Thesis Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Clinical trials, medical treatment and pathomechanisms, 2024, Rekeland

If we are revisiting the 2020 study, then have a look at some of the other metrics like fatigue score, steps, function level, etc. Like I said above I’m not a fan of the PF questions.

 

Thanks for clarifying. As you said, your patients had much more than six doses. It is also likely they had a history of other immunosuppressive treatments.

I accept that suppression of adverse events does happen, but the second and third cancer studies that I posted used data from Danish and Sweden registries of cancer patients which I think we can trust.

The 40% bladder cancer rate is for the (almost obsolete) long term oral protocol. 100mg a day for years results in huge cumulative doses. For pulsed IV doses bladder toxicity is reduced by consuming lots of fluids and urinating every hour to reduce contact time. This is difficult to sustain for long term oral dosing which also increases the risk for a given cumulative dose.

Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma
“Within a cohort of 6171 two-year survivors of non-Hodgkin's lymphoma (NHL), 48 patients with secondary cancer of the urinary tract were identified and matched to 136 control subjects with NHL who did not develop a second malignancy.”

“Among patients who received a total amount of cyclophosphamide of less than 20 g, a nonsignificant 2.4-fold risk of bladder cancer was apparent. Significantly elevated sixfold and 14.5-fold risks of bladder malignancy followed cumulative doses of 20–49 g and 50 g or more. For patients given cumulative doses between 20 and 49 g, the absolute risk of bladder cancer is on the order of three excess cancers per 100 NHL patients” This is at 15 year follow-up and no doubt a few more have been diagnosed since.

For arguments sake I will make a linear extrapolation from the above data assuming a mean cumulative dose of (20+49)/2 =34.5g. 34.5/7.5= 4.5 fold dose reduction. 3(excess cancers)/4.5= 0.65 excess cancers per hundred patients for a 7.5g cumulative dose.

However the real number is much lower because the risk is exponential not linear. This is another study using data from the Swedish cancer registry. “The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide”.

The risk of bladder cancer at 7.5G is not zero, but it is so low that it is unlikely there will ever be a study big enough to reach statistical significance.

 

No they only had two doses in fact, as IV pulses with fluids and meson. I am not saying that this is a statistically useful finding but the reality of supporting people who gradually become more and more incapacitated and then die from a complication of treatment is not easy.

Another part of the problem is the question as to whether risk is increased in people with certain conditions that you might treat.

I agree that the survey data make it look as if the risk is low but there are lots of unknowns and in my field of medicine cyclophosphamide has been steadily disappearing from the treatment options with time, mostly because of toxicity. And even in the conditions where it helps it tends not to be that dramatic, except perhaps sin the context of lupus or Wegener's crisis.

 

I guess if the CAR T-cell therapies work out for a big enough proportion of the patients where it's still used, it might disappear altogether?

 

But cyclo dosage for AI disease is typically 200 mg/kg, correct?

 

No, doses are usually around 750mg total. 200mg/kg would be about 10grams which is more like the dosage for immunoablation with stem cell rescue, which nobody uses routinely although Ann Trainor tried it for lupus about twenty years ago.

 

you mean doses are around 6-800mg per m2 over 6 infusions? Do you mean the specific Lupus low dose type stuff: https://www.jrheum.org/content/jrheum/49/6/607.full.pdf
thats a bit different, The EuroLupus regimen consists of a fixed dose of CYC (500 mg) administered every 2 weeks for a total of 6 doses.

It seems to vary a lot but i dont quite know what the pulse is:
https://www.researchsquare.com/article/rs-504049/v1

what do you mean by people only responding a little and then relapsing, was that from your clinic/work for jus RA or within wider literature?: "
i. In their 10 years follow up, they found that low dose of CTX is beneficial in the long term as 70% of patients that took this regimen did not require any pulse of CTX following their initial therapy. However, they reported that there was no significant difference in mortality between the two groups treated with low dose and high dose of CTX respectively [10]/" https://assets.researchsquare.com/f...-3f2c-45ea-a4b8-d1fe7ee3cdb3.pdf?c=1631883195

Seems to differ but the Norwegians protocol seems in line with a diversity of immune related disorders:
https://secure.library.leicestersho... (Intravenous) UHL Rheumatology Guideline.pdf

 

Dear @Jonathan Edwards

If you can please suspend your skepticism regarding cyclophosphamide for a moment, and accept and that some patients did in fact have a response, why do think that Rekeland/Fluge found that the cyclo responders had significantly lower IGG levels at baseline (please see figure), compared to non-responders. Would this indicate that perhaps patients with high baseline IGG levels had some auto-immune component to their disease that was not able to be treated by the cyclophosphamide? Thank you for your consideration.


In the CycloME trial, the mean baseline IgG and IgG1 levels were predictive for
clinical response, as the levels were significantly lower in the responder group (n=21)
compared to non-responders (n=16) (Figure 3). Significantly lower baseline serum
IgG levels were also found in responders compared to non-responders in a previous
study from our group (61), analysing serum samples from previous rituximab trials
(22, 138).
In the CycloME trial there were significant but modest decreases of IgG, IgM and
IgA during follow up, especially from baseline to 12 months (Figure 3).

 

I don't think the differences will tell us anything specific. Immunoglobulin levels in normal people vary greatly, and apparently of no relevance to health. The IgG differences shown are well in the normal range and give us no functional clues to anything.

I am happy to accept that cyclophosphamide may induce improvement in some people with ME/CFS. My problems with it are just that it is toxic and with the problem with blinding it seems a poor drug to use as a probe.

It does look as if there is something different about people who report improvement after cyclo. IgG is lower but IgM is higher. Both IgG1 and IgG4 are lower and have completely different functional roles so if anything I suspect this is telling us about some feedback effect on Ig production, possibly due to a shift in T cell behaviour. That would fit with the idea that some ME/CFS is a bit like Reiter's with an ongoing shift in T cells. I don't think it points to autoimmunity.

The problem is that reporting an improvement after cyclo might relate to some disease aspect that had only a very indirect epiphenomenal relation to the immune system. It might be just milder disease associated with more activity with a knock on effect on immune regulation. I doubt that particular example but something as indirect as that might explain it.

 

So as I m cognitively impaired ‍️‍️, question :
with **very indirect epiphenomenal relation to the immune system**
You basically mean the casualty is unknown/unclear?

Or are you implying more than that?

Like, for example, a subgroup also Developed some kind of auto immunity as comorbidity (that also perturbates M.E. even more and keeps patients having PEM) and by resolving the auto-immunity, the byproduct is that PEM decreasing ánd slowly disappearing?

 

I am implying that there may be no cause and effect relation between IgG and illness. The report of improvement and the lower IgG levels may both in some indirect way be effects of something very general - like being overweight for instance (a key factor in Covid-19 illness).

In autoimmunity specific populations of antibodies change in level a hundredfold or a thousandfold. You cannot miss it. But total IgG levels come and go and vary from person to person with no obvious consequence. The differences in IgG here look like that, not autoimmunity - the difference between grass and oak trees.

 

I thought Sjogren's especially is known for hypergammaglobulinemia. With early Sjogrens, presenting as dysautonomia, the levels of IgG can show rising trend, but still within limits. I don't know if there is a study on this, but seems to take a long time for Sjogrens to progress enough to have a real hypergammaglobulinemia, and most younger patients with confirmed Sjogrens diagnosis (presenting with dysautonomia and milder sicca, usually) but even when they're SSA positive and/or lip biopsy positive, still dont have high total IgG, and that comes later.

 

Sjogren's and lupus are exceptions. A small proportion of Sjogren's patients also have hypergammaglobulinaemia, which can be substantial. Nobody has much idea why. It probably has little to do with the other features of Sjogren's, which occur in people with normal IgG levels. Sjogren's is a complicated and atypical situation and there is a lot of confusion over diagnosis. I wasn't aware of it being associated with dysautonomia and suspect this is one of those confusions.

The other case is lupus where again a small proportion have hypogammaglobulinaemia. That is easy enough to make sense of in that lupus is an autoimmune disease that involves an error that generates a whole range of autoantibodies and pathologies. Presumably some have autoantibodies that interfere with Ig regulation in a negative way, just as some have thrombocytopenia.

My comments relate to autoimmunity in general.

 

Sjogrens hypergammaglobulinemia correlates with disease activity, severity and some extraglandular manifestations.
It seems to be reported to be common in Sjogrens but when i look younger patients with dysautonomia/MECFS/SFN etc dominant symptoms it is extremely rare to get to the stage of hypergammaglobulinemia

Still, there is no research, at least I didn't find it, on the correlation of overall IgG levels in Sjogrens with some other disease features, but I would say this MECFS report on responders to cyclophosphamide is well on the way to that.

That is strange, but common in rheumatologists, unfortunately.
The connection (better say the overlap) with dysautonomia/POTS/SFN is pretty well established?

https://www.youtube.com/watch?v=Zqwnr4IlujI

 

There is a vast amount f disinformation around 'dysautonomia', to the extent that I suspect 95% of material put out is pure fantasy. I spent my career studying and treating autoimmune diseases including Sjogren's. Most of it is secondary to lupus or rheumatoid. 'Primary Sjogren's' worth calling that is very uncommon and the patients who get the label are so heterogeneous I doubt it is a very useful term. But of course there are private clinics and also niche academics who collect such cases and write stories about them without any real epidemiological basis.

But it is in the opposite direction and well within the normal range as far as I can see?

 

lower IgG correlates with response because less active disease easier to treat?

 

Possibly, but that doesn't in any way require that antibodies are pathogenic and it is still upside down of Sjogren's.

I think we can be reasonably sure that whatever it indicates it suggests that ME/CFS has nothing to do with autoimmunity as we are familiar with it in other diseases.