Gremese, E., Alivernini, S., Tolusso, B. et al. (2 more authors) (2019) JAK inhibition by methotrexate (and csDMARDs) may explain clinical efficacy as monotherapy and combination therapy. Journal of Leukocyte Biology, 106 (5). pp. 1063-1068. ISSN 0741-5400
Abstract
Methotrexate (MTX) is recognized as the anchor drug in the algorithm treating chronic arthritis (RA, psoriatic arthritis), as well as a steroid sparing agent in other inflammatory conditions (polymyalgia rheumatica, vasculitis, scleroderma). Its main mechanism of action has been related to the increase in extracellular adenosine, which leads to the effects of A2A receptor in M1 macrophages that dampens TNFα and IL12 production and increases IL1Ra and TNFRp75. By acting on A2B receptor on M2 macrophages it enhances IL10 synthesis and inhibits NF‐kB signaling. MTX has also been shown to exert JAK inhibition of JAK2 and JAK1 when tested in Drosophila melanogaster as a model of kinase activity and in human cell lines (nodular sclerosis Hodgkin's lymphoma and acute myeloid leukemia cell lines). These effects may explain why MTX leads to clinical effects similar to anti‐TNFα biologics in monotherapy, but is less effective when compared to anti‐IL6R in monotherapy, which acting upstream exerts major effects downstream on the JAK1‐STAT3 pathway. The MTX effects on JAK1/JAK2 inhibition also allows to understand why the combination of MTX with Leflunomide, or JAK1/JAK3 inhibitor leads to better clinical outcomes than monotherapy, while the combination with JAK1/JAK2 or JAK1 specific inhibitors does not seem to exert additive clinical benefit.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2019 The Authors. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License(https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
Keywords: | adenosine; JAK inhibition; Methotrexate |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 18 Nov 2019 15:26 |
Last Modified: | 18 Nov 2019 15:26 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/jlb.5ru0519-145r |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:152772 |
Download
Filename: Gremese_et_al-2019-Journal_of_Leukocyte_Biology.pdf
Licence: CC-BY-NC-ND 4.0