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ID PMID Title PublicationDate abstract
30669854 Liquid Chromatography Based Methods for Analysis of Disease-Modifying Antirheumatic Drugs 2019 Rheumatoid arthritis (RA) is a common chronic disease with inflammatory and immunological background where treatments can only improve the symptoms and slow down the progress of the disease. Although there are several drugs with different therapeutic targets available in the market for the treatment of RA, conventional synthetic disease-modifying antirheumatic drugs (DMARDs) are the most effective option to date. Methotrexate, azathioprine, hydroxychloroquine, sulfasalazine, leflunomide, minocycline are commonly prescribed DMARDs by rheumatologists but they have the limitations of severe toxicity for which therapeutic drug monitoring is necessary. Many chromatographic methods are available for analysis of these drugs including their metabolites. However, they have not been critically reviewed for pre-chromatographic sample preparation, chromatographic separation and sensitive detection. This review article can be handy for quantitation of DMARDs in diverse biological matrices as it provides comprehensive information on the reported liquid chromatographic methods for last three decades covering all the aspects required for preclinical and clinical studies.
30809105 An Update on the Emerging Role of Resistin on the Pathogenesis of Osteoarthritis. 2019 BACKGROUND: Resistin may be involved in the pathogenesis of osteoarthritis (OA), but a systematic understanding of the role of resistin in OA is lacking. METHODS: We reviewed studies that evaluated the role of resistin in OA. The expression levels of resistin in vitro experiments and OA/rheumatoid arthritis (RA) patients were analyzed. We also studied potential resistin receptors and the signaling pathways that these receptors activate, ultimately leading to cartilage degeneration. RESULTS: Resistin levels in both the serum and synovial fluid were higher in OA and RA patients than in healthy subjects. Overall, resistin levels are much higher in serum than in synovial fluid. In human cartilage, resistin induces the expression of proinflammatory factors such as degradative enzymes, leading to the inhibition of cartilage matrix synthesis, perhaps by binding to Toll-like receptor 4 and the adenylyl cyclase-associated protein 1 receptor, which then activates the p38-mitogen-activated phosphate kinase, protein kinase A-cyclic AMP, nuclear factor-κB, and C/enhancer-binding protein β signaling pathways. CONCLUSION: Resistin levels are higher in OA patients than in healthy controls; however, the precise role of resistin in the pathogenesis of OA needs to be studied further. Resistin may be a novel therapeutic target in OA in the future.
31676691 Whole Blood Targeted Bisulfite Sequencing and Differential Methylation in the C6ORF10 Gene 2020 Nov 1 OBJECTIVE: Polymorphisms in human major histocompatibility complex (MHC) are the strongest genetic associations with rheumatoid arthritis (RA). Epigenome-wide methylation studies suggest DNA methylation changes within MHC may contribute to disease susceptibility. We profiled MHC-specific methylated CpG (5'-C-phosphate-G-3') in autoantibody-positive patients with RA and matched unaffected anticitrullinated protein antibodies-negative first-degree relatives (ACPA-/FDR) from an indigenous North American (INA) population that is known to have prevalent RA. METHODS: DNA was isolated from whole blood and targeted bisulfite sequencing was used to profile methylated CpG in patients with RA and ACPA-/FDR. Differentially methylated CpG loci (DML) were mapped and gene annotated. Ingenuity pathway analysis (IPA) was used for curating biomolecular networks of mapped genes. Transcript abundance was determined by quantitative (q)PCR. RESULTS: We identified 74 uniquely methylated CpG sites within the MHC region that were differentially methylated in patients with RA (p < 0.05), compared to ACPA-/FDR. Of these, 32 DML were located on 22 genes. IPA showed these genes are involved in regulating the nuclear factor-κB complex and processes involved in antigen presentation, and immune cell crosstalk in autoimmunity. Pearson correlation analysis demonstrated a negative association between differentially methylated CpG in the C6ORF10 gene and risk factors associated with RA. Analysis by qPCR confirmed differential abundance of C6ORF10, TNXB, and HCG18 mRNA in patients with RA compared to ACPA-/FDR. CONCLUSION: Our results confirm the presence of differential methylation at specific gene loci within the MHC region of INA patients with RA. These epigenetic signatures may precede disease onset, or alternatively, may be a result of developing RA.
30504510 Cost-effective Tapering Algorithm in Patients with Rheumatoid Arthritis: Combination of Mu 2019 May OBJECTIVE: To analyze the effect of a risk-stratified disease-modifying antirheumatic drug (DMARD)-tapering algorithm based on multibiomarker disease activity (MBDA) score and anticitrullinated protein antibodies (ACPA) on direct treatment costs for patients with rheumatoid arthritis (RA) in sustained remission. METHODS: The study was a posthoc retrospective analysis of direct treatment costs for 146 patients with RA in sustained remission tapering and stopping DMARD treatment, in the prospective randomized RETRO study. MBDA scores and ACPA status were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and direct treatment costs were evaluated every 3 months. MBDA and ACPA status were used as predictors creating a risk-stratified tapering algorithm based on relapse rates. RESULTS: RA patients with a low MBDA score (< 30 units) and negative ACPA showed the lowest relapse risk (19%), while double-positive patients showed high relapse risk (61%). In ACPA-negative and MBDA-negative (< 30 units), and ACPA or MBDA single-positive (> 30 units) groups, DMARD tapering appears feasible. Considering only patients without flare, direct costs for synthetic and biologic DMARD in the ACPA/MBDA-negative and single positive groups (n = 41) would have been €372,245.16 for full-dose treatment over 1 year. Tapering and stopping DMARD in this low-risk relapse group allowed a reduction of €219,712.03 of DMARD costs. Average reduction of DMARD costs per patient was €5358.83. CONCLUSION: Combining MBDA score and ACPA status at baseline may allow risk stratification for successful DMARD tapering and cost-effective use of biologic DMARD in patients in deep remission as defined by the 28-joint count Disease Activity Score using erythrocyte sedimentation rate.
30907116 Baricitinib: The Second FDA-Approved JAK Inhibitor for the Treatment of Rheumatoid Arthrit 2019 Sep Objective: To review the pharmacology, pharmacokinetics, safety, and efficacy of baricitinib, a recently approved selective Janus Kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA), and explore its potential role in therapy. Data Sources: Articles were identified using a PubMed search from inception through January 2019 using the terms rheumatoid arthritis, Olumiant, baricitinib, and LY3009104, its molecular name. Study Selection and Data Extraction: Articles relating to randomized clinical trials, pharmacology, pharmacokinetics, efficacy, and safety of baricitinib were evaluated. Data Synthesis: Baricitinib exerts its effects by inhibiting JAK1 and JAK2 enzymes, targeting cytokine and growth factor receptor stimulation, thus reducing downstream immune cell function. Four trials have demonstrated the efficacy of baricitinib with or without methotrexate in patients naïve to disease-modifying antirheumatic drugs (DMARDs) and those who had an inadequate response to or intolerance to both conventional and biological DMARDs. Furthermore, baricitinib was associated with delayed radiographic progression. Despite baricitinib 4 mg often demonstrating greater efficacy compared with the 2 mg dose, only the 2 mg dose is Food and Drug Administration approved because of safety concerns with the 4 mg dose, primarily thromboembolism. Relevance to Patient Care and Clinical Practice: Baricitinib provides an oral treatment option for patients failing tumor necrosis factor inhibitors (TNFis). Safety, cost, and comparative effectiveness to tofacitinib should be considered prior to prescribing baricitinib. Conclusion: Baricitinib is the second medication in its class and has been proven efficacious for the treatment of RA. Given concerns for adverse effects associated with baricitinib, it should be reserved for patients who have failed one or more TNFis.
31498068 Increased serum levels of microfibrillar-associated protein 4 (MFAP4) are not associated w 2020 Jan OBJECTIVES: To study circulating MFAP4 in rheumatoid arthritis (RA) and its associations with clinical phenotype. METHODS: Early RA (ERA): 47 patients with newly diagnosed, treatment naïve RA were included. Serum MFAP4, clinical and laboratory disease variables were recorded serially during 12 months of intensive synovitis suppressive treatment. Long-standing RA (LRA): 317 patients participated, all receiving DMARD treatment. Disease activity, autoantibody status, extra-articular manifestations and cardiovascular morbidity were recorded. Paired serum and synovial fluid samples were obtained from 13 untreated ERA patients. Healthy blood donors served as reference points. MFAP4 was quantified by AlphaLISA immunoassay. Univariate, multivariate and mixed effects regression models were applied in the statistical analysis. RESULTS: ERA: MFAP4 increased from baseline and was significantly elevated at the 12-month follow-up, 17.8 U/l [12.6;24.1] vs. healthy controls, 12.7 U/l [9.5;15.6], p<0.001. MFAP4 did not correlate with joint counts or C-reactive protein. LRA: MFAP4 was increased, 25.9 U/l [20.4;33.7] vs. healthy controls, 17.6 U/l [13.7;21.2], p<0.0001, but did not correlate with disease activity measures or presence of extra-articular manifestations. Notably, MFAP4 correlated inversely with smoking (p<0.0001) and presence of antibodies against cyclic citrullinated peptides (anti-CCP), p=0.005. There was a positive association with systolic blood pressure, p=0.001 and co-occurrence of three cardiovascular events and/or risk factors, p<0.0001. The serum:synovial fluid MFAP4 ratio was 2:1. CONCLUSIONS: MFAP4 increases from diagnostic baseline despite intensive treatment but does not associate with synovitis at early or late stages of RA. Correlation patterns indicate that increased MFAP4 may reflect enhanced RA-related vascular remodelling.
31394720 Infrared Thermography Sensor for Disease Activity Detection in Rheumatoid Arthritis Patien 2019 Aug 7 A recent review of thermography studies in rheumatoid arthritis shows limited data about disease activity and mostly focuses on differences between the thermography of rheumatoid arthritis patients and typical subjects. A retrospective study compared patients with high disease activity (n = 50), moderate disease activity (n = 16), and healthy participants (n = 42), taking into account demographic, clinical, laboratory, and thermography parameters. We applied an infrared thermography sensor and a fingers examination protocol. Outcomes included the mean temperature of five fingers of a hand: In static, post-cooling, post-rewarming, the total change in mean temperature of fingers due to cold provocation, the total change in mean temperature of fingers due to rewarming, the area under the cooling curve, the area under the heating curve, the difference between the area under the rewarming and the cooling curve, and temperature intensity distribution maps. For patients with high disease activity, a lower area under the heating curve and a lower difference between the area under the rewarming curve and the cooling curve were observed, as well as a smaller total change in mean temperature due to rewarming, compared to patients with moderate disease activity (p < 0.05). Our study findings could be helpful in patients with an equivocal clinical examination.
31285419 IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like syno 2019 Jul 8 Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovial inflammation. The major drivers of synovial inflammation are cytokines and chemokines. Among these molecules, TNF activates fibroblast-like synoviocytes (FLSs), which leads to the production of inflammatory mediators. Here, we show that TNF regulates the expression of the transcription factor interferon regulatory factor 1 (IRF1) in human FLSs as well as in a TNF transgenic arthritis mouse model. Transcriptomic analyses of IRF1-deficient, TNF-stimulated FLSs define the interferon (IFN) pathway as a major target of IRF1. IRF1 expression is associated with the expression of IFNβ, which leads to the activation of the JAK-STAT pathway. Blocking the JAK-STAT pathway with the Janus kinase inhibitor (JAKinib) baricitinib or tofacitinib reduces the expression of IFN-regulated genes (IRGs) in TNF-activated FLSs. Therefore, we conclude that TNF induces a distinct inflammatory cascade, in which IRGs are key elements, in FLSs. The IFN-signature might be a promising biomarker for the efficient and personalized use of new treatment strategies for RA, such as JAKinibs.
31787644 [Protection of the Skin Barrier Function in Inflammatory Disease]. 2019 The skin is the largest human organ, comprising the epidermis that is composed of epithelial tissue, the dermis composed of connective tissue, and the innermost subcutaneous tissue. Generally, skin conditions are due to aging and the influence of the external environment, but empirically patients with gastrointestinal diseases are more prone to pruritus and inflammation caused by dry skin. A decrease in the skin barrier function, involving immunocompetent mast cells and oxidative stress, was noted in indomethacin-induced small intestine inflammation, dextran sodium sulfate (DSS)-induced ulcerative colitis, and azoxymethane+DSS-induced colorectal cancer. A possible correlation was found to exist between inflammatory gastrointestinal diseases and the skin, and this correlation was investigated using a rheumatoid arthritis model as representative of inflammatory diseases. Similar to previously reported results, deterioration of the skin barrier function was observed, and new information was obtained by analyzing changes in inflammatory markers in the blood and skin tissues. Understanding the underlying mechanism of decreased skin barrier function will help in establishing effective prophylaxis and treatment methods and clarify the importance of crosstalk between organs. It will also help accelerate drug development.
31421936 A Minimum 5-Year Longitudinal Study of a New Total Wrist Arthroplasty in Patients With Rhe 2020 Mar PURPOSE: To evaluate the longitudinal clinical outcomes using a new semiconstrained wrist prosthesis for the treatment of severe rheumatoid arthritis of the wrist. METHODS: Twenty patients with rheumatoid arthritis (20 wrists) underwent total wrist arthroplasty with the prosthesis in a clinical trial. The preoperative Larsen classification was grade IV in 16 wrists and grade V in 4 wrists. Assessments were performed before surgery, 1.5 years after surgery, and at final follow-up (≥ 5 years after surgery) using the visual analog scale for pain, Figgie wrist score, Japanese version of the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire, and plain radiographs. RESULTS: At final follow-up, no patient had wrist pain. The preoperative flexion-extension arc at final follow-up was similar to the preoperative range. The mean 1.5-year postoperative Figgie score was significantly improved and was unchanged at final follow-up. The DASH score significantly improved from before surgery to 1.5 years after surgery; the DASH score was improved further at final follow-up, but not significantly. Five of the 19 wrists evaluated had radiographic findings indicating carpal component loosening at final follow-up; however, all patients with the loosening were asymptomatic and had not undergone revision surgery. CONCLUSIONS: Total wrist arthroplasty using this wrist prosthesis leads to favorable clinical outcomes regarding pain relief and retained range of wrist motion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.
31275320 The Rheumatoid Arthritis Risk Gene AIRE Is Induced by Cytokines in Fibroblast-Like Synovio 2019 The autoimmune regulator AIRE controls the negative selection of self-reactive T-cells as well as the induction of regulatory T-cells in the thymus by mastering the transcription and presentation of tissue restricted antigens (TRAs) in thymic cells. However, extrathymic AIRE expression of hitherto unknown clinical significance has also been reported. Genetic polymorphisms of AIRE have been associated with rheumatoid arthritis (RA), but no specific disease-mediating mechanism has been identified. Rheumatoid arthritis is characterized by a systemic immune activation and arthritis. Activated fibroblast-like synoviocytes (FLS) are key effector cells, mediating persistent inflammation, and destruction of joints. In this study, we identified AIRE as a cytokine-induced RA risk gene in RA FLS and explored its role in these pathogenic stroma cells. Using RNA interference and RNA sequencing we show that AIRE does not induce TRAs in FLS, but augments the pro-inflammatory response induced by tumor necrosis factor and interleukin-1β by promoting the transcription of a set of genes associated with systemic autoimmune disease and annotated as interferon-γ regulated genes. In particular, AIRE promoted the production and secretion of a set of chemokines, amongst them CXCL10, which have been associated with disease activity in RA. Finally, we demonstrate that AIRE is expressed in podoplanin positive FLS in the lining layer of synovial tissue from RA patients. These findings support a novel pro-inflammatory role of AIRE at peripheral inflammatory sites and provide a potential pathological mechanism for its association with RA.
30221841 Adverse Events and Resource Use Before and After Treat-to-Target in Rheumatoid Arthritis: 2019 Sep OBJECTIVE: Treat-to-target (TTT) is an accepted paradigm for care of patients with rheumatoid arthritis (RA). Because TTT can be associated with more medication switches, concerns arise regarding whether implementing TTT may increase adverse events and/or resource use. The aim of this study was to examine adverse events and resource use during the preintervention and intervention periods of the TTT intervention trial. METHODS: We used data from 6 practices enrolled in an 18-month cluster-randomized controlled trial to compare adverse events and resource use before (months 1-9) and during (months 10-18) a TTT intervention. The outcomes of interest, adverse events and resource use, were based on medical record review of all rheumatology visits for RA patients before and during the intervention. RESULTS: We examined records for 321 patients before the intervention and 315 during the intervention. An adverse event was recorded in 10.2% of visits before the intervention and 8.8% of visits during the intervention (P = 0.41). Biologic disease-modifying antirheumatic drugs were taken by 53.6% of patients before the intervention and 49.8% of patients during the intervention (P = 0.73). Rheumatology visits were more frequent before the intervention (mean ± SD 4.0 ± 1.4) than during the intervention (mean ± SD 3.6 ± 1.2; P = 0.02). More visits were accompanied by monitoring laboratory tests before the intervention (90.0%) compared with during the intervention (52.7%; P < 0.001). A greater percentage of visits before the intervention included diagnostic imaging (15.4%) versus during the intervention (8.9%; P < 0.001). CONCLUSION: We observed similar rates of adverse events before and during the implementation of TTT for RA. Rheumatology visits, use of laboratory monitoring, and diagnostic imaging did not increase during the TTT intervention.
30169706 Dose tapering and discontinuation of biological therapy in rheumatoid arthritis patients i 2019 Jan 1 OBJECTIVES: A cohort of routine care RA patients in sustained remission had biological DMARD (bDMARDs) tapered according to a treatment guideline. We studied: the proportion of patients whose bDMARD could be successfully tapered or discontinued; unwanted consequences of tapering/discontinuation; and potential baseline predictors of successful tapering and discontinuation. METHODS: One-hundred-and-forty-three patients (91% receiving TNF inhibitor and 9% a non-TNF inhibitor) with sustained disease activity score (DAS28-CRP)⩽2.6 and no radiographic progression the previous year were included. bDMARD was reduced to two-thirds of standard dose at baseline, half after 16 weeks, and discontinued after 32 weeks. Patients who flared (defined as either DAS28-CRP ⩾ 2.6 and ΔDAS28-CRP ⩾ 1.2 from baseline, or erosive progression on X-ray and/or MRI) stopped tapering and were escalated to the previous dose level. RESULTS: One-hundred-and-forty-one patients completed 2-year follow-up. At 2 years, 87 patients (62%) had successfully tapered bDMARDs, with 26 (18%) receiving two-thirds of standard dose, 39 (28%) half dose and 22 (16%) having discontinued; and 54 patients (38%) were receiving full dose. ΔDAS28-CRP0-2yrs was 0.1((-0.2)-0.4) (median (interquartile range)) and mean ΔTotal-Sharp-Score0-2yrs was 0.01(1.15)(mean(s.d.)). Radiographic progression was observed in nine patients (7%). Successful tapering was independently predicted by: ⩽1 previous bDMARD, male gender, low baseline MRI combined inflammation score or combined damage score. Negative IgM-RF predicted successful discontinuation. CONCLUSION: By implementing a clinical guideline, 62% of RA patients in sustained remission in routine care were successfully tapered, including 16% successfully discontinued at 2 years. Radiographic progression was rare. Maximum one bDMARDs, male gender, and low baseline MRI combined inflammation and combined damage scores were independent predictors for successful tapering.
30456455 Role of miR-9-5p in preventing peripheral neuropathy in patients with rheumatoid arthritis 2019 Jan MicroRNAs (miRNAs) are found to play a key role in neural cell differentiation, peripheral nerve injury, and rheumatoid arthritis (RA). However, no study has yet been conducted highlighting their role in RA-induced peripheral neuropathy. Here, we investigated the role of miRNAs in RA-induced peripheral neuropathy. Levels of six miRNAs were detected in serum collected from 15 patients with RA and peripheral neuropathy and 16 patients with RA. In vitro, Schwann cells were treated with 0.1 ng/mL IL-6 and 20 ng/mL TNF-α. The expression level of miR-9-5p and its association with the repressor element-1 silencing transcription factor (REST) were investigated. The roles of miR-9-5p and REST in Schwann cell injury were examined after transfection of miR-9-5p mimics or REST siRNA. In patients with RA and peripheral neuropathy, serum miR-9-5p was significantly downregulated when compared with RA. In IL-6- and TNF-α-stimulated Schwann cells, apoptosis was induced, while the cell viability and level of miR-9-5p were inhibited. A significantly negative correlation was observed between miR-9-5p and REST. Transfection of miR-9-5p mimics and REST siRNA significantly reversed the inhibition of cell viability and induction of apoptosis caused by IL-6 and TNF-α. In addition, overexpression of miR-9-5p upregulated the expression of miR-132, miRNA targeting E1A binding protein EP300 (EEP300), phosphatase and tensin homolog (PTEN) and forkhead box O3 (FOXO3). These results showed that Schwann cells were protected by miR-9-5p from inflammatory damage by targeting REST/miR-132 pathway, which could provide new targets for treatment of RA-induced peripheral neuropathy.
30936277 Investigating Dimensions of Stiffness in Rheumatoid and Psoriatic Arthritis: The Australia 2019 Nov OBJECTIVE: It is not known how the experience of stiffness varies between diagnoses or how best to measure stiffness. The aims of our study were to (1) compare stiffness in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) using patient-reported outcomes, (2) investigate how dimensions of stiffness are associated with each other and reflect the patient experience, and (3) analyze how different dimensions of stiffness are associated with physical function. METHODS: An online survey was sent to Australian Rheumatology Association Database participants (158 PsA, and 158 age- and sex-matched RA), assessing stiffness severity, duration, impact, importance, coping, and physical function [modified Health Assessment Questionnaire (mHAQ)]. Scores were compared between diagnoses and correlations among stiffness dimensions calculated. Multivariate regression was performed for stiffness severity, impact, and duration on mHAQ, adjusting for age, sex, disease duration, obesity, and pain. Cognitive debriefing was conducted through semistructured telephone interviews. RESULTS: Overall, 240/316 (75.9%) responded [124/158 RA (78.5%) and 116/158 PsA (73.4%)], with no significant difference in stiffness ratings between diagnoses. Scores for all stiffness dimensions were strongly correlated (r = 0.52-0.89), and severity and impact were associated with mHAQ in both diagnoses. Stiffness duration was not associated with mHAQ in RA. In cognitive debriefing, participants described stiffness severity and impact by their effect on daily activities (10/16 and 14/16 participants, respectively). CONCLUSION: Stiffness ratings were similar between PsA and RA. Different dimensions of stiffness were strongly correlated. Stiffness severity and impact both independently predicted mHAQ. Stiffness was important to participants; however, measuring multiple dimensions of stiffness may have minimal additive value.
31149012 Adaptation of a patient activation measure (PAM) into Turkish: reliability and validity te 2019 Mar BACKGROUND: Patient activation is a central concept in chronic illness care model. Activated patients have ability and willingness to manage their health. OBJECTIVE: Aim of this study was to test the reliability and validity of a Patient Activation Measure. METHODS: Research sample consisted of 130 patients who had diabetes, hypertension or rheumatoid arthritis. Data was collected through socio-demographic information form and a Patient Activation Measure (PAM). Reliability and validity of PAM were analyzed. RESULTS: Internal consistency reliability coefficient of the PAM was α: .81. Correlation coefficients between item and total scale scores varied from .38 to .66. Result of explanatory factor analysis Kaiser Meyer Olkin coefficient was .75 and Barlett test was x2: 646.870; p: 0. 000. Result of confirmatory factor analysis, model fit indexes were x2/df: 1.59, RMSEA: 0.071, CFI: 0.96, NNFI: 0.95. The result of Rasch analysis, reliability coefficient varied from 0.83 to 0.87 and in validity assesment, item fit statistics for INFIT varied from 0.68 to 1.53 and for OUTFIT varied from 0.65 to 1.54. CONCLUSION: PAM has enough validy and reliability for use in determining activation scores and level of the patients in Turkey. It could be used in planing appropriate interventions for the activation level and help to improve self management.
31332965 Contribution of Inflammation and Bone Destruction to Pain in Arthritis: A Study in Murine 2019 Dec OBJECTIVE: Arthritis is often characterized by inflammation and bone destruction. This study was undertaken to investigate the contribution of inflammation and bone destruction to pain. METHODS: Inflammation, bone resorption, pain-related behaviors, and molecular markers (activating transcription factor 3 [ATF-3], p-CREB, and transient receptor potential vanilloid channel 1) in sensory neurons were measured in murine glucose-6-phosphate isomerase (G6PI)-induced arthritis, a model of rheumatoid arthritis. Depletion of Treg cells before immunization changed self-limiting arthritis into nonremitting arthritis with pronounced bone destruction. Zoledronic acid (ZA) was administered to reduce bone resorption. RESULTS: Compared to nondepleted mice, Treg cell-depleted mice exhibited arthritis with more severe bone destruction and higher guarding scores (P < 0.05; n = 10 mice per group) as well as more persistent thermal hyperalgesia (P < 0.05), but displayed similar mechanical hyperalgesia at the hindpaws (n = 18-26 mice per group). These pain-related behaviors, as well as an up-regulation of the neuronal injury marker ATF-3 in sensory neurons (studied in 39 mice), appeared before the clinical score (inflammation) became positive and persisted in Treg cell-depleted and nondepleted mice. In the late stage of arthritis, Treg cell-depleted mice treated with ZA showed less bone resorption (<50%; P < 0.01) and less thermal hyperalgesia (P < 0.01) than Treg cell-depleted mice without ZA treatment (n = 15 mice per group), but ZA treatment did not reduce the clinical score and local mechanical hyperalgesia. CONCLUSION: Pain-related behaviors precede and outlast self-limiting arthritis. In nonremitting arthritis with enhanced bone destruction, mainly local thermal, but not local mechanical, hyperalgesia was aggravated. The up-regulation of ATF-3 indicates an early and persisting affection of sensory neurons by G6PI-induced arthritis.
30773876 Self-Nanoemulsifying Electrospun Fiber Enhancing Drug Permeation. 2019 Feb 27 Electrospun fibers are excellent drug carriers and tissue engineering scaffolds. However, approaches to promote drug permeation in tissues with such carriers remain of great interest. Here, we propose a Quality-by-Design strategy to enhance drug permeation with self-nanoemulsifying electrospun fibers. Owing to the nanoemulsion which formed spontaneously when the polymer contacts aqueous solution such as body fluid, the resulting drug-laden fibrous membrane exhibits an outstanding drug permeation and therapeutic enhancement effect in a Franz cell experiment with ex vivo abdomen skin of rats, an artificial connective tissue model, and an in vivo rheumatoid arthritis model in rats. Meanwhile, the material also shows the capacity of rational regulation on the rate of drug release. These features of the present strategy establish our material as a new efficient approach for various clinical conditions calling for cure.
31507112 [RITUXIMAB IN RHEUMATOID ARTHRITIS - THERAPEUTIC ASPECTS BASED ON 18 YEARS OF GLOBAL EXPER 2019 Sep Rituximab, a monoclonal antibody against CD20 positive B cell, depletes these cells peripherally, and is a successful treatment in rheumatoid arthritis (RA). It is the second efficacious biologic to be established in the treatment of RA after TNFα blockers. Eighteen years of global experience from diverse clinical trials and from "real world" data, have demonstrated clinical efficacy in various disease scenarios and patient populations - short and long disease duration, methotrexate naïve patients and those with incomplete response to methotrexate, biologic naïve patients and those with incomplete response to previous biologics. Moreover, it has demonstrated the inhibition of radiographic progression. It seems to be most efficacious in seropositive patients. Despite vast experience, the need for concomitant traditional disease-modifying anti rheumatic drugs (DMARD), the optimal retreatment dose, and the favored retreatment interval remain somewhat uncertain. The recommended dosage is 1000 mg, administered twice, with a 2 weeks interval, although in some cases, a reduced dosage of 500 mg, administered twice may be considered. The safety profile of rituximab includes mainly infusion-related reactions, which are usually mild. A small risk of major infections has remained stable over time and repeated courses. Opportunistic infections are infrequent. Nevertheless, reactivation of hepatitis B is still a concern. Tuberculosis, malignancies, cardiovascular events and deterioration of interstitial lung disease do not appear to be increased. Since rituximab severely impairs the humoral response to vaccinations, they should be administered prior to treatment whenever possible. Rituximab has been a powerful addition to the large armamentarium for the treatment of RA. Rituximab is indicated in Israel as a second line biologic treatment for active RA.
31210083 Suboptimal cardiovascular risk management in rheumatoid arthritis patients despite an expl 2019 Sep Objective: In 2011, we started to offer cardiovascular (CV) risk screening to rheumatoid arthritis (RA) patients with a high CV risk. After 1 year, we assessed whether patients labelled as high CV risk had started preventive treatment when indicated, and whether the CV risk score had changed. Methods: CV risk screening was performed in both a large outpatient rheumatology clinic and a general hospital in the Netherlands, and the general practitioner or the internist was informed about the results of the CV screening, including specific advice on the initiation or adjustment of cardiopreventive drugs. National guidelines were used to assess how many patients were eligible for preventive treatment. After 1 year, CV risk, lifestyle, and treatment were re-evaluated. Patients with a history of CV disease at baseline or who experienced a CV event during follow-up were excluded from the analyses. Results: A high 10 year CV risk (> 20%) was present in 58%, and 55% had an indication for anti-hypertensives, statins, or both. At follow-up, cardiopreventive drug treatment had been started or adjusted in only one-third of patients with an indication for treatment. After screening, 42% of patients reported having changed their lifestyle, through more exercise (24%), diet adaption (20%), and weight loss (11%). Conclusion: Despite clear guidelines to improve CV risk, the results of a programme comprising active screening, targeted advice, and referral to the general practitioner or internist prove that primary prevention remains a major challenge in high-risk RA patients.