TY - JOUR
T1 - Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients
AU - Humby, Frances
AU - Lewis, Myles
AU - Ramamoorthi, Nandhini
AU - Hackney, Jason A.
AU - Barnes, Michael R.
AU - Bombardieri, Michele
AU - Setiadi, A. Francesca
AU - Kelly, Stephen
AU - Bene, Fabiola
AU - Dicicco, Maria
AU - Riahi, Sudeh
AU - Rocher, Vidalba
AU - Ng, Nora
AU - Lazarou, Ilias
AU - Hands, Rebecca
AU - van der Heijde, D. sirée
AU - Landewé, Robert B. M.
AU - van der Helm-van Mil, Annette
AU - Cauli, Alberto
AU - McInnes, Iain
AU - Buckley, Christopher Dominic
AU - Choy, Ernest H.
AU - Taylor, Peter C.
AU - Townsend, Michael J.
AU - Pitzalis, Costantino
PY - 2019/6
Y1 - 2019/6
N2 - Objectives: To unravel the hierarchy of cellular/molecular pathways in the disease tissue of early, treatment-naïve rheumatoid arthritis (RA) patients and determine their relationship with clinical phenotypes and treatment response/outcomes longitudinally. Methods: 144 consecutive treatment-naïve early RA patients (<12 months symptoms duration) underwent ultrasound-guided synovial biopsy before and 6 months after disease-modifying antirheumatic drug (DMARD) initiation. Synovial biopsies were analysed for cellular (immunohistology) and molecular (NanoString) characteristics and results compared with clinical and imaging outcomes. Differential gene expression analysis and logistic regression were applied to define variables correlating with treatment response and predicting radiographic progression. Results: Cellular and molecular analyses of synovial tissue demonstrated for the first time in early RA the presence of three pathology groups: (1) lympho-myeloid dominated by the presence of B cells in addition to myeloid cells; (2) diffuse-myeloid with myeloid lineage predominance but poor in B cells nd (3) pauci-immune characterised by scanty immune cells and prevalent stromal cells. Longitudinal correlation of molecular signatures demonstrated that elevation of myeloid- and lymphoid-associated gene expression strongly correlated with disease activity, acute phase reactants and DMARD response at 6 months. Furthermore, elevation of synovial lymphoid-associated genes correlated with autoantibody positivity and elevation of osteoclast-targeting genes predicting radiographic joint damage progression at 12 months. Patients with predominant pauci-immune pathology showed less severe disease activity and radiographic progression. Conclusions: We demonstrate at disease presentation, prior to pathology modulation by therapy, the presence of specific cellular/molecular synovial signatures that delineate disease severity/progression and therapeutic response and may pave the way to more precise definition of RA taxonomy, therapeutic targeting and improved outcomes.
AB - Objectives: To unravel the hierarchy of cellular/molecular pathways in the disease tissue of early, treatment-naïve rheumatoid arthritis (RA) patients and determine their relationship with clinical phenotypes and treatment response/outcomes longitudinally. Methods: 144 consecutive treatment-naïve early RA patients (<12 months symptoms duration) underwent ultrasound-guided synovial biopsy before and 6 months after disease-modifying antirheumatic drug (DMARD) initiation. Synovial biopsies were analysed for cellular (immunohistology) and molecular (NanoString) characteristics and results compared with clinical and imaging outcomes. Differential gene expression analysis and logistic regression were applied to define variables correlating with treatment response and predicting radiographic progression. Results: Cellular and molecular analyses of synovial tissue demonstrated for the first time in early RA the presence of three pathology groups: (1) lympho-myeloid dominated by the presence of B cells in addition to myeloid cells; (2) diffuse-myeloid with myeloid lineage predominance but poor in B cells nd (3) pauci-immune characterised by scanty immune cells and prevalent stromal cells. Longitudinal correlation of molecular signatures demonstrated that elevation of myeloid- and lymphoid-associated gene expression strongly correlated with disease activity, acute phase reactants and DMARD response at 6 months. Furthermore, elevation of synovial lymphoid-associated genes correlated with autoantibody positivity and elevation of osteoclast-targeting genes predicting radiographic joint damage progression at 12 months. Patients with predominant pauci-immune pathology showed less severe disease activity and radiographic progression. Conclusions: We demonstrate at disease presentation, prior to pathology modulation by therapy, the presence of specific cellular/molecular synovial signatures that delineate disease severity/progression and therapeutic response and may pave the way to more precise definition of RA taxonomy, therapeutic targeting and improved outcomes.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85063083209&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30878974
U2 - https://doi.org/10.1136/annrheumdis-2018-214539
DO - https://doi.org/10.1136/annrheumdis-2018-214539
M3 - Article
C2 - 30878974
SN - 0003-4967
VL - 78
SP - 761
EP - 772
JO - Annals of the rheumatic diseases
JF - Annals of the rheumatic diseases
IS - 6
ER -