Methotrexate- welcome your comments, musings and insights

[peglem]

Allie is on a weekly dose of methotrexate since February. In April we discovered that she is compound heterozygous for MTHFR mutation. Methotrexate suppresses the immune system by blocking folic acid receptors. So I was concerned about using the methtrexate in light of the MTHFR results. The rheumy said she has other patients with that mutation who do okay with methotrexate and since it seemed to be helping my daughter, who is on a very low dose, she thought it would be okay to continue.

 

I give the methotrexate at bedtime on Saturday night and load her up with Deplin (methofolate rx) Sunday morning. She is wonderfully calm and cooperative all day Sunday and most of Monday. Its an amazing difference! Not just a little better- really, really great.

 

We haven't done 23andme yet. So what do you think might be going on here? Would just like people to throw out ideas for me to chew on....It seems strange to me that blocking folic acid would be so helpful when her ability to process it is what is causing her problems in the 1st place.

[LaurenK]

Perhaps the methotrexate is calming the inflammatory cascade and therefore suppressing symptoms. If your doctor has experience in prescribing this medication to other patients who have the same methylation problems, that I would not be overly worried.

Edited June 9, 2013 by LaurenK

[LNN]

It might not be the blocking of the folate receptor that's driving the improvement. I admit I only vaguely grasp the explanation, but Wiki lists two mechanisms of methotrexate. The first being that it blocks the enzyme (DHFR) that folate needs to play its role in DNA synthesis. By doing this, methotrexate leads to cell death and effects rapidly dividing cells, like cancer cells, more than other cells. So it's a cancer treatment drug.

 

The second mechanism of methotrexate is the "inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells.^[13] In these cases, patients should supplement their diets with folate." https://en.wikipedia.org/wiki/Methotrexate (by supplementing with methylfolate, I assume you avoid the cell death mentioned in the first mechanism)

 

What caught my eye in this paragraph is that methotrexate leads to an accumulation of adenosine. "Adenosine plays an important role in biochemical processes, such as energy transfer—as adenosine triphosphate (ATP) and adenosine diphosphate (ADP)—as well as in signal transduction as cyclic adenosine monophosphate, cAMP. It is also an inhibitory neurotransmitter, believed to play a role in promoting sleep and suppressing arousal." https://en.wikipedia.org/wiki/Adenosine

 

ATP (cell energy) is one of the products of an well functioning methylation cycle. But I didn't realize adenosine was an inhibitory neurotransmitter. Perhaps that's effect you're seeing, rather than a direct effect of folate receptor blocking?

Edited June 9, 2013 by LLM

[peglem]

It might not be the blocking of the folate receptor that's driving the improvement. I admit I only vaguely grasp the explanation, but Wiki lists two mechanisms of methotrexate. The first being that it blocks the enzyme (DHFR) that folate needs to play its role in DNA synthesis. By doing this, methotrexate leads to cell death and effects rapidly dividing cells, like cancer cells, more than other cells. So it's a cancer treatment drug.

 

The second mechanism of methotrexate is the "inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells.^[13] In these cases, patients should supplement their diets with folate." https://en.wikipedia.org/wiki/Methotrexate (by supplementing with methylfolate, I assume you avoid the cell death mentioned in the first mechanism)

 

What caught my eye in this paragraph is that methotrexate leads to an accumulation of adenosine. "Adenosine plays an important role in biochemical processes, such as energy transfer—as adenosine triphosphate (ATP) and adenosine diphosphate (ADP)—as well as in signal transduction as cyclic adenosine monophosphate, cAMP. It is also an inhibitory neurotransmitter, believed to play a role in promoting sleep and suppressing arousal." https://en.wikipedia.org/wiki/Adenosine

 

ATP (cell energy) is one of the products of an well functioning methylation cycle. But I didn't realize adenosine was an inhibitory neurotransmitter. Perhaps that's effect you're seeing, rather than a direct effect of folate receptor blocking?

Thank you. I won't pretend to understand all that- I'll have to study up on those links. Hmmm, she sleeps really lousy on her methotrexate night...

[peglem]

So, isn't CamKII involved in the whole ATP/ADP -signal transduction/cAMP thing? Or am I connecting the wrong dots?

[momofadult]

Did a search for methotrexate on the board and came across this post. Amazingly, it was essentially the same question that I wondered about! My son has been on methotrexate 10 mg. orally, once a week, for the past 4 weeks and I have not seen any improvement. If anything, the generalized movement problems are just a bit worse, but I can't be sure its directly related to the methotrexate since his symptom severity fluctuates naturally. I am sure, however, that it has not helped yet. His eye movement symptoms are the most problematic (involuntary blepharospams, random eyeball movements, and light sensitivity) and he rarely fully opens his eyes because of this. He's gotten quite a few bumps and bruises from trying to walk around with his eyes closed!

 

My son does not have a MTHFR mutation, but he has been on high doses of folinic acid for low cerebral folate. This was found in his inital work up for PANDAS. His folate is low in the csf but normal in blood. I can't really comment on how effective folate supplementation has been in protecting him from the folate depleting side effects of methotrexate but his white counts, liver enzymes, and blood folate have remained normal thus far. Tthere is no early way of knowing what effect methotrexzte has on his brain folate without doing another spinal tap. Yes, it makes me nervous too using a drug that works through the folate system knowing that there is a pre-existing folate problem. Yet, Allie's folate problem is different from my son's, she was improving when you posted, and your rheumy has had lots of experience giving methotrexate to individuals with a mthfr mutation. Is she continuing to improve? What dose of the methotrexate does he prescribe?