Browse

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

ID PMID Title PublicationDate abstract
25169728 Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuat 2015 Jan OBJECTIVE: To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission. METHODS: ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued. RESULTS: Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%). CONCLUSIONS: Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement. TRIAL REGISTRATION NUMBER: NCT00810199.
25373782 Whole mitochondrial genome sequence of a rat rheumatoid arthritis E3 strain. 2016 May We sequenced a complete mitochondrial genome sequence of a rat rheumatoid arthritis disease E3 strain for the first time. The total length of the mitogenome was 16,305 bp and coding 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes. This mitochondrial genome sequence will provide new genetic resource into rheumatoid arthritis disease.
25537265 Multivariate meta-analysis helps examine the impact of outcome reporting bias in Cochrane 2015 May OBJECTIVES: Outcome reporting bias (ORB) is a threat to validity of systematic reviews. Multivariate meta-analysis (MVMA) can potentially reduce the impact of ORB when outcomes are correlated. The aim of this study was to assess ORB in Cochrane systematic reviews of rheumatoid arthritis and to demonstrate how MVMA may examine its impact. STUDY DESIGN AND SETTING: Reviews were assessed for ORB in relation to eight outcomes for rheumatoid arthritis using a nine-point classification system. Impact of ORB was assessed by comparing estimates from univariate meta-analysis and MVMA models. RESULTS: ORB assessment was applied in 21 included reviews, and all contained missing data on at least one of the eight outcomes. ORB was highly suspected in 247 (22%) of the 1,118 evaluable outcomes from 155 assessable trials. MVMA and univariate results sometimes differed importantly. The maximum change in treatment effect estimate between MVMA and univariate meta-analysis approach was found to be 176% for one of the outcome considered. CONCLUSION: ORB has the potential to affect the conclusions in meta-analyses. This could be avoided if trialists reported on all measured outcomes in full. If missing outcome data are unobtainable, MVMA is useful to examine the impact of missing outcomes and ORB on conclusions.
25529033 Efficacy at 52 weeks of daily clinical use of iguratimod in patients with rheumatoid arthr 2015 Jul OBJECTIVE: In recent years, the use of one or more conventional synthetic disease-modifying antirheumatic drugs has been recommended for the treatment of rheumatoid arthritis (RA). We performed a 52-week study on the efficacy and safety of iguratimod (IGU) against patients with RA in daily clinical use. METHODS: Forty-one patients were enrolled in this study, and the clinical course of RA was regularly evaluated during the 52 weeks of treatment. RESULTS: The survival rate at week 52 was 53.7%. The disease activity score (DAS) 28-erythrocyte sedimentation rate, DAS28-C-reactive protein, simplified disease activity index, and clinical disease activity index were all significantly decreased at week 52. The matrix metalloproteinase-3 level was significantly decreased at week 52 by combination therapy of IGU and methotrexate. There were one case of the onset of interstitial pneumonia (IP), one exacerbation of IP, and one case of the onset of Pneumocystis jiroveci pneumonia. CONCLUSIONS: IGU is effective for RA patients when used for daily clinical treatment for 52 weeks.
25877910 Quality indicators in rheumatoid arthritis: results from the METEOR database. 2015 Sep OBJECTIVE: To test the feasibility of collecting, storing, retrieving and analysing necessary information to fulfil a preliminary set of quality indicators (QIs) that have been proposed by an international task force in a large multinational clinical practice database of patients with RA. METHODS: Data from all 12 487 patients with 46 005 visits in the Measurement of Efficacy of Treatment in the Era of Outcome in Rheumatology database from January 2008 until January 2012 were analysed to test the feasibility of collecting information on 10 QIs: time to diagnosis; frequency of visits; assessment of autoantibodies and radiographs, disease activity and function; disease remission, low disease activity, normal function; time to first DMARD and type of first DMARD. For each QI, two aspects were assessed: information availability and target achievement. RESULTS: Information was available for <50% of patients regarding the following QIs: time to diagnosis, assessment of ACPAs or radiographs, time to first DMARD and type of first DMARD. Information was available for function assessment in 49% of visits and 67% of patients and for disease activity assessment in 85% of visits and 86% of patients. Information relevant to the QI frequency of visits was available for all patients. Relevant information to calculate the proportion of patients who achieved a defined target could be obtained for all QIs. CONCLUSION: Collecting storing, retrieving and analysing the core data necessary to meaningfully assess quality of care is feasible in a multinational, practice-based electronic database.
26674526 Interventions to Improve Adherence in Patients with Immune-Mediated Inflammatory Disorders 2015 BACKGROUND: In patients with immune-mediated inflammatory disorders, poor adherence to medication is associated with increased healthcare costs, decreased patient satisfaction, reduced quality of life and unfavorable treatment outcomes. OBJECTIVE: To determine the impact of different interventions on medication adherence in patients with immune-mediated inflammatory disorders. DESIGN: Systematic review. DATA SOURCES: MEDLINE, EMBASE and Cochrane Library. STUDY ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Included studies were clinical trials and observational studies in adult outpatients treated for psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, spondyloarthritis, psoriatic arthritis or multiple sclerosis. STUDY APPRAISAL AND SYNTHESIS METHODS: Intervention approaches were classified into four categories: educational, behavioral, cognitive behavioral, and multicomponent interventions. The risk of bias/study limitations of each study was assessed using the GRADE system. RESULTS: Fifteen studies (14 clinical trials and one observational study) met eligibility criteria and enrolled a total of 1958 patients. Forty percent of the studies (6/15) was conducted in patients with inflammatory bowel disease, half (7/15) in rheumatoid arthritis patients, one in psoriasis patients and one in multiple sclerosis patients. Seven out of 15 interventions were classified as multicomponent, four as educational, two as behavioral and two as cognitive behavioral. Nine studies, of which five were multicomponent interventions, had no serious limitations according to GRADE criteria. Nine out of 15 interventions showed an improvement of adherence: three multicomponent interventions in inflammatory bowel disease; one intervention of each category in rheumatoid arthritis; one multicomponent in psoriasis and one multicomponent in multiple sclerosis. CONCLUSION: The assessment of interventions designed for increasing medication adherence in IMID is rare in the literature and their methodological quality may be improved in upcoming studies. Nonetheless, multicomponent interventions showed the strongest evidence for promoting adherence in patients with IMID.
26768270 [Medication treatment of rheumatoid arthritis with a history of malignancy. Epidemiologica 2016 Feb INTRODUCTION: Only insufficient data are available regarding the question whether treatment with immunosuppressants or biologicals is feasible and safe in patients with a history of malignancy. METHOD: Literature search via PubMed, EULAR abstracts and ACR abstracts from 2013 to 2015. RESULTS: The Société Francaise de Rhumatologie, the Canadian Rheumatology Association and the American College of Rheumatology have tried to make recommendations on this topic. Direct evidence mainly originates from data in three national registries which suggest that treatment with tumor necrosis factor (TNF) inhibitors and rituximab appears to be safe for carefully selected patients, at least if there is a longer interval between treatment with biologicals and oncological treatment. Furthermore, despite partly conflicting data all routine drugs for treating rheumatoid arthritis do not seem to show a consistently increased risk of de novo malignancies. The currently available data are presented for each drug of interest. CONCLUSION: Taking the current literature into account an attempt is made to formulate an algorithm for the medicinal treatment of patients with rheumatoid arthritis and a history of malignancy.
27219303 Does a Simplified 6-Joint Ultrasound Index Correlate Well Enough With the 28-Joint Disease 2016 Jun OBJECTIVE: Ultrasound (US) has become an important tool in the management of rheumatoid arthritis (RA) but it is time consuming in clinical practice. We compared 3 US indices (with different numbers of joints) with disease activity measured by the 28-Joint Disease Activity Score (DAS28) in order to find the most parsimonious index still useful in clinical practice. METHODS: Sixty consecutive RA patients were included. The DAS28 score was calculated by the attending rheumatologist, and later in the day, they underwent US examination by another rheumatologist trained in US (bilateral gray-scale and power Doppler examination of the wrist and metacarpophalangeal and proximal interphalangeal joints). Three different US indices were constructed: index A (22 joints), index B (10 joints), and index C (6 joints). RESULTS: All 3 US indices were significantly higher in patients with active disease versus inactive disease (P < 0.05 for all 3). Ultrasound index C showed the best correlation with DAS28 (rho = 0.5020, P < 0.0001) and a very good discriminative value for moderate to high disease activity (DAS28 >3.2) and for absence of remission (DAS28 >2.6) (areas under receiver operating characteristic curve = 0.75 and 0.80, respectively). A cutoff value of 3 in US index C showed sensitivity of 88.89% and specificity of 66.67% for absence of remission. Correlation between the 3 US indices was excellent. CONCLUSIONS: A US index of 6 joints (both wrists and second and third metacarpophalangeal joints bilaterally) correlated well with disease activity measured by DAS28 and may be used to evaluate RA patients in daily practice.
26892115 EuroQol-5 dimensions utility gain according to British and Swedish preference sets in rheu 2016 Feb 19 BACKGROUND: The development of EuroQol-5 dimensions (EQ-5D) utility over time in rheumatoid arthritis (RA) patients, treated with biologics other than tumour necrosis factor inhibitors (TNFi), based on the standard British (UK) and the new Swedish (SE) EQ-5D preference sets, has not been previously described. METHODS: Demographics, core set data, EQ-5D utility, and treatment characteristics for patients with established RA, receiving biologics in southern Sweden from January 2006 to March 2014, were retrieved from observational databases. Theoretical, UK, and experience-based, SE, EQ-5D mean utilities were plotted over time. RESULTS: Data regarding 2418 treatment courses with abatacept (ABA, n = 100), rituximab (RTX, n = 230), tocilizumab (TOC, n = 121), or TNFi (n = 1967) were included in the analysis. Patients starting TNFi treatment, as expected, had shorter disease duration and less previous biologics. Baseline utilities of patients commencing ABA and TOC, but not RTX, were also lower than in the TNFi group. Following treatment initiation, rapid utility improvements were seen with all therapies, reaching plateaus after approximately 1.5 months, and then remaining fairly stable throughout follow-up in patients adhering to therapy. SE utilities were consistently higher than UK, with baseline values at around 0.7 leaving little room for improvement. CONCLUSIONS: ABA, RTX, TOC, and TNFi treatments were all associated with favourable EQ-5D utility developments in RA patients adhering to therapy. The compression of the experience-based SE preference set towards higher utilities may compromise its ability to detect between-group differences in quality-adjusted life-years, thus making cost-effectiveness harder to demonstrate in cost-utility analyses applying this preference set, rather than the standard UK.
26727968 Hydroxychloroquine Use Is Associated With Decreased Incident Cardiovascular Events in Rheu 2016 Jan 4 BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in rheumatoid arthritis (RA) patients. This study is the first to report the association of hydroxychloroquine (an antirheumatic medication that has been associated with decreased risk of diabetes, a less atherogenic lipid profile, and antithrombotic properties) with CVD in RA. METHODS AND RESULTS: A retrospective incident RA cohort from January 1, 2001, to October 31, 2013, excluding patients with CVD prior to RA diagnosis, was constructed. Patients were categorized as hydroxychloroquine users versus nonusers and were allowed to contribute time to either group according to hydroxychloroquine exposure. The primary outcome was adjudicated incident CVD defined as a composite of coronary artery disease, stroke, transient ischemic attack, sudden cardiac death, and peripheral artery disease with arterial revascularization procedure. The secondary outcome was a composite of incident coronary artery disease, stroke, and transient ischemic attack. Cox time-varying regression models were used to estimate the association between hydroxychloroquine exposure and development of CVD, after adjusting for propensity score and relevant confounders, including demographics, CVD-related comorbidities, RA severity, and activity indicators and medications. We included 1266 RA patients, 547 hydroxychloroquine users, and 719 nonusers. During the observation period, 102 CVD events occurred, 3 in hydroxychloroquine users and 99 in nonusers. The fully adjusted Cox model showed a hazard ratio of 0.28 (95% CI 0.12-0.63, P=0.002) for incident CVD and 0.30 (95% CI 0.13-0.68, P=0.004) for incident composite coronary artery disease, stroke, and transient ischemic attack for hydroxychloroquine users versus nonusers, respectively. CONCLUSION: In this hypothesis-generating study, hydroxychloroquine use was associated with a 72% decrease in the risk of incident CVD in RA patients. If these preliminary results are confirmed in larger studies, our findings may be used as a rationale for a randomized study of hydroxychloroquine use for primary prevention of CVD in RA or nonrheumatic high-risk patients.
25593241 Personalizing treatment targets in rheumatoid arthritis by using a simple prediction model 2015 Mar OBJECTIVE: To develop a personalized treatment target approach in patients with rheumatoid arthritis (RA) based on baseline risk factors for joint damage progression in combination with disease activity over time. METHODS: Data were used from the Nijmegen early RA cohort. Presence or absence of anticyclic citrullinated peptide antibodies (anti-CCP), high erythrocyte sedimentation rate, and erosions were translated into 4 risk profiles: 0, 1, 2, and 3. Joint damage progression was assessed with the Ratingen score, and disease activity with the original Disease Activity Score (DAS) over 3 years. The probability for joint damage progression was calculated for each risk profile and each DAS category using logistic regression models. The probabilities were translated into personalized disease activity treatment targets. RESULTS: More risk factors at baseline as well as a higher DAS level resulted in a higher probability for joint damage progression in a dose-dependent way. Low DAS corresponded with a probability of 0.0, 0.08, 0.20, and 0.58 in patients with 0, 1, 2, and 3 risk factors, respectively. Moderate DAS corresponded with a probability of 0.06 in patients with 0 risk factors and 0.35 with 1 risk factor. High DAS resulted in a probability of 0.50 with no risk factors present at baseline. CONCLUSION: Presence of anti-CCP, acute-phase response, and erosions at baseline can be used to set individual treatment targets in RA. In patients without these risk factors, a moderate DAS as a target is sufficient, while for patients with all 3 risk factors, a low DAS is not strict enough to limit the risk for joint damage.
26301589 Heterogeneous Disease Trajectories Explain Variable Radiographic, Function and Quality of 2015 Our objective was to identify distinct trajectories of disease activity state (DAS) and assess variation in radiographic progression, function and quality of life over the first two years of early rheumatoid arthritis (ERA). The CATCH (Canadian early ArThritis CoHort) is a prospective study recruiting ERA patients from academic and community rheumatology clinics in Canada. Sequential DAS28 scores were used to identify five mutually exclusive groups in the cohort (n = 1,586) using growth-based trajectory modeling. Distinguishing baseline sociodemographic and disease variables, treatment required, and differences in radiographic progression and quality of life measures over two years were assessed. The trajectory groups are characterized as: Group 1 (20%) initial high DAS improving rapidly to remission (REM); Group 2 (21%) initial moderate DAS improving rapidly to REM; Group 3 (30%) initial moderate DAS improving gradually to low DAS; Group 4 (19%) initial high DAS improving continuously to low DAS; and Group 5 (10%) initial high DAS improving gradually only to moderate DAS. Groups differed significantly in age, sex, race, education, employment, income and presence of comorbidities. Group 5 had persistent steroid requirements and the highest biologic therapy use. Group 2 had lower odds (OR 0.22, 95%CI 0.09 to 0.58) and Group 4 higher odds (OR 1.94, 95%CI 0.90 to 4.20) of radiographic progression compared to Group 1. Group 1 had the best improvement in physical function (Health Assessment Questionnaire 1.08 (SD 0.68) units), Physical Component Score (16.4 (SD 10.2) units), Mental Component Score (9.7 (SD 12.5) units) and fatigue (4.1 (SD 3.3) units). In conclusion, distinct disease activity state trajectories explain variable outcomes in ERA. Early prediction of disease course to tailor therapy and addressing social determinants of health could optimize outcomes.
27974851 Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arth 2017 Feb A key unanswered question in the pathophysiology of rheumatoid arthritis (RA) is how systemic autoimmunity progresses to joint-specific inflammation. In patients with seropositive RA (that is, characterized by the presence of autoantibodies) evidence is accumulating that immunity against post-translationally modified (such as citrullinated) autoantigens might be triggered in mucosal organs, such as the lung, long before the first signs of inflammation are seen in the joints. However, the mechanism by which systemic autoimmunity specifically homes to the joint and bone compartment, thereby triggering inflammation, remains elusive. This Review summarizes potential pathways involved in this joint-homing mechanism, focusing particularly on osteoclasts as the primary targets of anti-citrullinated protein antibodies (ACPAs) in the bone and joint compartment. Osteoclasts are dependent on citrullinating enzymes for their normal differentiation and are unique in displaying citrullinated antigens on their cell surface in a non-inflamed state. The binding of ACPAs to osteoclasts releases the chemokine IL-8, leading to bone erosion and pain. This process initiates a chain of events that could lead to attraction and activation of neutrophils, resulting in a complex series of proinflammatory processes in the synovium, eventually leading to RA.
27336685 Safety of Repeated Open-Label Treatment Courses of Intravenous Ofatumumab, a Human Anti-CD 2016 OBJECTIVES: To investigate the safety of ofatumumab retreatment in rheumatoid arthritis. METHODS: Patients with active rheumatoid arthritis participating in two phase III trials (OFA110635 and OFA110634) and a phase II extension trial (OFA111752) received individualised open-label ofatumumab retreatment (700 mg X 2 intravenous infusions two weeks apart) ≥24 weeks following the first course and ≥16 weeks following further courses. Retreatment required evidence of clinical response followed by disease relapse. These studies were prematurely terminated by the sponsor to refocus development on subcutaneous delivery. Due to differences in study designs and populations, data are summarised separately for each study. RESULTS: 483 patients (243, 148 and 92 in OFA110635, OFA110634 and OFA111752 respectively) received up to 7 treatment courses of intravenous ofatumumab; cumulative duration of exposure was 463, 182 and 175 patient-years, respectively. Mean time between courses was 17-47 weeks. Ofatumumab induced a profound depletion of peripheral B-lymphocytes. Retreated patients derived benefit based on improvement in DAS28. Adverse events were reported for 93% (226/243), 91% (134/148) and 76% (70/92), serious adverse events for 18% (44/243), 20% (30/148) and 12% (11/92) and serious infections for 3% (8/243), 5% (7/148) and 1% (1/92) of patients in OFA110635, OFA110634 and OFA111752, respectively. The most common adverse events were infusion-related reactions during the first infusion of the first course (48-79%); serious infusion-related reactions were rare (<1% [1/243], 5% [8/148], and 1% [1/92] of patients). Two deaths occurred (fulminant hepatitis B virus infection and interstitial lung disease). CONCLUSIONS: Ofatumumab was generally well tolerated with no evidence of increased safety risks with multiple retreatments. Serious infections were uncommon and did not increase over time. TRIAL REGISTRATION: ClinicalTrials.gov 110635 ClinicalTrials.gov 110634 ClinicalTrials.gov 111752.
25979865 Electroacupuncture attenuates collagen-induced arthritis in rats through vasoactive intest 2015 Aug OBJECTIVE: Imbalance between T-helper 17 (Th17) cells and regulatory T (Treg) cells is causally linked to the development of rheumatoid arthritis (RA). In this study, we tested the hypothesis that electroacupuncture (EA) confers therapeutic benefits in RA through activation of vasoactive intestinal peptide (VIP)-dependent signalling and restoration of the Th17/Treg cell balance. MATERIALS AND METHODS: A collagen-induced arthritis (CIA) model was induced in Sprague-Dawley rats by injection of bovine type II collagen in incomplete Freund's adjuvant on day 0 and day 7. Three days after the second injection, EA was given at acupuncture points GB39 and ST36 three times per week for 4 weeks. To block VIP signalling, [D-P-Cl-Phe(6)-Leu(17)]-VIP, a VIP receptor antagonist, was administered intraperitoneally 30 min before EA. Inflammatory and pathological responses in the joint were assessed. Synovial VIP receptor mRNA levels and Treg and Th17 cell frequencies in the spleen were determined. RESULTS: EA significantly reduced the severity of CIA, as evidenced by reduced paw volumes, arthritis scores and inflammation scores. EA significantly increased mRNA expression of the VIP receptor VPAC1 and led to an elevation in CD4(+)FOXP3(+) Treg cell frequency and a reduction in CD4(+)IL17(+) Th17 cell frequency. Pre-injection of a VIP receptor antagonist significantly reversed EA-induced expansion of Treg cells, but did not alter the frequencies of Th17 cells. CONCLUSIONS: EA exerts anti-inflammatory effects in a collagen-induced rat model of arthritis. These effects appear to be mediated through activation of VIP signalling and re-establishment of the Th17/Treg cell balance.
27676277 Moving toward personalized medicine in rheumatoid arthritis: SNPs in methotrexate intracel 2016 Oct AIM: Evaluate the potential of selected SNPs as predictors of methotrexate (MTX) therapeutic outcome. PATIENTS & METHODS: In total, 35 SNPs in 14 genes involved in MTX intracellular pathways and Phase II reactions were genotyped in 233 rheumatoid arthritis (RA) patients treated with MTX. Binary logistic regressions were performed by genotype/haplotype-based approaches. Non-Response- and Toxicity-Genetic Risk Indexes (Non-RespGRI and ToxGRI) were created. RESULTS: MTX nonresponse was associated to eight genotypes and three haplotypes: MTHFR rs1801131 AA and rs1801133 TT; MS rs1805087 AA; MTRR rs1801394 A carriers; ATIC rs2372536 C carriers, rs4673993 T carriers, rs7563206 T carriers and rs12995526 T carriers; CC for GGH rs3758149 and rs12681874; CGTTT for ATIC combination 1; and CTTTC for ATIC combination 2. From overall Non-RespGRI patients with indexes 6-8 had more than sixfold increased risk for MTX nonresponse than those patients with indexes 0-5. MTX-related toxicity was associated to five genotypes and two haplotypes: ATIC rs2372536 G carriers, rs3821353 T carriers, rs7563206 CC and rs12995526 CC; ADORA2A rs2267076 T; CTTCC for ATIC combination 1; and TC for ADORA2A rs2267076 and rs2298383. From overall ToxGRI, patients with indexes 3-4 had more than sevenfold increased risk for MTX-related toxicity than those patients with indexes 1-2. CONCLUSION: Genotyping may be helpful to identify which RA patients will not benefit from MTX treatment and, consequently, important to personalized medicine in RA. Nevertheless, further studies are required to validate these findings.
27876072 High-specificity bioinformatics framework for epigenomic profiling of discordant twins rev 2016 Nov 22 BACKGROUND: Twin studies are powerful models to elucidate epigenetic modifications resulting from gene-environment interactions. Yet, commonly a limited number of clinical twin samples are available, leading to an underpowered situation afflicted with false positives and hampered by low sensitivity. We investigated genome-wide DNA methylation data from two small sets of monozygotic twins representing different phases during the progression of rheumatoid arthritis (RA) to find novel genes for further research. METHODS: We implemented a robust statistical methodology aimed at investigating a small number of samples to identify differential methylation utilizing the comprehensive CHARM platform with whole blood cell DNA from two sets of twin pairs discordant either for ACPA (antibodies to citrullinated protein antigens)-positive RA versus ACPA-negative healthy or for ACPA-positive healthy (a pre-RA stage) versus ACPA-negative healthy. To deconvolute cell type-dependent differential methylation, we assayed the methylation patterns of sorted cells and used computational algorithms to resolve the relative contributions of different cell types and used them as covariates. RESULTS: To identify methylation biomarkers, five healthy twin pairs discordant for ACPAs were profiled, revealing a single differentially methylated region (DMR). Seven twin pairs discordant for ACPA-positive RA revealed six significant DMRs. After deconvolution of cell type proportions, profiling of the healthy ACPA discordant twin-set revealed 17 genome-wide significant DMRs. When methylation profiles of ACPA-positive RA twin pairs were adjusted for cell type, the analysis disclosed one significant DMR, associated with the EXOSC1 gene. Additionally, the results from our methodology suggest a temporal connection of the protocadherine beta-14 gene to ACPA-positivity with clinical RA. CONCLUSIONS: Our biostatistical methodology, optimized for a low-sample twin design, revealed non-genetically linked genes associated with two distinct phases of RA. Functional evidence is still lacking but the results reinforce further study of epigenetic modifications influencing the progression of RA. Our study design and methodology may prove generally useful in twin studies.
26958193 Using Big Data to Evaluate the Association between Periodontal Disease and Rheumatoid Arth 2015 An association between periodontal disease and rheumatoid arthritis is believed to exist. Most investigations into a possible relationship have been case-control studies with relatively low sample sizes. The advent of very large clinical repositories has created new opportunities for data-driven research. We conducted a retrospective cohort study to measure the association between periodontal disease and rheumatoid arthritis in a population of 25 million patients. We demonstrated that subjects with periodontal disease were roughly 1.4 times more likely to have rheumatoid arthritis. These results compare favorably with those of previous studies on smaller cohorts. Additional work is needed to identify the mechanisms behind this association and to determine if aggressive treatment of periodontal disease can alter the course of rheumatoid arthritis.
26251236 In vitro response pattern of monocytes after tmTNF reverse signaling predicts response to 2015 Aug 7 BACKGROUND: Treatment with TNF inhibitors is very efficient in the majority of the patients with rheumatoid arthritis (RA), but it does not achieve a sufficient treatment response in 40-50% of the cases. Goal of the study was to assess functional ex vivo-tests of RA monocytes as prognostic parameters of the subsequent treatment response. METHODS: 20 anti-TNF naïve RA patients were enrolled in a prospective, open-label trial, and Etanercept therapy was initiated. Prior to treatment, reverse signaling was induced in peripheral blood monocytes by tmTNF crosslinking via TNFR2:Ig construct Etanercept in a standardized ex vivo-assay. Released cytokine and cytokine receptor concentrations were determined as parameters of the monocyte response. RESULTS: Crosslinking of tmTNF and consecutive reverse signaling led to production of pro- and anti-inflammatory cytokines and of soluble cytokine decoy receptors such as sTNFR1 and sIL-1R2. Several of the measured concentrations were found to correlate with the treatment response according to the EULAR criteria. The correlation was most pronounced in sTNFR1 concentrations (r = -0.657, p = 0.0031), which also predicted a good clinical response with the highest sensitivity and specificity according to EULAR criteria. CONCLUSIONS: Herein we propose that the tmTNF crosslinking-triggered shedding of soluble decoy receptors and production of anti-inflammatory cytokines could contribute to the clinical efficacy of TNF inhibitors, and that in vitro quantification of this secretion by RA monocytes prior to treatment can be used to predict the clinical response. Further development of such standardized tests could be a step towards personalized medicine by providing rheumatologists with a rational choice for first line biological therapy in patients with RA.
25618758 The impact of C677T and A1298C MTHFR polymorphisms on methotrexate therapeutic response in 2015 Jul Some single-nucleotide polymorphisms (SNPs) might be predictive of methotrexate (MTX) therapeutic outcome in rheumatoid arthritis (RA). The aim of this study was to determine whether SNPs in the methylenetetrahydrofolate reductase (MTHFR) gene are predictive of MTX response. Comparison was made using EULAR response criteria and according to the change of DAS28 (∆DAS28) after a 6-month MTX treatment in RA patient cohort. The two SNPs C677T (rs1801133) and A1298C (rs1801131) have been genotyped. A total of 120 patients were enrolled in the study, and all of them fulfilled the American College of Rheumatology 1987 RA criteria and are currently or previously taking MTX oral treatment, either as a monotherapy (n = 65) or in a combination with other disease-modifying antirheumatic drugs (n = 55). Genotyping was performed using qPCR allelic discrimination. We did not found any association of C677T and A1298C genotypes with MTX treatment inefficacy in dominant model (OR 1.23, 95 % CI 0.57-2.65, P = 0.697; and OR 0.98, 95 % CI 0.47-2.14, P = 1.0, respectively), or in recessive and codominant models. However, when ∆DAS28 after a 6-month therapy was used as a measure of treatment efficacy, the 677CT and 1298AC genotypes were found to be significantly associated with less favorable response to MTX (P = 0.025 and P = 0.043, respectively). In addition, even lower ∆DAS28 was determined for double-mutated 677CT-1298AC heterozygotes. It means that a synergistic effect of 677CT and 1298AC genotypes was observed. Nevertheless, the DAS28 baseline was lower here comparing to other genotypes. Unexpectedly, quite the opposite trend-i.e., better response to MTX-was found in genotypes 677CC-1298CC and 677TT-1298AA. It is an intriguing finding, because these double-mutated homozygotes are known for their low MTHFR-specific activity. Global significance was P = 0.013, η (2) = 0.160-i.e., large-size effect. Thus, our data show greater ability of 677CC-1298CC and 677TT-1298AA genotypes to respond to MTX treatment.