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Methotrexate for lupus: help it work better and prevent side effects

Methotrexate is one of the safest and most effective drugs for lupus. Since the 1980s, it has been used to treat rheumatic diseases such as rheumatoid arthritis (RA) and lupus. Because of its proven safety and effectiveness, most, if not all, major rheumatologic groups (including the American College of Rheumatology) worldwide recommend it as the first treatment of choice. 

APRIL 2024 Update

Recent studies show that low-dose methotrexate (used in lupus) does not cause liver problems. It is important to use it correctly. Click on this line to see this information. 

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NOTE: Very important. We NEVER want our patients to have any side effects from methotrexate. We want to help your lupus, but with medications that do not make you feel badly. On Social Media, I often see patients complaining about MTX. That is why I made this blog post. It will give you helpful, practical advice on things in your power to determine the right dosing for you. However, ALWAYS ASK YOUR DOCTOR before doing what I advise in this blog post. Feel free to print it out and share it.

Safe and Effective Use of Methotrexate for Lupus

Methotrexate is generally safe when used with other important treatments for lupus. However, methotrexate (MTX) can occasionally cause some nuisance side effects. There are things you can do to ensure methotrexate works better for you, such as how to prevent side effects. This blog post tells you how.

Note: methotrexate for lupus is a slow-working drug. After being on the maximum dose, it can take up to 3 months to see the full effects. The maximum dose we sometimes need is up to 30 mg weekly of injectable methotrexate.

Ask your prescribing doctor about any of these before implementing them. However, I suspect your doctor will be very happy you are being so proactive. You have a better chance of doing well if you follow this advice (but I cannot give formal medical advice since I do not know your medical situation).

Tips on helping methotrexate for lupus work better for you:

  • Absorb pills better by taking them on an empty stomach.
  • Suppose you are tolerating methotrexate well and still have active lupus inflammation. In that case, you can ask your doctor about increasing the dose every few weeks (as long as your blood counts and liver enzymes are checked regularly after the dose increases). We can go as high as 30 mg injectable weekly.
  • Do not take with dairy products or calcium; dairy products and calcium decrease absorption
  • Stop caffeine for 3 months while taking methotrexate; caffeine can reduce its effects
  • If you take pills once a week, ask your provider about either splitting up the dose over 24 hours or switching to injections. Both are absorbed better.

Take folic acid or leucovorin:

It is important to either take folic acid every day (1 mg to 5 mg daily), or the stronger vitamin called leucovorin (also called folinic acid) once a week (10 mg to 25 mg) to help decrease the risk of getting any side effects from methotrexate. Leucovorin is best taken 8-12 hours after your methotrexate dose.

Drug monitoring with your doctor

Remember to see your healthcare provider every 4-12 weeks while taking methotrexate so that they can monitor your blood counts and liver enzymes. If you ever have to reschedule an appointment, make sure you ask the phone person to put you in ASAP with any provider in their office if your doctor doesn’t have an appointment available right away. It is very important that your healthcare provider sees you before the 3-month point is up after your previous appointment.

What to do for methotrexate side effects

If you get sores in your mouth:

Take an over-the-counter vitamin A tablet of 8000 IU daily. You can also split up your methotrexate dose over a 24-hour period (such as taking half the dose on one day and the other half the next day). If you split up the dose and your doctor prescribed leucovorin, take your leucovorin 8-12 hours after your last dose of methotrexate.

If you get “the blahs,” headache, memory problems, fatigue, or tingling sensations:

Take one tablet of Mucinex DM with your methotrexate, then take another tablet 8 hours later. Dextromethorphan (the active ingredient) has been shown to decrease methotrexate side effects when it affects the central nervous system.

If you get stomach upset:

Split up your dose over 24 hours, as mentioned above. However, make sure to repeat your blood work sooner than later (split dosing increases overall blood levels of methotrexate).

If you develop any symptoms that could be due to infection:

Cough, fever, sore throat, pain with urination, increased urine frequency, painful red skin: Call and see your primary care doctor immediately. If it is a weekend or evening, visit your closest urgent care center to ensure you don’t have an infection. Do not take your methotrexate during active infections.

If you get hair thinning:

If you notice hair thinning, do not worry. Other people rarely notice, and it also grows back.

Ask your doctor if you could try taking 25 mg of leucovorin eight to twelve hours after each dose. This usually helps a lot. Also, ask your doctor if you should lower your methotrexate dose. In addition, use minoxidil twice a day on your scalp. Minoxidil stimulates the hair follicles and increases blood flow to them.

Hair is slow to grow back. If taking these measures (or even if you need to stop methotrexate), it takes 6-12 months later before you will notice the results of increased hair growth.

If you get any vaccination, ask your doctor if you should stop your methotrexate for 1 week after the vaccine:

A 2018 study showed that rheumatoid arthritis patients who were under good control and stopped their methotrexate for 2 doses after their flu (influenza) vaccination had a significantly better response to the vaccine than those who kept taking their methotrexate. Then, a 2023 study showed that just stopping one dose of methotrexate after getting a flu shot worked well without causing many rheumatoid arthritis flares. Only do this if your inflammation is under good control.

Does methotrexate cause liver problems?

Dr. Thomas’ experience using MTX or methotrexate for lupus

I’ve been using methotrexate since the late 1980s in patients. I must have treated thousands of patients with it. The only liver problem I ever saw was an alcoholic treated inappropriately by another doctor (he never had liver enzymes done, and he should have never been on methotrexate). 

Interestingly, several large studies recently came out showing no to rare problems with the liver when methotrexate is used as we do for RA and SLE. MTX can indeed increase liver enzymes. However, this is usually a mild, benign finding. We repeat labs to see if they normalize on their own; if they remain persistently high, we reduce the dose of MTX. The important question is, “Does this truly lead to liver inflammation and damage?”

Results of a very large recent study showed no liver problems from methotrexate

The largest of these studies looked at studies evaluating thousands of patients. It showed the actual liver problems that were seen in patients who actually had fatty liver disease as the cause (not methotrexate). The vast majority had other risk factors for fatty liver damage (diabetics and overweight patients). Today, in the general population (non-MTX takers), fatty liver is one of the top causes of cirrhosis (end-stage liver disease with irreversible scarring). I know this first hand. One of my closest relatives (nondrinker but overweight and had uncontrolled diabetes) died from fatty liver disease cirrhosis. 

If you have fatty liver, take it seriously. It is essential to work on weight loss through diet and exercise. Taking vitamin E supplements may help (ask your doctor). 

NOTE: Though the study above suggested that MTX does not cause liver problems, almost all drugs can potentially cause rare side effects and allergic reactions, including liver inflammation. The same is true for methotrexate. Therefore, still, get your labs done regularly. We go down on the dose or even stop MTX if the liver enzymes are persistently elevated or if the levels are higher than two to three times higher than the upper limits of normal. 

List of people who should not stay on methotrexate (regarding the liver)

  • Patients with fatty liver disease and persistently high liver enzymes (AST, ALT) or low albumin level
  • Alcoholics 
  • Anyone with liver damage (however, I have had some patients who safely stay on it with guidance from a liver expert)
  • Anyone unable to do blood laboratory work regularly (anywhere from every 1 to 6 months on MTX)
  • If your doctor says you are at high risk

Concensus: Actual liver problems from methotrexate are rare when used in patients who are not at high risk for liver problems

Can you drink alcohol while taking methotrexate for lupus?

Ask your doctor first.

However, studies show that low to moderate alcohol use is not associated with any liver problems from methotrexate. In addition, low amounts of alcohol intake may actually reduce autoimmune problems from lupus.

For more in-depth information on how to use methotrexate safely and effectively for lupus in greater detail:

Read chapter 32 of The Lupus Encyclopedia, edition 2

Look up your symptoms, conditions, and medications in the Index of The Lupus Encyclopedia.

If you enjoy the information from The Lupus Encyclopedia, please click the “SUPPORT” button at the top of the page to learn how you can help. 


What are your comments and opinions?

If you take methotrexate and have lupus, what has your experience been? What do you recommend for other patients?

Do you have any questions to ask Dr. Thomas?

Please click on “Leave a Comment” above to comment.

Please support “The Lupus Encyclopedia” blog post page

Click on “SUPPORT” at the top of the page to learn how you can support “The Lupus Encyclopedia


AUTHOR: Donald Thomas, MD

For more in-depth information on Methotrexate for lupus: help it work better and prevent side effects:

Read more in The Lupus Encyclopedia, edition 2

Look up your symptoms, conditions, and medications in the Index of The Lupus Encyclopedia

If you enjoy the information from The Lupus Encyclopedia, please click the “SUPPORT” button at the top of the page to learn how you can help. 


What are your comments and opinions?

If you have lupus, what has your experience been? What do you recommend for other patients?

Do you have any questions to ask Dr. Thomas?

Please click on “Leave a Comment” above to comment.

Please support “The Lupus Encyclopedia” blog post page

Click on “SUPPORT” at the top of the page to learn how you can support “The Lupus Encyclopedia

5 Comments

  1. I developed a massive blood clot while taking methotrexate. It was discontinued after my emergency admission to the hospital. Doctors agreed methotrexate was a contributing factor.

    • Hello Kathy,
      I’m sorry to hear you had a negative experience. I hope you are better now. could I ask, how many mg of methotrexate you were on weekly ?
      Siena

  2. I avoided taking it for years because of the testing worries the liver. Finally, 10 years into a UCDT Diagnosis (with lupus like features), I tried it because nothing else had worked. I was astonished how good I felt. 5 pills a week weren’t enough so my Rhuemetologist recommended 1 more. Perfect! I’ve been on 6 for the last 4 months and I like the results.

  3. I took methotrexate and my lungs were
    affected. For years I had nodules all over my lungs since 2014. A diagnosis comes up that I have systemic lupus from hematologists.Along with bone marrow cancer,multimyloma,did bone marrow biopsy and was told that both are in remission but could come back.☹️My
    Bones in my body especially in my back
    hurts something awful. Now I have fibromyalgia,noted! Inflammation noted,
    Rheumatoid arthritis noted the electrical pains runs thru body. Can’t do much for
    dealing with pain daily. Taking metrothrexate cause me to be on oxygen.
    Now has to have a pacemaker .

  4. Hi , I took hydroxychloroquine for 14 years without any problems . Just recently started to feel itchy , no rash . So my Dr . Said to change to a different generic . It worked for a year and 1/2 but then the same thing happened . So I tried another one and I had the same issue itching . So I stopped taking it for awhile . So now the Dr. Ordered the brand so I wanted to know if it would be better to follow your tips on starting with 1/4 tablet for a few days and so on ? I can only get the 200 mg tablet . Any suggestions greatly appreciated .


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