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Solid Ground at Last? Cytokines Make Good in Major ME/CFS Review

The immune system in chronic fatigue syndrome (ME/CFS) has been kind of like a mirage in the desert. Given the way the disease starts and its symptom presentation – so close to the “sickness behavior” produced during an infection – it seems that the immune system must be a major player in this illness.

desert lake

Powerful immune factors called cytokines seem like they must be involved in ME/CFS but inconsistent results have caused them, like a mirage in the desert, to slip away again and again (Image by TravelCoffeeBook from Pixabay )

Like a mirage in the desert, though, the powerful drivers of the immune system – the cytokines – seem to slip through our grasp again and again.  Interesting findings pop only to be dashed by another study.

Thirty plus years of study have left us – according to several immune reviews – with precious little solid ground. A recent review, however, suggested that larger studies were finally producing more consistent results.

Now we have the largest “study” of all – a meta-review of past cytokine (inflammatory protein) studies – that’s providing us a solid foundation, and from the unlikeliest of places, Kings College in the U.K., which has been better known as a bastion of cognitive behavioral therapy.

The senior author of the paper, the rather prolific Anthony Cleare, has focused for years on the HPA axis in ME/CFS. He and the lead author, Rebecca Strawbridge, have shared an interest in the role inflammation plays in HPA axis issues and depression. Strawbridge’s recent paper on the effectiveness of anti-inflammatories in depression clearly underscored how often inflammation instead of psychology is driving depression.

Their new paper’s rather emphatic title “Inflammatory proteins are altered in chronic fatigue syndrome-A systematic review and meta-analysis” seemed to give notice that things had changed. ME/CFS is, at least in part, an inflammatory disease after all.

The review was broad: any diagnostic criteria was allowed and the main exclusionary criteria was that no stimulation of any kind was involved; i.e. this was an assessment of the immune system at rest. The 42 studies involved highlight just how hard researchers in this small field have searched for an immune cause of ME/CFS.

The authors of the present paper pointed out why the immune system has been such a draw for this field. “Phenomenologically” they noted, “ME/CFS is often described as a ‘flu-like illness’ and the diagnostic criteria to some extent resemble the symptoms of sickness behaviour.” (Sickness behavior describes the symptoms produced by the brain during infection (fatigue, pain, cognitive problems, etc.) that serve to isolate an individual from the community – and thus help stop the spread of a pathogen).

The Review

The vast majority of studies used either the Fukuda or the 1994 criteria created by the CDC. Both criteria have been mostly discarded in favor of more recent criteria but it should be noted that most ME/CFS studies – including many with positive outcomes – used one or other of these definitions. (Only 8 of the 42 studies used the Canadian or International criteria – which may have issues of their own.)

Despite the broad criteria (Oxford definition, CDC definitions included) used in most of the studies, this meta-review actually found evidence for an inflammatory state in ME/CFS. The authors hypothesized that pro-inflammatory cytokines and acute phase protein levels would be significantly higher in people with ME/CFS than controls, and low and behold, they were.

cytokines

Cytokines and other inflammatory proteins turn on (or off) the immune system. High levels of pro-inflammatory cytokines produce inflammation.

Approximately 22 cytokines/immune factors were assessed in 42 studies dating from 1989 to 2016.  The review suggested that about a quarter of the immune factors assessed in ME/CFS were elevated.

Elevations of two cytokines (tumor necrosis factor-a (TNF-a), c-reactive protein (CRP)), both of which have wide ranging effects, suggested that ME/CFS was similar to other  “chronic immune conditions” which have a similar cytokine profile.

Synchronicity

A recent gene expression study highlighted both TNF-a and TGF-B as well.  In fact, that study identified precise pathways associated with TNF-a which might potentially be targeted in ME/CFS. The fact that these cytokines are popping up in independent studies suggests we may finally be honing in on some key cytokines that are producing fatigue, pain and other symptoms in ME/CFS.

New Pathways: A Step Towards Fine-Tuning Treatments for ME/CFS?

Cytokines involved in regulating inflammation ((IL-2, IL-4 and TGFβ) appeared to be particularly affected. Three cytokines (IL-6, IL-1 and IL-12) involved in the early response to infection (perhaps suggesting viral reactivation was present) tended to be increased as well but were less consistently elevated. Interestingly, given the hypothesis that immune exhaustion occurs over time in ME/CFS, no trends in reduced cytokine levels were found.

Capturing Smoke in a Bottle

The authors noted that some similar (but different) findings have been found in fibromyalgia and depression, and that given the widespread co-occurrence of all three disorders teasing what is caused by what is tricky. Noting that fatigue is found in both ME/CFS and depression, and that inflammation can produce “disabling fatigue”, the authors suggested  future studies more clearly delineate the extent of depression present. Activity levels and medication use – both of which can affect the HPA axis or immune system should be characterized. .

The review also noted, as did Van Elzakker’s rather scathing recent review of cytokine studies, that measuring cytokines is a bit like capturing smoke in a bottle. Their levels fluctuate constantly and can be effected by activity levels, diet, medication use, weight, age, sex and “numerous other factors”.

For instance, it’s clear that activity levels, diet, medication use – all factors which could skew cytokine findings – will probably be different in ME/CFS patients. Therefore, they could by themselves account for the altered levels found. Plus a bunch of other factors (severity and duration of illness, illness triggers, illness history, sample collection, processing, storage) could all tweak cytokine levels.

Given that few ME/CFS studies accounted for most of these factors (and mostly used outdated criteria) it seems remarkable that the review found consistent results at all.

A Plea for A Cytokine Study (To End All Cytokine studies)

Once again, for the umpteenth time it seems, the authors left us with a plea for larger, more rigorously controlled studies. The authors, in fact, recommended what sounded like a cytokine study to end all cytokine studies. That study would subgroup patients, assess all confounding factors and then follow the patients over time (longitudinal study).

drug trial ME-CFS

The authors “fervently” hoped a large, rigorous cytokine study could identify key cytokines that could be targeted with drugs.

A very large study using the best criteria available could tease out definitive immune biomarkers and pave the way for potential treatments. The increasing number of biologic drugs being developed to target specific cytokines make that drug arena a potentially very fruitful one for ME/CFS.

Dr. Klimas is certainly on board. Her Enbrel (plus mifepristone) trials in ME/CFS and GWI indicate she thinks she’s already found a target. Enbrel, interestingly, targets TNF-a – one of the cytokines the review found elevated in ME/CFS.

Breaking their British reserve a bit at the very end of the paper, the authors stated they “fervently” await better studies so that they can conduct a more comprehensive meta-analysis- and better understand the role that inflammatory proteins play in ME/CFS.

One wonders if we could be just one or two very big, rigorous and comprehensive cytokine studies away from identifying an FDA-approved drug that could help many. This review will surely provide support for studies like that.

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25 Comments

  • Dana

    November 25, 2019 at 11:09 pm - Reply

    I certainly look forward to future cytokine studies. The only thing that has ever made a dent in my crash cycle (apart from aggressive resting, on total bedrest) is a natural supplement that supposedly inhibits cytokines. I hate the DIY guesswork that goes into it. How much can I safely take? Is it compromising my immune system or other body systems that need the helpful work of cytokines… Many other questions and uncertainties. I would love to hear of a drug that targets specific cytokines. I’m sure it wouldn’t fix everything but it certainly seems like it could minimize some of the damage happening.

  • Jay

    November 25, 2019 at 11:34 pm - Reply

    May i ask what supplement you take that supposedly inhibits cytokines? I have overactive TH2 cytokines and am looking for something that will down regulate my TH2 cells.

  • konijn

    November 26, 2019 at 12:26 am - Reply

    money, we need money, lots of it!!!

  • Dana M.

    November 26, 2019 at 12:58 am - Reply

    May I know the name of the natural supplement, thanks. Is it by LifeExtension?

  • Dana

    November 26, 2019 at 3:17 am - Reply

    Yes, it is by life extension. I think it’s called cytokine suppress, and the main ingredient is mung bean extract. It seems to lessen the impact and duration of crash symptoms if I take it right after exertion. I’m also taking one every night. It doesn’t prevent crashes and I still have to be careful. But it did seem to help break the non-stop crash spiral I was in. That being said, I’m in the middle of an unexplained crash at the moment, so… Also I’ve not been able to have extensive testing beyond what a regular doctor has done and am basically taking this in the dark.

  • Dawn

    November 26, 2019 at 5:56 am - Reply

    I am happy at least these have it written that we do have something wrong and don’t just need graded exercise. I dislike psychiatry so much as they treat me for years before I found out I had Addison’s disease which can be responsible for horrible mental states.
    What can we do to get these studies going? What about that website where they raise money for things?
    Apparently they have changed the ingredients in that Life Extension product so I am emailing them to see what they changed as someone on Amazon responded to it at first and then the new batch triggered their inflammation due to the formula :O/

  • Silvia

    November 26, 2019 at 2:01 pm - Reply

    This is an interesting study. Only when I eat a very clean, organic, balanced plant-based diet and take several clean supplements (vitamins, probiotic, enzymes, ashawanda, ginko bilboa, anti-mold and allergin drops), meditate, pace myself, undertake short spurts of exercise, rest in the middle of the day, manage to obtain restful sleep and try hard to avoid social isolation do I feel like the fatigue, inflammation etc is manageable. If I veer off from this formula, I tank.
    The study of inflammatory cytokines is fascinating but I think the reality is that our threshholds are much more limited and a high degree of self-care is an imperative.

  • Silvia

    November 26, 2019 at 2:05 pm - Reply

    What test did you find most helpful other than testing for TH2 Cytokines. Did your insurance cover these tests?

  • Tracey Anne

    November 26, 2019 at 4:54 pm - Reply

    Another study came out of King’s College London, by Dr Alice Russell.

    King’s College: Clues to Chronic Fatigue Syndrome in overactive immune response. http://www.meassociation.org.uk

  • Cort Johnson

    November 26, 2019 at 5:50 pm - Reply

    I think it will just take big enough studies. Check out the last Simmaron blog where Dr. Klimas got down to very specific pathways associated with the TNF-a cytokine mentioned in this study. That’s getting precise!

  • Nancy B.

    November 26, 2019 at 8:41 pm - Reply

    Interesting article Cort! I was just about to mention how this meta analysis ties in with your last blog on JAK-STAT cytokine immune pathways (M41 and M18) which implicate TNF-alpha, B and T cell receptors, and TGF-beta. You beat me to it!

    I looked up the selective immuno-suppressants (for TNF-alpha) already in use and basically they fell into two categories; aminoquinolines such as Plaquenil and biologics like Enbrel, Remicade and Humira. Either can be dispensed to people with inflammatory autoimmune conditions like RA and such.

    This makes sense because I was advised that at my next appointment at Stanford’s ME/CFS Clinic (which I’m visiting tomorrow) they will be wanting me to try Plaquenil. Plaquenil (and it’s cousin chloroquine) are also used as a Malaria prophylaxis.

    I see a big insurance problem with the others like Enbrel, Remicade etc. as they cost about $5,000 per month for people with autoimmune conditions. Plaquenil, the aminoquinoline, is much, much less expensive. Trouble is that it can cause retinal damage and alter color perception, albeit that reaction is supposedly rare.

    I did come across a recent research article which says that the damage can occur at much smaller doses and at shorter periods of use than now thought. Because I already have one wonky retina and Ehlers-Danlos (retinas are also connective tissue!) I am very nervous about trying this.

    As for Stanford’s trial of micro doses of Abilify, at first I noticed a definite uptick in energy, but alas, several months later, my energy is worse than before–so I guess it stopped working.

    This last week I have been trying NADH and think it might be helpful–but time will tell…

    • Cort Johnson

      November 28, 2019 at 3:22 pm - Reply

      Tough decision and wow $5K a month. I guess that’s a big issue with biologics..they are not cheap. Good luck!

  • Jessica

    November 26, 2019 at 10:45 pm - Reply

    I was interested in trying the cytokine suppress, but I looked it up and it contains microcrystalline cellulose. This is a nano particle, used in supplements, as is titanium dioxide.

    Nano particles are implicated in crossing the blood brain barrier and being a magnet for proteins…which can cluster into plaques, which causes neurological problems when in the brain. I found Life Extension brand seems to use a lot of nano particles in their products…avoid anything “microcrystalline” that’s code word for nano. Nano particles are also found in most “antimicrobial” products, from pet dishes, to the filter in your humidifier. Its common in gum and cake frosting.

    The safety of ingesting or inhaling nano particles is not established.

    What is known is that nano particles are antimicrobial (why its used in gym clothes to prevent odor, or to prevent algae growing in a pet water dish), and our population shouldn’t ingest anything that will kill much needed gut bacteria!

  • Ian Hodgson PhD

    November 27, 2019 at 7:23 am - Reply

    Cytokine levels are regulated by Nkcell function.

    Nkcell cytotoxic function:
    Nkcells are the most heterogeneous of all immune cells resulting in a very wide range of functions and effects.
    Human NK cells can be classified into two subsets, depending on their immunophenotype and function: CD56dim and CD56bright. CD56dim constitutes 90% of the total NK cell population in peripheral blood and these express a low-affinity receptor for the constant region of immunoglobulin G, Fc γ RIIIa (CD16).10 Functionally, these have high cytotoxic activity. Approximately 10% of NK cells belong to the CD56bright subset and they are mostly involved in the production of cytokines.

    If Nkcell calcium ion channels are dysfunctional (as has been shown in ME/CFS) leading to poor calcium stores then we can expect a membrane receptors functional change and while different NK subsets vary in their responsiveness :TRPM3 dysfunctional Nkcells (NK cell cytolytic impairment) trigger an increased level of IL-6 production by unstimulated PBMCs. It remains to be seen the great effects of TRPM3 dysfunctional Nkcells on other cytokines but I predict there are many. So when we see many alterations in the cytokine network I look back on Nkcell dysfunction as a plausible initiator.

    Nkcells can be come “exhausted” and lose cytotoxic functions when chronically “stimulated” by viruses such as CMV and other HHVs. It remains to be seen whether TRPM3 is altered in such exhaustion. In addition CD56dim express a low-affinity receptor for the constant region of immunoglobulin G, Fc γ RIIIa (CD16). It is certainly known that an over representation of immunoglobulin G, Fc γ RIIIa (CD16) is present in recurrent periodontitis. It seems to be a key chronicity factor in infection. IgG binding levels are associated with the levels of rise in calciium levels. Not that the IgG binding necessarily induces the rise but they are associated. remember that in ME/CFS the calcium ion channel (TRPM3) is dysfunctional.

    Also, normally functional TRPM3 suppresses cytokine secretion from vascular smooth muscle.

  • Betty Mekdeci

    November 27, 2019 at 10:52 pm - Reply

    Hmm…Enbrel. Would you trade a “maybe” improvement in what you have for this potential list of side effects.

    Serious side effects of ENBREL

    These are not all the side effects of ENBREL.

    Infections, new or worsening of infections you already have
    Hepatitis B can become active if you have had it before
    Nervous system problems such as multiple sclerosis, seizures, or inflammation of eye nerves
    Blood problems (some fatal)
    Heart failure, new or worsening heart failure you already have
    Psoriasis, new or worsening psoriasis you already have
    Allergic reactions, with symptoms that include a severe rash, a swollen face, or trouble breathing
    Immune reactions, including a lupus-like syndrome, lymphoma (a type of cancer) and other cancers, and autoimmune hepatitis

    • Cort Johnson

      November 28, 2019 at 3:16 pm - Reply

      Since this appears to be hopefully a one-shot treatment plan – first the etanercep then later the mifepristone – hopefully those side effects which probably show up in longer term treatment plans wouldn’t apply.

  • Matthias

    November 28, 2019 at 6:23 am - Reply

    Still not convinced cytokines are central to the illness.
    As the article states, a definitive study and findings is required.
    My view is that CFS is an autoimmune illness, and some cytokine abnormalities may be secondary to this.

    • Cort Johnson

      November 28, 2019 at 3:20 pm - Reply

      I agree and more importantly Ron Davis does. I think he thinks that they’re like general markers of something going on – but what?

      If this is an autoimmune illness, though, I think cytokines must be involved. That would make them secondary factor, yes, but still a potential treatment target since the ravages of autoimmunity are, I think, mostly produced by cytokines (?). You wouldn’t stop whatever is driving the autoimmune process but you would stop at least some of the symptoms.

  • Jillian

    November 28, 2019 at 2:49 pm - Reply

    I thought I heard that the treatments were not ongoing, but rather temporary to correct the problem. Are those two drugs Dr. Klimas uses in her trials supposed to be delivered on an ongoing basis to patients? Anyone know?

    • Cort Johnson

      November 28, 2019 at 3:15 pm - Reply

      I don’t believe so. They were to be given in a staggered fashion – first Etanercept and then mifepristone; etanercept to tamp down the inflammation and mifepristone to reset the HPA axis. It sound like a one shot deal.

  • Tracey Anne

    November 29, 2019 at 6:32 am - Reply

    Have you come across Terry Wahl’s and her Wahl’s Protocol. Terry has MS and managed to turn her health around with diet and supplements. I can’t eat as wide a range of vegetables she eats – I can only eat kale and spinach but I learnt a great deal from her.

  • Steve M

    November 29, 2019 at 7:19 pm - Reply

    https://www.tandfonline.com/doi/full/10.3109/1547691X.2012.708366

    I havent met 1 person with cfs or autoimmune disease who hasnt been vaccinated

  • Nancy B.

    November 29, 2019 at 10:58 pm - Reply

    Do hope people are still reading this thread…

    Interesting drug combo in the Klimas trial…especially mifepristone since it is usually used as an abortive.

    So, I saw Dr. Bonilla at Stanford’s CFS clinic a couple of days ago and so since I experienced a very modest positive effect (which later disappeared) on my micro dose of Abilify, he didn’t progress to the hydroxychloroquine trial. He thinks I likely need to try it for a much longer time.

    His latest theory is that there are problems with TPSO pathways to the mitochondria and that chasing cytokines is rather a waste of time. He seems quite enamored with brain neuroinflammation and compares CFS sickness symptoms with disorders like bi-polar and schizophrenia. He thinks the outer membrane of the mitochondria is not functioning properly and therefore the mitochondria are not able to produce proper amounts of energy.

    Cort, I know you just put up a blog where there is some amount of agreement about certain cytokines which are frequently implicated in people with chronic fatigue–especially in that new comparative study. Well, Dr. Bonilla talks and talks and talks and hardly ever listens, so I couldn’t mention it.

    He did try to talk me into some kind of genetic test for P450 drug metabolism, but since I already had my exome sequenced, I had a hard time trying to explain that I could look up those myself or use an on-line interpretation to get some idea of what kind of metabolizer I was for certain pathways (i.e. drugs).

    He also had some kind of odd idea about why EDSers also experienced fatigue and used outmoded categories for the various ‘types.’ That made me suspicious that he only sometimes half way knows about some things–but may be B.S.ing his way through them. His broken English makes understanding him difficult at times, so I don’t know. He so thoroughly controls the meetings that I feel I cannot bring up all of my concerns, share stuff or ask questions.

    Not that I am trashing Dr. Bonilla, but with my first meeting, he claimed he never heard of researchers like Klimas, Navieux (sp?),Younger etc. Maybe he didn’t understand me, but when I had my second meeting with his PA, Ms. Kandan several months earlier, I sent her links to various articles and especially recommended your website. Suddenly, on this most recent meeting with Dr. Bonilla–he recognized all those researchers and was especially impressed with Jared Younger’s brain imaging study.

    Since I did not get the opportunity to ask many questions, I didn’t find out much about the next treatment protocols. I did however, get the names (albeit spelled incorrectly which made me have to try to figure out which ones he was talking about) of the next three medications he was interested in. Here they are; Leflunomide (usually used for RA and MS), Etafenoxine which binds to GABA receptors (in the same GABA ballpark as Abilify), and Mefoloquine (Larium), a very old anti-malarial which isn’t much used here anymore because of some rare psychiatric side effects.

    Dr. Bonilla confirmed that his patients were all part of Stanford’s CFS research project so I had to go through a long list of questions trying to rank things like brain function, energy and pain levels etc. which was difficult for me to do since they are all over the place–depending. I was surprised that when I finally got my BP tested it had settled to it’s usual of 103/73 and not the usually wildly high ‘white coat’ response–yet the doctor has not even broached autonomic dysfunction.

    I’m sorry I’m writing so much, but I’m doing it so others who do not have the opportunity to go to a clinic like this may get a glimpse of what is going on–helpful or not.

  • Tracey Anne

    November 30, 2019 at 7:44 am - Reply

    Hi Nancy B,

    I always keep a look out for later replies and find your comments, like others, very interesting as I believe we seem to have a lot of similarities. I react to food and medications and can induce all sorts of symptoms and then get rid of them again by avoiding that food/substance.

    My brain is definitely affected because I am aware of it happening and what it does to me – no mystery there. I know what I’m eating because I don’t eat anything processed, cook everything myself and really only eat meat, liver, mackerel, and I take supplementseggs, kale, spinach, linseeds, hemp and chia seeds, olive oil, rooibos tea, coffee, ginger, tumeric and an inhaler for asthma and that I think is it. No gluten, dairy – they are a disaster and very low carb. I’ve even had to ditch the sunflower seeds as I get a reaction in my left eye and brain from the carbs.

    There’s loads of info about low carb diets and epilepsy from the last 100 years or so. Dairy brings on very bad mental health symptoms – quite extreme. Gluten has been implicated in some kinds of schizophrenia. The list goes on…

    The internet is great for empowering and educating those of us who are outside of the norm.

    Thanks for taking the trouble to update us, Tracey

  • nila

    December 3, 2019 at 12:08 am - Reply

    Once again I say that cytokines have been found to cause inflammation but it is in my case, the beginning B /12 DNA not working right and then Mono. Then Epstein
    Barr comes along and really finished the job.. All those Immune Dysfunctions are triggered then I am an open pathway for all of the LATENT HERPES VIRUS’.. LATENT VIRIAL BUGS ARE MANY… 8 known herpes …look for cmv, epstein barr, Herpes Six A and separate.. Herpes Six B… YOU HAVE TO HAVE IGM TITERS OVER AND OVER IN YOUR BLOOD.. What about in the collagen tissues??? Would not a biopsy be appropriate? These viral illnesses like to be the tissue where they cause inflammation. Herpes Six B causes Brain inflammation. Does this not describe Encephlosapy. Low Oxygen blood flow in the Brain? I know I get reoccurring FLARE UP’S. Foggy Brain describes Herpes B six. inflammation. This I say because when I get Epstein Barr IGGM’ titers…I already know because of the sleepiness heavy in my symptoms. ..Not that there are other positives too. No sleepiness when I have CMV.–. The stomach and digestive colon is taking me out with inflammation or allergies…
    Cort, the painting that the girl did is so right on describing the pressure on the brain or/and inflammation. I used to say that if I could paint a picture it would be me in a fishbowl looking out at the world..not only affects emotions but makes you feel separated from others…NOT DEPRESSION… I only write all this to hope that someone can be helped by what I’ve been diagnosed with..Do not do aerobics if you want to stay feeling better. I also have been diagnosed with By Polar and I really felt like killing myself. It’s been proven over and over again in my history that I am not By Polar.. Once that’s on your records it’s very, very hard to express any emotion to a doctor. Thanks, Cort. I know I get really ANGRY at times and it comes through..I know this… It is a normal reaction to pain, long term illness and still no real answers… I think they are really not listening to symptoms and first-hand testimony from the US., with the illness.. You know I hate the name..Fatigue …..my Ass!! How does a person know where to start that doesn’t have the illness… I just report to you what my thoughts are and hope it helps some researchers along the way also. Nila