Reprinted with the kind permission of Simmaron Research.
By Cort Johnson
Part 1: The Montreal ME/CFS Conference: Metabolism and Exercise can be viewed here.
Dr. Nancy Klimas: From Biomarkers to Modeling and Clinical Trials; GWS and ME/CFS
Years of work appear to be coming to fruition for Dr. Klimas. Her ability to hook into GWS funding has made a huge difference in her ability to test out her modeling protocols. It’s remarkable to see the Dept of Defense lay down $40 million per year for the vets affected during the Gulf War 27 years ago, while ME/CFS gets so little. The vets undoubtedly deserve it and they deserve more – many lives were shredded as a result of the war and they’ve fought for years to get recognition. However, the disconnect between the way the feds have treated GWI and ME/CFS – a disease which affects far more people – is startling. The Dept of Defense hasn’t done great by its vets, but it’s been much more responsive to them than the feds have been to ME/CFS and fibromyalgia.
Dr. Klimas noted that the more we look, the more immune abnormalities are being found. Cytokines may not tell us what is causing ME/CFS, but they sure could help us find drugs to combat it. Klimas is comparing the immune signatures she’s seeing in ME/CFS with those of other diseases and then checking out what’s working in those diseases. The good news is that immune-affecting drugs are big business now, with more and more coming on the market. If ME/CFS is, at its heart, an immune disorder, or if the immune system plays a large role – as many think it does – drugs developed for other diseases may be able to help.
Dr. Klimas and her researchers have been asserting for years that ME/CFS patients are stuck in a kind of suboptimal, self-reinforcing homeostatic space; i.e. their systems have been rewired to produce a new normal.
That idea doesn’t seem to be all that far from Naviaux’s belief that people with ME/CFS are stuck in a Dauer state or Dr. Cheney’s report that while he could push patients towards health, something would pull them back. Both Klimas and Naviaux believe a series of structured moves will be needed to move the system back to normal. Neither believes it’s easy; Klimas says real “force” will be needed to move the system back into health.
Klimas should know – she’s been intensively charting how ME/CFS patients’ systems go off the rails during exercise for several years now. She’s measured every cytokine, neuropeptide, etc. she can at 8 timepoints before, during and after exercise in 50 women with ME/CFS, 25 women with FM, 50 men with ME/CFS and 50 men with GWI.
She’s gathered a vast amount of data and that data is telling her that ME/CFS patients’ immune systems basically go nuts during the first 15 minutes of exercise. Four hours later, oxidative stress kicks in and the autonomic nervous and endocrine systems and metabolism get hit — but it’s the immune system that kicks everything off.
The big surprise is how different chronic fatigue syndrome (ME/CFS) is from Gulf War Illness. The metabolism gets hit hard in ME/CFS – everything gets shut down – but in GWI, all the pathways are ramped up. They’re two completely different illnesses which from the outside look exactly the same.
Dr. Klimas and her team have been running sophisticated modeling techniques on supercomputers to figure out how to get our systems back to normal. Initially, they ran into trouble with women who, no surprise, have much more complex systems than men. Back to the drawing board they went. In the end, Dr. Klimas’s team was able to create a virtual clinical trial in GWS. First, they brought down brain inflammation using etanercept, and then readjusted the HPA axis with a glucocorticoid receptor blocker, mifeprestone.
It worked on the computer – their virtual GWS patient returned to health system – but the big test came with their Gulf War Syndrome mouse model. When the drug combo was able to return the GWS mouse to health they really knew they were onto something. An open label phase I trial in GWS is under way as we speak.
Dr. Klimas noted that the $30 million the DOD is providing for GWI has made a big difference where the rubber meets the road in medicine – in ten clinical trials that are underway. That’s in a disease that effects fewer people than ME/CFS but which receives federal funding for clinical trials. That’s not true for chronic fatigue syndrome (ME/CFS) – federal funding for clinical trials is pretty much blocked.
Researchers can apply for clinical trial funding at NINDS and other institutes, but ME/CFS doesn’t have a chance against diseases like Parkinson’s and Alzheimer’s. The big issue is that the program announcement for ME/CFS – which lists subjects researchers can apply to study – doesn’t allow them to submit clinical trials proposals.
Dr. Koroshetz’s promise last year to get that language embedded into the ME/CFS PA hasn’t paid off yet. Getting that wording embedded into the PA for ME/CFS could open up funding for clinical trials. That would be a big step forward.
Dr. Klimas doesn’t have a mouse model for ME/CFS but she’s been doing the same computer modeling she used in GWS on ME/CFS. It’s clear that nobody at this point understands more about what happens during exercise in ME/CFS than Dr. Klimas. Nobody has been able to translate mountains of exercise data into virtual clinical trials. Nobody has proposed a staggered two-drug approach to ME/CFS, and nobody probably has a better shot at stopping PEM than her. This is new stuff not just for us but for the medical field in general. Let’s hope it works out.
The GWS trial is underway and she hopes to get her chance at halting the PEM in its tracks in ME/CFS in a small trial later this year. Getting funding, of course, will be crucial.
ME/CFS rather suddenly has several drug/drug trial possibilities: they include Cortene, Dr. Klimas’s drug combo, immunoadsorption (see below), Fluge and Mella’s Norwegian cyclophosphamide trial, Ampligen and Dr. Kaiser’s Synergy drug-nutrient combination – and, of course, Rituximab is still surely in the picture for a subset of patients.Scheibenbogen is a mover and shaker. She’s published six papers on ME/CFS in the past three years, is a leader in the Euromene Group, has been talking to pharmaceutical companies about drugs, and is organizing a fatigue conference in Germany to get some good networking going.
Peter Rowe called her recent autoantibody papers one of the most exciting recent developments in the field. Scheibenbogen, interestingly, got the idea to do those studies from similar recent findings in POTS (postural orthostatic tachycardia syndrome).
Scheibenbogen rattled off some of the commonalities between autoimmune diseases and ME/CFS. Both predominantly affect women, both are often triggered by an infection and she’s found a high family history of autoimmunity in ME/CFS. Plus, Epstein-Barr virus – a common trigger in chronic fatigue syndrome (ME/CFS) – invades B-cells which are the main drivers of autoimmunity. The difficulty ME/CFS patients and others have fighting off the virus when exposed to it later in life apparently gives the immune system plenty of opportunity to make a mistake and begin attacking our own tissues.
Check out a recent breakthrough in EBV-associated autoimmunity.
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Rituximab is used to treat autoimmune diseases. The Rituximab ME/CFS trial’s main endpoint failed but Scheibenbogen asserted that we shouldn’t count Rituximab out at all. She believes, and she would know, because she’s studied Rituximab patients, that Rituximab will be shown to be effective in a subset of patients. An effective treatment in a subset of ME/CFS patients would be a big deal – particularly for those patients.
Scheibenbogen found increased levels of antibodies in about 40% of ME/CFS patients, and Bergquist’s study that is currently underway thankfully had similar results. At least right now it appears that the 40% figure is solid, but the search for antibodies in ME/CFS is not over. When I asked Scheibenbogen if other antibodies might be involved, she said, yes, other antibodies probably will apply. If that’s so, that 40% number could go up. Scheibenbogen noted that the B2 and muscarinic antibodies that have been showing up in ME/CFS are part of a larger network.
Interestingly, these are not autoantibodies; they’re natural antibodies which affect breathing, the circulation and the gut. Their high levels in ME/CFS appear to be throwing those systems off.
Immunoadsorption is another possible immune treatment for chronic fatigue syndrome (ME/CFS). Immunoadsorption, which is similar to, but more effective than plasmaphoresis, removes IgG autoantibodies from the blood. It’s an expensive treatment – about $20,000.
Like Rituximab it will probably be effective in a subset of patients. Scheibenbogen’s small immunoadsorption trial of ME/CFS patients with specific autoantibodies found that the treatment did what it was supposed to do – it significantly reduced antibody levels for at least six months.
Symptoms improved in most patients and some patients completely recovered. Three are still in remission a year after the treatment ended. One person completely recovered for 6-7 weeks but then relapsed. After she relapsed, she could hardly walk again. The trial suggested that Scheibenbogen is on the right track with her autoimmune studies. The fact that POTS is so prevalent in ME/CFS and has similar autoantibody issues suggests that the outcome is not such a surprise.
A follow-up study is beginning. If that works out, Scheibenbogen hopes for a big trial that will settle the issue definitively. In a good sign, she reported that the company that produces the immunoadsorption treatment (not available in the U.S.) is quite interested in ME/CFS.
(Even if the treatment is not available in the U.S., a successful trial could do a couple of things: it could prompt the company to make the treatment available in the U.S., and it would surely enhance autoimmunity research. We’ll see what happens, but if we can come up with several treatments – each of which is effective in a subset of patients – we’ll start to whittle the disease down.)
As she left for the airport, Scheibenbogen said she hopes that in the next five years ways to diagnose and treat ME/CFS will be found. Let it be so…
Guidelines to Biomarker Produced
Euromene, the new ME/CFS European research group Scheibenbogen is working with, recently laid out a step-by-step pathway to develop a biomarker. She noted that we have lots of interesting findings, but none that are unique to ME/CFS. Plus, the findings we do have overlap too much with healthy controls.
In short, we haven’t found that key signature – that key physiological mark – which says a person has ME/CFS. (That may not be a surprise: until we find the core of ME/CFS, we may not be able to find a unique biomarker). Scheibenbogen did wonder, however, given Maureen Hanson’s recent inability to find subsets in her metabolomic data, if the biomarker for ME/CFS will be metabolic in nature.
Unutmaz’s Big Surprise
Ron Davis has noted things often don’t work out the way researchers expect them to. Apparently, Derya Unutmaz feels the same way. Unutmaz got a T-cell result that pointed straight at the gut and then was pleasantly shocked when a look at the gut confirmed his findings. He was expecting a few more twists and turns from the body! It’s not usually so easy.
He noted that over the past decade a tremendous amount of work has been done on the effects the gut microbiome (gut bacteria) have on the immune system. It’s now clear that a shift toward more inflammatory bacteria in the gut can result in inflammation in other parts of the body. In fact, Unutmaz reported that just about every disease is associated with a change in gut bacteria. The bacteria play such a vital role that oncologists can even determine how effectively patients will respond to immunotherapies by assessing the kind of bacteria they carry in their guts.
That makes sense for ME/CFS, since every gut bacteria study has thus far found substantial alterations in the bacteria in ME/CFS patients’ guts.
Unutmaz is a T-cell guy. He knows that bacterial metabolic by-products trigger unusual T-cells called MAIT T-cells (Mucosal associated invariant T cells) to get into action. Once these cells, which are found in our gut lining, liver, lungs, etc., come across those metabolites, they secrete pro-inflammatory cytokines. Those cytokines turn monocyte cells into hairy monsters called macrophages which then gobble up the bacterial-infected cells.
MAIT cells, then, play a key role in turning on our immune response to the bad bacteria that can live in our guts. They apparently lurk in the gut lining as a kind of last line of defense against those bacteria getting into our blood stream and invading the rest of the body.
Unutmaz found that a high percentage of MAIT cells had been repeatedly activated in ME/CFS patients – suggesting a plethora of bad bacteria was present. In true ME/CFS fashion, Unutmaz also found that ME/CFS patients’ MAIT cells were activated — but “punked out” at the same time. (A wired and tired immune cell?). Seemingly exhausted by the continual stimulation, they (like their natural killer cell cousins) had problems killing infected cells. That hearkened back to the Lipkin/Hornig immune finding of activated immune systems in early-duration ME/CFS patients and depleted immune systems in longer- duration patients.
Unutmaz is now trying to identify which bacteria are tweaking ME/CFS patients’ MAIT T-cells so much as to possibly burn them out. If he’s successful, he may have found a target that could quiet down a possibly overworked and burnt-out immune system and allow it to rejuvenate.