EpicGenetics – a biotech firm in Los Angeles – is attempting an FM trifecta: produce a blood and genomic test and provide a treatment.
EpicGenetics is trying to make a big splash in fibromyalgia. A Los Angeles biotech firm, they focused on producing diagnostic tests for complex conditions and produced what they believe is a highly unusual trifecta for any disease: 1) development of the first blood test for FM; 2) development of a genomic diagnostic test and; 3) launch of a treatment trial.
They seem to be doing well. Buoyed by demand for their FM/a blood test, the Los Angeles firm recently quadrupled their footprint, moving their labs and offices into a 50,000 sq. ft, facility. It’s all coming to a head, though. Their blood test, genomic test and treatment effort are all of a piece and will likely all rise or fall together. With their treatment trial underway, we should know over the next year if EpicGenetics is the next big thing – more accurately, the first big thing in FM – or not.
When I learned they’d developed what they believe is an immune blood test for fibromyalgia (FM) (?), I felt like rubbing my ears. Researchers had been focusing on the immune system in chronic fatigue syndrome (ME/CFS) for decades but have given it little attention in FM. I wasn’t dreaming, though. An immune test was being touted for FM – not ME/CFS. How had that happened?
The FM/a story starts back in 2012 with a University of Illinois study, “Unique immunologic patterns in fibromyalgia“. Immune cells from a huge set of FM patients and healthy controls (n=201) were cultured overnight and then stimulated the next morning with profoundly irritating plant lectins (PHA (phytohaemagglutinin) or PMA (pokeweed mitogen)).
(PHA is found in red and white kidney beans, green beans and fava beans. It takes just 5 raw red kidney beans to induce poisoning. Wikimedia reports that cooking reduces the very high levels of lectins in red kidney beans to safe levels. Some ME/CFS/FM practitioners do tout a lectin-free diet, however.)
These kinds of mitogenic tests are commonly used to assess white blood cell activity. The levels of 8 cytokines (IL-5, IL-6, IL-8, IFN-γ, IL-10, MIP-1α, MIP-1β, MCP-1) were measured before and after the stimulation.
No differences were found in the cytokine levels of FM patients or healthy controls before stimulation but, as in ME/CFS, adding a stressor got things moving – or rather, in the case of FM – failed to get things moving.
After the mitogenic stimulation, no less than seven of the 8 cytokines measured were quite significantly lower (1.4-8x’s lower) in the FM patients. For some reason, the FM patients’ immune cells had reacted in a lackadaisical manner to the powerful stimulant given them. (Later analyses revealed that the test worked fine using just 4 cytokines.)
The authors noted that a similar pattern of reduced immune response to stimulation occurs in Sjogren’s Syndrome and depression.
The 2015 study by noted UCLA immunologist Daniel Wallace, “Cytokine and chemokine profiles in fibromyalgia, rheumatoid arthritis and systemic lupus erythematosus: a potentially useful tool in differential diagnosis“, was bigger (n=358) and, with its inclusion of rheumatoid arthritis (RA) and lupus patients, better. EpicGenetics was clearly hot on the trail of a diagnostic test.
The big question was whether people with autoimmune diseases like RA and lupus would have the same or a different cytokine profile as people with FM. By all rights, they should have been similar. FM, after all, got shoved in the rheumatology silo early on – which is packed with autoimmune diseases characterized by overactive immune responses.
Yet the results suggested FM was nothing like the other two autoimmune diseases. It demonstrated both high sensitivity (it picked out people with FM) and specificity (it rarely picked out people with RA, lupus or healthy controls). If you have FM, the test should show that. If you have RA, lupus or are healthy and don’t have FM, it’s unlikely you will test positive.
The increased cytokine production seen in RA and lupus suggested they’re not closely related to FM. (A subset of people with RA and lupus, and indeed, it seems all chronic pain diseases, do also have FM).
The authors noted that a similar pattern of reduced immune response occurs in Sjogren’s Syndrome and depression. The authors were careful to say that the findings do not necessarily mean that FM is caused by an immune dysfunction, but Gillis has stated that he believes the immune systems of FM patients are not producing enough protective cytokines.
Some of the findings, though, seemed strange. IL-6 – an important cytokine known to induce pain and sympathetic nervous system activation – was reduced in FM instead of increased. So was IL-8 – another major pain player – which also plays a role in pathogen defense. Low levels of MIP alpha and beta seemed to make more sense – both play a role in natural killer (NK) cell defenses.
FM researcher Daniel Clauw stated that the results flew in the face of past FM results – and he’s right: while mitogen-activated IL-6 tests have not been done in FM, both IL-6 and IL-8 have been found elevated in FM.
A 2016 study reported that “IL-6 and IL-8 are two of the most constant inflammatory mediators in FM” and that their levels correlated with symptom severity. A 2013 study found that a marker of inflammation (c-reactive protein) was correlated with IL-6 and IL-8 levels in FM and a 2014 review specifically pegged increased IL-6 and IL-8 levels as significant factors in FM.
In 2013, Clauw wanted the study to be replicated and in 2015, he got a replication in a very large study. Now – perhaps the best thing to do is to try to make sense of these seemingly paradoxical findings.
EpicGenetics has asserted (as did VanElzakker for ME/CFS) that the short life of cytokines, the effects of circadian rhythms on them, and other issues made assessing cytokine levels in the blood “unreliable”. Far better, they said, to isolate immune cells, smack them with an immune trigger, and see how they respond. They could be right.
Plus, who knows – maybe the weird pattern in ME/CFS where the system seems to be on alert – but folds when presented with a stressor – is showing up in FM as well.
What is Fibromyalgia Anyway?
IF FM isn’t a “normal” rheumatological disease, what is it? The authors proposed FM is a central sensitization disorder characterized by reduced responses to all sorts of different kinds of stimulation (sympathetic, hormonal, cytokine and chemokine).
All one may need, they suggested, to differentiate central sensitization from autoimmune disorders is to whack their immune cells with a trigger and see how they respond: the immune cells from people with central sensitization disorders will respond poorly, while the immune cells from people with autoimmune disorders will leap into action.
(Two years ago, Wallace found that another immune test – “cell-bound complement activation products (CB-CAPs)” – differentiated FM from lupus as well. Calling lupus the “prototypical autoimmune systemic disease in which hyperactivity of the immune system and production of autoantibodies lead to a variety of symptoms including chronic pain, arthralgia, fatigue, morning stiffness” and organ damage, Wallace demonstrated that these complement activation products were plentiful in lupus but were completely missing in FM.)
Few have linked – or have attempted to link – central sensitization with immune dysfunction as this group has. Gillis stated that his inquiry into FM began when he asked himself what could cause the many different symptoms in FM? The only system he could come up with was the immune system.
Sensitive AND Specific Test
Gillis said the sensitivity of the test is now up to around 99% and the specificity of the test is now around 95%.
EpicGenetics reports that the test requires about an ounce of blood and is available in most states, Canada, Europe, Turkey, Mexico, Central and South America, the Caribbean, Hong Kong, Australia and New Zealand. It states that the test is “FDA-compliant” and is covered by Medicare and most insurance plans. The company can also help FM/a® Test applicants arrange for their blood draws at a local facility at no cost.
If not covered by insurance, the test is expensive (>$1,000). Your doctor must provide authorization but EpicGenetics will even help you find a more amenable healthcare professional. (Complete the FM/a® Test Application Form.)
Why get the test?
- To rebut the doubters – whether they’re your doctor or your family or friends, that you have a real biological illness.
- To save time and money. Dr. Gillis, the CEO of EpicGenetics, stated that literature indicates the average patient will spend $4,800 – $9,300 a year for 3-5 years before all the tests prove negative and the doctor decides you have FM.
- To get the vaccine (see below).
The Genomic Test
- EpicGenetics is a Los Angeles biotech firm that specializes in developing diagnostic tests.
- Two quite large studies found that the white blood cells from FM patients responded to an immune stimulus poorly by producing significantly lower levels of immune mediators called cytokines than healthy controls’ cells did.
- The CEO of EpicGenetics proposed that reduced levels of protective cytokines may be responsible for FM.
- One study was able to use the response to an immune stimulus to clearly differentiate FM patients from rheumatoid arthritis and lupus patients.
- The reduced cytokine response found in FM suggested that it was not an autoimmune disease.
- The authors suggested that FM was a central sensitization disease characterized by a reduced reaction to immune, hormonal, etc. stimuli.
- In 2017, EpicGenomics began a genomic study designed to develop a genetic signature for FM.
EpicGenetics is all in with FM. They did not stop with the blood test. Their next steps were a genomic test and a treatment trial.
In 2017, the company announced it was embarking on “Campaign 250” an ambitious effort to conduct whole exome genetic testing on up to 250,000 FM patients who have tested positive on their FM/a test. Since, at $2,500 a pop, that campaign would cost $625 million, it hardly seems feasible (or worthwhile) to test that many people. (EpicGenetics is apparently asking people who test positive for FM on their test to participate in the study.)
The company reported it had received FDA approval for a treatment trial but put it on hold pending further work on FM genomics. Not only did the company feel they were on the cusp of uncovering a genomic biomarker but they reported that biomarker validated their hypothesis that FM was an immune disease.
“We are cautiously optimistic that we are on the throes of a breakthrough in better understanding fibromyalgia. If we find these [genetic] patterns are unique for fibromyalgia, it further and hopefully will forever legitimize in the minds of everyone that fibromyalgia is a real disease, that it’s a disease of the body’s immune system, and that consequently it’ll change how patients are diagnosed and treated, and hopefully how we may be able to cure or reverse the disease.” Gillis
A second slate of studies were underway. Hoping that they could use the genomic signature to assess the effects of their treatment trial, they held it off for a year or two, and then earlier this year began the treatment trial.
The Vaccine Trial
“Given what’s been published in the medical literature, we believe this vaccine will reverse the immune system abnormalities [of fibromyalgia].” Dr. Bruce Gillis, Epigenetics CEO
- This year the company began a clinical trial of the BCG vaccine used in tuberculosis.
- Vaccines stimulate immune responses. The BCG vaccine stimulates the cytokines the company believes are being underproduced in fibromyalgia. The trial is expected to wrap up in 2022
- People who have tested positive for the FM/a test are eligible for the genomics study and vaccine trial.
- A similar pattern of reduced immune response to stimulation has been found in chronic fatigue syndrome (ME/CFS)
- Carl Gottfries treated ME/CFS patients (and himself) for decades using a different vaccine (which is not longer available.
While vaccines are mostly used to fight off pathogens, they also stimulate the immune system. Carl Gottfries used another vaccine to treat himself and others with ME/CFS until the vaccine’s producer stopped production.
It just so happens that the BCG vaccine stimulates the same parts of the immune system EpicGenetics believes have taken a hit in FM.
The 300-person, randomized, triple-blinded, Phase II, Mass. General Hospital BCG vaccine trial started in January of this year and is expected to end in January 2022. A call went out earlier this year for more men and younger female patients.
Gillis was clearly excited by the vaccine:
“The expectation is that if the results are as good as we hope, potentially in as little as six months, we will have further opportunity to expand the treatment to many, many more people as we collect the data. We don’t expect significant side effects and we expect fairly rapid responses to the BCG by the people who participate in the trial who receive it.”
|Contact Denise L Faustman, MD, PhDfirstname.lastname@example.org if you’re interested|
An ME/CFS Connection?
Gillis has pointed out how similar the symptoms of ME/CFS and FM are. If the vaccine works out in FM, ME/CFS is probably next. In fact, the two have more in common than symptoms. Every mitogenic test done in ME/CFS has produced the same general result as the two EpicGenetics FM studies: a markedly reduced immune response.
Given that, it might be a good idea to keep an eye on EpicGenetics.
Is FM an immune disease? Will EpicGenetics turn the world of fibromyalgia on its head with its trifecta – a blood test, a genomic test and a cheap treatment? If it does, will it apply to ME/CFS?
EpicGenetics hasn’t reported on the results of its genomic testing. Unless they hit it out of the park with the vaccine and stop the trial early, we probably won’t know about the results of the vaccine trial until 2022.
Will EpicGenetics epic plans come to fruition? Breakthroughs, as we know from experience, don’t come easy in medicine but sometimes they do come. A cheap way to treat FM (and maybe ME/CFS) – even if it was a partial treatment – would be a godsend. Time will tell.
Update – as of Nov 2021 there’s still no sign of an EpicGenetics trial in sight. In fact, an investigative report “In a sea of skeptics, this physician was one of fibromyalgia patients’ few true allies. Or was he?” done by STAT news that digs deep into the founders rather unappealing past suggests one may not be forthcoming at all.
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