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
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