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Drug Hoped To Treat CFS Causes Impaired Immune Function

4/28/2018

Griffith Study Says:
Reports that a drug used to treat autoimmune diseases and cancer could also treat Chronic Fatigue Syndrome (CFS) have been refuted by a new Griffith University study.
To be published in BMC Pharmacology and Toxicology, the study by Griffith’s National Centre for Neuroimmunology and Emerging Diseases(NCNED) concluded that the use of Rituximab in CFS patients could incur problems with their immune cells and is not beneficial as a potential treatment.
The Natural Killer (NK) cells have vital functions in fighting viruses, bacteria and tumours.
“We found that these functions were significantly impaired when exposed to Rituximab in CFS patients,” says Scientific Co-Director of NCNED, Professor Sonya Marshall-Gradisnik.
CFS – sometimes known as ME (myalgic encephalomyelitis) – is a complex illness characterised by impaired memory and concentration, metabolic, cardiac, gut and immune dysfunction and debilitating muscle pain and fatigue on exertion (also known as neuroimmune exhaustion).
It is estimated that the prevalence rate of CFS/ME worldwide is between 1 and 2 per cent.
Related to the ion channels
The Gold Coast NCNED team has discovered the illness is related to problems in the ion channels that allow calcium into the body’s cells. Calcium is required by almost every cell in the human body and is vital in helping the immune system destroy a virus or infection.
The team has proven that patients with CFS/ME have lower levels of calcium coming into their cells, that their cells store less calcium and that this is the basis of their illness.
Professor Don Staines, Clinical Co-Director of NCNED, says: “These results are important as NK cells are already known to have impaired function in CFS patients, suggesting certain doses of Rituximab may not be beneficial for the treatment of this condition.”
“Undertaking an initial study has enabled us to secure additional research funding from the national competitive grants process from the Mason Foundation where we can now undertake a larger study using this drug in vitro to validate our novel findings,” says Professor Staines.
First author for these world-first scientific findings was PhD student, Ms Natalie Eaton. She will be presenting the study at an NCNED-sponsored conference later this year. The focus of the conference will be promoting greater understanding of pathology and pharmacothereapeutics for CFS, through a Research, Innovation, Discovery, Learning and Education (RIDLE) model.
Source: Press Release: Griffith University, March 27, 2018.

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Low dose naltrexone for chronic pain

4/28/2018

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Low-dose Naltrexone Explored as Option for Chronic Pain
Miriam E. Tucker
March 16, 2018
SALT LAKE CITY, UT — Low-dose naltrexone (LDN) holds promise for treating chronic pain associated with a wide range of conditions, including fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
In fact, pending further study, LDN might offer a low-cost, nonaddictive opioid alternative for patients with chronic pain, according to Jarred W. Younger, PhD, director of the Neuroinflammation, Pain and Fatigue Lab at the University of Alabama, Birmingham.
"Opioids work fast, but they may cause pain sensitivity when used long-term, so I think they should be used for only short periods of time. LDN lowers pain sensitivity over time, so may be a better choice for chronic pain," Younger told Medscape Medical News.
Naltrexone is an opiate antagonist currently available in a daily 50-mg tablet dose for the treatment of alcohol and opioid dependence. But in addition to opioid receptor antagonism, the drug also appears to exert anti-inflammatory effects via a separate mechanism targeting microglial cells.
Paradoxically, the dosage found to reduce pain is roughly one tenth the substance abuse treatment dose, around 4.5 mg per day. The low-dose version is not approved by the US Food and Drug Administration and must be specially compounded.
In studies of several known inflammatory conditions, including inflammatory bowel disease and multiple sclerosis, LDN reduced both self-reported pain and objective markers of inflammation and disease severity, Younger noted in a 2014 review article.
Evidence Supports LDN for Fibromyalgia, and Anecdotally for ME/CFS
At a 2-day summit held March 2 and 3, 2018, at the Bateman-Horne Center here in Salt Lake City, a panel of 13 clinicians who specialize in ME/CFS selected LDN as a top drug for that patient population, based on their clinical experience using it in their patients with ME/CFS who have hyperalgesia. The panel also placed LDN at the top of a wish list for randomized clinical trials of treatments for ME/CFS specifically.
There is currently no drug approved by the US Food and Drug Administration for ME/CFS, and treatment of the condition focuses on relief of symptoms including widespread pain. Many patients with ME/CFS also meet clinical criteria for fibromyalgia, for which LDN has shown benefit in several of Younger's studies.
Lucinda Bateman, MD, who directs the Bateman-Horne Center and chaired the ME/CFS summit, said she uses LDN frequently in her patients with fibromyalgia and those with ME/CFS for whom pain is a top complaint. "I'm totally convinced that in patients with pain amplification/hyperalgesia as their primary problem, it's great. It's as good as all the [approved fibromyalgia drugs], but cheaper."
However, she also noted, "The real unanswered question is, does LDN help cognition, fatigue, and other things related to neuroinflammation? We know that glial cells are involved in hyperalgesia, and we know LDN downregulates [microglia]. But that's not the same as downregulating everything about neuroinflammation."
Susan M. Levine, MD, an infectious disease and ME/CFS specialist in New York City, also prescribes LDN. "People think of it more for fibromyalgia, but it's definitely in our armamentarium for ME/CFS patients. I find it helps with both pain and sleep."
A typical protocol, Younger said, would be to start at 1.5 mg daily for 1 week, then titrate up to 3.0 mg for another week and then 4.5 mg daily. But as individual responses vary, it may take a bit of adjusting to find the right dose for a given patient. Some may respond better to 6.0 to 7.0 mg/day.
Levine explained that she starts at a much lower LDN dose, as low as 0.1 to 0.5 mg, as she is concerned about sensitivity in these patients.
Patients should be advised that it could take up to 2 months before they notice any changes with LDN, so they "should not give up too soon if they are not noticing beneficial effects right away," Younger noted.
Well-Tolerated, Lower Cost
Younger told Medscape Medical News that LDN is very well-tolerated in his studies, with the only common adverse effect being particularly vivid dreams in about 20% of patients. Smaller numbers have reported anxiety after taking LDN, or trouble falling asleep if they take it at bedtime.
"Everyone responds differently to medications, so patients and clinicians should track responses to any new medication carefully," he cautioned.
Although the low dosage of naltrexone used won't necessarily interact with opioid analgesics, care should be taken in combining the two, as naltrexone might block the effectiveness of hydrocodone and oxycodone.
Also, "There is also a small chance that LDN could interact with alcohol to make the person feel nauseated. After starting LDN, individuals should test alcohol before consuming a large amount," Younger advised.
As a generic medication, LDN is far less expensive than currently approved fibromyalgia drugs, at roughly $30 a month (including the cost of compounding) compared with approximately $500/month for Lyrica. In contrast, insurance doesn't currently cover LDN, as it's not yet approved for any indication.
Companies are currently working to secure US Food and Drug Administration approval for naltrexone in 1.0- and 4.5-mg versions. And in the United Kingdom, an entity called The LDN Research Trust is pushing for inclusion of LDN on the National Health Service's medical formulary list so it can be easily prescribed.
Meanwhile, Younger is hoping to conduct a clinical trial of LDN specifically for ME/CFS, but has not yet received grant money.
"So, as of now, we have no research data showing whether LDN is as effective in ME/CFS as it is in fibromyalgia. This trial is still a high priority for the lab and it needs to be conducted.... It is hard to determine from anecdotal reports whether the medication is truly beneficial. My hypothesis is that it will significantly help a good percentage of ME/CFS patients, but we cannot know for sure until a study is completed."

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Mast Cell Activation

4/28/2018

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Mast Cell Activation May Underlie 'Chronic Fatigue Syndrome'
Miriam E. Tucker
March 13, 2018

SALT LAKE CITY, UT — Mast cell activation syndrome (MCAS) may be an overlooked yet potentially treatable contributor to the symptoms of chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), say physicians who specialize in ME/CFS and its manifestations.
The subject was discussed during a 2-day clinician summit held March 2 to 3, 2018, during which 13 panelists met to begin developing expert consensus guidance for primary care and specialist physicians for the management of the complex multisystem illness ME/CFS, and to recommend research priorities.
"ME/CFS is a descriptive diagnosis of a bunch of symptoms, but it says nothing about what's causing the symptoms, which is probably part of the reason it's so hard for it to get recognition. So, the question becomes, What other pathology is driving this illness and making the person feel so ill? I think mast cell activation is one of those drivers, whether cause, effect, or perpetuator, I don't know," internist David Kaufman, MD, who practices in Mountain View, California, told Medscape Medical News.
MCAS is a recently described collection of signs and symptoms involving several different organ systems, that, as with ME/CFS itself, do not typically cause abnormalities in routine laboratory or radiologic testing. Proposed diagnostic criteria were published in 2010 in the Journal of Allergy and Clinical Immunology.
Kaufman first learned about MCAS about 5 years ago from a patient who introduced him to the published work of mast cell expert Lawrence Afrin, MD. "I spoke to him and then I started looking for it, and the more I looked, the more I found it," Kaufman said, estimating that he has identified MCAS in roughly half his patients who meet ME/CFS criteria.
Indeed, summit panel member Charles W. Lapp, MD, who recently retired from his ME/CFS and fibromyalgia practice in Charlotte, North Carolina, told Medscape Medical News, "I see a lot of this. I think it's one of the many overlap syndromes that we've been missing for years."
Another panel member, New York City ME/CFS specialist Susan M. Levine, MD, also said she sees MCAS frequently. "I suspect 50% to 60% of ME/CFS patients have it. It's a very new concept."
In Levine's experience, MCAS often manifests in patients being unable to tolerate certain foods or medications. "If we can reduce the mast cell problem, we can facilitate taking other drugs to treat ME/CFS," she said. However, she also cautioned, "It's going to be a subset, not all ME/CFS patients."
Clinical Assessment and Laboratory Testing
As discussed at the summit, for patients who meet ME/CFS criteria, the next step is to drill down into individual patients' symptoms and address treatable abnormalities. Investigation for MCAS may yield such findings among those who exhibit episodic symptoms consistent with mast cell mediator release affecting two or more of the following areas:

Skin: urticaria, angioedema, flushing
Gastrointestinal: nausea, vomiting, diarrhea, abdominal cramping
Cardiovascular: hypotensive syncope or near syncope, tachycardia
Respiratory: wheezing
Naso-ocular: conjunctival injection, pruritus, nasal stuffiness

Symptoms can wax and wane over years and range from mild to severe/debilitating. It is important to ask about triggers, Kaufman advised. "The patient is usually aware of what makes them feel worse."

Routine laboratory assessments include complete blood count with differential, complete metabolic panel, magnesium, and prothrombin time/partial thromboplastin time.
More specific laboratory testing can be tricky, as the samples must be kept cold. These include serum tryptase, chromogranin A, plasma prostaglandin D2, histamine, heparin, a variety of random and 24-hour urinary prostaglandins, and urinary leukotriene E4.
For patients who have had a prior biopsy, the saved sample can be stained for mast cells.
Kaufman said that initially after he learned about MCAS, he would only run the laboratory tests in patients with suggestive clinical history, such as food sensitivities/triggers, rashes, hives, temperature intolerance, or chemical sensitivities. "But ultimately, I had patients [for whom] I couldn't figure out what was going on; I would check, and started finding positives in patients I wasn't suspicious of."
So, now he just tests for it in all his patients with ME/CFS. "It's bigger than allergy," he remarked.
Treatment May Ease Some ME/CFS SymptomsTreatment of MCAS involves trigger avoidance as possible; H1 receptor antagonists such as loratadine, cetirizine, or fexofenadine (up to double the usual doses); H2 histamine receptor antagonists including famotidine or ranitidine; and mast cell membrane-stabilizers such as cromolyn sodium. Slow-release vitamin C can also help in inhibiting mast cells.
Over-the-counter plant flavonoids such as quercetin also may be helpful, typically at high doses (up to 1000 mg three times daily). "There's a long list of medications that either quiet down mast cell activation or block the receptor," Kaufman noted.
But despite that, without controlled trials, it is difficult to determine the exact clinical effects of blocking mast cells, especially as these patients tend to be taking many other medications. And in the context of ME/CFS, the extent to which suppressing mast cell activity addresses the core symptoms of fatigue, postexertional malaise, orthostatic intolerance, and cognitive dysfunction is unclear.
Kaufman noted, "I think treatment clearly helps with the fatigue because they're not reacting to everything. It improves gastrointestinal symptoms, so they can eat better.... I have seen [postural orthostatic tachycardia syndrome] improve, but I have to say I also give meds for dysautonomia, so I can't be sure."
Lapp said that in his experience, "[Patients with ME/CFS] aren't cured, but do get better. [Blocking mast cell activity] gets rid of dizziness, fatigue, nausea, and light sensitivity."
Levine pointed out, "We're just at the beginning of identifying this patient subset and thinking what makes sense to try.... One thing that's sure is that the drugs are pretty safe," she said, adding that when it comes to working up patients with ME/CFS for MCAS, "There only seem to be good things that can happen."
Kaufman, Lapp, and Levine have disclosed no relevant financial relationships.

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Bateman Clinicians' Summit

4/28/2018

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Much Can Be Done to Ease 'Chronic Fatigue Syndrome' Symptoms
Miriam E. Tucker March 12, 2018

SALT LAKE CITY, UT — The illness commonly known as chronic fatigue syndrome is complex and currently incurable, but clinicians can still do a great deal to manage symptoms and improve patients' quality of life, experts agree.
In a 2-day meeting held March 2 and 3, 2018, specialists in the condition, now termed myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), met to discuss their assessment and treatment approaches. The aim of the "summit," organized by Lucinda Bateman, MD, and held at her Bateman-Horne Center facility here, was to initiate development of expert consensus ME/CFS guidance for primary care and specialist clinicians, and to identify research priorities to address major knowledge gaps.
"One of the messages I'd like to send to physicians is not to have an all-or-nothing approach to this illness, but to break it down into its parts, and see what you can get hold of with the history, objective markers, and clinical intuition. And then, it's not unreasonable to try some things that are not harmful or expensive," Bateman told Medscape Medical News.
The 13 panelists, who hail from primary care, infectious disease, immunology, neurology, endocrinology, pediatrics, and integrative medicine, discussed and prioritized elements of history-taking, physical exam findings, diagnostic tests, and treatment approaches for each of the illness' major components. The core features include fatigue, impaired function, postexertional malaise, sleep dysregulation, neurocognitive impairment, and orthostatic intolerance; other commonly reported features are widespread pain, immune dysregulation, and infection.
Panel members focused on approaches they have found to be most helpful and that can be accomplished in primary care, as well as more advanced modalities that would be more feasible in specialty practices.
Assessing the Illness
The document the group produces will endorse the 2015 Institute of Medicine diagnostic criteria, which define ME/CFS as 6 months of unexplained fatigue with substantial functional impairment, postexertional malaise, unrefreshing sleep, and either cognitive dysfunction or orthostatic intolerance. The symptoms must be moderate to severe and present at least 50% of the time. (Five summit participants, including Bateman, were on the writing committee for that report, and three others served as reviewers for it.)
Assessing functional capacity is key, Bateman said. "It's an illness that impairs people's ability to function in their daily lives. Clinicians need to ask about function, and what happens when people exert themselves both physically and cognitively."
One revealing question is, "What would you be doing now if you weren't ill?" Typically, as opposed to depressed patients, those with ME/CFS will have a laundry list. "Our patients are trapped in bodies that don't work," Bateman said. "They're desperate to do more."
Laboratory tests such as complete blood count with differential, complete metabolic panel, erythrocyte sedimentation rate and C-reactive protein, antinuclear antibody, rheumatoid factor, lipid panel, thyroid-stimulating hormone, and celiac screen should all be performed to investigate symptoms, but are often unhelpful. (As reported previously by Medscape Medical News, evidence suggests that the inflammatory cytokines involved in ME/CFS are different from those that induce C-reactive protein.)

In contrast, assessments that often yield valuable information in patients with ME/CFS include evaluation for orthostatic intolerance and autonomic dysregulation (ideally via tilt-table, but also can be accomplished with the 10-minute "Lean" test), and laboratory tests for Lyme immunoglobulin G (IgG) and IgM; lymphocyte subsets; IgG subclasses; Epstein-Barr virus, including early antigen antibody; herpes viruses; urine or serum markers of mast cell activation syndrome; small intestinal bacterial overgrowth; and natural killer cell function (almost universally low in patients with ME/CFS).
Brain imaging with magnetic resonance imaging or electroencephalography may be indicated in patients who exhibit "brain fog," headaches, or other neurocognitive symptoms.
"A lot of the testing we do is the differential diagnosis, and we're looking for comorbid conditions, treatment targets, and subgroups, like people with [small intestinal bacterial overgrowth] or mast cell activation. In the clinical setting, we don't have to make sense of it all. We just have to identify it, and see if the patient responds to treatment," Bateman said.
Panel member Charles W. Lapp, MD, who recently retired from his ME/CFS and fibromyalgia practice in Charlotte, North Carolina, told Medscape Medical News, "We use most tests for exclusionary purposes. We don't want to miss something that's treatable."
But, he added, some tests are for conditions that often accompany ME/CFS and exacerbate the symptoms. For example, for patients with high Epstein-Barr virus early antigen antibody titer, "if we can reduce that viral load, it might make the patient feel better. We don't know if its treating ME/CFS per se, but it's reducing the perpetuators, and that might make a difference."
Treatments Aimed at Symptom Relief
There is currently no US Food and Drug Administration-approved drug for ME/CFS, so treatments need to be individualized and directed toward the patient's most troubling illness manifestations and symptoms.
Medications that were endorsed by a majority of the panel include low-dose naltrexone for patients with pain and cognitive dysfunction, low-dose beta blockers or fludrocortisone for those exhibiting orthostatic intolerance, and intravenous Ig for patients with a variety of immune dysfunction indications including low IgG or IgA or recurrent infections.
Also universally viewed as critical for primary management of ME/CFS is the concept of adaptive pacing. With it, patients learn to conserve their limited energy by carefully adapting their activity so as not to exceed their anaerobic thresholds and thereby precipitate a "crash." One helpful website to offer patients is the CFIDS & Fibromyalgia Self-Help Program website.
There was also some endorsement among panel members for, but less agreement about the optimal use of, interventions such as antivirals or antibiotics, methyl folate for patients with methylenetetrahydrofolate reductase mutations, and immune modulators for low natural killer cell activity and other identified immune dysfunctions.
In general, much of the approach involves thinking outside the box, and sometimes borrowing from other fields, Bateman said. For example, she points to data suggesting that amantadine may improve fatigue and cognition in multiple sclerosis. "There's no reason we can't give [patients with ME/CFS] a trial of amantadine. Just making these cross-connections is very helpful."
Panel to Call for Randomized Trials of Biological Treatments
Panel members are well aware that not only are the products they use not approved by the US Food and Drug Administration for ME/CFS, but many are supplements that aren't even regulated by the administration. Part of the summit's deliverables will be a call for addressing that deficiency via randomized controlled clinical trials, according to the organizers.
"Very few treatments have been rigorously studied in ME/CFS," summit comoderator Anthony Komaroff, MD, professor of medicine at Harvard Medical School in Cambridge, Massachusetts, told Medscape Medical News. "For one thing, with drugs that are off patent, it is hard to find funding to test off-label use. And with drugs still on patent, pharma needs some empirical evidence of benefit before investing in pursuing a new indication for use, and collecting such evidence takes money.... So clinicians are left to trying treatments that are unproven, but for which there is a plausible rationale for their use, and little chance of harm."

Notably missing from the recommended treatment list are cognitive behavioral therapy aimed at overcoming "false illness beliefs" and "graded exercise." (A trial published in 2011 suggested those interventions were helpful, but it has since been faulted by the ME/CFS community because of its patient selection criteria and methodological issues.) The summit panel voted unanimously to include a statement rejecting those modalities as inappropriate and potentially harmful.
What Does the Patient Need?In addition to treatments, patients with ME/CFS very often have other critical needs. Some will require disability verification, for which 2-day cardiopulmonary exercise testing may be necessary to prove impairment in function and postexertional malaise. Patients with ME/CFS will show distinct abnormalities on the second day of 2-day cardiopulmonary exercise testing, but several panelists said they believe that it's too taxing for patients to be used in routine clinical assessment.
Other patient needs may include disability parking permits, home healthcare, equipment such as canes or wheelchairs, and social services such as Meals on Wheels for those living alone.
Several panel members expressed concern about the future for patients who lack sufficient social support, and for adult bedbound patients being cared for by aging parents. One physician described a Munchausen case in which a healthy school-aged child was faking illness to stay home and care for her mother, who was disabled with the real illness ME/CFS.
Validating the Patient's ExperienceOf course, all of this requires that the clinician accept and communicate to the patient that ME/CFS is real, despite the lack of clarity about its etiology, Komaroff noted. "There is a literature of over 9000 publications that says this has a biological underpinning. It's not imaginary, and it's not fabrication."
He continued, "People don't understand how devastating it can be to be really sick and for people to not believe you. The personal invalidation that people with this illness have experienced...the spouse, the parent, the employer who at first are sympathetic, but when three doctors in a row say there's nothing wrong, patients begin to see their support systems in danger."
And, Komaroff added, "The importance of clinical validation to the patients, in my experience, has been enormous, even when you follow it by 'I'm going to do everything I can, but I can't promise that I'm going to be able to make you feel better.' "
Indeed, Bateman said of the panel's work, "I want to take the knowledge that we have and make it impossible for people to turn away from this disease."

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