Non-Canonical WNT5A Signaling Through RYK Contributes to Aggressive Phenotype of the Rheumatoid Fibroblast-Like Synoviocytes

We hypothesized that WNT5A could contribute to the enhanced migration and invasiveness of rheumatoid arthritis fibroblast-like synoviocytes (RA FLS), which is one of the incompletely understood aspects of the RA FLS aggressive phenotype. This hypothesis is based on the previous evidence of a WNT5A role in both, RA and cell migration. Migration and invasion of RA FLS were assessed after incubation with recombinant Wnt5a (rWnt5a) or silencing of the endogenous WNT5A expression. The expression of WNT5A, WNT receptors, cytokines, chemokines, and metalloproteinases was quantified with RT-PCR. The WNT pathway was explored with gene silencing, antibody and pharmacological inhibition followed by migration assays and phosphoprotein western blots. Here, we reported that rWnt5a promoted migration and invasion of RA FLS, whereas knockdown of the endogenous WNT5A reduced them. These effects were specific to the RA FLS since they were not observed in FLS from osteoarthritis (OA) patients. Also, rWnt5a induced the expression of IL6, IL8, CCL2, CXCL5, MMP1, MMP3, MMP9, and MMP13 from baseline or potentiating the TNF induction, WNT5A signaling required the RYK receptor and was mediated through the WNT/Ca(2+) and the ROCK pathway. These pathways involved the RYK and ROCK dependent activation of the p38, ERK, AKT, and GSK3beta kinases, but not the activation of JNK. Together these findings indicate that WNT5A contributes to the enhanced migration and invasiveness of RA FLS through RYK and the specific activation of ROCK and downstream kinases

Unravelling the Gut Microbiota of Cow’s Milk–Allergic Infants, Their Mothers, and Their Grandmothers

The gut microbiome constitutes a highly complex ecosystem in which bacteria are the most prominent components. Around 70% of primary colonization of the gut microbiota is maternal in origin [1], and the first 1000 days of life are crucial for the development of the intestinal microbiota [2]. Despite its early formation, the gut microbiota is highly dynamic and dependent on host-associated confounding factors such as age, diet, antibiotics, lifestyle, and environmental conditions [3,4]. Alterations in gut microbiota have been described in people with different types of allergy, including cow’s milk allergy (CMA)This work was supported by Instituto de Salud Carlos III (PI17/01087) and Fundación Sociedad Española de Alergia e Inmunología Clínica (FSEAIC_2016). It was cofunded by the European Regional Development Fund “Investing in your future” for the Thematic Network and Co-operative Research Centers ARADyAL RD16/0006/0015 and RD16/0006/0026. It was additionally supported by the Ministry of Science, Innovation in Spain (PCI2018-092930), cofunded by the European program ERA HDHL - Nutrition & the Epigenome, project Dietary Intervention in Food Allergy: Microbiome, Epigenetic and Metabolomic interactions (DIFAMEM). DR and EZ-V acknowledge funding from the Spanish Ministry of Science, Innovation and Universities (RTI2018-095166-B-I00). CU acknowledges funding from the Spanish Ministry of Economy (SAF2017-90083-R). TCB-T thanks CEUInternational Doctoral School (CEINDO) for his fellowship

Assessment of anti-malondialdehyde-acetaldehyde antibody frequencies in rheumatoid arthritis with new data from two independent cohorts, meta-analysis, and meta-regression

Autoantibodies are critical elements in RA pathogenesis and clinical assessment. The anti-malondialdehyde-acetaldehyde (anti-MAA) antibodies are potentially useful because of their claimed high sensitivity for all RA patients, including those lacking RF and anti-CCP antibodies. Therefore, we aimed to replicate these findings.The research done in Santiago was funded by Instituto de Salud Carlos III through the projects PI20/01268, PI17/01606 and RD21/0002/0003, co-funded by the European Union. L.R.-M. was supported by Xunta de Galicia (Spain) through a Gain pre-doctoral fellowship (IN606A-2017/015). The research in Barcelona was funded by the Spanish Ministry of Economy, Industry and Competitiveness and the European Regional Development Fund (Grant PID2021-122216OB-I00).Peer reviewe

Influence of MUC5B gene on antisynthetase syndrome

ABSTRACT: MUC5B rs35705950 (G/T) is strongly associated with idiopathic pulmonary fibrosis (IPF) and also contributes to the risk of interstitial lung disease (ILD) in rheumatoid arthritis (RA-ILD) and chronic hypersensitivity pneumonitis (CHP). Due to this, we evaluated the implication of MUC5B rs35705950 in antisynthetase syndrome (ASSD), a pathology characterised by a high ILD incidence. 160 patients with ASSD (142 with ILD associated with ASSD [ASSD-ILD+]), 232 with ILD unrelated to ASSD (comprising 161 IPF, 27 RA-ILD and 44 CHP) and 534 healthy controls were genotyped. MUC5B rs35705950 frequency did not significantly differ between ASSD-ILD+ patients and healthy controls nor when ASSD patients were stratified according to the presence/absence of anti Jo-1 antibodies or ILD. No significant differences in MUC5B rs35705950 were also observed in ASSD-ILD+ patients with a usual interstitial pneumonia (UIP) pattern when compared to those with a non-UIP pattern. However, a statistically significant decrease of MUC5B rs35705950 GT, TT and T frequencies in ASSD-ILD+ patients compared to patients with ILD unrelated to ASSD was observed. In summary, our study does not support a role of MUC5B rs35705950 in ASSD. It also indicates that there are genetic differences between ILD associated with and that unrelated to ASSD.We are indebted to the patients and healthy controls for their essential collaboration to this study. We also thank the National DNA Bank Repository (Salamanca) for supplying part of the control samples. This study was partially supported by grants from the Foundation for Research in Rheumatology (FOREUM). RL-M is a recipient of a Miguel Servet type I programme fellowship from the ‘Instituto de Salud Carlos III’ (ISCIII), co-funded by the European Social Fund (ESF, ‘Investing in your future’) (grant CP16/00033). SR-M is supported by funds of the RETICS Program (RD16/0012/0009), co-funded by the European Regional Development Fund (ERDF). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). VM is supported by funds of a Miguel Servet type I programme (grant CP16/00033) (ISCIII, co-funded by ESF). LL-G is supported by funds of PI18/00042 (ISCIII, co-funded by ERDF). OG is Staff Personnel of Xunta de Galicia (Servizo Galego de Saude, SERGAS) through a research-staff stabilization contract (ISCIII/SERGAS). OG,is member of RETICS Programme, RD16/0012/0014 (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) via Instituto de Salud Carlos III (ISCIII) and FEDER. The work of OG (PI17/00409), was funded by Instituto de Salud Carlos III and FEDER. OG is a beneficiary of a project funded by Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme (Project number 734899). OG is beneficiary of a grant funded by Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN), GPC IN607B2019/10

Influence of antisynthetase antibodies specificities on antisynthetase syndrome clinical spectrum time course

Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition

Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum TimeCourse

Introduction: Increased cardiovascular (CV) morbidity and mortality is observed in inflammatory joint diseases (IJDs) such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. However, the management of CV disease in these conditions is far from being well established.Areas covered: This review summarizes the main epidemiologic, pathophysiological, and clinical risk factors of CV disease associated with IJDs. Less common aspects on early diagnosis and risk stratification of the CV disease in these conditions are also discussed. In Europe, the most commonly used risk algorithm in patients with IJDs is the modified SCORE index based on the revised recommendations proposed by the EULAR task force in 2017.Expert opinion: Early identification of IJD patients at high risk of CV disease is essential. It should include the use of complementary noninvasive imaging techniques. A multidisciplinary approach aimed to improve heart-healthy habits, including strict control of classic CV risk factors is crucial. Adequate management of the underlying IJD is also of main importance since the reduction of disease activity decreases the risk of CV events. Non-steroidal anti-inflammatory drugs may have a lesser harmful effect in IJD than in the general population, due to their anti-inflammatory effects along with other potential beneficial effects.This research was partially funded by FOREUM—Foundation for Research in Rheumatolog

SECUKINUMAB improves axial manifestations in patients with psoriatic arthritis and inadequate response to NSAIDS: primary analysis of the maximise trial

Background Secukinumab (SEC) has provided significant and sustained improvement in the signs and symptoms of active psoriatic arthritis (PsA) and ankylosing spondylitis 1. Evidence on the efficacy of biologics in the treatment of PsA patients (pts) with axial manifestations affecting 30?70% of PsA pts is limited2, particularly as validated classification criteria for this subtype of PsA are not yet available; an effort to develop criteria is being undertaken by ASAS/GRAPPA. MAXIMISE is an ongoing study evaluating the efficacy and safety of secukinumab 300 or 150mg in managing axial manifestations in PsA pts Objectives To report the primary analysis results at Week (Wk) 12 from MAXIMISE (NCT02721966) trial Methods This phase 3b, double blind, placebo (PBO)-controlled, multicentre 52-wk trial included 498 pts (aged ?18 years) with PsA (CASPAR criteria), clinician-diagnosed axial involvements, spinal pain VAS >40/100 and BASDAI >4 despite trial of at least two NSAIDs. Pts were randomised to subcutaneous (SC) SEC (300/150 mg) or PBO weekly for 4 wks and every 4 wks thereafter. At Wk 12, PBO pts were re-randomised to SC SEC 300/150 mg. The primary endpoint was proportion of pts achieving ASAS20 response with SEC 300 mg at Wk 12. The key secondary endpoint was ASAS20 response with SEC 150 mg at Wk 12 after superiority of 300 mg was established. Analyses used multiple imputation Results Demographic and baseline (BL) disease characteristics were comparable across groups (Table). Primary and key secondary endpoints were met; ASAS20 response rates at Wk 12 were 63.1% (SEC 300 mg; P<0.0001) and 66.3% (150 mg; P<0.0001) vs 31.3% (PBO; Figure). ASAS20 responses in pts using concomitant MTX were 65.1% [300 mg], 67.3% [150 mg] vs 33.9% [PBO] and corresponding values in No MTX group were 60.5%, 64.4% vs 27.1%. The safety profile was similar across groups through Wk 12 Conclusion MAXIMISE is the first randomised controlled trial evaluating the efficacy of a biologic in the management of the axial manifestations of PsA. SEC 300 and 150 mg provided rapid and significant improvement in ASAS20 responses through Wk 12 in PsA pts with axial manifestations and inadequate responses to NSAID