What folate supplements are available and the dose that should be administered.
Folic acid supplementation, 1-2 mg daily prevents some potential undesirable side effects of weekly methotrexate such as stomatitis, and even liver function abnormalities,
Dear Mita, you will find this data in the published rheumatology literature of the 90's, having to do with the management of RA with MTX; there were a number of papers then published for example in Arthritis & Rheumatism (now Arthritis & Rheumatology), and other journals. Also, any rheumatology textbook chapter dealing with the treatment of RA with MTX would have references mentioning folic acid supplementation; hope this helps,
Folate metabolism is complex and having researched folate and related compounds for fifty years I find it impossible to give a straightforward answer.
Methotrexate affects several important metabolic pathways, in your case it inhibits dihydrofolate reductase which is needed to reduce synthetic folic acid to dihdrofolate and then to tetrahydrofolate which is its metabolically active form. Folic acid in supplements could potentially add to the effects of methotrexate. Dietary folate in fresh vegetables is already reduced so all this is a balancing act to maintain methotrexate at effective concentration without having the side effects. The methotrexate dose level for arthritis is well below that given to treat certain cancers. Have a normal balanced diet.
I hope this answered your question.
I use folate 5 mg 24 hours after methotrexate . Some side effects can be blocked or can improve as Emilio Gonzales write. Other side effects such as general malaise and nausea respond less, even anticipating folate supplementation, after 12 hours for example. In several patients, these side effects determine the suspencion or dosage reduction and folate supplementation is not effective . In course of therapy with MTX, I do not use folate supplementation in the same day .
YEs I agree, Folate definitely is needed once a week and NOT on the day of Methotrexate. evidence is historical and it works very well. UK MHRA guidance also suggests the same
Dear Mita,
the general answer to your question is "yes". Nevertheless, to all good questions, there are lots of particular considerations in the answer.
1. MTX have folate-dependent and folate-independent side effects. Folate supplementation will not help the latter.
2. Folates are part of the B vitamin complex: specifically B9. The word "vitamin" comes from "vital amine". They are essential to health/life. When the French explorer Jacques Cartier landed in Canada after weeks-months at sea, many of the sailors were sick with or died from scurvy (Vit C). It is said that if there had been ONE lemon on board and if they had shared tiny bits among them every few days, nobody would have been sick. So, it does not take much of any vitamin to prevent deficiency. A balanced nutrition usually suffice. My points:
a) most well nourished MTX treated patients will not have any folate-dependent side effects, making a good study on folate supplementation requiring a very large population sample and it will be nevertheless difficult to interpret because of the nutrition confounding factor.
b) documenting folate deficiency objectively is notoriously difficult in any patient.
c) there are some genetic differences in folate metabolism among patients. Those may or may not require specific supplements to overcome them: the use of more folic acid or the use of folinic acid..
3. How to use folate supplements?
a) MTX is activated in the liver and the blood concentration is obtained immediately and 24h later most of it is in the urine. So, avoid folate the day of MTX.
b) like other colleagues, we use folic acid 5mg, ONE tablet/week, the day after MTX. Compared to the usual dose of MTX, that is a large excess of vitamin. We call it tongue-in-check, "la pilule du lendemain". The rest of the week is off.
c) in the USA, they use folate daily except on the MTX day. I have no real data but I think that may decrease the efficacy of MTX. The American rheumatologists use more Biologicals than Canadian rheumatologists although we use roughly the same MTX doses (p.o. or s.c.). Could it be that less folate supplements, leads to a different net MTX dosage and more MTX-resistant patients? A related point about sub-optimal MTX treatment of patients admitted in most trials of Biologicals is being made recently in Ann Rheum Dis.
d) folic acid is cheap, folinic acid/leucovorin is expensive.
hope that helps the discussion.
HM
The point highlighted by Henry Menard are very interesting !
As said, I use folic acid 5 mg once a week the day after MTX. But in experience of some Italian collegues, the non-use of folic acid is not able to increase folate dependent side effects.......Some my collegues do not use folic acid in course of treatment with MTX and their patients have side effects equal to my patients.....
Median life of MTX can arrive until six months after its prolungated use, for example on the reproductive part.
The Italian societies of rheumatology recommended this dosage. Are rheumatic patients in America different from Italian patients ? Certainly in Italy it is difficult that a patient can be a dosage of MTX > 20 mg weekly. In America the dosages of MTX are often very high, biologicals or not biologicals.
Galileo Galilei might have to say something about these differencies......
I believe the average oral dose of MTX in the US for the treatment of RA is between 15-20 mg weekly, given orally, with daily folic acid, 1 mg. There is a trend to use greater doses with injectable MTX, using for example 25 mg weekly; however, I suspect that only some rheumatologists do this, not most. I don't either. The advantage of injectable MTX is that it is better absorbed than oral MTX. In addition, when a patient goes on a biologic agent, there is a tendency to gradually reduce the weekly MTX dose some, perhaps to an average of 12.5-15 mg weekly, sometimes less, according to the patient's clinical response,
To be more precise about my comments. For the average empirically treated CANADIAN RA patient,
- anything below MTX 20mg once-a-week PO or S/C, we consider under-usage and
- daily folate supplementation (except the day of MTX), I consider over-usage (likely further reducing the net effective MTX dosage).
That is why, currently, in the so-called MTX-resistant-RA pt-on-a-biological, increasing the dosage of MTX PO or switching to S/C administration will be more effective than varying the dosage of the biological.
Of course, these MTX considerations only apply to Caucasian RA patients as MTX tolerance is much lower in Orientals.
HM
Thanks Emilio for your considerations, very useful for me.
In Italy only a minority of rheumatologists (according to my knowledge) use MTX per os. MTX per os has significant differences in digestive absorption and this can realize significant differences in its avaliability .
Certainly as Henri Menard write, increasing the dosage of MTX in the so-called MTX resistant can be more logic and useful than varying the dosage of the biological. And I do so in my clinical practice.
Some RA patients are very well with 10 or 15 mg weekly especially when associated with Plaquenil or Salazopyrin (500 mg bis in die).
CM
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