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.
Apoptosis
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.
Cytokines
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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