Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study - 2020 - Rekeland, Mella, Fluge et al

[Jaybee00]

Well not different dosing rates but rather different dosage scheduling. Every 4 weeks the sixth dose is on week 20; every six weeks the sixth dose is on week 30. The total dosage in both cases is the same, about 9 grams.

Every 4 weeks: 0,4,8,12,16,20
Every 6 weeks: 0,6,12,18,24,30

 

[Jaybee00]

@Kitty

can you describe what improvements you’ve had with sulfasalazine?

Thanks

 

[Kitty]

can you describe what improvements you’ve had with sulfasalazine?

Just an improvement in daily function. It's always hard to pin these things down, but other people noticed before I did; one said I seemed to have got new batteries, another whom I met for coffee after a gap of several months said it was great to see me looking so much better.

Of course, some improvement was down to the fact that it reduced the symptoms of the psoriatic arthritis I was taking it for. But that never added much to the fatigue burden, and I'd only had it for a couple of years when I started on the drug. My ME had stopped me doing things a long time before the arthritis began – for instance, I can swim and garden now if I manage my energy, something I'd already been unable to do for more than a decade before my joints started seizing.

I've twice developed neutropenia significant enough for my consultant to take me off the drug, and I begin to feel the difference in my ME after a couple of weeks. They've now just decided to keep an eye on whether the low white cell count actually causes any problems (it doesn't seem to).

It's possible – even likely – that sulfasalazine wouldn't have any effect on other people with ME, or cause adverse reactions because they're sensitive to sulpha drugs. But if it did help some, the 20% improvement in function would be worth having.

I wish I could talk to my rheumatologist about monitoring other ME patients, but it's pointless...she's great on arthritis, but insists ME and fibromyalgia are the same thing.

 

[Jaybee00]

Thanks, interesting. I have one of the HLA risk alleles for psoriasis/psa, but do not have the disease. Maybe I should try sulf?



https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-015-0640-3

• Published: 07 May 2015

Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype

• Oliver FitzGerald,
• Muhammad Haroon,
• Jon T Giles &
• Robert Winchester

Arthritis Research & Therapy volume 17, Article number: 115 (2015) Cite this article
Abstract
This review focuses on the genetic features of psoriatic arthritis (PsA) and their relationship to phenotypic heterogeneity in the disease, and addresses three questions: what do the recent studies on human leukocyte antigen (HLA) tell us about the genetic relationship between cutaneous psoriasis (PsO) and PsA – that is, is PsO a unitary phenotype; is PsA a genetically heterogeneous or homogeneous entity; and do the genetic factors implicated in determining susceptibility to PsA predict clinical phenotype? We first discuss the results from comparing the HLA typing of two PsO cohorts: one cohort providing the dermatologic perspective, consisting of patients with PsO without evidence of arthritic disease; and the second cohort providing the rheumatologic perspective, consisting of patients with PsA. We show that these two cohorts differ considerably in their predominant HLA alleles, indicating the heterogeneity of the overall PsO phenotype. Moreover, the genotype of patients in the PsA cohort was shown to be heterogeneous with significant elevations in the frequency of haplotypes containing HLA-B*08, HLA-C*06:02, HLA-B*27, HLA-B*38 and HLA-B*39. Because different genetic susceptibility genes imply different disease mechanisms, and possibly different clinical courses and therapeutic responses, we then review the evidence for a phenotypic difference among patients with PsA who have inherited different HLA alleles. We provide evidence that different alleles and, more importantly, different haplotypes implicated in determining PsA susceptibility are associated with different phenotypic characteristics that appear to be subphenotypes. The implication of these findings for the overall pathophysiologic mechanisms involved in PsA is discussed with specific reference to their bearing on the discussion of whether PsA is conceptualised as an autoimmune process or one that is based on entheseal responses.

 

[Jonathan Edwards]

So might lengthening the dosing intervals be a way of harm reduction, at least for non-responders?

I would say it is as long as a piece of string. Since we have no idea whether cyclophosphamide is truly effective and no idea how it works if it does all we can say is that the more you give the more toxic it is likely to be and maybe also the more effective but who knows?

The main reason for a gap between cyclo infusions is to allow neutrophils to recover. That takes about two weeks. I don't know why it is given at longer intervals and I suspect nobody else does either.

 

[Kitty]

Maybe I should try sulf?

I wouldn't advise it, unless it's researched for ME – and that won't happen unless someone at least starts with an observational study on ME patients prescribed it for other conditions. It carries risks like all drugs, and needs regular blood tests to check liver & kidney function and blood counts.

By the way, no-one else in our family has PsA (I'd never heard of it till I got it). Simply carrying risk alleles probably doesn't mean very much; having the condition may mean that I carry them, but then so did people in my parents', grand-parents' and great-grandparents' generations. That's well over 100 people, but they lived in a small community, knew one another until they died, and no-one remembered a family member with problematic arthritis. I just drew the short straw!

 

[Jaybee00]

I don't know why it is given at longer intervals and I suspect nobody else does either.

Thanks, that’s what I figured.

 

[Jaybee00]

Some correspondence with Bergen...

"There have been no further updates since the cyclophosphamide study was published in April this year (https://www.frontiersin.org/articles/10.3389/fmed.2020.00162/full). I cannot tell you which proportion of the patients are still in remission, as we have no systematic follow-up of the patients beyond what is described in the article. Every time we contact the patients for follow-up, we need to apply for approval from the regional medical ethics committee. The last time we performed such an extended follow-up was at 38-48 months after the start of intervention, as described in the article.

We believe the results of the cyclophosphamide trial strengthen our hypotheses on the involvement of the immune system in ME/CFS, both in terms of symptom mechanisms and as a target for therapeutic interventions. We are working towards further clinical studies on ME/CFS, but we are as yet undecided on whether cyclophosphamide is the best drug candidate available. Placebo control is one challenging issue, as you point out, but our main concern is toxicity. Although there were few drug-related serious adverse events in the trial, risk of infertility remains an issue and many of the patients did suffer unpleasant, if not serious, side-effects. We are in the process of investigating other possible candidates which may affect the immune system in a beneficial way, before we reach a conclusion on the way forward" ....

[Re changes in cognitive score query]

"We asked the patients to complete a self-report form every two weeks, where they indicated improvement, worsening or no change of a long list of symptoms – among these cognitive symptoms including memory problems, concentration problems and reduced ability to think clearly (“brain fog”). The cognitive symptoms were not a part of the study endpoints and we have not performed formal analyses on these questionnaire items, but our impression during clinical follow-up was that changes in cognitive symptoms followed changes in fatigue symptoms. In other words, the patients who were classed as “responders” generally reported improvement in cognitive symptoms as well.

If you wish to follow the ME/CFS research groups for updates and/or new publications, you can find our web page here: https://helse-bergen.no/en/avdeling...ysikk/research-and-development/mecfs-research "

Comments from me:

1) I think it would be better to stick with cyclo, since it worked.

2) It would be nice if they could analyze the cognitive score data, even if not part of the study endpoints.

 

[Snow Leopard]

Not directly relevant to ME, but you guys might be interested in this:

 

[Andy]

1) I think it would be better to stick with cyclo, since it worked.

However, due to the lack of a placebo group, response data must be interpreted with great caution.

 

[Arfmeister]

I very much appreciate the work of Fluge and MeIla and the rest of the team. They’ve done a heck of a job for many years in a professional, cautious and emphatic way. Gained knowledge and also built a valuable bio bank. Hope they’ll stick around, if able to get the necessary funding for future projects.

I could add for the curious one, that when enrolled, I was a >10 year patient, moderate/severe. Mostly housebound. If I were to describe my course of illness in general terms, it’s been an endless journey of push-crash. Using every neuron of mental strength and going on pushing through as best possible, read: way beyond limits. In the aftermath from beginning of disease to May 2020; if I knew from the start what I knew many years ago, I would NOT have done the same thing over again, the approach of pushing on. And that’s about the only thing I’m sure of after all these years.

.

question @Peter

Did you participate at CycloME trial ?