Methotrexate: Where it All Began Save

It’s somewhat bizarre that a designer drug from over 65 years ago would become the cornerstone of treatment for rheumatoid arthritis in the 21st century. When Sidney Farber designed a molecule that would interfere with folate metabolism in the middle of the 20th century, he was looking for a ubiquitous antimetabolite to treat cancer.

What better target to choose than folate? Folate dependent enzymes are ubiquitous and essential for intracellular metabolism for all nucleated cells. Farber could not have anticipated the dose-dependent effects of methotrexate (MTX). Nor could he have understood the differential intracellular metabolic outcomes which, highly dependent on folate pathway single nucleotide polymorphisms (SNPs), cause the different effects of the drug in different human beings.

Farber was actually quite concerned with the potential side effects of a drug that competitively inhibits folate metabolism because it is a structural analogue designed to trick the cell into believing that MTX was actually folate. That is part of the reason he combined the “met” for metabolism with an “x”. The x was found on poison bottles and he thought it wise to include it in the name of this agent.

It is, parenthetically, worth considering that our history of comfort with the “X” in the name methotrexate has led to other names including Xeljanz, Cosentyx, rituximab, and others. Interesting how a symbol of bad things morphed into an indication of comfort.

In the 1950s, MTX was used for certain tumors and leukemia, but was also adopted at weekly lower doses by the dermatology community for the treatment of psoriasis. At the time, the best way to use the drug was unknown. While widespread use of MTX for psoriasis and rheumatoid arthritis would be a few decades off, MTX was increasingly used for psoriasis during the 1960s with clear-cut clinical improvements.

In 1973, a group of Scandanavian dermatologists led by Nyfors described some pretty awful side effects of MTX, including liver cirrhosis. It became evident MTX could be associated with severe liver injury. These Scandanavian psoriatics had ad libitum access to alcohol. In addition, some of them had prior exposure to arsenic, used to treat severe psoriasis at the time. Both of these are known hepatotoxins. In addition, patients often received MTX on greater than one day per week.

Thus, the use of MTX with other known hepatotoxins together with the too frequent dosing would inevitably cause more toxicity. As more cells entered the S phase of growth without opportunity to recover from the more frequent dosing, it was clear in retrospect the drug was given in a manner which created a ‘perfect storm’ for producing bad toxicities.

Indeed, Farber’s “x” was viewed as a prescient prophecy for a difficult drug.

In the meantime, RA patients were being treated with gold and penicillamine. There was lots of toxicity, without a great deal of efficacy, and some daring rheumatologists wanted to try other things. Early advocates and users of MTX such as Rex Hoffmeister in Spokane and the Cleveland Clinic in the 1960s and 1970s began to develop some experience with MTX in RA. They adopted the psoriatic formula of dosing, which had evolved to q 12 h x3 once a week. This regimen was thought to mimic the psoriatic skin cycle; it was adopted by these rheumatologists and advocated by John Ward and his colleagues at the University of Utah. But, there were still only anecdotal reports of its efficacy and safety, as well as how the drug should be used.

I first met Michael Weinblatt at the Pearl River Headquarters of Lederle labs in 1982. We were both young clinical faculty and frustrated with the therapeutic options for treatment of RA. I had actually called Lederle and expressed a desire to study MTX in this disease and Michael had done the same.

Weinblatt published the first landmark placebo-controlled studies of MTX in the New England Journal of Medicine in 1985, and I followed with long-term prospective descriptions of MTX effects published in Arthritis & Rheumatism starting in 1986. Sterling West and others also contributed to our understanding of the effects of MTX in RA.

By the late 1980s, MTX had become widely used in the US. It took another decade for MTX to displace sulfasalazine in Europe, but by the mid to late 1990s the drug became commonly used there as well.

Since then, we have learned a great deal about MTX metabolism. We know how to use it safely by monitoring liver enzymes, which predict MTX liver toxicity. Thus, a careful clinician can avoid liver disease simply by monitoring transaminase levels. We have learned that MTX can reduce anti-drug antibodies when used with TNF inhibitors and that the combination greatly improves the efficacy of either agent alone. A summary of the valuable insights about MTX would take many, many pages. It has been speculated that MTX is probably the best and most widely studied drug the world has ever seen.

It’s doubtful Farber had any idea the drug would achieve the position it presently occupies. Certainly Michael Weinblatt and I did not. MTX has become the cornerstone of treatment and the expected comparator with which the efficacy of new therapeutic agents are judged.

What’s next for MTX? Have we seen all that the drug can offer? I don’t know the answer, but I wouldn’t bet against its continued central position in our therapeutic approach to different diseases, including expansion to other rheumatic and inflammatory conditions where it is now being studied.

MTX is the drug that keeps giving and giving as we learn more about how to use it, along with its varied mechanisms of action.