In the previous tutorial, we introduced antirheumatics as a class of drugs, and outlined the differences
between small molecule and biologic DMARDs.
Now let’s look at a specific small molecule, or non-biologic DMARD, so we can better understand
the pathway by which these drugs elicit their effects.
For decades, methotrexate has been the most commonly prescribed and effective non-biologic
DMARD in the treatment of rheumatoid arthritis, or RA.
Despite its use in treating RA, methotrexate was originally developed to treat cancer;
however, as early as 1951, physicians used it to treat patients with the inflammatory
disease psoriasis, suggesting that it may have benefits in other inflammatory diseases.
Quoting Michael E. Weinblatt, a doctor who helped pioneer methotrexate’s use in RA
treatment, “The rheumatology community was not excited about using cancer drugs for such
a ‘benign’ disease like RA”.
Despite this, scattered reports of methotrexate efficacy in RA sparked larger clinical studies
in the 1980s, leading to its approval for RA treatment in 1988.
Methotrexate itself is not active, but rather functions as a prodrug.
This means that enzymes in the body alter methotrexate, converting it into a new, chemically
unique and pharmacologically active compound.
An enzyme called folylpolyglutamate synthetase, or FPGS, functions in the regulation of the
essential biologic molecule, folic acid, by sequentially adding glutamate molecules to
its structure.
Due to the highly similar structure of methotrexate to folic acid, FPGS can also add glutamate
moieties to methotrexate, generating methotrexate polyglutamate, or MTXPG.
Not only is MTXPG the active form of the drug, but it also leads to accumulation of MTXPG
within cells of the body, enhancing its pharmacologic effect.
So how exactly does a cancer drug treat rheumatoid arthritis?
Methotrexate was originally designed to compete with folic acid in binding to dihydrofolate
reductase, or DHFR.
This important enzyme uses folic acid in the synthesis of DNA and stimulation of cell proliferation.
Inhibition of this enzyme likely explains methotrexate’s chemotherapeutic effects;
however, the anti-inflammatory affects of methotrexate likely occur through a separate,
unique mechanism.
Methotrexate also inhibits another enzyme called 5-aminoimidazole-4-carboxamide ribonucleotide
tranformylase, or ATIC, which through a multistep pathway leads to the accumulation of the adenosine
nucleotide within the cell.
When released, this adenosine can stimulate adenosine receptors, which mediate various
anti-inflammatory effects, in surrounding cells and tissues.
While there are 4 adenosine receptors, the major anti-inflammatory effects of methotrexate
may be driven primarily through activation of one receptor: the adenosine 2A receptor.
Methotrexate therapy mediates multiple anti-inflammatory effects.
The production of biologic molecules which stimulate inflammation, called cytokines,
are inhibited by methotrexate.
Furthermore, multiple types of specialized cells involved in the immune response such
as neutrophils, macrophages, and T cells, are blocked from becoming activated.
Unlike NSAID drugs such as aspirin, which only treat symptoms of RA, methotrexate is
a disease modifying anti-rheumatic drug, and significantly lowers inflammation to a state
that achieves or at least approximates disease remission in many RA patients.
In patients with high disease activity, physicians often prescribe methotrexate in combination
with other non-biologic DMARDs to achieve the complete remission of symptoms.
The doses of methotrexate prescribed for the treatment of RA are much lower than those
used in chemotherapy; however, side effects still occur even at low doses.
Patients may experience mild side effects such as rash and upset stomach, but some side
effects can be more severe.
Methotrexate can disrupt the ability of cells in the bone marrow to divide, which must be
closely monitored by a physician during treatment, through regular blood tests.
Fibrosis, or the accumulation of scar tissue, can also occur in the liver, leading to liver
dysfunction.
Some side effects may be due to the displacement of folic acid by methotrexate, which can lead
to increased folic acid removal from the body, and ultimately a deficiency of this crucial
molecule.
For this reason, many physicians will also prescribe folic acid to be taken with methotrexate
treatment to limit potential side effects caused by folic acid deficiency.
Side effects increase with increased exposure to free methotrexate in the body.
While circulating throughout the body, about 50% of methotrexate binds to proteins within
the blood, while the other 50% remains free to stimulate both therapeutic effects and
side effects.
Other drugs which also bind these blood proteins, like probenecid, better known as Probalan,
and salicylates such as aspirin, may displace methotrexate, leading to increased levels
of the free, unbound drug and therefore increased side effects.
Concurrent treatment with a drug which displaces methotrexate in this way can be fatal, so
it is important to speak to a physician about concurrent use with other medications.
It is also extremely important to note that methotrexate should not be prescribed to those
who are pregnant or show signs of pregnancy, such as lactation.
Methotrexate is a potent abortaficient, meaning it causes the abortion of a fetus.
Despite these notable side effects, methotrexate is a relatively safe and cheap drug.
In contrast with the biologic class of DMARDs, methotrexate can be taken orally and is readily
absorbed, thereby simplifying dosing.
Most importantly, methotrexate is incredibly effective at relieving RA symptoms to the
point of disease remission, which is quite a surprise for a drug originally designed
to fight cancer.