After almost 70 years of use — first at high doses in cancer treatment and later also at small weekly doses for inflammatory arthritis — methotrexate’s benefits and side effects are well known.

Methotrexate works by blocking some of the actions of the vitamin folic acid in the body. That’s an important part of how high doses of MTX work to thwart cancer, because folic acid is required to help cells divide and replicate. In arthritis, however, patients take much lower doses of methotrexate, which causes the medication to work differently: by several pathways to dramatically ease inflammation, which can reduce pain and swelling and help prevent joint damage. Methotrexate also tamps down an overactive immune system in rheumatoid arthritis (RA) and other forms of inflammatory arthritis.

There’s no denying that MTX can lead to a host of side effects, ranging from the bothersome to the potentially deadly, but extreme side effects are very rare. Fortunately, because the mechanism of how methotrexate works is so well understood, rheumatologists are able to keep most patients comfortable and safe, and to detect possible problems before they become serious.

We talked about methotrexate use and monitoring with a rheumatologist who has studied and used methotrexate in his practice since the 1980s, Michael Weinblatt, MD, professor of medicine at Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts.

What Doctors Monitor When You Take Methotrexate

Liver damage

Long-term treatment with MTX can lead to the elevation of liver enzymes, liver scarring (fibrosis), and rarely even cirrhosis of the liver, generally after long-term treatment. Liver complications are more common in people who have psoriasis, fatty liver disease, who are obese, or who consume significant amounts of alcohol.

How liver damage is monitored: To protect your liver, you won’t be started on MTX if you are a heavy drinker or if baseline screening reveals elevated liver tests or untreated hepatitis B or C infection. The American College of Rheumatology (ACR) recommends monitoring with blood tests to check the liver enzymes alanine transaminase and aspartate transaminase and levels of serum albumin, a protein made by the liver (every two to four weeks when you start MTX, every eight to 12 weeks in the third to six month of treatment, and every three months thereafter).

“About 25 percent of patients have elevations in their liver blood tests in the first few months of starting MTX, but this does not mean the drug needs to be stopped,” says Dr. Weinblatt. “The liver appears to compensate and after six months the abnormalities go away. Serious MTX liver disease develops after years of use, not after a few months.”

Rheumatologists pay close attention to even subtle abnormalities of the liver blood tests, such as readings just above the normal level, especially if they persist for months. If that occurs, your doctor may use further blood tests or other non-invasive means (such as the specialized ultrasound FibroScan or a CT scan) to look for fibrosis in the liver. Biopsies used to be taken to check for serious fibrosis or cirrhosis, but now it’s more likely you’ll be given a noninvasive test or will be taken off MTX to see if your blood tests normalize.

“The key is monitoring your blood test results. Fortunately, I haven’t seen a case of serious liver disease in over a decade now, and I use a lot of methotrexate,” says Dr. Weinblatt.

What you can do to prevent liver damage: Don’t skip blood tests. Generally, try not to schedule them for the day you take your MTX or the day after. “Some people — primarily those with psoriasis — get a temporary bump in their liver test results when the tests are obtained the day that MTX is taken, and that can make everybody anxious,” says Dr. Weinblatt.

Also minimize your intake of alcohol when you take methotrexate. Dr. Weinblatt advises his patients to keep it below one cocktail or glass of wine every other day. Make sure your doctor knows how much you drink and all of the medications (especially non-steroidal anti-inflammatory drugs, NSAIDS) that you take. Sometimes stopping or reducing alcohol or NSAID use is all it takes for liver blood tests to return to normal.

Lung reactions

Very rarely, and generally in the first year of treatment, people may develop sudden lung inflammation in reaction to MTX treatment. When someone on MTX reports lung symptoms such as cough, fever, and shortness of breath, rheumatologists will want to determine whether the problem is an infection, due to RA, or a hypersensitivity reaction to MTX.

Patients may be hospitalized for the workup and treatment, including blood tests (half of those with MTX lung toxicity have high levels of eosinophils in the blood, which are a type of white blood cell), imaging, pulmonary function testing, and sometimes bronchoscopy or lung biopsy (which may be avoided if there is improvement when MTX is stopped).

How lung damage is monitored: Before starting MTX, you may receive a chest X-ray to ensure you don’t already have lung fibrosis or other pulmonary problems. During treatment, lung monitoring with pulmonary function tests doesn’t seem to be helpful. “This hypersensitivity reaction is sudden and unpredictable, so monitoring lung function is not worthwhile in identifying who might be at risk, says Dr. Weinblatt.

What you can do to prevent lung damage: Promptly report lung symptoms such as cough, fever, and shortness of breath.

Bone marrow suppression

Cells of your bone marrow produce red cells, white cells, and platelets. One extremely rare side effect of MTX treatment is suppression of the bone marrow, which rarely can be fatal. “It’s a serious side effect, but it is rare and shouldn’t be seen at all if people are alert to the risk factors,” says Dr. Weinblatt. Here’s what increases the risk:

  • Accidentally taking too much MTX, such as daily consumption of MTX when it is meant to be used weekly. This can occur if patients become confused or are given the wrong dose;
  • Unrecognized kidney disease. MTX is cleared from the body by the kidneys, so if yours aren’t working properly the drug can accumulate to toxic levels and suppress the bone marrow. “Dialysis is an absolute contraindication to MTX use,” warns Dr. Weinblatt.
  • Active infection. Infection raises the risk of bone marrow toxicity, and some antibiotics — particularly trimethoprim-sulfamethoxazole (brand name Bactrim) — can lead to bone marrow suppression if taken with MTX. “If your MTX prescription is filled by a mail-order pharmacy and your antibiotic is filled by a local pharmacy after being prescribed by your primary care doctor or at an urgent care center, the computers may not talk to each other and the pharmacist may not know that you are on MTX,” says Dr. Weinblatt.

How bone marrow suppression is monitored: The ACR recommends a complete blood count every two to four weeks when you start MTX, every eight to 12 weeks in the third to sixth month of treatment, and every three months thereafter. The blood count will tell if you’re deficient in platelets (symptoms can be bruising and bleeding), white blood cells (symptoms can be fever and chills) or red blood cells (symptoms can be extreme fatigue and paleness). The blood tests will also measure creatinine as a measure of kidney function to make sure your kidneys are working well enough to handle the MTX and prevent bone marrow suppression.

What you can do to prevent lung damage: Make sure every health professional you encounter knows that you are taking MTX and at what dose.

Skin changes

Sunburn: Methotrexate makes you more likely to get a sunburn, and if you burn it can be much worse, with widespread redness, inflammation, and peeling of your skin if you then take your weekly dose of MTX — the medically serious “cooked-lobster syndrome.”

What you can do to prevent sunburn: Protect your skin with sunscreen that’s at least SPF 30 during sun exposure, avoid prolonged exposure to the sun between the hours 10 AM and 2 PM, and don’t use tanning beds. “I tell patients to use a sunscreen and to skip that week’s dose of MTX if they get a bad sunburn,” says Dr. Weinblatt. Always talk to your own doctor before making any change in your medication routine.

Skin cancer: If you have psoriasis, you already know you’re at increased risk of nonmelanoma skin cancer, no matter what medications you take. Until this year, there had been no reported links between skin cancer and MTX use in RA. However, concerns were raised in 2019 when a large study testing the ability of low-dose MTX to reduce heart attacks (it didn’t) in diabetic patients found that those on the drug were more likely to develop non-basal cell skin cancer.

What you can do to prevent skin cancer: See a dermatologist every year for skin checks. “We’ve not seen an increased risk, but I’m telling my patients it makes prudent sense to get their skin checked regularly,” says Dr. Weinblatt.

Nodules: Anyone with inflammatory arthritis can develop rheumatoid nodules, but some people who take MTX start to rapidly grow small nodules not just in the typical locations near joints but on their palms and soles.

What you can do to prevent rheumatoid nodules: Make sure your rheumatologist sees any nodules you’ve developed. You may be taken off MTX or given a second drug to reduce the growths.

Folic Acid Supplements: Protection Against Methotrexate Side Effects

Some side effects from MTX aren’t considered dangerous signs of toxicity, but they are frequently cited as reasons people find the drug intolerable and stop taking it. The good news is that many of these — such as nausea, vomiting, mouth sores, diarrhea, hair thinning, and fatigue — can be blocked or reduced by taking daily folic acid while you’re on MTX.

Talk to your doctor about how much folic acid you need. The amount in a standard multivitamin isn’t enough. Learn more about taking folic acid along with methotrexate.

If folic acid doesn’t seem to be helping, your doctor can also prescribe folinic acid, which is a slightly different form of the vitamin that may be more effective in some patients. It’s called Leucovorin and is available by prescription.

“Nausea usually occurs early in the use of the drug, so if we can get you through it with folic acid and other medications, you are highly unlikely to get it again,” Dr. Weinblatt says.

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