Methotrexate in IBD
In high doses, methotrexate has strong antiproliferative and cytotoxic effects. It inhibits the dihydrofolate reductase enzyme in a competitive manner. Indirectly, this drug depletes the amount of tetrahydrofolate, which is required for the thymidylate synthase enzyme in order to synthesize thymidine for DNA synthesis.
For other applications of methotrexate, see the chapters on oncology and rheumatoid arthritis. In low doses, methotrexate has anti-inflammatory properties. In this mechanism, methotrexate interferes in various conversions in the adenosine metabolism (see additional graphic). Methotrexate inhibits the enzyme AICAR transformylase which converts AICAR (5-aminoimidazole-4-carboxamide
ribonucleotide) into formyl-AICAR. This results in AICAR accumulation, which in turn inhibits the enzymes AMP deaminase and adenosine deaminase. This results in accumulation of adenosine, which is transported out of the cell. Methotrexate stimulates the enzyme ecto-5-nucleotidase, which contributes to the increased extracellular adenosine concentration. Subsequent stimulation of adenosine receptors on all kinds of immune cells results in decreased expression, transcription, and release of inflammatory mediators (mainly interleukines and TNF). Low-dose methotrexate is now accepted as an effective and safe treatment in glucocorticoid-dependent and thiopurine-intolerant patients with Crohn’s disease, but not ulcerative colitis. It remains to be seen whether low dose methotrexate may also be useful in long term maintenance therapy in patients with inflammatory bowel disease. Furthermor, it is considered as an alternative steroid-sparing agent.