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ID PMID Title PublicationDate abstract
34257850 Comprehensive Medical Analysis of Clinical Diseases and Syndromes Based on Rheumatoid Fact 2021 Rheumatoid arthritis bothers people. According to statistics, the prevalence of rheumatoid arthritis represents about 3% of the world's population. Rheumatoid factors can interfere with immune blood cells, which is very harmful to human health. In order to solve the damage of rheumatoid factor to health and study its influence on immune blood cells, this paper constructs a case template through case investigation of rheumatoid arthritis patients and creates damage assessment matrix by using comprehensive quantitative and qualitative analysis. The horizontal coupling degree between rheumatoid factor and interference of blood cell system is investigated, and the relationship between them is studied. The experimental results show that there is a correlation between rheumatoid factor and immune blood cells, the correlation coefficient is 0.87, the presence of rheumatoid factor in blood cells, and the cell system damage rate is about 30% higher than that without rheumatoid factor; the study found that there is a great difference in the age of rheumatoid factor in the population, and the age of patients is generally above 45 years old. This shows that rheumatoid factor can cause great damage to immune blood cell system and affect people's health level.
33674988 Effects of melatonin supplementation on disease activity, oxidative stress, inflammatory, 2021 Sep OBJECTIVE: Considering the pathologic significance of inflammation and oxidative stress in rheumatoid arthritis (RA) as well as the antioxidant, anti-inflammatory and hypolipidemic effects of melatonin, the current research is designed to investigate the effect of melatonin supplementation on disease activity, oxidative stress, inflammatory, and metabolic parameters in RA patients. METHODS: In this randomized double-blind, placebo-controlled trial, 64 RA cases were selected and randomly assigned into 2 groups to take 6 mg/day melatonin or placebo for 12 weeks. Before and after trial, serum malondialdehyde (MDA), total antioxidant capacity (TAC), erythrocyte sedimentation rate (ESR), lipid profile, fasting blood sugar (FBS), and insulin levels were measured and disease activity was determined by disease activity score-28 (DAS-28). RESULTS: Compared to the baseline, melatonin significantly decreased DAS-28, ESR, MDA, and LDL-C by 50.5%, 59%, 97%, and 13%, respectively (P<0.001) and significantly increased TAC by 89% (P=0.013) and HDL-C by 22% (P<0.001). After treatment, considerable differences were only seen between the two groups in serum MDA (P<0.001) and LDL-C (P=0.007) concentrations, adjusted for baseline measures. Moreover, there were no significant changes in DAS-28, ESR, TAC, triglyceride, total cholesterol, HDL-C, FBS, and insulin levels compared to placebo group (P>0.05). CONCLUSIONS: Although melatonin supplementation had no beneficial effects on DAS-28, it could lower serum MDA and LDL-C levels. It seems that melatonin supplementation should not be used as a replace for routine drugs prescribed in RA treatment. Further investigations should be conducted to fully understand the effects of melatonin in RA. Key Points • Compared to baseline, melatonin significantly decreased DAS-28, ESR, MDA, and LDL-C and significantly increased TAC and HDL-C. • After treatment, considerable differences were only seen between melatonin and placebo groups in serum MDA and LDL-C concentrations. • After treatment, there were no significant changes in DAS-28, ESR, TAC, triglyceride, total cholesterol, HDL-C, FBS, and insulin levels compared to the placebo group.
33776015 Cardiac Tamponade During Tocilizumab Therapy in a Patient with Rheumatoid Arthritis and An 2021 Oct 15 Drug-induced lupus (DIL) is a drug-mediated immune reaction with the same symptoms as that of lupus erythematosus. We herein report the first case of tocilizumab-induced lupus syndrome presenting with cardiac tamponade. A 65-year-old man presented with cough, exertional dyspnea, and chest pain after 2 months of tocilizumab therapy for rheumatoid arthritis. Echocardiography revealed marked pericardial effusion. Antinuclear antibodies and anti-double-stranded deoxyribonucleic acid antibodies were positive. The diagnosis of cardiac tamponade due to tocilizumab-induced lupus syndrome was made. He had no recurrence of pericardial effusion after tocilizumab discontinuation. Clinicians should be alert for lupus syndrome in patients receiving tocilizumab.
34674083 Seroconversion of rheumatoid arthritis patients after yellow fever vaccination. 2022 Mar Vaccination is a current strategy used to prevent infections in patients with immune-mediated rheumatic diseases. However, the use of live-attenuated vaccines prepared from living microorganisms in these patients should be avoided due to the risk of acquiring infections. The present study aimed to investigate the effect of the yellow fever (YF) vaccine (a live-attenuated vaccine) in 12 patients with rheumatoid arthritis (RA). The sample comprised 12 patients (9 females and 3 males; mean age 52.2 ± 6.5 years) with RA, who inadvertently received fractionated 17D yellow fever vaccination during an outbreak of this disease. In this cohort, 10 were administered leflunomide; 7 were administered methotrexate; 6 were administered prednisone (median dose of 5.0 mg/day); 6 took biologic drugs; and 1 took tofacitinib. All but one patient (used rituximab, prednisone, and methotrexate) seroconverted. None of them developed clinical signs of infection after the procedure. The fractionated dose of the YF vaccine is effective and safe in the observed sample. Key Points • Patients with autoimmune inflammatory rheumatic diseases (AIIRD) are at a high risk of acquiring infections • The fractionated dose of the YF vaccine is effective and safe in the observed sample • Vaccination against YF should be avoided in patients with AIIRD under immunosuppression owing to the risks of inducing YF infection.
33771642 Deciphering the metabolic profile and pharmacological mechanisms of Achyranthes bidentata 2021 Jun 28 ETHNOPHARMACOLOGICAL RELEVANCE: Achyranthes bidentata Blume (AB) is a traditional Chinese medicine (TCM) widely used as a dietary supplement and anti-arthritis drug. Pharmacological studies have shown that Achyranthes bidentata Blume saponins (ABS) are the main bioactive ingredient. However, the metabolic profile and mechanisms of action of ABS against rheumatic arthritis (RA) remain to be established. AIM OF THE STUDY: Our main objective was to investigate the metabolic profile and pharmacological activities of ABS against RA. MATERIALS AND METHODS: In this study, an analytical method based on ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) coupled with a metabolism platform was developed for metabolic profiling of ABS in rat liver microsomes and plasma. Then, the in vivo metabolites of ABS and their targets associated with RA were used to construct the network pharmacological analysis. Gene ontology (GO) enrichment, KEGG signaling pathway analyses and pathway network analyses were performed. The therapeutic effect of ABS on RA was further evaluated using an adjuvant arthritis (AA) model and network pharmacology results validated via Western blot. RESULTS: Overall, 26 and 21 metabolites of ABS were tentatively characterized in rat liver microsomes and plasma, respectively. The metabolic pathways of ABS mainly included M+O, M+O-H(2), M+O(2), and M+O(2)-H(2). Data form network pharmacology analysis suggested that MAPK, apoptosis, PI3K-AKT and p53 signaling pathways contribute significantly to the therapeutic effects of ABS on RA. In pharmacodynamics experiments, ABS ameliorated the symptoms in AA rats in a dose-dependent manner and restored the homeostasis of pro/anti-inflammatory factors. Western blot results further demonstrated a significant ABS-induced decrease in phosphorylation of ERK in the MAPK pathway (P < 0.01). CONCLUSION: Application of an analytical method based on UPLC-QTOF/MS, network pharmacology and validation experiments offers novel insights into the components and mechanisms of ABS that contribute to its therapeutic effects against RA, providing useful directions for further research.
32948325 Adherence to biologic disease-modifying antirheumatic drugs in adult patients with rheumat 2021 Sep INTRODUCTION: The emergence of biologics has revolutionized the management of refractory rheumatic diseases (RD) by improving clinical outcomes. Unfortunately, the impact of non-adherence to the emerging therapy can limit their potential benefit. The objective of our study was to evaluate biologics' adherence in Tunisian patients with RD and to assess the determinants of non-adherence. METHODS: We conducted a cross-sectional study involving patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) treated with bDMARDs (biologic disease-modifying antirheumatic drugs) for at least three months. Socio-demographic, clinical and biological data were collected. Biologic adherence was assessed using the compliance questionnaire for rheumatology (CQR). RESULTS: One hundred patients with RD (45 RA and 55 SpA) were collected. Non-adherence to bDMARDs was found in 70% of cases. In univariate analysis, non-adherence to bDMARDs was statistically related to the absence of coxitis (P=0.003), to a low ASDAS-CRP (ankylosing spondylitis disease activity score) prior to the initiation of the bDMARDs (P=0.01), to a rate of administration of bDMARDs less than one injection per month (P=0.01), to the subcutaneous delivery route (P=0.02) as well as to non-adherence to csDMARDs (conventional disease-modifying antirheumatic drugs) (P=0.001). In multivariate analysis, the predictors of non-adherence were the absence of coxitis (OR=6.01; IC 95% [1.88-19.12]; P=0.002], and a rate of administration of bDMARDs less than one injection per month (OR=8.79; IC 95% [2.13-36.22]; P=0.003). CONCLUSION: This work has revealed the low rate of adherence to biological treatments in Tunisian patient with RD. Predictors of poor adherence were the absence of coxitis and a rate of administration of bDMARDs less than one injection per month. Detection of these factors could help us to adapt our strategies to improve adherence that are essentially based on therapeutic education program.
33404796 Immunomodulatory Effects of Curcumin in Rheumatoid Arthritis: Evidence from Molecular Mech 2021 Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disorder characterized by the destruction of the joint and bone resorption. The production of pro-inflammatory cytokines and chemokines, dysregulated functions of three important subtypes of T helper (T(H)) cells including T(H)1, T(H)17, and regulator T (Treg) cells are major causes of the initiation and development of RA. Moreover, B cells as a source of the production of several autoantibodies play key roles in the pathogenesis of RA. The last decades have seen increasingly rapid advances in the field of immunopharmacology using natural origin compounds for the management of various inflammatory diseases. Curcumin, a main active polyphenol compound isolated from turmeric, curcuma longa, possesses a wide range of pharmacologic properties for the treatment of several diseases. This review comprehensively will assess beneficial immunomodulatory effects of curcumin on the production of pro-inflammatory cytokines and also dysregulated functions of immune cells including T(H)1, T(H)17, Treg, and B cells in RA. We also seek the clinical efficacy of curcumin for the treatment of RA in several recent clinical trials. In conclusion, curcumin has been found to ameliorate RA complications through modulating inflammatory and autoreactive responses in immune cells and synovial fibroblast cells via inhibiting the expression or function of pro-inflammatory mediators, such as nuclear factor-κB (NF-κB), activated protein-1 (AP-1), and mitogen-activated protein kinases (MAPKs). Of note, curcumin treatment without any adverse effects can attenuate the clinical symptoms of RA patients and, therefore, has therapeutic potential for the treatment of the diseases.
33257093 Impact of a risk-sharing agreement in rheumatoid arthritis in Spain. 2021 Mar CONTEXT AND OBJECTIVE: Risk-sharing agreements(RSA) allow decision-makers to manage the uncertainty associated with effectiveness and costs of treatments. Our objective was to estimate the economic impact of RSA implementation on treatment of patients diagnosed with rheumatoid arthritis(RA) with certolizumab pegol(CZP) and assess the potential impact of alternative RSA. METHODS: Under original RSA, treatment with CZP was reimbursed when the response was optimal (DAS28 score <3.2) or satisfactory (DAS28 score ≥3.2 and reduction from baseline ≥1.2) at 12 weeks. Alternative RSA would additionally include a 50 % reimbursement for moderate responders(DAS28 score >3.2 and ≤5.1, and reduction from baseline between 0.6 and 1.2). We estimated average savings per patient for hospital's pharmacy service(HPS) at 12 weeks, taking into account the pharmacological cost of CZP. Uncertainty associated with effectiveness of CZP was assessed through 1000 Monte Carlo simulations. RESULTS: After 12 weeks of treatment, 57.8 % (n = 52) and 22.2 %(n = 20) of patients had optimal and satisfactory responses, respectively, and average disease activity improved by 1.77 points. Average savings for HPS amounted to 876.9€ and 706.4€ per patient under original and alternative RSA, respectively. Savings in simulated cohort reached 846.2€ and 681.8€ per patient, respectively, leading to estimated net savings for HPS of 846,209€ and 681,790€, respectively. CONCLUSIONS: RSA implementation on patients with RA treated with CZP has generated savings and improved efficiency within HPS.
33726867 Depressive symptoms are associated with impaired sleep, fatigue, and disease activity in w 2021 Mar 16 OBJECTIVES: To investigate the associations between sleep quality, fatigue, disease activity and depressive symptoms in women with rheumatoid arthritis (RA). METHODS: Female patients with previous diagnosis of RA from a Rheumatology Outpatient Clinic at a tertiary referral centre, in Fortaleza, Brazil, were consecutively recruited into the study. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI); fatigue by the Fatigue Severity Scale (FSS); daytime sleepiness by the Epworth Sleepiness Scale (ESS); and depressive symptoms by the Beck Depression Inventory II (BDI-II). RA activity was measured by the disease activity score (DAS28). RESULTS: One hundred ten women (mean age ± SD = 51.1 ± 13.0 y) were included in the study. On average, patients with depressive symptoms (BDI-II > 13), as compared to those without, showed poorer sleep quality (PSQI: 10.09 ± 4.1 vs 7.33 ± 3.55; p = 0.001 respectively), more fatigue (FSS: 4.69 ± 1.89 vs 3.34 ± 1.8; p = 0.001) and higher disease activity level (DAS28: 4.36 ± 1.53 vs 3.7 ± 1.39; p = 0,047). The logistic regression analysis showed that sleep quality is an independent predictor of depressive symptom severity. CONCLUSION: Depressive symptoms, impaired sleep and fatigue are common in women with RA. Poor sleep is associated with greater frequency and severity of depressive symptoms in these patients, suggesting that screening for sleep and mood problems may be relevant both in clinical research and routine patient care. Future studies investigating the impact of measures to promote healthy sleep on depressive symptom control in this patient population are warranted.
34733271 PADI4 Polymorphisms Confer Risk of Anti-CCP-Positive Rheumatoid Arthritis in Synergy With 2021 Peptidylarginine deiminases (PADs) catalyze citrullination, a post-translational modification playing a pathogenic role in anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). The interplay between single nucleotide polymorphisms (SNPs) in the PADI genes and known risk factors for ACPA-positive RA, including smoking, HLA-DR4 and -1, and the PTPN22 R620W polymorphism, was investigated. We typed four PADI2 SNPs, four PADI4 SNPs, and the PTPN22 R620W SNP in 445 Danish RA patients and 533 age-matched healthy controls, as well as in 200 North American RA patients and 100 age- and sex-matched controls. The HLA-DRB1 locus was typed in the Danish cohort. Logistic regression analyses, adjusted for age, sex, smoking status, and PTPN22 R620W, revealed increased risk of anti-CCP-positive RA in carriers of rs11203367(T) (OR: 1.22, p=0.03) and reduced risk in carriers of rs2240335(A) in PADI4 (OR: 0.82, p=0.04). rs74058715(T) in PADI4 conferred reduced risk of anti-CCP-negative RA (OR: 0.38, p=0.003). In HLA-DRB1*04-positive individuals, specifically, the risk of anti-CCP-positive RA was increased by carriage of PADI4 rs1748033(T) (OR: 1.54, p=0.007) and decreased by carriage of PADI4 rs74058715(T) (OR: 0.44, p=0.01), and we observed an interaction between these SNPs and HLA-DRB1*04 (p=0.004 and p=0.008, respectively) Thus, PADI4 polymorphisms associate with ACPA-positive RA, particularly in HLA-DRB1*04-positive individuals, and with ACPA-negative RA independently of HLA-DRB1*04.
33189451 Hypothesis: Rheumatoid arthritis and periodontitis: A new possible link via prolactin horm 2021 Jan Rheumatoid arthritis and periodontitis are two common chronic inflammatory diseases affecting human population worldwide. The association between the two conditions have been the focus of many researches, trying to explore the possible mechanisms underlying this association. Prolactin hormone, besides its known lactogenic effects acts as a cytokine secreted from various tissues other than the pituitary gland with multiple pleotropic actions in immunity and inflammation. Several data showed that prolactin levels are increased significantly in the synovial and periodontal tissues, and this increase is correlated with disease activity and tissue destruction. Our hypothesis suggests that local prolactin can represent a link between the two conditions. In this work, we suggest a possible mechanistic interactions, hypothesized to form a common path linking between rheumatoid arthritis, periodontitis and prolactin. This is because of the need to develop new treatment strategies for the most effective long term control of inflammation in both conditions.
34664865 Cross-sectional assessment of sleep and fatigue in middle-aged Japanese women with primary 2021 Sep 17 To investigate fatigue, health-related quality of life (HR-QOL), and sleep quality in women with primary Sjogren syndrome (pSS) or rheumatoid arthritis (RA) as compared with healthy controls using self-reports and wrist actigraphy.In this cross-sectional observational study, we evaluated a total of 25 patients (aged 40-75 years) with pSS, 10 with RA, and 17 healthy control subjects living in Japan. The HR-QOL was assessed using the Short Form-36. Fatigue was evaluated using the Short Form-36 vitality score, visual analog scale (VAS) for fatigue, and 2 questionnaire items using scores based on a 4-point Likert scale. Sleep quality was measured using the Japanese version of the Pittsburgh Sleep Quality Index, VAS for sleep quality, and wrist actigraphy for 14 days.Patients with pSS reported severer fatigue and lower HR-QOL than healthy controls, especially in mental health. Based on the Pittsburgh Sleep Quality Index score, 56% of the patients with pSS were poor sleepers, which was higher than healthy controls (29.4%). Furthermore, the patients with pSS scored significantly lower on the VAS for sleep quality than healthy controls (40.5 vs 63.7, P = .001). Although subjective assessments revealed slight sleep disturbances in patients with pSS, wrist actigraphy revealed no differences when compared with healthy controls for total sleep time (421.8 minutes vs 426.5 minutes), sleep efficiency (95.2% vs 96.4%), number of awakenings (1.4 vs 0.9), and wake after sleep onset (22.4 minutes vs 16.1 minutes). Poor subjective sleep quality was associated with enhanced fatigue. However, sleep efficiency, as determined by actigraphy, was not associated with fatigue. Notably, the patients with RA and healthy controls did not differ significantly in terms of fatigue or sleep quality, although patients with RA experienced more nocturnal awakenings than healthy controls (1.7 vs 0.9, P = .04).Patients with pSS experience severe fatigue, poor HR-QOL, and sleep disturbances, which are associated with fatigue. However, wrist actigraphy did not reveal differences in sleep quality, suggesting that it may not be an appropriate measure of sleep in patients with pSS.
33914203 Iguratimod combination therapy compared with methotrexate monotherapy for the treatment of 2021 Oct OBJECTIVE: We estimated the relative efficacy and safety of iguratimod combination therapy compared with methotrexate monotherapy for the treatment of rheumatoid arthritis. METHOD: We identified parallel randomized controlled trials from the Cochrane Central Register of Controlled Trials in The Cochrane Library (CENTRAL), MEDLINE, Embase, and other databases and trial registries for January April 2020. Independent assessment of the risk of bias and grading of the certainty of evidence was performed for the selected trials. We operated RevMan 5 software to compute the meta-analysis. We applied the random-effects model. The statistical methods applied were the Mantel-Haenszel method and the inverse-variance method for dichotomous and continuous outcomes, respectively. RESULTS: We included 12 trials involving 1095 participants. Based on our result, patients on iguratimod combination are likely to have 3.53 (95% CI 2.22 to 5.60, moderate-certainty), 3.24, and 2.73 times higher odds for attaining American College of Rheumatology criteria (ACR) 20, 50, and 70, respectively, than methotrexate monotherapy. Disease state measured using DAS28 score (MD -0.71 score, 95% CI -1.03 to -0.39, very low certainty) and functional ability indicated by HAQ (Health Assessment Questionnaire) (MD -0.23, 95% CI -0.34 to -0.11, very low certainty) may also be better. The combination therapy also produced better results for C-reactive protein, erythrocyte sedimentation rate, pain intensity, and patient's and physician's global assessment of disease state. Incidence of adverse events were similar between the groups (OR 1.30, 95% CI 0.92 to 1.83, moderate-certainty). CONCLUSION: Iguratimod combined with methotrexate may be considered a promising alternative for treating RA. Key Points • Iguratimod combination therapy produced better results in all the efficacy outcomes than methotrexate monotherapy. • Iguratimod combination therapy may be as safe as methotrexate monotherapy. • We recommend future clinical trials of iguratimod combination therapy in RA with iguratimod combined with DMARDs other than methotrexate and conducted in diverse population.
33565582 Opioid Prescribing Among Outpatients with Rheumatoid Arthritis. 2021 Oct 8 STUDY OBJECTIVES: To examine the outpatient opioid prescribing practices and the factors associated with opioid prescriptions in patient visits with rheumatoid arthritis (RA). DESIGN: This cross-sectional study used the 2011-2016 National Ambulatory Medical Care Survey. Descriptive weighted analyses were used to examine the trends in opioid prescribing practices for RA. Multivariable logistic regression was used to examine the factors associated with opioid prescriptions among RA visits. SUBJECTS: Adult patients (>18 years of age) with a primary diagnosis of RA based on the International Classification of Diseases. RESULTS: According to the national surveys, an average of 4.45 (95% confidence interval [CI], 2.30-6.60) million office visits were made annually for RA. Approximately 24.28% of these visits involved opioid prescriptions. The RA visits involving opioid prescriptions increased from 1.43 million in 2011-2012 to 3.69 million in 2015-2016 (P < .0001). Being in the age group of 50-64 years (odds ratio [OR] = 3.40; 95% CI, 1.29-9.00), being Hispanic or Latino (OR = 2.92, 95% CI, 1.10-7.74), visiting primary physician (OR = 4.67; 95% CI, 1.86-11.75), prescribing of muscle relaxants (OR = 64.32; 95% CI, 9.71-426.09), acetaminophen (OR = 93.40; 95% CI, 26.19-333.04), antidepressants (OR = 6.10; 95% CI, 2.63-14.14), and glucocorticoids (OR = 3.20; 95% CI, 1.61-6.38), were associated with an increased likelihood of receiving opioid prescriptions in RA. CONCLUSIONS: One in four adult RA visits resulted in opioid prescriptions, and the opioid visits more than doubled during the study period. Several patient and provider factors were associated with the opioid prescribing among RA visits. Understanding these prescribing practices can help to devise strategies for safe opioid prescribing practices in RA.
33674419 Fibrocytes in early and long-standing rheumatoid arthritis: a 6-month trial with repeated 2021 Mar OBJECTIVES: To correlate the level of fibrocytes in peripheral blood, synovial tissue and in vitro culture in rheumatoid arthritis (RA) with changes in disease activity, imaging and pulmonary function. METHODS: Twenty patients with early RA (ERA) and 20 patients with long-standing RA (LRA) were enrolled in a 6-month prospective study. Sixteen patients undergoing wrist arthroscopy were healthy controls. Patients with RA underwent pulmonary function tests, ultrasound and synovial ultrasound-guided needle biopsy of the same wrist at baseline and 6 months. Wrist MRI was performed at baseline (all) and 6 months (ERA). Circulating fibrocytes were measured by flow cytometry, in vitro by the number of monocytes that were differentiated to fibrocytes and in synovial biopsies by counting in histological sections. RESULTS: Fibrocytes were primarily located around vessels and in the subintimal area in the synovium. Fibrocyte levels did not decline during the trial despite effective RA treatment. In the ERA group, increased synovitis assessed by ultrasound was moderate and strongly correlated with an increase in circulating and synovial fibrocyte levels, respectively. Increased synovitis assessed by MRI during the trial in the ERA group was moderately correlated with both increased numbers of circulating and cultured fibrocytes. Absolute diffusion capacity level was overall weakly negatively correlated with the level of circulating and synovial fibrocytes. The decline in diffusion capacity during the trial was moderately correlated with increased levels of synovial fibrocytes. CONCLUSION: Our findings suggest that fibrocytes are involved in RA pathogenesis, both in the synovium and the reduction in lung function seen in a part of patients with RA. TRIAL REGISTRATION NUMBER: NCT02652299.
33440243 Pharmacokinetics analysis based on target-mediated drug distribution for RC18, a novel BLy 2021 Apr 1 BACKGROUND AND PURPOSE: RC18 is a novel recombinant fusion protein targeting on B lymphocyte stimulator (BLyS). We aimed to develop and qualify a population pharmacokinetics (PopPK) model for RC18 in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients, taking into account the mechanistic target-mediated drug disposition (TMDD) process. METHODS: A TMDD model of RC18 was developed using data from two phase I clinical trial (n = 23). The TMDD structural model was developed by simultaneous fitting of the serum free RC18 and serum RC18-BLyS complex. Potential covariates were screened using stepwise method, and predictive performance was qualified using a prediction-corrected visual predictive check (pcVPC) and bootstrap. RESULTS: A two compartment TMDD model with first order absorption for subcutaneous administration was built. The final model included a significant relationship between distribution volume of the central compartment and body weight. And the baseline of immunoglobulin IgG had significant effect on the baseline of target BLyS. The plots from goodness-of-fit and pcVPC confirmed good predictive performance of this TMDDmodel. CONCLUSIONS: This mechanistic TMDD model integrated the interaction of RC18 with its target BLyS and accurately predicts both RC18 and RC18-BLyS complex profiles in RA and SLE patients. Simulated target change profiles can be used to help guide rational dose regimen selection and used as a biomarker for efficacy evaluation.
34365877 Emerging protein kinase inhibitors for the treatment of rheumatoid arthritis. 2021 Sep INTRODUCTION: Protein tyrosine kinase inhibitors are emergent drugs in the treatment of rheumatoid arthritis (RA); they block the signal transduction in immune cells preventing the production and release of pro-inflammatory cytokines. AREAS COVERED: The current research aims to review the role of Janus, Bruton's and spleen kinase inhibitors for the treatment of RA. Mechanism of action, rationale for usage, and the main efficacy and safety outcomes in phase II and III clinical trials are described. EXPERT OPINION: In RA, the development of Bruton kinase inhibitors was interrupted because they failed to demonstrate superiority versus placebo. The spleen kinase inhibitors had their development deprioritized because their risk/benefit profile was unfavorable compared to janus kinase inhibitors (JAKi). JAKi proved to be effective in treatment naïve patients and in those with previous failure to methotrexate and/or biological therapy. There still remain important points about JAKi that need more studies: the clinical importance of JAKi selectivity should be further evaluated in head-to-head trials and the safety profile of JAKi, mainly regarding the risk of malignancy and thromboembolic events, must be analyzed in long-term real-life studies.
32920169 Adjuvant-induced arthritis is a relevant model to mimic coronary and myocardial impairment 2021 Jan OBJECTIVES: To determine if the adjuvant-induced arthritis model reproduced coronary and cardiac impairments observed in rheumatoid arthritis patients. The link between disease activity and circulating levels of angiotensin II and endothelin-1 have been studied, as well as the myocardial susceptibility to ischemia. METHODS: At the acute inflammatory phase, coronary reactivity was assessed in isolated arteries, and cardiac function was studied in isolated perfused hearts, before and after global ischemia/reperfusion. Ischemic insult was evaluated by the infarct size, lactate dehydrogenase and creatine phosphokinase levels in coronary effluents. Cardiac myeloperoxidase activity was measured, as well as angiotensin II and endothelin-1 levels. RESULTS: Compared to controls, adjuvant-induced arthritis had reduced coronary Acetylcholine-induced relaxation associated with cardiac hypertrophy, both being correlated with plasma levels of endothelin-1 and angiotensin II, and arthritis score. Although cardiac function at baseline was similar from controls, adjuvant-induced arthritis rats exhibited lower cardiac functional recovery, increased myeloperoxidase activity, higher infarct size and creatine phosphokinase levels after ischemia/reperfusion. CONCLUSIONS: The adjuvant-induced arthritis model displays coronary endothelial dysfunction associated with myocardial hypertrophy and a reduced tolerance to ischemia. This model might be useful for deciphering the pathophysiology of cardiac dysfunction in rheumatoid arthritis and paves the way for studying the role of endothelin-1 and angiotensin II.
32926346 The Outcome of Stem Cell-Based Therapies on the Immune Responses in Rheumatoid Arthritis. 2021 Rheumatoid arthritis as a common autoimmune inflammatory disorder with unknown etiology can affect 0.5-1% of adults in developed countries. It involves more than just the patient's joints and can be accompanied by several comorbidities and affect cardiovascular, pulmonary, and some other systems of the human body. Although cytokine-mediated pathways are mentioned to have a central role in RA pathogenesis, adaptive and innate immune systems and intracellular signaling pathways all have important roles in this process. Non-steroidal anti-inflammatory drugs, glucocorticoids, conventional disease-modifying anti-rheumatic drugs, and biological agents are some mentioned medications used for RA. They are accompanied by some adverse effects and treatment failures which elucidates the needing for novel and more powerful therapeutic approaches. Stem cell-based therapies and their beneficial effects on therapeutic processes of different diseases have been founded so far. They can be an alternative and promising therapeutic approach for RA, too; due to their effects on immune responses of the disease. This review, besides some explanations about RA characteristics, addresses the outcome of the stem cell-based therapies including mesenchymal stem cell transplantation and hematopoietic stem cell transplantation for RA and explains their effects on the disease improvement.
33799480 ACPA Status Correlates with Differential Immune Profile in Patients with Rheumatoid Arthri 2021 Mar 14 Rheumatoid arthritis (RA) is a progressive erosive autoimmune disease that affects 1% of the world population. Anti-citrullinated protein autoantibodies (ACPA) are routinely used for the diagnosis of RA, however 20-30% of patients are ACPA negative. ACPA status is a delineator of RA disease endotypes with similar clinical manifestation but potentially different pathophysiology. Profiling of key peripheral blood and synovial tissue immune populations including B cells, T follicular helper (Tfh) cells and CD4 T cell proinflammatory cytokine responses could elucidate the underlying immunological mechanisms involved and inform a treat to target approach for both ACPA-positive and ACPA-negative RA. Detailed high dimensionality flow cytometric analysis with supervised and unsupervised algorithm analysis revealed unique RA patient peripheral blood B cell and Tfh cell profiles. Synovial tissue single cell analysis of B cell subpopulation distribution was similar between ACPA- and ACPA+ RA patients, highlighting a key role for specific B cell subsets in both disease endotypes. Interestingly, synovial tissue single cell analysis of CD4 T cell proinflammatory cytokine production was markedly different between ACPA- and APCA+ RA patients. RNAseq analysis of RA patient synovial tissue highlighted disease endotype specific gene signatures. ACPA status associates with unique immune profile signatures that reinforce the need for a treat to target approach for both endotypes of RA.