Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
30184532 Comparison of Pain Characteristics in Patients with Rheumatoid Arthritis and Systemic Scle 2018 OBJECTIVE: The aim of the study was to compare characteristics of pain in terms of neuropathic pain (NeP) and to assess the association between the neuropathic component and quality of life (QoL) in patients with systemic sclerosis (SSc) and rheumatoid arthritis (RA). SUBJECTS AND METHODS: Fifty-four patients (47 females, 7 males) with SSc and 53 patients (46 females, 7 males) with RA were assessed for outcome measures including disease activity, physical functions, mental condition and health-related QoL (HRQoL) measures (Short Form-36; Hospital Anxiety and Depression Scale), and pain. NeP was assessed by the Douleur Neuropathique 4 (DN4) and PainDetect questionnaires in this cross-sectional study. RESULTS: The patients had similar education, smoking status, functioning, and HRQoL. However, the patients with RA declared a more severe visual analogue scale of pain and a higher BMI than those with SSc. The NeP component was detected in 42.6% (n = 23) of the SSc patients and in 45.3% (n = 24) of the RA patients (p > 0.05) according to DN4. On PainDetect, possible NeP was detected in 13.0% (n = 7) versus 15.1% (n = 8), whereas 16.7% (n = 9) versus 17.0% (n = 9) were likely to have NeP in SSc and RA, respectively (p > 0.05). Most of the NeP characteristics were similar in SSc and RA, except for numbness and painful cold, which were notably more common in patients with SSc. Having the NeP component (according to DN4) had no influence on functioning and HRQoL in SSc; however, the NeP component revealed a heavier burden of disease regarding functional status, HRQoL, and psychometric components in RA. CONCLUSION: The NeP component was similar between patients with SSc and RA. However, NeP was associated with a heavier burden of disease in patients with RA.
29526126 [Odontogenic foci and systemic diseases. A review]. 2018 Mar The aim of the present review is to provide an up-to-date picture of what we know about the connection between odontogenic foci and non-oral diseases. After a brief historical summary, we give an overview on how the odontogenic focus causes disease in distant areas of the body in general, and then we start the discussion of the particular conditions, such as cardiovascular diseases, pneumonia, diabetes mellitus, metabolic syndrome, rheumatoid arthritis and adverse pregnancy outcomes. The review is centered around the two main odontogenic foci: periodontitis and periapical periodontitis, the latter being a widely recognized but rarely discussed oral focus. Finally, we offer a few considerations that the practicing dentist may find useful when dealing with odontogenic foci. Orv Hetil. 2018; 159(11): 415-422.
30596097 Association of Angiogenic and Inflammatory Markers with Power Doppler Ultrasound Vasculari 2018 OBJECTIVE: Upregulation of various proinflammatory and angiogenic mediators orchestrates the typical pathological synovial alterations in rheumatoid arthritis (RA). DAS28-CRP is commonly used for assessment of RA disease activity and power Doppler ultrasonography (PDUS) is an important modality for assessing synovial vascularity. This study was intended to look for the association of various inflammatory and angiogenic mediators, with respect to different PDUS vascularity grades and disease activity status, in early RA patients. METHODS: 50 early RA patients (<6 months disease duration) with either moderate or high disease activity and 30 healthy controls were included in this study. RA patients were subcategorized based on PDUS vascularity grading of wrist joints. Serum levels of proinflammatory cytokines [tumor necrosis factor-α (TNF- α); interleukin-6(IL-6)] and angiogenic markers [angiopoietin-1 and 2 (Ang-1 and Ang-2); vascular endothelial growth factor (VEGF) ] were measured and compared among different patient subgroups. RESULTS: Among 50 patients, 22 and 28 patients had moderate and high DAS28-CRP score, respectively. Patients with grade 3 PDUS score, even with moderate DAS value, showed a significant rise in Ang-1 (p<0.02), VEGF (p<0.008), Ang-2 (p <0.001), and TNF-α (p<0.005) level compared to grade 2 PDUS patients with high DAS values. CONCLUSION: Higher serum level of angiogenic and inflammatory markers was noted among patients with moderate disease activity but with advanced PDUS vascularity (grade 3) in comparison to high disease activity group with less severe PDUS vascularity (grade 2). PDUS vascularity grading better reflects some markers of angiogenesis and inflammation, than composite disease activity index.
29764965 Effect of Treat-to-target Strategies Aiming at Remission of Arterial Stiffness in Early Rh 2018 Aug OBJECTIVE: To determine the efficacy of 2 tight control treatment strategies aiming at Simplified Disease Activity Score (SDAI) remission (SDAI ≤ 3.3) compared to 28-joint count Disease Activity Score (DAS28) remission (DAS28 < 2.6) in the prevention of arterial stiffness in patients with early rheumatoid arthritis (RA). METHODS: This was an open-label study in which 120 patients with early RA were randomized to receive 1 year of tight control treatment. Group 1 (n = 60) aimed to achieve SDAI ≤ 3.3 and Group 2 (n = 60), DAS28 < 2.6. Pulse wave velocity (PWV) and augmentation index (AIx) were measured at baseline and 12 months. A posthoc analysis was also performed to ascertain whether achieving sustained remission could prevent progression in arterial stiffness. RESULTS: The proportions of patients receiving methotrexate monotherapy were significantly lower in Group 1 throughout the study period. At 12 months, the proportions of patients achieving DAS28 and SDAI remission, and the change in PWV and AIx, were comparable between the 2 groups. In view of the lack of differences between the 2 groups, a posthoc analysis was performed at Month 12, including all 110 patients with PWV, to elucidate the independent predictors associated with the change in PWV. Multivariate analysis revealed that achieving sustained DAS28 remission at months 6, 9, and 12 and a shorter disease duration were independent explanatory variables associated with less progression of PWV. CONCLUSION: With limited access to biologic disease-modifying antirheumatic drugs, treatment efforts toward DAS28 and SDAI remission had similar effects in preventing the progression of arterial stiffness at 1 year. However, achieving sustained DAS28 remission was associated with a significantly greater improvement in PWV. [Clinical Trial registration: Clinicaltrial.gov NCT01768923.].
29765031 Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. 2018 May 15 Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Here we show the first comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS), including histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3), open chromatin, RNA expression and whole-genome DNA methylation. To address complex multidimensional relationship and reveal epigenetic regulation of RA, we perform integrative analyses using a novel unbiased method to identify genomic regions with similar profiles. Epigenomically similar regions exist in RA cells and are associated with active enhancers and promoters and specific transcription factor binding motifs. Differentially marked genes are enriched for immunological and unexpected pathways, with "Huntington's Disease Signaling" identified as particularly prominent. We validate the relevance of this pathway to RA by showing that Huntingtin-interacting protein-1 regulates FLS invasion into matrix. This work establishes a high-resolution epigenomic landscape of RA and demonstrates the potential for integrative analyses to identify unanticipated therapeutic targets.
29148406 High 3-year golimumab survival in patients with rheumatoid arthritis, ankylosing spondylit 2018 Mar OBJECTIVES: Our primary objective was to study the long-term survival on drug (SOD) of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) treated with golimumab (GLM) in real life settings. METHODS: This was a retrospective, observational study of all patients treated with GLM in 4 Academic Centres in Greece during a 4-year period (09/2010-06/2014). SOD was analysed using Kaplan-Meier survival analysis, while Cox regression analysis estimating hazard ratios (HRs) for different baseline variables associated with drug discontinuation was performed for each disease. RESULTS: 328 patients (RA: 166, PsA: 82, AS: 80) were included. The estimated SOD at 2 and 3 years was 68% and 62% overall and was better for AS (79% and 76%) compared to RA (69% and 60%, p=0.067) and PsA (58% and 53%, p=0.001) patients; no difference was noted between RA and PsA patients (p=0.204). There was no difference in SOD between biologic-naïve and experienced nor between non-biologic co-treated or GLM monotherapy treated patients. Seropositivity (rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies) was associated with a lower risk for GLM discontinuation by multivariate analysis (HR=0.5, 95% CI=0.0.25-1.1, p=0.05) in RA patients. During 606 patient-years of follow-up, 11 (3.3%) patients discontinued GLM due to adverse events (AE), accounting for 11% of treatment discontinuations. The rates of serious AEs and serious infections were 2.3 and 1.0/100-patient-years, respectively. CONCLUSIONS: In this real-life study, GLM showed a high 3-year SOD in patients with inflammatory arthritides with a low rate of discontinuation due to AEs.
29361749 Affinity Purification and Comparative Biosensor Analysis of Citrulline-Peptide-Specific An 2018 Jan 22 BACKGROUND: In rheumatoid arthritis (RA), anti-citrullinated protein/peptide antibodies (ACPAs) are responsible for disease onset and progression, however, our knowledge is limited on ligand binding affinities of autoantibodies with different citrulline-peptide specificity. METHODS: Citrulline-peptide-specific ACPA IgGs were affinity purified and tested by ELISA. Binding affinities of ACPA IgGs and serum antibodies were compared by surface plasmon resonance (SPR) analysis. Bifunctional nanoparticles harboring a multi-epitope citrulline-peptide and a complement-activating peptide were used to induce selective depletion of ACPA-producing B cells. RESULTS: K(D) values of affinity-purified ACPA IgGs varied between 10(-6) and 10(-8) M and inversely correlated with disease activity. Based on their cross-reaction with citrulline-peptides, we designed a novel multi-epitope peptide, containing Cit-Gly and Ala-Cit motifs in two-two copies, separated with a short, neutral spacer. This peptide detected antibodies in RA sera with 66% sensitivity and 98% specificity in ELISA and was recognized by 90% of RA sera, while none of the healthy samples in SPR. When coupled to nanoparticles, the multi-epitope peptide specifically targeted and depleted ACPA-producing B cells ex vivo. CONCLUSIONS: The unique multi-epitope peptide designed based on ACPA cross-reactivity might be suitable to develop better diagnostics and novel therapies for RA.
29472591 Early sclerostin expression explains bone formation inhibition before arthritis onset in t 2018 Feb 22 Periarticular bone loss in rheumatoid arthritis (RA) is considered to be mainly related to synovial inflammation. However, strong bone loss has also described at the time of arthritis onset. Recently, a paradoxical exacerbation of joint damage was described when blocking sclerostin in various arthritis models. Thus, we aimed to determine kinetics of bone loss and its mechanisms in the adjuvant induced arthritis (AIA) rat model of RA. AIA was induced (n = 35) or not (n = 35) at day 0. In addition to well-known arthritis at day 12, we showed with 3D-imaging and histomorphometry that bone microstructural alterations occurred early from day 8 post-induction, characterized by cortical porosity and trabecular bone loss. Active osteoclastic surfaces were increased from day 8 with RANKL upregulation. More surprisingly SOST and DKK1 were overexpressed from day 6 and followed by a dramatic decrease in bone formation from day 8. At the time of arthritis onset, SOST and DKK1 returned to control values, but frizzled related protein 1 (SFRP1), proinflammatory cytokines, and MMPs started to increase. Bone alterations before arthritis onset reinforce the hypothesis of an early bone involvement in arthritis. Kinetics of osteocyte markers expression should be considered to refine Wnt inhibitor treatment strategies.
30166627 Genome-wide association study of response to tumour necrosis factor inhibitor therapy in r 2018 Sep Rheumatoid arthritis (RA) is characterised by chronic synovial joint inflammation. Treatment has been revolutionised by tumour necrosis factor alpha inhibitors (TNFi) but each available drug shows a significant non-response rate. We conducted a genome-wide association study of 1752 UK RA TNFi-treated patients to identify predictors of change in the Disease Activity Score 28 (DAS28) and subcomponents over 3-6 months. The rs7195994 variant at the FTO gene locus was associated with infliximab response when looking at a change in the swollen joint count (SJC28) subcomponent (p = 9.74 × 10(-9)). Capture Hi-C data show chromatin interactions in GM12878 cells between rs2540767, in high linkage disequilibrium with rs7195994 (R(2) = 0.9) and IRX3, a neighbouring gene of FTO. IRX3 encodes a transcription factor involved in adipocyte remodelling and is regarded as the obesity gene at the FTO locus. Importantly, the rs7195994 association remained significantly associated following adjustment for BMI. In addition, using capture Hi-C data we showed interactions between TNFi-response associated variants and 16 RA susceptibility variants.
30565876 Association between cumulative methotrexate dose, non-invasive scoring system and hepatic 2019 Feb BACKGROUND: Methotrexate (MTX) is recommended by recent American College of Rheumatology and European League against Rheumatism guidelines as a first-line drug for rheumatoid arthritis (RA). Liver fibrosis, which occurs as a long-term side effect is of major concern. Monitoring aminotransferase and albumin is suggested in the guidelines, unfortunately this method is unreliable for detecting liver fibrosis. We try to find the association between clinical parameters, cumulative MTX dosage, liver fibrosis scoring systems and the presence of liver fibrosis assessed by transient elastography (TE; Fibroscan®). METHOD: Rheumatoid arthritis patients prescribed MTX were evaluated for liver fibrosis with TE. Two subgroups of patients were compared: non-fibrosis and fibrosis (TE > 7 kPa). Univariate and multivariate logistic regression analysis was performed to identify factors associated with liver fibrosis. RESULTS: One hundred and eight patients were recruited. Twenty-nine patients (26.8%) were classified by transient elastography as liver fibrosis cases. The multivariate analysis demonstrated statistical significance only in the association of body mass index (odds ratio [OR] = 1.22; 95% CI 1.05-1.41; P = 0.01); fatty liver (OR = 2.32; 95% CI 1.58-9.19; P = 0.02); alanine transaminase (OR = 1.04; 95% CI 1.02-1.09; P = 0.04) and cumulative MTX dosage (OR = 1.03; 95% CI 1.01-1.04; P = 0.001). CONCLUSIONS: Liver fibrosis measured with Fibroscan was associated with cumulative MTX. RA patients with metabolic syndrome including high body mass index and fatty liver, had a higher risk of MTX-induced hepatic fibrosis. RA patients with high cumulative MTX dose, especially patients with concurrent metabolic syndrome, should be cautiously monitored for liver fibrosis.
29967194 Systematic approach demonstrates enrichment of multiple interactions between non-HLA risk 2018 Oct OBJECTIVE: In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope (SE) alleles, is a highly influential genetic risk factor. Here, we investigated whether non-HLA single nucleotide polymorphisms (SNP), conferring low disease risk on their own, interact with SE alleles more frequently than expected by chance and if such genetic interactions influence the HLA-DRB1 SE effect concerning risk to ACPA-positive RA. METHODS: We computed the attributable proportion (AP) due to additive interaction at genome-wide level for two independent ACPA-positive RA cohorts: the Swedish epidemiological investigation of rheumatoid arthritis (EIRA) and the North American rheumatoid arthritis consortium (NARAC). Then, we tested for differences in the AP p value distributions observed for two groups of SNPs, non-associated and associated with disease. We also evaluated whether the SNPs in interaction with HLA-DRB1 were cis-eQTLs in the SE alleles context in peripheral blood mononuclear cells from patients with ACPA-positive RA (SE-eQTLs). RESULTS: We found a strong enrichment of significant interactions (AP p<0.05) between the HLA-DRB1 SE alleles and the group of SNPs associated with ACPA-positive RA in both cohorts (Kolmogorov-Smirnov test D=0.35 for EIRA and D=0.25 for NARAC, p<2.2e-16 for both). Interestingly, 564 out of 1492 SNPs in consistent interaction for both cohorts were significant SE-eQTLs. Finally, we observed that the effect size of HLA-DRB1 SE alleles for disease decreases from 5.2 to 2.5 after removal of the risk alleles of the two top interacting SNPs (rs2476601 and rs10739581). CONCLUSION: Our data demonstrate that there are massive genetic interactions between the HLA-DRB1 SE alleles and non-HLA genetic variants in ACPA-positive RA.
29498714 Targeting Receptor-Type Protein Tyrosine Phosphatases with Biotherapeutics: Is Outside-in 2018 Mar 2 Protein tyrosine phosphatases (PTPs), of the receptor and non-receptor classes, are key signaling molecules that play critical roles in cellular regulation underlying diverse physiological events. Aberrant signaling as a result of genetic mutation or altered expression levels has been associated with several diseases and treatment via pharmacological intervention at the level of PTPs has been widely explored; however, the challenges associated with development of small molecule phosphatase inhibitors targeting the intracellular phosphatase domain (the "inside-out" approach) have been well documented and as yet there are no clinically approved drugs targeting these enzymes. The alternative approach of targeting receptor PTPs with biotherapeutic agents (such as monoclonal antibodies or engineered fusion proteins; the "outside-in" approach) that interact with the extracellular ectodomain offers many advantages, and there have been a number of exciting recent developments in this field. Here we provide a brief overview of the receptor PTP family and an update on the emerging area of receptor PTP-targeted biotherapeutics for CD148, vascular endothelial-protein tyrosine phosphatase (VE-PTP), receptor-type PTPs σ, γ, ζ (RPTPσ, RPTPγ, RPTPζ) and CD45, and discussion of future potential in this area.
29213125 The role of semaphorins in immune responses and autoimmune rheumatic diseases. 2018 Jan Semaphorins have a well-characterized role in guiding axon repulsion during development; however, the important contribution of these proteins in immunity is becoming increasingly clear. Immunoregulatory semaphorins, termed 'immune semaphorins', have roles in regulating immune cell activation, differentiation, mobility and migration. These proteins are also intimately associated with the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This Review discusses the pathogenic functions of immune semaphorins, as well as the potential use of these molecules as diagnostic markers and therapeutic targets for the treatment of autoimmune diseases.
30168265 Retention rates of adalimumab, etanercept, and infliximab as first- or second-line biother 2018 Nov OBJECTIVE: To compare, in real-life settings, the retention rates of initial anti-tumor-necrosis factor (TNF) treatments (etanercept [ETN], adalimumab [ADA] and infliximab [IFX]) used as first-line biotherapy for axial spondyloarthritis (axSpA), and evaluate treatment switches to another anti-TNF inhibitor in the event of treatment failure. METHODS: We analyzed the medical records of all SpA patients (Assessment in Ankylosing Spondylitis International Working Group axial criteria) treated with ETN, IFX or ADA between 2001 and February 2015. Drug retention rates were calculated using the Kaplan-Meier method and compared by means of the Cox extended model. Sub-analyses were performed according to discontinuation reasons. RESULTS: Of the 249 SpA patients analyzed (135 radiographic cases, 114 non-radiographic), 102 received ETN, 62 ADA, and 85 IFX. In total, 103 discontinued treatment. The retention rates of IFX, ADA and ETN were 67%, 59% and 56% after 3 years; 62%, 42% and 47% after 5 years; 55%, 42% and 24% after 8 years; 53%, 42% and 12% after 10 years, respectively. In multivariate analyses, the predictive factors for retention were: low BASDAI score (hazard ratio [HR]: 1.02 [1.01-1.04]), high C-reactive protein levels (HR: 0.98 [0.97-0.99]), concomitant disease-modifying therapy (HR: 0.4 [0.21-0.75]), and radiographic SpA (HR: 1.5 [1.0-2.52]). In total, 61 patients switched to another anti-TNF therapy. No difference was observed among the three anti-TNF therapies regarding median retention duration, although the retention rate proved higher for treatment switches from one monoclonal antibody to another. CONCLUSION: The retention rate in SpA patients proved high, with retention for IFX superior to that of ETN.
29102955 Development and psychometric validation of a patient-reported outcome measure to assess fe 2018 Feb OBJECTIVES: To develop and validate an outcome measure for assessing fears in patients with rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA). METHODS: Fears were identified in a qualitative study, and reformulated as assertions with which participants could rate their agreement (on a 0-10 numeric rating scale). A cross-sectional validation study was performed including patients diagnosed with RA or axSpA. Redundant items (correlation >0.65) were excluded. Internal consistency (Cronbach's α) and factorial structure (principal component analysis) were assessed. Patients were classified into fear levels (cluster analysis). Associations between patient variables and fear levels were evaluated using multiple logistic regression. RESULTS: 672 patients were included in the validation study (432 RA, 240 axSpA); most had moderate disease activity and were prescribed biologics. The final questionnaire included 10 questions with high internal consistency (α: 0.89) and a single dimension. Mean scores (±SD) were 51.2 (±25.4) in RA and 60.5 (±22.9) in axSpA. Groups of patients with high (17.2%), moderate (41.1%) and low (41.7%) fear scores were identified. High fear scores were associated with high Arthritis Helplessness Index scores (OR 6.85, 95% CI (3.95 to 11.87)); high Hospital Anxiety and Depression Scale anxiety (OR 5.80, 95% CI (1.19 to 4.22)) and depression (OR 2.37, 95% CI (1.29 to 4.37)) scores; low education level (OR 3.48, 95% CI (1.37 to 8.83)); and high perceived disease activity (OR 2.36, 95% CI (1.10 to 5.04)). CONCLUSIONS: Overall, 17.2% of patients had high fear scores, although disease was often well controlled. High fear scores were associated with psychological distress. This questionnaire could be useful both in routine practice and clinical trials.
29924278 [Anti-Inflammatory Effect of The Flavonoid Fraction of Lepechinia meyenii (Walp.) Epling ( 2018 Jan OBJECTIVES: to assess the anti-inflammatory effect of the flavonoid fraction of Lepechinia meyenii (Walp.) Epling on leukocytes of patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: Plants of the species Lepechinia meyenii (Walp.) Epling were collected and then different flavonoid fractions were extracted by column and thin layer chromatography. The superoxide anion production was evaluated by means of the reduction of nitroblue tetrazolium assay technique in neutrophils obtained from the blood of patients with RA, divided into three groups: negative control, which consisted of neutrophils (5x105 cells); positive control, made up of PMA (phorbol myristate acetate)-activated neutrophils (150 ng/mL), and the treatments, comprised of neutrophils activated and treated with different concentrations of the flavonoid fraction LM8 (60, 120, and 180 ug/mL). The expression of pro- inflammatory genes was studied by RTqPCR in mononuclear leukocytes obtained from patients with RA, divided into three groups: negative control, which consisted of mononuclear leukocytes (5x105 cells); positive control, made up of phytohaemagglutinin (PHA) (150 ug/ml)-activated mononuclear leukocytes, and the treatment, comprised of mononuclear leukocytes activated and treated with the flavonoid fraction LM8 (120 ug/mL). RESULTS: Several flavonoid fractions were purified, with fraction LM8 showing the best immunomodulating effect. Said fraction diminished the superoxide anion production dependent on concentration. On the other hand, it diminished the expression of TNFα, IL8, and IL17 in mononuclear leukocytes. CONCLUSIONS: These results are encouraging in terms of the immunomodulating effect of this Peruvian medicinal plant and justify the continuation of their study for a potential clinical application.
29523830 Re-assessment of multiple testing strategies for more efficient genome-wide association st 2018 Jul Although enormous costs have been dedicated to discovering relevant disease-related genetic variants, especially in genome-wide association studies (GWASs), only a small fraction of estimated heritability can be explained by these results. This is the so-called missing heritability problem. The conventional use of overly conservative multiple testing strategies based on controlling the familywise error rate (FWER), in particular with a genome-wide significance threshold of P <5 × 10(-8), is one of the most important issues from a statistical perspective. To help resolve this problem, we performed comprehensive re-assessments of currently available strategies using recently published, extremely large-scale GWAS data sets of rheumatoid arthritis and schizophrenia (>50,000 subjects). The estimates of statistical power averaged for all disease-related genetic variants of the standard FWER-based strategy were only 0.09% for the rheumatoid arthritis data and 0.04% for the schizophrenia data. To design more efficient strategies, we also conducted an extensive comparison of multiple testing strategies by applying false discovery rate (FDR)-controlling procedures to these data sets and simulations, and found that the FDR-based procedures achieved higher power than the FWER-based strategy, even at a strict FDR level (e.g., FDR = 1%). We also discuss a useful alternative measure, namely "partial power," which is an averaged power for detecting the clinically and biologically meaningful genetic factors with the largest effects. Simulation results suggest that the FDR-based procedures can achieve sufficient partial power (>80%) for detecting these factors (odds ratios of >1.05) with 80,000 subjects, and thus this may be a useful measure for defining realistic objectives of future GWASs.
30159339 A DNA-Methylated Sight on Autoimmune Inflammation Network across RA, pSS, and SLE. 2018 Methylation variabilities of inflammatory cytokines play important roles in the development of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren's syndrome (pSS). With heightened focus on personalized and precise medicine, it is necessary to compare and contrast the difference and similarity of cytokine methylation status between the 3 most classic autoimmune diseases (AIDs). In this study, we integrated 5 Cytokine-Chips from genome-wide DNA methylation datasets of the 3 kind of AIDs, delta-beta value was calculated for intergroup difference, and comprehensive bioinformatics analyses of cytokine genes with aberrant methylations were performed. 125 shared differential methylation variabilities (DMVs) were identified. There were 102 shared DMVs with similar methylation status; 3 hypomethylated differential methylation regions (DMRs) across the AIDs were found, and all 3 DMRs were hypomethylated. DMRs (AZU1, LTBR, and RTEL1) were likely to serve as activator in the inflammatory process. Particularly, AZU1 and LTBR with hypomethylated TSS and first exon located in the promoter regions were able to trigger inflammation signaling cascades and play critical roles in autoimmune tautology. Moreover, functional epigenetic module (FEM) algorithm showed that different inflammatory networks are involved in different AIDs; 5 hotspots were identified as biologically plausible pathways in inducing or perpetuating of inflammation which are epigenetically deregulated in AIDs. We concluded methylation variabilities among the same cytokines can greatly impact the perpetuation of inflammatory process or signal pathway of AIDs. Differentiating the cytokine methylation status will serve as valuable resource for researchers alike to gain better understanding of the epigenetic mechanisms of the three AIDs. Even more importantly, better understanding of cytokine methylation variability existing between the three classic AIDs will aid in identification of potential epigenetic biomarkers and therapeutic targets. This trial is registered with ChiCTR-INR-16010290, a clinical trial for the treatment of rheumatoid arthritis with Warming yang and Smoothening Meridians.
30168259 Clinical utility of red blood cell distribution width in inflammatory and non-inflammatory 2019 Jan AIM: Current studies demonstrate red blood cell distribution width (RDW) as a possible surrogate biomarker of inflammation. The objectives of the present study were to examine RDW in patients with osteoarthritis (OA), fibromyalgia (FM), rheumatoid arthritis (RA) and spondyloarthritis (SpA) and to evaluate its clinical importance. METHODS: Six hundred and ninety-nine ambulatory patients were evaluated. RDW, hemoglobin, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were assessed. In order to compare groups, a Kruskall-Wallis test with post hoc Dunn's test was applied. A multiple logistic regression analysis was used to evaluate anisocytosis explanatory variables. RESULTS: Red blood cell distribution width values differed significantly among groups. Post hoc analysis demonstrated a significant increase in RDW within RA versus OA groups (P < 0.001), active SpA versus OA (P < 0.001), RA versus FM (P < 0.001) and active SpA versus FM groups (P = 0.001). Presence of anisocytosis was useful to discriminate between active articular inflammatory versus non-inflammatory diseases with 48-95% sensitivity and 66-95% specificity. Multivariate analysis showed a six-fold increase in anisocytosis for the presence of a possible articular inflammatory disease. CONCLUSION: In subjects with articular pain, RDW interpretation is a useful tool in clinical practice to distinguish between articular inflammatory and non-inflammatory joint diseases, as with CRP. RDW seems to be a surrogate marker of the inflammatory process.
30077546 Elevated levels of IL-37 correlate with T cell activation status in rheumatoid arthritis p 2019 Jan OBJECTIVE: To assess the association between serum levels of IL-37 in rheumatoid arthritis patients and percentage of peripheral blood T lymphocytes expressing the activation marker CD26 and investigate their correlation with disease activity. METHODS: The study included 48 rheumatoid arthritis patients and 42 age and sex matched healthy controls. Serum levels of IL-37 were determined using enzyme linked immunosorbent assay while percentage of CD3(+)CD26(+)T cells in peripheral blood mononuclear cells was assayed using flowcytometry. RESULTS: Serum levels of IL-37, as well as the percentage of CD3(+)CD26(+)T cells, were significantly higher in rheumatoid arthritis patients than in healthy controls. Also, serum IL-37 levels were higher in patients with severe disease activity than patients with moderate and low disease activity. In rheumatoid arthritis patients, both serum levels of IL-37 and percentage of CD3(+)CD26(+)T cells correlated with disease activity (DAS28), C-reactive protein levels and erythrocyte sedimentation rate. In addition, serum levels of the anti-inflammatory cytokine IL-37 positively correlated with the percentage of CD3(+)CD26(+)T cells in peripheral blood of rheumatoid arthritis patients. CONCLUSION: Our results indicate a strong correlation between serum levels of IL-37 and frequency of activated T cells in peripheral blood of rheumatoid arthritis patients. Our results suggest that in an active disease status, activated T lymphocytes may be a contributing source to the elevated levels of IL-37 trying to down-regulate the active inflammatory process.