What is the MOA for the immunologic effects of MTX at the doses currently used?
MTX enters the cell via the reduced folate carrier (RFC) and leaves the cell via members of the ATP-binding cassette (ABC) protein family. Intracellular MTX undergoes polyglutamation by the enzyme folylpolyglutamate synthase (FPGS). Polyglutamation of MTX prevents intracellular MTX from being transported out of the cell, resulting in its immune-modulating effects and long duration of action. It takes 4 to 6 weeks after starting MTX for the effect to be seen clinically. Polymorphisms of RFC, ABC proteins, and FPGS account for variations in efficacy and toxicity of MTX among patients. Erythrocyte MTX-polyglutamate levels can be measured that may correlate with response to therapy.
MTX has multiple effects on the immune system, including inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, thymidylate synthetase, and dihydrofolate reductase, with resultant antiinflammatory and antiproliferative effects. At the doses used in rheumatology, the effects of MTX are more likely via its antiinflammatory properties. MTX inhibition of AICAR transformylase leads to increases in the intracellular concentration of its substrate AICAR, which stimulates the release of adenosine. Adenosine is a tissue protective retaliatory metabolite with potent antiinflammatory properties, including counter-regulation of neutrophils and dendritic cells, downregulation of macrophages, cytokine modulation, and inhibition of collagenase synthesis. In addition, adenosine has multiple effects on the cardiovascular system. It is a potent vasodilator, has negative inotropic and chronotropic effects, and downregulates vascular smooth muscle cell proliferation. It is likely via these cardioprotective mechanisms that MTX has been shown to have a preferential effect on cardiovascular mortality when compared with other DMARDs in RA.
