Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease of the joints that has been associated with variation in the peripheral blood methylome. In this study, we aim to identify epigenetic variation that is associated with the response to tumor necrosis factor inhibitor (TNFi) therapy.Peripheral blood genome-wide DNA methylation profiles were analyzed in a discovery cohort of 62 RA patients at baseline and at week 12 of TNFi therapy. DNA methylation of individual CpG sites and enrichment of biological pathways were evaluated for their association with drug response. Using a novel cell deconvolution approach, altered DNA methylation associated with TNFi response was also tested in the six main immune cell types in blood. Validation of the results was performed in an independent longitudinal cohort of 60 RA patients.Treatment with TNFi was associated with significant longitudinal peripheral blood methylation changes in biological pathways related to RA (FDR<0.05). 139 biological functions were modified by therapy, with methylation levels changing systematically towards a signature similar to that of healthy controls. Differences in the methylation profile of T cell activation and differentiation, GTPase-mediated signaling, and actin filament organization pathways were associated with the clinical response to therapy. Cell type deconvolution analysis identified CpG sites in CD4+T, NK, neutrophils and monocytes that were significantly associated with the response to TNFi.Our results show that treatment with TNFi restores homeostatic blood methylation in RA. The clinical response to TNFi is associated to methylation variation in specific biological pathways, and it involves cells from both the innate and adaptive immune systems.The Instituto de Salud Carlos III.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

BACKGROUND Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING Intercept Pharmaceuticals

Assessing the effects of land-use changes on sediment yield and channel dynamics in the central Spanish Pyrenees

During the last 40 years land management of the central Spanish Pyrenees has changed much. For centuries, sunny, steep slopes were cultivated with cereals. At present, most of the hillslopes have been abandoned and the old fields are colonized by different shrubs or have been reforested with pines. These changes result in a decrease in runoff and sediment yield. At a basin scale changes in the location and extent of sediment sources have been detected, and as a consequence of these changes channels have partially stabilized their sedimentary structures

Evidence for the Permo-Triassic transtensional rifting in the Iberian Range (NE Spain) according to magnetic fabrics results

Anisotropy of magnetic susceptibility (AMS) techniques are applied to Permo-Triassic red beds from the Castilian Branch (Iberian Range, NE Spain) that were deposited in an extensional basin inverted during Cenozoic times. The main goal of this work is to characterize the tectonic evolution of the basinal stage by differentiating synsedimentary to early diagenetic magnetic fabrics from the secondary tectonic fabrics related to compression, which are scarcely developed because no penetrative structures related to compression have been recognized. Oblate magnetic fabrics, with k(min) axes perpendicular to bedding,are observed in most cases. Magnetic lineations are variable, showing a dominant ENE-WSW maximum, which fits with a dextral transtensional regime acting on NW-SE master faults during the Triassic. We propose that variations in the orientation of the magnetic lineation are associated with transfer faults which fragment the basin and trigger strain partitioning in different areas. Magnetic fabrics are locally modified by Cenozoic compression, with intermediate and minimum axes distributed along girdles perpendicular to fold axes. Comparing all these results with macrostructures and mesostructural kinematic indicators, we conclude that the fine-grained hematite-bearing rocks carry a consistent magnetic fabric which can be used to reconstruct the basin history. (C) 2015 Elsevier B.V. All rights reserved

ABATACEPT in rheumatoid arthritis with interstitial lung disease. A multicenter study of 181 patients

Background Interstitial Lung Disease (ILD) is a severe extraarticular manifestation of rheumatoid arthritis (RA). Objectives Our aim was to assess the efficacy of abatacept (ABA) in RA patients with ILD. Methods Retrospective multicenter study of RA patients with ILD treated with ABA. ILD was diagnosed by HRCT. We have analyzed the following variables: a) 1-point change the Modified Medical Research Council (MMRC); b) FVC improvement ≥10%; and improvement ≥10% in DLCO; c) radiological improvement in HRCT scan, d) changes in DAS28 score. Values were compared with baseline e) prednisone doses Results We studied 181 patients (94women/87 men) with ILD associated to RA. The follow-up was 12.1[6.2-24.1] months. The mean age was 64.54 ± 9.7 years. The median to progression of ILD was 12 [3-43.75] months. 81 patients were treated in monotherapy, 100 patients in combination therapy. The most frequent pattern was UIP 45,3%. The most of patients who did not have dyspnea remained asymptomatic. See results in Figure1. DAS28 also improved. We appreciate a decrease in the dose of prednisone compared to the initial dose. Conclusion ABA seems to be effective. However, should be verified in prospective and randomized studies