Methotrexate

General Information about Methotrexate (MTX, Mexate, Rheumatrex, Trexall)

Methotrexate (MTX), formerly known as amethopterin, is an immunosuppressant medication, which reduces or changes immune system activity, optimally resulting in less inflammation in the GI tract and alleviating the symptoms of Crohn’s disease. Used in IBD as a second-line treatment after the failure of Azathioprine, it is most commonly prescribed as a cancer chemotherapy agent. In Crohn’s disease, it acts as an immunosuppressant when used in lower doses, and is also used in psoriasis, lupus, sarcoidosis, eczema and rheumatoid arthritis. Additionally, it is used to treat ectopic pregnancies. It is available as a generic medication.

History of Methotrexate

Methotrexate was first synthesized by Yellapragada Subbarao, but it was Sidney Farber and his team at Harvard University in 1947 who discovered that it induced remission in pediatric leukemia patients. For that discovery, he is regarded as the father of modern chemotherapy and the Dana-Farber Cancer Institute bears his name. Jane C. Wright then demonstrated MTX’s effectiveness in breast cancer tumors in 1951, followed closely by other researchers who confirmed its effectiveness in other cancers. It was not until the late 1980’s when researchers began looking at MTX for Crohn’s disease. In 1995, Dr. Brian Feagan published a report on the use of MTX in Crohn’s disease showing that it was effective and well tolerated by patients. However, the United States FDA has not approved MTX for Crohn’s disease to date, so it is considered “off label.”

How Does Methotrexate Work?

Immunomodulators and immunosuppressant medications generally work by hindering the activity of white blood cells, which are at the core of the immune response. For many years, the prevailing theory of Crohn’s disease was that the immune system was attacking itself, and Crohn’s was called an “autoimmune” disease. Recently, the theory of Crohn’s disease has shifted away from an autoimmune model. Now, Crohn’s is termed an “immune related” disease, where a variety of factors (genetics, environment, bacteria, and unknown factors) cause a heightened immune response resulting in chronic inflammation and the damage seen in Crohn’s disease. Prior to this paradigm shift, many traditional treatments for Crohn’s disease sought to decrease this heightened immune response. In general, the immunosuppressant medications used in Crohn’s disease are based on the earlier autoimmune theory of Crohn’s disease, but they remain effective for some cases of Crohn’s disease. (For an alternate mechanism and theory of Crohn’s disease, see What is Map?.)

Generally, Methotrexate inhibits folic acid production in the body, which is necessary for building DNA. It does this by competitive inhibition. Competitive inhibition is where a chemical mimics another and binds in place of the correct chemical, thereby stopping a reaction from occurring. For life to exist, cells in the body must divide and make new cells. To make a new cell, the DNA in the original cell must double so each cell can have a complete copy. Humans need folic acid to build DNA. Methotrexate mimics folic acid and replaces it in the pathway which builds DNA, which then stops the duplication of DNA. Without the ability to build DNA, no new cells can be created, which is why MTX is effective at stopping certain cancers. For a detailed description of this process, see the article on 6MP.

In rheumatoid arthritis, Crohn’s disease and other immune mediated diseases, methotrexate is thought to have an additional mechanism of action. Research shows that at lower doses, MTX promotes the release of an anti-inflammatory chemical called adenosine at inflamed sites. High adenosine levels decrease chronic inflammation. Once released, adenosine inhibits the number of inflammatory white blood cells and also inhibits their function at inflamed sites, thus decreasing destructive inflammation. Adenosine may also decrease pro-inflammatory cytokines, like TNF-α, leading to less inflammation in Crohn’s disease patients.

Other researchers have proposed that methotrexate may also inhibit T-cell production, thus stopping the inflammatory response.

Treatment of Crohn’s Disease with Methotrexate

Some of the reasons methotrexate may be used in Crohn’s disease are:

To wean a patient who is steroid dependent
To help maintain steroid free remission
As a substitute to a first line medication (like 6MP/AZA) that has failed
In combination with anti-TNF therapy
Management of fistulas.

Taking MTX by mouth yields about three-quarters of the absorption capacity vs. when it is given by injection. MTX is classified as a maintenance therapy. It may take 3 months or more before patients begin to experience the effects of MTX.

Methotrexate is usually taken as a weekly injection, but infrequently can be taken orally. The average weekly adult dosage for Crohn’s disease is between 15mg and 25mg/week, but can be adjusted by weight or as a result of blood tests. Patients are typically instructed by their doctor or a nurse to administer these injections at home.

Methotrexate is sometimes used in combination with another Crohn’s disease therapy, such as biologic medications, to suppress antibody formation to the biologic. When used alone, the 2014 Cochrane review showed MTX maintained remission in about two-thirds of patients. (Cochrane Reviews are systematic reviews of primary research in human health care and health policy, and are internationally recognized as the highest standard in evidence-based health care resources.) However, this 2016 study showed that MTX was effective in inducing steroid-free remission in 37% of patients. There are numerous studies looking at the effectiveness of methotrexate, and the consensus seems to be that MTX is more effective than placebo in inducing and maintaining remission in Crohn’s disease.

Side Effects of Methotrexate

Methotrexate should not be used in pregnant women because usage may result in fetal death. Pregnancy should be avoided while taking MTX. Breast feeding while taking methotrexate should also be avoided, as it can cause serious adverse effects on nursing infants.

Patients with chronic liver disease or anemia should not take MTX. Similarly, patients taking proton pump inhibitors (PPIs) such as omeprazole, should use caution when taking MTX because some studies have shown the PPIs can increase the concentration of MTX in the blood, leading to MTX toxicity. This is a greater concern when the patient is on high doses of MTX. Folic acid supplementation may be necessary while taking MTX.

Severe side effects can occur when taking Methotrexate including:

Organ system toxicity, including liver or lung disease (including pneumonia).
Suppression of white blood cell production.
Severe rashes.
Cancer/Lymphoma.
Central nervous system reactions.
Neurological damage or memory loss.
Increased susceptibility to infections.

Less serious, more common side effects of Methotrexate include:

Nausea, vomiting and abdominal pain.
Elevated liver enzymes.
Gastrointestinal/ Mouth ulcers or inflammation.
Fever or chills.
Low white blood cell count.
Hair loss.
Skin pigmentation changes and sun sensitivity.

For complete information on this medication, please see the U.S. National Library of Medicine website article on Methotrexate.

Potential Interaction of Methotrexate on MAP

The earliest study examining the impact of Methotrexate on MAP was conducted in 2007 by Dr. Robert Greenstein. He hypothesized that MTX was effective in Crohn’s disease because it inhibited the growth of MAP. To test his theory, Dr. Greenstein grew 4 different MAP strains in culture and then subjected the cultures to MTX (among other antibiotics and Crohn’s treatments.) The results were that MTX was as effective as clarithromycin in inhibiting the growth of MAP. Additionally, all four MAP strains were more susceptible to MTX than 6-MP, though 6-MP also inhibited the growth of MAP.

Another 2008 study looked at the presence of MAP DNA in patients who were treated with traditional Crohn’s disease therapies vs. controls. The hypothesis was that MAP is detected in few Crohn’s patients because the traditional treatments for Crohn’s disease have unknowingly been killing MAP as well as reducing inflammation. The study concluded that Methotrexate actually clears MAP DNA from the blood of IBD patients. The researchers found no MAP DNA in the blood of patients on Methotrexate, compared to a significantly higher percentage of MAP DNA in the blood of controls. Therefore, Methotrexate may be a potent anti-MAP agent. The study has its limitations, and the authors freely admit that the presence of MAP DNA as measured in the study does not equate to viable MAP cultures.