BackgroundLiver alterations, especially nonalcoholic fatty liver disease (NAFLD) are associated with Rheumatoid Arthritis (RA). This abnormality appears as asymptomatic and can progress to a severe liver damage rapidly. Chronic inflammation, treatment with methotrexate (MTX) or even autoimmunity are factors that might be involved, however the mechanisms related to this comorbidity in RA are not completely stablished yet.Objectives1) To evaluate the liver disease risk in RA patients through feasible indexes to be used in the daily clinical practice and its relationship with clinical features of the disease; 2) To analyze the impact of antibodies to citrullinated proteins antigens (ACPAs) on hepatic function; 3) To examine the influence of MTX treatment on classical parameters and new indexes of hepatic dysfunction in a cross-sectional and longitudinal cohort.Methods1) Cross-sectional study in 307 body mass index matched subjects: 55 healthy donors (HDs), 190 RA patients and 62 non-RA patients diagnosed with NAFLD through echography. Obese patients were excluded from the study. 2) Longitudinal study with 50 RA patients treated with MTX for 6 months. Clinical and laboratory parameters, subclinical liver disease biomarkers and 4 indexes to evaluate the presence of fibrosis and steatosis (APRI, “AST to platelet ratio index”; FIB-4, “fibrosis 4 score”; HSI, “hepatic steatosis index” and TyG, “triglycerides and glucosa index”) were measured. Association studies of hepatic dysfunction with clinical parameters were performed; A panel of 15 proteins directly involved in hepatic disease was analyzed in serum (C1QTNF1, IL7R, TIE1, CCL5, REG3A, CA3, LCN2, CCL14, NRP1, ICAM3, CD59, TIMP1, CNDP1, GNLY, IGFB6). 3) In vitro experiments were carried out in hepatocyte cell line (HEPG2) treated with ACPAs.ResultsUsing NALFD patients as positive controls for the four liver disease indexes, RA patients showed significantly higher levels of HSI and TyG biomarkers. In fact, a high proportion of these patients (42.7%) were estimated to suffer NALFD. The association studies in RA patients showed that liver disease biomarkers (HSI and TyG) were related to the insulin resistance state, inflammation, complement component 3(C3), disease activity, and the levels of ACPAs. Serum levels of CNDP1, CCL5, GNLY, TIMP-1, CD59 and CCL14 were significantly increased in RA patients and correlated with hepatic damage indexes. Treatment with ACPAs on hepatocytes promoted the secretion of C3 in parallel with a significant alteration of genes related to glucose and lipid metabolisms, inflammation, fibrosis and apoptosis. MTX treatment, from the point of cross-sectional approach, was not associated with an increase of hepatic enzymes, serum proteins nor liver disease indexes. Treatment with MTX for 6 months did not affect those levels either.Conclusion1) A high proportion of RA patients present an alteration in markers of NAFLD, associated with insulin resistance state, disease activity, inflammation, component C3 and ACPAs levels; 2) the autoantibodies could directly impact hepatocyte biology altering the expression of genes related to glucose and lipid metabolisms, inflammation, fibrosis and apoptosis, 3) Treatment with MTX did not promote any alteration in subclinical liver disease biomarkers after 6 months of treatment.Funded by Institute of Health Carlos III (PI20/00079).Disclosure of InterestsNone declared
Backgroundpatients with Spondyloarthritis (SpA) have an increased risk of cardiovascular disease. Taking into account the strong relationship between inflammation and CVD, there is an urgent need to identify different molecular drivers of CVD signs and their association with inflammation.Objectivesto investigate the alteration of CVD-related proteins in the plasma of SpA patients, their association with clinical features, and to evaluate their potential role as biomarkers for the identification of persistent inflammation.Methodsa cross-sectional study including 120 patients with SpA and 30 age-sex-matched healthy donors (HDs) was carried out. Clinical and laboratory parameters and CVD risk factors were recorded. To measure the presence of persistent inflammation, levels of c-reactive protein (CRP) were collected retrospectively for 5 years previous to the study, a patient was considered to have persistent inflammation with increased CRP in at least 50% of the measures during the previous 5 years. Levels of 92 proteins with a recognized role in CVD were analyzed in the plasma using proximity extension assay (PEA) technology (Olink Target 96 CVD III panel, Cobiomic Biosciences).ResultsSpA patients showed higher rates of CVD comorbidities compared to HDs. Plasma levels of TNF-R1, RARRES-2, CHI3L1, PGLYRP-1, CTSD, UPAR, IL2RA, TIMP-4, CTSB, GDF-15, MMP-9, and PDGF-A were significantly increased in SpA compared to HDs. Specifically, these proteins are also related to biological processes such as neutrophil degranulation, immune response, cell activation, atherosclerosis, apoptosis, and inflammatory response. Besides, a significant alteration of these CVD-related proteins in SpA was also associated with the presence of arterial hypertension, insulin resistance, obesity, hyperuricemia, and high levels of acute phase reactants. 36% of SpA patients displayed persistence of inflammation. Interestingly, SpA patients with persistent inflammation showed higher levels of ankylosing spondylitis disease activity (ASDAS) score, CRP, glucose, complement component 3, and lower levels of HDL-cholesterol and apolipoprotein A compared to SpA patients with non-persistent inflammation, suggesting the relationship of inflammation with metabolic alterations. In addition, 8 out of 12 CVD-related proteins altered in SpA patients were specifically changed in patients with persistent inflammation: MMP-9, RARRES-2, PGLYRP-1, UPAR, TNF-R1, PDGF-A, IL-2RA and GDF-15, highlighting levels of MMP-9 protein as a potential biomarker for persistent inflammation in SpA (AUC=0.796 p>0.0001).Conclusion1) SpA patients show an altered CVD proteome profile which is strongly associated with CVD risk factors and clinical inflammatory markers, 2) SpA patients with persistent inflammation display a deeper alteration in their plasma CVD protein pattern suggesting the link between subclinical CVD risk and the chronic inflammation, and 3) this study identifies novel potential biomarkers to distinguish SpA patients with persistent inflammation. Funded by ISCIII (PI20/00079, PMP21/00119, and RICOR-RD21/0002/0033) co-financed by ERDF.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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