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ID PMID Title PublicationDate abstract
28595367 Limited value for ultrasonography in predicting flare in rheumatoid arthritis patients wit 2017 Sep 1 OBJECTIVE: Ultrasonography (US) can be used for treatment decisions in RA patients. This study investigated the added value of US to clinical variables in predicting flare in RA patients with longstanding low disease activity when stopping TNF inhibitors (TNFi). METHODS: Cox models with and without using US added to clinical variables were developed in the Potential Optimization of Expediency of TNFi-UltraSonography study. RA patients (n = 259), using >1 year TNFi and csDMARD with DAS28 < 3.2 for 6 months prior to inclusion, were followed for 52 weeks after stopping TNFi. The added value of US was assessed in two ways: first, by the extent to which individual predictions for flare at 52 weeks with and without US differed; and second, by comparing how US information improved the prediction to classify patients at 52 weeks in the low risk (<33% flare), intermediate risk (33-50%) and high risk (50-100%) groups. RESULTS: Although US was predictive of flare at group level (multivariate hazard ratio = 1.7; 95% CI: 1.1, 2.5), individual predictions for flare at 52 weeks with and without US differed little (median difference 3.7%; interquartile range: -7.8 to 6.5%). With US, 15.9% of patients were designated low risk; without US, 14.6%. In fact, 12.0% of patients were US-classified as low risk with/without knowing US. CONCLUSION: In RA patients with longstanding low disease activity, at time of stopping TNFi, US is a predictor for flare at group level, but at the patient level, US has limited added value when common clinical parameters are used already, though the predictive value of clinical predictors is modest as well.
28532395 Factors associated with hand joint destruction in Chinese patients with rheumatoid arthrit 2017 May 22 BACKGROUND: There have been no previous report of hand joint destruction prevalence in Chinese rheumatoid arthritis (RA) patients. Therefore, the aim of this study was to investigate the prevalence and potential factors of hand joint destruction among RA patients from Nantong China. In addition, we wanted to examine the differences between functional capacity, psychological status, and quality of life in patients with hand joint destruction compared to those without hand joint destruction. METHODS: A cross-sectional study was conducted from the Affiliated Hospital of Nantong University between July 2015 and June 2016. RA patients completed questionnaires for demographic or clinical variables, the 10-cm Visual Analog Scale for pain, the 28-joint Disease Activity Score-erythrocyte sedimentation rate for disease activity, the Health Assessment Questionnaire-disability index for physical function, the Hospital Anxiety and Depression Scale for anxiety and depression, and the Short Form 36 health survey for quality of life. Laboratory examinations were taken to obtain some biochemical indicators (e.g., rheumatoid factor, anti-cyclic citrullinated peptide antibody). X-ray assessment of hand was performed and hand joint destruction was defined as Sharp score > 0. Independent sample t-test, Mann-Whitney U-test, Chi-square test, and multivariate analysis using backward stepwise logistic regression model were used to analyze these data. RESULTS: One hundred and sixty-one RA patients were included in this study. Radiographic findings revealed that almost 47.2% (n = 76) of patients had hand joint destruction. Multivariate analysis found that education ≤ 9 years (p = 0.041), anti-cyclic citrullinated peptide antibody positive (p = 0.021), high disease activity (p = 0.020), and long disease duration (p < 0.001) were important potential risk factors of hand joint destruction. Participants with hand joint destruction tended to have lower physical function and quality of life, and more severe depressive symptoms compared to individuals without hand joint destruction. CONCLUSIONS: 47.2% of people with RA from Nantong China experienced hand joint destruction. Education, anti-cyclic citrullinated peptide antibody, disease activity, and disease duration had great impacts on hand joint destruction. The results suggested that rheumatologists should pay attention to RA patients' hand joint destruction, especially those with low education levels, anti-cyclic citrullinated peptide antibody positive, high disease activity, and long disease duration by patient education or other ways to improve patients' prognosis.
28411167 Mast cells in rheumatoid arthritis: friends or foes? 2017 Jun Mast cells are tissue-resident cells of the innate immunity, implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). They are present in synovia and their activation has been linked to the potentiation of inflammation in the course of RA. However, recent investigations questioned the role of mast cells in arthritis. In particular, animal models generated conflicting results, so that many of their pro-inflammatory, i.e. pro-arthritogenic functions, even though supported by robust experimental evidence, have been labelled as redundant. At the same time, a growing body of evidence suggests that mast cells can act as tunable immunomodulatory cells. These characteristics, not yet fully understood in the context of RA, could partially explain the inconsistent results obtained with experimental models, which do not account for the pro- and anti-inflammatory functions exerted in more chronic heterogeneous conditions such as RA. Here we present an overview of the current knowledge on mast cell involvement in RA, including the intriguing hypothesis of mast cells acting as subtle immunomodulatory cells and the emerging concept of synovial mast cells as potential biomarkers for patient stratification.
27792008 Of patents and patent disputes: The TNFα patent files. Part 1: Humira. 2017 This article discusses the patent strategy underlying the world's best selling drug, AbbVie's Humira®. Despite a non-optimal starting position, AbbVie has established an extensive portfolio to fend off biosimilar competition. This article is the first part of a trilogy that discusses IP issues related to anti-Tumor Necrosis factor α (TNFα) biologics.
28290525 Quantification of arthritic bone degradation by analysis of 3D micro-computed tomography d 2017 Mar 14 The use of animal models of arthritis is a key component in the evaluation of therapeutic strategies against the human disease rheumatoid arthritis (RA). Here we present quantitative measurements of bone degradation characterised by the cortical bone profile using glucose-6-phosphate isomerase (G6PI) induced arthritis. We applied micro-computed tomography (μCT) during three arthritis experiments and one control experiment to image the metatarsals of the hind paws and to investigate the effect of experimental arthritis on their cortical bone profile. For measurements of the cortical profile we automatically identified slices that are orthogonal to individual metatarsals, thereby making the measurements independent of animal placement in the scanner. We measured the average cortical thickness index (CTI) of the metatarsals, as well as the thickness changes along the metatarsal. In this study we introduced the cortical thickness gradient (CTG) as a new measure and we investigated how arthritis affects this measure. We found that in general both CTI and CTG are able to quantify arthritic progression, whilst CTG was found to be the more sensitive measure.
28962582 Low levels of antibodies against common viruses associate with anti-citrullinated protein 2017 Sep 30 BACKGROUND: Infection by common viruses has long been discussed in the aetiology of a number of autoimmune diseases, including rheumatoid arthritis (RA). However, studies investigating this hypothesis in RA show conflicting results. These studies often lack well-matched control populations, and many do not include data on autoantibodies, genetic risk factors and other environmental factors, which are known to contribute to disease only in subgroups of patients. In the present study, we have therefore examined the role of Epstein-Barr virus (EBV), cytomegalovirus (CMV) and parvovirus B19 (B19) in RA aetiology, by analysing anti-viral antibodies in relation to anti-citrullinated protein antibodies (ACPA), smoking, HLA-DRB1 shared epitope (SE) alleles, and clinical parameters, in both RA patients and matched controls. METHODS: Anti-viral antibodies were measured by ELISA in serum samples from 990 RA patients and 700 controls from the Swedish population-based Epidemiological Investigation of RA (EIRA) cohort. Data on ACPA, smoking, SE, inflammation (C-reactive protein) and disease activity score in 28 joints (DAS28) was obtained from the EIRA database. Fisher's exact test, the chi-squared test, and the Mann-Whitney U test were used to calculate differences in anti-viral antibody frequencies and levels; unconditional logistic regression was used to determine the association of anti-viral antibodies with different RA subsets. RESULTS: Antibodies against all viruses were highly prevalent in EIRA, with no major differences detected between ACPA-positive RA, ACPA-negative RA and controls. However, both anti-B19 and anti-EBV IgG levels were significantly lower in ACPA-positive RA compared to controls, and there were significant interactions between low levels of anti-B19 and anti-EBV antibodies and SE in the development of ACPA-positive RA. CONCLUSION: We could not detect an association between RA and elevated anti-viral antibody levels, for any of the three common viruses, EBV, CMV or B19. On the contrary, our study demonstrated association between low anti-EBV/anti-B19 antibody levels and ACPA-positive RA, in particular when HLA-DRB1 SE was present. These data could potentially suggest that high anti-viral antibody levels would be protective against ACPA-positive RA. Further investigations are required to address the mechanisms behind these findings.
27389847 Symptom Recognition and Perceived Urgency of Help-Seeking for Rheumatoid Arthritis and Oth 2017 May OBJECTIVE: Clinical outcomes in rheumatoid arthritis (RA) are improved if the disease is treated early. However, treatment is often significantly delayed as a result of delayed help-seeking by patients who fail to recognize its symptoms or the need for rapid medical attention. Two studies were conducted to investigate the role of symptom recognition in help-seeking for the symptoms of RA, and compared this to symptom recognition and help-seeking in angina and bowel cancer. METHODS: A qualitative interview study with 31 individuals and a survey of 1,088 members of the general public (all without RA) were conducted. Both studies used vignettes describing the symptoms of RA, bowel cancer, and angina. Participants made causal attributions and rated the perceived seriousness of the symptoms and the urgency with which they would seek medical help if confronted with these symptoms. RESULTS: Only a small proportion of participants in both studies recognized the symptoms of RA, whereas the symptoms of bowel cancer and angina were readily recognized by many participants and considered to be more serious and to require more rapid medical attention (Z = 14.7-34.2, P < 0.001). CONCLUSION: Accurate symptom attribution and the perception that symptoms are indicative of a serious underlying condition are both important drivers for rapid help-seeking. In the case of angina and bowel cancer, recent campaigns have promoted not only recognition of symptoms and their seriousness, but also emphasized the consequences of not seeking timely help. Our results suggest that these consequences should also be addressed in any public health campaign for RA.
28031164 Improvement in 5-year mortality in incident rheumatoid arthritis compared with the general 2017 Jun OBJECTIVE: Excess mortality in rheumatoid arthritis (RA) is expected to have improved over time, due to improved treatment. Our objective was to evaluate secular 5-year mortality trends in RA relative to general population controls in incident RA cohorts diagnosed in 1996-2000 vs 2001-2006. METHODS: We conducted a population-based cohort study, using administrative health data, of all incident RA cases in British Columbia who first met RA criteria between January 1996 and December 2006, with general population controls matched 1:1 on gender, birth and index years. Cohorts were divided into earlier (RA onset 1996-2000) and later (2001-2006) cohorts. Physician visits and vital statistics data were obtained until December 2010. Follow-up was censored at 5 years to ensure equal follow-up in both cohorts. Mortality rates, mortality rate ratios and HRs for mortality (RA vs controls) using proportional hazard models adjusting for age, were calculated. Differences in mortality in RA versus controls between earlier and later incident cohorts were tested via interaction between RA status (case/control) and cohort (earlier/later). RESULTS: 24 914 RA cases and controls experienced 2747 and 2332 deaths, respectively. Mortality risk in RA versus controls differed across incident cohorts for all-cause, cardiovascular diseases (CVD) and cancer mortality (interactions p<0.01). A significant increase in mortality in RA versus controls was observed in earlier, but not later, cohorts (all-cause mortality adjusted HR (95% CI): 1.40 (1.30 to 1.51) and 0.97 (0.89 to 1.05), respectively). CONCLUSIONS: In our population-based incident RA cohort, mortality compared with the general population improved over time. Increased mortality in the first 5 years was observed in people with RA onset before, but not after, 2000.
28547498 Interleukin (IL)-23 Receptor, IL-17A and IL-17F Gene Polymorphisms in Brazilian Patients w 2017 Dec Rheumatoid arthritis (RA) is a progressive, autoimmune disease for which the previous studies have shown that some functional polymorphisms can influence its etiology. Knowing this, the aim of this study was to investigate the association of +2199 A/C IL-23R (rs10889677), -197 G/A IL-17A (rs2275913), and +7488 A/G IL-17F (rs763780) gene polymorphisms with RA susceptibility and clinical features in a Brazilian population. A total of 127 RA patients and 134 healthy controls were recruited for the analyses of polymorphic variants. Genotyping was performed using RFLP-PCR. Logistic regression was used to analyze the genotype distribution of the polymorphisms. Individuals carrying the homozygous CC genotype for the IL-23R polymorphism seem to be at lower risk for RA development (OR 0.22; p = 0.004), as well as those carrying the variant C allele (OR 0.56; p = 0.002). For the -197 G/A IL-17A polymorphism, the wild-type genotype (GG) was significantly associated with a 3.18-fold (OR 3.18; p = 0.033) increased risk for RA. In relation to the +7488 A/G IL-17F polymorphism, no significant difference was found between RA cases and control subjects (p > 0.05). Moreover, when investigating the relationship between polymorphisms and clinical features, no evidence of an association was found. Our findings suggest that the variants +2199 A/C IL-23R and -197 G/A IL-17A could contribute to RA development in the studied population. However, larger studies are needed to fully understand this genetic predisposition.
28415811 IL-33/ST2-mediated inflammation in macrophages is directly abrogated by IL-10 during rheum 2017 May 16 IL-10 is an immunosuppressive cytokine produced and sensed by many immune cells and exerts a protective role in autoimmune diseases. However, the underlying mechanism by which IL-10 contributes to prevent the arthritic inflammation in macrophages is poorly understood. Herein we report on a novel anti-arthritic property of IL-10 through the inhibition of IL-33 signaling by macrophages during collagen-induced arthritis (CIA) development. We show that IL-33 expression rather than its receptor (ST2) is positively correlated with IL-10 level in active RA. IL-10 deficiency in mice leads to significant upregulation of IL-33 expression and aggravates the progression of CIA, while exogenous IL-10 treatment effectively diminishes IL-33 production in IL-10 knockout (IL-10-/-) CIA mice. We demonstrate further that the inhibitory effect of IL-10 in suppressing IL-33 production requires STAT3 activation in macrophages. Furthermore, IL-33 stimulated proinflammatory genes are notably increased in IL-10-/- CIA mice, whereas macrophages treated with recombinant IL-10 exhibit decreased IL-33 amplified inflammation and inhibited IL-33 activated NF-κB signaling pathway. Our findings indicate that IL-10 act as a negative regulator of IL-33/ST2 signaling pathways in vivo, suggesting a potential therapeutic role of IL-10 in autoimmune diseases.
28970207 Clinical and radiological outcomes of 5-year drug-free remission-steered treatment in pati 2018 Jan OBJECTIVES: To determine the 5-year outcomes of early remission induction therapy followed by targeted treatment aimed at drug-free remission (DFR) in patients with early arthritis. METHODS: In 12 hospitals, 610 patients with early (<2 years) rheumatoid arthritis (RA) or undifferentiated arthritis (UA) started on methotrexate (MTX) 25 mg/week and prednisone (60 mg/day tapered to 7.5 mg/day). Patients not in early remission (Disease Activity Score <1.6 after 4 months) were randomised (single blind) to arm 1, adding hydroxychloroquine 400 mg/day and sulfasalazine 2000 mg/day, or arm 2, switching to MTX plus adalimumab 40 mg/2 weeks. Treatment adjustments over time aimed at DFR. Outcomes were remission percentages, functional ability, toxicity and radiological damage progression after 5 years. RESULTS: After 4 months, 387 patients were in early remission, 83 were randomised to arm 1 and 78 to arm 2. After 5 years, 295/610 (48%) patients were in remission, 26% in sustained DFR (SDFR) (≥1 year) (220/387 (57%) remission and 135/387 (35%) SDFR in the early remission group, 50% remission, 11% SDFR in the randomisation arms without differences between the arms). More patients with UA (37% vs 23% RA, p=0.001) and more anticitrullinated protein antibody (ACPA)-negative patients (37% vs 18% ACPA-positive, p<0.001) achieved SDFR.Overall, mean Health Assessment Questionnaire was 0.6 (0.5), and median (IQR) damage progression was 0.5 (0-2.7) Sharp/van der Heijde points, with only five patients showing progression >25 points in 5 years. CONCLUSIONS: Five years of DFR-steered treatment in patients with early RA resulted in almost normal functional ability without clinically relevant joint damage across treatment groups. Patients who achieved early remission had the best clinical outcomes. There were no differences between the randomisation arms. SDFR is a realistic treatment goal.
27858176 Serum level of reactive oxygen metabolites (ROM) at 12 weeks of treatment with biologic a 2017 Feb We have shown that serum levels of reactive oxygen metabolites (ROM) were associated with C-reactive protein (CRP) and disease activity score based on the examination of 28 joints (DAS28) in patients with rheumatoid arthritis (RA); however, their clinical significance as biomarkers has not been elucidated. Forty-eight biologic agent (BA)-naïve RA patients were included in this study. Associations between serum levels of ROM, CRP, matrix metalloproteinase-3 (MMP-3), DAS28-erythrocyte sedimentation rate (ESR), and Health Assessment Questionnaire (HAQ) at 12 weeks of treatment and DAS28 (ESR) remission at 52 weeks (52-week remission) were investigated. The ROM serum level at baseline in the remission group (n = 34) was 527 ± 132 Carratelli units (U.Carr) (normal range <300), decreased to 335 ± 79.1 at 4 weeks, and remained low thereafter. In the non-remission group (n = 14), the ROM serum level at baseline was 592 ± 113 U.Carr, decreased to 450 ± 152 at 4 weeks, but gradually increased thereafter. Among significantly different factors at 12 weeks between the remission and non-remission groups, ROM and DAS28 (ESR) were identified as predictors of 52-week remission (p = 0.045, odds ratio 0.985, 95% confidence interval 0.97-1.000 for ROM). The cutoff value of ROM was determined to be 381.5 U.Carr (sensitivity 0.833, specificity 0.871). These results show that serum ROM levels can predict remission with high accuracy and could be a useful biomarker for achieving remission in the current treat-to-target strategy for RA.
28137612 Nutrition and fasting mimicking diets in the prevention and treatment of autoimmune diseas 2017 Nov 5 Complex and coordinated signals are necessary to initiate and sustain the activation, proliferation, and differentiation of lymphocytes. These signals, which are known to determine T-cell fate and function, also depend on the metabolic state of the organism. Recent studies indicate that both the type and levels of nutrients can influence the generation, survival and function of lymphocytes and therefore can affect several autoimmune diseases. Here, we review the dysregulation of lymphocytes during autoimmunity and aging, the mechanisms associated with loss of immune function, and how fasting mimicking diets and other dietary interventions affect autoimmunity and immunosenescence.
28521808 B cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides com 2017 May 18 BACKGROUND: B cell depletion with rituximab (RTX) is approved for treatment of rheumatoid arthritis (RA) and ANCA-associated vasculitides (AAV). Recently, RTX has been shown to be effective in AAV maintenance therapy, but an optimal RTX treatment schedule is unknown and the time to B cell repopulation after RTX has not been studied. METHODS: Retrospective single-center analysis of B cell repopulation in patients with AAV, RA or connective tissue disease (CTD) treated with RTX. RESULTS: Beginning B cell repopulation within the first year after RTX treatment was observed in 93% of RA and 88% of CTD patients. Only 10% of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and no patient with eosinophilic granulomatosis with polyangiitis (EGPA) showed B cell repopulation within this time. Median time of B cell depletion was 26 months in GPA/MPA, and 21 months in EGPA compared to 9 months in RA, and 8 months in CTD (p < 0.0001). In 25 AAV-patients B cell depletion lasted for at least 44 months. There was a significant decline in serum immunoglobulin concentrations in GPA/MPA patients, but not in patients with RA or CTD. Significantly more GPA/MPA patients developed hygogammaglobulinemia (IgG <7 g/L) compared to patients with RA or CTD. CONCLUSIONS: In contrast to RA and CTD, in AAV RTX induces long-lasting depletion of B cells that is associated with decreased antibody production. This observation points toward potential defects in the B cell compartment in AAV that are unmasked by immunosuppressive treatment and has important implications for the design of maintenance treatment schedules using RTX.
28391000 Prognostic Role of Subclinical Left Ventricular Systolic Dysfunction Evaluated by Speckle- 2017 Jun BACKGROUND: Speckle-tracking echocardiography allows early detection of subclinical left ventricular systolic dysfunction (LVSD) in patients with rheumatoid arthritis (RA). In this prospective study, we assessed the prevalence and the prognostic role of subclinical LVSD detected by speckle-tracking echocardiography in RA patients. METHODS: Two-dimensional global longitudinal strain (GLS) and global circumferential strain (GCS) were measured in 209 RA patients without overt cardiac disease. LVSD was defined as low GLS (> -16.0%), low GCS (> -17.8%), or both. The primary end point was all-causes hospitalization; the coprimary end point was hospitalization for cardiovascular causes. RESULTS: The study population had a mean age of 58 ± 11 years; 67% were female, 52% had hypertension, and the RA duration was 14 ± 10 years. Low GLS was detected in 51 patients (24%), low GCS in 42 patients (20%), and combined low GLS and GCS in 18 patients (9%). During a median follow-up time of 16 months (range, 10-21 months), a primary end point occurred in 50 patients (24%), and 25 patients were hospitalized for a cardiovascular event. Multiple Cox regression analyses revealed that combined low GLS and GCS was independently associated with the end point defined as all-causes hospitalization together with higher aortic stiffness. Examined individually, neither low GCS nor low GLS showed an independent association with this typology of clinical outcome. Conversely, both low GCS and low GLS (examined individually or as combined low GLS and GCS) emerged as strong independent prognosticators of cardiovascular events. CONCLUSIONS: Subclinical LVSD defined as low GLS, GCS, or both is common in RA patients without overt cardiac disease and provides additional prognostic information in these individuals.
27470303 A novel bedside test for ACPA: the CCPoint test is moving the laboratory to the rheumatolo 2017 Feb Rheumatoid Arthritis (RA) is an autoimmune destructive joint disease affecting 1 % of the general population. In recent years, the benefits of identifying RA at an early stage and initiating therapy before joint damage occurs have been acknowledged. An elevated anti-citrullinated peptide antibody (ACPA) level serves as a marker for the early diagnosis of RA. Often the diagnosis is delayed because conventional methods of antibody detection require referral to a specific laboratory. In the current study, we determined the diagnostic accuracy of a new lateral flow point-of-care kit available for ACPA detection in the rheumatologist office. The presence of ACPA was determined by the visually read, qualitative rapid CCPoint(®) test (Euro-Diagnostica, Malmö, Sweden) compared to routinely used ELISA assays (Immunoscan CCPlus(®)-Euro-Diagnostica, Sweden, and QuantLite(®) CCP3-INOVA Diagnostics Inc., USA), in the sera of 184 patients: early RA(n = 38), established RA (n = 84), inflammatory arthritis(n = 34) and systemic lupus erythematosus (SLE) (n = 28). ACPA was detected in 18/38(47 %), 53/84(63 %), 2/34(6 %) and 2/28(7 %) of patients with early RA, established RA, inflammatory arthritis and SLE, respectively. The sensitivity and specificity, negative and positive predictive values of the CCPoint(®) test were equivalent to the Immunoscan CCPlus(®) and Quanta Lite(®) CCP3 ELISA assays. Correlation between ACPA positive results detected in the different assays was 97 %, while negative agreement reached 98 %. Excellent correlation (100 %) was observed between CCPoint(®) results obtained using capillary blood versus serum. CCPoint(®) is a novel technology that allows for a rapid accurate analysis of ACPA and diagnosis during the patient's visit in the rheumatologist office.
28850019 Lipopolysaccharide-binding protein is a sensitive disease activity biomarker for rheumatoi 2018 Mar OBJECTIVES: This study was performed to evaluate the performance and clinical significance of lipopolysaccharide-binding protein (LBP) as a disease activity biomarker in rheumatoid arthritis (RA). METHODS: LBP levels were measured by enzyme-linked immunosorbent assay (ELISA). The associations between LBP and the clinical and serological features of RA and its clinical significance as a RA disease activity biomarker were analysed. RESULTS: The serum level of LBP in RA was significantly elevated compared to those in OA, SLE, pSS and HC. The level of LBP in RA synovial fluid (SF) was higher than that in OA SF. LBP was significantly correlated with RA disease activity parameters such as ESR, CRP, tender joint counts, swelling joint counts and DAS28. Furthermore, LBP positive RA patients were more likely to show higher disease activity (DAS28>5.1), positive APF, interstitial lung disease and metabolic disorders. The predictive value of LBP on high disease activity was comparable with those of CRP and ESR. In 52.5% of the patients with active disease but negative in CRP /ESR, LBP was still positive and correlated with swelling joint counts. CONCLUSIONS: LBP is a sensitive serum biomarker to evaluate RA disease activity, and it could be a promising laboratory marker to assist RA disease activity assessment in active RA patients with negative ESR or CRP.
28470264 Reconstruction and analysis of the lncRNA-miRNA-mRNA network based on competitive endogeno 2017 Jun 1 Rheumatoid arthritis (RA) is an autoimmune disease with an unknown etiology, occurring in approximately 1.0% of general population. More and more studies have suggested that long non-coding RNAs (lncRNAs) could play important roles in various biological processes and be associated with the pathogenesis of different kinds of diseases including RA. Although a large number of lncRNAs have been found, our knowledge of their function and physiological/pathological significance is still in its infancy. In order to reveal functional lncRNAs and identify the key lncRNAs in RA, we reconstructed a global triple network based on the competitive endogenous RNA (ceRNA) theory using the data from National Center for Biotechnology Information Gene Expression Omnibus and our previous paper. Meanwhile, Gene Ontology (GO) and pathway analysis were performed using Cytoscape plug-in BinGO and Database for Annotation, Visualization, and Integration Discovery (DAVID), respectively. We found that the lncRNA-miRNA-mRNA network was composed of 7 lncRNA nodes, 90 mRNA nodes, 24 miRNA nodes, and 301 edges. The functional assay showed that 147 GO terms and 23 pathways were enriched. In addition, three lncRNAs (S5645.1, XR_006437.1, J01878) were highly related to RA, and therefore, were selected as key lncRNAs. This study suggests that specific lncRNAs are associated with the development of RA, and three lncRNAs (S5645.1, XR_006437.1, J01878) could be used as potential diagnostic biomarkers and therapeutic targets.
28724439 Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid ar 2017 Jul 19 BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients. METHODS: We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro. RESULTS: Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase (MMP)2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein (DCSTAMP) and MMP9, that are necessary for osteoclast formation and activity. CONCLUSIONS: These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease.
28148302 Blood chemokine profile in untreated early rheumatoid arthritis: CXCL10 as a disease activ 2017 Feb 2 BACKGROUND: We have recently analyzed the profile of T-cell subtypes based on chemokine receptor expression in blood from untreated early rheumatoid arthritis (ueRA) patients compared to healthy controls (HC). Here, we compared the levels of the respective chemokines in blood plasma of ueRA patients with those of HC. We also studied the association of chemokine levels with the proportions of circulating T-cell subsets and the clinical disease activity. METHODS: Peripheral blood was obtained from 43 patients with ueRA satisfying the ACR 2010 criteria and who had not received any disease-modifying anti-rheumatic drugs (DMARD) or prednisolone, and from 14 sex- and age-matched HC. Proportions of T helper cells in blood, including Th0, Th1, Th2, Th17, Th1Th17, TFh, and regulatory T cells, were defined by flow cytometry. Fifteen chemokines, including several CXCL and CCL chemokines related to the T-cell subtypes as well as to other major immune cells, were measured in blood plasma using flow cytometry bead-based immunoassay or ELISA. Clinical disease activity in patients was evaluated by assessing the following parameters: Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), swollen joint counts (SJC), tender joint counts (TJC), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). The data were analyzed using multivariate factor analyses followed by univariate analyses. RESULTS: Multivariate discriminant analysis showed that patients with ueRA were separated from HC based on the blood plasma chemokine profile. The best discriminators were CXCL9, CXCL10, CXCL13, CCL4, and CCL22, which were significantly higher in ueRA compared to HC in univariate analyses. Among the chemokines analyzed, only CXCL10 correlated with multiple disease activity measures, including DAS28-CRP, DAS28-ESR, CDAI, SJC in 66 joints, CRP, and ESR. CONCLUSIONS: High circulating levels of CXCL10 in the plasma of ueRA patients and the association with the clinical disease activity suggests that CXCL10 may serve as a disease activity marker in early rheumatoid arthritis.