In the world of rheumatoid arthritis, the subject of folic acid is forever tied to methotrexate. A discussion of one is incomplete without the other. In searching the medical literature for articles related to ‘rheumatoid arthritis and folate (folic acid)’, I discovered that most of the titles of the articles include mention of methotrexate.
What is methotrexate?
Methotrexate (MTX) is one of the most common disease-modifying anti-rheumatic drugs (DMARDs) used to treat rheumatoid arthritis. It is often prescribed in combination with other DMARDs, as part of Triple Therapy, for patients diagnosed with RA. Methotrexate is prescribed in combination with a number of biologic drugs for RA as well. MTX helps to reduce pain and swelling and also slows the progression of arthritis over time.
Methotrexate is a chemotherapeutic drug, used at low doses in RA, which interferes with the metabolism of folate, a water-soluble B-vitamin. Folate (vitamin B9) is naturally present in many foods including dark green vegetables, fruit and fruit juices, nuts and beans, and fortified grain products. Our bodies need folate to perform many functions, including cell division, growth, and the production of new red blood cells.
Common side effects of methotrexate include those related to folate deficiency such as mouth sores, stomach problems such as nausea or abdominal pain, liver problems, or problems with producing blood cells. MTX can increase the sensitivity of the skin to sunlight (photosensitivity), cause minor hair loss, and aggravate lung problems. MTX can cause severe birth defects and miscarriage, must not be taken during pregnancy, and should be stopped at least 3 months prior to conception.
What are folic acid or folinic acid?
Folic acid and folinic acid are forms of vitamin B9. Folic acid is the synthetic form of B9 that is used in supplements and added to fortified foods. Folic acid is easily available in over the counter supplements and may be prescribed in higher doses to patients taking methotrexate. The recommended daily dose of folic acid for adults is 400-800 mcg.
Folinic acid, or calcium folinate, a derivative of tetrahydrofolic acid, is chemically different to folic acid but works in a similar way. Leucovorin, a prescription form of folinic acid, is used in combination with other chemotherapy drugs to either enhance effectiveness, or as a ‘chemoprotectant’ to counteract negative side effects of folate deficiency.
Are folic acid and folinic acid effective against methotrexate side effects in RA patients?
Yes, according to the Cochrane Review updated in 2013 that included six randomized controlled trials involving 624 RA patients taking MTX (â‰¤ 25 mg/week), of whom 385 also took low-dose folic acid (â‰¤ 7 mg/week). Studies using higher doses of folic acid were excluded because the high dose is no longer recommended or used in clinical practice.
For patients supplemented with either folic or folinic acid while receiving MTX therapy for RA, a 26% relative (9% absolute) risk reduction was seen for the incidence of gastrointestinal side effects such as nausea, vomiting, or abdominal pain. Folic and folinic acid also appear to be protective against abnormal serum transaminase (liver enzyme) elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction, as well as reducing patient withdrawal from MTX for any reason by 60.8% relative (15.2% absolute) risk reduction.
Importantly, there was no significant reduction in MTX efficacy, as measured by disease activity measures such as tender and swollen joint counts or physician’s global assessment scores.
How much folic or folinic acid should RA patients take?
The answer to this question is: it depends. Some rheumatologists recommend that patients take up to 1 mg of folic acid each day as soon as they begin MTX. Some rheumatologists may recommend that only patients who experience side effects of MTX take folic acid â‰¤ 1 mg daily. My doctor is fine with me taking an OTC supplement of 800 mcg folic acid daily, with the exception of skipping the day I take MTX.
The suggested dose/schedule of folic acid may vary by geography, however. Based on a systematic review of studies, a panel of RA experts in Spain recommend that folic or folinic acid is administered as a 5 mg dose once a week, but not within one day of (before or after) taking MTX.
It is important to avoid taking too much folic acid. Doses higher than 1 mg/day may disguise vitamin B12 deficiency, an early symptom of which is anemia. However, taking large amounts of folic acid treats the anemia without treating the B12 deficiency. If a vitamin B12 deficiency is not noticed, it may damage the nervous system.
Folate: Fact Sheet for Consumers. National Institutes of Health Office of Dietary Supplements. Accessed at https://ods.od.nih.gov/factsheets/Folate-Consumer/
Methotrexate (Rheumatrex, Trexall). American College of Rheumatology. Accessed at https://www.rheumatology.org/Practice/Clinical/Patients/Medications/Methotrexate_%28Rheumatrex,_Trexall%29/
Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013 May 31;5:CD000951. doi: 10.1002/14651858.CD000951.pub2.
Singh JA. Folic acid supplements for rheumatoid arthritis patients taking methotrexate: the good gets better [editorial]. Cochrane Database Syst Rev. 2013;7:ED000063. dx.doi.org/10.1002/14651858.ED000063
(Plain language summary)
Tornero Molina J, Ballina Garcia FJ, Calvo AlÃ©n J, et al. Recommendations for the use of methotrexate in rheumatoid arthritis: Up and down scaling of the dose and administration routes. Rheumatol Clin. 2015 January - February;11(1):3-8. doi: 10.1016/j.reuma.2014.02.012. Epub 2014 Apr 18.
Vitamins and minerals - B vitamins and folic acid. NHS choices: Your health, your choices. Accessed at https://www.nhs.uk/Conditions/vitamins-minerals/Pages/Vitamin-B.aspx
Lisa Emrich is a patient advocate, accomplished speaker, author of the award-winning blog Brass and Ivory: Life with MS and RA, and founder of the Carnival of MS Bloggers. Lisa uses her experience to educate patients, raise disease awareness, encourage self-advocacy, and support patient-centered research. Lisa frequently works with non-profit organizations and has brought the patient voice to health care conferences and meetings worldwide. Follow Lisa on Facebook, Twitter, and Pinterest.