Methotrexate and connective tissue changes

[GSD23]

Has anyone with a Connective tissue disorder such as Marfan Syndrome /EDS and taking Methotrexate for RA had any noticeable changes in their connective tissue? With possible added stiffness and pain in muscles- in permanent spasm and shortening of ligaments and tendons? Many thanks.

[Sarahg62]

hi. That’s interesting. I have problems with both elbows. Never really thought about it being connected to taking methotrexate. 🤷‍♀️

[cyberbarn]

Hi, I have hEDS/HSD and was on methotrexate for about 6 months. At first it worked for me, but then it wasn't working so well with a return of joint pain (I also have PsA) and I started getting stomach pain four days after the injection. I stopped the injections and immediately the stomach pain stopped. five weeks later all my original pain is back again, but I am feeling better in other ways.

The problem is, methotrexate doesn't work for everyone so whether or not someone has a connective tissue disorder or not, they may still find that metho doesn't suit them or gives them adverse effects.

Methotrexate is metabolised in the liver, and everyone has different genes for this. For example some people metabolise codeine normally, some are super fast metabolisers of codeine, so even a small dose can send them off with the fairies, and others are very slow metabolisers. For those people they often think they must have terrible pain because the codeine doesn't work, when they may actually have normal levels of pain, it is just that their body doesn't metabolise the drug properly.

Additionally EDS is heterogeneous and they don't know what the cause of hEDS/HSD is so it would be hard to say what interaction there would be between connective tissue disorders and methotrexate.

This paper talks about how MTX works as an anti-inflammatory. It is pretty technical but if you read the 'perspectives and conclusions' it will give you a taste of the complexity. So MTX has both an anti-inflammatory effect as well as acting on the JAK/STAT pathway. ard.bmj.com/content/60/8/729

I have done a quick search of the peer reviewed literature (I am an academic researcher currently doing a PhD looking at pain in EDS) and there is very little even mentioning EDS and methotrexate. Absence of evidence isn't evidence of absence, but if people with connective tissue disorders were having adverse effects to to MTX, it would have come to light just as the problems with certain antibiotics and connective tissue disorders.

[LippyLu in reply to cyberbarn]

This is an interesting and useful article - thanks for the reference.

[GSD23 in reply to cyberbarn]

Thank you for the paper Cyberbarn. I couldn't find much at all either on RA and Marfan/EDS but the Consultants tell us there is certainly an increased risk of all types of arthritis with hypermobility. In the US some specialists are looking at TGFb1's role in inflammation as TGFb1 levels as when tested TGFb1 levels can be found to be higher than normal in people with Marfan and EDS.

I wondered as a lay person if the Methotrexate can make changes in intracellular fluid levels? Or by reducing the inflammation levels could that in turn cause a desiccation effect in connective tissue at a cellular level?

[cyberbarn in reply to GSD23]

Yes, it is well documented in peer reviewed papers that some people with Marfan/EDS have early onset arthritis. All those micro tears lead to inflammation and if the inflammation cycle goes wrong osteoarthritis is likely to happen. But there will also be the genetic predisposition for the different arthropathies, especially when it comes to RA and PsA.

As for your second question, I am not sure if MTX would refuse levels of inracellualar fluid, MTX works via folic acid receptors, which is why people take extra folic acid but not on the days when they take MTX.

I haven't got time to go through this paper, but you might. It is a paper that shows how MTX works. exagen.com/wp-content/uploa...

As for reducing inflammation levels, inflammation isn't one thing, and isn't mediated by a single thing. Inflammation is part of the healing process, when the injured tissue is healed, inflammation dies back. The problem is sometimes it doesn't dial back and the inflammation becomes chronic and what previously was a Good Thing for the healing process begins to cause damage. But there are different critters as I like to call them, that cause the inflammation. You may have heard of cytokines? There are lots of different ones, but they don't cross into the cells, they target receptors on the outside of cells. The wikipedia page en.wikipedia.org/wiki/Cytokine

This isn't my area of expertise, but I wouldn't think they would make changes in cell fluid levels, but there could be something else going on. Sorry I can't help you any more than that, but I hope that paper might help set you in the right direction to find more information.

Do you know about Google Scholar? That is the search engine to use to find peer reviewed papers. scholar.google.co.uk/

[LippyLu]

I have classical-like EDS (TNXB mutations) and take methotrexate for biomarker-positive RA. I still have some pain, including in my subluxing elbows, but I don’t think it’s due to MTX. I never connected them, at any rate. The MTX continues to be somewhat helpful, after 9 years.