METHOTREXATE–Reincarnation of an Old Drug

Molecular structure of Methotrexate
Molecular structure of Methotrexate

Methotrexate (MTX) is by far the most popular oral agent used by dermatologists today for psoriasis and has been so for the last 40 years.  Its epitaph was nearly written after the more potent biologic immunomodulators such as Enbrel and Humira were predicted to render MTX obsolete.  Now it appears that MTX helps to diminish the body’s own immune response to the biologic drug which in turn gradually reduces its clinical efficacy.  It is fascinating how the pendulum swings back.  Our practice still has hundreds of patients taking MTX for psoriasis with and without biologics, and I expect their numbers to increase.

I was motivated to write this article after reading an excellent historical review of MTX by Luber and Lee in the Winter 2012 issue of Psoriasis Forum and an article in which Dr. Bruce Strober advocates starting MTX before adding the biologic agent.  It also gives me the opportunity to update my own chapter 16 on MTX in the Handbook of Psoriasis published in 2004

MTX inhibits the function of folic acid which is necessary for the synthesis of thymidine, an essential component of DNA.  The interruption of DNA synthesis in the highly proliferative epidermal cells and activated lymphocytes has the simultaneous effect of reducing overgrowth of skin cells and blunting the inflammatory response.

MTX was found to be effective in the treatment of psoriasis and rheumatoid arthritis by

Psoriasis of palms before treatment
Psoriasis of palms before treatment

dermatologists and rheumatologists.  Their respective specialty societies, the AAD and ACR, created prudent guidelines for the clinical use of MTX.  On the basis of these guidelines the FDA approved MTX for these indications.  Although MTX is also used in the treatment of psoriatic arthritis, that use is considered off-label.  In more recent years MTX was compared head-to-head with one oral and one injectable anti-psoriasis drug.  MTX was about equally effective in clearing psoriasis as the potent oral immunosuppressive cyclosporine (Neoral), but was far inferior to the injectable anti-tumor necrosis factor adalimumab (Humira).

Psoriasis of palms after Methotrexate 15 mg weekly for 3 months
Psoriasis of palms after Methotrexate 15 mg weekly for 3 months

MTX is metabolized inside the cells it affects, specifically, the red and white blood cells, liver cells, and cells lining joint spaces.  However, the majority of MTX is eliminated via the kidneys.  Therefore, when treating a patient with MTX, it is necessary to first obtain the results of a complete blood count and a liver and kidney function test.  These must be normal or near normal at baseline.  MTX has toxicity, especially at high doses, and as you might expect, that toxicity is greatest in the bone marrow and liver.

Myelosuppression and liver fibrosis are mitigated by keeping the dose as low as possible (5-25 mg weekly) while maintaining disease control.  Alcohol ingestion should be avoided. MTX is dosed either once weekly by tablets or by injection.  I favor the schedule of 3

Methotrexate 2.5 mg tablets
Methotrexate 2.5 mg tablets

divided oral doses in a 24-hour period devised by Weinstein and Frost in 1971.  For example, if the weekly dose is 15 mg (our average dose), the patient takes 5 mg at 8 am, 5 mg at 8 pm, and 5 mg at 8 am the next day.  This method reduces nausea and synchronizes the drug’s inhibitory effect with the DNA synthesis phase of the skin cells.

The most common side-effects of MTX are mild, usually well-tolerated, and probably not emphasized enough: headache, fatigue, nausea, and mouth sores may occur around the 1 or 2 days of administration.  Hair thinning may be noted after long-term use.  All of the adverse effects, mild and severe, may be prevented or reduced in severity by taking folic acid supplement 1-5 mg daily.  As mentioned above, if MTX is a folic acid antagonist, then folic acid is the antidote to MTX.  I prescribe the lower dose of folic acid and withhold it on the first day of MTX administration because I am concerned that it will also reduce the beneficial effect of MTX, that is, healing psoriasis.

There are two important drug interactions with MTX (three if you count ethanol).  Some of the non-steroidal anti-inflammatory drugs which may be used concomitantly to treat psoriatic or rheumatoid arthritis can increase the level of MTX in the blood which may increase toxicity.  The most important drug to avoid when taking MTX, however, is the antibiotic trimethoprim-sulfa (Bactrim, Septra, and generic) which is also a folic acid antagonist.  This combination mimics an overdose of MTX which could lead to bone marrow failure.

During treatment, the blood tests are monitored every 1-3 months depending on the results, and more frequently after the dose is increased.  The most important ones to watch closely are the white blood cell and platelet counts (which would be lowered by MTX toxicity), liver enzymes (for elevations), kidney function (just to make sure the MTX is being excreted appropriately).

The earlier guidelines for MTX use included baseline liver biopsy and repeat liver biopsies because of the risk of liver fibrosis which could lead to cirrhosis and eventually liver failure.  Over time, with experience gained in selecting lower risk patients to treat, abstaining from alcohol, keeping the dose of MTX low and administering only once per week, and folic acid supplementation, the risk of liver fibrosis has been significantly reduced.

In 2003, I stopped ordering liver biopsies for patients over 60 years of age.  Over the next decade, I stopped ordering liver biopsies altogether because of the inconvenience to the patient, risk of complications (pain, bleeding), and expense.  I now monitor the liver enzymes (transaminases).  If the level exceeds twice the normal range, I will lower the dose.  If we can’t control the disease with the lower dose of MTX, I would try combination therapy first before stopping MTX but probably wouldn’t order the liver biopsy unless the patient insisted.

In short and in sum: MTX has had a checkered past and a long run, almost made obsolete by new biotechnologic drugs, which ironically may now prolong the lifespan of MTX in the clinic.  The combination of MTX enhances the efficacy of the biologic drug.  MTX may in fact prolong the biologic’s duration of efficacy in an individual patient by preventing antibody formation and clearance of these foreign proteins from the body.  It appears that the two drugs will live on synergistically and symbiotically.

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