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Tocilizumab / IL-6 / Mitochondrial Dysfuction - A possible treatment option?

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
Tocilizumab (Actemra and RoActemra) is an immunosuppressive drug, mainly for the treatment of rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis.

It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer.

IL-6 has been found to be elevated in severe ME/CFS (1) and excess IL-6 has been linked to mitochondrial dysfunction (2).
L-6 treatment led to decreased mitochondrial membrane potential, decreased cellular ATP production, and increased intracellular ROS levels. The mitochondria in IL-6-treated cells became swollen and hollow with reduced or missing cristae.

I've not seen any discussion here or anywhere else on using Tocilizumab as a potential treatment of ME/CFS, and don't know of anyone ever trying it. It's likely that IL-6 is not the core driver of the disease, but blocking it could perhaps improve symptoms in some.

Of course it might end up being a game of a whack a mole in terms of treating abnormal immunological findings, but it seems to be quite effective for RA patients (3).

Perhaps the idiosyncrasies of each aberrant ME/CFS immune system in a certain subset require a unique monoclonal intervention, and this could be one.

Tocilizumab is given by injection once a week, its side effect profile seems to be gentler than Rituximab

My usual proviso that I have no scientific or medical background applies :)
 

Jonathan Edwards

"Gibberish"
Messages
5,256
No, because we can be pretty sure that IL-6 is not involved in ME. The body has a very sensitive self-assay for IL-6 which is the production of C-reactive protein. C-reactive protein is normal in ME. Moreover, the consensus of cytokine studies in ME seems to be that if there is anything different it is that IL-6 is low in ME (in particular Hornig's findings).
 

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
No, because we can be pretty sure that IL-6 is not involved in ME. The body has a very sensitive self-assay for IL-6 which is the production of C-reactive protein. C-reactive protein is normal in ME. Moreover, the consensus of cytokine studies in ME seems to be that if there is anything different it is that IL-6 is low in ME (in particular Hornig's findings).

This study shows IL-6 is elevated in severe ME, I believe Hornig's study showed it decreased after 3 years
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Decreased in moderate, increased in severe

'IL-6 was significantly decreased in moderate CFS/ME patients compared with healthy controls and severe CFS/ME patients.'

That would seem to mean that in severe patients it was normal. Otherwise the abstract would have said it was increased. This is sloppy writing of an abstract anyway - it should have figures - but there is nothing here to say it was actually up in the severe patients. Healthy controls and severe patients are put together in one group in this sentence.
 

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
'IL-6 was significantly decreased in moderate CFS/ME patients compared with healthy controls and severe CFS/ME patients.'

That would seem to mean that in severe patients it was normal. Otherwise the abstract would have said it was increased. This is sloppy writing of an abstract anyway - it should have figures - but there is nothing here to say it was actually up in the severe patients. Healthy controls and severe patients are put together in one group in this sentence.

Just double checked the main study, you're right professor, I stand corrected. IL-6 is strangely normal in the severe and healthy, and it's decreased for the moderate. I can't fathom what this means, perhaps we are looking at different diseases. I was likely biased when interpreting this by my own truly elevated IL-6 serology.

For those of us with idiosyncratic well out of range cytokine markers, do you think there's any value in attempting to nromalize them with drugs like tocilizumab?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Just double checked the main study, you're right professor, I stand corrected. IL-6 is strangely normal in the severe and healthy, and it's decreased for the moderate. I can't fathom what this means, perhaps we are looking at different diseases. I was likely biased when interpreting this by my own truly elevated IL-6 serology.

For those of us with idiosyncratic well out of range cytokine markers, do you think there's any value in attempting to nromalize them with drugs like tocilizumab?

What it means is that this is a chance result or a heterogeneous population or one of the usual confounders in this sort of study.

If your c-reactive protein level is raised then it is likely that a raised IL-6 measurement actually reflects something real in your physiology. A raised c-reactive protein (CRP) usually has an explanation - and not ME. If the CRP is normal then the IL-6 result is likely an artefact.
 

Hutan

Senior Member
Messages
1,099
Location
New Zealand
Speaking hypothetically of course, :), if your c-reative protein has been raised since illness onset, reliably over many tests but just mildly so (10 to 20), would it be a good idea to get IL-6 tested? Would it provide any more clues?

My doctor suggests that some people's normal CRP levels are just higher than the standard range and it probably isn't a problem. (But maybe they feel fine, while I feel rubbish...).
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Speaking hypothetically of course, :), if your c-reative protein has been raised since illness onset, reliably over many tests but just mildly so (10 to 20), would it be a good idea to get IL-6 tested? Would it provide any more clues?

My doctor suggests that some people's normal CRP levels are just higher than the standard range and it probably isn't a problem. (But maybe they feel fine, while I feel rubbish...).

The range for CRP is tenfold different in different countries so we need to be careful. In some countries 10-20 is normal. In the UK the upper limit of true normal is about 3. It is true that each person has a different CRP response range so 3 for one person would occur in the same situation as 1 for another, but above 3 in UK units probably means something is wrong whoever you are. That might be an old patch of damaged lung from childhood that is always a bit inflamed so sometimes no cause can be found but there probably is one.

In UK units a CRP of 10-20 is grossly abnormal and must indicate some fairly substantial pathology. It cannot be put down to ME. There is not much point in doing an IL-6 test because CRP often occurs in response to local IL-6 production in liver in response to Kupffer cell activation, in which case the serum IL-6 may be normal. I am also not sure that serum IL-6 assays are really reliable enough to be helpful.
 

Hutan

Senior Member
Messages
1,099
Location
New Zealand
Thanks very much @Jonathan Edwards. The unit for the CRP levels I'm quoting is mg/L. Reference ranges are given by the labs as <5.

One reason that I haven't got that excited about CRP is that my son and daughter got sick at the same time and we have/had very similar symptoms. But they don't have raised CRP, so I doubt it's the key to unravelling our problem. As you say, perhaps I had high CRP before the ME symptoms, I don't know.

I do have mildly elevated ACE (two tests, both elevated), so I've finally convinced my doctor to let me have a chest x-ray.

Sorry, Jonathan, I guess this is like when you are at a party and someone wants to tell you about their sore finger joint. And you nod understandingly and now they are showing you their bunions....
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Upping this thread given the strong response of @StrayCat's severe friend to Tocilizumab

I find it hard to believe that a physician would give tocilizumab to someone 'pretending to have RA'. RA is pretty obvious if it is bad enough to need tocilizumab. Maybe this person does have RA. If the physician was fooled then it seems that the patient is pretty good at giving misleading information!!! So...
 

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
I find it hard to believe that a physician would give tocilizumab to someone 'pretending to have RA'. RA is pretty obvious if it is bad enough to need tocilizumab. Maybe this person does have RA. If the physician was fooled then it seems that the patient is pretty good at giving misleading information!!! So...

Perhaps, what do you make of the NCNP wanting to run a trial of tocilizumab for ME?