Markedly disturbed immune signature in CSF with a shift towards a pattern associated with autoimmunity in ME/CFS

@ nature.com; 31 march 2015:

  Molecular Psychiatry , (31 March 2015) | doi:10.1038/mp.2015.29

  Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome

  M Hornig, G Gottschalk, D L Peterson, K K Knox, A F Schultz, M L Eddy, X Che and W I Lipkin

  Myalgic encephalomyelitis/chronic fatigue syndrome is an unexplained debilitating disorder that is frequently associated with cognitive and motor dysfunction. We analyzed cerebrospinal fluid from 32 cases, 40 subjects with multiple sclerosis and 19 normal subjects frequency-matched for age and sex using a 51-plex cytokine assay. Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment. Network analysis revealed an inverse relationship between interleukin 1 receptor antagonist and colony-stimulating factor 1, colony-stimulating factor 2 and interleukin 17F, without effects on interleukin 1α or interleukin 1β, suggesting a disturbance in interleukin 1 signaling. Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity.

Psychiatrist Dr Henderson: ME/CFS: in 85% (92% in adolescents) symptoms resolve in 3-5 months on valacyclovir

Theodore Henderson, MD, PhD, March 25, 2015:

A recent consensus review on Chronic Fatigue Syndrome (CFS) and Myalgic Encephalomyelitis (ME)1 concluded that CFS/ME is significantly underdiagnosed and that the condition is likely caused, in part, by viruses. These findings are in line with my clinical work. Together, these two sources of data point to a pathway which may help the 2.5 million sufferers of this disease in the United States.

In February, the Institute of Medicine (IOM) completed its committee review on CFS/ME. This study was sponsored by the Department of Health and Human Services, the National Institutes of Health, and the Centers for Disease Control, among others.1

A comprehensive literature review and critique was completed by the Agency for Healthcare Research and Quality in December  as part of this process.2 Many important advancements in the medical conceptualization of CFS/ME are included in this 282 page document.

Perhaps the most important evolutionary step was the clear message delivered on page 15 of the introduction: CFS/ME is underdiagnosed and misunderstood. More than 80% of patients go undiagnosed, while 65% of patients spend more than a year seeking the correct diagnosis. A lack of understanding of this disorder has contributed to many patients feeling maligned, blamed, and undertreated.

Some patients told the committee that they felt belittled, dismissed, and ignored by their health care professionals. Patients also have reported that some treatment strategies, including the oft-cited graded exercise regimen, exacerbated their symptoms.3

Equally striking in this report was the clear assertion that CFS/ME likely has an infectious etiology and that viruses, in particular Epstein-Barr virus (EBV), are high on the list of suspected agents.1

My clinical work has focused on the viral and immunological pathogenesis of CFS/ME. In my clinic, I have treated over 200 adults and over 30 adolescents with what the IOM now says should be called Systemic Exertion Intolerance Disease (SEID). While I have not published my adult cases, a case series of adolescents was published last year.4 What has emerged from my work is that over 85% of patients with SEID (diagnosed by Fukuda criteria5) respond to antiviral therapy. Among adolescents, the outcome is better with 92% responding.

A critical second conclusion of my work is that a subset of patients diagnosed with depression — particularly treatment-resistant depression — actually had SEID. The adolescents in the case series were all referred for evaluation of depression or mood disorder. They all presented with marked fatigue, exertion induced malaise, brain fog, and impaired academic performance.

In addition, most reported daily naps and unrefreshing sleep.4 They had not responded to adequate trials of antidepressants and the duration of symptoms ranged from 6-96 months. There was no history of abuse or neglect, although this has been suggested as an etiology of SEID in the past.6,7 Patients completed the Children's Depression Inventory8 and the mean score was 14 (+2.83), below the typical cut-off for depression.

Patients were treated with the antiviral, valacyclovir (Valtrex), at a dose of 1000 mg twice a day. Only one patient experienced nausea and discontinued the antiviral. Improvement occurred over the course of 3-5 months. Eighty-six percent of the patients responded by 3 months, and 92% responded by 5 months. Symptoms of fatigue, exertion induced malaise, excessive sleep, napping, unrefreshing sleep, headaches, cognitive symptoms, and emotional symptoms all resolved.

The Naked Scientists: Is ME an autoimmune disease? Interview with oncologists Prof Mella and Dr Fluge

Chris Smith,The Naked Scientists, 24TH MAR 2015:

INTERVIEW

TUE, 24TH MAR 2015

Is ME an autoimmune disease?

Øystein Fluge and Olav Mella, Haukeland University Hospital, in Bergen

Chronic Fatigue Syndrome(CFS), also known as ME, affects about 1 person in 500. Sufferers describe symptoms of profound tiredness and lethargy that doesn’t improve with sleep or rest. consensus on what might be causing the condition, there are no tests to confirm the diagnosis, and nor is there a cure. But now we may be closer to understanding what causes at least some of the cases of the condition thanks to research carried out in Norway, as Øystein Fluge and Olav Mella from Haukeland University Hospital, in Bergen, explain to Chris Smith...

Øystein - We are oncologists that work mainly on lymphomas and brain tumours. But in 2004, we observed a patient with longstanding ME who got lymphoma and she experienced a totally unexpected and very marked recovery of ME symptoms after she received lymphoma treatment with cancer chemotherapy. We speculated on this case and when we met new ME patients, it was striking to learn how similar the patients were in symptoms and how they described to be previously completely healthy and often, with an abrupt start of ME after infections. So, we reasoned that B-cells could be important in a subgroup of ME patients.

Chris - When you say, B-cells, these are the white blood cells, the lymphocytes that make say, antibodies and have a memory against infections we’ve seen before, aren't they?

Øystein - Yes, but we did a small pilot case series with a single infusion of the drug rituximab which targets these B-cells to 3 ME patients and they all had a marked but transient clinical response. We published this case series in 2009.

Chris - So, you were giving these people in the course of treating their blood cancer, their lymphoma, the drug rituximab which hits and destroys B-cells in the body which are in these patients, the cancer cells. And as a side effect almost of that treatment, these people who had previously said they had disabling symptoms of ME, chronic fatigue syndrome, they got better.

Øystein - That's correct.

Chris - Olav, I was going to bring you in and say, what actually happened to these people when you did this?

Olav - The 3 pilot patients all had response to treatment and one thing we observed in these 3 patients is that we have a pattern of responses and relapses after the rituximab treatment with a lag time of several months from initial and rapid B-cell depletion until they start getting clinical responses. Such patients are also seen in established autoimmune diseases after rituximab treatment. We believe that this fits with B-cells not being produced for a period after rituximab which allows a natural degradation of autoantibodies – that is antibodies that have adverse effects on bodily functions, with the symptom improving when the antibody level drops. We really think this points at ME at least in a large subportion is an autoimmune disease. It’s also spotted that 70% of the patients with ME, they get it immediately after an infection and there's, like in other autoimmune diseases, 3 to 4 times as many women as men who get the disease. And also, a big study from the US has shown a moderate and highly significant risk of B-cell lymphoma in elderly ME CSF patients, showing that the patients may have chronically activated B-cell system. We see the same lymphoma risk also in established autoimmune diseases like rheumatoid arthritis, lupus and Sjogren’s disease.

Chris - So, putting all of this together, you get these patients who, they happen to have a lymphoma – a cancer of the blood system – but they also have chronic fatigue syndrome. You treat their lymphoma with a drug which takes down their B-cells which are the cause of their cancer. They get this pattern of, their disease recovers when the B-cells go away but with the time lag corresponding to the time it takes the B-cells to go and the antibodies to go. And then when the B-cells come back in these patients, then the symptoms come back which looks like it’s tying the two things together, doesn’t it? So, what do you think that the B-cells are doing in these people to actually make, Olav, the symptoms of chronic fatigue syndrome in those patients?

Olav - Well, we think that it is a kind of an immune response and it obviously affects some very central function in the body. We’re not at all convinced that ME is kind of inflammatory condition in the brain. Probably, more important, I think what is happening in blood vessels, we have indications that the blood vessel do not function as they should, given the dynamic flow to different parts of the body when it is needed.

Øystein - It’s like the patients have a problem in the fine-tuning or regulation of blood flow according to the demands of the tissues for oxygen and nutrients. The patients often describe they feel like running a marathon when they have done a limited exertion and they get brain fog from exertion and so on. So, our hypothesis is that the immune system somehow disturbs the fine-tune regulation of blood flow and tissues including in the brain.

Chris - Øystein, what are you now doing to try to firm this up because your initial results as you published, while very interesting are on very small numbers of patients? Obviously, we’d like to see big numbers of patients in order to make sure that this is not a statistical blip, it’s not happening due to chance, it’s real.

Øystein - To try to convince ourselves, we first did, as you say, a small randomised study which was published in 2011 with 15 patients given two infusions of rituximab and 15 patients given placebo, turn out that the 15 that got rituximab had a clinical response while 2 of the 15 in the placebo group. So, that was some kind of sign of clinical activity to us. So then we did an open label study with no placebo group, further rituximab infusion, prolonging the period with low B-cells. We gave 6 infusions of rituximab up to 15 months and then followed the patient for 3 years. So, this study is now submitted for publication but we can say that again, 2/3 had a clinical response and the response durations were much prolonged when we gave maintenance treatment. But these two studies are not designed to give a definite answer to whether rituximab works in ME. So therefore, we are now performing a larger phase III study in Multicentre in Norway with 152 patients. Half of them will receive 6 rituximab infusions during the first year and half of them will receive placebo. And then we will follow the patients for 2 years. And we hope that this study will either verify or refute if rituximab may give benefit to ME patients in a significant proportion.

Oncologists squash Mats Reimer's Wesselyan psycho blah blah

By deleder2k, 20.3.2015:

Norwegian Daily Medicine 2015.03.20 

dr. Øystein Fluge and dr. Olav Mella comments on Reimer's concern regarding the upcoming cylophosphamide study

Can ME / CFS patients respond to immunomodulatory treatment?

We conduct our study because we believe ME / CFS is a serious illness, and because we have hypothesized that sufferers may respond to immunomodulatory treatment.


Olav Mella, Kari Sørland and Olav Dahl, all at Department of Cancer, Haukeland University Hospital
Alexander Fosså, Department of Cancer treatment, Oslo University Hospital (Norwegian Radium Hospital)

On Dagens Medisin webpage (Norwegian Daily Medicine) paediatrician Mats Reimer commented on a new, open phase II study using cyclophosphamide in ME / CFS. The study was reviewed and approved without objection in the Regional Ethical Committee, a decision Reimer discredits and characterizes as "strange."

Read Reimer's article: Experimental tests and treatments for CFS / ME

If one's starting point is that ME / CFS is a psychosomatic illness, the result of psychosocial problems, or a fashion phenomenon, any intervention with drugs that may have adverse effects would be both wrong and unethical.

Why are the Cancer Department at Haukeland University Hospital working to understand ME / CFS and tentatively develop possible treatment?

Hypothesis. We work on the basis of a hypothesis: that ME / CFS in a sub-group of patients may be a variant of an autoimmune disease. The pattern of response and relapse after rituximab intervention match the response seen in other recognized autoimmune diseases. ME / CFS is often triggered by infections, there is a clear predominance of women, and that there seems to be a genetic predisposition (1)

Older ME / CFS patients have shown increased risk of B-cell lymphoma (2), especially a type (marginal zone) associated with chronic infections or with autoimmunity. Occurrence of autoimmune disease among first-degree relatives of ME / CFS patients are in our studies (3) clearly higher than in the general population. These findings are not evidence that ME / CFS is an immunological disease, but constitutes one of the reasons for our hypothesis.

NO DEFEAT. We believe the results of the conducted clinical studies with rituximab treatment strengthen the basis for further testing. Should the ongoing Norwegian, multi-centre, randomized, double-blind phase III study with rituximab versus placebo not show a treatment effect, we can assure that the medical world will know the result.

A study with a negative result will not be a defeat for us. We want to make an adequate study to clarify knowledge about a possible effect of the drug.

UNCERTAIN FINDINGS. Many studies on ME / CFS are characterized by uncertain findings. We are still looking for clear pathogenic mechanisms. It is not easy to explain the complex clinical picture patients are presenting. The first (random) observations of clinical response for patients with ME / CFS after treatment with cytostatics or rituximab in patients who had both ME / CFS and cancer have anecdotal character. Such observations may still be legitimate and lead to a hypothesis.

It is the same with the planned phase II study with cyclophosphamide. The protocol is based on the observation of clinical meaningful responses to prolonged ME / CFS disease after adjuvant chemotherapy for breast cancer, as well as observation by cyclophosphamide treatment of three pilot patients with ME / CFS - without concurrent cancer. No one knows yet whether these observations will be representative of a larger group of ME / CFS patients.

Why? Why will we perform a study of cyclophosphamide in ME / CFS?

The rationale is an acknowledgment that ME / CFS for many patients, is a highly disabling disease with a variety of distressing symptoms that deprives patients much of their lives. Many previously healthy people have suffer from a miserable quality of life and are completely deprived of the opportunity to participate in familiar and social life, education and employment.

We conduct this study precisely because we believe ME / CFS is a serious illness, and because we have hypothesized that the disease may respond to immunomodulatory treatment.

RESPONSE. With the limitations imposed by an open design without placebo group, this study does not provide heavy support for any use of cyclophosphamide in ME / CFS. The purpose of this study is to evaluate the response pattern and response rates (or lack thereof), feasibility and side effects.

Cyclophosphamide has been used in autoimmune diseases for years. Although the cumulative doses of cyclophosphamide in this study is low, one cannot with certainty exclude rare but serious side effects. Patients are therefore well informed of the aspects of the treatment and are selected with respect to the severity and duration of illness.

THE CORRECT THING TO DO. ME / CFS affects many people, perhaps 0.1-0.2 percent of the population, equivalent to 5,000-100,00 patients in Norway. The disease has major implications for the patients themselves and their families, and there are large economic costs to society. The IOM report (5) estimates the cost of ME / CFS to be 17-24 billion dollars in the US alone.

For us working in the oncology field, the contrast in attitude, investments, research and understanding of disease mechanisms in ME / CFS are striking, and we have concluded that it is appropriate to conduct clinical trials, based on our clinical observations and consequent hypotheses. We are pleased, but not surprised, that the Regional Committees for Medical and Health Research Ethics is supporting our vision.

Conflicts of interest:
• Haukeland University Hospital have sought, and partially granted, the patent for treatment principle B-cell depletion in ME / CFS. Øystein Fluge and Olav Mella named in the application as "inventors".
• When Haukeland University has applied for a patent for the use of drugs in ME / CFS, it is it is because it is important so that as many patients as possible can benefit from treatment
• Bergen Teknologioverføring, owned by Haukeland University Hospital, University of Bergen and Marine Research, points out that the copyright for the indication is necessary to get treatment implemented if further clinical trials would show that treatment has clear benefits for patients.



References:
1. Albright F, Light K, Light A, Bateman L, Cannon-Albright LA. Evidence for a heritable predisposition to Chronic Fatigue Syndrome. BMC Neurol. 2011;11: 62.
2. Chang CM, Warren JL, Engels EA. Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults. Cancer. 2012;118: 5929-5936.
3. Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, et al. Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. PLoS One. 2011;6: e26358.
4. Fluge O, Risa K, Lunde S, Alme K, Rekeland IG, et al. B-lymphocyte depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An open-label phase II study with rituximab maintenance treatment. (Under approval)
5. http://www.iom.edu/Reports/2015/ME-CFS.aspx

Original article in Norwegian: http://www.dagensmedisin.no/debatt/-kan-mecfse-respondere-pa-immunmodulerende-behandling/
Translated by Google Translate and 

deleder2k

Reduced CD2, CD4 and CD8 lymphocytes and also reduced immunoglobulin (Ig) in ME / CFS

@ PubMed:

  Med J Aust.  1989 Aug 7;151(3):122-4.Immunological abnormalities in the chronic fatigue syndrome.Lloyd AR 1, Wakefield D , Boughton CR , Dwyer JM .Author information

  Abstract The chronic fatigue syndrome is a disorder of unknown aetiology which is characterized by debilitating fatigue. Recent evidence has suggested that viruses may persist in the tissues of patients with chronic fatigue syndrome. A concurrent immunological disturbance is likely to be associated with the persistence of viral antigens. Therefore, the humoral and cellular immunity of 100 patients who were suffering from chronic fatigue syndrome and that of 100 healthy, age- and sex-matched control subjects were compared.

  This study documents the frequent occurrence of abnormalities within the cellular and humoral immune systems of patients with well-defined chronic fatigue syndrome. Disordered immunity may be central to the pathogenesis of chronic fatigue syndrome.

  In patients with chronic fatigue syndrome, a significant (P less than 0.01) reduction was found in the absolute number of peripheral blood lymphocytes in the total T-cell (CD2), the helper/inducer T-cell (CD4) and the suppressor/cytotoxic T-cell (CD8) subsets. A significant (P less than 0.001) reduction also was found in T-cell function, which was measured: in vivo by delayed-type hypersensitivity skin-testing (reduced responses were recorded in 50 [88%] of 57 patients); and in vitro by phytohaemagglutinin stimulation.

  Reduced immunoglobulin (Ig) levels were common (56% of patients), with the levels of serum IgG3- and IgG1-subclasses particularly (P less than 0.05) affected.

Scientists Successfully Remove HIV From Human Cells

BY Dan Avery:

  "Researchers at Temple University in Philadelphia have been able to destroy HIV in human cells, rather than simply suppress it, a breakthrough in the ongoing fight against HIV/AIDS.

  “It’s an important finding because, for the first time in laboratory setting, we show that the virus can be eradicated from human culture, cell culture, said Dr. Kamel Khalili, who led the research team at Temple’s Center for Neurovirology.

  “Basically [we're] converting infected cells to un-infected cells,” he explains “And that is very important because the current therapy can not eliminate the virus from cells.”

  Dr. Khalili’s team developed molecular tools that can operate on DNA and delete HIV in cells."

  more

The NewYorker: People with ME/CFS are more “functionally impaired” than those with MS and congestive heart failure

BY MEGHAN O’ROURKE, FEBRUARY 27, 2015:

  "People with ME/CFS, the report noted, are more “functionally impaired” than those with Type 2 diabetes, multiple sclerosis, and congestive heart failure—diseases that we know to be very grave indeed."

  more @ newyorker.com