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Resumen Objetivo Elaborar recomendaciones para la prevencion de infeccion en pacientes adultos con enfermedades reumaticas autoinmunes sistemicas (ERAS). Metodos Un panel de expertos, seleccionados con base en su curriculum y experiencia, identifico preguntas clinicas de investigacion relevantes para el objetivo del documento. Se realizaron revisiones sistematicas de la evidencia, que se graduo de acuerdo con los criterios del Scottish Intercollegiate Guidelines Network. Tras ello, se formularon las recomendaciones. Resultados Se seleccionaron cinco preguntas, referentes a la prevencion de infeccion por Pneumocystis jirovecii con trimetoprim-sulfametoxazol, medidas profilacticas contra el virus de la hepatitis B, vacunacion contra el virus del papiloma humano, vacunacion contra el Streptococcus pneumoniae y vacunacion contra el virus de la gripe. Se formularon un total de 18 recomendaciones, estructuradas por pregunta, con base en la evidencia encontrada para las diferentes ERAS y/o consenso de expertos. Conclusiones Existe suficiente evidencia sobre la seguridad y eficacia de las vacunaciones y otras medidas profilacticas frente a los microrganismos revisados en este documento como para ser recomendadas especificamente en pacientes con ERAS.

Resumen Objectifs: Decrire la date de survenue de l’uveite anterieure aigue (UAA) par rapport aux premiers symptomes rhumatismaux et determiner son association a l’evolution de la spondyloarthrite (SpA) en ce qui concerne l’activite, les lesions structurelles, la capacite fonctionnelle et le traitement. Methodes: Il s’agit d’une etude transversale s’appuyant sur les donnees du registre REGISPONSER (registre national des SpA de la societe espagnole de rhumatologie). Trente-et-un centres ont participe et les patients atteints de SpA selon les criteres de l’ESSG ont ete inclus entre 2004 et 2007. La classification des patients s’est faite selon la date de survenue de l’uveite par rapport aux premiers signes rhumatismaux (anterieure, simultanee ou posterieure a l’apparition des symptomes). Nous avons compare les caracteristiques cliniques, l’activite de la maladie, les lesions radiographiques et la capacite fonctionnelle entre les « UAA survenues avant/simultanement aux premiers symptomes rhumatismaux » et les « UAA survenues apres les premiers symptomes ». Pour finir, nous avons analyse l’impact de la date de survenue de l’UAA sur le recours aux anti-rhumatismaux modificateurs de la maladie conventionnels et biologiques (respectivement DMARDcs et DMARDb) Resultats: Au total, 2 367 patients ont ete inclus dans le registre REGISPONSER avec une prevalence de l’UAA de 16,2 % (379 patients). Les patients dont l’UAA precedait/accompagnait les premiers signes rhumatismaux (n=59) affichaient une meilleure capacite fonctionnelle (BASFI, OR 0,85 [0,73-0,99]) et des lesions structurelles moins marquees (BASRI au rachis, OR 0,88 [0,79-0,99]). De plus, dans ce groupe de patients, l’âge d’apparition des premiers symptomes de SpA etait plus avance (OR 1,05 [1,02-1,09]) et le delai diagnostique plus court (OR 0,90 [0,84-0,96]) comparativement aux patients ayant developpe une UAA apres l’apparition des manifestations rhumatismales (n=229). Aucune difference statistiquement significative concernant l’utilisation des DMARD n’a ete observee (27,9 % vs 23,2 % pour l’utilisation des DMARDcs et 15,3 % vs 20,3 % pour l’utilisation des DMARDb chez les patients avec une UAA survenue respectivement avant/simultanement vs apres les premiers signes rhumatismaux). Conclusion: Les patients qui presentaient un premier episode d’UAA avant/simultanement aux premiers symptomes rhumatismaux avaient une forme moins severe de la maladie (meilleure capacite fonctionnelle et dommages structuraux limites) et un delai diagnostique plus court ; cependant, la date de survenue de l’UAA n’a montre aucun effet sur les traitements administres.

An inverse association between alcohol consumption and disease activity and functional impairment has been observed in patients with spondyloarthritis (SpA). However, neither this association nor the influence of smoking has been investigated in peripheral manifestations of SpA.The objective of this study was to analyze the association between smoking and alcohol consumption and the presence of peripheral musculoskeletal manifestations (arthritis, enthesitis or dactylitis) and to determine the specific location of these manifestations.Patients from the worldwide cross-sectional ASAS-PerSpA study with a diagnosis of axial SpA (axSpA), peripheral SpA (pSpA) or psoriatic arthritis (PsA) according to their rheumatologist were included. Generalised linear mixed models used peripheral manifestation (or location) as a dependent variable, smoking status and alcohol consumption as fixed effects and country as a random effect. The interaction between smoking and alcohol was tested. Analyses were performed for each diagnosis (axSpA, pSpA and PsA).A total of 4181 patients were included. In axSpA patients, smoking was associated with a lower prevalence of any peripheral manifestation, and current alcohol consumption was associated with a lower prevalence of both current arthritis and current enthesitis. In pSpA patients, current alcohol consumption was associated with a lower prevalence of current arthritis or enthesitis. In PsA patients, a significant association was found for arthritis with smoking and for enthesitis with alcohol consumption, and current alcohol consumption was associated with a lower prevalence of current arthritis or enthesitis.Taking into account the country, smoking and alcohol are associated with a lower prevalence of peripheral manifestations.

Objectives: To describe the frequency of COVID-19 and the effect of vaccination in patients with interstitial lung disease and systemic autoimmune disease (ILD-SAD) and to identify factors associated with infection and severity of COVID-19. Methods: We performed a cross-sectional multicenter study of patients with ILD-SAD followed between June and October 2021. The main variable was COVID-19 infection confirmed by a positive polymerase chain reaction (PCR) result for SARS-CoV-2. The secondary variables included severity of COVID-19, if the patient had to be admitted to hospital or died of the disease, and vaccination status. Other variables included clinical and treatment characteristics, pulmonary function and high-resolution computed tomography. Two logistic regression was performed to explore factors associated with “COVID-19” and “severe COVID-19”. Results: We included 176 patients with ILD-SAD: 105 (59.7%) had rheumatoid arthritis, 49 (27.8%) systemic sclerosis, and 22 (12.54%) inflammatory myopathies. We recorded 22/179 (12.5%) SARS-CoV-2 infections, 7/22 (31.8%) of them were severe and 3/22 (13.22%) died. As to the vaccination, 163/176 (92.6%) patients received the complete doses. The factors associated with SARS-CoV-2 infection were FVC (OR (95% CI), 0.971 (0.946–0.989); p = 0.040), vaccination (OR (95% CI), 0.169 (0.030–0.570); p = 0.004), and rituximab (OR (95% CI), 3.490 (1.129–6.100); p = 0.029). The factors associated with severe COVID-19 were the protective effect of the vaccine (OR (95% CI), 0.024 (0.004–0.170); p < 0.001) and diabetes mellitus (OR (95% CI), 4.923 (1.508–19.097); p = 0.018). Conclusions: Around 13% of patients with ILD-SAD had SARS-CoV-2 infection, which was severe in approximately one-third. Most patients with severe infection were not fully vaccinated.

Objectives: The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations. Methods: Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated. Results: Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples. Conclusions: We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc., This work was supported by eU/eFPia/innovative Medicines initiative Joint Undertaking PrecisesaDs Grant no. 115 565.

Objetivos Describir la metodología del Registro de pacientes con miopatía inflamatoria idiopática (MII) de España (Myo-Spain), así como sus fortalezas y limitaciones. El objetivo principal del proyecto es analizar la evolución y el manejo clínico de una cohorte de pacientes con MII. Material y método Estudio observacional, longitudinal, ambispectivo y multicéntrico de una cohorte de pacientes con MII atendidos en servicios de reumatología de España. Se incluirán todos los pacientes con diagnóstico de MII en seguimiento habitual por los centros participantes, sin tener en cuenta la edad de inicio del proceso. Los casos incidentes serán todos los pacientes que al inicio del estudio en cada centro estén diagnosticados desde hace menos de 12 meses y casos prevalentes desde hace más de 12 meses. Se construirá un registro en el que se incluirán los datos de la visita basal, del año y dos años. Se recogerán variables sociodemográficas, clínicas, analíticas, complicaciones, comorbilidad, asociación con otras enfermedades reumáticas, ingresos hospitalarios, mortalidad y tratamientos. Además, se determinarán índices, escalas y cuestionarios de actividad, afectación muscular, daño, discapacidad y calidad de vida. El periodo de reclutamiento será de 23 meses. El propósito es conseguir una cohorte de 400 pacientes con MII. Conclusiones El estudio Myo-Spain constituye la oportunidad para desarrollar una cohorte de pacientes incidentes y prevalentes con MII en España. Myo-Spain permitirá evaluar en detalle, las características clínicas de la enfermedad en diferentes momentos. Se espera que la información exhaustiva recogida en las visitas suponga una amplia fuente de datos para futuros análisis. Objectives: To describe the methods of the Spanish Registry of patients with idiopathic inflammatory myopathy (IIM) (Myo-Spain), as well as its strengths and limitations. The main objective of the project is to analyse the evolution and clinical management of a cohort of patients with IIM. Methods: Observational, longitudinal, ambispective and multicentre study of a cohort of patients with IIM seen in rheumatology units in Spain. All patients with a diagnosis of IMM will be included in the regular follow-up of the participating centres, regardless of age on initiation of the process. Incident cases will be all patients who at the beginning of the study have been diagnosed for less than 12 months and prevalent cases for more than 12 months. The registry will include data from the visit at baseline, one year and two years. Socio-demographic, clinical, analytical variables, complications, comorbidities, association with other rheumatic diseases, hospital admissions, mortality and treatments will be collected. In addition, indices, scales and questionnaires of activity, muscle involvement, damage, disability, and quality of life will be determined. The recruitment period will be 23 months. The purpose is to obtain a cohort of 400 patients with IMM. Conclusions: Myo-Spain registry provides the opportunity to develop a cohort of incident and prevalent patients with IMM in Spain. Myo-Spain will be able to assess in detail the clinical characteristics of the disease at different times. The comprehensive information collected during the visits is expected to provide a broad source of data for future analysis. Sin financiación No data JCR 2021 0.311 SJR (2021) Q3, 44/61 Rheumatology No data IDR 2021 UEM

Objectives: To describe the characteristics and progression of interstitial lung disease in patients with associated systemic autoimmune disease (ILD-SAI) and to identify factors associated with progression and mortality. Patients and methods: We performed a multicenter, retrospective, observational study of patients with ILD-SAI followed between 2015 and 2020. We collected clinical data and performed pulmonary function testing and high-resolution computed tomography at diagnosis and at the final visit. The main outcome measure at the end of follow-up was forced vital capacity (FVC) &gt, 10% or diffusing capacity of the lungs for carbon monoxide &gt, 15% and radiological progression or death. Cox regression analysis was performed to identify factors associated with worsening of ILD. Results: We included 204 patients with ILD-SAI: 123 (60.3%) had rheumatoid arthritis (RA), 58 had (28.4%) systemic sclerosis, and 23 (11.3%) had inflammatory myopathy. After a median (IQR) period of 56 (29.8–93.3) months, lung disease had stabilized in 98 patients (48%), improved in 33 (16.1%), and worsened in 44 (21.5%). A total of 29 patients (14.2%) died. Progression and hospitalization were more frequent in patients with RA (p = 0.010). The multivariate analysis showed the independent predictors for worsening of ILD-SAI to be RA (HR, 1.9 [95% CI, 1.3–2.7]), usual interstitial pneumonia pattern (HR, 1.7 [95% CI, 1.0–2.9]), FVC (%) (HR, 2.3 [95% CI, 1.4–3.9]), and smoking (HR, 2.7 [95%CI, 1.6–4.7]). Conclusion: Disease stabilizes or improves after a median of 5 years in more than half of patients with ILD-SAI, although more than one-third die. Data on subgroups and risk factors could help us to predict poorer outcomes.

Patients with rheumatoid arthritis (RA) have a significantly increased risk of sexual dysfunction. However, it is not properly included in commonly used questionnaires to assess health-related quality of life in RA. Qualisex is a questionnaire developed in France to assess the impact of RA on patients´ sexual function. Our aim was to adapt and validate this questionnaire for use with Spanish RA patients. Two independent translations and a backward translation were obtained. The final version was tested in a pilot study with 10 RA patients to detect any aspects that could hinder interpretation. The validity and reliability of the linguistically validated questionnaire were studied in a multicenter cross-sectional study, with a longitudinal component for reliability estimation. 125 RA patients were included. The response process, discrimination, internal consistency, internal structure, convergent validity (correlation with MGH-SFQ questionnaire, DAS-28, physician global assessment, patient global health assessment, RAID, HAQ, HADS and SF-12©) and reliability were analyzed. The inclusion of two extra items was proposed in the pilot study. The validity analysis detected responses for item 10 that were not coherent with responses for the rest of items. The Cronbach alpha coefficient was 0.971. The highest correlation (0.665) was obtained with MGH-SFQ (questionnaire measuring sexual functioning), followed by RAID (0.516). The intra-class correlation was 0.880 (95% CI 0.815; 0.923), higher than 0.85, which indicates excellent reliability. All parameters used to assess this questionnaire show highly acceptable values. Qualisex allows for a global score of RA patients’ sexual functioning and can be self-administered.

Disease severity, progression and response to therapy might be worse in obese rheumatoid arthritis (RA) patients, but paradoxically, obesity also might protect from radiographic joint damage. Thus, the intricate relationship between obesity and RA needs urgent clarification. The aim of this study was to assess the influence of obesity on the onset and development of RA and to determine whether arthritis could modify the adipose tissue biology and whether conventional Disease Modifying Anti-Rheumatic Drugs (cDMARDs) can modulate these alterations. Two strategies were followed: (1) clinical profiling of two cohorts of RA: non-obese and obese patients; and (2) mechanistic studies carried out in both a collagen-induced arthritis (CIA) in an obese mouse model and 3T3-L1 adipocytes treated with cDMARDs (leflunomide, methotrexate, and hydroxychloroquine). In our cohort of RA patients with low-moderate disease activity, the presence of obesity was not related to a higher activity of the disease; actually, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) was reduced in the obese RA patients. However, the induction of arthritis promoted transcriptomic changes in the adipose tissue under obesity condition in the obese CIA model. Treatment with hydroxychloroquine reduced weight and insulin resistance, accompanied by beneficial metabolic effects in the adipose tissue. These molecular changes in adipose tissue were also observed after methotrexate administration. In sum, arthritis might affect directly the inflammatory burden and metabolic alterations associated with obesity in adipose tissue. Clinicians should be cautious measuring the activity of the disease in obesity and managing the best therapeutic options for the metabolic comorbidities of these patients, where the combination of hydroxychloroquine and methotrexate should be considered to improve adipose tissue dysfunction in obese RA.

OBJECTIVE: Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. METHODS: Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. RESULTS: Four clusters were identified and validated. Three were pathologic, representing "inflammatory," "lymphoid," and "interferon" patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. CONCLUSION: Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases. ispartof: ARTHRITIS & RHEUMATOLOGY vol:73 issue:6 pages:1073-1085 ispartof: location:United States status: published

Background: This prospective multicenter study developed an integrative clinical and molecular longitudinal study in Rheumatoid Arthritis (RA) patients to explore changes in serologic parameters following anti-TNF therapy (TNF inhibitors, TNFi) and built on machine-learning algorithms aimed at the prediction of TNFi response, based on clinical and molecular profiles of RA patients.Methods: A total of 104 RA patients from two independent cohorts undergoing TNFi and 29 healthy donors (HD) were enrolled for the discovery and validation of prediction biomarkers. Serum samples were obtained at baseline and 6 months after treatment, and therapeutic efficacy was evaluated. Serum inflammatory profile, oxidative stress markers and NETosis-derived bioproducts were quantified and miRNomes were recognized by next-generation sequencing. Then, clinical and molecular changes induced by TNFi were delineated. Clinical and molecular signatures predictors of clinical response were assessed with supervised machine learning methods, using regularized logistic regressions.Results: Altered inflammatory, oxidative and NETosis-derived biomolecules were found in RA patients vs. HD, closely interconnected and associated with specific miRNA profiles. This altered molecular profile allowed the unsupervised division of three clusters of RA patients, showing distinctive clinical phenotypes, further linked to the TNFi effectiveness. Moreover, TNFi treatment reversed the molecular alterations in parallel to the clinical outcome. Machine-learning algorithms in the discovery cohort identified both, clinical and molecular signatures as potential predictors of response to TNFi treatment with high accuracy, which was further increased when both features were integrated in a mixed model (AUC: 0.91). These results were confirmed in the validation cohort.Conclusions: Our overall data suggest that: 1. RA patients undergoing anti-TNF-therapy conform distinctive clusters based on altered molecular profiles, which are directly linked to their clinical status at baseline. 2. Clinical effectiveness of anti-TNF therapy was divergent among these molecular clusters and associated with a specific modulation of the inflammatory response, the reestablishment of the altered oxidative status, the reduction of NETosis, and the reversion of related altered miRNAs. 3. The integrative analysis of the clinical and molecular profiles using machine learning allows the identification of novel signatures as potential predictors of therapeutic response to TNFi therapy.

ObjectivesTo characterise splicing machinery (SM) alterations in leucocytes of patients with rheumatoid arthritis (RA), and to assess its influence on their clinical profile and therapeutic response.MethodsLeucocyte subtypes from 129 patients with RA and 29 healthy donors (HD) were purified, and 45 selected SM elements (SME) were evaluated by quantitative PCR-array based on microfluidic technology (Fluidigm). Modulation by anti-tumour necrosis factor (TNF) therapy and underlying regulatory mechanisms were assessed.ResultsAn altered expression of several SME was found in RA leucocytes. Eight elements (SNRNP70, SNRNP200, U2AF2, RNU4ATAC, RBM3, RBM17, KHDRBS1 and SRSF10) were equally altered in all leucocytes subtypes. Logistic regressions revealed that this signature might: discriminate RA and HD, and anti-citrullinated protein antibodies (ACPAs) positivity; classify high-disease activity (disease activity score-28 (DAS28) >5.1); recognise radiological involvement; and identify patients showing atheroma plaques. Furthermore, this signature was altered in RA synovial fluid and ankle joints of K/BxN-arthritic mice. An available RNA-seq data set enabled to validate data and identified distinctive splicing events and splicing variants among patients with RA expressing high and low SME levels. 3 and 6 months anti-TNF therapy reversed their expression in parallel to the reduction of the inflammatory profile. In vitro, ACPAs modulated SME, at least partially, by Fc Receptor (FcR)-dependent mechanisms. Key inflammatory cytokines further altered SME. Lastly, induced SNRNP70-overexpression and KHDRBS1-overexpression reversed inflammation in lymphocytes, NETosis in neutrophils and adhesion in RA monocytes and influenced activity of RA synovial fibroblasts.ConclusionsOverall, we have characterised for the first time a signature comprising eight dysregulated SME in RA leucocytes from both peripheral blood and synovial fluid, linked to disease pathophysiology, modulated by ACPAs and reversed by anti-TNF therapy.

Objectives To develop recommendations for the prevention of infection in adult patients with systemic autoimmune rheumatic diseases (SARD). Methods Clinical research questions relevant to the objective of the document were identified by a panel of experts selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network criteria. Specific recommendations were made. Results Five questions were selected, referring to prevention of infection by Pneumocystis jirovecii with trimethoprim/sulfamethoxazole, primary and secondary prophylactic measures against hepatitis B virus, vaccination against human papillomavirus, vaccination against Streptococcus pneumoniae and vaccination against influenza virus, making a total of 18 recommendations, structured by question, based on the evidence found for the different SARD and/or expert consensus. Conclusions There is enough evidence on the safety and efficacy of vaccinations and other prophylactic measures against the microorganisms reviewed in this document to specifically recommend them for patients with SARD.

Background: Axial spondyloarthritis (axSpA) patients are known to have a higher prevalence of several comorbidities, including, among others, an increased risk of atherosclerosis, hypertension, dyslipidemia, and diabetes. The purpose of the present study was to determine whether the sum of traditional cardiovascular (CV) risk factors is related to disease characteristics, such as disease activity, in patients with axSpA. Methods: A cross-sectional study that encompassed 804 patients with axSpA was conducted. Patients were assessed for the presence of five traditional CV risk factors (diabetes mellitus, dyslipidemia, hypertension, obesity, and smoking status), and disease activity measurements. A multivariable regression analysis was performed to evaluate whether the number of classic CV risk factors was independently associated with specific features of the disease, to include disease activity. Results: A multivariable analysis showed that Ankylosing Spondylitis Disease Activity Score-C reactive protein (ASDAS-CRP) activity score was significantly higher in patients with 1 [beta coefficient 0.3 (95% confidence interval (CI) 0.1-0.5), p = 0.001] and ?2 [beta coefficient 0.5 (95% CI 0.3-0.7), p = 0.000] CV risk factors compared with those without CV risk factors. Similarly, patients with 1 [OR 2.00 (95%CI 0.99-4.02), p = 0.053] and ?2 [OR 3.39 (95%CI 1.82-6.31), p = 0.000] CV risk factors had a higher odds ratio for the presence of high disease activity compared with the zero CV category. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) activity score was significantly associated with the number of CV risk factors, being higher in patients with more CV risk factors. These relationships showed a CV risk factor-dependent effect being beta coefficients and ORs higher for the effect of ?2 over 1 CV risk factor. Conclusion: Among patients with axSpA, as the number of traditional CV risk factors increased, disease activity similarly increases in an independent manner. Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/ or publication of this article: This research was funded by a grant to MAG-G from the Instituto de Salud Carlos III (ISCIII) (Fondo de Investigación Sanitaria grants PI06/0024, PI09/00748, PI12/00060, PI15/00525, PI18/00043) and the ISCIII RETICS programs (RD12/0009 and RD16/0012).

Objectives To describe the methods of the Spanish Registry of patients with idiopathic inflammatory myopathy (IIM) (Myo-Spain), as well as its strengths and limitations. The main objective of the project is to analyse the evolution and clinical management of a cohort of patients with IIM. Methods Observational, longitudinal, ambispective and multicentre study of a cohort of patients with IIM seen in rheumatology units in Spain. All patients with a diagnosis of IMM will be included in the regular follow-up of the participating centres, regardless of age on initiation of the process. Incident cases will be all patients who at the beginning of the study have been diagnosed for less than 12 months and prevalent cases for more than 12 months. The registry will include data from the visit at baseline, one year and two years. Socio-demographic, clinical, analytical variables, complications, comorbidities, association with other rheumatic diseases, hospital admissions, mortality and treatments will be collected. In addition, indices, scales and questionnaires of activity, muscle involvement, damage, disability, and quality of life will be determined. The recruitment period will be 23 months. The purpose is to obtain a cohort of 400 patients with IMM. Conclusions Myo-Spain registry provides the opportunity to develop a cohort of incident and prevalent patients with IMM in Spain. Myo-Spain will be able to assess in detail the clinical characteristics of the disease at different times. The comprehensive information collected during the visits is expected to provide a broad source of data for future analysis.

Objectives: To analyze the efficacy and safety of rituximab (RTX) in connective tissue disease associated with interstitial lung disease (CTD-ILD). Methods: We performed a multicenter, prospective, observational study of patients with CTD-ILD receiving rituximab between 2015 and 2020. The patients were assessed using high-resolution computed tomography and pulmonary function tests at baseline, at 12 months, and at the end of follow-up. The main outcome measure at the end of follow-up was forced vital capacity (FVC) > 10% or diffusing capacity of the lungs for carbon monoxide (DLCO) > 15% and radiological progression or death. We recorded clinical characteristics, time to initiation of RTX, concomitant treatment, infections, and hospitalization. A Cox regression analysis was performed to identify factors associated with worsening ILD. Results: We included 37 patients with CTD-ILD treated with RTX for a median (IQR) of 38.2 (17.7–69.0) months. At the end of the follow-up, disease had improved or stabilized in 23 patients (62.1%) and worsened in seven (18.9%); seven patients (18.9%) died. No significant decline was observed in median FVC (72.2 vs. 70.8; p = 0.530) or DLCO (55.9 vs. 52.2; p = 0.100). The multivariate analysis showed the independent predictors for worsening of CTD-ILD to be baseline DLCO (OR (95% CI), 0.904 (0.8–0.9); p = 0.015), time to initiation of RTX (1.01 (1.001–1.02); p = 0.029), and mycophenolate (0.202 (0.04–0.8); p = 0.034). Only 28 of the 37 patients (75.6%) were still undergoing treatment with RTX: two patients (5.4%) stopped treatment due to adverse events and seven patients (18.9%) died owing to progression of ILD and superinfection. Conclusion: Lung function improved or stabilized in more than half of patients with CTD-ILD treated with RTX. Early treatment and combination with mycophenolate could reduce the risk of progression of ILD.

Funder: Europeo de Desarrollo Regional de la Unión Europea, Funder: Rheumatic Diseases Network, OBJECTIVE: To analyze the relationship between complement component 3 (C3) and the prevalence of cardiometabolic risk factors and disease activity in the rheumatic diseases having the highest rates of cardiovascular morbidity and mortality: rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: This is a cross-sectional study including 200 RA, 80 PsA, 150 axSpA patients and 100 healthy donors. The prevalence of cardiometabolic risk factors [obesity, insulin resistance, type 2 diabetes mellitus, hyperlipidemia, apolipoprotein B/apolipoprotein A (apoB/apoA) and atherogenic risks and hypertension] was analyzed. Serum complement C3 levels, inflammatory markers and disease activity were evaluated. Cluster analysis was performed to identify different phenotypes. Receiver operating characteristic (ROC) curve analysis to assess the accuracy of complement C3 as biomarker of insulin resistance and disease activity was carried out. RESULTS: Levels of complement C3, significantly elevated in RA, axSpA and PsA patients, were associated with the prevalence of cardiometabolic risk factors. Hard clustering analysis identified two distinctive phenotypes of patients depending on the complement C3 levels and insulin sensitivity state. Patients from cluster 1, characterized by high levels of complement C3 displayed increased prevalence of cardiometabolic risk factors and high disease activity. ROC curve analysis showed that non-obesity related complement C3 levels allowed to identify insulin resistant patients. CONCLUSIONS: Complement C3 is associated with the concomitant increased prevalence of cardiometabolic risk factors in rheumatoid arthritis and spondyloarthritis. Thus, complement C3 should be considered a useful marker of insulin resistance and disease activity in these rheumatic disorders.

Objective To evaluate whether the presence of psoriasis influences the clinical expression, disease activity and disease burden in both axial and peripheral phenotypes of spondyloarthritis (SpA). Methods Patients from the Spanish REGISPONSER registry classified as having SpA according to the ESSG criteria were included. Patients were classified as psoriatic or non-psoriatic depending on the presence of cutaneous or nail psoriasis; thereafter, they were classified as having either axial [presence of radiographic sacroiliitis OR inflammatory back pain (IBP)] or peripheral phenotype (absence of radiographic sacroiliitis AND absence of IBP AND presence of peripheral involvement). Pair-wise univariate and multivariate analyses among the four groups (psoriatic/non-psoriatic axial phenotypes and psoriatic/non-psoriatic peripheral phenotypes) were performed with adjustment for treatment intake. Results A total of 2296 patients were included in the analysis. Among patients with axial phenotype, psoriasis was independently associated (P Conclusion These findings suggest that, among all patients with SpA, psoriasis is associated with differences in clinical expression of SpA, a greater disease burden and increased use of drugs.

Background Clinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification. Methods With the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 918 patients with 7 SADs and 263 healthy controls was undertaken. An inception cohort prospectively followed for 6 and 14 months was studied to validate the results in early cases and analyze if cluster assignment was modified with time. Results Four clusters were identified Three aberrant clusters were ‘acute phase inflammatory’, ‘T cell immunity’, and ‘interferon’, each including all diagnoses, were defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern, to which 74% of healthy controls clustered with patients. The inception cohort showed that most patients were either assigned always to the same cluster or moved from the healthy-like cluster to a single aberrant cluster resembling the relapsing-remitting dynamic of these diseases, showing that single aberrant molecular signatures characterize each individual patient. Conclusions Patients with SADs share molecular signatures and can be therefore stratified into three disease clusters differentiating each patient into a specific molecular disease pathway. Such assignment is stable with time. These results have important implications for understanding disease progression and therapy design marking a paradigm shift in our view of SADs. Acknowledgment This work has been supported through a grant from the Innovative Medicines Initiative Joint Undertaking No. 115565 and in-kind and in-cash contributions from the EFPIA partners. G.B. is supported by the Instituto de Salud Carlos III (ISCIII, Spanish Health Ministry), through the Sara Borrell subprogram (CD18/00153). The authors would like to particularly express their gratitude to the patients, nurses and many others who helped directly or indirectly in the consecution of this study.

SUMMARYBackgroundClinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification.MethodsWith the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 918 patients with 7 SADs and 263 healthy controls was undertaken. In addition, an inception cohort was prospectively followed for 6 and 14 months to validate the results and analyze if cluster assignment changed or not with time.ResultsFour clusters were identified. Three clusters were aberrant, representing ‘inflammatory’, ‘lymphoid’, and ‘interferon’ patterns each including all diagnoses and defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern and accumulated also healthy controls. An independent inception cohort showed that with time, the molecular clusters remain stable, showing that single aberrant molecular signatures characterize each individual patient.ConclusionsPatients with SADs can be jointly stratified into three stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of therapy non-responsiveness marking a paradigm shift in the view of SADs.

Background and purpose The endocannabinoid system and PPARγ are important targets for the development of novel compounds against fibrotic diseases such as systemic sclerosis (SSc), also called scleroderma. The aim of this study was to characterize VCE-004.3, a novel cannabidiol derivative, and study its anti-inflammatory and anti-fibrotic activities. Experimental approach The binding of VCE-004.3 to CB1 and CB2 receptors and PPARγ and its effect on their functional activities were studied in vitro and in silico. Anti-fibrotic effects of VCE-004.3 were investigated in NIH-3T3 fibroblasts and human dermal fibroblasts. To assess its anti-inflammatory and anti-fibrotic efficacy in vivo, we used two complementary models of bleomycin-induced fibrosis. Its effect on ERK1/2 phosphorylation induced by IgG from SSc patients and PDGF was also investigated. Key results VCE-004.3 bound to and activated PPARγ and CB2 receptors and antagonized CB1 receptors. VCE-004.3 bound to an alternative site at the PPARγ ligand binding pocket. VCE-004.3 inhibited collagen gene transcription and synthesis and prevented TGFβ-induced fibroblast migration and differentiation to myofibroblasts. It prevented skin fibrosis, myofibroblast differentiation and ERK1/2 phosphorylation in bleomycin-induced skin fibrosis. Furthermore, it reduced mast cell degranulation, macrophage activation, T-lymphocyte infiltration, and the expression of inflammatory and profibrotic factors. Topical application of VCE-004.3 also alleviated skin fibrosis. Finally, VCE-004.3 inhibited PDGF-BB- and SSc IgG-induced ERK1/2 activation in fibroblasts. Conclusions and implications VCE-004.3 is a novel semisynthetic cannabidiol derivative that behaves as a dual PPARγ/CB2 agonist and CB1 receptor modulator that could be considered for the development of novel therapies against different forms of scleroderma.

To evaluate quality of life (QoL) in patients with axial spondyloarthritis (axSpA) and its association with disease activity, functionality, structural damage, and spinal mobility, using patient-reported outcomes. This was an observational, cross-sectional, and single-center study in which 100 consecutive patients with axSpA were included. We obtained from all patients’ sociodemographic data and values related to disease activity, functionality, structural damage, mobility, and quality of life. The Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) was considered as the primary outcome. Pearson r statistic, Student’s T test, and univariate and multivariate linear regressions were performed to relate ASQoL with the studied covariates. Mean ASQoL score in all patients was 4.02 ± 2.81, with statistically significant differences between male and female (3.61 ± 2.80 vs. 4.83 ± 2.70). Patients with high disease activity (measured by the ASAS-endorsed Disease Activity Score, ASDAS > 2.1) showed higher mean score in ASQoL than those with low disease activity (ASDAS ≤ 2.1) (3.21 ± 0.74 vs. 1.43 ± 0.43, p 0.60). However, disease duration was not significantly correlated with ASQoL. Finally, the 68.9% of the ASQoL variability (R2 = 0.689) was determined by BASDAI, BASFI, and mSASSS, presenting mSASSS a negative regression coefficient (− 0.035). In our study, the impairment of QoL was mainly associated with disease activity (BASDAI) and worsening of functionality (BASFI). However, there is an inverse relationship between the worsening of QoL and structural damage. In addition, disease duration does not seem to influence the patient’s welfare.

Objective: to identify new single-nucleotide polymorphisms (SNPs) in genes encoding proteins involved in methotrexate (MTX) metabolism and to evaluate the associations of these SNPs with MTX toxicity or intolerance in a southern Spanish cohort of patients with rheumatoid arthritis (RA). Methods: An observational, retrospective, and multicenter study was conducted at three participating hospitals in southern Spain. The main variable was intolerance to MTX (i.e., bDMARD monotherapy), defined as an interruption of treatment due to adverse events or toxicity. Patients being treated with MTX and bDMARDs (combined treatment) at the time of the study visit were considered “tolerant” of MTX. Ten polymorphisms were selected for sequencing in our patients according to a literature review. Each polymorphism was classified according to three possible genotypes (e.g., two homozygous (AA or GG) and one heterozygous (AG)), and the association of these combinations with MTX intolerance was evaluated. Results: A total of 227 patients were included in the final analysis (107 intolerant of MTX and 120 tolerant). A significant association was observed between MTX intolerance and the GGH-T401C AA/AG genotype (OR 2.13, 95% CI 1.06–4.29) in comparison with the GG genotype. On the other hand, an inverse association was observed between the ABCC2-C24T TT/TC genotype and intolerance to MTX (OR 0.59, 95% CI 0.35–1.00) in comparison with the CC genotype. Conclusion: This study provides new data on the association between genetic polymorphisms and MTX intolerance, which may contribute to the development of new biomarkers and personalized medicine in patients with RA.

Endothelial dysfunction (ED) is well known as a process that can lead to atherosclerosis and is frequently presented in radiographic axial spondyloarthritis (r-axSpA) patients. Here, we investigated cellular and molecular mechanisms underlying r-axSpA-related ED, and analyzed the potential effect of peripheral blood mononuclear cells (PBMCs) in promoting endothelial injury in r-axSpA. A total of 30 r-axSpA patients and 32 healthy donors (HDs) were evaluated. The endothelial function, inflammatory and atherogenic profile, and oxidative stress were quantified. In vitro studies were designed to evaluate the effect of PBMCs from r-axSpA patients on aberrant endothelial activation. Compared to HDs, our study found that, associated with ED and the plasma proatherogenic profile present in r-axSpA, PBMCs from these patients displayed a pro-oxidative, proinflammatory, and proatherogenic phenotype, with most molecular changes noticed in lymphocytes. Correlation studies revealed the relationship between this phenotype and the microvascular function. Additional in vitro studies confirmed that PBMCs from r-axSpA patients promoted endothelial injury. Altogether, this study suggests the relevance of r-axSpA itself as a strong and independent cardiovascular risk factor, contributing to a dysfunctional endothelium and atherogenic status by aberrant activation of PBMCs. Lymphocytes could be the main contributors in the development of ED and subsequent atherosclerosis in this pathology.

Objectives To describe the time of onset of acute anterior uveitis (AAU) relative to the appearance of rheumatic symptoms and to determine its association with the evolution of the spondyloarthritis (SpA) in terms of activity, structural damage, functional ability and treatment. Methods This was a cross-sectional study with data extracted from the REGISPONSER (SpA Registry of the Spanish Rheumatology Society). Thirty-one centres participated, and patients with SpA according to the ESSG criteria were included from 2004 to 2007. Patients were classified according to the time of uveitis appearance with regard to rheumatic symptom onset (before, concomitant with, or after rheumatic symptom onset). We compared the clinical characteristics, disease activity, radiographic damage and functional ability between “AAU before or concomitant with rheumatic symptoms” and “AAU after rheumatic symptoms onset”. Finally, we compared whether the time of appearance of AAU had an impact on the use of conventional and biological disease-modifying antirheumatic drugs (csDMARDs and bDMARDs, respectively). Results A total of 2367 patients were included in REGISPONSER, with an AAU prevalence of 16.2% (379 patients). Patients with AAU before/concomitant with rheumatic symptom onset (n = 59) exhibited better functional ability (BASFI, OR 0.85 [0.73-0.99]) and less structural damage (spinal BASRI, OR 0.88 [0.79-0.99]). Additionally, this group of patients was older at SpA symptom onset (OR 1.05 [1.02-1.09]) and had a shorter diagnosis delay (OR 0.90 [0.84-0.96]) compared patients with AAU after rheumatic symptom onset (n = 229). No statistically significant differences in the use of DMARDs were noted (27.9% vs 23.2% for csDMARD use and 15.3% vs 20.3% for bDMARD use in patients with AAU before or concomitant with rheumatic symptom onset vs after rheumatic symptom onset, respectively). Conclusion Patients presenting with a first episode of AAU before/concomitant with the onset of rheumatic symptoms had less severe disease (better functional ability and less structural damage) and a shorter diagnosis delay; however, the time of AAU onset did not impact the treatments received.

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by excess morbidity and mortality from cardiovascular disease. In addition, metabolic alterations have been observed in these patients, which significantly contributes to the cardiovascular risk burden. Thus, the identification of therapies able to mitigate the cardiometabolic alterations in RA is essential. In addition, numerous studies suggest that cardiometabolic risks are mediated through adipocytokines. However, this relationship is not completely defined in RA. Objectives: 1) To evaluate the relationship among cardiometabolic risk factors and the levels of adipocytokines and autoantibodies in RA patients. 2) To analyze the effects anti-TNFα and anti-IL6 therapies on the cardiometabolic alterations. Methods: 1.- A cross-sectional study including 100 RA patients and 50 age-matched healthy donors was carried out. Different parameters related to the cardiometabolic risk were analyzed, including: lipid profile, atherogenic index, ratio ApoB/ApoA, insulin resistance (IR), obesity, hypertension, and the SCORE. Levels of adipocytokines (TNFα, IL6, IL1β, visfatin, adiponectin, leptin and resistin) were evaluated in serum. Carotid intima media thickness (CIMT) was evaluated as atherosclerosis marker. 2.-A prospective study in 15 RA patients before and after 3 months of anti-TNFα therapy and 15 RA patients before and after 3 months of treatment with tocilizumab (TCZ) was performed. All the parameters evaluated in the cross-sectional cohort were tested in this prospective study. Results: RA patients had elevated levels of leptin/adiponectin ratio, visfatin, resistin and inflammatory markers in serum. Our cohort of RA patients displayed increased rates of cardiometabolic risk factors, such as insulin resistance, hypertension, SCORE, pathologic CIMT, atherogenic index and ratio apoB/apoA. The alteration in the levels of adipocytokines were closely related to the autoimmunity, disease activity and clinical inflammatory markers. Of note, visfatin and C3 complement levels were determinant for IR, high levels of SCORE, increased parameters of CVD risk defined by apoB/apoA ratio and pathologic CIMT. Both biological therapies reduced clinical inflammatory markers and disease activity after 3 months of treatment. Anti-TNFα therapy modulated the cytoadipokine profile, reducing serum levels of IL-6, IL-1β, resistin and visfatin, decreasing IR. After treatment with tocilizumab, serum levels of C3 complement, IL-1β and resistin were reduced. Conclusion: 1) Altered adipocytokine profile is closely related to the increased cardiometabolic risk factors associated with RA, where autoimmunity and systemic inflammation play a key role. 2) Anti-TNFα and anti-IL6R therapies, administered for 3 months, could have beneficial effects in the reduction of cardiometabolic risk factors in RA. Acknowledgement: Funded by ISCIII (PI18/00837, CP15/00158, PI17/01316 and RIER RD16/0012/0015) co-funded with FEDER Disclosure of Interests: None declared

Background The lack of efficacy of biological therapies in rheumatic patients causes a change of treatment, usually to another biological therapy. A significant number of studies have been published in relation to the reasons that cause this inefficacy, (1,2,3); however, no studies have evaluated the involvement of the weight and lipid profile of patients in this process. Objectives To analyze the influence of weight and lipid profile in the relapse and change of biological therapy. Methods Retrospective-descriptive study. Rheumatic patients in treatment with biological therapies were recruited from January 2016 to December 2018. Sociodemographic data were collected (age and sex), along with anthropometric variables (weight, height, waist circumference and hip perimeter), toxic habits, comorbidities and variables related to the treatment. Associations between variables were analyzed using a Chi-square and T student. P-values Results Two hundred and nine patients were enrolled, of which 80 (38.3%) were male and 129 (61.7%) were female. The mean age (SD) was 48.9 12.8 years. One hundred and twenty patients (57.4%) suffered rheumatoid arthritis, 35 (16.7%) spondylitis, 29 (13.9%) psoriatic arthritis and 10 (4.8%) spondyloarthritis. One hundred and fifty-three (73.2%) had not switches of biological therapy, 51 (24.4%) switched of biological therapy once and 5 (2.4%) three or more times. Statistically significant differences were found in the obese males who switched of biological therapy in relation to obese males who not switched (35.6% vs. 11.1%). Accordingly, the percentage of patients with hyperlipemia that switched of biological therapy was significantly higher than those who did not (29.4% vs. 13.1%). The years of evolution and diagnosis we also involved, so that patients with more years of evolution and more years from the diagnosis had a higher percentage of switched (p = 0.006 IC 95% -17.22, - 0.96 and p = 0.042 -18, 32; -037 respectively). Conclusion Being obese male and with hyperlipidemia could be a risk factor that would condition the lack of response to a biological therapy and thus the need of switching to another. References [1] Glintborg B1, stergaard M, Krogh NS, Tarp U, Manilo N, Loft AG, Hansen A, Schlemmer A, Fana V, Lindegaard HM, Nordin H, Rasmussen C, Ejstrup L, Jensen DV, Petersen PM, Hetland ML. Clinical response, drug survival and predictors thereof in 432 ankylosing spondylitis patients after switching tumour necrosis factor α inhibitor therapy: results from the Danish nationwide DANBIO registry. Ann Rheum Dis. 2013Jul;72(7):1149-55. doi: 10.1136/annrheumdis-2012-201933. Epub 2012 Aug 31. [2] Navarro-Compn V, Plasencia-Rodrguez C, de Miguel E, Diaz Del Campo P, Balsa A, Gratacs J. Switching biological disease-modifying antirheumatic drugs in patients with axial spondyloarthritis: results from a systematic literature review. RMD Open. 2017 Oct 10;3(2):e000524. doi: 10.1136/rmdopen-2017-000524. eCollection 2017. [3] Ganzetti G, Campanati A, Bettacchi A, Brandozzi G, Brisigotti V, Bugatti L, Cataldi I, Filosa G, Giacchetti A, Lemme G, Morresi L, Nicolini M, Postacchini V, Ricotti G, Rosa L, Simonacci M, Offidani A. Switching from a biological therapy to another biologic agent in psoriatic patients: the experience of PsOMarche group. G Ital Dermatol Venereol. 2018 Feb;153(1):5-10. doi: 10.23736/S0392-0488.16.05463-8. Epub 2016 Nov 15. Disclosure of Interests Rocio Segura: None declared, Maria del Carmen Abalos-Aguilera: None declared, Alejandra M. Patio-Trives: None declared, juan vacas: None declared, Joaquin Sosa: None declared, Celestino Gil: None declared, Maria del Rosario Navarro: None declared, Mara del Carmen Castro Villegas Paid instructor for: MSD, Abbvie, Pfizer, Janssen, Lilly, Roche, Rafaela Ortega Castro: None declared, Jerusalem Calvo Gutierrez: None declared, Desiree Ruiz: None declared, Montserrat Romero-Gmez: None declared, Ladehesa Pineda Lourdes: None declared, Alejandro Escudero Contreras: None declared, Eduardo Collantes-Estvez Consultant for: UCB Pharma, MSD, AbbVie, Novartis, Janssen, Font Ugalde Pilar: None declared, Luis Jurado: None declared

Objectives 1) To compare the real-world effectiveness among RA patients starting 3 biologic DMARDs (bDMARDs). 2) To evaluate whether patients’ clinical characteristics influence the response to specific bDMARDs. 3) To analyze the impact of bDMARDs on inflammatory profiles. Methods Eighty RA patients initiating TNFi, 22 patients treated with TCZ and 28 treated with RTX, the last ones after switching from TNFi and given as second bDMARDs, were included in the study. Effectiveness was assessed before and after 3 and 6 months of treatment by the European League Against Rheumatism (EULAR) criteria. Adjusted differences were estimated with multivariable linear regression. Differences in treatment outcomes were calculated as a function of patients’ characteristics, through regression modelling. Extensive analysis of the inflammatory profile using a multiplex were also performed. Results A high proportion of patients starting TNFi showed early EULAR Good Response (65,8% responders at 3 months). After 6 months of therapy this percentage even increased (70,6%), so that tender joints’ counts, swollen joints count, SDAI and HAQ improved significantly. After switching from a first TNFi, RTX treatment promoted better early response (81,8% responders after 3 months) than TCZ (67% responders). Differences remained significant after adjusting for potential confounders. Yet, after 6 months, efficacy was similar among both non-TNFi DMARDs, even improving the effectiveness in TCZ-treated RA patients based on EULAR response rate (DAS28 change: 5.09±1.4 to 2.7±1,17) vs RTX-treated patients (DAS28 change: 4.8±1.3 to 3-1±1.3). Patients older, and those suffering arterial hypertension (AH) or hyperlipidemia showed less effectiveness for both, TNFi and non-TNFi DMARDs, most remarkable for RTX and after 6 months of treatment. Analysis of the inflammatory profile, by evaluating 27 key biomarkers of inflammation, showed, in patients’ responders to therapy, specific profiles depending on the biologic DMARD administered. Thus, after 6 months of RTX, a generalized reduction in the expression levels of 22/27 proteins evaluated was observed, while TCZ mainly inhibited proteins involved in cell maturation, proliferation and leukocytes recruitment (IL6, GCSF, IP-10, IFNγ, RANTES). On the other hand, TNFi mainly reduced molecules related to leukocytes’ recruitment (IL-2, IL-8, MIP1β, RANTES). Conclusion 1) Treatment outcomes among RA patients treated with non-TNFi bDMARDs in standard clinical practice, are in line with a superior early effectiveness of RTX compared with TCZ. However, effectiveness in TCZ-treated RA patients increases after 6 months of treatment vs RTX. 2) Patients characteristics influence the response to bDMARDs, suggesting the need of evaluating the benefit risk/ratio based on a personalized clinical evaluation. 3) Anti-inflammatory benefits associated with bDMARDs treatments can differ despite similar drug efficacy against RA, indicating that drug-specific mechanisms are involved in regulating these processes. Acknowledgement Funded by PI-0285-2017, ISCIII, PI15/00837 and RIER RD16/0012/0015, co-funded with FEDER Disclosure of Interests Chary Lopez-Pedrera: None declared, Nuria Barbarroja Puerto: None declared, Carlos Perez-Sanchez: None declared, Alejandro Ibanez-Costa: None declared, Maria Luque-Tevar: None declared, Alejandra Patino-Trives: None declared, Ivan Arias de la Rosa: None declared, Maria del Carmen Abalos-Aguilera: None declared, Rafaela Ortega Castro: None declared, Alejandro Escudero Contreras: None declared, Perez Sanchez Laura: None declared, Carlos Rodriguez-Escalera: None declared, Dolores Ruiz-Montesinos: None declared, Carmen Maria Romero-Barco: None declared, Natalia Mena-Vazquez: None declared, Julia Uceda Speakers bureau: abbie, pfizer, novartis, janmsen, Ma Dolores Toledo-Coello: None declared, M angeles Aguirre-Zamorano: None declared, Eduardo Collantes Estevez: None declared

Objectives To describe the clinical-demographic characteristics and behaviour over time (12, 24 and 60 months) of a cohort of Undifferentiated Arthritis (UA), as well as to analyze which factors are associated with the evolution towards Rheumatoid Arthritis (RA), use of Biological Therapy (BT) and the development of Cardiovascular Disease (CVD). Methods Ambispective cohort study of patients with UA evaluated longitudinally from January 2009 to 2019. We analyzed baseline clinical and laboratory variables and a Multivariate Logistic Regression was performed to determine the factors associated with RA development after 5 years of follow-up. To analyze what factors were associated with the use of BT and the presence of CVD chi-square or Fisher’s test were used for binary variables, and U-Mann Whitney for continuous variables. Results 180 patients were included, 55% were women, with an average age of 49.3 (SD 16.1) years. The average duration of symptoms before the first visit was 6.9 (SD 9.9) months. 47.2% were FR+, 41% ACPA+, 20.6% HLA-DRB1 shared epitope. At the end of follow-up: 33.3% evolved to RA, 17.2% remained as palindromic rheumatism, 25% were diagnosed other chronic rheumatic diseases, 21.1% remitted spontaneously and 3.3% remained as UA. Of the 60 AR, 37 were diagnosed in the first year, 13 at second and 10 at 5 years of follow-up. During follow-up, 13 patients with RA started BT, and 12 patients presented CVD (7 of them died). Table 1 identifies the factors associated with the development of RA. The MLR identified ACPA +, OR (95% CI) = 10.69 (4.43 - 25.78), and the HLA-DRB1 shared epitope OR (95% CI) = 9.18 (2.96 - 28.48) p Conclusion 1) Useful clinical and laboratory characteristics have been identified to predict which patients are at risk of developing persistent arthritis. 2) HLADRB1 shared Epitope and ACPA are predictive factors of evolution to RA. 3) Possibly the continued use of glucocorticoids, even at low doses, may be related to the development of long-term CVD Disclosure of Interests Jerusalem Calvo Gutierrez: None declared, Rafaela Ortega Castro: None declared, Clementina Lopez-Medina: None declared, Ladehesa Pineda Lourdes: None declared, Maria del Carmen Castro Villegas Paid instructor for: MSD, Abbvie, Pfizer, Janssen, Lilly, Roche, Alejandro Escudero Contreras: None declared, Eduardo Collantes Estevez: None declared

Background: Studies suggest that radiographic damage is associated with cardiovascular (CV) risk in axial spondyloarthritis (axSpA). However, the relationship among disease characteristics directly related to structural damage and CV risk has not yet been fully clarified. Objectives: To analyze the association of structural damage with the presence of atherosclerotic plaques via carotid ultrasound (US) and the increased CV risk in a registry of patients with SpA. Methods: Eighty-five patients with SpA (ASAS criteria) from the SpA registry from Cordoba (CoSpaR) were selected for a cross-sectional study and underwent a complete clinical history, physical examination and biochemical analysis. Variables about demographics, clinical parameters and CV risk factors were collected. CV risk was evaluated by estimating SCORE index and assessing presence of atherosclerotic plaques through carotid US performed by a qualified radiologist. Independent-samples t test was used to evaluate the association between radiological characteristics and presence of atherosclerosis. Multiple lineal regression (MLR) was performed to assess the variables potentially associated with increased SCORE. All comparisons were bilateral. Results: Baseline characteristics are shown in the table. Values are mean±SD for quantitative and N (%) for qualitative variables. Regarding characteristics related with radiographic damage and CV risk, they exhibited a mSASSS of 14.84±18.4 (7.27±9.64 in cervical spine and 7.72±10.14 in lumbar spine). Average BMI 26.88±4.13, 33 (38.8%) were smokers, 16 (18.8%) had diagnosis of arterial hypertension, 1 (1.2%) of diabetes mellitus, 13 (15.3%) of hyperlipidemia, and 8 (9.4%) took lipid lowering drugs. Examination with carotid US found that 14 (16.5%) patients had previously unknown atherosclerotic plaques. After classification according to SCORE index, 60 (76.9%) had low CV risk, 10 (12.8%) moderate, and both high and very high CV risk categories had 4 (5.1%) patients each. In patients with atherosclerotic plaques, age, disease duration and variables related to radiographic damage (mSASSS [total, cervical and lumbar], and bone bridges) were significantly higher (p Conclusion: Presence of atherosclerosis is associated with age, disease duration and radiographic damage in SpA. Age and structural damage especially in the cervical spine predicted a greater CV risk. Thus, it is important to identify these patients in order to maintain tight control and avoid development of CV disease. Acknowledgement: Funded by: JA PI-0139-2017 Disclosure of interests: Ladehesa Pineda Lourdes: None declared, Gomez Garcia Ignacio: None declared, Maria del Carmen Castro Villegas Paid instructor for: MSD, abbvie, Pfizer, Janssen, Lilly, Roche, Pedro Segui azpilcueta: None declared, Maria del Carmen abalos-Aguilera: None declared, Bautista aguilar Laura: None declared, inmaculada Concepcion aranda-Valera: None declared, Rocio Segura: None declared, Rafaela Ortega Castro: None declared, Clementina Lopez-Medina: None declared, Perez Sanchez Laura: None declared, Puche Larrubia Maria Angeles: None declared, Chary Lopez-Pedrera: None declared, Font Ugalde Pilar: None declared, Garrido Castro Juan Luis: None declared, alejandro Escudero Contreras: None declared, Eduardo Collantes Estevez: None declared, Jimenez Gomez Yolanda: None declared

Background: Knee Osteoarthritis (KOA) is a common condition associated with pain and morbidity. The impact of this pathology makes it necessary to develop new procedures for joint regeneration. Regenerative treatments such as platelet-rich plasma (PRP) are being proposed as a safe alternative, capable of regenerating damaged tissues and improving the quality of life, reducing the need to surgical procedures (1-4). Objectives: To compare the effectiveness of PRP treatment vs Hialuronic Acid (HA) and Non-Arthroscopic Joint Lavage (NAJL) in patients with KOA. Methods: It was performed a prospective, 3-months observational study of 51 patients with KOA, from the OA clinic of the Reina Sofia Hospital of Cordoba. Patients were treated according to clinical practice in 1 of the 3 treatment arms (PRP, HA, NAJL). Pain and disability were evaluated using Visual Analogue Scale (VAS) of joint pain, WOMAC and OARSI. We compared the baseline data using simple ANOVA and chi-squared tests and the intra- and inter-group differences before and after treatment (0, 1 and 3 months) using the mixed ANOVA test. All comparisons were bilateral considering p≤0.05 as a significant result. Results: 51 patients were enrolled, of which 52.9% were female. The average age (±SD) was 58.47 ± 7.48 years. The average Body Mass Index (BMI) was 30.64 ± 4.25 Kg/m2. Characteristics at baseline were comparable among the 3 treatment groups (Table 1). An overall improvement was observed during the follow-up in the PRP group in terms of pain and disability with respect to the baseline, with a VAS MD of -3.00 [95% CI, -4.79 to -1.21] in the first month and -3.08 [CI 95%, -4.79 to -1.38] at 3 months (p Conclusion: Based on our results, the intra-articular infiltration with PRP could therefore constitute a safe and effective treatment option in KOA patients, with short-medium term results superior in terms of pain and disability to conventional treatment with HA and NALJ. Reference [1] Huang Y, et al. Orthopade. 2019 Jan 8. 2)Burke, et al. Clin trans Med (2016) 5-27. 3)Wroblewski AP, et al. Oper Tech Orthop 2010; 20: 98-105. 4) De La Mata J, et al. Reumatol Clinica. 2013; 9(3):166-71. Disclosure of Interests: Rafaela Ortega Castro: None declared, Rocio Segura: None declared, Jerusalem Calvo Gutierrez: None declared, Rocio Espino-Garcia: None declared, Maria del Carmen Castro Villegas Paid instructor for: MSD, Abbvie, Pfizer, Janssen, Lilly, Roche, Alejandro Escudero Contreras: None declared, Miguel A. Caracuel-Ruiz: None declared, Ladehesa Pineda Lourdes: None declared, Desiree Ruiz-Vilchez: None declared, Montserrat Romero-Gomez: None declared, Pilar Carreto-Font: None declared, Eduardo Collantes Estevez: None declared, Font Ugalde Pilar: None declared

Background The Splicing, a process of removing introns of RNA to produce mature messenger RNA, is exerted by an intricate macromolecular complex, the spliceosome. The alternative splicing, key mechanism that provides transcription and protein diversity, is dysregulated in various genetic, metabolic and inflammatory diseases. Splicing variants could contribute to the development and severity of pathologies of crucial importance. Objectives The aim of this study was the identification and characterization of alterations in the splicing machinery of leukocyte subsets of Rheumatoid Arthritis (RA) patients, as well as their influence on the activity of the disease and its atherothrombotic profile. Methods Monocytes, lymphocytes and neutrophils from 74 RA patients and 29 healthy donors (HD) were purified, and 45 elements of the splicing machinery were evaluated using a microfluidic qPCR array (Fluidigm). In parallel, the clinical status of the patients and the carotid intima-media thickness (CIMT) were assessed, along with an extensive serological evaluation, including autoantibodies, oxidative stress markers, inflammatory molecules and prothrombotic mediators. Correlation and association studies and logistic models among those clinical and analytical parameters were performed. Finally, leukocytes from HD were incubated with purified ACPAs-IgG from RA patients and changes promoted in both, splicing machinery and leukocyte inflammatory profile, were assessed. Results A significantly altered expression of spliceosome components was found in all the leukocyte subsets: 21, 17 and 27 components were differentially expressed in monocytes, lymphocytes and neutrophils, respectively, in RA patient’s vs HD. The levels of those altered components were associated to ACPA positivity, high disease activity (DAS28>5.1), early atherosclerosis and radiological involvement. Correlations with inflammatory mediators, oxidative stress markers and NETosis were further identified. Interestingly, eight components, belonging to the major spliceosome (SNRNP70, SNRNP200 and U2AF2), minor spliceosome (RNU4ATAC), and splicing factors (RBM3, RBM17, KHDRS1 and SRSF10) were found simultaneously altered in the three leukocyte subtypes. Logistic regression models, built with levels of simultaneously altered spliceosome components, generated several signatures related to RA disease features that were able to: i) discriminate between RA patients and HD; ii) classify patients with high disease activity (DAS28>5.1); iii) recognize patients with radiological involvement; and iv) identify patients showing atheroma plaques. In vitro studies showed that the purified ACPAs of RA patients modulated the expression of these components. Conclusion 1) The splicing machinery is profoundly altered in leukocytes from RA patients and closely related to the activity of the disease, including inflammation, autoimmunity and articular involvement, as well as with the occurrence of early atherosclerosis. 2) Evaluation of the common altered components of the spliceosome in leukocytes subsets might be used to typify the disease, avoiding complementary ultrasound or radiological tests. Acknowledgement MINECO (FJCI-2016-30825) and ISCIII (PI18/00837 and RIER RD16/0012/0015) co-funded with FEDER. Disclosure of Interests None declared

Objective To investigate the genetic background influencing the development of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). Methods We performed a genome-wide association study (GWAS) in which, after quality control and imputation, a total of 6,308,944 polymorphisms across the whole genome were analyzed in 2,989 RA patients of European origin. Data on subclinical atherosclerosis, obtained through assessment of carotid intima-media thickness (CIMT) and presence/absence of carotid plaques by carotid ultrasonography, were available for 1,355 individuals. Results A genetic variant of the RARB gene (rs116199914) was associated with CIMT values at the genome-wide level of significance (minor allele [G] beta coefficient 0.142, P = 1.86 x 10(-8)). Interestingly, rs116199914 overlapped with regulatory elements in tissues related to CV pathophysiology and immune cells. In addition, biologic pathway enrichment and predictive protein-protein relationship analyses, including suggestive GWAS signals of potential relevance, revealed a functional enrichment of the collagen biosynthesis network related to the presence/absence of carotid plaques (Gene Ontology no. 0032964; false discovery rate-adjusted P = 4.01 x 10(-3)). Furthermore, our data suggest potential influences of the previously described candidate CV risk loci NFKB1, MSRA, and ZC3HC1 (P = 8.12 x 10(-4), P = 5.94 x 10(-4), and P = 2.46 x 10(-4), respectively). Conclusion The present findings strongly suggest that genetic variation within RARB contributes to the development of subclinical atherosclerosis in patients with RA., Supported in part by the European Union FEDER fund and the Instituto de Salud Carlos III (ISCIII) (Fondo de Investigacion Sanitaria grants PI06/0024, PS09/00748, PI12/00060, PI15/00525, and CP16/00033), the ISCIII RETICS programs (RD12/0009 and RD16/0012), the European IMI BTCure Program. Dr. Lopez-Mejias is recipient of the Miguel Servet type I Program Fellowship from the ISCIII and the European Social Fund (ESF) (grant CP16/00033). Dr. Carmona's work was supported by the Spanish Ministry of Economy and Competitiveness (Ramon y Cajal Program grant RYC-2014-16458). Dr. Genre is recipient of a Sara Borrell postdoctoral fellowship from the ISCIII and ESF (grant CD15/00095). Dr. Remuzgo-Martinez' work was supported by the ISCIII and European Regional Development Fund (ERDF) (RETICS Program RD16/0012/0009). Ms Pulito-Cueto's work was supported by a predoctoral grant from the Instituto de Investigacion Sanitaria Valdecilla (PREVAL 18/01). Ms Mijares' work was supported by the Miguel Servet type I Program from the ISCIII and ESF (grant CP16/00033). Dr. Gualillo is staff personnel of Xunta de Galicia (Servizo Galego de Saude [SERGAS]) through a research-staff stabilization contract (ISCIII/SERGAS) and his work is funded by ISCIII and FEDER (grants RD16/0012/0014 [RIER] and PI17/00409). He is beneficiary of project funds from the Research Executive Agency (REA) of the European Union in the framework of MSCA-RISE Action of the H2020 Programme, project 734899-Olive-Net.

Objectives: To describe a prospective cohort of patients with rheumatoid arthritis associated with interstitial lung disease (RA-ILD) and identify risk factors associated with disease progression and mortality in this cohort. Patients and methods: We performed a multicenter, prospective, observational study of patients with RA-ILD receiving disease-modifying antirheumatic drugs (DMARDs) between 2015 and 2020. The patients were assessed using high-resolution computed tomography and pulmonary function tests at baseline and at 60 months. The main endpoint was “Progression to ILD at the end of follow-up” in terms of the following outcomes: (1) improvement (i.e., improvement in forced vital capacity (FVC) ≥ 10% or diffusing capacity of the lungs for carbon monoxide (DLCO) ≥ 15% and absence of radiological progression), (2) nonprogression (stabilization or improvement in FVC ≤ 10% or diffusing capacity of the lungs for carbon monoxide (DLCO) &lt, 15% and absence of radiological progression), (3) progression (worsening of FVC &gt, 10% or DLCO &gt, 15% and radiological progression), or (4) death. We recorded demographic and clinical characteristics, lung function, and the incidence of adverse events. A Cox regression analysis was performed to identify factors associated with the worsening of ILD. Results: After 60 months, lung disease had stabilized in 66 patients (56.9%), improved in 9 (7.8%), and worsened in 23 (19.8%). Eighteen patients (15.5%) died, with a mean survival of 71.8 (1.9) months after diagnosis of ILD. The Cox multivariate analysis revealed the independent predictors of worsening of RA-ILD to be usual interstitial pneumonia (hazard ratio (HR), 2.6 (95%CI, 1.0–6.7)), FVC &lt, 80% (HR, 3.8 (95%CI, 1.5–6.7)), anticitrullinated protein antibody titers (HR, 2.8 (95%CI, 1.1–6.8)), smoking (HR, 2.5 (95%CI, 1.1–6.2)), and treatment with abatacept, tocilizumab, or rituximab (HR, 0.4 (95%CI, 0.2–0.8)). During follow-up, 79 patients (68%) experienced an adverse event, mostly infection (61%). Infection was fatal in 10/18 patients (55.5%) during follow-up. Conclusions: Lung function is stable in most patients with RA-ILD receiving treatment with disease-modifying anti-rheumatic drugs (DMARDs), although one-third worsened or died. Identifying factors associated with worsening in RA-ILD is important for clinical management.

Background In recent years it has become increasingly important the evaluation of the global impact of the disease in patients with Spondyloarthritis (SpA) through the use of the Patient-reported Outcomes (PROs) (1). One of the most used PROs is the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire, which refers to Health-Related Quality of Life (HRQoL). Since this is a subjective and multifactorial outcome (2), our goal is to detail the most important factors which are related with the Quality of Life (QoL) in these patients. Objectives To evaluate QoL in patients with SpA and to define its association with disease-related factors and patient9s features. Methods A cross-sectional multicenter study which includes 2229 patients with SpA selected from the national Spondyloarthropaties Spanish Registry (REGISPONSER). The main outcome was the assessment of QoL performed through the ASQoL questionnaire. Subsequently, we studied its relation with different factors organized into 5 groups: sociodemographics, emotional, functionality, disease-related factors and disease activity. Univariate logistic regressions and a multiple linear regression (considering ASQoL as a qualitative dichotomous and quantitative variable respectively) were performed to relate QoL with the studied covariates. Results The mean ASQoL score in the entire population studied was 6.09±5.12. The average age was 47.74±13.26 years old and 698 (31.31%) were women. In univariate logistic regressions, significant differences (p Finally, multivariate linear regression showed that 61.1% of the variability of ASQoL (R2 =0.611, p Conclusions Poor QoL in SpA patients can be explained by high disease activity and by a deterioration in functionality and mental status. However, clinical form of SpA, disease duration and structural damage in spine do not explain this decrease of QoL. References Machado P, Landewe R, Braun J, Hermann KG, Baraliakos X, Baker D, et al: A stratified model for health outcomes in ankylosing spondylitis. Ann Rheum Dis 2011;70:1758–64. Fernandez-Carbadillo C, Navarro-Compan V, Castillo-Gallego C, Castro-Villegas MC, Collantes-Estevez E, de Miguel E. Disease activity is the major determinant of quality of life and physical function in patients with early axial Spondyloarthritis: Results from the ESPERANZA Cohort. Arthritis Care Res (Hoboken) 2016 Apr 25.1. Disclosure of Interest None declared

Background A significant percentage of genetic and inflammatory diseases derive from splicing alterations. Therefore, the understanding of what modifications in spliceosome determine an alternative splicing and its association with the development of such pathologies is of critical importance. Objectives To identify the alterations present in the spliceosome machinery of patients with rheumatoid arthritis (RA),its influence on the development and activity of the disease and their atherothrombotic profile. Methods An array of selected components of the major- (n=12) and minor-spliceosome (n=4) and associated splicing factors (n=28) was developed, and their expression levels were evaluated using a Fluidigm methodology, in purified leukocytes from 14 RA patients and 14 healthy donors (HD). In parallel, an extensive clinical/serological evaluation was performed. Carotid intimate media thickness (CIMT) was used as atherosclerosis marker. Endothelial activity was monitored by laser-doppler flowmetry, and pro-inflammatory and oxidative stress markers were quantified. Association of these splicing components with clinical and analytical features were investigated. Results A significant alteration in various components of spliceosome and splicing factors was found in all the leukocytes subtypes from RA patients vs HD. Interestingly, we found a specific altered profile of splicing factors and spliceosome components when compared monocytes (CA150, PRP8, SRM160, U2AF1, RNU4atac, PTBB1, RAVER1, RBM17, SRSF4, SRSF10), lymphocytes (RNU12, RNU4, RNU6, PRP8, MAGOH, NOVA1, SRSF3) and neutrophils (RNU11, RNU6, SC35, RBM3). Altered levels of various spliceosome elements in monocytes were associated with the presence of atheromatous plaques, while in neutrophils were found related to radiological involvement. In lymphocytes, the alteration of these components were linked to the positivity for Rheumatoid Factor and anti-CCPs antibodies, indicating that modifications in the spliceosome machinery could contribute to the increase in the production and assembly of autoantigens, inducing autoantibody production. Correlation studies showed a significant relationship between altered levels of various spliceosome components in different leukocyte subtypes and high disease activity (DAS, HAQ), increased expression of proinflammatory mediators (CRF, TF, TNF, IL-8, TLR4) and oxidative stress markers (peroxides, GPX, SOD)as well as with parameters associated with insulin resistance. Conclusions These results reveal that there is a significant alteration of spliceosome components in RA patients that could be associated with the development and activity of this autoimmune condition, and influence mechanisms that drive the development of cardiovascular disease. Studies in progress will help to clarify the physiological implications of these findings, which could constitute new diagnostic biomarkers, as well as new therapeutic tools for the treatment of RA. Acknowledgements Funded by CTS7940, and ISCIII (PI15/01333, CP15/00158, and RIER RD16/0012/0015). Disclosure of Interest None declared