Are Infections Just a Trigger of ME/CFS, or an Ongoing Cause of ME/CFS?

[Hip]

Behan, Gow, and Mcgarry published findings from a patient that committed suicide. Sadly the full text isn't available, there is only this excerpt:

Actually that excerpt you linked to is the full paper, short though it is. I have a pdf of the original publication, and the original is only in fact a brief article about half a page in length published in the Annals of Internal Medicine journal. The only additional material in the original pdf is an image of the PCR bands, and some references.

 

[Eeyore]

@Hip -

Wouldn't the use of an IL-1β receptor antagonist like anakinra be more of a "suck it and see" situation? When it comes to immunosuppressants or anti-inflammatories, it not just a case of trying them out, and empirically observing whether the infection is worsened or improved?

Anakinra would likely cause life threatening illness exacerbation or even death if given to someone with an active infection. Patients are extensively tested for infectious diseases before being started on drugs like that (also true of TNF-alpha inhibitors, rituximab, etc.) If you test positive for serious infections (especially intracellular, e.g. tb, viral), they would be very unlikely to treat with these drugs.

You don't treat infections with immunosuppression. The reasons are probably obvious. If interferon works, IL-1 blockers would almost definitely exacerbate the illness.

Sometimes steroids are used during infections to control inflammation and prevent tissue destruction. This is done when the body's immune response is so severe that the patient will die or suffer major side effects if untreated, but it can also cause increased risk of death from infections or the development of serious complications. Steroids, however, don't unlink entire parts of the immune response in the same way - they mostly just reduce the magnitude of certain inflammatory responses. Vascular permeability and immune cell adhesion and chemotaxis are inhibited, and the degree of inhibition is dynamically adjustable as prednisone has a half life on the order of hours, not months (antibodies have half lives of a few months or so - you can't undo it).

 

[Hip]

@Eeyore
Well there is a clinical trial for anakinra as an ME/CFS treatment, and of course the TNF-α inhibitor etanercept ha sen used to treat ME/CFS. ME/CFS patients are not short of ongoing active viral infections.

 

[Eeyore]

I'm not aware of any active trials (past or present) of anakinra or etanercept in ME patients, although I know Dr. Klimas has attempted to get funding for them. The closest I can think of is rituximab, which works somewhat differently, but is also immunosuppressive.

The whole point is that if etanercept or anakinra is safe and effective in ME, it would strongly argue against significant active viral infection. So I think that it would say that yes, ME patients probably do not have them.

Obviously it doesn't mean that if someone is on etanercept or anakinra that they will die if they get a cold - but even a flu can be dangerous, and any virus that was causing major systemic symptoms over years would get worse on immunosuppressives, so if the enteroviruses that Dr. Chia has found are causing the symptoms, blocking antiviral cytokines would worsen those symptoms and encourage viral proliferation and tissue destruction, not the reverse.

The rituximab phase 3 trial, if it proves efficacy as many think it will, would imply that some aspect of immune dysregulation or autoimmunity is at the root of ME symptoms, and that the symptoms that improve are not caused by viral infection.

The Fluge and Melle theory posted in this thread (which I haven't read elsewhere) that there is some so far unknown endothelial autoantibody would be consistent with rituximab being effective, but it would not be the only explanation consistent with that theory, and of course they'd have to actually show the antibody. They may have more than they are letting on - it will be very interesting to see their results. I think this is probably the most exciting trial in ME history by a huge margin - and if the evidence is there, it will change forever the way the medical profession views ME.

 

[nandixon]

@Eeyore

This is the Anakinra trial here:
https://clinicaltrials.gov/show/NCT02108210

Also see this thread:

Anakinra/Kineret (IL-1 inhibitor) in ME/CFS - Dutch study + discussion

 

[Hip]

Some of the ME/CFS doctors have used etanercept, see: Etanercept (Enbrel)

 

[Sidereal]

Some of the ME/CFS doctors have used etanercept, see: Etanercept (Enbrel)

Unless I am misremembering, Fluge/Mella started a study using this drug and it was terminated early due to causing a deterioration in the patients' condition.

I hope the Dutch IL-1 study doesn't maim too many people.

 

[leokitten]

The Fluge and Melle theory posted in this thread (which I haven't read elsewhere) that there is some so far unknown endothelial autoantibody would be consistent with rituximab being effective, but it would not be the only explanation consistent with that theory, and of course they'd have to actually show the antibody. They may have more than they are letting on - it will be very interesting to see their results. I think this is probably the most exciting trial in ME history by a huge margin - and if the evidence is there, it will change forever the way the medical profession views ME.

@Eeyore @Jonathan Edwards mentioned in a rituximab thread that there are potentially other mechanisms other than autoantibodies which would result in autoimmunity. Interesting stuff.

http://forums.phoenixrising.me/inde...chanisms-by-which-rtx-might-be-working.37669/

 

[Hip]

Unless I am misremembering, Fluge/Mella started a study using this drug and it was terminated early due to causing a deterioration in the patients' condition.

I hope the Dutch IL-1 study doesn't maim too many people.

Your memory seems to be working: I found this brief report:

Etanercept - We started a clinical open-label phase-II study on weekly subcutaneous etanercept (a TNF-alpha inhibitor). Only four patients were included, and we decided to stop the trial because two patients had a clear worsening of ME/CFS symptoms, while two were unchanged (no response). Ideally, we should have included additional patients to gain experience for a more solid conclusion; we however decided to stop the trial.

Source: here.

 

[Eeyore]

That's interesting. So now we are left with trying to figure out why patients improve on rituximab and do not improve on etanercept (and in fact worsen).

The etanercept study isn't that high quality - open label and quite small, so I'm not sure how much can be read into it (vs rituximab which is quite large and double blinded / phase 3) - so it could just be noise.

No results yet on the anakinra, but that would be interesting to see. Looks larger / better designed than the etanercept.

Of course the mabs are not all identical, and patients respond differently to different mabs - but if there is a clear pattern that emerges in ME it could tell us about pathology. Off the top of my head, if rituximab works and etanercept exacerbates the condition (no anakinra results yet), then I'd start by guessing that that is because rituximab is th1 shifting (b-cell depleting) and etanercept is th2 shifting (tnf-alpha is a th1 effector cytokine).

That's speculative though.

 

[Hip]

Of course the mabs are not all identical, and patients respond differently to different mabs - but if there is a clear pattern that emerges in ME it could tell us about pathology. Off the top of my head, if rituximab works and etanercept exacerbates the condition (no anakinra results yet), then I'd start by guessing that that is because rituximab is th1 shifting (b-cell depleting) and etanercept is th2 shifting (tnf-alpha is a th1 effector cytokine).

That's speculative though.

That is an interesting speculation.

 

[Jonathan Edwards]

That's interesting. So now we are left with trying to figure out why patients improve on rituximab and do not improve on etanercept (and in fact worsen).

The etanercept study isn't that high quality - open label and quite small, so I'm not sure how much can be read into it (vs rituximab which is quite large and double blinded / phase 3) - so it could just be noise.

No results yet on the anakinra, but that would be interesting to see. Looks larger / better designed than the etanercept.

Of course the mabs are not all identical, and patients respond differently to different mabs - but if there is a clear pattern that emerges in ME it could tell us about pathology. Off the top of my head, if rituximab works and etanercept exacerbates the condition (no anakinra results yet), then I'd start by guessing that that is because rituximab is th1 shifting (b-cell depleting) and etanercept is th2 shifting (tnf-alpha is a th1 effector cytokine).

That's speculative though.

Dear Eeyore,
I would suggest that if rituximab works in ME, and not etanercept, it is for the same reason that this applies to immune thrombocytopenia, myasthenia gravis, Graves' disease and a whole lot of other autoimmune diseases. These are diseases mediated by autoantibodies but through effector mechanisms that do not trigger inflammatory cytokine production. So B cells are involved but not TNF. Since the ESR and CRP are normal in ME one would assume that any autoantibody mediation would similarly not be through inflammatory cytokines.

The TNF produced in RA has nothing to do with T cells. It is made by macrophages in response to immune complexes binding to Fc receptors. Nobody has found anything wrong with T cells in RA and when they are activated it seems to be through a bystander pathway. They produce tiny amounts of TNF locally.

I keep saying it but it needs repeating - the th1/th2 shift idea is as far as I can see completely imaginary and nothing to do with any known human disease. Antibody production in RA is probably dependent on both IL-10 and TNF (both are needed in germinal centres). T cell hyperactivity in reactive arthritis seems to involve IL-17. I don't see a th1/th2 issue anywhere, even if my colleagues have been using this incantation for the last twenty five years!

 

[Marco]

Since the ESR and CRP are normal in ME one would assume that any autoantibody mediation would similarly not be through inflammatory cytokines.

Sorry; I don't want to take this off topic, and you may have answered this before, but in discussions it appears that many of us (although not all) report consistently very low ESR and while elevated sed rates are what usually rings bells, very low rates (there's a bit of a floor effect with sed rates it seems) may be indicative of a range of problems linked to oxygen transport/hypervisosity. 'If' this was a consistent finding would it be consistent with vascular/hypoperfusion problems?

 

[Jonathan Edwards]

Sorry; I don't want to take this off topic, and you may have answered this before, but in discussions it appears that many of us (although not all) report consistently very low ESR and while elevated sed rates are what usually rings bells, very low rates (there's a bit of a floor effect with sed rates it seems) may be indicative of a range of problems linked to oxygen transport/hypervisosity. 'If' this was a consistent finding would it be consistent with vascular/hypoperfusion problems?

I doubt that a low ESR in ME means much other than an absence of acute phase protein response (no increase in fibrinogen) or hypergammaglobulinemia. A low ESR occurs in polycythaemia, which increases blood viscosity because of the increase in red cell volume. Most other hyperviscosity states have high ESRs.

 

[Marco]

I doubt that a low ESR in ME means much other than an absence of acute phase protein response (no increase in fibrinogen) or hypergammaglobulinemia. A low ESR occurs in polycythaemia, which increases blood viscosity because of the increase in red cell volume. Most other hyperviscosity states have high ESRs.

OK - thanks. I must have picked the hyperviscosity thing up wrong.

 

[Hip]

I keep saying it but it needs repeating - the th1/th2 shift idea is as far as I can see completely imaginary and nothing to do with any known human disease.

Surely there is no doubt that the Th1 response is responsible for activating cell mediated immunity. And if we are presuming ME/CFS might be driven by intracellular pathogens like non-cytolytic enteroviruses (defective enteroviruses), then the activation of the Th1 mode, or lack thereof, should be an area of exploration in ME/CFS.

Couldn't a failure to mount an adequate Th1 response be a factor that helps maintain ME/CFS?

Dr Chia found an increase in Th1 cytokines occurred, along with a reduction in viral load, in all his enterovirus-associated ME/CFS patients who improved while taking oxymatrine; and those who did not improve on oxymatrine, and did not reduce their viral load, were the ones who failed to generate this Th1 response.

Likewise, in his Valcyte study, Jose Montoya found that ME/CFS patients receiving this drug tended to move towards a Th1 profile.

So here is indication that improvements in ME/CFS are associated with a shift to Th1.


I was collecting factors that decrease Th1. For example, one study I came across said that LPS decreases Th1. Then EBV, CMV and HHV-6 all make an IL-10 homologue that shifts to Th2, which might mean that the reactivations of these infections found in ME/CFS can hamper viral clearance.

The general idea was that possibly ME/CFS patients may be exposed to several factors like these that prevent an adequate Th1 response, thereby stopping them from clearing viral their intracellular infections.

Is there anything that is intrinsically wrong about thinking along these lines?

 

[Eeyore]

@Jonathan Edwards - I was probably a bit sloppy in my wording there, but as is common now, th1/th2 are often taken to represent shifts towards humoral or cellular (inflammatory) immunity - which is closer to what you are suggesting, although you aren't positing a shift so much as a particular autoantibody. I agree this is not well phrased and obviously th1/th2 implies a central causal role for t-helper cells, something I didn't mean to imply. I was essentially saying something similar to what you are - there is no inflammatory cytokine mediated cellular immunity active (hence no elevation in CRP). I'm not convinced that means there is an antibody in play though - although I would certainly not rule it out and consider it a strong possibility. I think ME may be an autoimmune state but it may also be a state of failed communication between various immune cells - i.e. a form of cellular immune deficiency, leading to a compensatory upregulation of humoral immunity and antigen presentation. I tend to favor this theory right now, although that may be a personal bias based on what I know of my own immune system, genetics, and biochemistry.

I think there is more to the low ESR in ME than lack of cytokine mediated inflammation. I agree that there is no hyperviscosity as would be seen in many neoplastic diseases such as PV or hypergammaglobulinemia as in a monoclonal gammopathy. Curiously, there often is frequently elevated hematocrit in ME (Dr. Hyde and many other clinicians have described this) - not due to a neoplastic, clonal expansion of blood cells but rather due to a loss of plasma volume, which may be caused by problems with neuropeptides such as vasopressin (undetectable in me and that is also not a rare finding, low blood volume is found much more often than would be expected in the ME population, hence the OI and POTS and other similar fluid depletion syndrome symptoms). This could also be related to an as yet undiscovered endothelial antibody that fluge and melle have recently suggested may exist.

Even Medscape lists a low ESR as essentially required for a diagnosis of ME, stating that it is the most consistently found sign and its absence should call the diagnosis into question. My own has usually been 0. This can occur in healthy people, but it is not truly "normal." There is a difference between absence of elevation in ESR and depression in ESR - the latter may be a significant finding, whereas the former would generally indicate normal health.

 

[Eeyore]

@Hip - I was being imprecise - personally I do not believe there is, in general, cd4 cell dysfunction or that the root of the problem in ME is CD4 th cells failing to mount a normal immune response. I sometimes use it as a shorthand for cellular inflammatory vs humoral immunity - which is not exactly correct. I sometimes refer to a Th1 dominant state as one in which cytotoxic cytokines are dominant in general (the effector cytokines associated with th1 cells) - but not specifically due to a problem with cd4 th cells. Sure, if there's a problem with the immune system in a major way, th cells will also get dragged in in many cases, but I do not believe they are the root of the problem, either numerically or in terms of polarization. If there is a shift in th cell polarization I suspect it's a downstream effect.

Going back to the original discussion of etanercept vs rituximab, a better way to describe my theory is that rituximab depletes B-cells and thus antibodies, reducing the humoral immune response. Etanercept blocks TNF-alpha, which would drive a cellular inflammatory immune response. If ME involves a weakened/dysfunctional cellular immune response, then further weakening it would be counterproductive. Dr. @Jonathan Edwards suspects an autoantibody is in play here, and that rituximab depletes the b-cells that produce it (which is also consistent with a delayed onset of action, as antibodies have a long half life and are not directly affected by rituximab) - and this is a highly plausible theory, although no such antibody, to my knowledge, has yet been isolated (however, it hasn't really been sought either as far as I know). I believe that a defect in cellular immunity may result in a compensatory upregulation of the humoral immune response - in that case there might not be any particular antibody involved. It may be a manifestation of abnormal cellular immunity.

 

[Misfit Toy]

So, in case some don't know-I just took Enbrel a few weeks ago and developed serum sickness. Etanercept. I've been sick ever since and am much worse. I continue to be on steroids.

It caused a major rash, flu like episode and I'm more exhausted than before.

 

[Jonathan Edwards]

@Eeyore
Yes, we have the same understanding here. I would just emphasise the situation for TNFa, though.

Either TNFa, or lymphotoxin, is absolutely necessary for follicle centre development because TNF receptors have to be ligated to get stromal cells to take on an FDC function. So all antibody responses are totally dependent on TNF. Moreover, TNFa is the dominant cytokine produced in response to immune complexes. In fact Il-1 production in response to complexes is dependent on the presence of TNFa. And in our immune complex assays we estimated that we had 100 times the TNFa production documented in T cell responses in synovial cell cultures. So basically TNFa is as 'humoral' a cytokine as you can get. It is certainly not an indicator of cell mediated immunity. Many of my immunology colleagues fail to realise this because they do not understand compartmental dynamics. They think in sound bits like TH1/TH2.