Øystein Fluge

Øystein Fluge, MD, is the Senior Consultant supervising the ME/CFS research group at the Department of Oncology and Medical Physics at the University of Bergen, Haukeland University Hospital, Bergen, Norway. He worked with Professor Olav Mella in the Norwegian Rituximab and cyclophosphamide trials employing the depletion of B cell lymphocytes in ME/CFS patients.

Dr. Fluge is a member of the Working Group which offers their expertise and resources to the ME/CFS Collaborative Research Center at Stanford University.

Rituximab work in ME/CFS

Øystein Fluge's and Olav Mella's discovery was found by accident, in that three ME/CFS patients who had B-cell lymphoma improved remarkably following treatment with Rituximab. Not only had their lymphomas improved, but all symptoms of their ME/CFS diminished with the treatment. The positive responses were delayed for up to 6-12 weeks, despite their B cells being eliminated by the drug in 2 weeks. Since that accidental discovery, a larger study has been undertaken. Initial reports were promising in that there is a positive response in 67% of the patients receiving Rituximab vs a 13% improvement in the placebo group. After the effects wore off, there was a decline in the numbers who responded to the second and subsequent infusions. The clinical trial, named RituxME, was a multicenter, phase III study. It was randomized, double-blind and placebo controlled, with 152 participants, of which half will receive treatments with rituximab and the other half will be treated with placebo (saline).

On Nov 21, 2017, Drs. Øystein Fluge and Olav Mella announced that their Rituximab trial had failed. They stated that they would focus their efforts on attempting to identify a subgroup of ME/CFS patients with an immune profile that would be responsive to Rituximab. The Drs. will publish a paper next year with the specifics of the failed trial.

The discovery of ME/CFS patients responding positively to an autoimmunity drug has radically changed how many have viewed ME/CFS, to the point that Bjørn Guldvog, the Deputy Director General of Norwegian Directorate of Health, has apologized for the way in which ME patients in Norway have been treated: "I think that we have not cared for people with ME to a great enough extent. I think it is correct to say that we have not established proper health care services for these people, and I regret that." The European ME Alliance believes that such a public apology from a governmental health agency has never occurred before.

In 2015, a second clinical trial for ME/CFS by the same group headed by Fluge and Mella, was started using the chemotherapy drug, cyclophosphamide. Called CycloME part A​, this study will involve 40 patients with moderate and severe ME/CFS and will be ongoing until January 2017. If the results indicate a clinically relevant response, i.e., an improvement in symptoms, in a minimum of 40% of the patients, the trial will move into CycloME part B and may be extended to include patients with very severe ME.

Talks and interviews

• 2011, 6th Invest in ME International ME Conference 2011 - B-cell Depletion Therapy Using Rituximab in ME/CFS - Part II
• 2012, 7th Invest in ME International ME Conference 2011 - B-cell Depletion Therapy Using Rituximab in ME/CFS - Part II
• 2013, 8th Invest in ME International ME Conference 2012 - B-cell Depletion Therapy Using Rituximab in ME/CFS - Part II
• 2015, The Naked Scientists Podcast -"Is ME an autoimmune disease?"
• 2016, 12th International IACFS/ME Biennial Clinical and Research Conference, Emerging Science and Clinical Care, Plenary Speaker
• 20 Oct 2016, Ongoing Clinical Research in the ME/CFS Research Group of the RituxME and CycloME studies"
• 26 Jan 2017, BBC Look East: Research in Norwich could offer ME/CFS breakthrough
• Jan 2017, Public talk in Norwich on ME/CFS biomedical research hosted by Institute Food Research and Invest in ME Research
• Jan 2017, TV 2 Nyhetskanalen interview about ME/CFS and Dr. Øystein Fluge's latest research (with English subtitles)
• 29 Sep 2018, Keynote Address: Clinical Trials and Metabolic Features of ME/CFS, given at Second Annual Community Symposium on the Molecular Basis of ME/CFS, sponsored by Open Medicine Foundation - (Video)

Notable ME/CFS Studies

• 2011, Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study - (Full text)
• 2015, B-lymphocyte depletion in myalgic encephalopathy/chronic fatigue syndrome. An open-label phase II study with rituximab maintenance treatment - (Full text)
• 2016, Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome - (Full text)
• 2016, Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome. - (Full text)
• 2016, Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. The study abstract states: "The association of autoantibodies with immune markers suggests that they activate B and T cells expressing β adrenergic and M acetylcholine receptors. Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS."
• 2018, Immunosignature Analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - (Full text)
• 2018, Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome - (Abstract)
• 2019, B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial - (Full text)
• 2019, Searching for Serum Antibodies to Neuronal Proteins in Patients With Myalgic Encephalopathy/Chronic Fatigue Syndrome - (Full text)
• 2020, Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - (Full text)
• 2020, Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study - (Full text)

See also

• CycloME
• Olav Mella
• RituxME

Learn more

• 2015 Fluge & Mella’s pre-trial study highlights life-changing potential of rituximab

See myalgic encephalomyelitis.

See chronic fatigue syndrome.

B cell B lymphocyte, or a type of white blood cell, which is involved in the immune response by secreting antibodies to ward off infections. In mammals, they are mostly matured in the bone marrow.

B cell B lymphocyte, or a type of white blood cell, which is involved in the immune response by secreting antibodies to ward off infections. In mammals, they are mostly matured in the bone marrow.

phase three Last phase of clinical trials before a drug can be approved for public use. Whereas Phase one assesses basic safety, and Phase two assesses basic efficacy, Phase three uses many trial participants to fully assess both safety and efficacy, and overall benefit/risk.

double blinded trial A clinical trial is double blinded if neither the participants nor the researchers know which treatment group they are allocated to until after the results are interpreted. This reduces bias. (Learn more: www.nottingham.ac.uk)

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

phase two A trial involve patients to assess side effects and effectiveness for a particular clinical condition. Typically 100-300 patients.

An alternate term that is sometimes used for myalgic encephalomyelitis, by people who believe the evidence for inflammation in ME is insufficient. This terminology reflects the belief that the "-itis" suffix implies inflammation.

myalgic encephalopathy An alternate term that is sometimes used for myalgic encephalomyelitis, by people who believe the evidence for inflammation in ME is insufficient. This terminology reflects the belief that the "-itis" suffix implies inflammation.

myalgic encephalomyelitis (M.E.) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.

serum The clear yellowish fluid that remains from blood plasma after clotting factors have been removed by clot formation. (Blood plasma is simply blood that has had its blood cells removed.)

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

myalgic encephalopathy An alternate term that is sometimes used for myalgic encephalomyelitis, by people who believe the evidence for inflammation in ME is insufficient. This terminology reflects the belief that the "-itis" suffix implies inflammation.

myalgic encephalomyelitis (M.E.) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

β / Β. Greek letter beta (a symbol used in science), equivalent to "b".

β β / Β. Greek letter beta (a symbol used in science), equivalent to "b".

Involving the neurotransmitter acetylcholine. Cholinergic side effects include diarrhea, blurred vision, decreased intraocular pressure, contricted pupil in the eyes, sweating, increased saliva and mucus on the lungs, bronchial constriction, increased gastrointestinal tone, decreased blood pressure, slow heart rate, and contraction of bladder detrusor muscle. muscle spasms/cramps, low blood pressure, slowed heart rate, nausea and vomiting, increased saliva and sweating, shortness of breath, and urinating more often.

cholinergic Involving the neurotransmitter acetylcholine. Cholinergic side effects include diarrhea, blurred vision, decreased intraocular pressure, contricted pupil in the eyes, sweating, increased saliva and mucus on the lungs, bronchial constriction, increased gastrointestinal tone, decreased blood pressure, slow heart rate, and contraction of bladder detrusor muscle. muscle spasms/cramps, low blood pressure, slowed heart rate, nausea and vomiting, increased saliva and sweating, shortness of breath, and urinating more often.

autoantibody An antibody that works against the body's own antigens, a hallmark of autoimmune diseases. Autoantibodies are the opposite of an antibodies.

T cell A type of white blood cell which is mostly produced or matured in the thymus gland (hence T-cell) and is involved in the adaptive immune response on a cellular level. Also known as a T lymphocyte. (Learn more: www.youtube.com)

myalgic encephalomyelitis (M.E.) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.