Fibromyalgia: Cytokines Testing?

Discussion in 'Fibromyalgia Main Forum' started by RadioFM, Sep 18, 2014.

  1. RadioFM

    RadioFM Active Member

    Last edited: Dec 17, 2014
  2. RadioFM

    RadioFM Active Member

    Cytokines and Fibromyalgia Syndrome

    "Cytokines are small molecules that do not stay around very long in the body before they are either taken up or degraded. They act as chemical messengers to affect immune responses, tissue repair, or cell growth. Their production is influenced by both the central nervous system and the immune system. The sympathetic nervous system, through the secretion of catecholamines, will activate the hypothalamic-pituitary-adrenal axis (HPA) and stimulate the release of cytokines. If you don’t know about HPA axis then read the two short reports on “The Neuroendocrine Theories Behind Fibromyalgia.” Catecholamines are the “fight or flight” hormones produced by the adrenal glands – epinephrine and norepinephrine and they primarily act through the sympathetic nervous system. For more information about epinephrine and norepinephrine you can read the short reports on “Dysautonomia, ”and the two-part series on ‘The Neuroendocrine Theories of Fibromyalgia.”

    "The most common cytokines are “interleukins,” and they are abbreviated and numbered, e.g. IL-1, IL-6, IL-8, and so on. IL-8 is a key cytokine that plays a role in inflammation. It is released by macrophages, cells that are activated in response to tissue injury. They help promote pain in laboratory animals and will cause pain in a dose dependent manner, meaning the higher the concentration of IL-8, the greater the pain the animal will experience. The secretion of IL-8 by macrophages can also be induced by substance P, which is a major nerve transmitter that you will read quite a bit about in the sections on pain in fibromyalgia syndrome (FMS) that are coming up in the near future. IL-8 is of particular importance because it also activates the sympathetic nervous system. IL-6 and another cytokine called tumor necrosis factor-alpha (TNF-alpha) are also major inflammatory cytokines and have been implicated in the generation of a particular type of pain called neuropathic pain."

    "A group of researchers first proposed a link between cytokines and FMS when they observed that patients given IL-2 cell therapy for melanoma or terminal renal cell carcinoma developed FMS-like symptoms such as myalgia, cognitive impairment, and tender points. The IL-2 therapy was part of the treatment for these cancers. Since that time, there have been numerous studies that have attempted to correlate the role of cytokines to clinical manifestations of FMS based, in part, between their relationships with the HPA axis and the sympathetic nervous system. If you haven’t done so, it’s definitely time to read the two part series on the “Neuroendocrine Theories Behind Fibromyalgia.”

    "Part of the interest is driven by what is known by psychiatrists as the “sickness behaviour” noted in FMS – pain, fatigue, cognitive changes, and depression that tends to match those signs seen with activation of the immune response system as a result of an infection. Remember, people with FMS will tend to say they feel like they have the “flu” all the time, that’s been one of the best ways used to describe FMS to other people. Psychiatrists are doctors, they like to have more medical ways to say things, so they called that common way of expressing FMS, “sickness behaviour.”

    " Although patterns have tended to emerge, there are some subtle differences. The discordant results may reflect the small sample sizes used in the studies, differences in patients’ conditions, the amount of adipose tissue (which affect how cytokines are produced), as well as dissimilarities in laboratory techniques; no two studies were exactly alike."

    "If you’re ready – here’s a rundown on what’s been found so far (take a deep breath). One group of researchers have published two studies that found significantly elevated levels of IL-8 that correlated to pain intensity as measured by tender points. Another group has also found high levels of IL-8 in FMS patients, but not IL-10 or TNF-alpha. On the other hand, different researchers noted high levels of IL-8 as well as IL-10 and TNF-alpha. Then some other folks found elevated IL-8 and TNF-alpha but not IL-10. Wait a minute, here’s a group that reported no differences in IL-10 or TNF-alpha but now this fellow found decreased levels of TNF-alpha. Another common inflammatory cytokine, IL-6, was not found to be higher in four studies of FMS patients, including a major report from the National Institute of Health, although a major FMS researcher group noted higher levels in patients, provided they had symptoms for more than two years. Confused? So is everyone else." See more here:

    "Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels."


    "Activation of glia cells resulting in intrathecal elevation of cytokines and chemokines has been hypothesized in chronic pain syndromes such as fibromyalgia. To our knowledge, this is the first study assessing intrathecal concentrations of pro-inflammatory substances in fibromyalgia. We report elevated cerebrospinal fluid and serum concentrations of interleukin-8, but not interleukin-1beta, in FM patients. This profile is in accordance with FM symptoms being mediated by sympathetic activity rather than dependent on prostaglandin associated mechanisms and supports the hypothesis of glia cell activation in response to pain mechanisms." See more here: Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels.

    "This analyses showed that fibromyalgia patients have increased levels of IL-17A. They also reveal that plasma concentrations of IL17A correlate with levels of IL-2, IL-4 and IL-10, TNF and IFNγ."

    "As far as we are aware, this is the first study to demonstrate increased levels of IL17A in fibromyalgia patients. The positive correlation between the levels of IL-17A and of other cytokines strengthens the hypothesis of the involvement of inflammatory mechanisms in the development of this syndrome.
    Pernambucomet al. Clin Ex Rheum. 2013 Nov-Dec;31 " Increased levels of IL-17A in patients with fibromyalgia.

    Dysfunction of the Nervous, Endocrine and Immune Systems

    Fibromyalgia and chronic fatigue syndrome have been associated with dysfunction of the immune system that either leads or results in viral infections. A defect in T-cell activation was traced in fibromyalgia patients. Research suggests that dysregulation of interactions between the immune and the nervous system may possibly cause neuroendocrine changes and immunologic dysfunction.

    Interleukin-2 (IL-2) production was studied in T lymphocytes and isolated CD4+ T lymphocytes from 12 patients with primary fibromyalgia syndrome and 10 healthy volunteers. The dose and time kinetics of IL-2 production by concanavalin A-stimulated T cells and CD4+ T cells of fibromyalgia patients differed from findings in controls by 1) a need for a higher concentration of mitogen in order to achieve optimal IL-2 secretion and 2) a delay in the peak time of optimal IL-2 secretion. Unlike normal IL-2 secretion, which was higher after removal of CD8+ T cells, the pattern and degree of IL-2 secretion by cells from fibromyalgia patients were not changed following removal of CD8+ T cells. Addition of calcium ionophore in assays using suboptimal concanavalin A concentrations did not correct the reduction in IL-2 secretion by fibromyalgia patient T cells, but addition of phorbol myristate acetate induced normal secretion of IL-2. These findings suggest that there is a defect in the IL-2 pathway, which is related to protein kinase C activation and does not involve impairment of Ca2+ elevation, in patients with fibromyalgia. Altered interleukin 2 secretion in patients with primary ...
    Last edited: Dec 17, 2014
  3. Mikie

    Mikie Moderator

    As I mentioned under another one of your threads, we can't treat the root cause of our illnesses because no one knows the cause, or causes. We know there are various triggering events, such as infection, stress, illnesses, and injuries, but that doesn't prove those triggering events are THE CAUSE of what ails us. Right now, we can treat our various infections and other symptoms and that will likely bring about some healing. There is NO CURE.

    I think you are one the right path by researching factors which have relationships to our illnesses. That research will likely reveal treatments which may help you heal but they are not a cause nor a cure.

    Love, Mikie
    Sherpa_ likes this.
  4. RadioFM

    RadioFM Active Member

    We need to ask the right questions in order to have full understanding of the contributing factors to our illnesses. I do believe recovery is possible for many and that is my goal. I feel it's important we document our experiences and help others understand that we do have non-toxic treatment options and functional comprehensive testing that may be beneficial.

    Never give up the fight!
    Last edited: Dec 17, 2014
  5. RadioFM

    RadioFM Active Member

    Various Causes of Fibromyalgia ( Fibromyalgia and pseudo fibromyalgia)

    "A 2001 article from the Journal of Manipulative and Physiological Therapeutics, Fibromyalgia Syndrome: a New Paradigm for Differential Diagnosis and Treatment, states:"

    “It is our opinion that the original premise of FMS [fibromyalgia syndrome] as representing one grand, all-encompassing clinical syndrome is … an oversimplified classification scheme that lumps together several distinct conditions that all happen to share a common cluster of symptoms.” [3]

    "In other words, two different people can both have a diagnosis of fibromyalgia, yet their pain is caused by entirely different conditions."

    "The article goes on to classify fibromyalgia as either “classic fibromyalgia” or “pseudo fibromyalgia.”

    Classic Fibromyalgia
    "These people seem to have a pain perception problem. Generally they do not sleep well, feel fatigued upon waking, have low energy, can not tolerate heavy exercise and have a lowered pain threshold. There is often an associated clinical depression or anxiety disorder. Symptoms often first begin after a period of emotional stress or trauma and studies have shown that these people have decreased levels of serotonin."

    Pseudo Fibromyalgia
    "Pseudo fibromyalgia describes people who have been misdiagnosed as having fibromyalgia when they have another cause for their widespread pain. Pseudo fibromyalgia has been broken down into three categories: organic diseases, functional disorders and musculoskeletal disorders."

    Organic Diseases
    "Many other diseases such as hypothyroidism, inflammatory arthritis, anemia, Lyme disease, auto-immune disorders, multiple sclerosis and cancer can cause widespread pain. A diagnosis of fibromyalgia should only be given after these other causes of pain have been excluded. Many conditions in this category are also associated with fatigue, especially hypothyroidism."

    Functional Disorders
    "Functional disorders are not true pathological conditions or diseases. These are things such as vitamin and mineral deficiencies, intestinal dysbiosis, dehydration and subtle hormonal imbalances. What these functional disorders have in common is that they can cause low energy and widespread pain."

    Musculoskeletal Disorders
    "The tender points of classic fibromyalgia are different than the trigger points from sore or overused muscles. Classic fibromyalgia is not a disorder of the muscles, but is a pain perception disorder. Pain from problems such as sore muscles, inter-vertebral disks, joints, herniated disks, or nerve impingement is not fibromyalgia."

    For more information on this there is an excellent article posted on, Fibromyalgia Syndrome: Reclassification is Definitely Needed.
    Last edited: Sep 25, 2014
  6. IanH

    IanH Active Member

    While mycoplasma infections can cause chronic fatigue as well as other symptoms we have not found an association between mycoplasma infection and ME or FM.

    My associate did his MD on this. (An MD in our countries is a much higher specialist degree than the American MD which is a general medical degree.) He was convinced that the mycoplasma infections were causing these illnesses and spent 7 years investigating this possible association.

    While a small proportion of people had a clear mycoplasma infection most did not.

    After treatment to remove the mycoplasma spp. the symptoms of chronic fatigue syndrome were alleviated in only one of those people. Three people with FM and mycoplasma were worse after their treatment, which as you know is very invasive and extensive in order to remove the mycoplasma spp, involving many different antibiotics and intravenous treatment.

    So while it is easy to theorize, as I have done too, in clinical practice very little happens.

    By the way, I was one of those patients in the above studies but I had no mycoplasma infection identified.
  7. RadioFM

    RadioFM Active Member

    Hello IanH,

    Did you test for a broad range of mycoplasma species?

    Garth Nicolson has been researching Mycoplasma for some time now. He recommends a specialized PCR test for Mycoplasma he says the antibody tests are "relatively insensitive". He specifically recommends VIPdx's Mycoplasma PCR panel, which tests for a range of species.

    See more here:

    Last edited: Sep 21, 2014
  8. RadioFM

    RadioFM Active Member

    Interesting...Sound like possible Herx reaction/Die off to me. The problem with killing these infections is the pro-inflammatory cytokines. If there is a impaired detoxification, killing these infections may cause more inflammation, ROS, mitochondrial damage.
    Last edited: Dec 17, 2014
  9. IanH

    IanH Active Member

    He used the EZ-PCR test system. It is an industry standard. I do not recall all the spp tested for but it included:
    pneumoniae, homonis, penetrans and fermentans and I think genitalium. There were 7 species/subspecies in all.
    The treatment used three drugs serially, tiamutin, minomycin, salazapyrin or ciprofloxacine depending on the persons HLA B27 SNPs profile. (As you may know that people with several HLA B27 SNPS are more prone to mycolpasma infection and intracellular penetration of the mycoplasma). The treatment period was 8 months to 3 years again depending on the person.

    As a clinician he did a good job(as far as clinical work can) and it convinced me that mycoplasma infection was probably not at the root of either ME or FM. At that time FM was narrowly diagnosed, not like today's wild widening diagnostics. (every man and his dog has FM). However it certainly was probably a heterogeneous he was looking at even then. I still doubt this type of infection lies at the root of much ME or FM. I also consider much of the serious FM to be a variant of ME. Is infection at the base of ME or FM (or even some of it)? Possibly! But I think it is more likely to be a quirk of the immune system rather than any specific infection.

    For example, I know of 11 people who were diagnosed with ME, who later "developed" FM. I know 9 people who were diagnosed FM who later had their diagnosis changed to ME. Of the 11 people who were first diagnosed with ME, 5 could clearly identify their illness arising after mononucleosis, yet the EBV was not active one year after the initial infection. Possibly EBV triggered their illness. What we need is more genetic profiles paired with this sort of information, possibly even with other infection such as mycoplasma to see what the immune system is doing in response to these events. At this stage we cannot even subgroup people - not enough data.

    While Garth Nicholson means well and his Integrative Medicine ideas are topical he talks a bit loosely about infection and CFS. He is typical of Scientists who have a theory then searches for all the facts that fit the theory. This can lead you down a track with some good spin-off but often not the theory you are trying to prove. Only rigorous peer reviewed laboratory testing will get us the answers about these illnesses. I never trust a clinician's stats. Given that I still follow Garth Nicholson's progress with interest.
    Last edited: Sep 20, 2014
  10. IanH

    IanH Active Member

    Oh by the way, All patients were treated even if mycobacteria were not identified - just in case a spp was not identified. (I was one of those who was on the drugs for 13 months) He was well aware of the difficulty in identifying the presence of infection.
  11. IanH

    IanH Active Member

    I do not quite follow your chart What is Fibromyalgia?

    The symptoms of FM as you list ARE the symptoms of FM, whatever the person. Certainly way more than 2% of diagnosed FM patients have this set of symptoms. With the exception of low serotonin. Only some people with FM have low serotonin, some have low melatonin. However these parameters vary over time. You can get a low serotonin result one time but later get a normal level in the same person.

    I am not sure what you mean by "central allodynia" do you mean allodynia which is caused by CNS abnormality. If so this is also not clearly proven, only a theory. There are enough peripheral abnormalities to cause allodynia. I am not saying that central sensitization does not exist but it is only a theory that this is the core problem in FM. I do not believe it to be. There is plenty of evidence for peripheral neuropathy and neurovascular abnormalities.

    I have a colleague who has found mis-shapen (flattened) RBCs in ME and recently has found this same abnormality in some people diagnosed with FM (not ME). This causes excessive AV shunting to develop to compensate for the hypoxia caused by the poor "circulation".

    This work implies that ME/FM could be a neuro-vascular problem leading to nociceptive abnormalities like allodynia.

    The point I am making is : If you really look HARD at all the evidence FM is mystery and many studies do not point to infection per se. I am not ruling infection(s) out but we are along way off and many studies are showing many different paths.
  12. RadioFM

    RadioFM Active Member

    I have posted a thread that may indicate a possible relationship with Pseud subgroups fibromyalgia.
    Last edited: Dec 17, 2014
  13. RadioFM

    RadioFM Active Member

    The link I Posted was a old 2001 article from the Journal of Manipulative Physiological Therapeutics pointing out that there are possible differential diagnosise relating to FM.

    “It is our opinion that the original premise of FMS [fibromyalgia syndrome] as representing one grand, all-encompassing clinical syndrome is … an oversimplified classification scheme that lumps together several distinct conditions that all happen to share a common cluster of symptoms.”
    Last edited: Sep 20, 2014
  14. IanH

    IanH Active Member

    "The neuro-vascular problem could be possibly related to vasculitis?"

    Not really, vasculitis is an inflammation of the blood vessels. The pathology identified relates to red blood cell abnormality not the vessels.

    Flattened RBCs cannot pass through the arterioles. Normal RBCs are a disc shape with hollowed centres. They have this shape partly to enable distortion to get through narrow arterioles which are only the thickness of the rbc itself. This ensures oxygen passes from the cell to the vessel wall and out into the tissue.

    When RBCs are flat discs they cannot distort and therefore block the arteriole. This causes local pressure to increase and of course a lack of oxygen in the end tissue. Eventually a shunt is formed to alleviate the pressure. (These shunts have been shown to be elevated in ME and FM. However the shunt is also maladaptive because the tissue is still starved of oxygen and flow is disrupted. This disrupted flow in the end tissue causes a rise in ROS and NOS as a result of catabolism. This has an effect on mitochondrial function as well as calcium and sodium pump function.

    In soft tissues the result is both rapid fatigue and in some people pain (the FM group).

    The possible result of this pathology is that the immune system becomes more involved with many varied symptoms. One would expect immune attack on this "toxic" tissue. The immune system is partly to deal with toxicity in tissue.

    So you can see from this that the neuro-vascular aspects of the illness are quite significant. It is early days in this research so I cannot say definitely that this pathology exists in all cases of ME and FM but it looks like there is a significant number of people with ME + FM who have this pathology. What caused the RBC abnormality - who knows? This abnormality showed up some time ago because it was known that ESR was abnormal - but at that stage it wasn't known why.

    It is probably a genetic tendency triggered by some environmental factors. Like many of these gen-env interactions the phenotypes show up as a normal distribution of pathology. That is, around 60+% of people with the gen-env interaction have moderate symptoms and the most common symptoms. Around 12% of people have severe or very mild symptoms and then around 3% have very severe symptoms or very very mild or infrequent symptoms. (This is a simplified version of a normal distribution of phenotypes).
  15. IanH

    IanH Active Member

    Just adding to what you have been saying. I just talked with my colleague who is doing the work on RBC abnormalities in ME/FM. He is looking at the possibility that this abnormality may be caused by one or more of the mycoplasma like organisms. It is possible, and known from some animal studies that some spp. of micro-organism (mycoplasma like) do bind to the RBC wall. In some cases this causes agglutination which he has also found in patients with ME and FM. However flattened RBCs are also known to agglutinate a small but observable amount. At this stage it is not known whether flattened RBCs are associated with mycoplasma.

    Of course, agglutination causes blockage at the arterioles as does flattening of the RBC. Other than the rare but deadly illnesses autoagglutination is associated with both mycoplasma like infections and mononucleosis. However the mycoplasma-like infection-caused agglutination also requires hypothermia. (Known as cold-agglutination). Also this usually leads to RBC destruction rather than a chronic condition such as FM.

    However to complicate matters : Inflammatory acute phase proteins in humans which include C-reactive protein, haptoglobin, fibrinogen, serum amyloid A protein (SA-A); alpha-1 proteins including alpha-1 antitrypsin, ceruloplasmin; and components of the complement cascade, especially C3 can also be associated with changes in ESR and agglutination. The agglutination is possibly caused by additional antibodies binding to the RBC wall.

    I suspect that an immune system change causes the rise in mycoplasma population in ME and FM which are normally kept within safe limits. Whether the rise in the population is causing problems is as yet unknown but maybe a by-stander reaction. Cause and effect are completely lacking.
    Last edited: Sep 20, 2014
  16. RadioFM

    RadioFM Active Member

    Wow, thank you for that intriguing informative post. I have been looking for this kind of feed back.

    My vasculitis question is more about the possible connection to Anti–Endothelial Cell Antibodies damage association with these infectious agents.

    Also, what testing is available to support this research related to the red blood cell RBCs abnormalities?

    What are your thoughts about the Inflammatory cytokine profile testing I have been advocating?

    • NeuroScience click on Immunology...look for "Inflammatory cytokine profile TEST" IL-1beta, IL-6, IL-8, IL-17, IFNgamma, and TNFalpha. C3a and C4a
    Last edited: Sep 22, 2014
  17. RadioFM

    RadioFM Active Member

    I had to run a comprehensive DNA stool analysis to help identified my mycobacterial infection. Tests for DNA, not by culture.

    Last edited: Sep 21, 2014
  18. IanH

    IanH Active Member

  19. RadioFM

    RadioFM Active Member

    Radio: Here is some more cytokines information and natural non toxic anti-inflammatory support idea's...

    Neuropathic pain may result from NF-kappaB activation by cytokines, especially IL-8.

    "How might neuropathic pain arise in fibromyalgia syndrome? Perhaps in part as the result of excess cytokine production."

    "The study briefly summarized below discusses pro-inflammatory cytokines. It was observed that pro-inflammatory cytokines in and around the spinal cord can turn on NF-kB. NF-kB is something like an inflammation ‘master switch’. As a result of NF-kB activation, cells ‘turn on’ inflammation and begin generating mediators of inflammation, including more cytokines. The net result, the authors conclude, is neuropathic pain. So at least some neuropathic pain might be attributed to cytokine activation of NF-kB in and around the spinal cord."

    "That might explain neuropathic pain in fibromyalgia, because cytokines, especially IL-8, are consistently elevated in those with fibromyalgia. At least six studies document elevated IL-8 in those with fibromyalgia (one study found normal levels.) Further, at least three studies have shown a direct correlation between the level of IL-8 and pain severity."

    "While IL-8 is not specifically mentioned in the abstract, IL-8 is a pro-inflammatory cytokine that is known to activate NF-kB. And it is NF-kB activation that the authors suggest is responsible for generating neuropathic pain."

    "In summary:"

    1. "Pro-inflammatory cytokine levels (especially IL-8) are elevated in fibromyalgia."

    2. "Pro-inflammatory cytokines (including IL-8) turn on NF-kappaB."

    3." NF-kappaB activation in and around the spinal cord appears to play a significant role in generating neuropathic pain."

    "Therefore it’s likely that pro-inflammatory cytokine excess is largely responsible for the neuropathic pain of fibromyalgia."

    What’s the solution?

    "Inhibition of NF-kB should lead to an immediate reduction in neuropathic pain. And, because it was excess activation of NF-kappaB that led to pro-inflammatory cytokine excess in the first place (can you see the vicious cycle?) – inhibiting NF-kB should provide a long-term benefit by lowering pro-inflammatory cytokine levels." See more here: How can we explain nerve pain in fibromyalgia?

    Last edited: Sep 22, 2014
  20. RadioFM

    RadioFM Active Member

    Last edited: Feb 12, 2015

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