Wednesday, 22 May 2019

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Methotrexate and Folate Use by Rheumatologists - Survey Results

The February 2017 RheumNow “Live Vote” surveyed US and non-US rheumatologists about their beliefs and practices regarding folic acid and methotrexate (MTX) use. A total of 495 responses were tabulated in 2 weeks. In the first week the survey only went to US rheumatologists from the RheumNow database and had 298 responses (most occurring in the first day). In the 2nd week we invited from rheumatologists and practitioners on social media and had an additional 174 responses from 33 countries, 55% of whom were from the United States (US).

Overall, these results indicate that regardless of the source, rheumatologists are consistently conservative. All use folate when prescribing MTX, with nearly two-thirds using folate 1 mg per day. Less than 11% hold folate on the day that MTX is given, even though there is not sufficient data to support this practice. Leucovorin use (instead of folate) is rare (<1%).

Roughly half of rheumatologists will permit 1-3 alcoholic drinks per week while on MTX. A quarter are a bit more restrictive allowing only 1-3 drinks per month. While 15-20% forbids any alcohol use, 6-7% has no restrictions on alcohol (provided there is no underlying liver disease).

MTX monitoring for those on chronic, stable doses of MTX is usually done every 12 weeks (74%), with fewer (18-19%) doing labs every 6-8 weeks.

Below are the responses and comments from Dr. Kremer on his preferred answers to these questions.

Question 1. With MTX use, what dose/schedule of folate do you prescribe?



Results (US Rheums- Social Media Rheums)

Comments by Dr. Kremer


1 mg qd




1-2 mg qd (not on MTX Day)


There is no reason to hold folate on MTX day. Somehow this has taken hold in Europe. Folate is not taken up via the reduced folate carrier (RFC;that functions to take up MTX and folinic acid and dietary folate [which is always methyl tetrahydrofolate CH3-FH4). But supplemental folate we give our pts is fh2 and this enters the cell through a different, not active, transport. You are not interfering with MTX function or uptake when you give folate the day of MTX. Leucovorin (FH4) is however taken up via the RFC, as is sulfasalazine!  Leucovorin will compete with MTX for FPGS (folyl polyglutamate synthetase; the enzyme that polyglutamates FH4 and MTX); but supplemental folate does not. That's why we never give leucovorin simultaneously with MTX, but at least 8-10 hours later when most of the uptake at the RFC has already occurred.


5 or 10 mg folate once weekly


This makes no sense. The excess will just be renally excreted.


Leucovorin post-MTX dose

1%- 0

I use leucovorin for alopecia (works really well in most cases) and oral ulcers. Some with transaminitis may also respond. Also for patients who mistakenly take MTX > 1 day per week and have bone marrow and other toxicities. Leucovorin is known to "chase" MTX from the cell


No folate


Big mistake! This is why we had so much trouble with MTX when it was first used in the early and mid-1980s; Always use daily folate!




Question 2. What is your rule about how many alcoholic drinks you allow your patients while on MTX?





This will be very variable and depends on patients’ alcohol dehydrogenase and folate pathway snps. No one has ever studied the amount of alcohol that is safe.


There are 1-2 reports of no cirrhosis or ascites when people have 2-4 drinks per night. but they report transaminase enzymes <3x. Our studies have shown that if one measures transaminase enzymes monthly and that if 6/12 are anywhere in the abnormal range, that the annual liver biopsy deteriorates. 


Bottom line: start out by recommending that "1-3" drinks per week. This is probably ok for most patients; but consider measuring hepatic enzymes monthly for the first 6 mos., and if any elevations, lower the alcohol allowed.



1-3 drinks per month




1-3 drinks per week




No limit




Question 3. With chronic, stable MTX use, how often do you do monitor CBC and LFT’s? 




Mandatory when starting; unnecessary with chronic stable MTX use


Q 6-8 weeks


 Excessive unless warranted by safety issues


Q 12 weeks


This is the correct answer when a patient has demonstrated that they are reliable and on a stable dose


Q 24 weeks


Insufficient monitoring

The graphic results show no difference in survey results for Question 3 (monitoring) between those Rheums from RheumNow (US Rheums) and Rheums invited from social media.

US vs. Non- US Rheums.

Comparison of US and non-US rheumatologists revealed the same results for Questions 2 (EtOH) and 3 (monitoring). However, interestingly different results were seen with regard to methotrexate dosing (see table results below). Whereas the standard for folate dosing in the US is 1 mg qd (90%), non-US rheumatologists tend to use either 5 or 10 mg once weekly (76%). While the biology appears to favor daily folate use, the largely European practice of weekly folate is supported by clinical success.


US vs. Non-US Rheumatologists Answer:  With MTX use, what dose/schedule of folate do you prescribe?



US (n=295)

Non-US (n=157)


1 mg qd




1-2 mg qd (not on MTX Day)




5 or 10 mg folate once weekly




Leucovorin post-MTX dose




No folate



The author has no conflicts of interest to disclose related to this subject

Rheumatologists' Comments

Hello!In Algeria (North Africa) we use the dose of 5 to 10 mg per week, with a dose always lower than that of methotrexate, taken 48 hours after methotrexate; you should know that folic acid exists as a single dose of 5 mg per tablet
In a patient whose mother has a MTHFR mutation, do you check for a MTHFR gene mutation prior to starting methotrexate? Do we need to worry about adjusting the methotrexate dose or using a different agent if a patient has a mutation of the MTHFR gene? Thanks in advance for your input in this.

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