Upadacitinib (rinvoq)--could it reduce fatigue in ME/CFS?

https://en.wikipedia.org/wiki/Upadacitinib
https://www.rinvoq.com/

Janus kinase inhibitor that is selective for the JAK1 subtype of this enzyme--for the treatment of RA


@Jonathan Edwards Any chance that this might also work for ME/CFS?

I ask because I am bombarded with TV commercials for Rinvoq where they say that it can significantly reduce the fatigue found in RA.

I think you said elsewhere that RA fatigue might be physiologically different from MECFS fatigue?



Thanks.

 

Lots of different treatments that reduce cytokine-driven inflammation in RA reduce fatigue. A Janus kinase inhibitor would work through that route so would be expected to reduce fatigue. But that means we only expect it to reduce fatigue in conditions with cytokine-driven inflammation. Cytokine-driven inflammation is reasonably well indicated by CRP levels - which are normal in ME. So there does not appear to be any cytokine-driven inflammation in ME and we would not expect a Janus kinase inhibitor to help.

There are possible exceptions to this argument but at present I don't think we have much to suggest they apply.

 

https://www.medpagetoday.com/rheumatology/arthritis/89124


Upadacitinib, Abatacept Go Head to Head in RA

 

Do JAK inhibitors have the potential to work better compared to steroids (methylprednisolone, prednisone, deflazacort etc) when it comes to fatigue associated with cytokine inflammation, or is the main benefit the lack of side effects compared to steroids?

In other words, what I suppose I'm asking is: are there cases of cytokine inflammation fatigue that doesn't respond to steroids but responds to Jak inhibitors?

 

Not that I know of. High dose steroids block inflammation very broadly.
The advantage would be selectivity.

 

Filgotinib was mentioned by Robert Phair among others as being a possible treatment option. There's a trial ongoing, funded by SolveME. Lombardi is the PI:

https://solvecfs.org/research-and-r...grants/meet-the-researchers/vincent-lombardi/

 

Here is the personal story of the lady that is in remission from Rinvoq.
- Came out on Health Rising today

Very interesting what she mentions about ‘cytokine-storm.’
- what strikes me as odd is that normally a cytokine storm comes with fever, high heart rate, etc.

is it Possibly linked to T-cell/Nk-cell exhaustion as there was no real high fever reaction ?
– when I asked she mentioned that she never had a high fever since she got sick


Note: myself I do have - some consistently - high Cytokine markers for a bunch
- Specifically IL8, MCP1, IL1, IL6. IL10 and TGF Beta
- next to consistently low CD 56 natural killer cells and a recent low CD 57 (which could imply T-cell exhaustion?)

If anyone can Give meaning to this panel, I would be interested
@Jonathan Edwards


https://www.healthrising.org/blog/2024/11/20/jen-rinvoq-chronic-fatigue-recovery/

 

None of these things mean much in clinical practice. They are done by fringe physicians who over-interpret them as a rule.

I see no reason to think anyone with ME/CFS has had a cytokine storm. we are talking the difference between a gentle breeze of a few slightly high cytokines in some people with ME/CFS and a 120MPH category 5 hurricane - a genuine cytokine storm - that occurs in sepsis and kills people within hours.

This sort of talk is just unhelpful - ill-informed and misleading. Health Rising has had a habit of over-egging things like this.

If an adverse event to a kinase inhibitor was followed by improvement of an illness that someone diagnosed as ME/CFS, albeit together with EDS, which calls everything into question yet again, then (a) correlation is not causation and (b) any flicking of a switch seems very unlikely to have had anything to do with damping a gentle cytokine breeze. More likely an idiosyncratic toxicity flipping something completely unrelated.

 

Possibly, yes. I do not know enough about these Cytokine panels, but these fringe physicians dó try to research blood panels more in depth vs 99% of doctors.
I appreciate their effort to dive deeper in ME CFS, although sometimes at financial cost of the patient

Note: T-cell exhaustion is some thing studied by various ME CFS Researchers (Stanford, Liisa Selin, etc)
Although I don’t know if measuring CD 56 and CD 57 is a good marker for it
- I háve had these consistently low - measured over various time points during my +10 year Illness
(Same accounts for various of the high cytokines values mentioned)

yes, I agree, it’s inflation of the term ‘cytokine storm’.
- But maybe it could be called a ‘low grade sepsis’ - or a Continuous 24/7 365 days cytokine breeze ?
- low-grade sepsis is exactly how my PEM-crashes feel (i’ve had severe sepsis, requiring immediate hospitalization)

That is too easy IMO.
I’ve seen enough patient anecdotes with patients improving - and at least 3 cured - by Jak-inhibitors (like 20-35% iirc from a small pool of ptntns) that it is at least worthy of more research.

 

I don't think they research them so much as use them as leverage for income. Research requires rigour and common sense. I have spent my life researching inflammatory disease and these panels are, as far as I am concerned, unable to tell us anything useful. When cytokines matter you see their effects in terms of fever, CRP, shifts in sodium and so on. In practice measuring cytokines themselves - at least for the ones we know about - is virtually never useful in the clinic. I don't think these people are 'diving deeper' at all. They are mostly bullshitting about stuff we already know is unhelpful.

It is studied by the fashion followers as far as I can see. My understanding of T cell biology is that 'exhaustion' is again an unhelpful concept. It is a label people have given to finding certain markers that in stereotyped immune responses in mice indicate a decline in ability to proliferate. But poorly understood human disease does not follow those stereotypes - that is why it is poorly understood. It involves disordered maturation pathways. So these sort of functional labels just mislead.

The basic problem is that most immunologists are fashion followers rather than people who actually understand complex regulatory failure. The 'received wisdom' is mostly a sort of superficial journalism.

They aren't markers for it - period.

Another nonsense fashion buzzword I am afraid.

There are patient anecdotes for everything, including the Lightning Process. Loads of them - with cures two a penny. Rituximab seemed to cure several people but we found out it does nothing. Believe me, I have been involved in drug trials for thirty years. Improvements occur with everything that doesn't work as well as what does. And in this case history the person did not feel improvement on the drug - they felt better after stopping it because it made them feel awful didn't they? There is no way I can see you can fit that into a stereotyped immune response story.

 

I find the fact that cytokines could have a relationship with a shift in sodium interesting. Some people with ME have reduced sodium = hyponatremia on becoming severe and it persists. Could looking at certain cytokines in those people to see if they have a distinct pattern (whatever that is) provide a clue to the disease present in that subset?

 

I am not very optimistic it would help. Hyponatremia in ill people probably involves a secondary hypothalamic/endocrine shift that can be activated by a whole range of signals including cytokines and other things. I think if problems in severe ME involved known cytokine pathways someone would have picked something up by now.

 

The white cells in this case would be neutrophils. Having low B cells is not considered dangerous - nobody even bothers to measure them normally and you can manage without them for five years at least (we discovered). Neutrophils carry no individual memory so getting rid of them and getting new ones makes no difference - they all die within about five days anyway. There are rare conditions in which neutrophil populations show mutations based on myeloid precursor clone changes (myeloid leukaemia and paroxysmal nocturnal haemoglobimuria) but that would not be relevant here.

On the other hand a sudden drop in neutrophils probably indicates some form of auto reactive bone marrow process knocking out the myeloid precursor lineage. That auto reactive process might engage a range of new signals that could conceivably break some pre-existing signal cycle. My main thought is that this would almost certainly have nothing to do with the original intended kinase blockade.

 

What would that shift look like in those patients who have it ? I mean like certain tests coming up as abnormal?

 

Low serum sodium.

 

Just adding the 2nd part from Healy Rising Cort Johnson’s blog on Rinvoq.

https://www.healthrising.org/blog/2...8624653db6d460451b2fa1dc008a8#comment-1107042

There is an interesting remark from Dr Herbert Renz-Polster in comments

This is a very interesting remark - and a big problem with a lot of ME CFS research: not measuring at baseline vs during PEM crash.

So just checked AI FWIW and it’s really short:
“Many cytokines have a short half-life, typically ranging from minutes to a few hours.”

Heightened cytokine levels during PEM seems very plausible, just going off my ‘gut feeling’. During a PEM crash, I literally feel a lot of inflammation (e.g. joints, brain, gut, muscles, etc) and pain.
And it might also be (partially) the reason of the flu-ish type symptoms ??

Regarding your comment, it also reminds me of Cyclophosphamide (and the experience of patients I talked to who had recovered after Cyclo).
A very intensive course of immune suppression / even cytotoxic drugs can reverse illness in a relatively short time.
Not going to speculate which mechanism, but there might be an analogy.


LAST comment/question :

I myself have taken a short 3 month course with Filgotinib - which did not affect me much, positive or negative (I am very severe). Did not feel much like any immune suppression.

I was wondering what exactly the difference is in potency and target mechanisms between Filgotinib and Rinvoq. And if that makes the difference?

As the immunosuppressive effect of JAK inhibitors varies by selectivity.
- Filgotinib, with focus selectivity for JAK1, is less immunosuppressive than Rinvoq - with less significant effects on infections, viral reactivations, or immune cell levels.

The question is:
- did stronger immune suppression by Rinvoq (incl. JAK2 and JAK3) help “reset the immune system”, contributing to Patient Jen’s improvement?
- Or was it primarily the JAK1 inhibition (like Filgotinib) ?
- Or “idiosyncratic toxicity flipping something completely unrelated” ?

 

It looks like there was early evidence cytokine changes with PEM here:

Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2018) Montoya et al. (Thread)

Edit: Also, Sex-Dependent Transcriptional Changes in Response to Stress in Patients with ME/CFS: A Pilot Study, 2023, Nathanson, Klimas et al (Thread)

 

What do you think of this research on T-Cell exhaustion ?

https://www.umassmed.edu/news/news-...udy-links-between-viral-infections-and-mecfs/

"The researchers are investigating the presence and role of T cell exhaustion and double positive CD4+/CD8+ T cells in ME/CFS, Long COVID and Multiple Sclerosis. They were the first to investigate CD8 T cell exhaustion in ME/CFS patients, defining T cell exhaustion by immunophenotype and functional assays."

 

Cytokines have short half lives but inflammation caused by cytokines does not as a rule. Getting cytokine driven inflammation started and then settled down takes a few days generally. Also, the short lived cytokines give rise to elevations in CRP that last days. It seems unlikely that this has been missed in hundreds of thousands of people with ME/CFS. People who are very severe would seem to be in permanent PEM but there isn't any evidence of inflammation clinically or in terms of acute phase response.

Doing continuous monitoring of a cohort seems a very sensible idea but I very much doubt that anything important has been missed in terms of well known cytokines.