Methotrexate in rheumatoid arthritis  :  

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Methotrexate is a folate antagonist and was first used in 1947 for childhood leukemia.
In 1951 Gubner noted positive effects of methotrexate for Rheumatoid Arthritis and Psoriasis.
In 1971 it was approved by the FDA for Psoriasis.
In 1988 it was approved for Rheumatoid Arthritis.

The effects of methotrexate are one of three modalities.

1. Anti- proliferative effect -- for example in the treatment of cancer.
2. Immune modulation -- this modulates cytokine production, in particular IL-1, IL-6, IL-8, and tumour necrosis Factor Alpha.
3. Anti-inflammatory effects.

The side effects of methotrexate are either dose dependent for example:


Dose independent side effects include:

Hepatocellular changes.
Pulmonary changes -- pneumonitis.

The side effects of methotrexate are related to the interaction with the folic acid pathway.

Dihydrofolate is converted to tetrahydrofolate, with dihydrofolate reductase enzyme.
In addition methotrexate also interacts with the homocysteine / methionine pathway. The main folic acid metabolite in the serum, is five methyl tetrahydrofolate. Folates enter the cell and are converted into polyglutamated forms. These are retained in the cell, and are involved in carbon transfer reactions. They have a role in purine metabolism. They are required in the formation of nucleic acid. Five methyl tetrahydrofolate is necessary in the formation of homocysteine from methionine.

Methotrexate is structurally similar to dihydrofolate. It is absorbed completely from the intestine, and metabolized via the kidney. It enters the cell and is polyglutamated like folic acid, therefore retaining within the cell and providing its effectiveness. It replaces dihydrofolate and therefore results in reduced production of tetrahydrofolate. As a result, there is a reduction in purine and pyrimidine -- nucleic acid, metabolism.
Methotrexate tends to work foster and more effectively compared to most disease modifying antirheumatic drugs. It has a considerable interaction with many drugs. Caution should be applied when used together with trimethoprim, probenecid, and nonsteroidal anti-inflammatory drugs, especially in the face of renal impairment.

Combination with hydroxychloroquine, has been shown to reduce the overall side effect profile.
The is also some evidence regarding a reduction in the nodules seen in rheumatoid arthritis.
Combination with folic acid has been shown in some studies to reduce toxicity by up to fifty percent.
There is no evidence for a reduction in efficacy.

The use of folinic acid has been shown to reduce toxicity, but in high dose may reduce efficacy.
It is therefore largely used as a rescue therapy for patients with methotrexate toxicity, in particular, marrow suppression.


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