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The Pridgen Revolution? Dr. Pridgen on Bringing His Antiviral Approach to Fibromyalgia To Market

The Pridgen Revolution?

Almost three years ago, Dr. Pridgen threatened to turn the world of fibromyalgia treatment on its head. Few had connected fibromyalgia with viruses or even immune problems when Pridgen announced that a) FM is caused herpes simplex virus reactivation and b) that it could be treated with antivirals. Then he shocked a chronic fatigue syndrome community (ME/CFS) well acquainted with antivirals with his assertion that one antiviral drug was not enough.  (Pridgen believes the same process is going on in ME/CFS). Pridgen wasn’t done, though, instead of using the usual anti-herpes virus drugs he used an anti-inflammatory (Celebrex) that had antiviral properties as his second antiviral.

pridgen_skipPridgen was knocking down received wisdom at every turn. One would not have been remiss to think that he and his unusual protocol would, as other supposed cures have, disappear at some point, but he hasn’t.

Instead, touting his success with the drug combo, Pridgen embarked on the long and difficult task of bringing a new treatment to market. After joining up with a University of Alabama virologist, Dr. Carol Duffy, Pridgen formed a biotech company aptly named Innovative Med Concepts, hired an ex-Pfizer vice-president, put together a strong scientific board, raised the money for a Phase 2 trial, and embarked on toxicology testing.

The Phase II trial was successful enough for the drug combo to move forward. Then Innovate Med Concept got a break when FDA granted fast-track status to its IMC-1 formulation, allowing the drug combo to move forward as quickly as possible.  (Fast-track status is granted to serious diseases that have “substantial impact on day-to-day functioning.”)

Now comes the real work – raising money for some very, very expensive Phase 3 trials. It’s been about a year since we checked in. In an interview, I asked Pridgen how it was going.

The Pridgen Interview

The Phase II trial results were certainly quite good, but they weren’t spectacular.  How did the Phase II trial inform the Phase III trial and how will it be different?

We wanted to prove the concept first with a dose that we knew would be effective.  Additionally, we chose this lower dose, as it would allow us to begin without first performing the very expensive and time-consuming toxicology studies. We will be beginning the final 2 toxicology studies necessary to be Phase 3 ready, this month, and we expect to have these completed late this winter or in early spring 2017.

This was a year to prep for the big Phase III trials. How much money do you need to raise? Do you need to do one or two trials and how big does the trial or trials need to be? How much money do you need to raise?

Typically, two Phase 3 studies are required, the studies require 500-1000 patients per study, and these studies cost $25-50 million each.

One report suggested that some pharmaceutical companies have shown interest. Can you say anything about that?

drug-developmentWe have met with a dozen different pharmaceutical companies. All knew that we would be either forming a strategic partnership, or continuing the drug development ourselves once we near Phase 3 readiness. We will meet with these pharmaceutical companies to discuss a possible partnership at the upcoming JP Morgan meeting Jan 2017 in San Francisco.

We’ve seen a couple of high-profile Phase III trial failures recently. One may have been due to doctors misidentifying a side effect as something else and using a drug that interfered with the results. Another got excellent results in the Phase II trial but then didn’t meet its primary endpoint (but did meet some of its secondary endpoints) in the Phase III trial.  In another trial a very high placebo rate surfaced. What can you do to ensure that IMC-1 trial goes as well as possible?

We have actually been using a variant of this combination at my office for 2-3 years, so we are extremely confident in, not only its efficacy, but also know the combination is quite well tolerated and safe. Though providing the necessary optimal dose is incredibly time-consuming for the office staff, and complicated for the patients, we endure this hardship because of the dramatic improvement they experience.

Dr. Pridgen remains very, (very) confident in the effects of his protocol; he’s so confident that he anticipates raising the bar for the primary endpoint of his Phase 3 trials. Drugs have failed because they chose the wrong primary endpoint or too difficult of a primary endpoint, but Pridgen reports the study will use the most difficult primary endpoint to attain of any fibromyalgia trial to date:

Finally, because IMC-1 is so effective, we will use a primary endpoint that represents the highest bar ever used for any of the drugs previously studied for FM. We feel that this will negate to some degree the placebo effect.

We can see from studies and patient comments that the fibromyalgia population is pretty heterogeneous one. Some people do well on Lyrica – others do terribly. Low dose naltrexone works very well for some and others do poorly on it, etc., etc. The heterogeneity seen in the reactions to pain medications, in general, is pretty daunting. Is there any way you can target FM patients who are more likely to do well on the drug?

Again, Pridgen waxed confident in how efficacious this drug combination is. He believes his is the only protocol that gets at the source of fibromyalgia.

We believe IMC-1 is targeting the possible cause of fibromyalgia, not just modifying the body’s perception of pain.

Emedicine lists four antivirals (Famvir, Valtrex, Acyclovir, Penciclovir) used to treat herpes simplex infections. You’ve found that you need to add Celebrex to Famvir to get the best results in FM. Why do you think this is?

Penciclovir is not available in the PO form because it is not well absorbed, so it is a better topical agent.  Actually, Famvir turns into the active form, penciclovir, once it is acted on by human and viral enzymes. Celebrex is effective as an antiviral also. Herpes viruses are known to up-regulate the Cox-1 and Cox-2 enzymes to maximize viral activation. Though Celebrex (celecoxib) is known as a Cox-2 inhibitor, it actually has substantial Cox-1 inhibition.

viral-attack-cfsAre the herpes simplex infections harder in FM harder to get at than in other diseases? Do you need to reach into the central nervous system?

Essentially all adults have HSV-1, but we believe there is an immune defect in place in some patients, which results in an inability to force the virus into dormancy after an acute infection. In other words, patients with FM, have an ongoing HSV-1 infection, which we feel results in a chronic stress response. The meds can act centrally, however, the virus lives in the Trigeminal, and Nodose ganglia which are intracranial, but technically not in the CNS. The dorsal sacral root ganglia are the third major site (in the pelvis) where the virus resides.

Note: The herpes virus is known to hide out all three of these ganglia or cell bodies.

  • Trigeminal ganglia – is the largest and most complex of the 12 cranial nerves. The trigeminal ganglia provides sensations to the face and other parts of the head. It also sends signals that allow us to chew and even helps with balance. People with trigeminal neuralgia can experience high levels of pain when doing things like brushing their teeth or putting on makeup.
  • Nodose ganglia – are sensory ganglia or nerve cell bodies of the vagus nerve that are found near the top of the spine..
  • Dorsal sacral root ganglia – are associated with vertebrae in the pelvic area. The nerves emanating from them impact all areas of gut and pelvic functioning. In between bouts of genital herpes virus reactivation, the herpes simplex virus hides in these ganglia.

Like the other herpesviruses, almost everyone is infected with HSV-1, and when reactivated these infections can be pretty harmful. They’ve been shown to cause gastrointestinal and esophageal disorders, acute viral encephalitis, and approximately 25% of all genital herpes infections. Fibromyalgia is a bit different; it causes widespread pain, fatigue, sleep and sometimes mood problems as well as other symptoms- and is thought more of as a central nervous system disorder than anything else. Can you explain what the herpes simplex virus is doing differently in FM to cause this extraordinary range of symptoms?

The ongoing stress response affects nearly every system in the body. The immune response to this stress response over time affects sleep, mood, anxiety, thyroid, adrenal function, GI tract, HA’s and much more.

Dr. Duffy was reportedly writing up a paper on her gut findings. Can you tell us that the status of that is?

We have one last sample (of 60 total) to obtain to complete the study.

(At a conference Duffy was reported to find HSV-1 in 100% of FM gut biopsies and a protein found only in cells that are actively infected with HSV-1 in 80% of patients.)

With another year under your belt have you learned anything new treating FM using Famvir and Celebrex?

We have found that anything that was previously part of the functional somatic syndrome will improve on this treatment. At the risk of sounding like a snake oil salesman, we have patients who have chronic non-seasonal sinusitis, HA’s, brain fog, and even libido issues who swear by IMC-1.

Dosing – I also asked Dr. Pridgen about dosing information. He replied that the dosing information has to be proprietary right now. This is because pharmaceutical companies or other funding sources would not back a product composed of already approved drugs if the dosages were put in the public realm. Given the enormous costs of the Phase 3 trials, Pridgen’s drug combo would never make it to market without their backing.

That means FM patients will have to wait before Dr. Pridgen publicly reports on the appropriate dose. For many people this conversation is moot – their doctors would not prescribe antivirals now anyway. People seeing Dr. Pridgen or people seeing doctors in touch with Dr. Pridgen will obviously get the right doses.

If the trials are successful and the FDA approves the IMC-1 formulation everyone should be able to get a shot at these drugs.

Can you give us a timeline regarding the Phase III trial(s)?

They will start next year.

____________________________

For more on Dr. Pridgen’s antiviral approach to fibromyalgia:

Simmaron’s Fifth Anniversary Event Updates ME/CFS Community on Dynamic Research Underway

5th-birthday-258x300

Simmaron recently held a patient update session with its Scientific Advisory Board and key collaborators in Incline Village, Nevada. The event celebrated the Simmaron Research Foundation’s fifth year anniversary.  I don’t know if anyone would have predicted five years ago that patients would be hearing from the likes of Mady Hornig, Maureen Hanson, Konstance Knox and Elizabeth Unger but here they were in little Incline Village talking about their work.

CDC Collaboration

The surprise guest at the event was Elizabeth Unger. Dr. Unger was a fitting guest at the Simmaron’s 5th year anniversary meeting; it’s been, after all, just over five years since she took over the helm of CDC’s Chronic Fatigue Syndrome (ME/CFS) program.  Who would have thought five years ago that the head of CDC’s CFS program would show up at a Simmaron information meeting.

Certainly not Dr. Peterson. About five years ago I asked him if the CDC  had ever shown interest in his work,  and he just laughed.  His relationship with the CDC was frosty to say the least. That’s not true any longer.Dr. Elizabeth Unger

Under Dr. Reeves, the CDC developed a definition in-house that received zero support from researchers (and patients). Under Dr. Unger, the CDC has made ME/CFS experts a core feature of its work, is meeting with patient groups, has worked with CFSAC on its website, and is engaging with patients and experts in its educational materials.

Instead of a stumbling block, Dr. Unger turned out to be a collaborator who’s committed an enormous amount of time, energy and her (limited) budget to learning about ME/CFS doctors and their patients.  What a shift that has been.

Dr. Unger threw all the definitions out the window in the multisite ME/CFS expert study. Realizing that doctors, most of whom had decades of experience in this disease, were a better source of what ME/CFS was than any definition, she cleared the decks; anyone the expert doctors believed had ME/CFS, whether they met x or y definition or not, she would study. They were, by default, ME/CFS patients. Dr. Peterson thought it was a brilliant move.

At Dr. Peterson’s invitation, Dr. Unger stayed following a routine site visit to hear the presentations from Simmaron’s Scientific Board and attend the patient gathering.  At the patient meeting she had some good news; the first paper from the ME/CFS experts multisite study was finally under review for publication.

It had been a long time coming. Simmaron and Dr. Peterson are already deeply immersed in the greatly expanded second phase of the trial, and had just gotten a contract for the third phase of the study. The study was already slated to continue at least into 2017 and now will continue further.

This now immense study involving over 800 patients and controls will surely supplant the infamous PACE trial as the largest and longest ME/CFS study ever done. With a third phase slated to begin shortly, it’s going to provide an unprecedented look at a very large group of ME/CFS patients, and how they are tested and treated by doctors over time.

Dr. Unger quickly went over a few of the highlights; the greatest heterogeneity, surprisingly, was found within the ME/CFS expert’s sites, not between them. By and large, the practitioners are not seeing different kinds of patients; instead each is seeing a similarly wide variety of patients. How wide? The standard functional tests being done, for instance, indicate that some people with ME/CFS experience high rates of pain while others experience no pain at all.

The constant is that ME/CFS is producing high reductions in vitality and physical functioning but has relatively little effect on mental or emotional functioning.  Dr. Unger said the multisite studies will go a long way to helping the public understand how severe a disease ME/CFS is.

Konstance Knox  

Konstance Knox, PhD, is collaborating with Simmaron on her insect infection study at Coppe Healthcare. She posited the interesting idea of ME/CFS having a similar trajectory to Lyme Disease. Lyme Disease,she noted, first showed up in pediatrician’s offices in children with arthritis in Old Lyme, Connecticut in the 1970’s.  Eventually the children were found to be infected with bacteria carried by ticks.

KKnox

ME/CFS patients have been showing up in doctor’s offices with unexplained fatigue, post-exertional malaise, pain and debilitating symptoms for years. Could a similar scenario prevail for at least a subset of ME/CFS patients? Knox thinks it might. Her large study, using samples from 300 ME/CFS and healthy controls gathered in the NIH’s XMRV study, is looking for evidence of pathogens that aren’t always tested for in chronic fatigue syndrome (ME/CFS). They include three different kinds of Borrelia bacteria, the Powassan and Dengue viruses, and the most widespread insect borne disease in the U.S., West Nile Virus.

Each demonstrates how rapidly insect borne pathogens can invade a country. Borrelia was identified as the cause of Lyme in 1981, and according to one estimate, is believed to effect 300,000 people a year.  West Nile Virus was first found in New York in 1999 and has spread across the country.  Now the Zika virus is beginning to touch upon our southern shores in Florida as well.

In Dr. Knox’s mind, the Powassan virus is the big mystery. Carried by the same ticks that cause Lyme disease, Powassan is similar to tick-borne encephalitis virus which has long been shown to cause serious illnesses in Eurasia.

Unlike the Lyme bacteria, which needs the tick to be attached for quite some time for the bacteria to get transmitted, the Powassan virus can be transmitted in just 15 minutes. Knox found that 11% of the 2,000 ticks she studied in Wisconsin  carried Lyme disease and 6% carried the Powassan virus.  She found 55% of people infected with Lyme disease also were infected with the Powassan virus.

Dr. Knox’s preliminary data of ME/CFS patients with an acute flu-like onset found a low incidence of Lyme disease (3%) but a pretty high incidence (11%) of people who had antibodies which looked like they might be to TBEV; i.e. the Powassan virus. The NIH samples offer an opportunity to study these infections in well characterized patients and controls from multiple clinical sites.

Dr. Mady Hornig

The Hornig/Lipkin team at Columbia’s Center for Infection and Immunity (CII) isn’t just looking at ME/CFS to understand the disease. It’s mining clues from a wide range of disorders – from autism to narcolepsy – to try to understand the disease processes that are occurring. They believe the “omics” revolution – which attempts to understand diseases in terms of their genomics, proteomics, metabolomics (and probably other “omics”) – holds the key to understanding and finding the subsets present in ME/CFS.

Mady Hornig sits on the Simmaron Research Foundations Board. She and the Simmaron Research Foundation are frequent collaborators. Until they get to a cause, Dr. Hornig is unwilling to rule out any possibilities. ME/CFS could be caused by an immune response to a wide range of pathogens (which may be present or not) or to an as yet undiscovered agent. That statement suggested that Dr. Hornig doesn’t consider the earlier CII study which found little or no evidence of pathogens to be the end of the story.

Of course few researchers have looked in the tissues. Dr Chia believes he’s found enteroviruses and Dr. Duffy herpesviruses in the gut tissues of ME/CFS and/or fibromyalgia patients. Hornig and Lipkin have looked in the blood but they’re also raising money to do analyses of the flora in the stool and saliva over time. (Check out the Microbe Discovery Project  for more.) Plus, as we’ve seen, a Simmaron/Konstance Knox project is looking for evidence of insect borne illnesses that have not been tested for before.

If  pathogens are involved, the heterogeneity in the disease could reflect genetic differences in how each person responded to them, how old the person was when the infection occurred, the state of each person’s microbiome at the time, etc.  The take-away message was that different symptoms don’t necessarily mean different diseases.

The CII is doing a lot, but Dr. Hornig started out by focusing on a hot topic these days – metabolomics.  The CII team believes that metabolomics may provide the link between what’s happening in the microbiome and the rest of the body. Metabolomics uncovers the breakdown products of metabolism. If a substance, say tryptophan is not being metabolized properly in the gut, it can leave a metabolic signature in the blood that can be picked by metabolomics tests.  From the blood it’s apparently a pretty straight shot to the brain.

Marrying gut (microbiome) and blood (metabolomics) data would be the cat’s meow, and it’s begun to happen. Several small studies have been able to link altered gut bacteria to the presence of gut metabolites in the blood.  A small Solve ME/CFS Initiative study carried that idea one step forward by adding exercise to the mix. It suggested that exercise could, probably by increasing leaky gut issues, result in increased levels of gut metabolites in the blood.

Dr. Hornig believes that aberrant tryptophan metabolism in the gut could provide a major clue for ME/CFS patients.  These metabolic by-products have already been associated with several neurological diseases and are known to cause symptoms similar to those found in chronic fatigue syndrome (ME/CFS). If she finds problems with tryptophan metabolism in the gut and then can pick up their metabolic by products in the patient’s blood she can make a strong case for a gut-brain connection in ME/CFS.

While she was at it, she also noted that these bacteria can affect NAD+ and energy production.  To sum up, Dr. Hornig is gathering data on a process that could be affecting cognition, the gut and energy production in ME/CFS.

No Mady Hornig talk it seems is complete without an emotional moment. Every event I’ve seen her at has left her and others in tears at some point, and it happened again. I watched an older gentleman come over and clasp her hands. Five minutes later there they were hugging each other and sobbing away.

Top Poop Crew

Dr. Peterson and Simmaron won the top poop collector award

Dr. Peterson and Simmaron won the top poop collector award

While on the microbiome she noted, with a smile, that of all the groups they were working with, Simmaron was the best poop collector; Dr. Peterson gathered more stool samples (hundreds of them apparently) from more patients than any other doctor they were working with. (Go Simmaron :))

Maureen Hanson

Maureen Hanson, PhD, presented some  interesting news recently when she announced during an SMCI webinar that her small metabolomics had duplicated the Naviaux study’s core finding that ME/CFS was a disorder of reduced metabolism; i.e. it’s a hypometabolic disorder.

Maureen Hanson

That finding helps us understand her Simmaron talk a bit better. Hanson explored the subset question more deeply than anyone I’ve seen before.  Chronic fatigue syndrome (ME/CFS), she said, could be a bunch of different diseases, or one core pathology could be driving it.

Whatever it is, the diversity of symptoms found in the disease has produced a credibility problem because diseases which produce lots of symptoms have long been considered “psychosomatic”. The many different triggers ME/CFS and outbreaks has been associated with, and the many different bodily systems it effects, have been confusing as well.

Hanson thought it was intriguing that the symptom presentations seen in different locales appears to be similar! If ME was the result of different agents producing different diseases in different places then the locales should look very different but they don’t.  Hanson then fished out a bevy of factors which could affect symptom preSimmaron Research | #ShakeTheCFSstigmasentation; the age at which ME/CFS occurred, gender, genetic background, co-infections present, pathogen variations, treatments tried, degree of exercise attempted – all of these could conceivably tweak one disease into producing different symptoms. (Consider what happens to some people who collapse and appear to revert to a different state after overexertion or after using the wrong drug.)

She noted that her mitochondrial DNA study suggested that slight alterations in ME/CFS patients’ mitochondrial DNA could result in different symptoms. That sure presents just the tip of the iceberg with regards to genetics.  (Ron Davis and the Open Medicine Foundation will be attempting to marry genetic data and metabolomics in one of their studies.)

Hanson’s microbiome project was powered by a small NIH grant and took place in a Cornell lab famous for its microbiome work.  The project was a small one but it made a big splash and was picked up by over 50 media outlets.

The study’s finding – a reduced diversity of bacterial species (about 20% less) similar to that found in two potentially devastating gut diseases (Crohn’s and ulcerative colitis) gave Hanson the opportunity to tell the media again and again that ME/CFS is a real disease.  The study also found that ME/CFS patients’ gut bacteria tended to be more dominated by a smaller number of bacteria.

Bacteria of the Ruminococcaceae family –  important in fighting inflammation  – were significantly reduced in ME/CFS.  The representatives of another bacterial family called Enterobacteriaceae – which contains some rather nasty pathogens but hundreds of other species – doubled in ME/CFS patients.

At the genus level, Faecalibacterium prausnitzii, a butyrate bacteria, which produces an anti-inflammatory protein and protects the intestine was reduced in ME/CFS. A similar finding is found in irritable bowel syndrome.

The low butyrate findings in both Hornig and Hanson’s microbiome studies suggest they are both on the right track. That’s actually a big win given how complex (and new) microbiome analysis is, but perhaps it is not surprising given the pedigree of the labs doing the analyses.

As did a Solve ME/CFS Initiative study, Hanson also found evidence that gut materials were leaking into the blood of ME/CFS patients – a process that could spark an inflammatory process that makes its way all the way up to the brain.

[Butyrate – One neurobiologist calls butyric acid – which is produced by butyrate bacteria – “an ancient controller of metabolism and inflammation”. He reports that butyrate is the primary source of energy for the lining of the large intestine. Butyrate is such an effective anti-inflammatory that butyrate enemas (which reportedly smell horrible) and oral supplements are being used to combat inflammatory bowel diseases like Crohn’s and ulcerative colitis.  Butyrate also appears to reduce intestinal permeability – which Hornig’s/Lipkin’s and Hanson’s studies suggest many be happening in some people with ME/CFS.

Butyrate may also increase the levels of T regulatory cells which help reduce inflammation and autoimmune processes.

Hanson is a careful researcher and she spoke carefully regarding treatment. She noted that the inability of researchers at this point to clearly determine which gut species are present hampers them from recommending treatments. They can determine which families are present but because bacterial families can contain many different kinds of gut species -some of which have opposite functions – the study’s impact on treatment recommendations is not clear.

Atypical vs Typical Patients – the Peterson Subset

For many years Dr. Peterson has speculated about what he calls typical vs atypical ME/CFS patients. It’s not clear to me what the groups consist of but my sense is that  typical ME/CFS patients tend to plateau over time and they tend to have familiar co-morbid disorders such as fibromyalgia, migraine, IBS, etc. Atypical ME/CFS patients, on the other hand, tend to have other serious disorders and/or have really serious cases of ME/CFS. Whitney Dafoe and Corinne Blandino are two examples of atypical patients; Whitney because he’s so ill and Corinne Blandino because she has a strange spinal lesion.

Dr. Peterson

Dr. Hornig reported earlier that a cerebral spinal fluid (CSF) tests results had found dramatically different results.

At another event, Mady Hornig talked about the dramatic differences found in the CSF of classical versus atypical patients. Virtually all the immune factors tested were higher in the complex atypical vs the classical patients. In fact, the findings in the two subsets were so different that the atypical patients had to be removed from a study comparing healthy controls and ME/CFS patients. Simmaron and the Center for Infection and Immunity have taken a deeper look at the cerebrospinal fluid in these two types of patients.

I asked Dr. Hornig if she thought the atypical patients had a different disease or were an offshoot of more typical patients? She simply said that she thought that the atypical patients needed to be more closely watched.  Later Dr. Peterson suggested, however, that they may be profoundly different biologically.

We should know more about the similarities and differences between these two subsets soon. A Simmaron/CII spinal fluid study comparing the two in greater detail has wrapped up. The metabolomics data from the Ron Davis/Open Medicine Foundation severely ill patient study and the Naviaux study examining more typical ME/CFS patients will give us some guidance as well. Plus, the CDC will be comparing the test results of severely ill patients and healthy controls in the third phase of its multisite study.

A talk with Dr. Peterson found him in a more optimistic frame of mind than I’d seen before. While the promised funding package at the NIH hasn’t shown up yet, he was clearly impressed by the Nath Intramural study, the continuing work of the CDC, and the work Ron Davis is doing at the Open Medicine Foundation.

We didn’t talk about Ampligen and Rituximab but advances with both those drugs may make his job easier. Peterson’s stated that his patients have about a 70% response rate to Ampligen. That high percentage probably reflects two things: Dr. Peterson’s feel for who will respond to the drug, and his ability to dose this drug optimally for each patient.

At the IACFS/ME Conference, Hemispherx Biopharma will report a breakthrough in their understanding of the drug effects in ME/CFS. It appears that they’ve found a way to identify which ME/CFS patients respond to Ampligen – a finding that should help doctors and patients decide whether to try the drug, and make their next clinical trial that much easier. Dr. Patrick of Canada appears to have done the same with Rituximab – a very expensive powerful drug that many doctors are probably leery of trying in their patients without more guidance.

  • Dr. Peterson will be co-leading a session with Drs. Fluge and Mella on Rituximab and Emerging Treatments, and will be a panelist on a session devoted to diagnosing difficult cases of ME/CFS, and will be highlighting a fellowship opportunity with Simmaron, at the International IACFS/ME Conference at the end of October.

With groundbreaking spinal fluid publications, more collaborative studies lined up, and additional findings on their way to publication, the Simmaron Research Foundation (SRF) has made pivotal contributions to the rising science of ME/CFS in its first five years. The Simmaron Research Foundation is committed to translational research efforts that produce solid gains for patients. With collaborators like these, the next five years promise much.

Simmaron Research | Give | Donate | Scientifically Redefining ME/CFS

More is Better: Rituximab Trial Boosts Hopes for Chronic Fatigue Syndrome

The Rituximab  Story

“I was completely revitalized. Suddenly, I could be sociable again. I would go to work, go home, eat dinner and feel restless.” An ME/CFS patient in the study

The Rituximab story started in 2004 when Fluge and Mella two Norwegian oncologists noticed that some of their cancer patients with chronic fatigue syndrome were doing very well on a drug called Rituximab. In fact, they were doing too well. Not only had their cancer gone into remission but so had their chronic fatigue syndrome symptoms.

tweaking treatment protocol RItuximab

In this study Fluge and Mella tweaked their original treatment plan to produce more powerful and lasting results

Fast forward 11 years, one case series and another study later and we find Fluge and Mella not just treating ME/CFS patients with Rituximab but aggressively tweaking their formula to achieve a lasting remission in the responders and to provoke a remission in treatment resistant patients.

In the initial Rituximab trial published in 2011 Fluge and Mella gave 30 chronic fatigue syndrome patients two Rituximab infusions  two weeks apart and then followed them for 12 months. Three months into the trial there was no evidence the drug was working but 6-12 months later two-thirds of the participants had responded and some had responded in truly dramatic fashion. Years of disability and pain dropped away as some patients almost miraculously achieved normal lives.

Many of the responders, however relapsed later. In this study Fluge and Mella tried to do something about that. They gave Rituximab to 29 ME/CFS patients more often and for longer and they followed them for longer.

Rituximab

Rituximab induces B-cells to kill themselves by attaching to the CD20 receptor on them. It also enhances the ability of natural killer cells to kill them.

Originally developed and FDA approved to treat cancer (lymphoma) Rituximab is also FDA approved to treat rheumatoid arthritis and is used off-label to treat multiple sclerosis, lupus, chronic inflammatory demyelinating polyneuropathy, autoimmune anemia, Sjogren’s Syndrome and many others.  Chronic fatigue syndrome may be the first disease outside of known autoimmune disorders, that Rituximab has been tested in.

The Study

B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, Kristoffersen EK, Sørland K, Bruland O, Dahl O, Mella O. PLoS One. 2015 Jul 1;10(7):

After the two infusions in the first two weeks (500 mg/m2 (maximum 1000 mg) Rituxmab was given four more times at 3, 6, 10 and 15 months (500 mg/m2 (maximum 1000 mg) and the patients were followed for no less than three years. The participants assessed their symptom levels every two weeks and health related quality of life using the SF-36 form.

Lymphocyte subpopulations, including CD19 positive B-cells were assessed before the infusions and at 3, 6, 10, 15, 20, 24, 30 and 36 months.

In an attempt to boost their response seven of the patients who showed slow and gradual improvement after twelve months received up to six additional infusions at two month intervals.

The Participants

This was Norway but the study population looked like that found anywhere else. Sixty-nine percent of the participants were women and 31% were men. The average age was forty and the average duration of illness was nine years. The severity of their illness ranged from mild (n=5), mild/moderate (n=4); moderate (mainly housebound) (n-13), moderate/severe (n=4), severe (bedridden) (n=3). Almost 60% associated an infection with their illness, 34% did not and 7% were not sure.

Seven patients had had Rituximab before but relapsed later and three had tried it and received no or a minimal response. Nine participants had been in the placebo arm of the former study.  All met both the Fukuda and Canadian Concensus Criteria for ME/CFS.

The Results

The Responders

As in the first trial over 60% of the participants reported significant clinical improvement; i.e. they achieved an improvement in their Fatigue score ≥ 4.5 for at least six consecutive weeks. Fourteen or 78% of those  who did were described as “major responders” and four (22%) were described as moderate responders.

more is better Rituximab

More was indeed better as many of the responders maintained their response a year and a half after receiving their last treatment

Some evidence suggested that the major responders were close to functioning normally or in some cases were fully recovered.  With their average SF-36 scores showing remarkable increases it appeared that many of the responders really responded. (More is better with the SF-36).

The average social functioning score – which denotes how much a person is inhibited from functioning socially – increased from 18.4 to 70.8, the average vitality score tripled from  17.7 to 61.3, the average physical functioning score – probably a really difficult one to improve on in ME/CFS – almost doubled (42.9 – 83.3), and bodily pain scores more than doubled (32.2 to 72.3).

At the end of the trial the responders average SF-36 score meet population norms; i.e. you wouldn’t be able, using this test, to tell them from healthy people. It didn’t mean they were all healthy- the test is not precise enough for that – but they were much, much improved.

Some limited Sensiware armband data validated the findings: the number of steps the responders took at the end of the trial indicated they were about as active as normal people.

The Non-Responders

The ten people who did not respond – really didn’t respond; no significant increases in any of the SF-36 scores were seen. It appears that most of the responders do pretty well while nothing much happens for the non-responders.

Maintaining Health – the Maintenance Strategy Mostly Works

The maintenance strategy of providing Rituximab more often to produce a longer-last effect was mostly successful.  Again, those who responded to it responded well. Those did not respond – really did not respond.

The duration of the response zoomed in the responders from 25 weeks (half a year) in the first study to almost 100 weeks (two years) when taking maintenance infusions in the second study.  The responders stayed healthier longer once they were off the drug as well. Three years after beginning the treatment and a year and a half after their last infusion  the treatment was sticking for about 60% of the responders. Some former patients were clearly well.

“Eleven of the 18 responders were still in remission three years after beginning the treatment, and some have now had no symptoms for five years,” Fluge.

B-cell tests indicating the B-cell numbers of all the responders were back to normal suggested their systems may have been reset. If they’d had an autoimmune problem it had disappeared during their long period of immune suppression.

The maintenance dose did not enhance the duration of the response in everyone, however; about forty percent had relapsed a year after receiving their last dose.

The More Is Not Better (Except When it Is) …..Group

Giving Rituximab more often (at the end of one year) to patients who’d had a moderate initial response to it failed to turn them into major responders.  One person, however, who didn’t respond to the two-dose first trial, did respond to five dose second trail.

More doses of Rituximab early on, then, might help but if a year of increased dosage is not helping then it’s time to try something else. Why some people respond and others don’t isn’t clear. Sophisticated immune analyses, however, are underway to attempt to figure that out.

Concerns

Placebo Response

There’s concern about the lack of a placebo group. No treatment will ever get approval without having a placebo controlled study but I wonder how serious the placebo concern is. The long time to the response seen (several months) and the long duration of the response argue (a year and a half in some) argues against a placebo response making a difference for many.

Study Size

A bigger concern is probably the small study size.  Thus far we have  response data on a small slice of the ME/CFS population in an ethnically homogeneous region.  (The upside to doing the study in Norway is that they can apparently get things done pretty quickly; the downside is that the country simply doesn’t have the ethnic diversity the U.S. has.)

subset

The biggest questions facing the two studies done so far is how closely the study participants resemble the ME/CFS population as a whole.

We can say that Rituximab works well  and sometimes very, very well in a subset of patients but we don’t know how big that subset is. I expect the response rates to drop as more types of ME/CFS patients sample the drug. Even a thirty or twenty percent response rate would be very exciting.

The results from the multicenter trial will not be available until 2017 or 18 – two or three years. If the 152 person trial goes well it’s hard to imagine – at least from this layman – that large trials will not quickly open up in the U.S. The infrastructure and the network of physicians needed to engage in a major trial is present. They will simply need access to the drug.  With all the federal reports citing the need for better treatments a way has to be found to get the” big lug” to mount a major trial.

The Severely Ill Study

Thus far in a separate study none of the four severely ill ME/CFS patients in a small open-label study have responded to Rituximab. Four more patients are being assessed. They do not encourage the use of this very strong drug in the severely ill at this time.

The Autoimmune Question – If it Looks Like A Duck…

Chronic fatigue syndrome with it’s female predominance, it’s often infectious trigger, it’s symptoms and the changes that sometimes occur in pregnancy has always looked like it might be, at least in part, an autoimmune disorder.

Fluge and Mella’s autoimmune hypothesis ties several aspects of ME/CFS together in a neat package. First an infection triggers the body to produce antibodies that target the blood vessels and stop them from delivering normal amounts of blood to the tissues. The drop in oxygen to the mitochondria resulting from explains the fatigue, lowered aerobic capacity and exercise problems. Given the brain’s enormous need for oxygen it also explain the brain fog. Several studies back up the muscle and brain issues – the question is whether antibodies are the result.

duck autoimmunity ME/CFS

If it looks like a duck and walks like a duck… is it a duck?

Thus far the Rituximab findings suggest autoantibodies play a role at least in a subset of patients. As before the responders took their sweet time – several months – to respond to the drug.  That several month time lag, though, is about how long it would take Rituximab to clear auto-antibodies from the body. That time-lag strongly suggests an autoimmune process is going on.

Increased rates of autoimmunity (41%) in the first-degree relatives of the patients buttressed the autoimmune hypothesis; a genetic predisposition is often present in autoimmune disorders.

If auto-antibodies are the key Fluge and Mella and others, however, have not found them yet.  They do have a hypothesis, though that ties several aspects of ME/CFS together in a neat package. They believe an infection triggers the body to produce antibodies that target the blood vessels and stop them from delivering normal amounts of blood to the tissues. The drop in oxygen to the mitochondria resulting from the reduced blood flows explains the fatigue, lowered aerobic capacity and exercise problems. Given the brain’s enormous need for oxygen it also explains the brain fog. it’s a theory with a nice foundation: several studies back up

We should see a paper explaining Fluge/Mella’s hypothesis soon and studies embedded in the 150 person trial will help assess whether their hypothesis is correct.

Norway!

It’s worth noting again what a remarkable role the small country of Norway has played in this unlikely scenario.  Size doesn’t always matter – and one suspects that it may be a hindrance in some cases. Two Norwegian physicians birthed the Rituximab findings, Norwegian advocates raised money and pressured the Norwegian government to do what nobody else has been able to do – fund and produce a very expensive and large treatment trial.  Not only did they do that but they did much more quickly than anyone else.

It’s a scary thing to have to depend on a small country with almost no history of ME/CFS research or on private donors in another country to follow up on the most exciting treatment finding in ME/CFS’s history.  If Rituximab works out – and it’s hard to imagine that it will not at least in part work out – the worldwide ME/CFS community will owe the two doctors, the Norwegian advocates and the Norwegian government a huge debt.

The UK is on board. It may be that UK advocates – driven by their awful circumstances – try harder when it comes to jumping on a hot treatment finding. Since June, 2013 Invest in ME has raised over $600,000 US dollars for its own Rituximab trial. According to Dr. Jonathan Edwards, who pioneered Rituximab’s use in autoimmune disorders, Invest in ME has enough money now for a small trial involving 30-40 patients.

That’s great and Norway  has already produced a much larger study and is years ahead of everyone.  That quick start is important given how long these treatment trials take and how long it can take to get approval for a drug.

A Rituximab Timeline

Let’s look at a Rituximab timeline. Fluge and Mella identified their first Rituximab responsive ME/CFS patient in 2004. Their three person case study was published in 2009.  Their 30 person placebo-controlled study was published in Oct. 2011. They began the 152 person multicenter trial at the end, if I remember correctly, of 2014. That study should end in late 2016/early 2017. It will take some time to analyze the results and then get them published. Perhaps we’ll see a paper in early 2018.

You can argue that moving from a small case-study in 2009 to a large multi-center trial beginning in 2014 is good progress and it probably is, but it’s still five years in the life of an ME/CFS patient.

The Big Lug

Much of the innovative research, both inside and outside the public sphere, is occurring in the U.S. but the Rituximab trials might never have happened for all the work that’s been done here. That’s something that ought to give one pause.  A possible new treatment for a disorder with no FDA-approved drugs occurs and the biggest and richest country in the world does nothing.

head in sand

The country with the biggest medical system in the world hasn’t figured in the Rituximab story at all yet

How does that happen? Norway got funding from both advocates and the government. UK advocates have raised $600,000 by themselves. No group has mounted a serious effort in the U.S. and federal funding for clinical trials is difficult to achieve.

It’s pretty clear right now that nothing’s going to happen around Rituximab in the U.S. until the Norwegian trial ends up in mid 2017. Say the Norwegian results published in 2018 are impressive and the U.S. gets a major year-long trial started in early 2019.  The results are in by mid-2020, they’re submitted for publication in early 2021, are published in mid-2021. The FDA examines the data from the US, Norwegian and UK trials and in early 2022 seven years from now, approves Rituximab for use in a subset of ME/CFS patients.

When U.S. – because of bureaucratic or institutional barriers or whatever, is simply sitting on the its hands everything takes longer. In another disorder the Oct 2011 Fluge/Mella study might have sparked an extensive U.S. treatment trial in 2012.  The first results of that multi-year trial might have been published in say 2015.  In this scenario with the big Norwegian study underway we’d have enough data to apply for FDA approval in two years.

An Unlikely Ally

The two studies have created an unlikely ally. Simon Wessely – the foremost proponent of the idea that ME/CFS is caused by poor coping and deconditioning – has been impressed enough by the results to call for a large trial. “There is now a strong case” he said  “to be made for a larger trial”.  Whatever you think of Wessely that’s a very helpful statement coming from a man of his background.

The silver in the lining of the United Kingdom’s embrace of CBT/GET is the extent to which they’ve funded it. The UK, per capita, has been far more generous with ME/CFS funding than the U.S. and they’ve shown the willingness to put significant dollars (or pounds) behind a treatment trial. Drug trials in the U.S., on the other hand, appear to be almost solely funded by pharmaceutical companies. Wessely – recently knighted – has a lot of pull in the U.K.  Could Wessely prod the UK government to get behind an enlarged Invest in ME Rituximab study? That would a be flip of major proportions.

Wessely also said “The belief that [CFS] is all in the mind has been around since the beginning,” he says. “It’s tragic that it might take a study like this to take sufferers seriously.” That’s quite a statement given his history. Check out how that statement jives with Wessely’s past ones in Simon Wessely’s Big Shift? CBT Icon Calls For Big Rituximab Trial

Conclusions

It was a remarkable thing to see almost half the study population exhibiting normal or near normal SF-36 and activity scores after three years.  Even if this is a small study the almost identical response rates (a strong 60 plus percent) found in it and the first study  are encouraging.

This study also demonstrated that give doses more often eliminates many of the relapses that dogged the patients in the first study and it presented more evidence that this powerful drug  is generally safe for use in ME/CFS patients.

As promising as the results of the first two studies are it should be noted that they are small studies and surprises may show up in the larger study underway. It is using the same improved treatment protocol used in this study. It’s results will probably not be published for several years.

In the meantime, this study prompted a major CBT advocate to call for larger studies and a smaller UK trial is in the process of being produced. (You can support that study here.)

Dr. Pridgen on Doses, Fixing Broken Bodies and Why the Next Fibromyalgia Trials Will Be Better

If Dr. Pridgen is right, his protocol for treating fibromyalgia could end up turning the medical world’s conception of FM (and perhaps even chronic fatigue syndrome) on its head. The first treatment trial had good results but they didn’t exactly turn the FM world upside down. Geoff Langhorne asked him about that in an interview a couple of months ago and I followed up with my own questions.

A confident Dr. Pridgen explained why the first trials result were good but not earth-shattering and why the next trial results will be better. First some background.

How it Happened

“It was never my intention to be involved in Fibromyalgia” William Pridgen

Pridgen didn’t start out to treat fibromyalgia – he was simply trying to get at what was causing the diarrhea/constipation and abdominal pain in his patients.  Both he and his mother – a virologist – recognized that the pattern he kept seeing –stubborn symptoms which got better with treatment then got worse, and then better and then worse – could reflect a virus getting reactivated, then knocked down, reactivated then knocked down. Throw in the fact that his patients gut problems typically got worse during stressful events and a herpesvirus infection became a viable option.

herpesvirus

The pattern of remission and then relapse, particularly, after stressful situation, suggested herpesviruses.

Pridgen started off giving a couple of his patients a single antiviral herpesvirus drug. The fact that some of the patients did get better encouraged him, but it was not until he combined it with the anti-inflammatory Celexicob (Celebrex) that he really began to see results.

The big surprise was that his patients were reporting relief from a whole panoply of other symptoms. Their fatigue, their headaches, their muscle and joint pains, their sleep problems, their difficulty relaxing – all were improved. By the time twenty or thirty patients had reported this he really began to take notice.

“Holy crud!” in the interview he stated, “I discovered something.”

He switched gears and began offering the drug combo to people with chronic fatigue syndrome and fibromyalgia. He lambasted the idea that fibromyalgia or chronic fatigue syndrome are difficult diagnoses to make. As soon as he knew what these illnesses looked like, he said, anyone working in his office could spot them immediately.

Fixing What’s Broken

Patients tended to sporadically improve early with the full effects showing up after about three months. He wasn’t just treating herpesvirus infections, however. Asserting that these diseases “break things”,  he also worked on their treatment resistant sinusitis, acid reflux, thyroid issues, insomnia, anxiety, and depression.

fixing what's broken

Pridgen asserted it’s necessary to fix what else is broken for his protocol to have full effect.

In fact, his first step was to figure out what was broken and fix it and then put them on the drug combo “. He said “if you’ve done a good job with the first half” then 12 to 14 weeks into the treatment program a “switch” often gets flipped with people feeling a whole lot better.

Geoff then asked a great question – would you characterize this as a cure or a successful treatment?  Pridgen stated that you can’t “cure” or eliminate viruses, but that he did feel that his treatment protocol was getting at the core of the disease. Note, however, that Dr. Pridgen did put that qualifier – “If you’ve done a good job with the first half” – in. It’s important to treat the depression or generalized anxiety disorder, symptomatic gallbladder disease, severe reflux and chronic nonseasonal sinusitis, etc. for his combination treatment to optimally work.

His protocol, he believes, is much more effective at symptom reduction than the drugs currently approved for fibromyalgia. He does not feel those meds get at the core of the disorder: his does.

Herpes Simplex Virus-1

The predominant virus he believes that is causing the pain in fibromyalgia is herpes simplex virus-1 (HSV-1). HSV-1 has been put in the “fever-blister” category; it causes some unpleasant symptoms and nothing more. Pridgen believes that view and the accompanying attitude of benign neglect towards the virus HSV-1 are disappearing.

HSV-1, it turns out, isn’t always so benign, after all. Yes, the initial infection is usually mild. And yes, essentially everyone, including healthy people, is exposed to and carries HSV-1 in their body.

neurons HSV--1

HSV-1 hangs out in the neurons. In susceptible people that could be a problem.

Like the other herpesviruses, however, HSV-1 persists in the body hanging out in the neurons. After the initial infection, HSV-1 is able, in some people, to become reactivated, travel up the axon of the neuron to the nerve centers – waiting to be reawakened by a stressor.

Studies indicate that  almost any stressor including colds, eczema, menstruation, emotional and physical stress, stomach upset, fatigue or injury can reactivate it. It can cause encephalitis and blindness, and some evidence suggests it’s associated with Alzheimer’s disease.

Vaccines for HSV-2, a close cousin to HSV-1, are being worked on. If HSV-1 does end up being the cause of fibromyalgia, Pridgen believes widespread HSV-2 vaccination could, just as vaccines have put an end to measles, chickenpox, hepatitis and other viral illnesses, help put an end to fibromyalgia. A vaccine, by the way, could also potentially help some people who already have fibromyalgia much like the shingles vaccine helps people with Varicella Zoster reactivation.

The First Trial

“We didn’t get a 60-70% efficacy, because it wasn’t our ideal dose and a lot of patients had other conditions they couldn’t get fixed in a trial like that.”

If you’ve been following the Pridgen story you’ve probably heard of people who’ve tried the Famvir/Celebrex combination who’ve done well and others who haven’t. Pridgen addressed the variability in results in his protocol by asserting that the doses aren’t set and that many of the participants had more than fibromyalgia to deal with.

The trial was less restrictive than most other phase 2 (FDA approved) FM trials where men or people with severe depression weren’t allowed to enroll. He said they pretty much let everybody with FM in.

He also stated that if the patients failed to commit to fixing the secondary problems they didn’t do as well. The FDA also required only one dose be used in the trial – and that dose was not their “favorite” one.

Fifty-three percent of the patients in the trial had at least a thirty percent reduction in pain. That’s a good but not great figure, but Pridgen noted that almost forty percent had at least a fifty percent reduction in pain – and that’s a very good figure for FM. Already their stats, he stated, may prove to be better than the three FDA approved drugs for FM – and he hasn’t been able to use the dose he ultimately intends to market. He stated that some of the world class experts on IMC’s scientific advisory board have said they had “never seen pain data like this” for FM before.

The Next Trials

The next phase three trials, though, will be slightly more selective as the fibromyalgia patients will not have as many “extra conditions”.

It’s going to take time to raise the money and then do two phase III trials – which can be run side by side. While there may be one dose that works best for the most people, Pridgen asserted that no dose is perfect for this variable population and they’ll probably do a dose-ranging study to get at the variability.

They’re trying to get FDA to fast-track the next trials. My guess is that patient enrollment will not be a problem; they expected it to take nine months to enroll the last study and they did it in three.

When asked how the phase three trials are coming Pridgen stated, “We’re moving as fast as we can….This is not an easy process.”

Confident

“I feel very confident that the next two trials will be far more impressive”.

Dr. Pridgen appears to be utterly confident he’s on the right track. He said he’s seen a 1,000 plus FM patients and an equal number of chronic fatigue patients.

recovery from fibromyalgia

Prigen asserts many people have gotten well using his protocol.

“If a patient does what we tell them to do and they jump through the appropriate hoops it’s unbelievable what happens to these people – they do so much better” Skip Pridgen

When the Blue Ribbon Project came to Tuscaloosa, it was the only place, he said, they saw people getting better.

He said he’s seen “countless” patients get well and go on with their lives, including very ill patients.  “I’ve had some tremendously ill patients who get their life back….get back to working again.”

They come from all over. He gets the protocol started and then refers them back to their physicians. His Canadian and Australian  patients have a good chance of continuing with the protocol because their physicians are more open minded, but the Brits often run into a wall so unless they can cross the Atlantic, presently they are receiving little support from their own medical profession.

Dr. Pridgen Talks

When do you expect the study to be published?

Dr. Carol Duffy is feverishly working on the manuscript and should be submitting it for publication this summer, hopefully in one of the premier pain journals.

How did you, a surgeon, end up treating people with gut problems?

Many general surgeons perform endoscopies in their practice of medicine.

How did you get the idea to combine the antiviral with an anti-inflammatory?

I was merely giving them a NSAID for their joint pains, and serendipitously noticed the two drugs when combined had unexpected benefits. I’d never heard of anti-inflammatories used to hit viruses before. Virologists have known for two decades, though, that NSAID had antiviral properties.

You presented a very different model of fibromyalgia at the Rheumatology Conference than rheumatologist are used to. I don’t know if anyone has looked at fibromyalgia as a herpesvirus disorder let alone treated people with antivirals. What kind of reception did your talk receive?

Lot’s of questions, none too difficult to answer and generally it was well received even if the attendance was not ideal.

neurons

Pridgen and Duffy believe three sites in the body may be particularly affected in fibromyalgia: the gut, the vagus nerve and the sinus area

I know someone who couldn’t tolerate the Famvir but did very well on Celebrex for six months when everything fell apart again.

There are other options, and if his physician had reached out to me, I would have given the physician everything they needed to help that patient.

What can you say about the gut tissue biopsy results?

The preliminary data was presented a little over a year ago at an international virology meeting, and for patients who have FM 100% of those patients have HSV-1 data in their biopsies and 80% have a protein that is found only in cells that are actively infected with HSV-1.

If HSV-1 is found in the guts of FM patients is it your guess that it’s probably reactivating elsewhere?

The vagus nerve is the nerve that controls the gut and the virus lives in its ganglion. We postulate that there are two other major sites, the sinuses, and the urinary bladder, that are also likely sites of chronic reactivation.

If it’s active in the gut would you expect to see an increased incidence of cold sores in FM?

Approximately 30% of the population suffers from cold sores. If you go to the innovativemedconcepts.com site you will be able to watch a couple of video’s that explain this better.

big fibromyalgia studies are next for Pridgen

Has Pridgen cracked at least part of fibromyalgia? Time will tell. The big studies are next…

You tried several different combinations of drugs and Famvir turned out to be the antiviral of choice for the fibromyalgia patients in your study. Do you have any idea why Famvir was more effective than the other drugs?

(Dr. Pridgen said that’s a trade secret for now.)

In your experience are people who improve dramatically able to get off the drugs and maintain their improvement for a considerable amount of time?

Absolutely not! The moment they stop the meds the next time they are severely stressed the condition returns. You can’t stop diabetes, hypertension, and cholesterol medications and you can’t stop these.

What is the timeline for the phase III study or studies?

Plans are underway for the near future.

 

The Biggest Chronic Fatigue Syndrome Treatment Trial Begins: Fluge/Mella On Rituximab

Doctor’s Fluge and Mella shocked the ME/CFS world with their 2009  case series and the 29-person 2011 study which found that about 2/3rds  of ME/CFS patients had a significant and positive response to the chemotherapy  and autoimmune drug Rituximab. With some patients achieving near miraculous recoveries, the results from Norway had the ME/CFS world buzzing.

rituximab-chronic-fatigue

The big question is – what percentage of ME/CFS patients will respond?

As encouraging as the results were, however, they were but a prelude to the big study ahead – the one that will definitively tell us how effective Rituximab is in this disorder.

As they begin the study, the doctors appear to be both cautious and optimistic. There’s no doubt now that Rituximab doesn’t significantly help some people with ME/CFS – the question is how many and how much – and that’s what this 152 person, multi-center study will tell us

Multi-dimensional in scope, it’s actually four studies in one – some of which are almost as exciting as the trial itself – that  could tell us much about ME/CFS. This very long study started up in the last quarter of last year – a bit later than expected. As  it did I asked the doctors some questions.

(Check  out the study on the ClinicalTrials.gov database).

How is the Rituximab (RituxME) study going? 

The RituxME study has just started recruiting patients. We plan to include 152 patients, in five centers in Norway. There will be 1:1 randomization between rituximab and placebo.

We will give the first two infusions two weeks apart (500 mg/m2, max 1000 mg, or placebo) followed by maintenance infusions 500 mg fixed dose (or placebo), at 3, 6, 9 and 12 months. The placebo solution with saline and some added albumin will look identical to the Rituximab solution. The study will be double-blinded and placebo-controlled.

The follow-up will be for 24 months, and the code for intervention will be revealed after the last included patient has been to 24 months visit and the database is locked.

measuring activity levels - me/cfs

Many measurements will be done – including activity levels.

Patients from 18-65 who have ME/CFS according to Canadian criteria (2003), age 18-65 ME/CFS for at least 2 years up to 15 years can be included.  People with severe, moderate/severe, moderate, mild/moderate and mild ME/CFS may be included.  If they have “mild” ME/CFS they need to have had the disease for at least 5 years. People with very severe ME/CFS (completely bedridden with need for help for all tasks) will not be included.

Self-reported symptom scores will be recorded every second week, and SF-36 questionnaires every third months. Activity levels will be assessed for seven consecutive days using the Sensewear armband at baseline, and repeated at the17-21 month follow-up.

Do you plan to publish the results of the open-phase trial? If not can you say anything about the results? (This was an open label (patients knew what they were taking) study with 29 patients using rituximab induction and maintenance treatment (six rituximab infusions over 15 months, with follow-up for three years, unpublished). This trial continued patients on Rituximab (a maintenance dose) for much longer, in a effort to reduce the relapses seen in some patients after they went off Rituximab.)

We have used the experience from our open-label phase-II study using rituximab maintenance. This study ended in February 2014, but due to all the work with the new study we have not had time to complete the manuscript. However, we are now completing the manuscript, and hope to submit soon.

We included 29 patients in the open-label phase-II study (KTS-2-2010). In this study there was no placebo group, and that will of course be the main criticism of the study. The reason for doing an open-label study was to gain experience on dose-response relationships in order to better design the randomized phase-III study. We also wanted to give patients who had taken the placebo in our first randomized study (Plos One 2011, KTS-1-2008) an opportunity to take part in a study without being randomized again (that was in agreement with the ethical committee approving the KTS-1-2008 study).

One patient had an allergic reaction at the first infusion and did not get further intervention, leaving 28 patients to receive rituximab maintenance treatment. The patients received two infusion with rituximab two weeks apart,  followed by maintenance rituximab infusions after 3, 6, 10 and 15 months (7 patients received further infusions according to an approved amendment in the study).

We will not give details on the results here, even though the study has been presented at some meetings the last year. For now we can state the response rate was quite similar to the first KTS-1-2008 study, and that the response durations seem to be much prolonged (as compared to the Plos One study) when giving rituximab maintenance treatment.

Rituximab-chronic-fatigue

Fluge and Mella’s data indicated that maintenance doses of Rituximab worked: i.e. they largely kept patients from relapsing

To us, the most important issue now is to do a proper phase-III study which will determine if the results of the first trial can be trusted. It is important to understand that our first phase-II study (Plos One, 2011) – the first to evaluate the treatment principle of B-cell depletion in ME/CFS – had several limitations.

We do not know how much selection bias was present in our first two studies. If the putative immunological disease that we have seen is commonly found in the broad groups of ME/CFS patients that fulfill the Canadian criteria, we have a chance to get a significant result in favor of rituximab in the ongoing study.

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.

The Substudies

Blood vessel, exercise and gastrointestinal substudies occurring alongside the major study could tell us much about ME/CFS as well. Some of the substudies are, to my mind, almost as interesting as the Rituximab study itself. I asked Dr. Fluge about them. 

For the RituxME study, we will perform three substudies. (We originally planned to use these in the main study, with some parameters as secondary endpoints, but because all centers could not perform the analyses they were designed as substudies.)

All three substudies will be performed at baseline and repeated at the 17-21 months follow-up, which is the time interval our previous experience suggests that the therapeutic effect of rituximab maintenance to be most evident.

Endothelial Functioning Substudy

Our substudy of endothelial function (Bergen Notodden) in 72 patients will use flow-mediated dilation to test large blood vessel endothelial functioning.  We will also test microvascular endothelial function in Bergin using skin laser-doppler measurements.

blood vessels chronic fatigue

Is a problem in the blood vessels triggering the sympathetic nervous system activation found in ME/CFS?

We believe that endothelial function is important in ME/CFS. Even though many symptoms can be ascribed to the central nervous system we are not convinced that ME/CFS is primarily a central nervous system disorder. We believe the sympathetic nervous activation seen in ME/CFS may be (partly) secondary to an underlying (peripheral) pathology.

It is important to get an understanding of which symptoms that are caused by the primary pathology, and those which may be ascribed to secondary (compensatory) mechanisms.  We are working to elucidate whether endothelial dysfunction, and subsequent inadequate fine-tuned autoregulation of blood flow to meet the demands of tissues, may be an important feature of ME/CFS.

A study from Dundee in 2011 showed endothelial dysfunction to be present in ME/CFS. Our pilot studies in a group of ME/CFS patients suggest it is as well.

In the substudy to RituxME, we ask if we can reproduce the endothelial dysfunction in a larger cohort of ME/CFS patients? Is there a relation between endothelial dysfunction and disease severity? Is there a relation between endothelial function and a later clinical response (in the rituximab group)? In patients that improve after B-cell depletion therapy (Rituximab) is there a relation between improvement in self-reported symptoms or in physical activity levels, and changes in endothelial function?

We have written a manuscript on our thoughts and hypotheses including the relation between immune response, endothelial function, and the possible effector system for symptom maintenance in ME/CFS. However, we still believe that we need more data to underpin out thoughts and have therefore not submitted the paper yet.

[Dysfunction of the endothelial cells lining the blood vessels in the circulatory system has been a subject of interest in ME/CFS since MERUK’s pioneering efforts in the early 2,000’s. These cells  – present everywhere from largest arteries to the small capillaries – control how dilated or narrowed the blood vessels are, affect inflammation, control blood clotting and more.  Each of these factors have been implicated in ME/CFS at one time or the other. In 2012 Newton et al.  reported both small and large blood vessel dysfunction was present in ME/CFS.

The finding last year that  autoantibodies to the adrenergic receptors found on endothelial cells are present in postural orthostatic tachycardia syndrome (POTS) suggested an autoimmune process was knocking out one group of POTS patients. Now Fluge/Mella appear to be proposing that a similar autoimmune process is messing up the blood vessels and producing the sympathetic nervous system activation in ME/CFS. If that’s so Rituximab’s efficacy could lie in its ability to restore proper blood flows (and presumably blood volume) to ME/CFS patients allowing them to exercise, think, digest, etc. as healthy people do.  This is a hypothesis that is pregnant with possibilities.

Fibromyalgia patients should note that Rice has found evidence of small blood vessel dysfunction in the hands that may also be impeding normal blood flows throughout the body. – Cort. ]

 Exercise Substudy

The cardiopulmonary exercise tests for two following days will be performed at baseline and repeated in the 17-21 months follow-up. We will do this substudy in Bergen, Notodden and Oslo, but only for patients with mild and moderate disease (not severe), The total number may be 50, perhaps more.

exercise chronic fatigue syndrome

The ultimate test of Rituximab’s effectiveness – an aerobic exercise test.

We want to see (in a double-blind fashion) if the performance (VO2max, VO2 at anaerobic threshold, workload at max and at anaerobic threshold) of patients who respond to Rituximab will improve on day two of the exercise test.

It may be a disadvantage that we exclude patients with a high symptom burden from this substudy, but we did not want to put patients with moderate/severe or severe ME/CFS through such physical exertion because they may worsen for many following weeks. They will also start the intervention (Rituximab or placebo) three weeks after these tests  – maybe too soon for some moderate/severe or severely ill patients to fully recover.

Gastrointestinal Functioning Substudy

The substudy on gastrointestinal function will only performed in Bergen, and only for patients with GI symptoms resembling functional dyspepsia or irritable bowel disease. Approximately 15-20 patients will be included.

Gastroenterologists in Bergen will evaluate the patients using several self-reported forms, and with a soup meal followed by ultrasound assessment, and also with endoscopy and biopsies from those willing to participate in this (in fact, most of those we have evaluated are willing to do the endoscopy!). The GI studies will be performed at baseline and repeated after 17-21 months.

Genetics Study

Dr’s Fluge and Mella will  also be looking at the genetics of ME/CFS patients and their families. Dr. Fluge wrote

genetics-chronic-fatigue

The list goes on…Fluge and Mella are also looking at genetics

To further elucidate possible clues, we are also working on exom-sequencing of families with many affected individuals among first- and second-degree relatives, sequencing all coding parts of the genome (with flanking introns) both from affected and healthy family members. We test candidate genes with targeted sequencing in all patients included in our studies. We hope to be able to link the genetic and clinical data, to underpin the hypotheses.

An Autoimmune Disorder?

I asked Dr. Fluge why they thought the patients responding to Rituximab may have an autoimmune  disorder?

Why we think this is a variant of an autoimmune disease? First, we have not shown that ME/CFS is an autoimmune disease. However, we believe that in a subgroup of patients an autoimmune pathogenesis involving B-lymphocytes and possible immunoglobulins (autoantibodies) makes sense.

The arguments are as follows:

  • The observed pattern of responses and relapses after rituximab treatment, with a lag time of several/many months from initial and rapid B-cell depletion until start of clinical responses. Such patterns are also seen in established autoimmune diseases after rituximab treatment, such as Wegener’s granulomatosis and rheumatoid arthritis.
  • A high proportion of women with ME/CFS
  • Our studies suggest a high occurrence of autoimmune diseases exists among relatives of ME/CFS patients (could also be a marker for a selected population in our studies?)
  • A moderate, but highly significant risk of B-cell lymphomas in elderly ME/CFS patients, shown in a large case-control study from National Cancer Institute in 2012. To me, this is an important study, showing that patients may have a chronically activated B-cell system.
  • Emerging data from a few other poorly understood diseases (POTS, Chronic Regional Pain Syndrome, CRPS) which have some common characteristics and possibly to some extent may overlap with ME/CFS, in which research groups have detected (functional) autoantibodies.

Long Lag Time Also Suggests Autoimmunity

Epstein-barr chronic fatigue

The different responses Fluge/Mella’s ME/CFS patients and their chronically activated EBV patients have had to Rituximab suggest to them autommunity, not EBV reactivation, is ocurring.

The long lag time from rapid initial B-cell depletion to start of the clinical response (2-8 months) is why we do not think elimination of EBV or CMV is the principle mechanism for symptom relief in our patients. In my work as a lymphoma oncologist, I have treated a few patients with chronic EBV infection, with moderate lymphadenopathy, night sweats and general symptoms for several years, and with no clear clinical benefit from valganciclovir.

In one patient, the B-cells in bone marrow and in lymph nodes were packed with EBV and she had a high EBV titer in her peripheral blood. When given rituximab, her symptoms waned in a few days after start of treatment – very different from what we see when treating ME/CFS patients.

Two Cautionary Notes

Dr. Fluge wanted to make two cautionary notes: 

caution rituximab chronic fatigue

Caution! Rituximab use in severely ill patients is not recommended…

Very severely ill ME/CFS patients – We are also conducting a study (KTS-3-2010), which includes very severely ME/CFS patients. Only four very severely ill ME/CFS patients have been at our hospital, and it is very difficult to give them the care they need in a very busy oncology ward. For these for patients, although rituximab has influenced their disease in a slightly positive manner for two, none of the four could be characterized as responders. We do not encourage treatment of patients with very severe ME/CFS with rituximab outside clinical trials!

In fact, until further scientific data and evidence are available, all patients receiving rituximab for ME/CFS should be treated within clinical trials.

Etanercept - We started a clinical open-label phase-II study on weekly subcutaneous etanercept (a TNF-alpha inhibitor). Only four patients were included, and we decided to stop the trial because two patients had a clear worsening of ME/CFS symptoms, while two were unchanged (no response). Ideally, we should have included additional patients to gain experience for a more solid conclusion; we however decided to stop the trial.

New Open Phase-II Trial

After observing a few pilot patients for one year, we have decided to begin another open-label phase-II study in Spring 2015 on another immunomodulatory drug, in three sets of ME/CFS patients:  ME/CFS patients who have not treated before with rituximab, in nonresponders to rituximab treatment, and in patients with a clear response to rituximab but with evidence of gradual relapse the last year. This study has been approved by the Ethical Committee, and will occur at a single center study in Bergen (Haukeland University Hospital)

Conclusion

In conclusion, we hope our efforts will help to increase our knowledge of ME/CFS, and that the results of the new randomized study will provide some important answers to aid further research, either by us or others in the research community. We need a better understanding of the disease with regards the genetic predisposition, the immune disturbances and the endothelial dysfunction present and the effector systems for symptom maintenance in order to develop rational treatments for this devastating and misunderstood disease.

 

 

 

 

 

 

 

 

 

 

 

 

Drug Combo in Pridgen Antiviral Fibromyalgia Trial Identified – Some Results Available

A lengthy article originating on the University of Alabama website and an  abstract presented to the American College of Rheumatology Conference indicates that the two drugs Dr. William “Skip” Pridgen and virologist Carol Duffy PhD used in their Fibromyalgia antiviral trial were Famciclovir, better known as Famvir and Celexicob, best known as Celebrex.

The report also indicates that  Duffy found only herpes simplex – 1 viruses (HSV-1) in the gastrointestinal tissues of the FM patients. Neither of these drugs nor this type of herpes virus have been commonly used or associated with chronic fatigue syndrome.

HSV-1

Duffy found only herpes simplex-1 viruses in the gut tissues of FM patients

We also learned Pridgen discovered the two drug combo similar to the way Fluge/Mella uncovered Rituximab in chronic fatigue syndrome – by observation. Suspecting that herpes viruses might be to blame for the gastrointestinal issues in his patients, Pridgen started them off on Famvir.  The drug helped but symptoms remained.

After Pridgen noticed much greater improvement in the symptoms of the patients also put on Celebrex for their arthritis he combined the two drugs – for everyone.

In the University of Alabama article, Duffy reported the improvement on the two drug combo was immense.

““The patients who took both drugs, however, came back and said everything was better. Their fibromyalgia was gone. Their chronic fatigue was gone. Their headaches were gone. All of these things had cleared up. When the first few patients approached him, he thought it was a fluke, but as more and more and more patients said the same thing, he knew it couldn’t be a coincidence.”

The Triad

That drug combo never been used in herpes virus infected patients before, but it made sense to Duffy. She knew that some herpes viruses  increase the production of COX-2, a pro- inflammatory enzyme. While Famvir stopped the herpes viruses from replicating, Celebrex weakened the viruses, making them “unstable”.  Since Celebrex also has some antiviral properties, the drug combo hit the virus in three ways.

Famvir

Famvir

Famvir – rarely mentioned in ME/CFS – was the antiviral of choice for Pridgen

Valtrex, Valcyte and Vistide are often used to treat herpesvirus infections in chronic fatigue syndrome but Famvir is rarely mentioned. (Dr. Dantini appears to use Famvir frequently to treat his ME/CFS/FM patients.)

One of the reasons may be that Famvir is mostly used to treat herpes virus infections such as herpes simplex virus, herpes simplex virus 2 (genital herpes) and herpes labialis that have not been typically associated with ME/CFS.

The Newcomer – Herpes Simplex

Duffy scoured the gastrointestinal tissues of 45 patients for a virus. In the end it wasn’t EBV, cytomegalovirus or HHV-6 that showed up, but herpes simplex virus-1 (HSV-1) – the very virus she’s been studying in her lab.  (That’s a little scary, but a technique called immunoblotting was used to ensure contamination had not occurred.)

Herpes simplex virus is best known for its ability to cause cold sores and genital herpes, but according to a Wikipedia article can also cause  herpetic whitlowherpes gladiatorumocular herpes, cerebral herpes infection encephalitisMollaret’s meningitisneonatal herpes, and possibly Bell’s palsy.

HSV-1

The group believes HSV-1 could be affecting many different tissues in FM and other disorders

HSV-1 can infect various organs in the body including the peripheral and central nervous systems, upper respiratory tract, and gastrointestinal tract. It may play a major role in Alzheimer’s. It’s able to deplete mitochondrial DNA. One article suggests herpes simplex virus may be better adapted to take advantage of poorly functioning natural killer cells than any other herpes virus.

The group believes HSV-1 may be responsible for fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome and perhaps other disorders. A video on the Innovative Med Concepts website indicates the virus can attack the facial, gastrointestinal and pelvic regions and that it ultimately takes up residence in the vagus nerve.

It took Pridgen and Duffy about a year to raise the $4 million dollars for the 100 person plus phase II trial to assess the drug combo’s efficacy and safety.  Along the way they enrolled a member of the drug team that brought Savella to market in FM, and a past president of Pfizer in their effort at Innovative Med Concepts.  Noted FM researcher Daniel Clauw joined their advisory board.

Conference Abstract Provides Results

An abstract presented at the ACR conference yesterday suggested the drug combo produced strong improvement in some measures and not as strong improvement in others. The changes in pain using the revised Fibromyalgia Impact Form appeared impressive (p< 001) as did changes in function and symptoms (p<.004) and overall impact (p<.003). Fatigue was significantly improved but less so (p<.02).

stop-pain

Changes in pain were impressive. Fatigue was improved but not as much

However, only 33% of patients (vs 19% of those not on it) met the criteria for a secondary measure called the  Global Impression of Change Scale which asked about changes in a person’s activity, limitation, symptoms, emotions and quality of life. It‘s not clear how to parse the more impressive results in some of the tests with less impressive results in the last one.

The drug combination was judged very safe with more adverse events found in the placebo group than in the patients taking the drug.

Improving Efficacy Efforts Underway

If the trial wasn’t a complete win it nevertheless produced significant improvements in a notoriously difficult to treat illness.  Since fibromyalgia, like chronic fatigue syndrome, is believed to be a quite heterogeneous illness asking any drug or drug combo to be effective in everyone is unrealistic.

Phase III Trial Will Tell the Tale

tablets

Finding the optimum dose will be a key aim of the big trial

Designed to  assess basic aspects of efficacy and safety, Phase II trials are not the last word in efficacy. As the Pridgen/Duffey team proceeds to the Phase III trial  they’re exploring several ways to bump up efficacy. Duffy is working on diagnostic tests to identify which FM patients are most likely to benefit from the combo, and is doing toxicology tests to determine if higher doses are feasible. The optimum doses of the drug combo will also be determined in the Phase III trial. Expect efficacy rates to rise.

Big Trial Ahead

Next up is the big third phase trial – a jaw dropping $50-100 million trial the FDA needs in order to approve the drug combo for the treatment of fibromyalgia.

No one is satisfied with the state of fibromyalgia treatment – and few have looked to the immune system or to pathogens. If the results of this trial are not breathtaking – they are still very good –  and will hopefully improve as the therapy becomes better targeted.  They should begin to prompt a revaluation of what’s going on FM.

The publication of the study is probably just around the corner….

Symposium Calls For Use of Immunotherapy To Treat Chronic Pain

October 2, 2014

“Despite the availability of different drugs, most patients with chronic nociceptive pain do not receive satisfactory pain relief…”

We all know the medical profession is poor at providing pain relief in general, but its record with regards to neuropathic or nerve pain is something else indeed. Despite the fairly large array of drugs physicians use (few of which were developed to reduce nerve pain), no more than 30-40% of  nerve pain patients receive as much as 50% relief from the medications doctors  provide.

pain

The medical profession is poor at treating pain. The experience of these doctors and researchers suggests it may be missing some options.

Despite research that has uncovered important factors in the production of pain, much clearly remains to be learned.  The production of pathological pain has been shown to be a very complex process. Researchers know, for instance, that damage to the ion channels on nerves, increased levels of excitatory neurotransmitters and reduced activity in the pain inhibition pathways in the brain all play a role.

These authors suggest, though, that a critical component of the pain production pathway – the immune system – has been, if not ignored, then not fully investigated.  Studies show that a variety of immune components, from mast cells to macrophages and cytokines to the microglia play a role in pain production.

Recent studies suggest that autoantibodies to the potassium channels – the dorsal root ganglia – key pain processing sites located just outside the spinal cord -are opening up new windows on how pathological pain may be produced.

Other than corticosteroids and anti-inflammatories, however, few immune affecting drugs are used to fight pain.  Human immunoglobulin G (IgG) is an immune drug these authors believe may be useful in pain disorders where evidence of increased cytokine production can be found. IgG can be delivered intravenously (IVIg) or subcutaneously (SCIg) and may work by suppressing the immune system.

The fifteen members of this workshop came from Italy, Sweden, Switzerland, Japan, Canada, the U.K., and the U.S. to report on where and when IgG may be useful in treating chronic pain. Some studies were reported on and a good deal of the information derived from case studies.

Symposia Report Immunoglobulin G for the Treatment of ChronicPain: Report of an Expert Workshop, Stefano Tamburin, MD, PhD,* Kristian Borg, PhD,†Xavier J. Caro, MD,‡ Stefano Jann, MD,§Alexander J. Clark, MD,¶ Francesca Magrinelli, MD,* Gen Sobue, PhD,** Lars Werhagen, PhD,†Giampietro Zanette, MD,†† Haruki Koike, PhD,**Peter J. Späth, PhD,‡‡ Angela Vincent, FRCPath,§§ and Andreas Goebel, MD, PhD¶¶ Pain Medicine 2014; 15: 1072–1082

 Sjogrens Syndrome

Sjogrens Syndrome (SS) is an autoimmune disorder mostly affecting women.  Often misdiagnosed as other disorders, including ME/CFS and Fibromyalgia, SS can cause a wide variety of neuropathic (nerve) problems.

IVIG

IVIG is the focus of this review -but other immune drugs may apply.

Some evidence suggests that the neuropathic pain in SS, which can be quite severe, comes from neuron loss in the dorsal root ganglia perhaps caused by ‘cytotoxic autoimmunity” – a intriguing result given similar findings in some Chronic Regional Pain Syndrome patients.

Of five patients treated with IgG for SS with severe neuropathic pain, all showed ‘remarkable’ reductions in pain (73% reduction VAS scale) within two weeks which lasted from two to six months.  Long term follow-up indicated two had relapsed, but resumption of treatment was successful.

Fibromyalgia

Several findings including increased cytokine levels in the skin and blood suggest the immune system plays a role in Fibromyalgia.  An inverse correlation between Il-2 receptor levels and reduced nerve density in the skin (small nerve fiber neuropathy) suggested immune mediated nerve destruction had occurred.

myelinated nerves

Caro finds immune therapies to be the most effective for his Fibromyalgia patients

Studies reporting large nerve fiber demyelination in the periphery and reduced nerve fiber density in the skin suggest FM may in part be a neuropathic disorder.  Pain symptoms in FM are similar to those reported by people with neuropathic pain.

Caro found that from fifty to seventy percent of 45 FM patients responded positively (<50% reduction in pain) to IVIG ((0.4 g/kg/day for 5 days followed by 1.2 g/kg every 3 weeks, given as 0.4 g/kg/day). The pain reduction usually started five days after the end of the first course of IVIG and then peaked at 3-6 months.  Relapse may occur after that.

Caro, who has been treating and studying Fibromyalgia for decades, stated that he’s had more success using immune modulating treatments than using traditional approaches using  FDA approved drugs.

Post Poliomyelitis Syndrome (PPS)

Pain associated with poliomyelitis relapse decades after apparent recovery presents an interesting case for immune mediated therapies. The pain, which usually occurs in combination with muscle weakness and atrophy, and can be severe, is localized to the muscles and joints.  Neuropathic pain usually occurs in combination with nerve compression or disc herniation.

Structural components do not tell the entire story, however. Increased cytokine levels in the cerebral spinal fluid, serum and peripheral blood suggest systemic inflammation is present and may be contributing to pain.

Four studies examining IVIG effectiveness in PPS found significant reductions in CSF cytokines, reduced TNF-a levels in the blood, significant clinical improvement, increased muscle power, quality of life and/or reduced pain. Decreased pain levels were still evident a year after treatment in one study.

One of the authors reported 35% of PPS patients experienced a greater than 50% reduction in pain

Complex Regional Pain Syndrome (CRPS)

CRPS is one of the most painful disorders known. We saw in a recent blog that autoimmune processes appear to play a significant role in some CRPS patients.

An open-label trial of low-dose IVIG (0.5g/kg) found that 3/11 CRPS patients received >70% pain relief – an astounding feat in CRPS – after repeated treatments. Six of eleven received no benefit.  The pain, unfortunately, returned to baseline levels within three months.

wow!

Long term use of IVIG completely eliminated CRPS in some patients

In a small follow up trial three patients who had received >30% relief continued on a weekly maintenance dose (0.5g/kg or 1g/kg). Not only did two of the three patients experience ‘profound and sustained pain reduction” during the 3-12 months they were on the drug, but both remained in remission 12 months after the termination of the treatment.

Given the successes the following “Liverpool” protocol was suggested in CRPS:

  1. Patients should first be treated with an intravenous loading dose of 0.5 g/kg; if >40% pain relief is achieved, patients should—commencing 2 weeks after the loading dose—be offered
  2. a trial of 6–12 months of low-dose maintenance treatment; either 0.5 g/kg/month divided into weekly portions (or even smaller portions if a “push technique” is used instead of a pump) for subcutaneous therapy, or 0.5 g/kg every 3 weeks intravenously
  3. after 3–6 months an attempt should be made to halve these doses,
  4. after 6–12 months an attempt should be made to stop treatment.

A multicenter trial examining the efficacy of long term IVIG use in CRPS is currently underway in the UK.

Diabetic Polyneuropathy

Diabetes mellitus is the commonest cause of peripheral neuropathy.  The most intense kind of peripheral neuropathy in diabetes is diabetic lumbosacral radiculoplexus neuropathy (DLRPN), an extremely painful and difficult to treat form of peripheral neuropathy.

Eighty percent of five patients with diabetic polyneuropathy responded well to IVIG with pain intensity dropping from 77/100 on the Visual Analogue Scale (VAS) to 33.  Pain reduction peaked at one to two months and one patient relapsed at seven months.

diabetic-neuropathy

Some diabetic neuropathy patients that didn’t respond to steroids – did respond to IVIG

The fact that general inflammatory markers (erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibodies) are negative in DLRPN, yet anti-inflammatory treatments may be helpful suggests DLRPN consists of a local microvasculitis.  Indeed, the reduction in pain with IVIG makes sense if ischemic damage to the nerve roots and peripheral nerves has been caused by a microvasculitis.

Some patients that responded to IVIG do not respond to the immune suppressant effects of steroids.

Distal Symmetric Painful Polyneuropathy is another form of polyneuropathy found in diabetes. Twelve patients for whom standard treatments were ineffective received either IVIg (0.4 g/kg/day for 5 days) or continued with their standard treatments.

In the five diabetic patients treated with IVIg, mean pain intensity significantly dropped and 80% of patients were responders (i.e., pain reduced by >50%).  The study was very small, but this was a far higher percentage of relief than achieved by traditional pain medications.

Autoantibody Caused Pain 

Autoantibody attack of neurons and glial cells has been definitively linked to central nervous system problems. In acquired neuromyotonia antibodies to the VGKC complex causes peripheral nerve hyperexcitability and pain symptoms similar to those found in FM (aching, cramping, shooting, lancing, or burning pains). (One study has found peripheral nerve excitability in Fibromyalgia.)

These same antibodies have been linked to pain in Morvan’s syndrome and people with idiopathic pain.  Immune therapies including IVIG and steroids have effectively reduced pain levels in some of these patients.

These findings suggest that pain in autoimmune disorders such as multiple sclerosis and neuromyelitis optica may be amenable to IVIG. The authors called the arena of autoantibody induced pain via neuronal  attack  “ripe  for investigation”.

Conclusions

“Polyvalent IgG represents a promising treatment in a number of chronic pain (neuropathic, nociceptive, and complex) conditions”

The Workshop participants propose that, in contrast to prevailing thought, that nerve or neuropathic pain may at times be immune mediated and respond well to immune therapies, in particular, antibody therapy. They note IgG is generally well tolerated with mild side effects, if any, but that costs are high (up to $8500 per protocol  in the U.S.), and insurance reimbursement for pain can  be problematic.

step-by-step

The authors hope to spark rigorous study to assess the effectiveness of IVIG and other immune therapies in treating chronic pain.

Most of the evidence for IgG use in pain comes from case studies and rigorously controlled trials are needed.  Much work remains to be done to validate these findings and at least study is underway. A successful outcome to the British IVIG study of CRPS – one of the most intractable and painful of all pain disorders – would surely open eyes.

IVIG administration appears to be successful in a subset of patients with these pain disorders.   Long term IVIG treatment has been rarely tried but has lead to complete remission in a few cases.  Future immune analyses should be able to identify those patients in pain who would benefit from immunotherapies such as IgG.

Given the poor track record of treating chronic pain, immunotherapy will hopefully be given the funding and study it needs.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Treatment Resistant Depression or Chronic Fatigue Syndrome? Child Psychiatrist Finds Success With Antivirals

September 23, 2014

A Different Kind of Psychiatrist

“I have now treated dozens of adults and adolescents who came to me with the diagnosis of “treatment-resistant depression” and instead they had Chronic Fatigue Syndrome. With proper treatment, this viral illness can be successfully controlled.”

ted-henderson

Dr. Henderson is one of the rare psychiatrists to acknowledge the role the immune system and viruses can play in producing symptoms many associate with psychiatric disorders like fatigue

Chronic Fatigue Syndrome in all its forms is difficult to treat, but one doctor in Centennial, Colorado is apparently having some success with antivirals. Dr. Theodore Henderson is not a virologist or even an infectious disease specialist. He’s a child psychiatrist – perhaps the last profession one might expect to be open to viral theories of ME/CFS or childhood depression.  (I remember Environmental Medicine specialist Dr. William Rea telling me that he could count on the fingers of one hand the number of psychiatrists who didn’t believe environmental illness was mental.)

On his website Dr. Henderson descries the DSM approach that attempts to pigeonhole patients and put them in one category or the other. Instead he tries to approach the neurobiological problems of each patient uniquely.

I approach psychiatry from a brain-based biological perspective.. Most people cannot be pigeon-holed into a single category and most psychiatric conditions are actually a range of disturbed neurobiological processes. As a result, I approach each patient, child or adult, as an individual with a unique brain.

While Dr. Henderson uses traditional approaches to treat mental  disorders, he also recognizes the role the immune system and  viruses can play in producing some psychiatric symptoms.

“More importantly, growing evidence suggests that not all psychiatric symptoms, such as anxiety, fatigue, listlessness, low mood, or poor concentration, result from intrinsic flaws in the patient’s brain. Extrinsic causes, such as infections and toxins, can cause these psychiatric symptoms. The resulting cluster of symptoms might mimic anxiety, depression and other psychiatric disorders, leading to misdiagnosis and ineffective treatment.

Certain rare autoimmune disorders can lead to the formation of antibodies against specific neurotransmitter receptors. Much more widespread autoimmune disorders, such as systemic lupus erythematosus, can lead to cognitive changes, anxiety, seizures, and mood disorders”

Dr. Henderson reported he has been effectively treating both adolescent and adult Chronic Fatigue Syndrome patients with antivirals for several years. He recently published a paper describing his results with adolescents.

The Paper

Henderson TA.  Adv Mind Body Med. 2014 Winter;28(1):4-14. Valacyclovir treatment of chronic fatigue in adolescents.
pathogens

Dr. Henderson cites Dr. Lerner’s work with antivirals and ME/CFS on his website

In the paper, Dr. Henderson first cites the low diagnostic rates for Chronic Fatigue Syndrome (20%).  Then he argues that studies suggest reactivated herpesvirus infections, particularly HHV-6, are common in ME/CFS.  Arguing – as did Dr. Brewer at the Simmaron Research Foundation’s Immunology Workshop in San Francisco – that IgM antibodies are not diagnostic in this disease, Dr. Henderson asserted that primary cell cultures in combination with antibody or PCR tests indicate HHV-6 infection rates are very high in ME/CFS.

The Antiviral Subset?

In Dr. Henderson’s experience (approximately 65 patients treated) ME/CFS patients whose illness began with flu-like onset and who have:

  • have elevated IgG levels against a herpesvirus
  • low natural killer cell activity
  • high ribonuclease activity
  • high levels of angiotensin converting  enzyme (>35)
  • high TNF-a levels
  • elevated total IgM or IgG levels

responded well to antivirals.  He undertook a retrospective chart review of 15 adolescents he had treated with valacyclovir (Valtrex) between 2007 and 2013.

Valtrex is used to treat herpes zoster and herpes simplex and, in Chronic Fatigue Syndrome, Epstein-Barr Virus reactivation. Two studies by Lerner suggest Valtrex can be effective in ME/CFS.

young-man

Many of the adolescents who responded to antivirals had been referred to Dr. Henderson for treatment resistant depression

Dr. Henderson evaluated these patients like any good child psychiatrist would: He looked for mood disorders, a history of childhood abuse, assessed their sleep quality, and reviewed their school performance. He looked for any other significant symptoms and did laboratory work.  He noted that most of them had been referred to him for having ‘treatment-resistant depression’. All experienced fatigue, low motivation, academic problems, and unrefreshing sleep. Most had tried antidepressants or other mood altering drugs without effect. They did not, however, meet the CDI self-report test for depression.

Upon further evaluation six were given a diagnosis of Chronic Fatigue Syndrome, four were given an ME/CFS diagnosis plus anxiety, and three were given a diagnosis of ME/CFS diagnosis plus mood disorders.

Eleven were receiving failing grades in at least one class, and almost half had dropped out of school.  A third were sleeping more than 12 hours a day.

Ten could remember an infectious event they didn’t recover from.  Interestingly, a third of the group reported that they had always experienced significant fatigue.

fatigued-young-woman

The fatigue levels of his young patients were incredibly high

Their self-reported fatigue levels were almost off the charts.  While ‘significant fatigue’ is indicated by a score of 39 on the Fatigue Symptom Index (FSI), their mean score was 95. Similarly, they topped out on the Fatigue Severity Scale with almost two-thirds of the participants scoring near maximum fatigue levels (56 out of a possible 63).

The doctor provided them with the option of going on Valacyclovir, noting that the published evidence that it would work was small and confined to adults, not adolescents.  They began on an oral dose 500 mg BID and worked their way up to 1000 mg BID over a couple of weeks.

Results

“The medical understanding of CFS has been impeded to a degree by the resistance to the concept  of chronic viral infections of the central nervous system.”

Almost all of the adolescents responded quickly to the antivirals. Within three months 12 out of 15 reported greater than an 80% improvement in symptoms. After 8 months 14 out of 15 adolescents reported increased energy, improved sleep, increased motivation, and “return to normal functioning”. Ten of the 14 reported a “complete resolution of fatigue” and their depressive symptoms disappeared. Five of the seven who had dropped out of school returned to school and ultimately enrolled in college.

upwards graph

Fatigue scores generally dropped dramatically in response to antiviral therapies

The changes in the fatigue self-report scores were astonishing. Mean Fatigue Symptom Index (FSI) scores for nine of the fifteen dropped from the whole group FSI score of 56 to and FSI score of 12.  Fatigue Severity Scale scores dropped from 95 to 19. All ME/CFS symptoms measured by the MFSI dropped significantly.

The impressive results bring to mind Dr. Montoya’s initial Stanford valganciclovir trial in adults (9/12 recover) and the reminder that the results of his more rigorous double blinded, placebo-controlled trial, while positive, were much less successful.  Still, Dr. Henderson has clearly experienced real success with his adolescent ME/CFS patients, none of whom had responded to other approaches.

Noting that his adolescent patients were more likely to have acute infectious onset than adults and less likely to experience depression, Dr. Henderson suggested adolescents might have more success with antivirals.

While he didn’t mention it, one wonders if late exposure to Epstein-Barr Virus is playing a major role in adolescent onset ME/CFS.  Adolescence is becoming a more and more likely time of first exposure to Epstein-Barr virus (EBV).  Early exposure to EBV (during childhood) often doesn’t cause symptoms, but as cytotoxic T-cells decline after early childhood, later exposure causes a much more virulent illness. Some researchers believe delayed exposure to EBV is behind the increased levels of autoimmune disorders seen.

As do some others in the field, Dr. Henderson, took issue with the medical community’s unwillingness to more fully investigate the impact central nervous system viruses have on a range of disorders including ME/CFS, multiple sclerosis, schizophrenia, Alzheimer’s, and Autism.

Follow-up

The average duration on the drug was over two years.  Four patients discontinued treatment after about 18 months and remained well at the time of this report. Five patients who discontinued treatment in a similar time frame, however, immediately relapsed and had to go back on the drug.

Treatment Resistant Depression = Chronic Fatigue Syndrome?

“The authors secondary hypothesis is that treatment-resistant depression may often, in fact, be CFS that has been misdiagnosed.”

Dr. Henderson proposed that a significant number of adolescents diagnosed with treatment-resistant depression actually have a form of chronic fatigue syndrome that may respond to antivirals.

question-mark

Remarkably, most of the adolescent referred to Henderson for treatment resistant depression….did not meet the criteria for it

The medical profession’s eagerness to diagnose adolescents experiencing severe fatigue with depression was evident. Despite the fact that most of his adolescent patients did not met the DSM criteria for depression nor did they have CDI scores consistent with depression, many of them were still diagnosed with depression.  Other findings, such as low cortisol and cerebral hypoperfusion, were at odds with a depression diagnosis, yet over half the adolescents had been treated for depression and had not responded.

One is reminded of the saying that if your only tool is a hammer, everything begins to look like a nail.  But Dr. Henderson’s specialty is psychiatry.  He recognizes true depression when he sees it.

In fact, adults with inflammation-associated depression who make up perhaps a third of all cases of depression – do not respond to antidepressants either. Interestingly, a subset of depressed patients without inflammation-associated depression get worse when given anti-inflammatories. (For them some inflammation is good!)

The doctor provided a case report involving an adolescent experiencing fatigue, brain fog, and depression diagnosed with ‘treatment resistant depression’ who had failed to respond to either SSRIs or SNRIds.  Tests showed she had reduced NK cell counts and high IgG titers to EBV and HHV-6. Three months after going on 1000 mg a day of Valacyclovir she had experienced a complete resolution of all her symptoms. Three months later, after forgetting her meds on a trip to Disneyland, her symptoms quickly returned and she spent most of the vacation in bed at her hotel. One week after resuming the medication her symptoms completely disappeared again.

Dr. Henderson proposed a placebo-controlled trial be done involving seropositive (antibody positive) and seronegative ME/CFS patients. The trial should not, he emphasized, employ acyclovir, an antiviral he asserted has low bioavailability and is rapidly eliminated by the body.

Conclusion

In a retrospective case analysis Dr. Henderson reported very high response rates to Valacyclovir (Valcyte) in a small group of adolescents with ME/CFS. Fatigue and other symptoms virtually disappeared for many in the study, a significant portion of whom had been diagnosed with treatment-resistant depression.

He proposed that that many adolescents diagnosed with treatment-resistant depression may have Chronic Fatigue Syndrome.  Dr. Henderson also suggested that the high incidence of infectious onset and low incidence of depression in adolescents with ME/CFS made them good targets for antiviral therapy.

Check out Dr. Henderson’s website and blog here.

 

 

 

 

 

 

 

 

Brief Report From Dr. Prigden on the Fibromyalgia Antiviral Trial – and the Future Chronic Fatigue Syndrome One

It’s not too much to say that if successful, the Pridgen antiviral trials for Fibromyalgia would be a paradigm changer – turning FM from a poorly treated central nervous system disorder to a  disorder characterized by a (hopefully) treatable herpesvirus infection.

Is it a breakthrough? The results look good so far - stay tuned!

Is it a breakthrough? The results look good so far – stay tuned!

Pridgen’s approach is new in several ways. Not only has no one targeted herpesviruses in FM before, but the  herpesvirus Pridgen is targeting, herpes simplex virus, is one no one has connected with either FM or ME/CFS before.

Pridgen has also combined an antiviral with an anti-inflammatory (with antiviral properties).  Rumors have abounded regarding the identity or identities of the drugs, but we won’t know officially which they are until the report is made.

The fact that we haven’t had a press release by now regarding the Phase II trial has lead to some concern. (Phase two trials are typically larger trials (1-several hundred people) that further assess a treatment’s efficacy and safety. Pridgen’s Phase II trial was a large multi-center trial.)

I contacted Dr. Pridgen to see what he could say at this point. This is what he said.

  • They hope to present their research mid-Nov
  • A press release will predate that
  • The treatment was statistically significantly effective in improving nearly every primary and secondary endpoint
  • The treatment was significantly superior to placebo (p<.oo1) (not sure which  endpoints)
  • The treatment was better tolerated than placebo
  • The results in the FM trial are good enough that preliminary plans are being made for toxicology studies that will allow them to move forward on a similar Proof of Concept Phase 2 CFS (ME/CFS) trial; i.e. they’re beginning to work on a similar ME/CFS trial.
  • They will be looking for government/humanitarian funding for that.

The Earlier Video

Check out a confident Dr. Pridgen as he talks about the Fibromyalgia trial sometime around April at a local news station.

 

Conclusion

It’s going to take longer for the final results than many had hoped but the news otherwise is good.  The significant improvement in almost all the endpoints is promising (and I would say somewhat unusual).  The fact that they’re beginning preliminary planning for an ME/CFS trial suggests that the FM trial went well indeed.

Still, we won’t know how significant the significant improvements are until the press and study release probably in November.

That will be frustrating to those who want to get going on treatments now, but my understanding is that this period – prior to publication – is a delicate period in the development of any drug. If that’s true think how much more so it is for a startup company that’s going to need to raise significant funds for the  big Phase III trial.  Publicly releasing the full results and the drug combo they’ve identified this far in advance of publication would be a mistake.

For more on Pridgen’s antiviral trial check out

Big Antiviral Trial Could Usher in New Treatment Era for Fibromyalgia

 A New Approach to Fibromyalgia

Infections are a common trigger for fibromyalgia (FM), and fibromyalgia patients are experience many ‘sickness behavior’ symptoms, but we haven’t usually associated FM with viruses or immune system problems.

woman questioning

So it’s going to be Fibromyalgia that gets the really big antiviral trial ….

That’s been changing  recently. A immune biomarker has been proposed. Small fiber neuropathy - possibly caused by immune dysregulation – has been found. Dr. Dantini has been treating FM with antivirals for years.  The immune system’s starting to get some respect in FM.

Now, in a surprising twist, it’s going to be fibromyalgia rather than chronic fatigue syndrome, that’s getting the big, placebo controlled, double-blinded multi-center antiviral trial.

Last year we heard that Dr. William Pridgen in  Alabama was getting his ducks in a row for a major antiviral trial. Four weeks ago in an email exchange he confirmed that the money – $3.3 million dollars – all gathered from ‘angel investors’ is in  hand, and the four-month 143 patient trial began  in early October.

Pridgen’s Innovative Med Concepts biotech startup is producing the study.

A Different Path

The pathways researchers and doctors take to get to disorders like FM or chronic fatigue syndrome are nothing but diverse, and it’s worth taking a look at how Dr. Pridgen, a surgeon, came to fibromyalgia. (Dr. Julia Newton’s pathway to ME/CFS was through elderly people experiencing dizziness and, to her surprise, a great deal of fatigue.) Dr. Pridgen’s pathway to fibromyalgia was through the gut.

Pridgen saw a pattern emerge in his  treatment of thousands of patients with chronic gastrointestinal issues that intrigued him. A patient would get better, but then experience a stressful event that would send him/her back into the soup.  They would get better, but during the next relapse they would stay sick longer and their recovery period would be shorter. Eventually they would be sick all the time.

virus

Shorter and shorter relapses over time in his patients lead Pridgen to conclude that a virus must be involved.

The problem, he thought, had to be some sort of pathogen that was steadily increasing with every recurrence. Giving his patients antivirals helped, but problems remained. Then he found that adding an anti-inflammatory (which also had anti-viral properties) reduced their fatigue, gastrointestinal complaints, depression and anxiety markedly and improved their energy.

An observational study indicating that the combination drug approach had a 90% ‘efficacy rate’ led Pridgen to start a company, enlist investors and create the large treatment trial.

Pridgen’s theory fits glove and hand with several other fibromyalgia/chronic fatigue syndrome theories. As with Van Elzakkers’ vagus nerve infection theory for ME/CFS, Pridgen’s theory begins with a nerve loving virus that takes up residence – for life – in nerves in the sensory ganglia found across the body.

Instead of HHV6 or EBV Pridgen believes herpes simplex viruses, are the key in FM/ME/CFS. Other than a 1993 theory proposing herpes simplex virus was at play in ME/CFS, interest has been scanty. HSV-1’s ability to affect many of the genes and gene pathways suspected of playing a role in nervous system disorders such as Alzheimer’s, Parkinson’s, depression, chronic fatigue syndrome and autism, however, lead one researcher to propose it could play a role in all of them.

HSV-1 has been found in the esophagus, stomach and duodenum of the gastrointestinal system. In fact, HSV-1 was proposed to  cause ‘recurrent functional gastrointestinal disorders’ such as IBS, as far back as 1996.

Pridgen’s patent application indicates that he believes that stressors and  peptides and hormones released by the sympathetic nervous system and HPA axis  set the stage for herpes simplex-1 reactivation. Pridgen proposes that repeated HSV reactivation can  kill the sensory nerve cells ( small fiber neuropathy?) and destroy part of the nerve ganglion.  (Stress induced HSV-1 reactivation has been documented in laboratory animal studies.)

Once  these neurons and ganglia are damaged, Pridgen believes they send out signals that ultimately muck up the pain processing centers in the central nervous system. The over-generation of neurotransmitters such as glutamate, Substance P, serotonin, norepinephrine, dopamine, brain-derived neurotrophic factor (BDNF) involved in this process then causes central sensitization.

Antiviral Plus

Pridgen proposes to stop the viral reactivation and the central sensitization with antivirals; an approach that’s been tried before in chronic fatigue syndrome, but not in the way Pridgen’s doing it.

connections

Are two ‘antivirals’ better than one? We’ll find out sometime next year.

One of Pridgen’s patent applications suggests that one of his unique insights has been to combine valacyclovir (valtrex) with an anti-inflammatory, Celecoxib (Celebrex) that has antiviral properties.  Other combinations are being tested and Pridgen stated  they have not released the make-up of IMC formulation used in the trial. It’s not clear, then, what drugs at what doses were used in the study or which will prove most effective. 

Celexcoxib (Celebrex) is a non-steroidal antinflammatory (NSAID) COX-2 inhibitor usually used  in the treatment of osteoarthritisrheumatoid arthritisacute pain, painful menstruation and menstrual symptoms. It down regulates the activity of inflammation producing  cells.

Pridgen proposes that the  two drugs hit the virus at different stages of its life-cycle. Pummeling the virus with that one-two punch, he believes, will finally stop the virus from reactivating.

Pridgen and Duffy are looking for herpes simplex virus, but other herpes viruses could be affected by this treatment. We won’t know if they are until further studies are done.

Inflammation Gone Awry

Pridgen and his partner, molecular virologist, Carol Duffy will also attempt to develop a diagnostic test for fibromyalgia using cytokine arrays they believe will document high levels of  pro-inflammatory cytokines and low levels of anti-inflammatory cytokines.

Like VanElzakker, Pridgen believes the body is over-reacting to the virus.

“It’s basically exaggerating its reaction to the virus. Any little stress reactivates the virus, and, rather than the body saying, ‘Oh, this is just a virus I’ve been living with this since I was five,’ the body keeps saying, ‘Oh, my God,’ and throws on all this inflammation, and that gives these people this pain.”

“There is a theory that all pain, one way or another, is inflammation,” Duffy says. “It’s inflammation gone awry.”

Not just Fibromyalgia

Pridgen and Duffy have their eyes on more than Fibromyalgia.  Pridgen’s provisional patent proposes this treatment will work for chronic fatigue syndrome, irritable bowel syndrome, chronic pain, chronic headache, chronic neck pain, chronic back pain, chronic depression, chronic clinical anxiety disorder, post-traumatic stress disorder (PTSD), brain fog, cognitive dysfunction and chronic interstitial cystitis.

Celebrex – The Antiviral?

We don’t hear anything about Celecoxib as a virus fighter in ME/CFS, but some evidence suggests it could be efficacious against herpes simplex virus. The ability of COX-2 inhibitors to decrease prostaglandin production is believed to push the immune system towards a Th1 (antiviral) response and away from the Th2 response often found in ME/CFS.

stop sign

Pridgen believes Celexicob’s antiviral properties, in concert with Valtrex, will knock down the herpes viruses causing FM and ME/CFS

Celebrex was shown to reduce stress induced herpes virus reactivation in the nervous systems of mice.  Another study found that reactivation of HSV-1 in mice was associated with upregulation of COX-2 gene expression in their nerve ganglia.  HHV-6 can also induce COX-2 expression.  Both COX-1 and COX-2 are needed for viral replication.

(One mother found that VIOXX (now off the market) reduced her daughters IL-6 levels and eliminated the ‘panic attacks’  she’d experienced following a central nervous system infection.)

(Aspirin and flavanoids, vitamin E and fish oils also inhibit COX-2. The efficacy some ME/CFS patients experience from using omega-3 fatty acids could be due to antiviral effects.)

Tissue Biopsies

Along with treating the virus, Pridgen and his partner, molecular virologist Carol Duffy, will be using PCR to test for the virus, not in the blood, but in gut tissue samples.

One of the most intriguing aspects of the Pridgen-Duffy study is the search for HSV-1, not in the blood, but in the tissues. We know the Chronic Fatigue Initiative’s Pathogen study  failed to find evidence of viral infection in the blood. Now, Pridgen and Duffy are testing gut samples for herpes virus simplex in their study.

First PCR will be used to search for herpesviruses in both the control and FM gut samples. Then antibodies will be used to determine if an active infection is present.  In subsequent studies, electron microscopy will look for the herpesviruses particles themselves.

In preliminary studies 18/19 fibromyalgia patients with gut issues contained herpes simplex virus DNA in their gut tissues. No other herpesviruses were found. Immunoblot testing indicated that an active infection was present in eight of nine positive biopises.

Dr. Pridgen reported in an email they are still trying to determine  the optimum doses and cautioned everyone to wait until the results of the phase three trial are done before starting this treatment.  He also stated he feels  they are ‘very close’ to helping many people with this condition.  The results of trial will be released mid-year, 2014. 

Conclusion

breakthrough arrow

A successful trial could usher in a new era of treatment for fibromyalgia and perhaps chronic fatigue syndrome

Pridgen and Duffy’s big multi-center antiviral trial in Fibromyalgia is nothing if not exciting in its scope and approach. Pridgen’s ability to come up with over $3,000,000 in startup funding suggests he and Duffy have got some solid data backing their trial up. .

If they results are positive, Pridgen and Duffy could usher in an entirely new way of treating both fibromyalgia and chronic fatigue syndrome.