (coefficient −0.27, P = 5.67−05). The minor allele of rs1532269, mapping to the PDZD2 gene, was associated with a reduced treatment response (coefficient 0.20, P = 7.37−04). The remaining associated SNPs mapped to intergenic regions on chromosomes 1, 4, 11, and 12.ConclusionUsing a genome-wide strategy, we have identified and validated the association of 7 genetic loci with response to anti-TNF treatment in RA. Additional confirmation of these findings in further cohorts will be required.

Análisis farmacoeconómico de Metoject ® en el tratamiento de la artritis reumatoide en España

Objectives The aim of this study was to compare the clinical and economic consequences of using subcutaneous methotrexate (Metoject ®) with respect to oral methotrexate in the management of rheumatoid arthritis (RA) in Spain. Methods A cost-effectiveness analysis was performed to compare early treatment of RA using a Markov model. The model allowed us to estimate long term efficacy of RA treatment based on data from the literature and expert opinion, and to combine this data with costs of managing RA in Spain. The perspective of the study was from the National Health System point of view, using a time horizon of 5 years and patient lifetime. All costs were expressed in 2009 euros and a 3% discount rate was applied. Results The cost (only pharmacologic costs) per quality-adjusted life year (QALY) gained with Metoject ® went from 25,173 to 35,807 € at 5 years and from 19,056 to 25,351 € for patient lifetime. When direct costs in RA treatment were considered, it was observed that cost-effectiveness at 5 years went from 29,682 to 42,175 €/QALY gained, and for patient lifetime from 22,514 to 29,848 €/ QALY gained. Conclusions Additional costs of Metoject ® with respect to oral methotrexate would be offset by their improved effectiveness, expressed in QALY, showing that Metoject ® could be a cost-effective treatment option for RA in the Spanish Health System assuming a spanish threshold.

Bone ankylosis of the wrist as a possible indicator of treatment efficacy in rheumatoid arthritis

Bone ankylosis of the wrist as a possible indicator of treatment efficacy in rheumatoid arthritis

Pharmacoeconomic analysis of Metoject® in the treatment of rheumatoid arthritis in Spain

ObjectivesThe aim of this study was to compare the clinical and economic consequences of using subcutaneous methotrexate (Metoject®) with respect to oral methotrexate in the management of rheumatoid arthritis (RA) in Spain. MethodsA cost-effectiveness analysis was performed to compare early treatment of RA using a Markov model. The model allowed us to estimate long term efficacy of RA treatment based on data from the literature and expert opinion, and to combine this data with costs of managing RA in Spain. The perspective of the study was from the National Health System point of view, using a time horizon of 5 years and patient lifetime. All costs were expressed in 2009 euros and a 3% discount rate was applied. ResultsThe cost (only pharmacologic costs) per quality-adjusted life year (QALY) gained with Metoject® went from 25,173 to 35,807 € at 5 years and from 19,056 to 25,351 € for patient lifetime. When direct costs in RA treatment were considered, it was observed that cost-effectiveness at 5 years went from 29,682 to 42,175 €/QALY gained, and for patient lifetime from 22,514 to 29,848 €/QALY gained. ConclusionsAdditional costs of Metoject® with respect to oral methotrexate would be offset by their improved effectiveness, expressed in QALY, showing that Metoject® could be a cost-effective treatment option for RA in the Spanish Health System assuming a spanish threshold.

The evolution of biomarkers in rheumatoid arthritis: From clinical research to clinical care

Background: Treatment efficacy in rheumatoid arthritis (RA) has been measured by clinical response, gross radiological results and some biochemical markers. With the new biologic treatments, markers for disease development, progress, severity and therapy response have evolved. Objectives: This review focuses on a selection of current markers and the need for better markers for determining RA treatment susceptibility and success. Methods: A review of the literature was conducted and expert opinions expressed. Results/conclusion: Current biomarkers mainly focus on disease activity and severity. Biomarkers for treatment response and susceptibility that help clinicians make initial treatment decisions are lacking or insufficient, yet required for optimal control of RA. A combination of biomarkers is necessary to classify a complex immune disease, such as RA.

The effect of 3435C&gt;T MDR1 gene polymorphism on rheumatoid arthritis treatment with disease-modifying antirheumatic drugs

Rheumatoid arthritis (RA) is a multifactorial disease, with immunological, genetical as well as environmental factors being implicated in its pathogenesis. Treatment of RA is based mainly on drugs modulating the course of the disease, e.g. methotrexate (MTX) or sulfasalazine (SL). The MDR1 gene product, P-glycoprotein (P-gp), is probably one of the most important and best defined transporters for drug delivery in humans. P-gp transports a wide range of substrates with diverse chemical structures, among them anticancer agents, cardiac drugs, and immunosuppressants. The aim of this study was to examine the effect of the 3435C>T MDR1 gene polymorphism on the efficacy of RA treatment with disease-modifying antirheumatic drugs, i.e. MTX plus methylprednisolone (MP), and SL. The study was carried out on 255 patients with RA treated according to two regimes: (1) MTX (7.5-15.0 mg weekly) plus low doses of MP (n=174), (2) SL (1.5-3 g daily, n=81). The probability of remission of RA symptoms after MTX plus MP therapy was 4.65-fold higher in carriers of the TT genotype compared to patients with CC genotype (P=0.003, OR 4.65, 95%CI 1.66-13.05), whereas the probability of remission of RA symptoms in patients treated with SL was 2-fold higher in carriers of TT genotype compared to patients with CC genotype, but did not reach statistical significance (P=0.358, OR=2.00 95% CI=0.58-6.87). The results from the present study suggest that the 3435C>T MDR1 gene polymorphism may influence the efficacy of RA therapy with disease-modifying antirheumatic drugs.