Molecular signature of methotrexate response among rheumatoid arthritis patients

Frontiers in Medicine

Medicine

Leonid Padyukov¹  Nancy Vivar Pomiano¹  Anca Catrina¹  Lars Klareskog¹  Peter Sahlström¹  Louise Berg¹  Malin Müller¹  Aase Hensvold²  Lasse Folkersen³  Scott A. Jelinsky⁴  Mateusz Maciejewski⁴  Daniel Ziemek⁴  Tinna Bjorg Ulfarsdottir⁵  Boel Brynedal⁶  Helga Westerlind⁷  Niyaz Yoosuf⁸ 

[1] Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden;Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden;Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden;Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden;Center for Rheumatology, Academic Specialist Center, Region Stockholm, Stockholm, Sweden;Nucleus Genomics, New York, NY, United States;Pfizer, Cambridge, MA, United States;Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;Centre for Epidemiology and Community Medicine, Region Stockholm, Stockholm, Sweden;Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden;Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden;Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden;

关键词: rheumatoid anhritis;    treatment response;    methotrexate;    gene expression;    flow cytometry;    plasma proteins;    transcriptomics;   

DOI  :  10.3389/fmed.2023.1146353

 received in 2023-01-17, accepted in 2023-02-22,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundMethotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but failure of satisfying treatment response occurs in a significant proportion of patients. Here we present a longitudinal multi-omics study aimed at detecting molecular and cellular processes in peripheral blood associated with a successful methotrexate treatment of rheumatoid arthritis.MethodsEighty newly diagnosed patients with RA underwent clinical assessment and donated blood before initiation of MTX, and 3 months into treatment. Flow cytometry was used to describe cell types and presence of activation markers in peripheral blood, the expression of 51 proteins was measured in serum or plasma, and RNA sequencing was performed in peripheral blood mononuclear cells (PBMC). Response to treatment after 3 months was determined using the EULAR response criteria. We assessed the changes in biological phenotypes during treatment, and whether these changes differed between responders and non-responders with regression analysis. By using measurements from baseline, we also tried to find biomarkers of future MTX response or, alternatively, to predict MTX response.ResultsAmong the MTX responders, (Good or Moderate according to EULAR treatment response classification, n = 60, 75%), we observed changes in 29 partly overlapping cell types proportions, levels of 13 proteins and expression of 38 genes during treatment. These changes were in most cases suppressions that were stronger among responders compared to non-responders. Within responders to treatment, we observed a suppression of FOXP3 gene expression, reduction of immunoglobulin gene expression and suppression of genes involved in cell proliferation. The proportion of many HLA-DR expressing T-cell populations were suppressed in all patients irrespective of clinical response, and the proportion of many IL21R+ T-cells were reduced exclusively in non-responders. Using only the baseline measurements we could not detect any biomarkers or prediction models that could predict response to MTX.ConclusionWe conclude that a deep molecular and cellular phenotyping of peripheral blood cells in RA patients treated with methotrexate can reveal previously not recognized differences between responders and non-responders during 3 months of treatment with MTX. This may contribute to the understanding of MTX mode of action and explain non-responsiveness to MTX therapy.

【 授权许可】

Unknown   
Copyright © 2023 Brynedal, Yoosuf, Ulfarsdottir, Ziemek, Maciejewski, Folkersen, Westerlind, Müller, Sahlström, Jelinsky, Hensvold, Padyukov, Pomiano, Catrina, Klareskog and Berg.