Wednesday, January 29, 2014

Methotrexate – mode of action

Methotrexate (MTX) is the workhorse of rheumatology. What would we do without it? We already use this drug for about 30 years in rheumatology, yet we know so little about its’ mode of action. I had been researching MTX for a while and even started some blogposts, but didn’t get too far in rendering this complicated matter readable, but I thought of starting again, when I listened to Prof. Burmester’s talk on methotrexate at this year’s TNF alpha Forum in Munich.
In one of his slides Burmester pointed out five proposed mechanisms of action: anti-inflammatory, apoptosis, cytokines, cytostatic, and immunosuppressive (I chose an alphabetical order).

Anti-inflammatory effects
Methotreaxate is polyglutamatized, which leads to increase intracellular AICAR (5-aminoimidazole-4-carboxamide ribonucleotide). The increased AICAR level leads to the extra cellular release of adenosine. Adenosine is a key mediator of anti-inflammatory effects. There are effects on neutrophils chemotaxis, prostaglandin E2 release, peroxide production, angiogenesis, and levels of metaloproteinases.
To sum it up: MTX has direct anti-inflammatory effects, long known, but it’s still unclear, how much these effects add to concert.

Cancer cells reproduce rapidly and need thymine (dTMP [deoxythymidine monophosphate]), which is inhibited by MTX und thus leads to cell death by scarcity. This is probably not what happens in the treatment rheumatoid arthritis. But there have findings suggesting an induction of apoptosis of in vitro activated T lymphocytes. And again adenosine seems to be the key player. Swierkot discusses the importance of apoptosis of the cells in the inflammatory tissue.

MTX leads to a down regulation of IL-1 activity and levels of IL-6 and IL-8 are reduced. This might be a reason why there’s stronger evidence for a combination of MTX and TNF-inhibitors than a combination of tocilizumab with MTX; differences might be called slight, though. Other effects like gene expression of interleukins have been found, too. Most of the effects have been studied in vitro and still need to be reproduced in vivo.

Cytostatic effects
Cytostatic effects are due to inhibition of DHFR (dihydrofolate reductase). It is unclear, how much of this plays into treatment and how much is responsible for side effects. Anyway, inhibition of DHFR might only contribute little in the treatment of rheumatoid arthritis. Most side effects can be avoided by the supplemention with folate. “In RA patients,” inhibition of DHFR “is rather not the main element of action because the doses required for MTX’s antiproliferative effect are considerably higher.” (Swierkot)

Immunosuppressive effects
MTX reduces the production of immunoglobulins (IgA, IgG, IgM) and levels of circulating rheumatoid factor. Though B-cell function isn’t the main target of MTX (Swierkot).

What’s the take home message? Methotrexate is still an interesting and valuable drug. I hope that research is going on to make its’ use safer.


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