Background In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA. Results In comparison to controls, we show that RA patients have multiple and strong differences in the B cell receptor repertoire including reduced diversity as well as altered isotype, chain, and segment frequencies. We demonstrate that therapeutic tumor necrosis factor inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific T cell receptor repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool. Conclusions Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases.

The aim of this study was to identify single-nucleotide polymorphisms (SNPs) in bone remodeling-related genes associated with disease severity and bone mineral density (BMD) in early arthritis (EA) patients. For this purpose, the genotyping of 552 SNPs located in gene regions of semaphorins 4b, 4d, 4f, DKK1, 2 and 3, sclerostin, OPG, RANK and RANKL was performed using Immunochip from Illumina Inc. in 268 patients from the Princesa Early Arthritis Register Longitudinal (PEARL) study. Measurements of BMD and disease activity were chosen as outcome variables to select SNPs of interest. The relationships of SNPs with the BMD of the forearm, lumbar spine and hip (Hologic-4500 QDR) were analyzed by linear regression adjusted for age, sex, body mass index and presence of anti-citrullinated peptide antibodies (ACPAs). The association of each SNP with activity variables was analyzed by linear regression, logistic regression or ordered logistic regression according to the variable, and multivariate models were adjusted for potentially confounding variables, such as age, sex and presence of ACPAs. These analyses showed that four SNPs located in the genes coding for RANK (TNFRSF11A) and OPG (TNFRSF11B) were significantly associated with clinical variables of severity. SNP rs1805034 located in exon 6 of TNFRSF11A, which causes a non-synonymous (A/V) mutation, showed significant association with BMD and therefore may be considered as a possible biomarker of severity in RA patients. SNPs in the OPG gene showed an association with serum OPG levels and predicted disease activity after two years of follow-up.

Background: At the beginning of the COVID-19 pandemic there were controversial opinions regarding the possibility of temporary interrupting immunomodulatory treatments in rheumatic patients to enhance the immune response to the COVID-19 vaccine. Previous published works have raised the concern that methotrexate (MTX) might have a negative effect on immune response upon COVID-19 vaccine administration in this population. In this context, we postulated that temporary MTX interruption after COVID-19 vaccine administration could be beneficial for rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients in terms of improving both humoral and cellular responses, based on prior data on influenza vaccine. Objectives: Primary Objective: To evaluate the impact on B and T cell responses to COVID-19 vaccine of 1 or 2 weeks of MTX withdrawal following each vaccine dose in patients with RA or PsA. Secondary Objective: To analyze the adverse events in terms of flares of the disease. Methods: Single-centre, randomized, prospective study. Adult RA and PsA patients treated with MTX at stable dose were recruited between March and September 2021 (first vaccination campaign) and randomly assigned to 3 groups: MTX-maintenance, and MTX-withdrawal for 1 wk or 2 wks after each COVID-19 vaccine dose. Samples were collected before and 30 days after complete vaccination. Multi-antigen cytometric bead array assays to detect specific antibodies to several SARS-CoV-2 antigens and ELISPOT assays measuring interferon (IFN)-y and interleukin (IL)-21 were performed. Multivariable analyses with Stata v.14 were used to control the effect of possible confounding variables. The rates of disease relapses were recorded. Results: 216 Patients were included (178 RA, 38 PsA), of whom 72 maintained MTX unchanged, and 71 and 73 withdrew MTX for 1 wk and 2 wks, respectively. Population characteristics are shown in Table 1. COVID-19 occurred in 47 patients before complete vaccination. Participants were vaccinated with BNT162b2 (71%), ChadOX-1-S (14%), mRNA-1273 (6%) and Ad26.COV2.S (9%). There were no significant differences in comorbidities (HT, DL, DM, COPD, asthma, CV disease, cancer), types of vaccines or previous COVID-19 infection across groups. On average COVID-19 vaccination elicited good levels of humoral and cellular responses, which were higher in patients previously infected with SARS-CoV-2. Humoral response was higher with mRNA vaccines. MTX withdrawal was associated with a significantly higher number of good responders for anti-S antibodies and significantly higher titres of anti-S IgA and IgM antibodies, anti-RBD IgG antibodies and neutralising antibodies in patients without previous COVID-19, especially in the 2-wks withdrawal group (Figure 1). Regarding cellular response, MTX withdrawal, especially the 2 wks group, was associated with higher IFN-γ secretion both in patients without and with previous COVID-19, but no differences were found for IL-21 across groups. Regarding safety, the rate of relapse was low, either using the DAS criteria (15%) or the physician's criteria (12%), and the majority were mild or moderate. To highlight, there were no significant differences in the number of RA/PsA relapses across groups. Higher baseline CRP was the only factor associated with relapse: OR 1.77, 95%CI [1.03-3.03], p=0.037. Conclusion: Our data suggest that a brief MTX interruption following COVID-19 vaccination doses in patients with RA or PsA improves humoral and cellular immune responses, without significant increase of relapses, especially in patients without previous COVID-19 infection and with good disease control. REFERENCES: NIL. Acknowledgements: All members of the Rheumatology and Immunology Departments of Hospital Universitario de La Princesa. Disclosure of Interests: Santos Castañeda: Ministerio de Economía y Competitividad (Instituto de Salud Carlos III) (grant no. PI21/0147 to SC, PID-2020-120412RB-I00 and PDC2021-121797-I00 to FS-M) and co-funded by European regional development fund (ERDF) "A way to make Europe", and also by REACT-EU-INMUNOVACTER-CM and P2022/BMD7209-INTEGRAMUNE from Comunidad Autónoma de Madrid., Esther Vicente-Rabaneda: None declared, Pedro Martínez-Fleta: None declared, Ana Triguero-Martinez: None declared, Miren Uriarte-Ecenarro: None declared, Francisco Gutiérrez-Rodríguez: None declared, Patricia Quiroga Colina: None declared, Ana Romero: None declared, Noelia García Castañeda: None declared, Jesús A. García-Vadillo: None declared, Cristina Valero: None declared, Irene Llorente: None declared, Ana Ortiz: None declared, Eva Tomero Muriel: None declared, Maria Aranzazu Alfranca: None declared, Rosario Garcia-Vicuña: None declared, Francisco Sánchez-Madrid: None declared, Isidoro González-Álvaro: None declared.

Background: The window of opportunity is well established in patients meeting the criteria for rheumatoid arthritis (RA) but is unclear in patients presenting with undifferentiated arthritis (UA). This study described changes in the management of patients with UA over 20 years in a registry of patients with recent-onset arthritis in a tertiary hospital in Madrid and analysed whether the concept of a window of opportunity could exist in these patients. Objectives: To describe the influence of the prescription of disease-modifying treatment (DMARD) on activity and disability in patients with UA over the 20 years of a registry of patients with recent-onset arthritis in a tertiary hospital in Madrid. Methods: All patients classified as UA[1] at the first visit of the registry from September 2001 to December 2019 were included. Demographic, clinical, analytical and treatment data were collected in a protocolised manner at four consecutive visits (baseline, 6 months, 1 and 2 years). To assess management changes, patients were grouped into four five-year periods (Q1 from 2001 to 2004, Q2 from 2005 to 2009, Q3 from 2010 to 2014 and Q4 from 2015 to 2019). Statistical analysis was performed with Stata 14.1 using the appropriate tests for bivariate analysis according to the type and distribution of variables. A multivariable model nested by patient and visit (xtgee command) was fitted to analyse the influence of the different variables on disease activity. All variables differing between five-year periods and those related to arthritis activity were included. Results: 309 patients were included in the analysis (77.7% female; age at disease onset 52 years [RIQ: 39-63]). The percentage of non-smokers decreased from the first to the last five-year period (67 vs 42.3%; p<0.0001). There was a trend towards an increase in seropositive cases (RF and anti-CCP) from the first to the last five-year period (p=0.013 and p=0.001, respectively). Time to first consultation and initiation of first DMARD decreased respectively from 6.6 (RIQ: 4.1-10.0) and 14.1 (RIC 5.2-31.5) months in the first five-year period to 3.5 (RIQ: 1.8-7.6) and 6.4 (RIC 2.8-18.4) months in the last five-year period (p=0.0019 and p=0.0001). Over the five-year periods, the use of methotrexate increased (16.7% more, p=0.004), and the use of antimalarials and sulfasalazine decreased (28.9% and 13.7% less, respectively, p=0.014). Disease activity progressively decreased, with a higher percentage of patients in remission at two years (25% more in the last five years p=0.046) and a progressive improvement in functionality, with a higher percentage of patients with mild disability in the last five-year period (26.3% more p=0.028) (Figures 1 and 2). After two years of follow-up, 45.4% of patients maintained the diagnosis of UA, 23.6% changed the diagnosis to RA, 4.6% to spondyloarthropathies and 26.4% to other processes, with no significant changes over time. Adjusting for all variables differing between the five-year periods (seropositivity, smoking and treatments), as well as those affecting disease activity (sex and age), a decrease in arthritis activity was observed in all five-year periods compared to the first (Q2 and Q4 p=0.032, Q3 p=0.003). Conclusion: Our preliminary results suggest that the therapeutic window of opportunity also exists in patients with UA by showing improvement in disease activity and functional capacity. REFERENCES: [1] Verpoort KN, van Dongen H, Allaart CF, Toes RE, Breedveld FC, Huizinga TW. Undifferentiated arthritis-disease course assessed in several inception cohorts. Clin Exp Rheumatol. 2004;22(5 Suppl 35): S12-7. Acknowledgements: NIL. Disclosure of Interests: None declared.

Objective: To develop a joint proposal for screening criteria of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and vice versa, which serves as a guidelines in patient referral between the Rheumatology and Pneumology departments to early detection of these patients.Methods: A systematic literature review was carried out on the risk factors for the development of ILD in RA patients, and for the referral criteria to Rheumatology for suspected early RA. Based on the availa-ble evidence, screening criteria were agreed using the Delphi method by a panel of pneumologists and rheumatologists with expertise in these pathologies.Results: Screening criteria for ILD in patients with RA and for the early detection of RA in cases with ILD of unknown etiology have been developed. In both cases, a detection strategy was based on clinical risk factors. Recommendations also included the complementary tests to be carried out in the different clinical scenarios and on the periodicity that screening should be repeated.Conclusion: A selective screening strategy is recommended for the first time in the early diagnosis of patients with ILD-RA. This multidisciplinary proposal aims to solve some common clinical questions and help decision-making, although its usefulness to identify these patients with good sensitivity must be confirmed in a validation study.& COPY; 2022 Published by Elsevier Espana, S.L.U.

Elaborar una propuesta multidisciplinar de criterios de cribado de enfermedad pulmonar intersticial difusa (EPID) en pacientes con artritis reumatoide (AR) y, a la inversa, que sirvan de referencia en la derivación entre los servicios de Reumatología y Neumología para la detección precoz de estos pacientes. Se revisó de forma sistemática la literatura sobre factores de riesgo para el desarrollo de EPID en la AR, la utilidad de los distintos métodos diagnósticos para su identificación en pacientes con AR y las diferentes propuestas de criterios de derivación a Reumatología por sospecha de AR precoz. Basándose en la evidencia disponible y en su experiencia clínica, un comité científico formado por dos reumatólogos y dos neumólogos propuso unos criterios de cribado que fueron evaluados mediante el método Delphi por un panel de siete neumólogos y siete reumatólogos. Todos los participantes eran expertos en esta patología. Se han elaborado unos criterios para el cribado de EPID en pacientes diagnosticados de AR, y unos criterios para la detección precoz de AR en casos de EPID de causa no filiada. Se incluyen también propuestas sobre las pruebas complementarias a realizar en los diferentes escenarios clínicos considerados y sobre la periodicidad con la que debe repetirse el cribado. Se propone por primera vez una estrategia de cribado selectivo para el diagnóstico precoz de los pacientes con EPID-AR. Esta propuesta pretende resolver algunos interrogantes clínicos habituales y facilitar la toma de decisiones. Los criterios propuestos deben ser evaluados en futuros estudios de validación. To develop a joint proposal for screening criteria of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and vice versa, which serves as a guidelines in patient referral between the Rheumatology and Pneumology departments to early detection of these patients. A systematic literature review was carried out on the risk factors for the development of ILD in RA patients, and for the referral criteria to Rheumatology for suspected early RA. Based on the available evidence, screening criteria were agreed using the Delphi method by a panel of pneumologists and rheumatologists with expertise in these pathologies. Screening criteria for ILD in patients with RA and for the early detection of RA in cases with ILD of unknown etiology have been developed. In both cases, a detection strategy was based on clinical risk factors. Recommendations also included the complementary tests to be carried out in the different clinical scenarios and on the periodicity that screening should be repeated. A selective screening strategy is recommended for the first time in the early diagnosis of patients with ILD-RA. This multidisciplinary proposal aims to solve some common clinical questions and help decision-making, although its usefulness to identify these patients with good sensitivity must be confirmed in a validation study.

Lupus anticoagulant hypoprothrombinemia syndrome (LAHPS) is a rare entity associated with an increased risk of hemorrhage. Corticosteroids have been used in its treatment with favorable results. We present the case of a 54-year-old female patient with a personal history of Lupus diagnosed with LAHPS following an episode of cerebellar hemorrhage.

Galectin 1 (Gal1) exerts immunomodulatory effects leading to therapeutic effects in autoimmune animal models. Patients with rheumatoid arthritis have been reported to show higher Gal1 serum levels than the healthy population. Our study aimed to find genetic variants on the Gal1 gene (LGALS1) modulating its expression and/or clinical features in patients with early arthritis (EA). LGALS1 was sequenced in 53 EA patients to characterize all genetic variants. Then, we genotyped rs9622682, rs929039, and rs4820293, which covered the main genetic variation in LGALS1, in 532 EA patients. Gal1 and IL-6 serum levels were measured by ELISA and Gal1 also by western blot (WB) in lymphocytes from patients with specific genotypes. Once disease activity improved with treatment, patients with at least one copy of the minor allele in rs9622682 and rs929039 or those with GG genotype in rs4820293 showed significantly higher Gal1 serum levels (p < 0.05). These genotypic combinations were also associated with higher Gal1 expression in lymphocytes by WB and lower IL-6 serum levels in EA patients. In summary, our study suggests that genetic variants studied in LGALS1 can explain heterogeneity in Gal1 serum levels showing that patients with higher Gal1 levels have lower serum IL-6 levels.

Exercise is recommended as a non-pharmacological therapy for osteoarthritis (OA). Various exercise regimes, with differing intensities and duration, have been used in a range of OA rodent models. These studies show gentle or moderate exercise reduces the severity of OA parameters while high intensity load bearing exercise is detrimental. However, these studies were largely conducted in rats or in mouse models induced by severe injury, age or obesity, whilst destabilization of the medial meniscus (DMM) in mice has become a widely accepted model due to its lower variability, moderate progression and timescale. The present study was undertaken to provide insight into the effect of moderate exercise on early joint pathology in the DMM mouse model. Exercise was induced a week after induction by forced wheel walking for three or 7 weeks. Joints were analyzed by microcomputed tomography and histology. Assessment of skeletal parameters revealed that exercise offered protection against cartilage damage after 7 weeks of exercise, and a temporary protection against osteosclerosis was displayed after 3 weeks of exercise. Furthermore, exercise modified the metaphyseal trabecular microarchitecture of the osteoarthritic leg in both time points examined. Collectively, our findings corroborate previous studies showing that exercise has an important effect on bone in OA, which subsequently, at 8 weeks post-induction, translates into less cartilage damage. Thus, providing an exercise protocol in a surgical mouse model of OA, which can be used in the future to further dissect the mechanisms by which moderate exercise ameliorates OA.

ObjetivoElaborar unas recomendaciones multidisciplinares para mejorar el manejo de la enfermedad pulmonar intersticial difusa asociada a la artritis reumatoide (EPID-AR).MétodosUn panel de reumatólogos y neumólogos expertos identificó preguntas clínicas de investigación relevantes para el objetivo del documento. Se realizaron revisiones sistemáticas de la evidencia, que se graduó de acuerdo con los criterios del SIGN. Tras ello, se formularon las recomendaciones.ResultadosSe seleccionaron seis preguntas PICO, tres de las cuales específicamente evaluaron la seguridad y la eficacia de los glucocorticoides, fármacos de acción lenta moduladores de la enfermedad (FAME) sintéticos clásicos e inmunosupresores, FAME biológicos, FAME sintéticos dirigidos y antifibróticos en el tratamiento de los pacientes con EPID-AR. Se formularon un total de 12 recomendaciones específicas sobre este tema con base en la evidencia encontrada y/o consenso de expertos.ConclusionesSe presenta el primer documento oficial SER-SEPAR de recomendaciones específicas para el abordaje terapéutico de la EPID-AR con el fin de ayudar en la toma de decisiones a los clínicos directamente implicados en su manejo.

ObjetivoElaborar unas recomendaciones multidisciplinares para mejorar el manejo de la enfermedad pulmonar intersticial difusa asociada a la artritis reumatoide (EPID-AR).MétodosUn panel de reumatólogos y neumólogos expertos identificó preguntas clínicas de investigación relevantes para el objetivo del documento. Se realizaron revisiones sistemáticas de la evidencia, que se graduó de acuerdo con los criterios del Scottish Intercollegiate Guidelines Network (SIGN). Tras ello, se formularon las recomendaciones.ResultadosSe seleccionaron seis preguntas PICO, tres de las cuales específicamente evaluaron la incidencia y la prevalencia de esta complicación, los factores de riesgo para su desarrollo, y los factores pronósticos de mortalidad y de progresión de la EPID-AR. Se formularon un total de 6 recomendaciones específicas sobre estos aspectos, estructuradas por pregunta, con base en la evidencia encontrada y/o consenso de expertos.ConclusionesSe presenta el primer documento oficial SER-SEPAR de recomendaciones específicas para el abordaje la EPID-AR, con el fin de ayudar en la toma de decisiones a los clínicos directamente implicados en su manejo y aproximar la práctica asistencial a la mejor evidencia posible.

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

Objective: To develop multidisciplinary recommendations to improve the management of rheumatoid arthritis-related interstitial lung disease (RA-ILD).Methods: Clinical research questions relevant to the objective of the document were identified by a panel of rheumatologists and pneumologists 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 (SIGN) criteria. Specific recommendations were made.Results: Six PICO questions were selected, three of which analysed the safety and effectiveness of glucocorticoids, classical synthetic disease-modifying anti-rheumatic drugs (DMARDs) and other immunosuppressants, biological agents, targeted synthetic DMARDs, and antifibrotic therapies in the treatment of this complication. A total of 12 recommendations were formulated based on the evidence found and/or expert consensus. Conclusions: We present the first official SER-SEPAR document with specific recommendations for RA-ILD management developed to resolve some common clinical questions, reduce clinical healthcare variability, and facilitate decision-making for patients. (c) 2022 Elsevier Espana, S.L.U. and Sociedad Espanola de Reumatologia y Colegio Mexicano de Reumatologia. All rights reserved.

Galectin-1 (Gal1) plays a regulatory role in the immune system. We have recently validated that Gal1 serum (sGal1) levels are increased in rheumatoid arthritis (RA) patients compared to healthy donors (HDs); however, there is no information on Gal1 in spondyloarthritis (SpA). Objective: To compare Gal1 levels in patients with SpA versus RA as a diagnostic biomarker. Methods: We studied sGal1 levels in HD (n = 52), SpA (n = 80) and RA patients (n = 64) who were randomly divided into discovery and validation sets. Synovial fluid (SF) from osteoarthritis (OA) (n = 28), peripheral SpA (n = 28) and RA (n = 28) were studied. In SpA patients, we analyzed the association between clinical parameters and sGal1 levels. Results: sGal1 levels were significantly lower in patients with SpA with respect to RA and similar to those of the HD. A cut-off of 20.50 ng/mL (sGal1) allowed one to differentiate RA patients from SpA and HD (Odd Ratio (OR) 8.23 and 12.64, respectively). Gal1 SF levels in SpA were slightly lower than OA patients and significantly lower than RA patients. No correlation was observed between sGal1 levels and clinical parameters in SpA patients. Conclusion: Gal1 could act as a diagnostic biomarker of RA and would allow one to distinguish SpA and RA patients.

ObjectiveTo develop multidisciplinary recommendations to improve the management of rheumatoid arthritis-related interstitial lung disease (RA-ILD).MethodsClinical research questions relevant to the objective of the document were identified by a panel of rheumatologists and pneumologists 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 (SIGN) criteria. Specific recommendations were made.ResultsSix PICO questions were selected, three of which analysed the incidence and prevalence of RA-ILD, associated risk factors, and predictors of progression and mortality. A total of 6 specific recommendations on these topics, structured by question, were formulated based on the evidence found and/or expert consensus.ConclusionsWe present the first official SER-SEPAR document with specific recommendations for RA-ILD management developed to resolve some common clinical questions and facilitate decision-making for patients.

ABSTRACTRheumatoid arthritis (RA) is an immune-mediated inflammatory disease characterized by a defective adaptive immune receptor repertoire (AIRR) that fails to distinguish self from non-self antigens. The AIRR is vast, encompassing four T cell receptor (TCR) and three B cell receptor (BCR) chains, each of which displays an extraordinary amino acid sequence variability in the antigen-binding site. How the concerted action of T and B cell clones is associated with the development and clinical evolution of immune-mediated diseases is still not known. Using a new immunosequencing technology that allows the unbiased amplification of the seven receptor chains, we conducted an in-depth quantitative analysis of the seven-receptor chain variability in RA. Compared to healthy controls, the AIRR in RA was found to be characterized by a lower BCR diversity, the depletion of highly similar BCR clones, an isotype-specific signature as well as a skewed IGL chain and gene segment usage. A predictor based on quantitative multi-chain AIRR information was able to accurately predict disease, including the elusive seronegative subset of RA patients. AIRR features of the seven immune receptor chains were also different between patients with distinct clinically relevant phenotypes. Incorporating HLA variation data, we were able to identify the TCR clones that are specifically associated with the main disease risk variants. The longitudinal analysis of the AIRR revealed that treatment with Tumor Necrosis Factor (TNF) inhibitors selectively restores the diversity of B cell clones in RA patients by reducing the frequency of clones with a similar biochemical profile. The biochemical properties of the TNFi-modulated clones were also found to differ between responders and non-responders, supporting a different antigenic reactivity in the B cell compartment of these two groups of RA patients. Our comprehensive analysis of the TCR and BCR repertoire reveals a complex T and B cell architecture in RA, and provides the basis for precision medicine strategies based on the highly informative features of the adaptive immune response.

Background:Gout is the most prevalent inflammatory arthritis. Gout is chronic inflammatory deposition disease related to an increase of cardiovascular (CV) events and mortality. Subclinical chronic inflammation has been demonstrated in this patients but not its relation with the monosodium urate (MSU) crystal deposit size and the number of CV risk factors.Objectives:To study the subclinical inflammation in intercritical gout patients and its possible relation to the estimated size of the crystal deposition and the number of CV risk factors.Methods:To analyze subclinical inflammation we performed a secretome analysis and a cytokine and adiponektine plasma levels quantification (IL-1β, IL-18, IL-6, sIL-6R, TNFα, CXCL-5, RANTES, leptin, resistin and adiponectin) in a cohort of gout patients. As nowadays it is not feasible to determinate the whole body deposit of MSU crystals we created three different MSU crystal deposit size patient groups using an indirect clinical and analytical classification to estimate it. Then we compared cytokine levels between healthy donors and gout patients. We also compared cytokine levels between the different crystal size deposition groups and studied its association to the number of CV risk factors.Results:Ninety consecutive patients attending a Crystal Arthritis Unit were studied. Mean age was 68.27 (28-101) years. 81.1% were male. Clinical gout evolution was of 10.1±9.8 years. 77.5% were on urate lowering treatment. 24% had tophaceous gout. Mean uric acid was 6.3±2.1 mg/dl with 47.1% of them being on target. Hypertension was present in 68.9%, diabetes mellitus in 18.9%, dislipemia in 48.9%, BMI>30 in 32.9%, abdominal obesity in 50% and 16.1% suffered from ischemic heart disease. From the 102 molecules studied in the secretome analysis in 56 there was at least a 20% difference between donors group and any of the deposition groups. In 74% of them gout patients secreted lower levels. IL-18, sIL-6R, RANTES, leptin and adiponectin were higher in patients than in healthy donors. IL-18, sIL6-R, RANTES and CXCL5 levels were associated to the size of the crystal deposits. IL-18, sIL-6R, RANTES and leptin were higher in gout groups with CV risk factors. IL-18, sIL6-R, RANTES and leptin were higher in gout patients with no risk factors when compared to healthy donors with no risk factors. We found no differences when comparing urate lowering treated and non-treated patients.Conclusion:Our results demonstrate that some proinflammatory cytokines and metabolic proteins are raised in intercritical gout patients. Some of them are different from the flare/inflammasome expected ones. In some cytokines this elevation is related to the size of the monosodium urate crystal deposit and/or to the number of cardiovascular risk factors. This cytokine changes could help to explain the increase of the cardiovascular events in gout patients.Disclosure of Interests:Cesar Diaz-Torne Grant/research support from: Received a grant from Grünenthal, Maria Angels Ortiz: None declared, Sicylle Jeria Navarro: None declared, Andrea Garcia-Gullien: None declared, Lluis Sainz: None declared, Hector Corominas: None declared, Silvia Vidal: None declared