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31619364 Evidence of Diagnostic and Treatment Delay in Seronegative Rheumatoid Arthritis: Missing t 2019 Nov OBJECTIVES: To compare the time from first joint swelling to fulfillment of the American College of Rheumatology/European League Against Rheumatism classification criteria between patients with seropositive and seronegative rheumatoid arthritis (RA) and to assess the impact of seronegative status on the time from first joint swelling to initiation of disease-modifying antirheumatic drug (DMARD) therapy and achievement of remission. PATIENTS AND METHODS: Times from first provider-documented joint swelling to fulfillment of the 1987 and 2010 American College of Rheumatology/European League Against Rheumatism criteria and to the clinical diagnosis of RA were measured in a population-based cohort of adults with incident RA between January 1, 2009, and December 31, 2014. Disease characteristics and achievement of remission were compared between seropositive (rheumatoid factor positive and/or anti-citrullinated peptide antibody positive) and seronegative (rheumatoid factor negative/anti-citrullinated peptide antibody negative) patients. RESULTS: The median time from first joint swelling to fulfillment of the 1987 (48 [interquartile range (IQR), 0-300] days vs 2 [IQR, 0-45] days; P=.001) and 2010 (14 [IQR, 0-196] days vs 0 [IQR, 0-29] days; P=.004) classification criteria and the median time from first joint swelling to the clinical diagnosis of RA (187 [IQR, 13-503] days vs 11 [IQR, 0-76] days; P<.001) were significantly longer in seronegative patients than in seropositive patients. The median time from first joint swelling to first prescribed DMARD therapy was significantly longer in seronegative patients (40 [IQR, 5-199] days vs 14 [IQR, 0-73] days; P=.01). Patients with seronegative RA were less likely to achieve remission (28% vs 50% at 5 years after fulfillment of the 2010 criteria; P=.007), but there was no difference when the patient global score was removed from the remission definition. CONCLUSION: Patients with seronegative RA experienced a delay in diagnosis, according to both the 1987 and 2010 classification criteria, as well as a delay in the initiation of DMARD therapy. Patients with seronegative RA were also less likely to attain remission, suggesting that the window of opportunity for intervention may be more frequently missed in this group.
31474598 The Prevalence of Rheumatoid Arthritis in Chile: A Nationwide Study Performed as Part of t 2020 Jul 1 OBJECTIVE: Genetic and environmental backgrounds influence the development of rheumatoid arthritis (RA). In Latin America, epidemiologic data are scarce. We aimed to determine the prevalence of RA in Chile in a population-based study. METHODS: The National Health Survey was a cross-sectional household survey with a stratified multistage probability sample of 6233 participants performed between August 2016 and March 2017. A screening instrument for RA was applied to a random sample of 3847 subjects > 30 years old. Positive screening was defined by at least 1 of the following: 2 swollen joints for at least 4 consecutive weeks (past/present), and/or a diagnosis of arthritis in the past. Individuals with positive screening had rheumatoid factor, anticitrullinated protein antibodies, and C-reactive protein measured, as well as clinical examination performed by a rheumatologist. Self-report of doctor-diagnosed RA was also performed. RESULTS: The screening questionnaire was applied to 2998 subjects. A positive screening was found for 783 (22.1%). Among subjects with positive screening, 493 (66%) had a clinical evaluation performed by a rheumatologist. Using the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria, prevalence was 0.6% (95% CI 0.3-1.2). Prevalence was higher in women, and 3.3% of subjects self-reported having RA. CONCLUSION: According to this national population-based study, RA prevalence in Chile is 0.6% (0.3-1.2), a value similar to what has been found in developed countries and slightly lower than some Latin American countries. Self-reporting leads to overestimating RA.
30408585 Arthritis in primary Sjögren's syndrome: Characteristics, outcome and treatment from Fren 2019 Jan OBJECTIVE: To describe the characteristics and the outcome of primary Sjögren Syndrome (pSS) associated arthritis and to compare the efficacy of different therapeutic regimen. METHODS: We conducted a retrospective study using Club Rhumatisme and Inflammation (CRI) and French Internal Medicine Society (SNFMI) networks. All patients with a diagnosis of pSS and at least one episode of clinical and/or echographic synovitis were included. Patients with synovitis (cases) were compared to pSS patients without synovitis (controls). RESULTS: 57 patients (93% women) were included with a median age of 54 years [45-63]. Patients with synovitis had more frequently lymph node enlargement (12.3% vs. 1.8%, p = .007) and a higher ESSDAI score (8 [6-12] vs. 2 [1-4], p < .0001). There was no difference concerning CRP levels, rheumatoid factor and cyclic citrullinated peptide (CCP)-antibodies positivity. Among 57 patients with synovitis, 101 various treatment courses have been used during the follow-up of 40 [22.5-77] months. First treatment course consisted in steroids alone (3.5%), steroids in association (79%) with hydroxychloroquine (HCQ) (49%), methotrexate (MTX) (35%), rituximab (RTX) (5.3%) or other immunosuppressive drugs (7%). HCQ, MTX, and RTX were associated with a significant reduction of tender and swollen joint count, and a significant steroids-sparing effect. No difference could be shown for the joint response between these treatment regimens. CONCLUSION: pSS articular manifestations may include synovitis which could mimic rheumatoid arthritis but differ by the absence of structural damage. Even if the use of HCQ, MTX, and RTX seem to be effective for joint involvement, the best regimen remains to be determined.
31722023 Demographic Characteristics of Participants in Rheumatoid Arthritis Randomized Clinical Tr 2019 Nov 1 IMPORTANCE: Racial/ethnic minority groups, women, and elderly people experience a disproportionate burden of disease in rheumatoid arthritis (RA), making it particularly important to examine drug therapies in these populations. Despite a national health agenda to improve representation of diverse populations in randomized clinical trials (RCTs), there have been few large-scale analyses examining RCT demographic characteristics within rheumatology and none focusing on RA. OBJECTIVE: To characterize the representation of racial/ethnic minority groups, women, and elderly people through a comprehensive systematic review of RA RCTs. DATA SOURCES: A literature search of PubMed's MEDLINE database was conducted to identify RA RCTs in adults 19 years and older published in English between January 1, 2008, and January 1, 2018. STUDY SELECTION: Randomized double-blind RCTs examining any systemic, disease-modifying therapy were included. Secondary analyses of previously published RCTs were excluded. Of 1195 identified records, 240 articles (20.1%) met final selection criteria. The analysis focused on RCTs with at least 1 US-based site. DATA EXTRACTION AND SYNTHESIS: Data were extracted and synthesized according to the PRISMA guidelines for systematic reviews. Studies were screened for eligibility criteria. Demographic data on the age, sex, and race/ethnicity of RCT participants were extracted. Data analysis was conducted from October 25, 2018, to March 15, 2019. MAIN OUTCOMES AND MEASURES: Representation of race/ethnicity and sex, defined as the proportion of total participants that belonged to each racial/ethnic group or sex. Trends in proportions over time were examined and compared with US demographic data. RESULTS: A total of 240 RCTs with 77 071 participants were included. Of 126 RCTs with at least 1 US-based site (52.5%), the enrollment of minority racial/ethnic groups was significantly lower than their representation within the US Census population (16% vs 40%; P < .001), and the enrollment of men was significantly lower than the incidence of RA in men nationally (20.4% vs 28.6%; P < .001). There was no trend toward improved representation of racial/ethnic minority groups or men over time. CONCLUSIONS AND RELEVANCE: Given the disproportionate burden of RA among racial/ethnic minority groups, it is imperative that policy makers better incentivize the inclusion of racial/ethnic minority groups in RA RCTs.
31491879 Different Original and Biosimilar TNF Inhibitors Similarly Reduce Joint Destruction in Rhe 2019 Sep 5 The effect of five approved tumour necrosis factor inhibitors (TNFi: infliximab, etanercept, adalimumab, certolizumab, and golimumab) on joint destruction in rheumatoid arthritis (RA) have been compared versus methotrexate (MTX) in randomized controlled trials (RCTs) but have not been compared directly to each other or to an otherwise untreated placebo control. The present analysis compares effects of standard doses, high doses, and low doses of TNFis on radiographic joint destruction in RA and relate these effects to MTX and placebo by means of a Bayesian network meta-analysis. We identified 31 RCTs of the effect of TNFis on joint destruction and 5 RCTs with controls, which indirectly could link otherwise untreated placebo controls to the TNFi treatments in the network. The previously untested comparison with placebo was performed to estimate not only the effect relative to another drug, but also the absolute attainable effect. Compared to placebo there was a highly significant inhibitory effect on joint destruction of infliximab, etanercept, adalimumab, certolizumab, and golimumab, which was about 0.9% per year as monotherapy and about 1.2% per year when combined with MTX. Although significantly better than MTX and placebo, golimumab seemed inferior to the remaining TNFis. There was no difference between original reference drugs (Remicade, Enbrel) and the almost identical copy drugs (biosimilars).
30506510 Association between activity and genotypes of paraoxonase1 L(55)M (rs854560) increases the 2019 Feb Rheumatoid arthritis (RA) is considered as a long-term autoimmune disorder. Gene polymorphism and oxidative stress might be involved in the pathogenesis of the disease. We aimed to determine the association between PON-1L55M polymorphism and its effects on inflammatory markers such as anti-cytroline circulated-peptide (CCP)-antibodies, C-reactive protein (CRP), neopterin serum concentration, arylesterase (ARE) and butyrylcholinesterase (BuChE) activities and total-antioxidant-capacity (TAC) level with the activity of disease in RA patients. This case-control study consisted of 419 RA patients and 397 gender-age-matched unrelated healthy controls from the west of Iran. PON1-L55M polymorphism was detected by real-time-PCR. The TAC level, serum BuChE and ARE activities were determined spectrophotometrically. Anti-CCP-antibody and CRP were measured by ELISA and neopterin level was detected by HPLC. The PON1-M55 allele was associated with increased risk of the RA in cases with moderate or high activity (OR = 1.43, p = 0.023) and also in cases with the presence of anti-CCP antibody (OR = 1.51, p = 0.009). Synergistic effects of PON1 M55 and Q192 alleles resulted in 2.14 times (p = 0.021) increased disease activity among RA patients with moderate or high activity of the disease. RA patients carried both M (PON1 L55M) and Q alleles (PON1Q192R) had higher concentrations of neopterin (p = 0.003), anti-CCP-antibody (p < 0.001) and CRP (p = 0.026) and significantly lower TAC level (p < 0.001) and ARE (p < 0.001) activity compared to controls. The current study suggests there might be a relationship between genetic and activity of PON. Also, the PON1L55M and PON1Q192R could act in synergy to increase the risk of RA and enhance the level of oxidative stress markers.
30635304 Rheumatoid arthritis presenting as rheumatoid meningitis. 2019 Jan 10 Rheumatoid meningitis (RM) is a rare extra-articular manifestation of rheumatoid arthritis (RA). A 59-year-old man presented with a 10-day history of right-sided frontal headache and a 7-day history of subacute left-sided weakness. He had no history of RA. He was febrile (38.2°C). Left ankle dorsiflexion and plantarflexion were graded at 4+/5. He developed focal onset motor seizures. He was intermittently febrile with minimal improvement despite intravenous antivirals and antimicrobials. Serology revealed elevated rheumatoid factor 88.2 IU/mL and anti-cyclic citrullinated peptide (anti-CCP) IgG >340 AU/mL. Initial cerebrospinal fluid (CSF) was predominantly lymphocytic 96%, with elevated protein 672 mg/L and normal glucose 3.4 mmol/L. Interval CSF revealed newly low glucose 2.6 mmol/L. Extensive CSF microbiology tests were negative. CSF cytology confirmed reactive lymphocytes. MRI brain revealed right frontoparietal leptomeningeal enhancement. Brain and leptomeningeal biopsy demonstrated florid leptomeningeal mixed inflammatory infiltrate without granulomas. The combination of elevated anti-CCP IgG, erosive arthropathy, CSF lymphocytosis, asymmetrical leptomeningeal enhancement and biopsy findings confirmed RM.
31011897 CCL5 and related genes might be the potential diagnostic biomarkers for the therapeutic st 2019 Sep OBJECTIVE: Rheumatoid arthritis (RA) is a common disease of rheumatic diseases. The aim of this study was to identify gene signatures in RA and uncover their potential mechanisms. METHOD: Gene expression profiles of GSE1919, GSE55235, GSE55457, and GSE77928 were downloaded from GEO database. The above four series contained 76 samples, including 44 RA patients and 32 normal controls. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, and protein-protein interaction (PPI) network of the differentially expressed genes (DEGs) was constructed by Cytoscape software. RESULTS: Up-regulated DEGs were significantly enriched in biological processes, including immune response, positive regulation of immune system process and regulation of immune system process, while down-regulated DEGs were significantly enriched in biological processes, including response to oxygen-containing compound, cellular lipid metabolic process, and lipid metabolic process. KEGG pathway analysis showed the up-regulated DEGs were enriched in cytokine-cytokine receptor interaction, chemokine signaling pathway, and primary immunodeficiency. The 104 hub genes, which were significantly differently expressed between patients and normal controls in at least two datasets, were identified from the PPI network, and subnetworks revealed that these genes were involved in significant pathways, including cytokine-cytokine receptor interaction, chemokine signaling pathway, and primary immunodeficiency. CONCLUSION: The present study indicated that the identified DEGs and hub genes promote our understanding of molecular mechanisms underlying the development of RA, such as C-C motif chemokine 5 (CCL5), might have a negative impact in the development of RA. CCL5 and its related genes might be the potential diagnostic biomarkers for the therapeutic strategies of RA.
30620280 Geriatric syndromes in patients with rheumatoid arthritis: a literature overview. 2019 May Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease of unknown aetiology which principally affects the small joints of the hands and feet. The incidence of RA increases with age and peaks within the age range of 70 to 79 years. In the ageing population, therefore, it is expected that the number of patients with RA will grow proportionally and more patients will have comorbidities but also so-called geriatric syndromes (GS). GS are clinical and multifactorial conditions in older persons that are associated with poor health outcomes, do not fit into disease categories (comorbidities) and require a multidimensional treatment approach. Patients suffering from RA may be at increased risk for GS. Therefore, it is important that rheumatologists are knowledgeable about the constructs represented by GS, understand the main risk factors, and gain insight in how to recognise these syndromes. Limited awareness of the (risk for) GS in patients with RA among rheumatologists may lead to ineffective management of RA. Our objective was to provide a comprehensive overview about the prevalence, aetiologic factors and health consequences of the most important GS in patients with RA.
31515704 The Design and Rationale of the Trail1 Trial: A Randomized Double-Blind Phase 2 Clinical T 2019 Nov INTRODUCTION: Rheumatoid arthritis (RA) is the most common of the connective tissue diseases (CTD), affecting up to 0.75% of the United States (U.S.) population with an increasing prevalence. Interstitial lung disease is prevalent and morbid condition in RA (RA-ILD), affecting up to 60% of patients with RA, leading to premature death in 10% and accruing an average of US$170,000 in healthcare costs per patient over a 5-year period. Although there have been significant advances in the management of this joint disease, there are no ongoing randomized clinical trials looking at pharmacologic treatments for RA-ILD, and there currently are no U.S. Food and Drug Administration-approved drugs for RA-ILD. METHODS/DESIGN: We describe the Treatment for Rheumatoid Arthritis and Interstitial Lung Disease 1 (TRAIL1) trial, a multicenter randomized, double-blind, placebo-controlled, phase 2 study of the safety, tolerability and efficacy of pirfenidone in patients with RA-ILD. The study will enroll approximately 270 subjects across a network of sites who have RA and ILD as defined by a fibrotic abnormality involving greater than 10% of the lung parenchyma. The primary endpoint of the study is the incidence of the composite endpoint of decline in percent predicted forced vital capacity of 10 or greater or death during the 52-week study period. A number of secondary and exploratory endpoints have been chosen to evaluate the safety and efficacy in different domains. DISCUSSION: The TRAIL1 trial is designed to evaluate the safety and efficacy of pirfenidone in RA-ILD, a disease with significant impact on patients' quality of life and outcome. In addition to investigating the safety and efficacy of pirfenidone, this trial looks at a number of exploratory endpoints in an effort to better understand the impact of therapy on areas such as changes in quantitative high-resolution computed tomography scores and a patient's quality of life. Biospecimens will be collected in order to investigate biomarkers that could potentially predict the subtype of disease, its behavior over time, and its response to therapy. Finally, by creating a network of institutions and clinician investigators with an interest in RA-ILD, this trial will pave the way for future studies of investigational agents in an effort to reduce or eliminate the burden of disease for those suffering from RA-ILD. TRIAL FUNDING: Genentech, a member of the Roche Group. TRIAL REGISTRATION: Clinicaltrials.gov, identifier NCT02808871.
30706334 2-Stage classification of knee joint thermograms for rheumatoid arthritis prediction in su 2019 Mar Presence of inflammation in knee joint is the early indication of arthritis. In this paper, we performed the inflamed region segmentation from knee joint thermograms for structural feature extraction based knee abnormality prediction. Existing four popular segmentation techniques are investigated, namely K-means, Fuzzy C-means, Otsu, Single seeded region growing. We proposed modified multi-seeded region growing method that generates 98.6% accurate segmentation rate compared to ground truth of inflammation. Based on the spread of the inflammation oriented structural feature analysis, in the first stage of classification we classified arthritis affected knee joint thermograms, and all other types of thermograms (non-arthritis) with 91% accuracy. Among different types of arthritis, the most damaging type that causes disability of joints in long run is known as rheumatoid arthritis (RA). Early diagnosis of RA in subclinical stage enormously helps clinicians to decrease the disease affect. In second stage of classification, we integrated the RA and non-RA categorization by extracting texture, shape and frequency level features. Experiment shows that the combination of all features decreases the accurate detection rate of RA classification. To increase the classification rate, we incorporated the accuracy based feature selection procedure. The RA classification rate obtained with accuracy based feature selection is 73% whereas existing support vector machine-recursive feature elimination (SVM-RFE) and RELIEF methods provide 67% and 71% correct classification rate respectively. The area under the curve (AUC) of accuracy based feature selection, SVM-RFE, and RELIEF for RA classification are 0.72, 0.65 and 0.67, respectively and it indicates better classification outcome of the accuracy based feature selection method.
30989961 [Regularity of prescription and medication of Jiang Quan in treating rheumatoid arthritis] 2019 Jan The data mining method was used to analyze and summarize the prescription and medicate regularities of chief physician Jiang Quan in the treatment of rheumatoid arthritis,in order to provide references for the clinical treatment of rheumatoid arthritis. Totally 121 prescriptions of rheumatoid arthritis treated by chief physician Jiang Quan from 2007 to 2017 were collected and input into the Chinese medicine inheritance auxiliary system. The " prescription statistics" function of the software " statistical report" system,and the " prescription analysis" function of the " data analysis" system,the data mining methods such as rule analysis,integration correlation,complex system entropy clustering,and unsupervised entropy hierarchical clustering,were used to analyze the prescription regularity of chief physician Jiang Quan. A total of 121 prescriptions were included,involving 144 herbs,in which 30 herbs had a higher frequency of more than 20 times,20 two-herb combinations had a frequency of more than 59 times; after evolution,14 core combinations and 7 new prescriptions were obtained. Among the prescriptions in the treatment of rheumatoid arthritis,those for clearing heat and dampness,promoting blood circulation and removing blood stasis had a higher frequency,and the core prescriptions were modified " Qingre Huoxue Decoction" and modified " Ermiao Pills". The newly evolved prescriptions not only reflected director Jiang Quan' s method of treating rheumatoid arthritis by clearing away heat and dampness and promoting blood circulation by the,but also included the treatment methods of removing wind and removing dampness,dredging collaterals and removing phlegm,nourishing Yin and clearing heat,nourishing Yin and nourishing kidney,nourishing blood and nourishing Qi. The method can be used to analyze the pathogenetic changes of the mutual knot of phlegm and blood stasis,injury of Qi and blood,long-term implication on liver and kidney. At the same time,it also reflects the treatment principles of treating phlegm and strengthening the evil.
30942638 Expressions of circadian clock genes represent disease activities of RA patients treated w 2020 Mar Objectives: Rheumatoid Arthritis (RA) is the autoimmune disease representing the circadian variations of symptoms such as morning stiffness of joints or increased production of cytokines around midnight. Clock genes have been reported to affect on the pathogenesis of RA, however, the detailed relation between clock genes and disease activities of RA has remained unclear.Methods: In this study, 15 RA patients treated with biological disease modifying anti-rheumatic drugs (bDMARDs) were enrolled (TNF inhibitor, 5; IL-6 inhibitor, 5; CTLA4-IgG, 5). Blood samples were collected from RA patients before treatment and at the study end-point fulfilling DAS28-ESR < 3.2. Total RNA was extracted from leukocytes to examine the expressions of the clock genes. We then evaluated the correlation of the clock gene expression with disease activity and the diagnostic values of the clock genes.Results: The expressions of the clock genes were significantly modulated by bDMARDs treatments. Disease activities were significantly correlated with the clock genes expressions, and disease remission/low disease activity could be distinguished from moderate/high disease activity due to the sensitivities, the specificities and the areas under the curves of that.Conclusion: The expressions of the clock genes in leukocytes could be useful as novel biomarkers predicting disease activities and therapeutic efficacies for bDMARDs in RA treatments.
31266534 Ultrasound inflammatory parameters and Treg/Th17 cell profiles in established rheumatoid a 2019 Jul 2 BACKGROUND: Imbalance and disfuntion in regulatory T-cells (Tregs) and IL-17 producer lymphocytes (Th17) have been implicated in the pathogenesis of rheumatoid arthritis (RA). Gray scale synovial proliferation (GS), power Doppler signal (pD) and bone erosions seen on high resolution muskuloskeletal ultrasound (MSUS) are hallmarks of destructive articular disease. OBJECTIVE: To evaluate the association of peripheral Tregs and Th17 with MSUS findings in RA. METHODS: RA patients (1987 ACR criteria) treated with disease-modifying antirheumatic drugs (DMARDs) were included. Lymphocytes were isolated and immunophenotyped by flow cytometry to investigate regulatory FoxP3+ T cells and IL-17+ cells. MSUS (MyLab 60, Esaote, Genova, Italy, linear probe 6-18 MHz) was performed on hand joints, and a 10-joint US score was calculated for each patient. RESULTS: Data on lymphocytes subsets were avaiable for 90 patients. The majority of patients were Caucasian women with a median disease duration of 6 years (interquartile range: 2-13 years). Mean DAS28 was 4.28 (SD ± 1.64) and mean HAQ score was 1.11 (SD ± 0.83). There was no significant correlation of 10-joint GS score (rS = 0.122, 95% CI: - 0.124 to 0.336, P = 0.254) and 10-joint pD score (rS = 0.056, 95% CI: - 0.180 to 0.273, P = 0.602) with the mean percentage of peripheral Treg cells. Also, 10-joint GS score (rS = 0.083, 95% CI: - 0.125 to 0.302, P = 0.438) and 10-joint pD score 10 (rS = - 0.060, 95% CI: - 0.271 to 0.150, P = 0.575); did not correlate to Th17 profile. No association of bone erosions on MSUS with Treg and Th17 profiles (P = 0.831 and P = 0.632, respectively) was observed. CONCLUSION: In this first study addressing MSUS features and lymphocytes subtypes in established RA, data did not support an association of circulating Tregs and Th17 lymphocytes with inflammatory and structural damage findings on MSUS.
31472320 Accumulation of cytosolic dsDNA contributes to fibroblast-like synoviocytes-mediated rheum 2019 Nov The accumulation of cytosolic dsDNA plays important roles in the regulation of cellular processes. However, whether cytosolic dsDNA is involved in the pathogenesis of rheumatoid arthritis (RA) is not clear. Therefore, the present study investigated the roles of cytosolic dsDNA in the modulation of inflammatory responses of fibroblast-like synoviocytes (FLS) in patients with RA. FLS were obtained from active RA patients. dsDNA accumulation in the cytosol was detected by immunofluorescence staining and the Qubit® dsDNA HS Assay. Immunohistochemistry was employed to detect the dsDNA and cGMP-AMP synthase (cGAS) expression in the synovium. Short hairpin RNA (shRNA) was used to knockdown the expression of cGAS and stimulator of interferon genes (STING). Protein expression was detected by Western blotting and immunofluorescence staining. We observed increased cytosolic dsDNA and cGAS expression in FLS and synovium from RA patients. dsDNA and cGAS expression correlated with the severity of rheumatoid synovitis. Transfection of dsDNA into the cytosol of RA FLS promoted pro-inflammatory cytokines production. DNaseII overexpression downregulated cytosolic dsDNA expression and inhibited dsDNA-induced cytokines secretion. We also found that dsDNA and TNF-α enhanced cGAS and STING expression, and dsDNA-induced cytokine secretion was reduced by cGAS or STING knockdown. Furthermore, we determined that the dsDNA-induced phosphorylation of IRF3 and NF-κBp65 was decreased by DNaseII overexpression or cGAS/STING knockdown. Overall, our findings show that increased cytosolic dsDNA level promoted inflammatory responses via the cGAS/STING pathway in RA FLS, which suggests that cytosolic dsDNA accumulation is an important contributor to FLS-mediated rheumatoid synovial inflammation.
30822342 SNR analysis of contrast-enhanced MR imaging for early detection of rheumatoid arthritis. 2019 OBJECTIVE: To investigate whether signal to noise (SNR) analysis of contrast-enhanced MRI gives additional benefit for early disease detection by Magnetic Resonance Imaging (MRI) of experimental rheumatoid arthritis (RA) in a small animal model. METHODS: We applied contrast-enhanced MRI at 7T in DBA mice with or without collagen-induced arthritis (CIA). Clinical score, OMERACT RAMRIS analysis and analysis of signal to noise ratios (SNR) of regions of interest in RA bearing mice, methotrexate/methylprednisolone acetate treated RA and control animals were compared with respect to benefit for early diagnosis. RESULTS: While treated RA and control animals did not show signs of RA activity in any of the above-mentioned scoring methods at any time point analyzed, RA animals revealed characteristic signs of RA in RAMRIS at the same time point when RA was detected clinically through scoring of the paws. The MR-based SNR analysis detected signs of synovitis, the earliest indication of RA, not only in late clinical stages, but also at an early stage when little or no clinical signs of RA were present in CIA animals and RAMRIS did not allow a distinct early detection. CONCLUSION: SNR analysis of contrast-enhanced MR imaging provides additional benefit for early arthritis detection in CIA mice.
31433680 Economic burden of fatigue or morning stiffness among patients with rheumatoid arthritis: 2020 Jan Objective: Determine healthcare resource utilization (HCRU) and costs associated with fatigue and stiffness among patients with rheumatoid arthritis (RA).Methods: A retrospective claims analysis compared RA patients with fatigue or stiffness to matched RA control patients with neither. Claims from a large US commercial insurance database identified new cases of stiffness/fatigue among newly diagnosed patients. Study patients had ≥2 medical claims for RA ≥45 days apart, continuous insurance coverage ≥12 months before RA index (baseline period) and ≥12 months after fatigue/stiffness index (follow-up period). Controls had no diagnosis of fatigue or stiffness ≥12 months before index. Cases had ≥1 claim of fatigue/stiffness after RA index; the first such claim was the index date. Multivariate logistic regressions, adjusting for baseline demographics, comorbidities, medication use and HCRU, were used to predict the propensity of having a fatigue/stiffness diagnosis. Controls were propensity-score matched to cases. Generalized linear models estimated all-cause and RA-specific costs associated with resource use as well as prescription drugs, adjusting for any unbalanced covariates after propensity-score matching.Results: Approximately 32% of newly diagnosed RA patients suffer from fatigue/stiffness. Matched cohorts were analyzed: fatigue vs. control; stiffness vs. control; fatigue and stiffness vs. control. After RA diagnosis, hospitalizations increased: 83% for fatigue, 117% for stiffness and 148% for both; total office visits increased 63%, 113% and 135%, respectively. Greater HCRU yielded significantly greater (all p < .001) per-patient-per-year hospitalization costs vs. matched controls: fatigue ($2554 vs. $1293); stiffness ($2792 vs. $892); fatigue and stiffness ($3322 vs. $1033). Per-patient-per-year costs of office visits increased significantly (all p < .001) vs. matched controls: fatigue ($1373 vs. $908); stiffness ($1580 vs. $761); fatigue and stiffness ($1989 vs. $921).Conclusions: RA patients with fatigue and/or stiffness report more HCRU and incur significantly higher medical costs than RA patients without them.
31040848 Mesenchymal Stem Cells Improve Rheumatoid Arthritis Progression by Controlling Memory T Ce 2019 In the last years, mesenchymal stem cell (MSC)-based therapies have become an interesting therapeutic opportunity for the treatment of rheumatoid arthritis (RA) due to their capacity to potently modulate the immune response. RA is a chronic autoimmune inflammatory disorder with an incompletely understood etiology. However, it has been well described that peripheral tolerance defects and the subsequent abnormal infiltration and activation of diverse immune cells into the synovial membrane, are critical for RA development and progression. Moreover, the imbalance between the immune response of pro-inflammatory and anti-inflammatory cells, in particular between memory Th17 and memory regulatory T cells (Treg), respectively, is well admitted to be associated to RA immunopathogenesis. In this context, MSCs, which are able to alter the frequency and function of memory lymphocytes including Th17, follicular helper T (Tfh) cells and gamma delta (γδ) T cells while promoting Treg cell generation, have been proposed as a candidate of choice for RA cell therapy. Indeed, given the plasticity of memory CD4(+) T cells, it is reasonable to think that MSCs will restore the balance between pro-inflammatory and anti-inflammatory memory T cells populations deregulated in RA leading to prompt their therapeutic function. In the present review, we will discuss the role of memory T cells implicated in RA pathogenesis and the beneficial effects exerted by MSCs on the phenotype and functions of these immune cells abnormally regulated in RA and how this regulation could impact RA progression.
30799358 Effect of Biological Disease-modifying Anti-rheumatic Drugs on Airway and Interstitial Lun 2019 Jun 15 Objective Biological disease-modifying anti-rheumatic drugs (bDMARDs) represent an important advance in alleviating rheumatoid arthritis (RA), but their effect on rheumatic airway disease (AD) and interstitial lung disease (ILD) is still unclear. This study was performed to evaluate the association of the use of different bDMARDs with new-onset or worsening of RA-AD/ILD. Methods We performed a retrospective cohort study of RA patients who received bDMARDs and assessed their AD/ILD before and after drug initiation in our hospital over the past 10 years. We evaluated the serial changes in computed tomography (CT), classified patients according to AD/ILD progression, and analyzed associations between clinical characteristics and outcomes. Results We enrolled 49 patients. Thirty patients received tumor necrosis factor inhibitors (TNFis), 12 received abatacept (ABT), and the remaining 7 received tocilizumab (TCZ). Seventeen patients had ILD, 10 had AD, and 6 had both AD and ILD before the initiation of bDMARDs. New emergence or exacerbation of AD/ILD was observed in 18 patients after drug initiation, while the remaining 31 remained stable or improved. Multiple logistic regression analyses revealed that pre-existing AD was an independent risk factor against the emergence or exacerbation of RA-AD/ILD, and ABT use was a protective factor against it. Conclusion Our study showed that pre-existing RA-AD is associated with future worsening of RA-AD/ILD, and ABT over other bDMARDs was associated with a better prognosis. Future studies to confirm our results are needed.
30324535 Clinical immunity in bone and joints. 2019 Jan The immune system and bone metabolism influence each other. An imbalance in the immune system, resulting in inflammatory stimuli may induce an imbalance in bone turnover via induction of osteoclast differentiation and inhibition of osteoblast differentiation, leading to various pathological conditions including osteoporosis. T-cell subsets, helper T (Th)1 and Th17, which activate the immune system, induce osteoclasts, whereas regulatory T (Treg) cells, responsible for immunosuppression, inhibit osteoclastic differentiation. In addition, inflammatory cytokines, such as the tumor necrosis factor (TNF), also cause an imbalance in bone turnover, induction of osteoclasts and inhibition of osteoblasts. Treatments targeting the immune system may regulate abnormalities in bone metabolism, while also controlling immune abnormalities. In rheumatoid arthritis (RA), a representative autoimmune disease, immune abnormality and accompanying prolongation of synovial inflammation cause bone and cartilage destruction, periarticular osteoporosis, and systemic osteoporosis. Joint damage and osteoporosis in RA occur through totally different mechanisms. Stimulation by inflammatory cytokines induces the expression of the receptor activator for nuclear factor-κB ligand (RANKL) in T cells and synovial cells, thereby inducing bone destruction due to osteoblast-independent osteoclast maturation. However, biological products targeting TNF or interleukin-6 not only control disease activity, but also inhibit joint destruction. However, these biological products are not effective for osteoporosis. Conversely, anti-RANKL antibody inhibits osteoporosis and bone destruction, but exerts no influence on RA disease activity. Such differences in therapeutic efficacy may indicate the necessity for rethinking current theories on the mechanism of bone metabolism abnormality and joint destruction. Understanding the mechanisms underlying these pathologies via commonalities existing between the immune system and the metabolic system may lead to the development of new treatments.