Methotrexate (Rheumatrex, Trexall) is a disease-modifying anti-rheumatic drug (DMARD) indicated (approved for use) for the treatment of adults with RA. It has become the cornerstone of RA treatment since it was first introduced over five decades ago as an anti-cancer drug.1

Given at a low dose, it has been shown to be effective in controlling inflammation and related symptoms, while slowing or preventing damage to joints and related structures. Additionally, with experience in over half a million patients with RA, methotrexate has a strong safety record when monitored appropriately.1


How does methotrexate work?

Methotrexate is a type of drug called an antimetabolite or antifolate. It is an immunosuppressant that inhibits the metabolism of folic acid, which is necessary in the production of key immune system cells. Therefore, it results in a dampening of immune processes at work in RA.


How is methotrexate taken?

Methotrexate can be taken orally (as a tablet) or by injection (subcutaneously or intramuscularly). Your doctor will determine the optimal dose of methotrexate for you based on your level of disease activity and response to the treatment. Taken orally, methotrexate is typically started at a single dose of 7.5 mg given once weekly or in three divided doses of 2.5 mg given at 12 hour intervals. Dosing of methotrexate is adjusted gradually until optimal response is achieved. The maximum weekly dose of oral methotrexate for adults with RA usually does not exceed 25 mg.2


How long does it take for methotrexate to achieve full effect?

It may take 3 to 6 weeks of treatment before you start to experience a therapeutic response to methotrexate, then up to 12 weeks or more for the full effect to be achieved.2


What should I do if I miss a dose of methotrexate?

If you miss a dose of methotrexate, take the missed dose as soon as you remember it. However, if it is close to the time for your next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.3

Your doctor may suggest that you temporarily cease taking methotrexate if you are taking antibiotics for an acute infection.


How should I store methotrexate?

You should store methotrexate in the original container that it came in. Make sure that it is tightly sealed and kept out of reach of children. Keep the container at room temperature and away from moisture (not in your bathroom). Make sure that you discard any methotrexate that is outdated. Your pharmacist can tell you how to safely dispose of outdated or unused medication.3


Are there people who should not take methotrexate?

You should not take methotrexate if you are pregnant or planning to become pregnant. This is because methotrexate can cause birth defects or death to a fetus. Also, you should not breastfeed while you are taking methotrexate because it can harm your infant.2 You should use effective birth control while taking methotrexate and stop taking methotrexate for at least 3 months before attempting to get pregnant (women and men alike).

You should not take methotrexate if you have another health condition where your immune system is weakened (immunodeficiency conditions).2

You should not take methotrexate if you drink alcohol or liver disease from alcohol abuse.2 Regular testing of liver function should be conducted every 2-3 months if you are taking methotrexate, whether you drink alcohol or not.

You should not take methothrexate if you2:

  • Have a condition where your bone marrow does not make enough blood cells, such that you have a low white blood cell count, a low platelet count, or anemia (low red blood cell count)
  • Have chronic liver disease
  • Are allergic to methotrexate or its ingredients


Before starting methotrexate, make sure to tell your doctor if you have kidney or liver problems, fluid in your stomach area, or lung problems. Also, make sure you tell your doctor about all the medications (both prescription and over-the-counter) and vitamins and supplements that you are taking.2


What evidence do we have that methotrexate works in RA?

Evidence of the effectiveness of methotrexate in RA comes from studies comparing it to other DMARDs and newer biologic DMARDs, including tumor necrosis factor (TNF)-inhibitors (or anti-TNF drugs).

Efficacy versus other DMARDs

Methotrexate was tested in a double-blind, randomized trial comparing it to the immunosuppressant azathioprine in patients with RA who had failed therapy with gold salts and/or D-penicillamine. Methotrexate resulted in significantly greater improvement in disease activity and pain scores versus azathioprine and resulted in significantly fewer side effects. Methotrexate was also shown to be more effective than another conventional DMARD (auranofin, a gold compound) in RA patients who had not yet received DMARD treatment. In a randomized, controlled trial conducted in 281 RA patients, methotrexate resulted in a significantly greater response, with fewer side effects. The rate of ACR20 response with methotrexate was 68% compared with 30% for auranofin.1


Slowing radiographic progression

In another double-blind, randomized trial comparing methotrexate with azathioprine, methotrexate resulted in fewer new bone erosions and less change in joint score as evaluated by plain x-ray images of the hands and feet taken at 24 and 48 weeks. Follow-up 4 years after the trial started showed that methotrexate still had a greater beneficial effect in slowing joint damage compared with azathioprine.1


Studies of DMARD combinations

Several studies have been conducted to evaluate methotrexate given in combination with other DMARDs. Selected DMARDs, including intramuscular gold, cyclosporine, hydroxychloroquine and sulfasalazine (together), and doxycycline, given in combination with methotrexate appear to result in increased efficacy compared with methotrexate alone.1

Results from a recent study demonstrated that a combination of conventional DMARDs (triple therapy) including methotrexate, sulfasalzine, and hydroxychloroquine, can provide significant benefits in patients with RA who have failed to respond adequately to monotherapy with methotrexate. The 48-week, double-blind, randomized, controlled trials was conducted in 353 patients with RA who continued to have active disease despite treatment with methotrexate. Participants in the study were randomly assigned to a triple therapy combination of the conventional DMARDs, methotrexate, sulfasalazine, and hydroxychloroquine or etanercept (Enbrel) plus methotrexate. Subjects who did not have sufficient improvement by 24 weeks were switched to the other treatment group.4

At 24 weeks, both treatment regimens resulted in a similar significant improvement in disease activity scores for 28-joint counts (DAS28) compared with measurements at the start of the study (baseline) (P=0.001). Twenty-seven percent (27%) of subjects in each group switched to the other treatment group at the 24-week point in the study and a similar proportion of switching patients derived significant benefit from the new treatment. Overall, the triple therapy regimen was found to be similar in efficacy to etanercept (Enbrel) and methotrexate, with no significant differences between treatment groups in outcomes, including radiographic progression, pain, quality of life, or major side effects or adverse events.4


Efficacy versus biologic DMARDs

Because of its superior efficacy and safety record, methotrexate is the conventional DMARD against which new classes of biologic treatments are usually compared. Results from three key randomized, controlled trials comparing methotrexate alone and in combination with the anti-TNF drugs etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade), demonstrated both the effectiveness of methotrexate as monotherapy (used alone) and the superior efficacy of each combination, in terms of controlling disease activity and slowing joint damage. In these studies (TEMPO, PREMIER, and ASPIRE), methotrexate as monotherapy  resulted in ACR20 response in 54% to 73% of patients.1


Efficacy of methotrexate alone in comparative studies with anti-TNF biologics

ACR20 (% patients)
ACR50 (% patients)
ACR70 (% patients)

TEMPO=Study comparing methotrexate and etanercept, alone and in combination.
PREMIER=Study comparing methotrexate and adalimumab, alone and in combination.
ASPIRE=Study comparing methotrexate alone with infliximab plus methotrexate.


What are the side effects of methotrexate?

Common side effects associated with methotrexate include3:

  • Dizziness
  • Drowsiness
  • Headache
  • Hair loss
  • Redness in eyes
  • Reduced appetite
  • Swelling and/or tenderness of gums and mouth sores


In some patients, methotrexate can cause serious side effects. These include blurred vision or a sudden loss of vision, confusion, loss of consciousness, seizures, and weakness or difficulty moving one side of your body. If you experience any of these side effects or any other unusual problems while you are taking methotrexate, call your doctor immediately.3


Warnings and precautions with methotrexate

Methotrexate can cause damage to your liver, especially if it is used over a long period of time. So, if you drink or have ever drunk large amounts of alcohol or if you have or have ever had liver disease, you may not be a candidate for treatment with methotrexate.3

Methotrexate can cause damage to your lungs. If you are considering taking methotrexate, make sure your doctor knows if you have or have ever had lung disease. If you experience shortness of breath, a dry cough, or fever, contact your doctor immediately.3

Methotrexate can increase your risk for developing lymphoma, a type of cancer that affects immune system cells.3

Methotrexate may cause serious skin reactions, including photosensitivity. If you experience rash, fever, blisters, or skin peeling while taking methotrexate, contact your doctor immediately.3

Because methotrexate dampens or decreases your immune system activity (this is why it is effective in RA), your risk for developing serious infections is increased while you take methotrexate. Alert your doctor immediately if you develop any infection while taking methotrexate. Also, let your doctor know if you have ever had a condition that affects your immune system function.3

You should not take methotrexate if you are pregnant or planning to become pregnant. This is because methotrexate can cause birth defects or death to a fetus. Also, you should not breastfeed while you are taking methotrexate, because it can harm your infant.3 You should use an effective form of birth control while you are taking methotrexate.


Drug interactions

Taking non-steroidal anti-inflammatory drug (NSAIDs), such as aspirin, Tricosal or Trilisate (choline magnesium trisalicylate), Advil or Motrin (ibuprofen), Doan’s (magnesium salicylate), Aleve or Naprosyn (naproxen), or salsalate while you are taking methotrexate can increase your risk for certain serious side effects. However, because you may be receiving a low dose of methotrexate, your doctor may decide that you can safely continue to take an NSAID treatment while receiving methotrexate. Make sure to talk to your doctor about which drugs are safe to take while you are being treated with methotrexate.

Certain oral antibiotics (eg. tetracycline, chloramphenicol) can affect intestinal absorption of methotrexate. Your doctor may suggest that you temporarily cease taking methotrexate if you are taking antibiotics for an acute infection.

Penicillins can decrease the clearance of methotrexate from the body. Therefore, you should be monitored carefully if you are receiving penicillin while being treated with methotrexate.

Vitamins containing folic acid may decrease response to methotrexate. Make sure you talk to your doctor about any and all vitamins and supplements you take while you are receiving methotrexate. Daily doses of folic acid or folinic acid are often taken with methotrexate to lessen some of the possible side effects, such as mouth sores or hair loss.


Is a generic available for methotrexate?

Yes. Generic methotrexate is available.

Written by: Jonathan Simmons | Last reviewed: September 2013.
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