Do you recommend patients hold folic acid on the day they take methotrexate?

The proposed mechanism of action (MOA) of methotrexate in rheumatic disease is not from the antimetabolite angle (given its oncologic MOA as a dihydrofolic acid reductase inhibitor), but rather as a potent anti-inflammatory and immunomodulatory medication through the MOA of extracellular adenosine accumulation. At the doses given for rheumatic purposes, there is no strong rationale to hold folic acid on the day of use since its rheumatic MOA is thought to be unrelated to the oncologic MOA as a dihydrofolic acid reductase inhibitor.

I think it is worth considering what actions are taken during clinical trials when considering this practice. Without referencing all clinical trials performed, I can comment on my recollection of the clinical trials in which I acted as an investigator. To my recollection, weekly methotrexate dosing is paired to daily folic acid use, without stopping or holding folic acid doses. While it is reasonable to consider the possibility that efficacy of methotrexate may be reduced by the presence of folic acid, we have good evidence that the desired effect (decreased tender/swollen joint count, relief of pain, improved control of disease) is achieved while minimizing methotrexate side effects. The pill seems to suggest this is, in fact, the clinica...