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Side Effects of Methotrexate (Anti-Rheumatic) Oral

Written by
Dr. Saumya Mittal
and medically reviewed by iCliniq medical review team.

Published on Nov 29, 2013 and last reviewed on Mar 14, 2022   -  5 min read


This article speaks about the side effects of the drug Methotrexate, which is used to treat \'Rheumatoid Arthritis.\'

Side Effects of Methotrexate (Anti-Rheumatic) Oral

Methotrexate, an antifolate agent, synthesized in 1948, is a commonly used medicine for certain cancers, and since 1970, after it was realized that it prevents joint deformity and precludes the progression of bony erosion, it is used in the treatment of rheumatoid arthritis. It belongs to the group of drugs called antirheumatics. As Methotrexate interferes with certain cell growth like bone marrow cells, tumor cells, and skin cells, it is also used in the treatment of leukemia, psoriasis, and polyarticular-course juvenile rheumatoid arthritis.

The drug, in low doses as well as high doses, is known to cause numerous side effects.

Common Side Effects

The common side effects include the following:

Systemic Side Effects

Methotrexate affects multiple systems, which are manifested by the following symptoms:

1. Renal Failure- Acute renal failure is commonly known. The cause behind this is the tubular necrosis associated with the accumulation of the drug and its metabolites in the tubules, possibly due to their insoluble nature in acidic urine. Alternatively, Methotrexate may be directly toxic to tubules. This may cause a rise in serum Methotrexate levels.

Little or no urination and swelling in the ankles or legs are the signs of renal dysfunction.

2. Neurological Manifestations- Despite the occurrence of acute, subacute, and chronic neuropathy, the mechanisms of neurotoxicity are not well established. Manifestations of acute neuropathy are in the form of aseptic meningitis, leukoencephalopathy affecting the brain and spinal cord, headache, nausea, and vomiting. Subacute neuropathy presents as seizure, paraplegia, or cerebellar dysfunction. Necrotizing leukoencephalopathy is amongst the most common manifestations of chronic neuropathy.

Drowsiness, irritability, problems with coordination, stiffness of the neck, problems in vision, confusion, weakness, loss of body movements, etc., are the associated nervous problems.

3. Hematopoietic Side Effects- Pancytopenia or reduction in any one of the three cell line lineages is frequently seen in the Methotrexate toxicity affecting the hematopoietic system. Megaloblastic anemia, leukopenia (especially neutropenia), thrombocytopenia may all be seen individually or in combinations. An elderly patient with folate deficiency or hypoalbuminemia, dehydration, and renal dysfunction is more predisposed to developing these hematological manifestations. In such cases, even an accidental overdose may lead to pancytopenia.

Lightheadedness, shortness of breath, fatigue, fever, chills, bruises, sores in the skin and mouth, cold extremities, and pale skin are the manifestations of low blood cell count.

4. Hypersensitivity Reactions- Methotrexate, in low as well as high doses, may cause the expression of drug-derived antigens on keratinocytes. These, when detected by cytotoxic-T lymphocytes and mononuclear cells, can result in keratinocyte apoptosis. Hypersensitivity reactions may be considered in both mucocutaneous as well as hematological manifestations.

Ulcers of the oral mucosa and skin, with erythema and urticaria, are frequently seen.

5. Pneumonitis- The patients present with a non-productive cough. This may be associated with fever, dyspnea, or malaise. The patient may be found to have pneumonitis (activated T cells induce a hypersensitivity reaction) or diffuse interstitial disease (lung fibroblasts induced eosinophils, occasionally with peripheral eosinophilia).

6. Hepatic Problems- Abdominal pain is a constant feature of Methotrexate toxicity. This may occasionally be associated with vomiting and diarrhea. Hepatotoxicity, with raised aminotransferase, is frequently seen. Liver damage may be seen with fatty infiltration to fibrosis to frank cirrhosis. Diabetic patients and alcohol users are prone to more severe hepatic involvement.

Right upper abdominal pain, dark-colored urine, yellowish discoloration of skin and whites of the eyes, nausea, loss of appetite, and swelling around the midsection are the signs of liver problems.

7. Tumor Cell Breakdown- The signs of tumor cell breakdown include the following:

8. Fertility Issues- Methotrexate may produce problems with fertility in both men and women.

9. Teratogenic Side Effects of Methotrexate- Methotrexate has abortifacient and teratogenic side effects, and therefore, its use is contraindicated in pregnancy. Also, it is advisable to use effective birth control methods while taking Methotrexate because of its adverse effects on the fetus. It has the following teratogenic side effects:

10. Breastfeeding and Methotrexate- The use of Methotrexate is not recommended in breastfeeding women because it can pass through breast milk. It is advisable to breastfeed the baby only after a week of stopping the medication.

Serious Side Effects

Methotrexate also causes serious side effects which need immediate medical intervention. These include the following:


Methotrexate Overdose:

Overdose of Methotrexate causes serious complications. Seek immediate help in case of overdosing Methotrexate which shows the following symptoms:

How Should Methotrexate Be Taken?

Methotrexate should not be consumed daily and should be consumed only as per the prescription of the treating doctor. It is usually given weekly, once or two to four times a week. In a few cases, Methotrexate is given daily, followed by a rest period of one week or more. Taking Methotrexate daily without the doctor’s advice may result in the death of the individual.


Methotrexate should not be consumed without the advice of the doctor. It is also advised to tell the doctor that you are taking Methotrexate before starting any medicine or doing any surgical or dental procedure. Pregnancy planning should be avoided while taking Methotrexate, and also it should not be used in the gestation and postpartum period without the advice of the doctor.

Frequently Asked Questions


What Are the Uses of Methotrexate?

Methotrexate is a medication that is given for controlling cancer cells. It is also helpful in treating psoriasis. It prevents the formation of scales in the skin. The activity of the immune system is reduced, and so it can treat rheumatoid arthritis.


How Can the Effectiveness of Methotrexate Be Identified?

The effectiveness of Methotrexate can be identified by measuring the levels of polyglutamate. It might usually take a few months for Methotrexate to show its action. If the polyglutamate levels are low, then the drug is not a suitable one. You should ask your doctor to suggest some alternative medicines.


Is Methotrexate a Steroid Drug?

Methotrexate is a steroid. It is a safe drug that is widely used for treating any inflammatory conditions. It is necessary to avoid alcohol consumption while consuming this drug as it might cause damage to the liver. You should get recommendations from your doctor before taking these medications.


Can Weight Increase After Using Methotrexate?

In a study that calculated the range of weight changes in patients, weight gain was seen in patients after six months of usage. This was highly noted in patients who lost weight due to the condition of rheumatoid arthritis.


It Is Necessary to Drink a Larger Amount of Water Along With Methotrexate?

Yes, you should take plenty of water along with Methotrexate. It can be approximately around seven to eight cups of water. It is not necessary to take all eight cups of water at once. You can increase the water content throughout the day.


How Long Should a Person Take Methotrexate for the Treatment of Rheumatoid Arthritis?

For the treatment of rheumatoid arthritis, the patient should consume this drug for a prolonged period of 20 years. If the condition is not perfectly cured, the patient will be asked to continue the medication or will be advised of any other treatment option. The duration of the dosage is decided based on the health status of the individual.


Can I Consume Vitamin D Along With Methotrexate?

Reports suggest that there are no drug interactions identified to date. So it might be safe to consume vitamin D along with Methotrexate. It is necessary to look for the actual purpose of consuming vitamin D. If it is required only for poor nutrition, then you can try to supplement it in other ways.


What Are the Foods to Be Avoided While Consuming Methotrexate?

While you are taking Methotrexate drugs, you have to avoid foods that are rich in folic acid. This is due to the fact that folic acid can interfere with the mechanism of action of Methotrexate. The efficiency of Methotrexate medications is also known to reduce when folic acid levels are increased.


What Are the Drugs to Be Avoided Along With Methotrexate?

Below are the medicines that should be avoided while consuming
- Methotrexate.
- Celecoxib.
- Duloxetine.
- Etanercept.
- Cyclobenzaprine.
- Adalimumab.
- Pregabalin.
- Esomeprazole.
- Acetaminophen.


Can Coffee Be Consumed Along With Methotrexate?

Yes, you can drink coffee along with Methotrexate. The intolerance to Methotrexate drugs can be greatly reduced in patients who drank coffee. You can get help from your doctor before drinking coffee along with Methotrexate.


What Are the Alternative Drugs to Methotrexate?

The alternate drugs for Methotrexate are:
- Leflunomide.
- Azathioprine.
- Mycophenolate.


Do the Side Effects of Methotrexate Subside?

Most of the patients do not have any side effects at all. The patients who have side effects need reduction in the dosage of the drugs. After the reduction of dosage, the side effects are gradually reduced. If you experience any severe abnormal symptoms, then you have to consult the doctor immediately.


What Are the Side Effects of Methotrexate?

The side effects of Methotrexate are:
- Hair loss.
- Headaches.
- Rashes.
- Vomiting.
- Diarrhea.
- Feeling sick.
- Shortness of breath.
- Mouth ulcers.

Last reviewed at:
14 Mar 2022  -  5 min read




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