Chronic Fatigue Syndrome and Rituximab

IV rituximab has been used to treat chronic fatigue syndrome. A large, well-designed new study shows it doesn’t work.


Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME or ME/CFS), is a poorly-understood condition characterized by profound fatigue and a constellation of other symptoms. The diagnostic criteria, cause, pathophysiology, and treatment have been embroiled in controversy. One hypothesis is that in a subgroup of patients it could be caused by an autoimmune disease mechanism, an immunologic dysfunction mediated by B-lymphocytes. Depleting B-cells with rituximab has been investigated as a possible treatment. Does it work? A new, large, well-designed study says no.

Research history

All the CFS/rituximab research has been done by a single group of researchers in Norway. It started when doctors Fluge and Mella observed that a patient’s CFS symptoms improved during chemotherapy for a malignancy. They speculated that it might have been due to depletion of B-cells, so they treated three CFS patients with IV infusions of the monoclonal antibody rituximab (brand name Rituxan), with good results, and published it as a preliminary case series in 2009.

Next they did a double-blind study of 30 patients, comparing IV rituximab to a placebo, IV saline. That study was represented as positive, but actually was negative for the primary end-point of self-reported symptoms at 3 months. B-cell depletion was rapid but the symptomatic response was delayed, with 2/3 of the patients reportedly showing a transient improvement after 6-10 months of followup.

In 2013 I wrote about patients from Norway with ME/CFS who were traveling to the US to have Dr. Andreas Kogelnik in San Francisco treat them with expensive IV infusions of rituximab, apparently to no avail. The protocol he was using was different from the study protocol. I was concerned that he was experimenting with patients outside of a formal study, with a drug that is known to have serious and potentially deadly side effects.

At that point, two more studies were pending, both open label and without a control group. In 2016 I wrote a followup article. One of the uncontrolled studies was still ongoing. The other had been completed. It reported “clinically significant” responses in 18 out of 29 patients. Symptoms were self-reported, and the responses were delayed. One major responder had a full relapse after 32 months and dropped out. Since there was no control group, it is impossible to interpret the significance of the findings.

Next they did an open-label study of four patients with very severe symptoms; the researchers classified all four as non-responders, and they warned against using rituximab outside of clinical trials.

The new study

Eventually they embarked on a large multicenter randomized double-blind placebo-controlled trial of151 patients. The study was published in the Annals of Internal Medicine on April 2, 2019. Dr. Fluge was the lead author. The results were negative:

B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS.

Two IV infusions of either 500 mg of rituximab or an equal volume of saline (with added albumen to ensure no visible difference) were given 2 weeks apart, followed by maintenance infusions at 3, 6, 9, and 12 months. Follow-up lasted 24 months. Subjects were aged 18 to 65 years, had had the disease for at least 2 years (or over 5 years if mild) but less than 15 years, and met the Canadian consensus criteria for diagnosis. Patients with very severe disease were excluded. All subjects were premedicated with oral acetaminophen, cetirizine, and dexamethasone to minimize the chance of reactions.

Subjects self-reported symptoms at various points using numeric scales. At baseline and between 17 and 21 months, they wore a SenseWear armband for 5 to 7 days to record physical activity as measured by number of steps. Only one patient in each group withdrew and none were lost to follow-up. In an exit poll, only 19 of the 151 patients correctly guessed whether they were in the rituximab or the placebo group. 81.8% of the rituximab group and 64.9% of the placebo group had any adverse event. 26% of the rituximab group and 18.9% of the placebo group had serious adverse events requiring hospitalization. No subjects withdrew from the study because of adverse events.

30% of each treatment group reported improvements over time in symptoms and activity levels. 10% reported sustained worsening. Response rates were better for placebo (35.1%) than for rituximab (26%). There was no difference in fatigue scores or in any of the secondary endpoints.

The authors point out the limitations of their studies (self-reports rather than objective measures, unreliable recall, limited knowledge of natural symptom variations over time, and unintended patient selection effects) and predictably, they call for more research. I’m not sure that’s warranted. The same researchers are doing a similar study on cyclophosphamide, because they observed improvement of CFS symptoms in two breast cancer patients who got adjuvant chemotherapy including cyclophosphamide.

Doctor disciplined

My correspondent in Norway tells me there is a Norwegian oncologist, Dagfinn Øgreid, who has treated 250 patients with rituximab since 2015, charging the equivalent of $25,000 US. The cost is not covered by insurance and has caused financial difficulties for patients. He disregarded the preliminary negative study results and the advice of the researchers to only use rituximab in the context of clinical studies. He says he has seen many patients get a better life. Maybe, but how can he know whether it was better because of rituximab or in spite of it? That’s the whole point of doing controlled scientific studies. Someone who prefers stories to studies doesn’t deserve the name of scientist.

The health authorities issued a warning in 2018, saying his choice of treatment seems haphazard and with poor medical reasoning. He said he would heed the warning but didn’t agree with it. 30 of his patients protested, writing letters to the authorities asking them to stop the case against him. My correspondent has been following the stories in the Norwegian press; they are not available in English. They contain reports from many of his patients who did not get better. When interviewed, Dr. Øgreid said 1/3 recover completely, 1/3 are a bit better, and 1/3 have no response. At least one patient who told him she was better reported that she subsequently relapsed and did not inform him, and a survey of his patients on a Facebook group found that hardly anyone improved, and those who did, later relapsed.

Øgreid is a controversial figure. He has been the subject of a dozen medical board investigations, with four still active. They involve prescribing rituximab for ME/CFS, experimental treatment of cancer patients with immunotherapy, prescribing large doses of antibiotics over time, prescribing large doses of benzodiazepines without seeing the patients, prescribing 12 times the recommended dose of addictive drugs, and not getting informed consent. After reading all the details in the press, my correspondent says she is shocked that he still has a license.

Conclusion: rituximab is not an effective treatment for CFS

In my opinion, we now know enough to reject any use of rituximab for CFS outside of well-designed controlled studies. Treating patients willy-nilly just because some of them seem to get better is unscientific and unethical. And I think research funds could probably be better spent elsewhere. This whole enterprise strikes me as a wild goose chase based on anecdotal observations from a single research group. It was reasonable to investigate, but they have done so and the results were negative. We need to learn much more about CFS, but isn’t it time to look elsewhere?

This article was originally published in the Science-Based Medicine Blog

Dr. Hall is a contributing editor to both Skeptic magazine and the Skeptical Inquirer. She is a weekly contributor to the Science-Based Medicine blog and is one of its editors. She has also contributed to Quackwatch and to a number of other respected journals and publications. She is the author of Women Aren’t Supposed to Fly: The Memoirs of a Female Flight Surgeon and co-author of the textbook, Consumer Health: A Guide to Intelligent Decisions.