Code to support Peripheral blood cellular dynamics of Rheumatoid arthritis treatment informs about efficacy of response to disease modifying drugs

Åsa K. Hedman1*, Eitan Winter4*, Niyaz Yoosuf1,2, Yair Benita4, Louise Berg1, Boel Brynedal2, Lasse Folkerse1, Lars Klareskog1, Mateusz Maciejewski3, Alexandra Sirota-Madi4, Yael Spector4, Daniel Ziemek3, Leonid Padyukov1, Shai S. Shen-Orr4,5, Scott A. Jelinsky3#

1 Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; 2Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden; 3Departament of Inflammation and Immunology, Pfizer, Cambridge, Massachusetts, USA; 4CytoReason, Tel-Aviv, Israel 5¬¬Technion – Israel Institute of Technology

*Co-first authors #Corresponding Author: Scott Jelinsky 1 Portland Street Cambridge, MA 02139 [email protected]

  ABSTRACT Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation and is mediated by multiple immune cell types. In this work we aimed to determine the relevance of changes in cell proportions in peripheral blood mononuclear cells (PBMCs) during development of disease and during treatment.
Methods Samples from healthy blood donors, newly diagnosed RA patients, and established RA patients that had an inadequate response to MTX and were about to start tumor necrosis factor inhibitors (TNFi) treatment were collected before and after 3 months treatment. We used in parallel a computational deconvolution approach based on RNA expression and flow cytometry to determine the relative cell-type frequencies. Results Deconvolution of gene expression suggest that monocytes (both classical and non-classical) and CD4+ cells (Th1 and Th2) were increased in RA patients compared to controls, while NK cells and B cells (naïve and mature) were significantly decreased in RA patients. Treatment with MTX caused a decrease in B cells (memory and plasma cell), and a decrease in CD4 Th cells (Th1 and Th17), while treatment with TNFi resulted in a significant increase in the population of B cells.
Conclusion Characterization of the RNA expression patterns and found that most of differentially expressed genes in RA subjects after treatment can be explained by changes in cell frequencies (98% and 74% respectively for MTX and TNFi).