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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 TNF\u03b1 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-TNF\u03b1 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.<\/jats:p>","DOI":"10.1002\/jlb.5ru0519-145r","type":"journal-article","created":{"date-parts":[[2019,7,17]],"date-time":"2019-07-17T03:21:40Z","timestamp":1563333700000},"page":"1063-1068","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["JAK inhibition by methotrexate (and csDMARDs) may explain clinical efficacy as monotherapy and combination therapy"],"prefix":"10.1093","volume":"106","author":[{"given":"Elisa","family":"Gremese","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Fondazione Policlinico Universitario A. 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