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Norwegian Rituximab Chronic Fatigue Syndrome (ME/CFS) Trial Fails

November 26, 2017

Over the past five years or so, Rituximab has been the great hope for the ME/CFS community. The anecdotal stories of dramatic recoveries were beyond enticing. A successful trial could ultimately have led to the first FDA-approved drug for ME/CFS and relief for many, a huge shift in how the disease is viewed, and surely more research funding.

That unfortunately is not to be. At a talk in Norway on Nov 21st, Dr. Mella revealed that the Rituximab trial that many laid their hopes on has failed. We don’t know and won’t know the details of the failure until the paper is published next year, and Drs. Fluge and Mella talk more about the study.  Dr. Mella said they provided the result so that ME/CFS patients won’t try the drug on their own.

The Norwegian trial was never by itself going to lead to FDA approval for Rituximab’s use in ME/CFS. The trial was large and rigorous enough, though, to ensure that, if successful, another trial which could lead to FDA approval would follow. The trial’s rigor had equally negative consequences; it’s hard to imagine in this funding-hampered disease that anyone is going to fund a large Rituximab trial in the future.

Ritxuimab's future in ME/CFS

The main finding of the Norwegian Rituximab trial was negative but Rituximab’s ,may role in ME/CFS may not be at an end.

Rituximab may never be an FDA-approved drug for the general ME/CFS population, but its role with ME/CFS may not be over, and smaller, targeted trials are still a possibility. From the beginning, Fluge and Mella recognized the possibility of a trial failure and had a backup plan in case it failed:

However, if our selection bias in the first studies is large (i.e. if we selected out patients that are not representative of ME/CFS patients as a whole) the new study might very well turn out negative (i.e. no difference to placebo). Should that happen we would then focus our efforts on figuring out how to select the subgroup that has an immunological, rituximab-responsive disease.

Efforts to find biomarkers that identify the responders will be critical and are already underway. David Patrick of Canada reported on his use of microarrays to try and tease out which ME/CFS patients might respond to Rituximab at the 2016 IACFS/ME Conference. Nancy Klimas suggested that the Rituximab sera could very well hold the key to Rituximab’s future with ME/CFS. If autoantibodies are present in the Rituximab responders’ sera, they could be used to screen patients for future trials.  She questioned whether the autoantibody patterns she’s seen in her studies might be predictive.

Norwegian journalist Jorgen Jelstad pointed out that antibodies are used to identify responders to Rituximab and other immune-suppressing drugs in osteoarthritis. Patients with positive antibody findings get the drugs and patients with negative findings do not.

We know that some people with ME/CFS do respond very well to Rituximab. We’ll know more about them and the next steps Fluge and Mella will take with the drug and their other studies in early 2018.

The Rituximab Saga

The Rituximab saga began in 2004 when two oncologists noticed that Rituximab – a B-cell depleting drug often used in cancer – not only cured one of their patient’s cancer but eliminated their chronic fatigue syndrome (ME/CFS) as well. After two more ME/CFS patients responded similarly, they began their work on ME/CFS in earnest.

Several small case studies or trials ensued, all of which produced excellent results. The first one – called a preliminary case series in 2009 – reported on the three ME/CFS patients who’d improved on Rituximab.  The second – a 2011 double-blinded, placebo-controlled 12 month trial of 30 patients – found Rituximab produced “major or moderate” results in 2/3rds of the participants.

The third, a 2015 open-label (the patients knew they were getting Rituximab) study, which involved giving the participants doses over a longer period of time, achieved similar results.  The SF-36 scores of the major responders – about 50% of the study participants – suggested that they might be back to near normal. Not only did the trial succeed, but the trial suggested that the relapses dogging the patients from the first study could be prevented by continuing to take the drug.

The 152 person, double-blinded, placebo controlled trial that eventually resulted was spread across five hospitals in Norway. The trial had a rocky start with the Norwegian government pulling its support, but ultimately patient advocacy and patient support prevailed. The trial began in 2015 and wrapped up on time in September of this year.

Why the Trial Failed

We won’t know why the trial failed or how many people the drug worked for until the paper is published in the first half of next year but speculation is rampant.

Was “Failure”Always the Most Likely Outcome (?) –  My probably minority opinion is that “failure” may have always been the most likely outcome of the study given the heterogeneity this community displays every day on Forums, Facebook and elsewhere on the internet. It may be too much to ask for many drug trials aimed at the entire ME/CFS community to succeed.

It’s important to note that Rituximab may still have a role to play in ME/CFS – just not as a drug for everyone. The key question now is how many people actually did respond to it.  If a substantial number did, and a biomarker to identify them can be identified, the Rituximab trial will not go down as a failure at all.

Patient Bias? – Inadvertent patient bias – a possibility Fluge and Mella considered as the trial started – is probably the best candidate at this point. It could be that the smaller early studies inadvertently plucked out a more receptive set of patients. Once more patients were added to the mix, the effect disappeared. This is not an uncommon result in large Phase III drug trials:

“However, if our selection bias in the first studies is large (i.e. if we selected out patients that are not representative of ME/CFS patients as a whole) the new study might very well turn out negative (i.e. no difference to placebo).” Fluge and Mella

Placebo Effect? – Jorgen Jelstad put forth the intriguing idea that a high placebo effect could have doomed the drug. A similar situation appears to have doomed the Synergy trial. The Synergy compound actually did quite well but the placebo effect – possibly due to patients’ excitement about the treatment – was so strong that it was impossible to show clear separation between the effects of the drug and the placebo. Given the excitement around Rituximab, it’s possible that a similar situation has prevailed.

Endpoint – Not Disease? – It’s also possible that ME/CFS is not a single disease, but represents an endpoint or condition that can be reached in any number of different ways. Both Gulf War Illness and Lyme disease, after all, symptomatically appear to be the same as chronic fatigue syndrome but studies suggest that the three diseases are probably quite different biologically.

If different pathways exist to the same symptomatic or even cellular endpoints, then different treatment pathways will be needed. Alzheimer’s is possibly an excellent example of a complex endpoint – not a single disease – which will need a variety of approaches to resolve. Dale Bredesen MD believes that hundreds of millions of dollars and hundreds of prospective drugs have failed to make a significant dent in Alzheimer’s because the disease has been misidentified. Dale Bredesen’s studies suggest that an approach which assesses and treats a wide range of factors may actually work quite well in Alzheimer’s.

See Reversing Alzheimer’s: What Could it Mean for Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia

Drug Trial Failures Not Uncommon in Medicine

The ME/CFS and FM communities have recently, unfortunately, been getting acquainted with the fact that disappointments in drug trials are more common than successes.  Rituximab had two small, but good, Phase II trials and seemed likely to succeed, but surprises in medical research, as Ron Davis has pointed out so many times, are common.

Rituximab subsets

The next step will be determining who did respond to Rituximab and why

Jelstad’s interesting blog “The ME Rituximab Trial is Negative” (translated by Google into English) noted that Rituximab also failed in lupus despite the fact that it seemed hand-made for a B-cell associated disease. In fact, researchers were so shocked at the failure of the first large Rituximab lupus study that they immediately started another one – which subsequently bombed as well.  (Despite all that, Rituximab can still work in lupus and is used in patients who haven’t responded to other treatments. )

Closer to home, two major Phase III fibromyalgia trials, one involving 10,000 patients, failed over the past year. As with ME/CFS and Rituximab, their Phase II trials had produced stellar results. Likewise, Wyller’s Clonidine trial seemed set up to reduce the “arousal” that seems manifest in this disease. Not only did the trial fail, but the drug actually made Wyller’s young ME/CFS patients worse.  Medicine is full of surprises. It’s unrealistic to assume that ME/CFS won’t fall prey to some of them.

The Big Hurt: Second Major Drug Trial for Fibromyalgia Fails

Cautionary Findings?

The result is disappointing but it’s perhaps not entirely surprising.  Rumors from doctors using the drug in the U.S. on ME/CFS suggested the success rates might be lower than hoped for. If I’m reading them right, the immune B-cell studies in ME/CFS which sought to identify the issue Rituximab has addressed haven’t exactly been sterling successes.

Fluge and Mella proposed that long-lived autoantibodies or some other “slow alteration in the immune function governed by B-cells” could be causing ME/CFS.  That idea was buttressed by a study finding increased rates of B-cell lymphoma in elderly ME/CFS patients.

When a German study found significantly reduced levels of muscarinic and B-adrenergic antibodies in Rituximab responders, the way forward seemed clear. Rituximab’s B-cell depleting properties were preventing B-cells from producing autoantibodies that were affecting blood flows and other processes.

The study possibly provided a cautionary note, however, when only 30% of the ME/CFS patients not given Rituximab (n=268) displayed the antibodies – a far smaller percentage than had responded in the early Rituximab trials. If those antibodies were what Rituximab was affecting – which was certainly not clear – many patients simply didn’t have them.

Meanwhile, studies that had focused on the B-cells in ME/CFS didn’t seem encouraging. Several studies prior to the Rituximab finding had not shown consistent B-cell differences between ME/CFS patients and healthy controls.  A more recent found mostly modest alterations in B-cells in ME/CFS patients. Bradley’s conclusion that ME/CFS patients exhibited a “subtle tendency to autoimmunity” didn’t seem to jive with the idea that ME/CFS is a B-cell mediated autoimmune disorder”. Another study which found some B-cell abnormalities was unclear what their functional impact might be.  A 2013 study simply found no differences in the B-cells of ME/CFS patients and controls.

Finally, researchers have had trouble figuring out what Rituximab was doing when it did work. Lunde’s 2016 study of ME/CFS patients receiving Rituximab found no difference in several immune measures (serum BAFF, T-Lymphocytes, T-cell activation) and just slight (but significant) reductions in immunoglobulin levels.

There’s certainly more to know about B-cells in ME/CFS – the Solve ME/CFS Initiative’s (SMCI) is funding a small study of B-cell energetics – but if B-cells are causing ME/CFS, they haven’t been giving up their secrets easily.

Enormous Impact

While the Rituximab trial failed in its main objective – to provide a drug for ME/CFS patients – there’s no denying that its impact has been enormous. Two highly creative researchers, Oystein Fluge and Olav Mella, have entered the field and say they intend to remain. Their wide-ranging efforts have and are touching on everything from autoantibodies to blood vessel functioning to metabolomics to exercise.

They and the Norwegian ME/CFS community put together the largest non-CBT/GET trial ever in ME/CFS, produced one of the largest biobanks, and created collaborations with researchers in Europe and the U.S.  It proved that ME/CFS patients and their supporters from across the world will respond (Dr. Maria Gerpe reported that over 90 days, 5000 donors from more than 49 different countries contributed to the study). The Rituximab saga has provided a jolt of energy across the entire ME/CFS community.

fluge_mella_research_team

Fluge and Mella and their supporters did the seemingly impossible: put on a large and expensive ME/CFS drug trial in a small country

Plus, the trial was not just about Rituximab. Several other studies baked into the study will add to our understanding of ME/CFS. A study examining endothelial function and skin microcirculation should tell us about blood flow issues – very possibly a key issue in ME/CFS. Their two- day exercise test should validate the highly unusual decline seen in the ability of ME/CFS patients to produce energy after exercise. Their gastrointestinal functioning test should, likewise, tell us about gut functioning in this disease.

Plus, Fluge and Mella are continuing with their cyclophosphamide trial. Cyclophosphamide has some real advantages over Rituximab. While Rituximab selectively targets B-cells, a more broadly based immune drug like cyclophosphamide may be more effective than Rituximab and has the decided benefit of being much, much cheaper.  The drug is being tested in several hospitals across Norway.

Fluge and Mella have also published studies indicating breakdowns in energy production and the effects of cytokines on ME/CFS. Jorgen Jelstad pointed out that Katrina Lien’s multi-center Norwegian study is examining lactic acid production in ME/CFS.  RItuximab’s early success prompted researchers to examine B-cells and autoantibodies more closely.  Maureen Hanson is working with Norwegian researchers to assess the effectiveness of fecal transplants. None of this work would have been possible if Rituximab had not come to the fore.

The Rituximab saga showed that there’s no need to look to the U.S. for potential breakthroughs in this disease.  Activists in smaller countries should be encouraged. Norway put the U.S. to shame in its ability to put together and fund the largest non-behavioral ME/CFS treatment trial ever. The Rituximab saga has shown that an active community and dedicated researchers in small countries can make a major impact on this disease.

We’ll know more about the next steps with Rituximab and Fluge and Mella’s work in 2018.

The Clinical Trials Picture

The loss of Rituximab puts renewed focus on Hemispherx Biopharma’s Ampligen – the other major drug possibility for ME/CFS.

Nancy Klimas at the Institute for Neuro-immune studies feels she has treatments to test now.  Klimas has been chafing against federal restrictions that make it difficult to get ME/CFS clinical trials funded for years now. Neither the Research Centers grant nor, advocates take note, the Program Announcements for the ME/CFS SEP grant review panel, allow for the submission of clinical trial proposals. That means Dr. Klimas has go to rheumatology review panels to try and get her ME/CFS clinical trials funded.

Dr. Klimas reports that she’s received private funding for a phase I exploratory trial for women to start in Jan/Feb of next year and has raised half the money needed for a men’s study to hopefully begin shortly after that. (More on those later.)

Other Reports on the Rituximab Finding

Put simply, clinical trials of treatments for ME/CFS are the missing link and the next mandate, and experience suggest we consider designing them around disease subsets.

 

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28 Comments

  • Eimear

    November 26, 2017 at 10:38 pm - Reply

    Thanks Cort, I understood from Vicky Whitmore at one point that proposals for clinical trials would be looked at by NIH at any stage. That was after questions were raised when she suggested that clinical trials for ME/CFS would not take place for at least another five years. Is that correct? Also, really looking forward to hearing updates on what Nancy Klimas has in relation to potential treatments…if only funds could be pumped in to get things moving. Does a rheumatology review panel mean less chance of funding for Nancy Klimas?

    • Cort Johnson

      November 27, 2017 at 1:33 am - Reply

      I don’t know. There’s probably a difference between the NIH being willing to contemplate ME/CFS trials and being really interested in funding them/ Koroshetz has been very cautious – saying that what he thought were premature stroke trials ruined the opportunity for that disease for years afterwards. It may very well be that the NIH wants more research and it wants subsets identified. Time will tell

      With regards to the rheumatology panel – yes, much less chance for ME/CFS there than in the ME/CFS SEP.

  • JL

    November 26, 2017 at 11:43 pm - Reply

    I haven’t read the whole article yet. I will on a different day. I hope there is something very positive coming out soon to counter this. It’s a bad time of year for bad news!…but I haven’t read the whole article yet, maybe it’s not as bleak as it appears. Thanks for letting us know though.

    • Cort Johnson

      November 27, 2017 at 1:28 am - Reply

      Something very positive coming out soon….glad to hear it!

  • Marcie Myers

    November 27, 2017 at 2:11 am - Reply

    Bummer…

  • Sue Klaus

    November 27, 2017 at 8:29 am - Reply

    Is it possible that some patients feel better after getting IV saline, that using that as the placebo may not have been the wisest choice to make? I ask this because if indeed IV saline helps us feel better, then if there were people in the cohort that may not have been reactive, this may have been a problem with using that as a placebo. What do you think?

    • Marie

      November 27, 2017 at 9:50 am - Reply

      Sue, that was my thought too. I have heard many feeling better getting IV saline (helps with orthostatic intolerance, my most debilitating symptom). But there were to other thing to give as the rituximab is given in bags…

    • Cort Johnson

      November 27, 2017 at 3:24 pm - Reply

      As I understand it, Rituximab is given only once in the beginning (or something like that) and the effects show up months later – so saline which has immediate and very temporary effects – could not be the answer. The effects of saline would have long passed by the time the researchers began asking questions regarding how the participants were doing.

      • dejurgen

        November 30, 2017 at 10:25 pm - Reply

        Sue may be on to something. Although saline has quick and relatively short lasting effects, ME has some properties of a “memory disease”.

        Theoretically it must be possible to have a sequence of actions / treatment scheme that interrupts a cascade of negative events at regular and luckily chosen intervals. If such thing could be done long enough it could again theoretically yield a boost to a higher and relatively stable level.

        If so, they may have actually found an improved treatment regime with saline in a subgroup of patience. Chances are slim, but one could always strike gold.

      • dejurgen

        December 1, 2017 at 11:08 am - Reply

        Here it may be:

        https://www.healthrising.org/blog/2017/04/15/saline-pots-chronic-fatigue-syndrome/

        “At some point 50 of the participants reported no need for further infusions, except during times of stress, within six months of starting the infusions. ”

        “So how did the authors believe that IV infusions every ten days or so which provided symptom relief for about three days translate into long-term relief? They didn’t know, but their best idea was that IV infusions gave the POTS patients a window to increase their activity levels and relieve the effects of deconditioning that often come with the disease. Ultimately, many didn’t feel the need to have more IV infusions at all.”

        => THE PLACEBO MAY NOT BE THE PLACEBO BUT (part of) THE WORKING INGREDIENT!
        => Few research is done on long term effect of regular IV saline, so doses and interval in the few trials might have been far less than optimal. Rituximab and Cyclophosphamide chemotherapy may provide better doses and intervals by chance.
        => If this could be true, optimal dosed IV saline may be cheaper, safer and would need no long test and approval faze.

        Kind regards,
        dejurgen

        • dejurgen

          December 1, 2017 at 1:39 pm - Reply

          In my enthusiasm I forgot to mention the study is about POTS patients. Many ME/FM patients however have POTS so improvement in POTS would reduce symptoms and increase abilities for the POTS subgroup present in the trial. The use of IV Saline as a placebo therefore could strongly bias the Rituximab studies outcome (and improve long term health of POTS subgroup patients).

          See also “This study has some significant limitations. Because no placebo-controlled group was present, placebo effects may have contributed to the patients’ symptom reduction. The study group was also relatively young (average age mid-30’s) and healthy (few other comorbidities). It’s not clear if ME/CFS/POTS patients were part of the study or not.” in the Saline trial link.

          • Cort Johnson

            December 7, 2017 at 5:49 pm -

            Interesting…

            POTS is certainly another comorbidity that needs to be taken into account. Hopefully the CME’s (CME’s?) the NIH is working on will be helpful in that regard.

  • rebar

    November 27, 2017 at 1:12 pm - Reply

    One again thanks Cort, well done job.
    Of course this is the way science works, I was deeply troubled initially by the results, for 2 years I’ve tried to make a trip to Norway a reality. Now life must go on, we are so much closer to understanding this complex illness. We have never been in a better place and there is a very good chance 2018 will prove to be decisive.

    “There is no success like failure and a failure is no success at all”,
    Bob Dylan, Love Minus Zero

    • Cort Johnson

      November 27, 2017 at 3:30 pm - Reply

      Thanks – a disappointing initial result but we shall see how the Rituximab story finally ends. If a subset of people that respond to Rituximab can be identified the experiment will end up being a success. I imagine that the percentage of people that ended up responding will play a role in how vigorously researchers try to find out how to identify them in advance. If its a fairly large percentage then a biomarker may have a good chance of being found, a subset of ME/CFS patients will be uncovered, and many people may end up being helped by the drug. That would be a huge breakthrough!

      If that doesn’t happen, then Rituximab has still energized this field enormously and will in the future continue to provide us with insights.

  • DR PACO VICTORIA

    November 27, 2017 at 5:36 pm - Reply

    CORT, GREETINGS FROM MEXICO. I AM DOCTOR. IN MY FAMILY FCS ME HAS OCCURRED IN THREE GENERATIONS. I WAS PRESCRIBED AND TREATED WITH RITUXIMAB FOR TWO YEARS UNFORTUNATELY, I DIDN’T GET ANY BETTER. MY ILLUSION OF GETTING BETTER FAILED………….

    • TK

      November 30, 2017 at 7:35 am - Reply

      Have you tried other drugs that affect the immune system like IVIG? I am starting to wonder if CFS/ME is an autoimmune disorder anymore…

  • aquafit

    November 27, 2017 at 6:00 pm - Reply

    “Some cancers secrete cytokines which lead to fatigue.”
    https://www.verywell.com/is-fatigue-a-symptom-of-cancer-514435

    All chronic fatigue has a trigger. For those with cancer, their chronic fatigue, which is sometimes a first symptom, is triggered by cancer. Rituxamab gets rid of cancer.

    I maintain that most chronic fatigue patients have a genetic connective tissue disorder which makes our skin, blood brain and gut barriers more permeable and therefore vulnerable. And as we age the myelin sheath covering our nerves wears away faster, causing the POTS, etc. symptoms. Only my opinion, but following that theory has led to a lot of answers for me.

    • Cort Johnson

      November 28, 2017 at 2:53 pm - Reply

      That’s definitely an issue for at least some with ME/CFS/FM – and another good example of the need to ferret out the subsets found in this disease. Watch for a Health Rising blog on EDS diagnosis in ME/CFS coming up.

      • aquafit

        November 28, 2017 at 6:26 pm - Reply

        Well, yes, Cort, all cytokines mean is that our body is out of homeostasis. It could be used interchangeably with the word “sick”. What makes a cancer patient sick is cancer, sometimes a symptom is fatigue before the cancer shows up. But until manufactured toxins are examined for its affects on us we will have no answers. There’s no new CDC research money for that. It’s all for going over territory that’s already been covered, especially the worn out territory of infection.

  • Bonnie

    November 28, 2017 at 10:42 pm - Reply

    Thank you for more hope. I’ve been bedridden for 15 years and chronically ill for 22. I have been reading up on every kind of natural resources to get well. I lost my children over this illness. I have been in the hospital too many times for so called depression I always new I was depressed because walking, talking and god forbid showing were hell. But I’m hopeful. If there is anything I could do please let me know!! Grateful

  • Marie Kroun

    November 29, 2017 at 5:36 am - Reply

    Were the participants divided into subgroups after length of disease duration before Tx study?
    In the Lipkin/Hornig cytokine study, there was a difference between “early” ME/CFS with high proinflammatory cytokines in the first 2-3 years of disease activity, followed by later reduced cytokine activity / immune exhaustion in “later” disease stage..

    Shoemaker found that after a few years low MSH and low VIP would not correct as it did in most after 1. elimination of trigger of CIRS 2. Detoxifying with his Cholestyramine protocol.. There was a chronic restgroup where MSH stayed low, who did not recover from their CFS like symptoms, but the latest.. when giving the mold sensitive with continued inflammation and low MSH, these measures and symptoms corrects, when given VIP intranasal spray in pilot study .. These patients does not seem to have any autoimmune disease component, driving continued inflammation. Will not have any positive effekt of depleting B cells..

    Some chronic Lyme with CFS like symptons are immune suppressed but without autoimmune markers, have persistent / recurrent infection driving continued / recurrent episodes of inflammation, where spirochetes are visible in blood and detectable by direct specific test methods (immune stain, DNA stain) (these I follow); as long as they get antibiotic and suppress growth and spread of spirochetes, they reduce their inflammatory response and get 50-100% back to normal, but when they stop antibiotics their immune system can not keep spirochete recurrence down, so the infection flourish again (if they have immune suppressing coinfections creating immune depression, detecting and treating the coinfections may make a huge difference; some with Borrelia + Ehrlichia could not recover on penicillin like drugs, which doesn’t hit the Ehrlichia, but recovered after targeting Ehrlichia with doxycycline, but that did not work well for patients that were coinfected with ringforms with or without ehrlichia on top of Borrelia ..
    Depleting B cells will not help, rather create more immune depression..

    Then there is a subset of chronic Lyme patients with certain HLA DR and DQ genotypes that have probable autoimmune component with cross reacting autoantibodies against OspA antigen that reacts towards myelin, myosin, and/or TPO antibodies are the most commonly measured (those with high TPO develop Hashimoto thyroiditis, ending after many years of more or less inflammation (where rituximab or other immune suppression might help) they end up permanently in low thyroid status when the thyroid gland after years of recurrent inflammation is totally destroyed after resulting in permanent CFS like symptoms (where they have gone way beyond point of no return to normal, thus try stopping the inflammation with trial immune depression whether rituximab or other drugs, can not be expected to make any difference at all in the end-stage ..

    So were the patients examined genetically for HLA types and divided into subgroups after their genetics?
    If not they bundle very different subgroup that response differently and get “negative” non significant study result!

    Shoemaker find different HLA genotypes make susceptible to different triggers; there is a dreaded multi susceptible genotype, where CFS like illness, or CIRS for Chronic Inflammatory Response Syndrome as he call it, can be triggered by many diffent biotoxins, while other genotypes are more selectively sensitive to few triggers, Lyme sensitive, mold sensitive ..
    In the mold sensitive / triggered CIRS (as in allergy cases) removal of the patient from getting unspecific inflammation triggered early enough after exposure to the mold exposure, may be enough to stop the inflammation and patient return to homeostasis and get well “spontaneously”.

    In the remaing rest group some cases, detoxifying with Shoemakers cholestyramin protocol, may help some more get well by removing mold toxins they have difficulty excretion (as long as they have not yet developed damaged hormones regulation in hypothalamus / pituitary too much by prolonged cytokine storm, that is, their MSH can return to normal by just removing trigger and resulting inflammation, and their CDs like symptoms resolve ..
    – then there is a smaller rest group, where unspecific inflammation continues, indicating that the first two steps (elimimation and detoxifying) is not enough, where treatment with VIP can get the immune “overdrive” to calm down, cytokines and complement activation resolves / go back to homeostasis and the patient feel better/normal, but if reexposed to mold toxins they still have their genetic susceptibility, and enter chronic inflammatory status again .. So knowing trigger and how to avoid it is of paramount importance to keep improved status!

    In Lyme disease some late cases (past 1-2 years after getting infected) they have immune depression (low MBL, no measurable Bb IgG, low or no Bb IgM or recurrent IgM tops after flareup that fade away within 1-2 months without seroconversion to IgG, thus no immune memory, low CD57-NK cell count (aging?
    without specific immune defense, have to rely only on their reptilian unspecific immune response?) microbes – especially not the complement resistant types of Borrelia can not be eradicated! – so PERSISTENT infection, continue to drive inflammation, as long as the microbes can not be eradicated by neither their malfunctioning immune defense, microbes must be gunned down and kept down by antibiotic treatment… treatment and other adverse conditions for the spirochete form, cause borrelia spirochetes to change to sporelike round forms that reduce their metabolism / go dormant under prolonged adverse conditions; in dormant staga the microbes does not produce much, no biotoxin, and stay put, hidden behind biofilm, in deeper tissues and can wait there inactive for at least 2-3 years, possibly for decennials, without creating much harm / inflammatory response, but when patient drop antibiotic TX the dormant sporelike round forms may wake up and enter growth phase, return to spirochete form, that can spread through even dense tendons to reach the blood stream – where they enter blood cells – in about weekly intervals new spirochetes sprout out from the cells…
    The spirochetes change surface antigens, leaving previously formed antibodies against the no longer expressed antigen un-useful, and it take the normal immune system about 3-4 months to raise sufficient specific IgG response against the new surface antigens, when that happen the wellfunctioning immune system regain control over the blood, spirochetes entering blood get eradicated fast again by flagging their presence by binding specific antibodies to surface antigens, removed by immune cells, can be killed, and are not allowed to produce many sporelike round forms, not reproduce in weekly pattern, the inflammation calm down and patient return to monthly or rarer relapse cycle, a tolerable life, until next time borrelia get lucky and create a new antigenic variant so the host immune defense lose control again for a while, so borrelia can flourish ..
    There may be 6 months to years between lange and long “big relapses” where they have monthly or rarer “small flares” lasting 3-5 days with 2-3 weeks post attack inflammation before nearly normal, until next time enough new spirochetes enters blood to create enough unspecific immune storm.
    Some of us shift spontaneously between weekly cycle – in spring and autumn = high tick seasons, where borrelia must be in the blood, mainly hide inside host cells, in order to survive immune attack and have chance to get eaten if a tick happen to bite the host, but shift back to rarer, monthly, relapses in the winter and in warm and dry summertime, where ticks are not questing for a mammal blood meal…

    If immune dysfunction can not be corrected the immune deficient patients stay on weekly relapse cycle all the time (Hell, people may attempt suicide because they can’t stand being so sick, cytokines cause depression) and are very very sick, but effective antibiotic treatment can make up for lack in immune defense, as long as taken, and the patients course emulate the “natural course” of untreated relapsing fever in the immunocompetent person ..
    After 2-3 months on abx their flare activity change from weekly to monthly, and after long time relapses get smaller, and coming at longer interval (as if the remaining dormant forms on stock get fewer, and perhaps less able to revive into growth, too aged?)

    … Then there is another subset of certain HLA-DR and DQ genotypes who are prone to get “reactive arthritis” and “autoimmune” cross reactions, where antibodies formed against microbes unfortunately mimic host antigens, so antibodies binds to and result in destroying host cells (releasing nuclear and other intracellular components, which their dysfunctional immune system may then also react to, resulting in (low) positive ANA, positive reuma-factor, that may go away after early antibiotic treatment.. Those may develop chronic non antibiotic responsive arthritis after OspA immunization, without having met borrelia sp!

    If you lump all these pretty different subgroups, that all have similar CFS like symptoms because of CIRS, into a treatment study, without subgrouping, the result of treatment study will by “negative” / no significant difference ..

    Only the subgroup with autoimmune / cross reacting antibodies may respond to immune suppressive Tx, like B cell depletion
    – while patients with immune depression and having persistent / recurrent infection to drive their continued chronic inflammation, may become much more sick eventually die, when further immune depression is added by taking away the antibodies they can make against their microbes
    – make even more room for flirourishing infections by adding another immune depressing factors to their already insufficient immune defense!

    Those with both immune deficiency and persistent infections, plus bad HLA genes, are the worst cases and difficult to help .. Antibiotics don’t do anything against cross reactive antibodies and if depressing immune system too much the infection get worse (combined anxiety plus immune depression)
    – add on top of that that after years with recurrent high cytokines, their hormones may get dysregulated too.. Brain does not respond as expecred to low peripheral HORMONES, not responsive to leptin, do not release POMC (=> low MSH => low endorphin AND low ACTH) nor increase TRH/TSH when T3 is low..
    They have MULTIPLE ADDING FACTURE TO FATIGUE!

    That is my theory!

  • Marie Kroun

    November 29, 2017 at 6:27 am - Reply

    Very sorry for many not corrected typos and repetitions; entering too long text with one finger on mobile keyboard, into a small write box where I lose overview ..
    Bad autocorrections.
    When I scroll back and re-read and correct found errors, the autocorrection often change other correct words to something not meaningful ..
    I wrote “combined autoimmunity plus immune depression”.. the bad autocorrection exhanged ‘autoimmunity’ to ‘anxiety’ 🙁

    CFS is complex with many different components, and changing with duration!

    Much different can cause acute inflammation, that return to homeostasis in about a month after trigger is effectively removed by a patients wellfunctioning immune system and detox system = the normally expected course in natural healing.
    After exposure to a microbe and / or its toxin(s), and successful transition from the starting innate unspecific “reptile” immune defense reactions – proinflammatory cytokine storm calling T cells to the place of invasion of foreign material and in blood activation of complement cascade..
    Local antigen presenting cells take up and break up and present parts of antigens to specific B cells in lymph nodes and alike (clusters of lymphoid cells with germinal centers perivascular is hall mark of micropathology in borrelia, “streu” lymphocytoma along small vessels) to develop high specific immunity by IgG antibodies, that flag foreign materiale to be removed by immune cells.. Leaving immune memory reacting fast if same trigger come back.

    B cells mature to antibody producing plasma cells..
    Lymphoid and plasma and eventually giant cells, are Chronic Inflammatory cells.. When foreign material is removed, the inflammatory cells disappear, fibrocytes heals eventual tissue damage, perhaps leaving a scar ..

    Many individual steps in the chain of developing immunity to foreign invaders can go wrong, resulting in non elimination of triggers and sustained or recurrent inflammatory response, that in time result in more and more damage, that may become permanent..

    Bad genes, antigen mimicry where immune reaction become directed against host own material is luckily the rare few (in which B cell depletion may help in early disease, but not in end stages when too much important tissue has been destroyed beyond repair by continuing or recurrent inflammatory attacks!

    Cytokines set “brain on fire” and if fierce and not stopped early, may create damages that may not be repairable.

  • Francis Martin

    November 29, 2017 at 10:57 pm - Reply

    Hi, if you check out the recently publicised studies regarding NMDAR auto antibodies, by Angela Vincent’s laboratory in Oxford, you’ll see that the number of people who responded positively to immune suppressant treatment was much higher than the number of people who tested positive for the auto antibodies. I.e. there are auto antibodies which are not detected by the current tests. Angela’s lab were interested in looking at auto antibodies in ME/CFS but I’m not clear that they got significant funding.

    Maybe there is a sub-group of people with ME/CFS who have causal autoimmune antibodies.

    Great article.

    Fluge & Mella, demonstrated impaired pyruvate dehydrogenase kinase functioning and a lot of stuff you mentioned above that were new to me. A bitter blow but thanks for the work they have done.

    • Cort Johnson

      November 30, 2017 at 4:28 pm - Reply

      Thanks for pointing out the auto-antibody findings. That’s encouraging.

      Yes, indeed. Hopefully their funding will continue and they can continue their creative work. It is much needed.

  • paula burns

    December 3, 2017 at 7:12 pm - Reply

    I can’t pretend to have a handle on the complexity of all this – all I know is that not a single blood test has come back ‘abnormal’ in my 30 years of ME/CFS. I just feel we are light years away from understanding this illness and its very important not to live our lives in a continual state of hope of a major breakthrough because as a patient group we are incredibly heterogeneous. Naturally we long for a breakthrough but at 66 years of age I have made my peace with the fact I’m possibly never going to know what happened to my body that blew my life/career away virtually overnight. My daughter has Wegeners – a very rare autoimmune disease – that has the potential to kill without treatment. She has had both cyclophosphamide and Rituximab – this no doubt saved her life – but I have to say she still has chronic fatigue – as severe as anyone with ME/CFS. On that score these drugs have done little to improve the quality of her life. Rituximab is a very expensive drug – (in the UK) – I couldn’t see there was any way that this would be given on approval when we can not say with certainty who will benefit. Taking these drugs is not a walk in the park and personally I would want hard evidence before signing up for this kind of treatment.

  • Francis Martin

    December 7, 2017 at 8:48 pm - Reply

    I suspect you are right in much of what you’ve said. However, earlier this year I was at a rare disease day, one of the presentations was (from memory) on cystic fibrosis and looked at a new drug which treated the disease rather than the symptoms. So there are breakthroughs.

    I haven’t seen the data from this study but I’ve seen a slide which shows a statistical value of less than 0.001 re orthostatic intolerance. Here’s a quote from this website “Fluge and Mella are pursuing autoantibodies in their Rituximab work, and autoantibodies appear to play major role in some cases of postural orthostatic intolerance syndrome (POTS)”*.

    I think the patient for Rituximab is due to expire in November 2018 in the UK/Ireland see “Rituximab How approval history is reflected by a corresponding patent filing strategy”; allowing generic products to enter the market. The cynic in me wonders if extending patients (the Rituximab was extended) benefits company funded lobbyist/politicians; I can’t see how it benefits patients.

    I still hold out hope that interest in alzheimers etc. may bring on technologies which will help [check out Baraniuk’s recent publication (mRNAs) – he’s recruiting patients for an MRI study now].

    One of your Members of the European Parliament (MEP) has recently asked a question re funding for ME/CFS research; check out the European Parliament website for details or Google “E-006901/2017” i.e. question number.

    Lyme disease research got 40 million euros funding from the European Commission in the period 2007 – 17 (Horizon 2020). How about we try for some funding e.g. by asking MEPs to ask questions/raise awareness etc.

    *DN: Ian Lipkin & Simmaron to Collaborate in New NIH ME/CFS Research Center by Cort Johnson and Courtney Miller October 7, 2017.

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