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Utility of Baseline Transcriptomic Analysis of Rheumatoid Arthritis Synovium as an Indicator for Long-Term Clinical Outcomes

OBJECTIVE: Rheumatoid arthritis is a chronic inflammatory autoimmune disease that can lead to synovial damage, persistent joint pain, and functional disability. Our objective was to evaluate baseline synovial transcriptome from early inflammatory arthritis patients (EIA) and identify pretreatment bi...

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Autores principales: Anaparti, Vidyanand, Wiens, Dana, O'Neil, Liam J., Hubbard, Erika, Robl, Robert, Smolik, Irene, Hitchon, Carol, Lipsky, Peter E., El-Gabalawy, Hani
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9110862/
https://www.ncbi.nlm.nih.gov/pubmed/35592852
http://dx.doi.org/10.3389/fmed.2022.823244
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author Anaparti, Vidyanand
Wiens, Dana
O'Neil, Liam J.
Hubbard, Erika
Robl, Robert
Smolik, Irene
Hitchon, Carol
Lipsky, Peter E.
El-Gabalawy, Hani
author_facet Anaparti, Vidyanand
Wiens, Dana
O'Neil, Liam J.
Hubbard, Erika
Robl, Robert
Smolik, Irene
Hitchon, Carol
Lipsky, Peter E.
El-Gabalawy, Hani
author_sort Anaparti, Vidyanand
collection PubMed
description OBJECTIVE: Rheumatoid arthritis is a chronic inflammatory autoimmune disease that can lead to synovial damage, persistent joint pain, and functional disability. Our objective was to evaluate baseline synovial transcriptome from early inflammatory arthritis patients (EIA) and identify pretreatment biomarkers that could potentially provide insights into long-term functional outcomes of rheumatoid arthritis (RA). METHODS: Synovial biopsies from clinically inflamed knee joints were procured from either 17 EIA patients before initiation of disease modifying anti-rheumatic drug (DMARD) therapy (DMARD-naïve EIA) using the minimally invasive closed needle biopsy technique or advanced RA patients undergoing arthroplasty. Affymetrix Human Genome U133 Plus 2 microarray platform was used to profile the synovial transcriptome. The cohort was followed clinically for a median of 12.3 years, and patient data was collected at each visit. Short-term and long-term clinical outcomes were determined by assessing RA-associated clinical parameters Statistical adjustments were made to account for asynchronous clinical visits and duration of follow up. RESULTS: Based on the transcriptomic analysis, we identified 5 differentially expressed genes (DEGs), including matrix metalloproteinase (MMP)-1 (fibroblast collagenase) and MMP-3 (stromelysin-1) in DMARD-naïve EIA patients, relative to advanced RA patients (q < 0.05). Dichotomous expression of MMP-1 and MMP-3 mRNA and protein was confirmed by qPCR and immunohistochemistry respectively, based on which DMARD-naïve EIA subjects were classified as MMP-high or MMP-low. Hierarchical clustering of transcriptomic data identified 947 DEGs between MMP-high and MMP-low cohorts. Co-expression and IPA analysis of DEGs in the MMP-high cohort showed an enrichment of genes that participated in metabolic or biochemical functions and intracellular immune signaling were regulated through NF-κB and β-catenin complexes and correlated with markers of systemic inflammation. Analysis of short-term clinical outcomes in MMP-high cohort showed a significant reduction in the DAS-CRP scores relative to baseline (P <0.001), whereas area under the curve analyses of modified HAQ (mHAQ) scores correlated negatively with baseline MMP-1 (R = −0.59, P = 0.03). Further, longitudinal mHAQ scores, number of swollen joints, number of DMARDs and median follow-up duration appeared to be higher in MMP-low cohort. CONCLUSION: Overall, our results indicate that the gene expression profiling of synovial biopsies obtained at the DMARD-naive stage in patients with EIA categorizes them into subsets with varying degrees of inflammation and can predict the future of long-term clinical outcome.
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spelling pubmed-91108622022-05-18 Utility of Baseline Transcriptomic Analysis of Rheumatoid Arthritis Synovium as an Indicator for Long-Term Clinical Outcomes Anaparti, Vidyanand Wiens, Dana O'Neil, Liam J. Hubbard, Erika Robl, Robert Smolik, Irene Hitchon, Carol Lipsky, Peter E. El-Gabalawy, Hani Front Med (Lausanne) Medicine OBJECTIVE: Rheumatoid arthritis is a chronic inflammatory autoimmune disease that can lead to synovial damage, persistent joint pain, and functional disability. Our objective was to evaluate baseline synovial transcriptome from early inflammatory arthritis patients (EIA) and identify pretreatment biomarkers that could potentially provide insights into long-term functional outcomes of rheumatoid arthritis (RA). METHODS: Synovial biopsies from clinically inflamed knee joints were procured from either 17 EIA patients before initiation of disease modifying anti-rheumatic drug (DMARD) therapy (DMARD-naïve EIA) using the minimally invasive closed needle biopsy technique or advanced RA patients undergoing arthroplasty. Affymetrix Human Genome U133 Plus 2 microarray platform was used to profile the synovial transcriptome. The cohort was followed clinically for a median of 12.3 years, and patient data was collected at each visit. Short-term and long-term clinical outcomes were determined by assessing RA-associated clinical parameters Statistical adjustments were made to account for asynchronous clinical visits and duration of follow up. RESULTS: Based on the transcriptomic analysis, we identified 5 differentially expressed genes (DEGs), including matrix metalloproteinase (MMP)-1 (fibroblast collagenase) and MMP-3 (stromelysin-1) in DMARD-naïve EIA patients, relative to advanced RA patients (q < 0.05). Dichotomous expression of MMP-1 and MMP-3 mRNA and protein was confirmed by qPCR and immunohistochemistry respectively, based on which DMARD-naïve EIA subjects were classified as MMP-high or MMP-low. Hierarchical clustering of transcriptomic data identified 947 DEGs between MMP-high and MMP-low cohorts. Co-expression and IPA analysis of DEGs in the MMP-high cohort showed an enrichment of genes that participated in metabolic or biochemical functions and intracellular immune signaling were regulated through NF-κB and β-catenin complexes and correlated with markers of systemic inflammation. Analysis of short-term clinical outcomes in MMP-high cohort showed a significant reduction in the DAS-CRP scores relative to baseline (P <0.001), whereas area under the curve analyses of modified HAQ (mHAQ) scores correlated negatively with baseline MMP-1 (R = −0.59, P = 0.03). Further, longitudinal mHAQ scores, number of swollen joints, number of DMARDs and median follow-up duration appeared to be higher in MMP-low cohort. CONCLUSION: Overall, our results indicate that the gene expression profiling of synovial biopsies obtained at the DMARD-naive stage in patients with EIA categorizes them into subsets with varying degrees of inflammation and can predict the future of long-term clinical outcome. Frontiers Media S.A. 2022-05-03 /pmc/articles/PMC9110862/ /pubmed/35592852 http://dx.doi.org/10.3389/fmed.2022.823244 Text en Copyright © 2022 Anaparti, Wiens, O'Neil, Hubbard, Robl, Smolik, Hitchon, Lipsky and El-Gabalawy. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Anaparti, Vidyanand
Wiens, Dana
O'Neil, Liam J.
Hubbard, Erika
Robl, Robert
Smolik, Irene
Hitchon, Carol
Lipsky, Peter E.
El-Gabalawy, Hani
Utility of Baseline Transcriptomic Analysis of Rheumatoid Arthritis Synovium as an Indicator for Long-Term Clinical Outcomes
title Utility of Baseline Transcriptomic Analysis of Rheumatoid Arthritis Synovium as an Indicator for Long-Term Clinical Outcomes
title_full Utility of Baseline Transcriptomic Analysis of Rheumatoid Arthritis Synovium as an Indicator for Long-Term Clinical Outcomes
title_fullStr Utility of Baseline Transcriptomic Analysis of Rheumatoid Arthritis Synovium as an Indicator for Long-Term Clinical Outcomes
title_full_unstemmed Utility of Baseline Transcriptomic Analysis of Rheumatoid Arthritis Synovium as an Indicator for Long-Term Clinical Outcomes
title_short Utility of Baseline Transcriptomic Analysis of Rheumatoid Arthritis Synovium as an Indicator for Long-Term Clinical Outcomes
title_sort utility of baseline transcriptomic analysis of rheumatoid arthritis synovium as an indicator for long-term clinical outcomes
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9110862/
https://www.ncbi.nlm.nih.gov/pubmed/35592852
http://dx.doi.org/10.3389/fmed.2022.823244
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