The American College of Rheumatology recommends methotrexate as the first-line treatment for individuals with moderate to severe rheumatoid arthritis (RA). Approximately 19,000 myRAteam members report that they have taken this medication. Methotrexate is available in pill form or by injection, and members have reported a wide range of experiences.

“I have been taking methotrexate for a few years now, and I find that I get extremely exhausted and nauseated for a few days after and almost brain-fogged,” one member wrote. “The doctor upped my dose due to flares but had to lower it again because of side effects. He suggested trying the injections instead, and I am wondering if anyone has been successful on injections with little to no side effects.”

Another myRAteam member replied, “I actually had worse symptoms with the injections but noticed it would only be for 24 hours or less and then I was great the rest of the week.” Another member shared: “I had metho injections for two years with no side effects.”

If you take methotrexate or are thinking about taking it for your RA, you may be wondering about the differences between methotrexate injections and pills. This article provides information that may help you and your doctor decide which form of methotrexate might be best for you.

What Is Methotrexate?

Methotrexate is a disease-modifying antirheumatic drug (DMARD) approved by the U.S. Food and Drug Administration (FDA). It is an immunomodulator, meaning that it influences or controls the immune system to reduce RA disease activity. Doctors believe it works by blocking the production of the white blood cells (immune cells called lymphocytes) that cause inflammation in the joints.

Oral methotrexate is available in pill form (Rheumatrex and Trexall). If you are prescribed a methotrexate injection (Otrexup and Rasuvo), it is given either just under the skin (subcutaneous injection) or into the muscle (intramuscular injection). Injectable methotrexate is available as a prefilled pen (Otrexup and Rasuvo). Or, your physician may prescribe a vial of methotrexate that you can inject using a syringe. Pens are more expensive than syringes, and some insurance companies encourage people to use a syringe and vial setup.

What Are the Differences Between Methotrexate Pills vs. Injection?

There are many similarities between the two methods of taking methotrexate. Both the pill form and the injectable version of methotrexate are usually prescribed to be taken as a single dose once a week, on the same day each week.

Additionally, neither form of methotrexate should be used if you are pregnant or breastfeeding. Do not drink alcohol or take nonsteroidal anti-inflammatory drugs (NSAIDS) while taking methotrexate.

Side Effect Differences

The potential side effects of oral and injectable methotrexate are nearly identical but may affect different individuals in unique ways. The most common side effects of methotrexate are gastrointestinal problems such as nausea, vomiting, and diarrhea. Some people taking methotrexate may experience sores on their lips, mouth, or throat. A few myRAteam members have also reported hair loss, but it is uncommon at the methotrexate doses commonly prescribed for RA. These possible side effects typically disappear or are reversed once you stop taking the medication.

Rare but serious side effects of methotrexate may include:

• Liver damage
• Lung damage
• Kidney damage
• Severe birth defects
• Decreased white blood cell and/or platelet counts, which can cause additional complications

Efficacy Differences

Your rheumatologist will likely prescribe methotrexate as a means of reducing your RA disease activity. Oral versus injectable methotrexate may have different efficacies, meaning one may be more effective than the other in reducing your symptoms.

Researchers have found that when methotrexate is taken by mouth (oral administration), the full amount may not be absorbed in the intestines. Also, different people absorb the drug in different ways, which can change the drug’s effectiveness.

Current clinical evidence from an article in Therapeutics and Clinical Risk Management shows that methotrexate injections result in better absorption and higher levels of the drug in the blood compared to methotrexate taken orally. If you aren’t seeing a beneficial reduction in your RA disease activity from the oral form of methotrexate, your doctor may prescribe the injectable version instead.

The Injection Experience

Although the frequency of taking the medicine is usually the same, you may not be comfortable with the injections. The injectable form of methotrexate has been designed for home use to avoid extra trips to the doctor, but some people may prefer not to do it themselves, so they go to the doctor’s office for medication administration.

Both brands of methotrexate injections (Rasuvo and Otrexup) come as a single-dose autoinjector. The autoinjector is prefilled with the correct amount of methotrexate that your doctor prescribed, making it easy to give yourself the injection. The autoinjectors do not have a visible needle and deliver a minimally painful injection of methotrexate under the skin.

How To Manage Methotrexate Side Effects

Both oral and injectable methotrexate may have side effects. Your health care provider will likely monitor your response to the medication through routine blood tests that assess your liver function to ensure that your organs remain healthy.

Supplements, such as folic acid, can help prevent some of the common side effects. Your rheumatologist may prescribe 1 milligram of folic acid per day to reduce mouth sores and gastrointestinal side effects. Be sure to discuss any new or concerning side effects from methotrexate use with your rheumatology doctor.

Talk With Others Who Understand

On myRAteam, the social network for people with rheumatoid arthritis and their loved ones, more than 193,000 members come together to ask questions, give advice, and share their stories with others who understand life with rheumatoid arthritis.

Have you taken methotrexate or are you thinking of taking it for rheumatoid arthritis? If so, do you take the pill or injectable form, and what has been your experience? Please share your story in the comments below — or start a conversation or ask a question by posting on your Activities page.