Ask the Pharmacist – Rheumatoid arthritis

Q. My rheumatologist wants to put me on methotrexate (MTX) for my rheumatoid arthritis (RA) but after reading about it I am not sure I want to. Can you provide me with more information to help me make my decision?

A. The fact that you have seen a rheumatologist tells us that you have some signs and/or symptoms to indicate you have an auto-immune disorder, more than likely rheumatoid arthritis (RA). This type of arthritis is chronic and progressive, meaning it will continue to be persistently bothersome and will worsen as time goes on. Most people think of rheumatoid arthritis as a disease that affects only the joints but it also can affect the organs such as your heart and lungs. If it is left untreated, the continued joint damage will eventually lead to significant mobility impairment and the inability to function with daily tasks such as dressing, toileting and eating. This can affect the quality of life drastically. Which brings us back to your question.

Methotrexate, a folate metabolism inhibitor, is the recommended first line treatment for RA. MTX can help keep symptoms under control and therefore maintain a good quality of life and often result in remission (a temporary recovery). Despite this great outcome, a study in the US reported that 42% of patients reported they were not taking their MTX as prescribed. A study in Canada further reported that 44% of women and 36% of men were not in remission after one year of MTX therapy and concluded it was due to not taking the MTX as prescribed. As you alluded to in your question, MTX looks like a scary medication and many wait as long as possible before deciding to go forward with it. Hopefully, this article will help you be more comfortable with the idea of taking MTX and be more successful with its treatment.

When MTX is prescribed for autoimmune disorders such as RA, it is given once weekly. This dosing differs from MTX dosing for other disorders such as cancer where it is taken daily and at much higher doses. It is important to adhere to the weekly schedule and take it at the same time each week. MTX can either be taken orally using incremental doses of 2.5mg tablets or by subcutaneous (just under the skin) injection. As we mentioned earlier, MTX is a folate inhibitor which induces a deficiency of folate in the body. Anybody who is prescribed MTX will also be prescribed folic acid to offset this effect. Folic acid can either be taken as 5mg once weekly, 24 to 48 hours after the MTX dose, OR 1mg every day.

With respect to side effects, if you are finding you are not tolerating the MTX, consider that it might be your RA symptoms you are experiencing. Many people misconstrue their RA symptoms with MTX side effects. If your RA is not well controlled, which very well might be the case if you are just starting your MTX therapy, you may be feeling fatigued, experience weight loss and a general feeling of being unwell. Compare this to the more common side effects of MTX such as nausea, vomiting, diarrhea, mouth sores, fatigue and headaches.

Here are a few suggestions to help alleviate some of these side effects.

Gastrointestinal side effects:

· Take your MTX at bedtime
· Split the weekly MTX dose and give in 2 doses separated by 12 hours
· Switch to the injectable form of MTX since the injectable bypasses the stomach


· Fatigue can be reduced by splitting the weekly dose in 2 doses separated by 12 hours
· Often, fatigue usually improves after 4 to 6 weeks of MTX treatment

Mouth sores and Stomatitis:  Folic acid and sometimes Vitamin B12 can help minimize mouth sores

Liver Function and Hematology (related to the blood):  Folic acid reduces the rise of liver function tests and also major effects to our blood

  • To help detect these side effects, your rheumatologist will request routine bloodwork to check your CBC (complete blood count), liver function tests, creatinine, eGFR (estimated glomerular filtration rate- a kidney function test) and CRP (C-reactive protein – a marker for inflammation to help monitor RA activity)
  • Anyone with reduced kidney function may find they have too much MTX up in the body
  • It is vital that anybody taking MTX get their blood work done as requested by their rheumatologist. The best time to book your blood work is a day or two before your weekly MTX dose. Bloodwork within 24 hours after MTX dosing may give a false elevation of liver function tests
  • MTX is not recommended in anyone with end-stage kidney disease or liver disease. Since MTX is a teratogen (may cause birth defects in fetus), it is not recommended for pregnant women or anyone planning to be pregnant in the near future

There may be times that you skip a dose, either due to forgetfulness or because it was suggested to get the most of a vaccine such as influenza, covid, pneumonia among others. The thought behind missing a dose for a planned vaccine injection is to give your body an improved immune response to the vaccine. Missing one weekly dose does not appear to affect RA activity too much for most people but if you miss two or more consecutive weeks it may induce a flare up in your symptoms.

Potential drug interactions with MTX:

· Trimethoprim – The antibiotic, trimethoprim, which can be administered on its own or in combination with sulfamethoxazole (sulfatrim) should be avoided for anyone taking MTX, even though the MTX is dosed only once weekly. The combination can result in life-threatening myelosuppression, mucositis and nephrotoxicity.

· Anti-inflammatories and proton pump inhibitors – Though there is a theoretical interaction between MTX and NSAIDs (nonsteroidal anti-inflammatory drugs) and proton pump inhibitors (these are stomach protector medications often prescribed alongside NSAIDs), it is not considered a serious interaction with the weekly MTX dosing and therefore it is not necessary to avoid. Some rheumatologists will prescribe NSAIDs and PPI’s to help with pain management. If somebody is taking MTX in much higher doses as is seen in some cancer treatment regimes, the interaction will then be clinically significant to warrant avoidance of these medications.

· Alcohol – Though the literature states that alcohol should be avoided when you are taking MTX, this is a conversation that should happen with the rheumatologist to discuss its use. The physician may allow a low to moderate amount of alcohol depending on each individual situation. Since the risk of hepatotoxicity (liver disease) is increased when people are on MTX and consume alcohol, it is advised to avoid alcohol on the day that MTX is taken each week.

· Tobacco – It has been shown that smoking can affect the MTX and reduce its benefit and efficacy. If you are a smoker, it is strongly suggested to quit smoking sooner than later. This will not only improve your body’s response to the MTX but also lower your risk of cardiovascular disease.

It takes about 6 to 12 weeks of MTX therapy to reach the full benefit and see a reduction in your RA symptoms, prevent joint damage and improve how well you function. Therefore, it is likely that your rheumatologist will assess how well it is working as well as how well you are tolerating the MTX at around the six-week mark. Thereafter, you will likely be monitored every 3 months for awhile.

Flare-ups are bound to happen so try not to get discouraged if/when it happens. So many things can trigger a flare such as stress, infections and surgery among others. It is difficult to know the difference between a flare and a progression or change in your RA disease. If you are unsure, it would be a good time to reach out to your rheumatologist and request a sooner appointment if that is possible.

So, though MTX does come with its downsides, it continues to be the first line treatment for those suffering from RA. In many cases, the RA progresses and the MTX is no longer sufficient to reduce the symptoms and improve or at least maintain your functionality. In these cases, a biologic disease modifying anti-rheumatic drug (DMARD) can be considered. These medications block specific inflammatory pathways made by immune cells in the body. DMARDs would not replace your MTX therapy but rather be taken along with it.

For more information on this or any other topic, contact the pharmacists