Methotrexate for Rheumatoid Arthritis: Side Effects Guide

Why is methotrexate used for rheumatoid arthritis?

Methotrexate is a disease-modifying antirheumatic drug (DMARD) — meaning it reduces the underlying immune-driven inflammation that causes joint damage in RA, rather than only relieving pain temporarily. The 2021 American College of Rheumatology guideline recommends methotrexate as the preferred initial DMARD for most people with RA, given its effectiveness, long track record, manageable side-effect profile, and low cost 1Ref 1Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, et al. (2021).2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.Methotrexate as preferred first-line DMARD; folic acid co-prescription; liver and CBC monitoring requirements; alcohol avoidance; pregnancy contraindication; dose adjustment strategies. The 2022 EULAR update reinforces this position as the anchor drug in RA management 2Ref 2Smolen JS, Landewé RBM, Bergstra SA, et al. (2023).EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update.Methotrexate as anchor DMARD in RA; biologic and targeted synthetic DMARD alternatives when methotrexate insufficient or not tolerated.

Methotrexate for RA is taken once a week (not daily, as it is used for cancer at much higher doses). It takes several weeks to months to reach its full effect, which is why short-term anti-inflammatory treatment (NSAIDs or a short corticosteroid course) is often used alongside it in the early weeks.

What are the most common side effects?

Nausea and gastrointestinal discomfort are the most frequently reported side effects, typically occurring in the 24–48 hours after the weekly dose 1Ref 1Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, et al. (2021).2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.Methotrexate as preferred first-line DMARD; folic acid co-prescription; liver and CBC monitoring requirements; alcohol avoidance; pregnancy contraindication; dose adjustment strategies. Strategies that often help:

• Taking the dose in the evening, so any nausea occurs during sleep
• Splitting the dose into two halves taken 12 hours apart
• Taking methotrexate with food
• Adequate hydration
• Folic acid supplementation (see below) — this is one of the most effective approaches 3Ref 3Onda K, Honma T, Masuyama K (2023).Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system.Folic acid reduces hepatotoxicity and myelosuppression reporting odds ratios; methotrexate adverse events include interstitial lung disease (ILD), hepatotoxicity, and myelosuppression; ILD as a serious rare complication
• In persistent cases, switching from oral to injected methotrexate (subcutaneous) is often better tolerated

Fatigue — sometimes called "methotrexate hangover" — is the day-after tiredness that some people experience. This often improves over time or with the same strategies used for nausea.

Hair thinning can occur, typically as diffuse shedding rather than patchy loss. It is usually mild and often reversible if the dose is reduced or folic acid is optimized. Severe hair loss is uncommon 1Ref 1Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, et al. (2021).2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.Methotrexate as preferred first-line DMARD; folic acid co-prescription; liver and CBC monitoring requirements; alcohol avoidance; pregnancy contraindication; dose adjustment strategies.

Mouth sores (mucositis): Occasional ulcers inside the mouth can occur. Folic acid supplementation reduces this significantly 3Ref 3Onda K, Honma T, Masuyama K (2023).Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system.Folic acid reduces hepatotoxicity and myelosuppression reporting odds ratios; methotrexate adverse events include interstitial lung disease (ILD), hepatotoxicity, and myelosuppression; ILD as a serious rare complication.

What is folic acid and why does everyone on methotrexate take it?

Methotrexate works in part by interfering with folate metabolism in rapidly dividing cells. Folic acid (vitamin B9) supplementation compensates for this, significantly reducing the incidence of nausea, mouth sores, and hair loss without meaningfully reducing the drug's anti-inflammatory benefit 1Ref 1Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, et al. (2021).2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.Methotrexate as preferred first-line DMARD; folic acid co-prescription; liver and CBC monitoring requirements; alcohol avoidance; pregnancy contraindication; dose adjustment strategies3Ref 3Onda K, Honma T, Masuyama K (2023).Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system.Folic acid reduces hepatotoxicity and myelosuppression reporting odds ratios; methotrexate adverse events include interstitial lung disease (ILD), hepatotoxicity, and myelosuppression; ILD as a serious rare complication.

Most rheumatologists prescribe folic acid to be taken on the days when methotrexate is not taken. The typical dose is 1–5 mg daily (except on the day of methotrexate). Some use leucovorin (folinic acid) instead in cases of severe side effects. If you are taking methotrexate without folic acid, ask your clinician about adding it.

What about more serious side effects?

Liver effects: Methotrexate is metabolized by the liver, and long-term use can cause liver inflammation or, rarely, fibrosis. The risk is substantially higher in people who drink alcohol regularly, have pre-existing liver disease, or are obese 1Ref 1Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, et al. (2021).2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.Methotrexate as preferred first-line DMARD; folic acid co-prescription; liver and CBC monitoring requirements; alcohol avoidance; pregnancy contraindication; dose adjustment strategies. Regular blood tests (liver function tests every 4–12 weeks initially) are part of standard monitoring 4Ref 4National Library of Medicine (2024).Methotrexate Injection: MedlinePlus Drug Information.Requirement for regular laboratory monitoring (liver function, CBC) before, during, and after methotrexate treatment; potential for liver damage, bone marrow suppression, and serious infection risk. Most people on methotrexate should minimize or avoid alcohol.

Lung effects: A rare but serious complication called methotrexate pneumonitis (lung inflammation) can occur 3Ref 3Onda K, Honma T, Masuyama K (2023).Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system.Folic acid reduces hepatotoxicity and myelosuppression reporting odds ratios; methotrexate adverse events include interstitial lung disease (ILD), hepatotoxicity, and myelosuppression; ILD as a serious rare complication. Symptoms include a new dry cough, shortness of breath, or fever. Contact your rheumatologist promptly if these develop while on methotrexate — this is not something to wait on.

Bone marrow suppression: In rare cases, methotrexate can lower blood cell counts. CBC monitoring is part of routine follow-up 4Ref 4National Library of Medicine (2024).Methotrexate Injection: MedlinePlus Drug Information.Requirement for regular laboratory monitoring (liver function, CBC) before, during, and after methotrexate treatment; potential for liver damage, bone marrow suppression, and serious infection risk.

Infection risk: Methotrexate suppresses the immune system, which can reduce the body's ability to fight infections. It does not carry the same degree of infection risk as high-dose biologics, but live vaccines should not be given while on methotrexate.

Is methotrexate safe to take long-term?

For most people, yes — with proper monitoring 1Ref 1Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, et al. (2021).2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.Methotrexate as preferred first-line DMARD; folic acid co-prescription; liver and CBC monitoring requirements; alcohol avoidance; pregnancy contraindication; dose adjustment strategies. Methotrexate has one of the longest and most studied safety track records among RA medications. Decades of real-world use and clinical trial data support its safety profile at the doses used for RA. The key is adherence to monitoring: regular blood tests for liver function and complete blood count allow your rheumatologist to catch any problems early and adjust treatment if needed 4Ref 4National Library of Medicine (2024).Methotrexate Injection: MedlinePlus Drug Information.Requirement for regular laboratory monitoring (liver function, CBC) before, during, and after methotrexate treatment; potential for liver damage, bone marrow suppression, and serious infection risk.

Pregnancy: Methotrexate is not safe during pregnancy or while trying to conceive — it is teratogenic (can cause fetal harm). It must be stopped before conception; the recommended washout period should be discussed with your rheumatologist. Reliable contraception is essential during methotrexate use in people who could become pregnant 1Ref 1Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, et al. (2021).2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.Methotrexate as preferred first-line DMARD; folic acid co-prescription; liver and CBC monitoring requirements; alcohol avoidance; pregnancy contraindication; dose adjustment strategies.

What if I cannot tolerate methotrexate?

If you cannot tolerate methotrexate despite adequate folic acid supplementation and dose adjustments, other DMARDs are available — hydroxychloroquine, sulfasalazine, leflunomide, and biologic agents 2Ref 2Smolen JS, Landewé RBM, Bergstra SA, et al. (2023).EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update.Methotrexate as anchor DMARD in RA; biologic and targeted synthetic DMARD alternatives when methotrexate insufficient or not tolerated. Your rheumatologist will choose based on which organs are affected, how active your RA is, your other medical conditions, and your preferences. Do not stop methotrexate without talking to your rheumatologist first — abrupt discontinuation can allow RA to flare.