Trial Report Exercise capacity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) treated with long-term pyridostigmine, 2023, Systrom

[Dolphin]

https://erj.ersjournals.com/content/62/suppl_67/PA4639

Exercise capacity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) treated with long-term pyridostigmine
Johanna Squires, Sarra Al-Zayer, David Systrom
European Respiratory Journal 2023 62: PA4639; DOI: 10.1183/13993003.congress-2023.PA4639

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Abstract
Background: The pathophysiology underlying exertional intolerance in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains poorly understood. Previously, a single-dose of 60 mg pyridostigmine, a reversible acetylcholinesterase inhibitor, was found to acutely improve aerobic capacity (Joseph, P. et al. Chest 2022; 162:1116–26).

Aims: To build upon these prior findings, this study aimed to evaluate the long-term effect (>1 month) of pyridostigmine treatment on exercise intolerance in ME/CFS.

Methods: Between 2017-2022, patients who met the National Academy of Medicine criteria for ME/CFS, and had a minimum of two clinical, constant load, submaximal exercise tests (Shape Medical System, MN) were evaluated. Patients who began pyridostigmine after their baseline test were considered the treatment group. Measurements were taken at baseline (T0) and most recent follow-up (T1).

Results: At the follow-up evaluation (690 ± 547 days), the treatment group (n=37, dose range: 24-360mg/d) demonstrated a significant increase in oxygen uptake efficiency slope (OUES) (T0: 1.82 ± 0.56, T1: 1.98 ± 0.53; p=0.044) and pulmonary vascular capacitance (PVCAP) (T0: 486.19 ± 169.89 ml*mmHg, T1: 540.03 ± 170.59 ml*mmHg; p=0.040). These differences were not observed in the control group (n=16) OUES (T0: 1.62 ± 0.40, T1: 1.77 ± 0.47; p=0.268) and PVCAP (T0: 446.94 ± 144.80 ml*mmHg, T1: 465.81 ± 124.34 ml*mmHg; p=0.590).

Conclusion: Long-term treatment with pyridostigmine improved aerobic capacity in ME/CFS as demonstrated by an increase in OUES, mediated by improvements in central hemodynamics (PVCAP).

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• Physical activity

Footnotes

Cite this article as: European Respiratory Journal 2023; 62: Suppl. 67, PA4639.

This abstract was presented at the 2023 ERS International Congress, in session “Inflammatory endotyping: the macrophage across disease areas”.

This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).

https://twitter.com/user/status/1719714712898654547

 

[Hutan]

As much as I'd love mestinon to be an answer, and as much as I want Systrom to keep investigating, and as much as I think a problem related to acetylcholine is plausible, the result isn't overwhelming.

The sample size is small: 37 in the treatment group, 16 in the control group

The effects are small:

• oxygen uptake efficiency slope - treatment group 1.82 to 1.98 = 0.16; control group 1.62 to 1.77 =0.15
• pulmonary vascular capacitance - treatment group 486 to 540 =54; control group 447 to 466 = 19

We aren't told how many outcomes were measured - are these cherry-picked results?

The control group appears to be quite a lot worse at baseline, raising issues of how matched the controls were with the treatment group. And also if the decision to try pyridostigmine was random.

The p-values for the improvement in the treatment group are close to suggesting the results aren't significant - p=0.044 and p=0.04. What I assume are standard deviations are really very large in both treatment and control groups. The apparent benefit of mestinon could, I think, easily be a result created by natural variation, improvement over time, and the larger sample giving better significance.

Open label, although objective outcomes. Perhaps there is a little room for assessor bias (reading instruments?, choosing which participants would be in the study), although it probably isn't a big factor.

 

[LarsSG]

"the treatment group (n=37, dose range: 24-360mg/d) demonstrated a significant increase in oxygen uptake efficiency slope (OUES) (T0: 1.82 ± 0.56, T1: 1.98 ± 0.53; p=0.044) [...] These differences were not observed in the control group (n=16) OUES (T0: 1.62 ± 0.40, T1: 1.77 ± 0.47; p=0.268)"

This is a bizarre and misleading way of presenting these results. The difference for the treatment group and control group is basically the same (a 9% increase, actually slightly higher in the control group in terms of percentage), but here they are reporting that one difference is significant and the other isn't. But the reason the difference in the treatment group is significant is because there were 37 patients in that group and the reason the control group difference wasn't significant was because there were only 16 patients in the group! What they have measured looks like it is the same thing in both groups (though we can't know for sure without more data).

What they should be reporting is the statistical significance of the change in OUES between the two groups.

In any case, this is not a difference and shouldn't be reported as one. I'd expect better than this kind of basic statistical error from someone like Systrom.

The difference in PVCAP does look like it might be meaningful (11% versus 4%), but there are also some pretty wide standard deviations on those measurements, so it's hard to be sure. It's not a huge difference, in any case.

 

[Hutan]

Another thought, given the apparent high variability in CPET results depending on prior exertion, we could expect that there would be a lot of noise in a study that looked at the change in results from one CPET at time 'x' and another CPET at time 'x + approx two years'. You would need to be controlling pre-study exertion I think.

I think that's true for the oxygen uptake efficiency slope. I don't know about the pulmonary vascular capacitance - do we know how that changes in a 2xCPET? I think if people with ME/CFS were materially better after two years, there would be, on average, an increase in fitness, so we would expect to see an increase in Vo2max, but this was not reported here.

 

[LarsSG]

I'm searching for pulmonary vascular capacitance and finding that it seems to be defined as stroke volume divided by pulse pressure, but here they seem to be defining it as stroke volume times pulse pressure. Not clear why.

Without a full study to look at here, my worry would be that, even if PVCAP is significantly different, it might not be in the context of multiple comparisons, as I recall Systrom's work involved quite a few different measured variables and calculated values.

I agree, if this is the best they came up with after a couple years of treatment, it looks pretty weak.

 

[Sid]

This is incorrectly analysed. The abstract doesn't present statistical difference between the groups.

 

[SNT Gatchaman]

And also if the decision to try pyridostigmine was random.

It doesn't read as if it was.

Patients who began pyridostigmine after their baseline test were considered the treatment group.