Methotrexate Intolerance: A Patient's Story

When college professor Andrew Lumpe, Ph.D., found out he had rheumatoid arthritis in 2009, methotrexate was one of the first drugs he tried. His doctor warned him to take the first dose on a weekend so he'd have time to recover from any nasty side effects.

"I immediately just felt like a truck had run over me," said Lumpe, who lives in Washington state and blogs at https://livingwithra.wordpress.com/. "Tired, nauseous, sort of feeling like you had the flu."

Lumpe, who is also a Cure Arthritis Ambassador for the National Arthritis Research Foundation, stuck with the drug for a year anyway, and later tried injectable methotrexate when oral methotrexate failed to impact his disease. The injections triggered regular migraines. After another year, Lumpe told his rheumatologist he couldn't take methotrexate anymore. She quickly agreed that he needed another option.  [[{"type":"media","view_mode":"media_crop","fid":"48244","attributes":{"alt":"Andrew Lumpe PhD","class":"media-image media-image-right","id":"media_crop_2231513880243","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5747","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"Andrew Lumpe PhD","typeof":"foaf:Image"}}]]

Lumpe, of course, is not alone in finding methotrexate intolerable. While methotrexate works for many patients, studies generally find that around 30 percent of patients experience nausea after taking the drug. Others deal with vomiting, mouth ulcers and hair loss. Behavioral symptoms can include moodiness and irritability. Folic acid supplementation can help, though debate remains over the proper dosage. And even with supplementation, many people can't tolerate methotrexate. A 1989 study found that about 30 percent of people stop using the treatment after a year, and nearly half drop out by year three of treatment. The most common reason for quitting, that study found, was intolerable side effects.

A recent study out of Pakistan highlights the problems of methotrexate for patients who have very few other options. In Pakistan and other developing nations, most rheumatoid arthritis patients have access only to oral methotrexate and certainly can't afford newer biologics, rheumatologist Nibah Fatimah and colleagues at the Fauji Foundation Hospital in Rawalpindi wrote in April in the journal Clinical Rheumatology. To understand how their patients were tolerating this option, the researchers administered the methotrexate intolerance severity score (MISS) questionnaire to 150 female patients in the hospital's rheumatology department. They defined scores of six and above as representing methotrexate intolerance.

Fifty patients, or a third of the sample, were intolerant, the researchers found. Behavioral symptoms (restlessness, irritability and refusal to take the medication) were the most common, at 44 percent. About 35 percent reported abdominal pain and 34 percent experienced nausea. Thirty-one percent experienced fatigue, and 11 percent said the drug had made them vomit. All of the participants were taking folic acid supplements. Unsurprisingly, patients taking higher doses of methotrexate were more likely to qualify as intolerant according to the MISS scores. Those with doses of 20 mg a week, the highest in the study, had a 46.2 percent prevalence of intolerance. Those taking the lowest dose of 7.5 mg had only a 20 percent prevalence of intolerance. Counseling and early detection of side effects could help keep patients from medication noncompliance, the researchers concluded.

The study was the first to use a standardized tool to look at methotrexate side effects in Pakistan. Research in other countries has shown similar results, with some variations in symptoms. A study of rheumatoid arthritis and psoriatic arthritis patients at four hospitals in The Netherlands found that about 10 percent of rheumatoid arthritis patients were intolerant of methotrexate (with intolerance again defined as a MISS score of 6 or above). Forty-two percent of the 291-patient sample experienced at least one methotrexate side effect, with 32 percent reporting nausea. Parenteral injections of methotrexate were associated with a greater likelihood of intolerance compared with oral methotrexate.

For some patients, folic acid supplementation makes methotrexate more tolerable, leading to a suggested "pragmatic dosing" of 5 mg folic acid the day after a dose of methotrexate, according to a 2004 review. That review examined studies on folic acid and methotrexate in rheumatoid arthritis, going back to the first clinical trials in the 1990s. The evidence suggests that folic acid works, both to reduce patient-reported side effects and to keep more patients using methotrexate. The researchers did not find that folic acid reduced the efficacy of methotrexate. They did, however, find evidence of cardiovascular protection. Folic acid supplementation counteracts methotrexate's tendency to raise plasma homocysteine, a risk factor for cardiovascular disease.

Lumpe was taking folic acid supplements, but a combination of side effects and lack of efficacy meant methotrexate didn't work for him. He's struggled to find a medication that does work, and urges doctors to be sensitive to their patients' individual responses to pharmaceuticals. It can be easy to study statistics and expect a certain treatment to work, but it's important not to dismiss those who don't respond, Lumpe said. He's pleased that his doctor tracks his disease carefully and starts every visit by letting him tell her about symptoms and drug side effects.  

"My doctor is really good about listening," Lumpe said.

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