BackgroundSystemic autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are characterised by aberrant autoimmune and inflammatory processes, which are directly associated with the development and progression of these disorders. Novel biomarkers associated with the severity of these diseases are needed to better characterise and monitor their progression as well as to develop new and more effective therapeutic strategies.ObjectivesTo identify common and distinctive novel biomarkers of disease activity in SLE and RA using high-throughput proteomics.MethodsSerum samples from 170 patients, including 100 RA and 70 SLE, were profiled with the disruptive technology “proximity extension assay” from Olink, which analysed the levels of a panel of 92 inflammatory proteins. The methodology involves protein-specific antibodies linked to DNA-encoded tags which are amplified by RT-PCR.Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Disease activity score in 28 joints (DAS28) were assessed in SLE and RA patients respectively to characterise the disease status of all patients.Pearson´s correlation studies were performed using molecular information and clinical data to identify biomarkers of disease activity in each disease (FDR<0.05). Gene ontology enrichment analysis were performed to gain insight about the biological meaning of the biomarker signatures.ResultsSLE patients were characterised by an average SLEDAI of 5.2 (min-max, 0-29) while RA patients exhibited an average DAS28 of 4.6 (min-max, 1.5-7.8).Correlation studies revealed 14 proteins directly associated with SLEDAI in SLE patients, including ADA, CCL25, CD40, CDCP1, CSF1, FGF21, FLT3L, IL10RB, LAP-TGFB1, MMP20, OPG, SLAMF1, TNFRSF9 and uPA. The subsequent enrichment analysis revealed that those molecules were associated with pathways such as cytokine-cytokine receptor interaction and MAPK signalling.In RA patients 26 proteins were directly correlated with DAS28 including AXIN1, BNGF, CASP8, CCL23, CD40, CSF1, CXCL9, CXCL10, CXCL11, EN-RAGE, FGF23, GDNF, HGF, IL10RB, IL15RA, IL6, IL7, IL19, IL20, IL33, LAP-TGFB, MCP3, OPG, SLAMF1, TNFRSF9 and TWEAK which were enriched in biological pathways such as chemokine-chemokine receptor interaction and JAK-STAT signalling.The levels of five pro-inflammatory mediators were commonly associated with the disease activity status of both diseases such as IL10RB (receptor for IL10, IFNL2 and IFNL3), CSF1 (macrophage colony-stimulating factor 1 receptor), SLAMF1 (Signaling lymphocytic activation molecule), TNFRSF9 and OPG (both, tumor receptor factor ligand superfamily members), suggesting a key common role of these molecules in the underlying molecular mechanisms associated with both diseases.ConclusionThe analysis of the inflammatory profile of systemic autoimmune diseases with novel high-throughput proteomic technologies in non-invasive samples allow the identification of relevant biomarkers associated with the disease activity, which can improve the monitoring of the disease and the development of new targeted therapies.AcknowledgementsSupported by ISCIII (PI21/005991 and RICOR-RD21/0002/0033) co-financed by FEDER, Fundacion Andaluza de Reumatología (FAR) and Consejería de Conocimiento, Investigación y Universidad de la Junta de Andalucía (P20_01367).Disclosure of InterestsNone declared
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
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