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ID PMID Title PublicationDate abstract
31059310 JAK3-selective inhibitor peficitinib for the treatment of rheumatoid arthritis. 2019 Jun Introduction: Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by synovitis as well as symmetric and destructive arthropathy. Although several disease modified antirheumatic-drugs (DMARDs) have widely used in clinical practice, certain patients are nonresponsive to or cannot take such medications due to adverse reactions. It is evident that Janus kinase (JAK) inhibitors have the potential to provide a significant breakthrough in the treatment of RA. These potent, orally administered, JAK inhibitors simplify the treatment options for patients. Areas covered: We discuss the pharmacodynamics, pharmacokinetics, efficacy, and safety of peficitinib for the treatment of RA. Expert opinion: Peficitinib is a novel JAK3 inhibitor potently inhibiting JAK3 enzymatic activity and JAK1/3-mediated cell proliferation. Its selectivity for JAK family kinases is similar to that of tofacitinib, but slightly less potent for JAK2. It is currently being evaluated by the FDA to treat adult patients with moderately to severely active RA who show inadequate response to or are intolerant of methotrexate. It can be used either as monotherapy or combination therapy with methotrexate, or other DMARDs. However, we think that more cautious consideration and measurement for adverse events are needed, after considering the safety results of ongoing clinical studies of peficitinib.
30874838 Theaflavin-3, 3'-Digallate Attenuates Rheumatoid Inflammation in Mice Through the Nuclear 2019 Jun Rheumatoid arthritis (RA) is a common autoimmune disease which impacts a large number of patients worldwide, and new drugs are required for lower the disease burden. Theaflavin-3, 3'-digallate (TFDG) is polyphenol exhibiting inhibition on inflammatory factors. This study aimed to explore the attenuation of TFDG on RA. The collagen-induced arthritis (CIA) mouse model was established and administered with TFDG. The arthritis score and incidence was recorded to assess the amelioration of TFDG on arthritis. Histopathological change of the mouse joint tissues was evaluated by haemotoxylin and eosin staining. The expression of pro-inflammatory mediators including interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 was quantified by ELISA. The activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways in the synovium were determined by Western blotting. In comparison with the control, administration of TFDG significantly reduced arthritis score and incidence in the CIA mouse model. TFDG significantly suppressed the expression of IL-1β, TNF-α, and IL-6, as well as the levels of MMP-1, MMP-2, and MMP-3 in the synovium. TFDG also showed remarkable inhibition on the activation of NF-κB and the phosphorylation of P38, JNK2, and ERK. This study puts up evidence that TFDG exerts protection on RA via inhibiting the activation of NF-κB- and MAPK-signaling pathways.
31845616 Pathological findings in central nervous system demyelination associated with infliximab. 2020 Aug BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) inhibitors, such as infliximab, are commonly used to treat rheumatoid arthritis (RA) and other immune-mediated disorders. OBJECTIVE: To determine whether infliximab-associated central nervous system (CNS) demyelination can be differentiated from multiple sclerosis (MS). METHODS: We present a case of pathologically proven CNS demyelination in a patient treated with infliximab and describe clinical-radiographic-neuropathological findings. Putative mechanisms of TNF-alpha inhibitor-associated CNS demyelination are described. RESULTS AND CONCLUSION: Infliximab treatment is associated with CNS inflammatory demyelinating activity, which is histopathologically indistinguishable from MS.
30985568 Blood Loss of Posterior Lumbar Interbody Fusion on Lumbar Stenosis in Patients With Rheuma 2019 Sep 1 STUDY DESIGN: Case-control study. OBJECTIVE: To compare intraoperative bleeding, drainage, and hidden blood loss (HBL) of posterior lumbar interbody fusion (PLIF) on lumbar spinal stenosis (LSS) in patients with rheumatoid arthritis (RA) and non-RA and identify the risk factors of HBL with RA. SUMMARY OF BACKGROUND DATA: Exploration on PLIF on LSS and HBL has been reported before while the comparison on total blood loss (TBL), especially HBL of PLIF or PLF on LSS between patients with RA and without RA has not been studied. METHODS: Sixty-one patients diagnosed LSS with RA (RA group) and 87 matched patients without RA (NRA group) were enrolled and demographic characteristics, RA-related parameters, operation and blood loss information were extracted. Intraoperative blood loss, drainage, and HBL were primary outcomes and secondary measures included operation time, hematocrit (Hct) and hemoglobin (Hb), the number of anemia and blood transfusion. RESULTS: There was no statistical difference in total blood loss (TBL), intraoperative blood loss, and postoperative drainage while HBL and the proportion of HBL in TBL were lower in NRA group (P < 0.001 and P = 0.012, respectively). Stratified analysis based on the number of surgical levels suggested HBL and the proportion of HBL in NRA group was superior in long-segment surgery (>2 segments). The secondary outcomes showed the change of Hct was lower in NRA group (P = 0.021) but not the reduction of Hb. In addition, there was no significant difference in neoformative and grade-aggravated anemia, as well as the number of allogeneic blood transfusion and operation time showed Steinbroker classification, disease-modifying anti-rheumatic drugs (DMARDs), hange of Hb and allogeneic blood transfusion were risk factors for HBL with RA. CONCLUSION: There was no difference in TBL, intraoperative bleeding, and operation time, but HBL were higher in RA patients particularly in long-segmental operation. Steinbroker classification, DMARDs, the change of Hb, and allogeneic blood transfusion were independent risk factors for HBL in RA patients. LEVEL OF EVIDENCE: 3.
30872593 Assessing whether the association between rheumatoid arthritis and schizophrenia is bidire 2019 Mar 14 Since many studies have shown a reduction in the incidence of rheumatoid arthritis (RA) in patients with schizophrenia (SCZ), little effort has been devoted to studying this link in the Asian population. Moreover, the relationship between these two disorders could be bidirectional, but the influence of RA on the SCZ incidence is unclear. The study aims to determine whether there is a bidirectional association between RA and SCZ in an Asian population. We analyzed a 10-year population- based longitudinal cohort using the National Health Insurance Research Database of Taiwan. In the first analysis, we included a total of 58,847 SCZ patients and 235,382 non-SCZ controls, and in the second analysis, a total of 30,487 RA patients and 121,833 non-RA controls, both matched by gender, age, and index date. Cox regression analyses were performed to examine the risk of RA incidence in the first analysis and the risk of SCZ incidence in the second analysis. The main finding of this study was the discovery of a lower incidence of RA in patients with SCZ (hazard ratio (HR): 0.48, 95% confidence interval (95% CI): 0.31-0.77) after adjustment for baseline demographics and comorbidities. Additionally, the presence of RA predicted a reduced incidence rate for SCZ, but the estimate was not statistically significant (HR: 0.77, 95% CI: 0.44-1.37). The study found a unidirectional association between RA and SCZ. However, RA has an age of onset later than RA, and the protective effect of RA on SCZ incidence would be biased due to the limited number of cases.
30612588 KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes a 2019 Jan 7 BACKGROUND: Fibroblast-like synoviocytes (FLS) and CCR7(-) effector memory T (T(EM)) cells are two of the major cell types implicated in the progression of rheumatoid arthritis (RA). In particular, FLS become highly invasive, whereas T(EM) cells proliferate and secrete proinflammatory cytokines, during RA. FLS and T cells may also interact and influence each other's phenotypes. Inhibition of the pathogenic phenotypes of both FLS and T(EM) cells can be accomplished by selectively blocking the predominant potassium channels that they upregulate during RA: KCa1.1 (BK, Slo1, MaxiK, KCNMA1) upregulated by FLS and Kv1.3 (KCNA3) upregulated by activated T(EM) cells. In this study, we investigated the roles of KCa1.1 and Kv1.3 in regulating the interactions between FLS and T(EM) cells and determined if combination therapies of KCa1.1- and Kv1.3-selective blockers are more efficacious than monotherapies in ameliorating disease in rat models of RA. METHODS: We used in vitro functional assays to assess the effects of selective KCa1.1 and Kv1.3 channel inhibitors on the interactions of FLS isolated from rats with collagen-induced arthritis (CIA) with syngeneic T(EM) cells. We also used flow cytometric analyses to determine the effects of KCa1.1 blockers on the expression of proteins used for antigen presentation on CIA-FLS. Finally, we used the CIA and pristane-induced arthritis models to determine the efficacy of combinatorial therapies of KCa1.1 and Kv1.3 blockers in reducing disease severity compared with monotherapies. RESULTS: We show that the interactions of FLS from rats with CIA and of rat T(EM) cells are regulated by KCa1.1 and Kv1.3. Inhibiting KCa1.1 on FLS reduces the ability of FLS to stimulate T(EM) cell proliferation and migration, and inhibiting Kv1.3 on T(EM) cells reduces T(EM) cells' ability to enhance FLS expression of KCa1.1 and major histocompatibility complex class II protein, as well as stimulates their invasion. Furthermore, we show that combination therapies of selective KCa1.1 and Kv1.3 blockers are more efficacious than monotherapies at reducing signs of disease in two rat models of RA. CONCLUSIONS: Our results demonstrate the importance of KCa1.1 and Kv1.3 in regulating FLS and T(EM) cells during RA, as well as the value of combined therapies targeting both of these cell types to treat RA.
29023282 Abatacept Monotherapy Versus Abatacept Plus Methotrexate for Treatment-Refractory Rheumato 2019 May/Jun BACKGROUND: Methotrexate combination therapy improves abatacept efficacy as a first-line biologic agent for the treatment of rheumatoid arthritis, but it is unclear when abatacept is used later on, particularly after non-TNF inhibitor (TNFi) failure. STUDY QUESTION: The objective of this study was to determine whether treatment response after non-TNFi inadequate response is different in patients with rheumatoid arthritis (RA) treated with abatacept in combination with or not with methotrexate. METHODS: Patients treated with abatacept monotherapy or in combination with methotrexate after non-TNFi failure were included. RESULTS: Data from 46 patients aged 56 years [49-61] with 12 years [8-16] of disease duration were examined. Rituximab was the treatment used in the previous line for 75.0% of the combination therapy group (15/20) and 34.6% (9/26) in the monotherapy group. At 12 months, 38.5% (10/26) of patients were in good-to-moderate EULAR response in the monotherapy group compared with 25.0% (5/20) in the combination therapy group (P = 0.33). Treatment persistence at 12 months was 61.5% (16/26) in the monotherapy group and 35.0% (7/20) in the combination therapy group (P = 0.07). CONCLUSIONS: Adding methotrexate to abatacept did not improve treatment response in patients with RA after non-TNFi inadequate response.
31169700 Moxibustion for rheumatoid arthritis: Protocol for a systematic review. 2019 Jun BACKGROUND: Rheumatoid Arthritis (RA) is a serious chronic disease which will result in serious syndrome such as joints stiffness, disability, and death. The major medications treating RA usually make sense and side effects, while moxibustion is known as a safe and effective treatment for RA. This review aims to systematically evaluate the effect and safety of moxibustion for treating RA. METHODS: The following databases will be searched from their inception to March 2019: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Wan-Fang Databases, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Citation Information by National Institute of Informatics, Chinese Scientific Journal Database (VIP Database). Two reviewers will search these databases, select data and measure the quality of studies independently. The methodological quality will be assessed by the Cochrane risk of bias tool. Data will be synthesized by either the fixed-effects or random-effects model according to a heterogeneity test. The primary outcome is symptom evaluation including morning stiffness, pain and joint swelling. The number of joints affected by RA, adverse effects, quality of life, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and Rheumatoid factor (RF) will be evaluated as secondary outcomes. Risk ratio for dichotomous data and mean differences with a 95% confidence interval for continuous data will be adopted to express the effect and safety of acupuncture for RA. RESULTS: This study will provide a high-quality synthesis of current evidence of moxibustion for asthma from several aspects including morning stiffness, pain and joint swelling. The number of joints affected by RA, adverse effects, quality of life, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and Rheumatoid factor (RF). CONCLUSION: The conclusion of our study will provide updated evidence to judge whether moxibustion is an effective and safe intervention for patients with RA. ETHICS AND DISSEMINATION: As individuals will not be involved, the ethical approval will not be required. This review will be published in a peer-reviewed journal or at a relevant conference. PROSPERO REGISTRATION NUMBER: CRD42019126685.
30920392 Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis. 2019 Mar 28 Skeletal muscle weakness in patients suffering from rheumatoid arthritis (RA) adds to their impaired working abilities and reduced quality of life. However, little molecular insight is available on muscle weakness associated with RA. Oxidative stress has been implicated in the disease pathogenesis of RA. Here we show that oxidative post-translational modifications of the contractile machinery targeted to actin result in impaired actin polymerization and reduced force production. Using mass spectrometry, we identified the actin residues targeted by oxidative 3-nitrotyrosine (3-NT) or malondialdehyde adduct (MDA) modifications in weakened skeletal muscle from mice with arthritis and patients afflicted by RA. The residues were primarily located to three distinct regions positioned at matching surface areas of the skeletal muscle actin molecule from arthritis mice and RA patients. Moreover, molecular dynamic simulations revealed that these areas, here coined "hotspots", are important for the stability of the actin molecule and its capacity to generate filaments and interact with myosin. Together, these data demonstrate how oxidative modifications on actin promote muscle weakness in RA patients and provide novel leads for targeted therapeutic treatment to improve muscle function.
30407753 Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthriti 2019 Apr OBJECTIVE: To obtain the comprehensive transcriptome profile of human citrulline-specific B cells from patients with rheumatoid arthritis (RA). METHODS: Citrulline- and hemagglutinin-specific B cells were sorted by flow cytometry using peptide-streptavidin conjugates from the peripheral blood of RA patients and healthy individuals. The transcriptome profile of the sorted cells was obtained by RNA-sequencing, and expression of key protein molecules was evaluated by aptamer-based SOMAscan assay and flow cytometry. The ability of these proteins to effect differentiation of osteoclasts and proliferation and migration of synoviocytes was examined by in vitro functional assays. RESULTS: Citrulline-specific B cells, in comparison to citrulline-negative B cells, from patients with RA differentially expressed the interleukin-15 receptor α (IL-15Rα) gene as well as genes related to protein citrullination and cyclic AMP signaling. In analyses of an independent cohort of cyclic citrullinated peptide-seropositive RA patients, the expression of IL-15Rα protein was enriched in citrulline-specific B cells from the patients' peripheral blood, and surprisingly, all B cells from RA patients were capable of producing the epidermal growth factor ligand amphiregulin (AREG). Production of AREG directly led to increased migration and proliferation of fibroblast-like synoviocytes, and, in combination with anti-citrullinated protein antibodies, led to the increased differentiation of osteoclasts. CONCLUSION: To the best of our knowledge, this is the first study to document the whole transcriptome profile of autoreactive B cells in any autoimmune disease. These data identify several genes and pathways that may be targeted by repurposing several US Food and Drug Administration-approved drugs, and could serve as the foundation for the comparative assessment of B cell profiles in other autoimmune diseases.
31055792 Population Pharmacokinetics of Sarilumab in Patients with Rheumatoid Arthritis. 2019 Nov BACKGROUND AND OBJECTIVE: Sarilumab binds to the interleukin-6 receptor with high affinity, inhibiting cis and trans signaling by interleukin-6. Sarilumab has demonstrated efficacy and safety in patients with rheumatoid arthritis. The objective of this study was to develop a population-pharmacokinetic model using data from 1770 patients with rheumatoid arthritis across phase I-III studies. METHODS: Potential covariates were identified using a stepwise forward-addition and backward-deletion strategy, and the final model was evaluated by visual predictive check and bootstrap methods. RESULTS: Sarilumab pharmacokinetics is described by a two-compartment model with first-order absorption and parallel linear and nonlinear Michaelis-Menten elimination. A subcutaneous dose of sarilumab 200 mg every 2 weeks resulted in more pronounced saturation of the nonlinear clearance pathway over the dosing interval than 150 mg every 2 weeks. Steady-state exposure (area under the plasma concentration-time curve from day 0 to day 14) increased twofold with dose escalation from 150 to 200 mg every 2 weeks. Body weight, anti-drug antibody status, sarilumab drug product, sex, creatinine clearance, albumin, and baseline C-reactive protein levels were identified as significant covariates according to the predefined statistical significance criteria in stepwise covariate searches. The main intrinsic source of pharmacokinetic variability in exposure was body weight. Compared with a typical 71-kg patient, the area under the plasma concentration-time curve from day 0 to day 14 was 20-23% lower for an 83-kg patient and 20-25% higher for a 62-kg patient. CONCLUSIONS: These findings, combined with the safety and efficacy data, indicated limited clinical relevance of body-weight effect on sarilumab exposure. No adjustment in sarilumab dose is required for body weight or any other demographics assessed.
31883358 Resveratrol ameliorates rheumatoid arthritis via activation of SIRT1-Nrf2 signaling pathwa 2020 May The present study was designed to explore the biological role of resveratrol (RES) in rheumatoid arthritis (RA) and the underlying mechanism. The adjuvant-induced arthritic rats were administered RES on the 12th day after model establishment, and then arthritis assessment, oxidative stress measurement, histological examination, and immunohistochemical staining were performed. The primary rat fibroblast-like synoviocytes (FLS) were isolated and treated with RES in vitro and then cell proliferation and apoptosis assay were examined. Chromatin immunoprecipitation assay, luciferase reporter assay, intracellular reactive oxygen species (ROS) determination, western blot, and quantitative real time-polymerase chain reaction (qRT-PCR) were performed to investigate the mechanisms. RES administration decreased arthritis scores and serum levels of antioxidant enzymes, attenuated paw swelling, synovial hyperplasia, inflammatory cell infiltration, and cartilage degradation, as well as inhibited synoviocyte proliferation in synovial tissues. Further investigation indicated that RES inhibited ROS production and FLS proliferation through activating the silent information regulator 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. NF-κB was confirmed to negatively regulate miR-29a-3p and miR-23a-3p expression by directly binding to its promoter. Mechanistic analyses further revealed that Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1), a negative regulator of Nrf2, was a downstream target of miR-29a-3p, while miR-23a-3p directly targeted cullin3 (cul3), a master regulator of ubiquitination and degradation of Nrf2. Together, the present study provided evidence that RES ameliorated RA through activation of Nrf2-ARE signaling pathway via SIRT1/NF-κB/miR-29a-3p/Keap1 and SIRT1/NF-κB/miR-23a-3p/cul3 signaling pathway.
31072629 Increased circulating Wnt5a protein in patients with rheumatoid arthritis-associated inter 2019 Jul An early diagnosis of interstitial lung disease (ILD) is important for guiding treatments of rheumatoid arthritis (RA)-associated ILD (RA-ILD) in clinical settings. The non-canonical Wnt signaling representative ligand Wnt5a was recently found to involve in idiopathic pulmonary fibrosis (IPF) and pathogenesis of RA. The goal of this study was to examine the clinical relevance of Wnt5a in RA-ILD. In this report, the clinical relevance of plasma Wnt5a protein was evaluated in 40 RA-ILD patients and 41 non-ILD RA cohorts. The results showed an elevated Wnt5a protein in plasmas of RA-ILD patients compared with non-ILD RA patients (p < 0.01), which was positively correlated with the plasma level of rheumatoid factor (RF). Of note, more abundant Wnt5a was also found in patients with usual interstitial pneumonia (UIP) than those with nonspecific interstitial pneumonia (NSIP) and other ILD patterns. More importantly, the disease severity was correlated with the circulating Wnt5a as ascertained by high-resolution computed tomography (HRCT)-UIP scores. The multiple-factor non-conditional logistic regression analysis further revealed that the age, RA duration, smoking and plasma Wnt5a were risk factors with clinical significance for RA-ILD. Interestingly, more Wnt5a-positive patients were identified in RA-ILD smokers relative to RA-ILD never-smokers, and longer smoking duration was strongly correlated with Wnt5a in RA-ILD patients. In consistence, ROC curve also suggested that the Wnt5a was a potential candidate biomarker for identifying patients with RA-UIP. These results demonstrate that the circulating Wnt5a may be a risk factor and potential biomarker for identifying UIP and accessing the severity and progression of ILD in RA patients.
30932438 The Italian version of rheumatoid arthritis pain scale (IT-RAPS): psychometric properties 2019 Apr 1 This paper describes the validation process of the Italian version of the Rheumatoid Arthritis Pain Scale (ITRAPS), describing its translation and adaptation to Italian culture. The cultural adaptation and validation were based on data from a sample of people affected by rheumatoid arthritis (RA). The process required a forward and backward translation of the original language, reviewed by an expert panel. The adapted version of the RAPS was then tested on a community and clinical sample, in order to test its psychometric properties. The IT-RAPS was submitted to 122 people affected by RA. The data was analyzed using Cronbach's coefficient alpha and the Pearson product-moment correlation coefficients. The IT-RAPS showed an internal consistency reliability coefficient of 0.96. This is the first study reporting the validation and cross-cultural adaptation of the RAPS in Italian. The study's findings provided support for the IT-RAPS as a reliable and valid measurement of multidimensional pain in RA patients.
31465725 Novel findings from determination of common expressed plasma exosomal microRNAs in patient 2019 Jul BACKGROUND: Circulating exosomal microRNAs modulate not only cancer cell metabolism but also the immune response, and therefore plasma exosomal microRNAs might have the potential to be the biomarkers for a number of immune disorders. OBJECTIVE: This study was conducted to identify the common mechanisms among psoriatic arthritis (PsA), psoriasis vulgaris (PV), rheumatoid arthritis (RA), and gouty arthritis (GA). The common expressed plasma exosomal microRNAs in these diseases were determined. METHODS: The expression of microRNAs derived from plasma exosome of patients with PsA (n=30), PV (n=15), RA (n=15), GA (n=15), and healthy controls (n=15) was evaluated via sequencing. Function analysis of common expressed microRNAs was conducted by the Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses. Coexpression analysis was conducted to identify novel and significant genes and proteins by using the Search Tool for the Retrieval of Interacting Genes (STRING). A systematic literature review was conducted to uncover the role of the common microRNAs in the pathogenesis of PsA, PV, RA, and GA. RESULTS: A total of 36 common expressed microRNAs were detected in patients with PsA, PV, RA, and GA. The most significantly enriched biological processes, cellular components, and molecular functions were "homophilic cell adhesion via plasma membrane adhesion molecules," "CCR4-NOT complex," and "calcium ion binding," respectively. "Antigen processing and presentation" was the most significantly enriched pathway. A total of 91 validated coexpressed gene pairs were identified and 16 common expressed microRNAs and 85 potential target genes were screened based on Cytoscape. Of 36 common expressed microRNAs, 5 microRNAs, including hsa-miR-151a-3p, hsa-miR-199a-5p, hsa-miR-370-3p, hsa-miR-589-5p, and hsa-miR-769-5p, were considered to be connected with the common pathogenesis of PsA, PV, RA, and GA. Systemic review revealed that the roles of these 5 microRNAs are related to immune disorder and bone injury, which matches the conclusion from GO and KEGG analyses. CONCLUSION: (1) Both immune disorder and bone metabolic dysregulation could be the shared mechanism in the development of PsA, PV, RA, and GA. (2) Immune dysfunction is involved in GA. Our study may shed new light on the diagnosis and treatment strategy of these autoimmune diseases and GA, which warrants further studies.
31173126 Prevalence of Periodontal Disease and Periodontopathic Bacteria in Anti-Cyclic Citrullinat 2019 Jun 5 IMPORTANCE: The prevalence of periodontitis is increased in patients with rheumatoid arthritis (RA) and periodontopathic bacteria can citrullinate proteins. Periodontitis may, therefore, be an initiator of RA and a target for prevention. Periodontal disease and periodontal bacteria have not been investigated in at-risk individuals with RA autoimmunity but no arthritis. OBJECTIVE: To examine periodontal disease and periodontopathic bacteria in anti-cyclic citrullinated protein (anti-CCP) antibody-positive at-risk individuals without arthritis. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study took place at a teaching hospital from April 27, 2015, to May 8, 2017. Forty-eight anti-CCP-positive individuals without arthritis (CCP+ at-risk) were recruited nationally. Twenty-six patients with early RA (ERA) and 32 healthy control individuals were recruited locally. Data were analyzed between June 1, 2017, and December 1, 2017. INTERVENTIONS: Periodontal assessment and examination of joints using ultrasonography. MAIN OUTCOMES AND MEASURES: Prevalence of diseased periodontal sites, clinical periodontitis, and periodontal inflamed surface area in CCP+ at-risk individuals compared with patients with ERA and healthy individuals matched for age and smoking. Paired-end sequencing of DNA from subgingival plaque from diseased and healthy periodontal sites was performed and DNA was profiled and analyzed. RESULTS: A total of 48 CCP+ at-risk individuals (mean [SD] age, 51.9 [11.4] years; 31 [65%] female), 26 patients with ERA (mean [SD] age, 54.4 [16.7] years; 14 [54%] female), and 32 healthy individuals (mean [SD] age, 49.4 [15.3] years; 19 [59%] female) were recruited. Of 48 CCP+ at-risk individuals, 46 had no joint inflammation on ultrasonography. Thirty-five CCP+ at-risk individuals (73%), 12 healthy individuals (38%), and 14 patients with ERA (54%) had clinical periodontitis. The median (interquartile range) percentage of periodontal sites with disease was greater in CCP+ at-risk individuals compared with healthy individuals (3.3% [0%-11.3%] vs 0% [0%-0.7%]) and similar to patients with ERA (1.1% [0%-13.1%]). Median (interquartile range) periodontal inflamed surface area was higher in CCP+ at-risk individuals compared with healthy individuals (221 mm2 [81-504 mm2] vs 40 mm2 [12-205 mm2]). Patients with CCP+ at-risk had increased relative abundance of Porphyromonas gingivalis (but not Aggregatibacter actinomycetemcomitans) at healthy periodontal sites compared with healthy individuals (effect size, 3.00; 95% CI, 1.71-4.29) and patients with ERA (effect size, 2.14; 95% CI, 0.77-3.52). CONCLUSIONS AND RELEVANCE: This study found increased prevalence of periodontitis and P gingivalis in CCP+ at-risk individuals. This suggests periodontitis and P gingivalis are associated with disease initiation and could be targets for preventive interventions in RA.
30562482 Role of small ubiquitin-like modifier proteins-1 (SUMO-1) in regulating migration and inva 2019 Feb 1 Rheumatoid arthritis (RA) is featured by erosive cartilage and bone destruction. The enhancing aggressive property of fibroblast-like synoviocytes (FLSs) plays a critical role in this process. Small ubiquitin-like modifier (SUMO) proteins, including SUMO-1, SUMO-2, SUMO-3 and SUMO-4, participate in regulating many cellular events such as survival, migration and signal transduction in some cell lines. However, their roles in the pathogenesis of RA are not well established. Therefore, we evaluated the role of SUMO proteins in RA FLSs migration and invasion. We found that expression of both SUMO-1 and SUMO-2 was elevated in FLSs and synovial tissues (STs) from patients with RA. SUMO-1 suppression by small interference RNA (siRNA) reduced migration and invasion as well as MMP-1 and MMP-3 expression in RA FLSs. We also demonstrated that SUMO-1 regulated lamellipodium formation during cell migration. To explore further into molecular mechanisms, we evaluated the effect of SUMO-1 knockdown on the activation of Rac1/PAK1, a critical signaling pathway that controls cell motility. Our results indicated that SUMO-1-mediated SUMOylation controlled Rac1 activation and modulated downstream PAK1 activity. Inhibition of Rac1 or PAK1 also decreased migration and invasion of RA FLSs. Our findings suggest that SUMO-1 suppression could be protective against joint destruction in RA by inhibiting aggressive behavior of RA FLSs.
31605072 Gums and joints: is there a connection? Part two: the biological link. 2019 Oct Rheumatoid arthritis (RA) and periodontitis (PD) are inflammatory diseases characterised by an exacerbated immune-inflammatory reaction that leads to the destruction of bone and other connective tissues that share numerous similarities. Although a significant and independent association between these two conditions has been described, the pathophysiological processes that may explain this relationship remain unknown and multiple theories have been proposed. This review presents the most important theories currently proposed to explain the biological link between RA and PD.
31455419 Relationship of rheumatoid arthritis and coronary artery disease in the Korean population: 2019 Aug 27 BACKGROUND: Rheumatoid arthritis (RA) is known to be associated with coronary artery diseases (CAD). Previous studies of the association between RA and CAD were reported mainly in non-Asian groups. We aimed to examine the prevalence of RA and the relationship between RA and CAD in South Korea. METHODS: We conducted a nationwide cross-sectional study by using the Korea National Health and Nutrition Examination Survey, which collected data for four years between 2008 and 2012. A total of 25,828 eligible participants were included. To balance the distribution of baseline characteristics, we used propensity score-matching. A multivariable logistic regression model was employed and we calculated the odds ratios (ORs) and 95% confidence intervals (CI) for the odds of the participants with RA on CAD prevalence. RESULTS: The prevalence of RA in Korea from 2008 to 2012 was 0.6% and RA was predominant among elderly women. The prevalence of CAD in patients with RA was significantly higher than in general population. After propensity score-matching to balance the confounding factors, RA was significantly associated with CAD (OR 2.97, 95% CI 1.15-7.68, P = 0.02). CONCLUSIONS: The prevalence of RA in South Korea was comparable to the worldwide data, and the presence of CAD in RA patients was more than two-fold.
31284794 Population pharmacokinetics of PF-06438179/GP1111 (an infliximab biosimilar) and reference 2019 Oct Background: PF-06438179/GP1111 (PF-SZ-IFX) is an infliximab (IFX) biosimilar. Pharmacokinetic (PK) similarity of PF-SZ-IFX and reference IFX authorized in the European Union (ref-IFX-EU) and in the US (ref-IFX-US) was demonstrated in healthy subjects. Safety and efficacy of PF-SZ-IFX were investigated in a multinational, double-blind, randomized study in rheumatoid arthritis (RA) patients. This work aims to evaluate the population pharmacokinetics (PopPK) of ref-IFX-EU and PF-SZ-IFX in RA patients. Research design and methods: Patients with moderately to severely active RA (N = 650) were randomized 1:1 to PF-SZ-IFX or ref-IFX-EU. PopPK modeling with data collected from the study was performed using a nonlinear mixed-effects approach (NONMEM 7.2.0). Results: The PK of ref-IFX-EU and PF-SZ-IFX were adequately described using a two-compartment model with linear elimination. Clearance (CL) estimates were 0.014 L/h and 0.015 L/h for PF-SZ-IFX and ref-IFX-EU, with inter-individual variability (IIV) on CL of 43.1% and 40.1%, respectively. Volumes of distribution in the central compartment (V(1)) were 3.38 L and 3.57 L, with IIV on V(1) of 28.1% and 23.7%, respectively. The same covariates of sex and antidrug antibody titers on CL, and body weight on V(1), influenced the PK variability of ref-IFX-EU and PF-SZ-IFX. Conclusions: PopPK analysis revealed no appreciable differences between the PK of ref-IFX-EU and PF-SZ-IFX in RA patients. Trial registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02222493).