Methotrexate mechanism in treatment of rheumatoid arthritis

Abstract

Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often the first line medication for RA treatment. In this review, we examine multiple hypotheses to explain the mechanism of methotrexate efficacy in RA. These include folate antagonism, adenosine signaling, generation of reactive oxygen species (ROS), decrease in adhesion molecules, alteration of cytokine profiles, and polyamine inhibition amongst some others. Currently, adenosine signaling is probably the most widely accepted explanation for the methotrexate mechanism in RA given that methotrexate increases adenosine levels and on engagement of adenosine with its extracellular receptors an intracellular cascade is activated promoting an overall anti-inflammatory state. In addition to these hypotheses, we examine the mechanism of methotrexate in RA from the perspective of its adverse effects and consider some of the newer genetic markers of methotrexate efficacy and toxicity in RA. Lastly, we briefly discuss the mechanism of additive methotrexate in the setting of TNF-α inhibitor treatment of RA. Ultimately, finding a clear explanation for the pathway and mechanism leading to methotrexate efficacy in RA, there may be a way to formulate more potent therapies with fewer side effects.

Keywords: Adenosine A2A receptor; Adenosine signaling; Methotrexate; Methotrexate efficacy; Methotrexate toxicity; Rheumatoid arthritis.

Figure 1.. Methotrexate’s effect on adenosine formation.

Methotrexate blocks AICAR leading to accumulation of AICAR, which blocks adenosine deaminase. Adenosine formed intracellularly is transported out of the cell by ENT1. ATP and ADP in the extracellular space are dephosphorylated sequentially by transmembrane CD39 to form AMP and AMP is converted to adenosine by transmembrane CD73 and adenosine can be converted to inosine or act via the adenosine receptors to activate various downstream pathways. Adapted from Cronstein and Sitkovsky (2017) (14). Abbreviations: AICAR, amidoimidazolecarboxamidoribonucleotide; ENT1, extracellular nucleoside transporter; ATP, adenosine triphosphate; ADP, adenosine diphosphate; CD39, nucleoside triphosphate phophohydrolase; AMP, adenosine monophosphate; CD73, ecto-5’nucleotidase (CD73).

Figure 2.. Adenosine receptors and signaling pathways.

The A1 and A2A receptors are the high affinity adenosine receptors while the A2AB and A3 receptors are lower affinity receptors. Demonstrated in the figure are the different coupled G-proteins with each adenosine receptor and some of the effects this signaling has on certain immune cells. Adapted from Cronstein andSitkovsky (2017) (14).

Figure 3.. Methotrexate inhibition of polyamine and lymphotoxin formation.

As demonstrated in the figure methotrexate is polyglutamated and then works upstream in the folate reduction pathway to block dihydrofolate reductase. This in effect decreases the levels of 5-CH3-THF and therefore there is less conversion of homocysteine to methionine. Lower levels of methionine decreases formation of SAM and hence methotrexate may be able to decrease polyaminelevels. Adapted from Chan and Cronstein (2010) (39).