How do we know that common immune suppressants don’t work in ME?

[Verity]

I was thinking about how it’s generally assumed that immune-suppressing treatments used for various autoimmune diseases don’t work in ME, even though there are quite a few reports of remission after chemotherapy.

We know for sure Rituximab doesn’t work. Cyclo and dara might. But what about other immune-modulating drugs that are used to treat autoimmune diseases, like CellCept or Benlysta or Imuran or high doses of steroids? Do people believe that these probably don’t work because someone would’ve noticed by now if they did, because their action is very similar to Rituximab, or for some other reason? (Or maybe actual researchers don’t assume these drugs don’t work.)

I have a personal interest in this because I have improved for months twice after hefty doses of steroids. I’m curious if some ME patients might in fact be steroid-responsive, and it’s just been assumed that we aren’t for some reason and therefore never tried. I have never seen a study on it. Are we really 100% sure that steroids used how they’re given in autoimmune disease—not low-dose daily steroids—don’t work?

 

[ScoutB]

Yeah I have the same question, especially about steroids. We have anecdotes going both ways about them (for instance, in this thread). The fact that steroids make healthy people feel better too kind of confounds things. On the other hand, going with the theory that ME/CFS may involve some overzealous interferon (or other flu-response machinery), could it be that that stuff is often on at a low level in healthy folks, and having it knocked from 2% to 0% is why steroids feel good even when you're not sick?

Also, I know steroids affect many parts of the immune system (my sense is they are early in some immune pathways?) but if we knew more about how they affected ME/CFS would that help us narrow down what's going on at all?

 

[Verity]

The fact that steroids make healthy people feel better too kind of confounds things.

For the purpose of this particular question, I actually think we’re fairly safe from this as a confounding factor. People with autoimmune diseases (and me with ME, oddly) feel much better for months on end after stopping a steroid. This does not happen to healthy people as far as I know. They feel great while taking it but not semi-longterm afterward.

It is definitely true that ME patients report improvement while taking steroids, but I’m curious if patients have ever been given a high enough dose for long enough to know if there’s sustained improvement after the fact.

if we knew more about how they affected ME/CFS would that help us narrow down what's going on at all?

If it turned out they could induce semi-lasting improvement, I think that would definitely be helpful information. The fact that they apparently cause temporary improvement while taking them is interesting, but I’m not sure how much we can gather from it. Others might have more informed thoughts.

 

[ScoutB]

I’m curious if some ME patients might in fact be steroid-responsive, and it’s just been assumed that we aren’t for some reason and therefore never tried. I have never seen a study on it.

Yes, searching around a bit I found this review from 2017 where they have the below blurb on steroids. I looked up the studies they link, and indeed researchers seem to have only tried low-dose hydrocortisone, or regular-dose fludrocortisone (and, according to wiki, fludrocortisone is not much of an immunosuppresant -- it acts mostly as a mineralocorticoid instead of as a glucocorticoid, meaning it mostly influences salt and water balances).

Treatment with steroids such as cortisol and thyroid hormones has been also studied. Seven RCTs have been performed, four trialling hydrocortisone (McKenzie et al., 1998; Cleare et al., 1999; Friedman et al., 1999; Cleare et al., 2001), two fludrocortisone (Peterson et al., 1998; Rowe et al., 2001) and one with hydrocortisone plus fludrocortisone (Blockmans et al., 2003).

Trying to figure out what the amounts actually were...
The 1998 McKenzie et al., study calls their dose "low", with 20-30 mg daily (depending on the patient).
The 1999 Cleare et al. study also say "low dose", and were having patients take 5 mg or 10 mg daily.
The 1999 Friedman et al. turned out to be a dead link, but they also say "low dose" in the title so I'm going to trust them on that.
The 2001 Cleare et al. study did 5 or 10 mg per day.
The 2003 Blockmans et al. did 5 mg/d of hydrocortisone and 50 microg/d of 9-alfa-fludrocortisone.

Based on googling, it seems none of these doses are in the range we consider immunosuppressive (though to be clear they can still cause side effects).

 

[Verity]

@ScoutB Thanks for looking into that! It does look like a study that would answer this question doesn’t exist.

 

[Jonathan Edwards]

I think steroids have to be considered separately from other drugs. Drugs like azathioprine and mycophenylate aren't that good for autoimmune disease either. People have mostly give up using azathioprine and also cyclo because of long term cancer problems. Methotrexate has been used a lot for RA but isn't much use for a lot of other things and it may work through a different mechanism in RA. I think if any of these drugs were really useful for ME/CFS someone would have noticed. The Norwegians think cyclo is helpful and it may be, but the toxicity is severe.

Steroids almost certainly make people with ME/CFS feel better and it is quite likely they make healthy people feel good partly because cytokines are always being produced at low levels. But the downside of steroids is huge and benefits from introducing steroid tend to wane unless you use very toxic doses.

Autoimmune disease does not usually go on staying good after reducing steroids. In RA if you reduce a dose of 7mg of prednisolone (quite small) just to 5mg the joints will flare up and the person will be immobilised within a day. Courses of steroids are given in lupus and people can stay well after stopping but lupus is an intermittent disease anyway.

The bottom line is that steroids always come with a high price in toxicity. They are used to prevent acute damage during disease flares but minimised otherwise.

There is also the fact that there are no inflammatory changes in ME/CFS that would be logically targeted by steroids.

 

[ryanc97]

Well we need something to reduce the impact of aabs or decrease their production from LLPC.

 

[Jonathan Edwards]

Well we need something to reduce the impact of aabs or decrease their production from LLPC.

Only if autoantibodies are involved and the chances of that look to be significantly less than 50:50.

And if you want to reduce autoantibodies you don't use old-fashioned immunosuppressants. They are hopeless for that.

 

[ScoutB]

Pivoting a bit from steroids then, I started reading about the new interleukin and interferon receptor agonists (they all seem to be drugs ending in "-mab" aka monoclonal antibodies). I guess there is at least one now targeting interferon-1 receptors (Anifrolumab). I haven't looked very hard yet, but I'm not immediately coming across any research into this kind of drug with ME/CFS.

Steroids almost certainly make people with ME/CFS feel better and it is quite likely they make healthy people feel good partly because cytokines are always being produced at low levels.

If an interferon receptor agonist improved ME/CFS symptoms, would that support interferon being pretty important to the disease? Or are these immune-system-targeting antibody treatments like steroids in that they make a lot of people feel better?

Edit: Meant to say antagonists (receptor-blocking) not agonists (receptor activating), luckily JE answered the sensible version of my question anyway

 

[Jonathan Edwards]

I started reading about the new interleukin and interferon receptor agonists (they all seem to be drugs ending in "-mab" aka monoclonal antibodies).

My guess is that antagonists might be more relevant but drugs with this sort of specificity are certainly what are likely to be more use than 'immunosuppression'.

If an interferon receptor agonist improved ME/CFS symptoms, would that support interferon being pretty important to the disease?

Probably an antagonist would. It might lead to an understanding of the main pathway, even if it turned out to link to interferon only indirectly. I doubt specific receptor targeting would make healthy people feel better. (Most of the feeling good with steroids is probably an effect on the brain producing euphoria.)

 

[V.R.T.]

A review of the development of type 1 interferon antagonists in SLE

Type I interferon antagonists in clinical development for lupus - PMC

Systemic lupus erythematosus (SLE) is a severe chronic and incurable autoimmune disease. Treatment includes glucocorticoids and small molecule immunosuppressants which typically result in partial responses, and hence there is a great need for new ...

pmc.ncbi.nlm.nih.gov

Sounds like this is the only interferon antagonist on the market right now.

Anifrolumab - Wikipedia

en.wikipedia.org

Don't think anyones got one for IFNg out yet.

 

[V.R.T.]

Probably an antagonist would. It might lead to an understanding of the main pathway, even if it turned out to link to interferon only indirectly.

What sort of evidence would we need to justify a trial like this? Interferon signalling can be hard to get evidence of sometimes right? Could/should someone just go straight to setting up a theraputic experiment?

 

[Jonathan Edwards]

What sort of evidence would we need to justify a trial like this? Interferon signalling can be hard to get evidence of sometimes right? Could/should someone just go straight to setting up a theraputic experiment?

It is easier if you want to use a drug that has already been tested for another disease. But I would welcome a pilot study of interferon antagonists if well thought out. You could probably treat five patients in sequence, watching out for adverse events before moving to the next patient. If the strategy i good I would expect immediate and obvious relief within 24 hours.

 

[V.R.T.]

It is easier if you want to use a drug that has already been tested for another disease. But I would welcome a pilot study of interferon antagonists if well thought out. You could probably treat five patients in sequence, watching out for adverse events before moving to the next patient. If the strategy i good I would expect immediate and obvious relief within 24 hours.

Sounds like it might be worth doing then, if there are any researchers that could take it on.

 

[Verity]

Sounds like this is the only interferon antagonist on the market right now.

There is one person on Reddit with ME/CFS who says this drug caused major improvement for them. However, they also have an autoimmune disease, so I’m not sure if they truly have the same thing as most ME patients or some other kind of similar-looking exercise intolerance.

I think steroids have to be considered separately from other drugs. Drugs like azathioprine and mycophenylate aren't that good for autoimmune disease either. People have mostly give up using azathioprine and also cyclo because of long term cancer problems. Methotrexate has been used a lot for RA but isn't much use for a lot of other things and it may work through a different mechanism in RA. I think if any of these drugs were really useful for ME/CFS someone would have noticed. The Norwegians think cyclo is helpful and it may be, but the toxicity is severe.

Steroids almost certainly make people with ME/CFS feel better and it is quite likely they make healthy people feel good partly because cytokines are always being produced at low levels. But the downside of steroids is huge and benefits from introducing steroid tend to wane unless you use very toxic doses.

Autoimmune disease does not usually go on staying good after reducing steroids. In RA if you reduce a dose of 7mg of prednisolone (quite small) just to 5mg the joints will flare up and the person will be immobilised within a day. Courses of steroids are given in lupus and people can stay well after stopping but lupus is an intermittent disease anyway.

The bottom line is that steroids always come with a high price in toxicity. They are used to prevent acute damage during disease flares but minimised otherwise.

There is also the fact that there are no inflammatory changes in ME/CFS that would be logically targeted by steroids.

Thank you! This is the sort of information I was looking for. Is lupus the only disease that behaves that way in response to steroids? I was sure I’d heard of others. Interesting about azathioprine; I think it is still used in the US for dermatomyositis.

It is easier if you want to use a drug that has already been tested for another disease. But I would welcome a pilot study of interferon antagonists if well thought out. You could probably treat five patients in sequence, watching out for adverse events before moving to the next patient. If the strategy i good I would expect immediate and obvious relief within 24 hours.

Can I ask why you’d expect such quick relief? I had read that Saphnelo often does not show noticeable effects immediately, even though the interferon-antagonist action starts immediately, so I’m surprised to hear that.

 

[Jonathan Edwards]

Can I ask why you’d expect such quick relief? I had read that Saphnelo often does not show noticeable effects immediately, even though the interferon-antagonist action starts immediately, so I’m surprised to hear that.

If interferon receptor binding is causing symptoms directly you would expect a rapid response. The model would be a TNF inhibitor which produces systemic symptomatic relief in a day or so. Interferons might be acting a bit more upstream so it might take longer. But taking longer tends to relate to getting rid of accumulated tissue pathology, like in RA joints and swelling. In ME/CFS there does not seem to be any such accumulation.

It might take longer.

Is lupus the only disease that behaves that way in response to steroids?

The sister disease ITP does as well. Other diseases I am less convinced. Doctors use high dose steroids to get pathology under control and I think that makes both patient and doctor feel good. But then you have to reduce dose and the patient realises it is all a compromise. Whether the initial high dose was worth it is unclear.

Interesting about azathioprine; I think it is still used in the US for dermatomyositis.

Azathiopine is still used for a number of conditions where we have no good data (usually uncommon ones) on the assumption that it helps but without hard facts. It is probably useful in suppressing antibody production and inflammation but it may often be a placebo. Doctors are slow to move on to new things. Rituximab works very well for dermatomyositis in many cases, but the drawback is that the doctor has to understand B cell biology an most don't.

 

[jnmaciuch]

If the strategy i good I would expect immediate and obvious relief within 24 hours.

Interferon modulators have weird dynamics compared to most other immunomodulators. For both saphnelo and more standard JAK-inhibitors, the most common report is that people feel worse for a few weeks/months and then it starts to show clinical benefit. My best guess is it has something to do with a compensatory mechanism, probably tied to constitutive interferon production.

There are a few JAK inhibitors being trialed for LC but the inclusion criteria will probably wind up recruiting such a heterogenous group that im not sure we’d see results there even if it does work for ME/CFS-like LC

 

[Verity]

@Jonathan Edwards Thank you for the explanations! Very interesting. Medicine moves so slowly sometimes.

 

[V.R.T.]

For both saphnelo and more standard JAK-inhibitors, the most common report is that people feel worse for a few weeks/months and then it starts to show clinical benefit.

Is this in ME/LC or other conditions?

And what do you think of the idea of a Saphnelo pilot trial in MECFS?

There are a few JAK inhibitors being trialed for LC but the inclusion criteria will probably wind up recruiting such a heterogenous group that im not sure we’d see results there even if it does work for ME/CFS-like LC

That's really frustrating. I know the Ely trial is at least monitoring whether people report PEM, even though the focus is neurological issues.

 

[Felis Catus]

Pivoting a bit from steroids then, I started reading about the new interleukin and interferon receptor agonists (they all seem to be drugs ending in "-mab" aka monoclonal antibodies). I guess there is at least one now targeting interferon-1 receptors (Anifrolumab). I haven't looked very hard yet, but I'm not immediately coming across any research into this kind of drug with ME/CFS.

There's a tocilizumab trial for LC in the UK, with inclusion criteria "CRP >5 mg/L persistently raised after contracting COVID-19 and prior to randomisation".

My CRP has been <4 mg/L throughout the illness, and I see they will be doing a respiratory health substudy and multi-organ substudy which makes me think that pwLC with CRP >5 mg/L might have some other abnormalities and not be ME/CFS cases. We'll see.