Diseases and Conditions

10 frequently asked questions when starting methotrexate

February 22, 2017
Methotrexate is one of the mostly frequently prescribed medications in rheumatology. It has great joint-saving potential but also has a considerable list of potential side effects. In this week's edition of RheumDoctor, we address frequently asked questions when starting methotrexate.

Hands down, methotrexate is one of the most frequently prescribed medications in the field of rheumatology as it is the cornerstone medication for rheumatoid arthritis.  As a rheumatologist, I tend to classify time as, “the time before methotrexate” and “the time after methotrexate”.

Methotrexate was first reported by Sidney Farber in 1948 for the use of childhood leukemia.  By 1951, Gubner observed that people with rheumatoid arthritis and psoriasis improved while taking the medication and soon worsened after stopping it.  Unfortunately and fortunately, during this time Dr. Phillip Hench received a Nobel prize for the discovery of corticosteroids.  At that point, interest for methotrexate waned.  It’s only in the mid-1980’s that a renewed interest for this paradigm-shifting medication occurred.  The rest is history.

I don’t believe anyone can argue the significant benefits methotrexate can give.  The scientific evidence is overwhelming.  But it also boasts a considerable list of potential side effects.  In this week’s edition of RheumDoctor, I address frequently asked questions when starting methotrexate.

Before starting, the information below does not constitute medical advice.  Every person and every situation is unique.  Please address questions about your care with your rheumatologist.

1. Why do I have to take methotrexate?  I went online and it sounds dangerous.

Do an image Google search with the term “rheumatoid arthritis”.  Yep, not so pretty.  Remember when I said that I tend to classify time as, “the time before methotrexate” and “the time after methotrexate”.  There’s a pretty good chance that the people with the gnarly hands are the people who received methotrexate very late into their diagnosis.  Methotrexate is a disease modifying anti-rheumatic drug (DMARD).  What this means, is that it potentially halts the natural progression of rheumatoid arthritis.  If left untreated, rheumatoid arthritis causes joint deformities and permanent joint destruction.  Deformities can occur within 3 months of disease onset.  That’s fast!  Uncontrolled rheumatoid arthritis increases the risk of cardiovascular disease and can also directly affect major organs such as the lungs, eyes, and bone marrow.  Methotrexate has a good chance of preventing all the above.

Untreated rheumatoid arthritis

By James Heilman, MD (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons

2. Why do I have to take folic acid with methotrexate?

Methotrexate competitively inhibits dihydrofolate reductase (DHFR).  This is in turn decreases the amount of bioavailable folic acid in your body.  You need folic acid to make new cells.  What does this mean?  Side effects: mouth ulcers, hair loss, nausea, heartburn, abdominal pain, fatigue, anemia, liver problems.  By taking supplemental folic acid, you are trying to overwhelm the system with folic acid so that you don’t develop side effects.  It’s important to note, that if you take too much folic acid, it will negate the therapeutic benefits of your medication.

3. Why must I have bloods drawn on regular intervals while I’m taking methotrexate?

Simply put, safety. Before starting methotrexate you need to screen for hepatitis B and hepatitis C.  This isn’t personal, it’s just safe.  You will also need a chest x-ray done before starting the medication.  Methotrexate can cause you to develop lung nodules and rarely can cause inflammation of the lungs.  Basically, you want to make sure that everything is okay before starting the medication.  For example, if I find many lung nodules before doing anything, I’ll probably want to start treatment with a different DMARD.  It’s also important to check a complete blood panel and check your liver and kidney levels before starting methotrexate.  This is for the same reasons as the chest x-ray, safety.

Now once you are on methotrexate, it’s important to watch for side effects.  Typically, you need bloods every 3-4 weeks in the beginning and then every 3 months once you are on a stable dose.  This is important because you may not necessarily physically feel you are becoming more anemic or that your liver is inflamed.

On a side note, if you check the bill you received from your insurance company, you might see the code “high risk medication monitoring – Z79.899”.  This does NOT mean you are participating in questionable or “high risk activities”, if you know what I mean.  It simply means that your doctor needs to check your labs on a frequent basis because of the medications you are taking.

4. What about combining other medications with methotrexate?  Is it safe?

Methotrexate is commonly combined with other medications.  About 1/3 of people treated with methotrexate for rheumatoid arthritis will either have very little symptoms or will go into remission.  The other 2/3 will need to use combination therapy.  Methotrexate is commonly called the “anchor” in rheumatoid arthritis treatment regimens.  Some medications are safe to combine and some are not.  This will depend on many factors like lifestyle choices, your other different medications, liver status, and your other medical conditions.

5. How much alcohol is safe for me to drink with methotrexate?

Methotrexate can potentially cause inflammation of the liver.  So technically, it’s probably not a good idea to drink any alcohol while taking methotrexate.  That being said, drinking one standard glass of alcohol once a week probably is safe.  This is a bit of a touchy subject, and you should discuss this more with your doctor.  If you click the following link, I have a full article dedicated to this topic.

These are the NIH's standard alcohol units

By National Institutes of Health [Public domain], via Wikimedia Commons

6. Do I have to worry about infections with methotrexate?

Whether methotrexate significantly increases your risk of infections is poorly understood and there is a lot of conflicting data out there.  Most serious infections tend to occur in people receiving both methotrexate and prednisone or with another biologic agent at the same time.  To be extra cautious I would say, low dose methotrexate (i.e., max 25 mg once weekly) could predispose you to have more infections but the risk is probably very small.  In fact, recent data even suggests that continuing methotrexate during the time around orthopedic surgeries is probably fine.  More data is needed though.  That being said, it’s important to be up-to-date with vaccines and to regularly wash your hands especially during flu season.

7. What do I do if I’m planning to become pregnant?

Methotrexate can cause miscarriages and can cause fetal abnormalities.

You absolutely, cannot be on this medication during pregnancy.

It sticks around your body for a long time.  If you plan to become pregnant, you need to come off the medication 3 months before trying to conceive.  Before making any changes, please discuss with your rheumatologist.  Open communication is key!

8. What does my husband do if we want to have children and he is on methotrexate?

Same as the above.  The rules for men are the same for women.

9. Is breast-feeding safe while taking methotrexate?


10. Does methotrexate cause cancer?

To answer this question, I need to discuss methotrexate dosage.  In rheumatology, we use low doses of methotrexate (i.e., max 25 mg once a week).  When using methotrexate for cancer, we’re talking a dose of at least 500 mg/m².  The doses vary from cancer to cancer but we’re talking massively larger doses than for rheumatoid arthritis.  Increased risk of malignancy caused by methotrexate has been described in people with concurrent Epstein Barr infection and lymphoma as well as MALT (mucosa-associated lymphoid tissue) lymphomas.  Moreover, MALT lymphomas tend to regress when you stop methotrexate.  There actually isn’t any good quality data supporting the theory that low dose methotrexate directly causes solid cancer, skin cancers, or leukemias.

This isn’t to say that you will not develop cancer while taking low dose methotrexate.  It’s just that it probably wasn’t the methotrexate that caused the cancer.

It all boils down to benefit versus risk.  What is the risk of not treating rheumatoid arthritis?  What is the risk of developing a serious side effect from methotrexate?  Does methotrexate have a good chance of halting the progression of rheumatoid arthritis?  The answer to these questions is different for everyone.

What I would say is that the potential benefits of methotrexate more often than not, vastly outweigh the risks.  Again, this is an important discussion you should have with your doctor.


Weinblatt ME. Methotrexate in rheumatoid arthritis: a quarter century of development. Trans Am Clin Climatol Assoc. 2013;124:16-25.

Rheumatology Secrets, 3rd edition

Saitoh M, Matsushita K. Prevention of surgical site infection for orthopedic surgery in rheumatoid arthritis. Nihon Rinsho. 2016 Jun;74(6):993-9.

Malaviya AN. Low-dose methotrexate (LD-MTX) in Rheumatology Practice – A widely misunderstood drug. Curr Rheumatol Rev. 2016;12(3):168-176.

Hellgren K, et al. Rheumatoid arthritis and risk of malignant lymphoma- Is the risk still increased? Arthritis Rheumatol. 2016 Dec 19. doi: 10.1002/art.40017.

10 frequently asked questions when starting methotrexate
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10 frequently asked questions when starting methotrexate
Methotrexate is one of the most frequently prescribed medications in rheumatology, yet it is poorly understood. Her are 10 frequently asked questions.
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