Smoking and Methotrexate Inefficacy in Rheumatoid Arthritis: What About Underlying Molecular Mechanisms?

The study by Safy-Khan, et al in the current issue of The Journal of Rheumatology 1 reports that in a methotrexate (MTX)-based treatment regimen for patients with early arthritis, current smoking was significantly associated with a smaller reduction of Disease Activity Score in 28 joints (DAS28) over time compared to noncurrent smoking. This negative effect of current smoking on DAS28 was dose-dependent: patients who smoked 10–19 cigarettes per day did worse than patients who smoked 1–9 cigarettes per day. Moreover, the effect was independent of concomitant prednisone use. These results support data from other clinical studies (reviewed in Ling, et al 2) referring to smoking as a contributing factor to MTX nonresponse in patients with rheumatoid arthritis (RA). However, within these observations, questions related to underlying molecular mechanisms by which smoking adversely affects MTX efficacy have been largely underexposed. Here we will discuss some relevant factors emerging from MTX nonresponse prediction models from the perspective of the mechanism of action of MTX, drug resistance, and the role of smoking therein. In brief, the mechanism of action of low-dose MTX treatment in RA involves MTX uptake in immune-competent cells, followed by its intracellular retention through conversion to polyanionic MTX-polyglutamate (MTX-PG) forms by the enzyme folylpolyglutamate synthetase. Polyglutamylation of MTX prevents MTX from being extruded from cells by selected members of the adenosine triphosphate (ATP)-binding cassette (ABC) drug efflux transporter family, including ABCC1–5 and ABCG2. Intracellularly, MTX-PGs inhibit several key enzymes in folate metabolism and purine biosynthesis de novo . These pharmacological inhibitions ultimately lead to the release of adenosine exerting antiinflammatory effects as well as inhibition of downstream signaling pathways driving inflammation.3 Polyglutamylation and efflux by ABC transporters are also critical processes in cellular homeostasis of natural folates, which … Address correspondence to Dr. G. Jansen, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, location VUmc, CCA - Rm 2.46, De Boelelaan 1117, 1081 HV Amsterdam, Amsterdam, the Netherlands. Email: g.jansen{at}amsterdamumc.nl.