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Folic acid or folinic acid for reducing side effects of methotrexate for people with rheumatoid arthritis

Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, Bombardier C, Wells GA, Tugwell P
Published Online: 
25 June 2013

Researchers in The Cochrane Collaboration conducted a review of the effect of folic acid or folinic acid for people taking methotrexate for rheumatoid arthritis. After searching for all relevant studies, six studies with up to 624 people were included in the review. Their findings are summarized below.

In people with rheumatoid arthritis who take methotrexate (MTX):

- Taking either folic or folinic acid probably improves some side effects of MTX such as nausea and abdominal pain

- Taking either folic or folinic acid probably reduces the chance of developing abnormal liver blood tests

- Taking either folic or folinic acid probably helps people continue on their MTX treatment

- Taking either folic or folinic acid may improve some side effects of MTX such as mouth sores

- We are unable to ascertain whether or not taking folic or folinic acid with MTX prevents neutropenia (problems with producing white blood cells)

- Taking folic or folinic acid with MTX probably has no effect on how well MTX is able to treat rheumatoid arthritis.

What are folic acid and folinic acids and why do people take them with MTX?

Folic acid and folinic acid are forms of vitamin B9. The human body needs folate to perform many functions, including cell division, growth, and the production of new red blood cells. Folinic acid is chemically different to folic acid but both work in a similar way. If a person does not have enough folic acid or folinic acid, it is called a folate deficiency. MTX (a medication that is commonly prescribed to treat rheumatoid arthritis) works by blocking some of the effects of folic acid. A folate deficiency may cause side effects such as mouth sores, stomach problems such as nausea or abdominal pain, liver problems or problems with producing blood cells. These side effects are sometimes bad enough that they cause people to stop taking MTX (discontinue treatment).

Best estimate of what happens to people who take folic acid or folinic acid while on MTX

Stomach problems such as nausea, vomiting or abdominal pain:

- 9 fewer people out of 100 experienced stomach problems such as nausea up to 6 to 12 months after starting folic acid or folinic acid with their MTX (9.0% absolute improvement);

- 35 people out of 100 experienced stomach problems such as nausea when they took MTX alone for their rheumatoid arthritis;

- 26 people out of 100 experienced stomach problems such as nausea when they took folic acid or folinic acid with their MTX.

Liver problems (as measured by abnormal liver blood tests):

- 16 fewer people out of 100 had liver problems up to 6 to 12 months after they starting folic acid or folinic acid with their MTX (16.0% absolute improvement);

- 21 people out of 100 experienced abnormal liver blood tests when they took MTX alone for their rheumatoid arthritis;

- 5 people out of 100 experienced abnormal liver blood tests when they took folic acid or folinic acid with their MTX.

Ability to continue on MTX treatment:

- 15 fewer people out of 100 who took folic acid or folinic acid dropped out of the studies for any reason (15.2% absolute improvement);

- 25 people out of 100 who took a placebo (fake folic acid or folinic acid) with their MTX dropped out of the studies for any reason;

- 10 people out of 100 who took folic acid or folinic acid with their MTX dropped out of the studies for any reason.

Mouth sores or ulcers:

- 6 fewer people out of 100 who took folic acid or folinic acid with their MTX developed mouth sores (6.2% absolute improvement);

- 22 people out of 100 who took a placebo (fake folic acid) with their MTX developed mouth sores or ulcers;

- 16 people out of 100 who took folic acid or folinic acid with their MTX developed mouth sores or ulcers.

This record should be cited as: 
Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, Bombardier C, Wells GA, Tugwell P. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD000951. DOI: 10.1002/14651858.CD000951.pub2
Assessed as up to date: 
2 March 2012