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A new study reveals two possible biomarkers for methotrexate resistance, and also reveals more about how methotrexate works.
Peresa RS, Liew FY, Talbota J, et al. Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis. Proc Natl Acad Sci. 2015; doi:10.1073/pnas.1424792112
Methotrexate (MTX) will work for rheumatoid arthritis (RA) patients who have regulatory T cells (Tregs) that express the cell surface marker CD39. If their Tregs don’t have the CD39 marker, MTX is likely to fail.
Therefore, low CD39 expression could be a biomarker for identifying patients who are likely to be MTX resistant.
This study also gave some insights into how MTX suppresses inflammation.
The authors recruited 122 RA patients (53 responsive to MTX, 69 unresponsive) and 33 healthy controls. Three months later, the MTX-responsive patients had a higher frequency of peripheral blood CD39+CD4+CD25+FoxP Tregs than healthy controls. The MTX unresponsiveTregs had a lower density of CD39, produced less adenosine (ADO), and had less immunosuppressive activity.
In a mouse model of RA, blocking CD39 blockade made the animals unresponsive to MTX.
Tregs produceADO through ATP degredation by CD39 and CD73. In addition to its anti-folate effect, MTX also dampens inflammation by maintaining high levels of extracellular ADO. MTX inhibits the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformase, which moves ATP to the extracellular compartment, where it is hydrolyzed to AMP. Then CD73 degrades AMP to ADO.
Low ADO, therefore, could also be a biomarker for identifying MTX-resistant RA patients.