Back to the Future? Immunoglobulin Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2021, Brownlie and Speight

Abstract
The findings of controlled trials on use of intravenous immunoglobulin G (IV IgG) to treat myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are generally viewed as representing mixed results. On detailed review, a clearer picture emerges, which suggests that the potential therapeutic value of this intervention has been underestimated.

Our analysis is consistent with the propositions that:
(1) IgG is highly effective for a proportion of patients with severe and well-characterised ME/CFS;
(2) responders can be predicted with a high degree of accuracy based on markers of immune dysfunction. Rigorous steps were taken in the research trials to record adverse events, with transient symptom exacerbation commonly experienced in both intervention and placebo control groups, suggesting that this reflected the impact of participation on people with an illness characterised by post-exertional symptom exacerbation.

Worsening of certain specific symptoms, notably headache, did occur more commonly with IgG and may have been concomitant to effective treatment, being associated with clinical improvement. The findings emerging from this review are supported by clinical observations relating to treatment of patients with severe and very severe ME/CFS, for whom intramuscular and subcutaneous administration provide alternative options.

We conclude that:
(1) there is a strong case for this area of research to be revived;
(2) pending further research, clinicians would be justified in offering a course of IgG to selected ME/CFS patients at the more severe end of the spectrum.

As the majority of trial participants had experienced an acute viral or viral-like onset, we further suggest that IgG treatment may be pertinent to the care of some patients who remain ill following infection with SARS-CoV-2 virus.

https://www.mdpi.com/2227-9032/9/11/1546

 

I had IVIG treatments in 2016-2017. Prior to that I had subcutaneous immunoglobulin treatment, with no resulting improvement in health from either.

I notice more people with ME saying they’re being prescribed this treatment recently though, in particular after being diagnosed with small fiber neuropathy.

I’m interested in what others’ experiences or opinions of this are.

I was prescribed these treatments because of ME and low immmunoglobulin levels.

 

IVIG was used a lot for inflammatory and autoimmune conditions in the 1980s largely because it seems to have a useful immediate effect in immune thrombocytopenia - probably for rather complicated and unique reasons.

In pretty much all other conditions it was never shown to be of significant benefit and it has a lot of side effects and is expensive. In addition, IVIG is in very short supply with primary IG deficiency and its use for other conditions threatens these people's survival.

By 2000 IVIG had pretty much stopped being used for anything inflammatory or autoimmune because it just didn't do much and there was never any good theoretical reason anyway.

Giving IVIG for low immunoglobulin levels is a completely different issue that has nothing to do with inflammatory disease or, as far as we know, ME. I don't think the original reason for using IVIG in ME had anything to do with low immunoglobulins. If it did it was because of theories about immunodeficiency which are no longer held.

So basically there is no background reason to think IVIG would be useful for ME.
That leaves the trial evidence. Last time I looked at it I thought it was unconvincing too. Certainly nothing major in the way of benefit. I personally think it should be left well alone.

In simple terms I cannot think that IVIG is going to be any use to PWME and like other things I think it raises false hope. That is something Dr Speight has put a lot of emphasis on - not to raise false hope.

 

@Jonathan Edwards

What’s your take on an increasing number of PwPE being diagnosed with small fiber neuropathy (by skin punch biopsy) and being prescribed ivig as treatment.

I know a number of PwME in that situation. Other PwME are being diagnosed with Sjogren's and are being prescribed ivig as treatment.

As I noted above I had ivig and had no health improvement. The reason for prescribing it to me was low immunoglobulin levels. That’s why insurance covered it. But the idea behind it was that it would improve ME symptoms. It didn’t improve anything of course.

Anyway I am just wondering if people getting diagnosed with small fiber neuropathy or Sjogren's have a condition that may respond to ivig?

I myself am now too sick to any longer leave the house for further testing.

After I typed my questions above
I reread your post above ☝️ mine and I think you are saying that there is no evidence that ivig would be an appropriate treatment for small fiber neuropathy and Sjogren's. I just want to confirm that I am understanding correctly. (Brain fog is thick right now).

 

One doctor I saw wanted me to get a punch biopsy as a sort of “lottery ticket” to qualify me for insurance-covered IVIG. It had nothing to do with actually having SFN or not.

 

As @5vforest says this is just a ticket for reimbursement for the private physician I suspect.

The diagnosis of SFN by punch biopsy is probably mostly a scam. The test is to count the number of nerves and that is the easiest thing in the world to get a 'positive' result on. Counting things on microscope slides is wildly subjective.

The bit about having low Ig levels is the same. Almost everyone will have a lowish level on one of the Its at some time and that can be used to tick the insurance box. It has nothing to do with actual being immunodeficient, which requires profoundly low levels of certain specific Igs and evidence of infective consequences.

 

Now I understand why my neurologist told me that looking for SFN by punch biopsy was too unreliable.

 

To be fair though, high dose IVIG (2g/kg) is very effective in autoimmune illnesses of the CNS that are mediated by autoantibodies like autoimmune encephalitis and Guillain-Barre. But maybe you are talking about low dose IVIG...

 

No, I am talking about high dose IVIG. I don't think it is really that effective in those conditions. Most of the accounts of benefit are uncontrolled and may well involve other factors. All these conditions are now treated other ways with rituximab or major immunosuppression as far as I know. Guillain Barre probably isn't an autoimmune disease and has a remitting course in many cases so has always been difficult to study.

Are there any decent controlled trials that show that IVIG really does much in any of these conditions?

 

It has been a while but back when i was looking at autoimmune encephalitis studies IVIG was always referred to as first line immunotherapy. Given the nature of AE (it usually kills the patient quickly if untreated, catastrophic neurological failure etc) i assume it's not hard to see if a treatment is really working or not, especially if it's a treatment that targets the root cause of the disease. If a patient goes from nearly dying with severe focal symptoms to remission (which is what ought to happen if IVIG is working, not just a modest improvement) then it's quite apparent that the treatment is working, there is little room for bias (of course not a single patient but over hundreds of treated patients). Since the patients die if untreated and it's a rare illness i doubt there are any studies that compared IVIG to placebo, but if it's considered a first line treatment surely they compared it to high dose methylprednisolone, rituximab plasmapheresis etc and saw similar efficacy.

 

I really doubt it. Professor Angela Vincent is probably the most knowledgeable person on this and I have not heard her talking of good evidence for efficacy of IVIG. I think plasmapheresis, azathioprine and steroids are preferred to rituximab because they work quicker and that is important.

 

@Jonathan Edwards

How useful do you view autoantibodies tests to diagnosis small fiber neuropathy?

The paper above cites https://www.medscape.com/viewarticle/936745


“A significant proportion of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia may have potentially treatable underlying autoimmune-associated small-fiber polyneuropathy (aaSFPN), pilot data suggest.

The findings, from a single-site study of 61 patients with ME/CFS, were presented August 21 at the virtual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis by Ryan Whelan, BS, a research assistant at Simmaron Research Institute, Incline Village, Nevada.”

….

“They identified 61 patients as possibly having comorbid aaSFPN. Of those, 52% tested positive for at least 1 of 4 autoantibodies, including antimuscarinic cholinergic receptor 4 (47%), anti-beta-2 adrenergic (27%), antimuscarinic cholinergic 3 (25%), and anti-beta-1 adrenergic (13%). These autoantibodies were linked to ME/CFS in a recent Swedish cohort study.

"Evidence supports that these autoantibodies may bind to receptor sites, blocking ligands from reaching these receptors. Disturbances of adrenergic and cholinergic receptors by these autoantibodies may contribute to symptoms of autonomic dysfunction in ME/CFS," Whelan said.”

…


“In addition, he described anecdotal data from a single patient with ME/CFS who had neuropathic symptoms. The patient was treated at Simmaron. The 56-year-old received two IVIG infusions given 6 months apart. The patient experienced a dramatic reduction in levels of all four of the relevant autoantibodies and favorable symptom reduction, as shown in clinician follow-up records. "With the success of this case study, we intend to further evaluate IVIG as a potential treatment in ME/CFS patients. With this research, we hope to identify a subset of ME/CFS patients who will respond favorably to IVIG," Whelan concluded.”

 

They are not relevant.
Whether or not there is neuropathy can only be judged by neurological tests.

Autoantibodies occur in lots of normal people.
The autoantibodies quoted occur in almost as many normal people as PWME and may be the same proportion. I don't think they mean anything. Measuring them has become a fashion. Unfortunately when medical science is short on positive findings it is dominated by such fashions.

 

https://www.youtube.com/watch?v=SLVzBn0D-s4

Here is a video of Angela Vincent talking about IVIG's immunosuppressive activity in the context of antibody mediated CNS disease. She says: "i'm surprised it works so well". (15:48)

 

That's interesting, seems to be very recent. As far as I could see the literature was mostly anecdotal until recently and there has been a randomised controlled trial that was at least positive. Angela's comment suggests that she was surprised - so had previously not been convinced?

I still have major reservations in that it seems unlikely that IVIG would hold off these conditions for very long and that if someone is actually o recover they will need steroids and immunosuppressives. This is a bit similar to the ITP situation where IVIG is life saving in the short term.

 

If Angela Vincent was talking about a particulate publication (evidence that IVIG worked) then it might be useful to post that study on his forum.

 

I couldn't find a formal trial report. Maybe it is still in press.
Unfortunately, PubMed has changed format and does not list things automatically bey date any more.

 

Patient experience: my daughter had these IVs and around the 4 th one developed severe allergic reaction ( swelling of lips and tongue) and required IV Benadryl

no noticeable benefit in terms of ME symptoms

I’m so tired of treatments when we don’t seem yet to know what has gone wrong and really where.

 

What a informative and interesting video! thanks, @Hubris.

I really appreciated Angela Vincent's clear communication of her knowledge. They also discuss the difficulties and of following antibody levels over time in a patient and the importance of case study publications and more.

@FMMM1, I thought Angela said in the video that we don't really know why IVIG can sometimes work and states her knowledge may be a little out of date. She doesn't cite any specific studies and speculates that it may be a form of immunosuppresion.

 

Not sure if these are helpful or not: 1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292678/ 2. https://onlinelibrary.wiley.com/doi/10.1111/dmcn.13349 3. https://onlinelibrary.wiley.com/doi/10.1111/dmcn.13159 4. https://sci-hub.se/10.1007/s10072-019-03930-3