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Three years ago I wrote about an experimental treatment for chronic fatigue syndrome (CFS): rituximab (brand name Rituxan). I was concerned that doctors who offered it, like Andreas Kogelnik, were jumping the gun by offering it before the evidence was in, and that they might be putting patients at risk.

A correspondent who has been following the CFS forums asked me to revisit this issue. She sent me links to forum posts indicating that Dr. Kogelnik is treating CFS patients with the drug, that they are not being enrolled in clinical trials, that information about results is not available, and that at least one patient may have developed a life-threatening side effect. I want to stress that I don’t have any evidence that those statements are true. These are only posts on a forum, and I have no way to verify the information. I tried to get more information from Dr. Kogelnik’s clinic, but was unsuccessful. Nevertheless, even if everything in those forum posts is false, I think the issue is serious enough to bring it to the attention of the public again. My purpose is to provide accurate information about rituximab and to get people to think about the principles involved, not to make claims or accusations or cast any blame.

What is rituximab?

Rituximab is a monoclonal anti-CD20 antibody. It destroys B cells that have the CD20 antigen on their surface. B-cells are an important component of the immune system, and depleting B-cells makes patients more vulnerable to infections. Rituximab is licensed only for a few specific indications such as B-cell lymphomas and refractory rheumatoid arthritis, although it has been prescribed off-label for a number of other autoimmune diseases. If it works in CFS, that would support the hypothesis that CFS is an autoimmune disease (though this is far from a clearly-supported hypothesis, as the primary defining characteristic of CFS is exercise intolerance).

Side effects can be deadly

Rituximab is marketed with black box warnings about a number of serious side effects that can cause death and disability. It is given intravenously; infusion reactions are common, and severe infusion reactions have been fatal. Infusions require premedication and special safety precautions. Infusion reactions occur in up to 50% of patients, usually with the first dose; they typically develop within 30 minutes to 2 hours but can be delayed for up to 24 hours. Severe mucocutaneous reactions can also be fatal. Hepatitis B virus can be reactivated. Fatal bacterial, fungal, and viral infections can occur. It can cause cardiac arrhythmias, renal toxicity, bowel obstruction and perforation, and many other side effects.

One of the most serious side effects is progressive multifocal leukoencephalopathy (PML). It is a rare and usually fatal disease caused by the JC virus. Up to 58% of the general population has been infected with this virus, and a third of the adult population has a persistent asymptomatic infection. It only becomes a problem when the immune system has been severely damaged. PML is a demyelinating disease similar to multiple sclerosis but much worse. The symptoms vary with the location of lesions in the brain; they can include clumsiness, progressive weakness, and visual, speech, and sometimes personality changes. The prescribing information for Rituximab warns that if any new neurologic symptom develops during treatment, the drug should be stopped and the patient should be evaluated for PML. There is no treatment. It is usually fatal within a few months. Survivors are left with permanent neurologic disabilities. A recent study found 231 confirmed cases of PML with rituximab and suggested it occurs far more often than has been recognized.

The evidence to date

When I wrote about this before, the evidence for rituximab in CFS boiled down to a case series of three, and one small randomized controlled trial in 2008. That RCT was negative for the primary end-point of self-reported symptoms at 3 months but 2/3 of the subjects showed a delayed transient improvement after 6-10 months of followup. The protocol in that study was not the same as the protocol Dr. Kogelnik was using.

At the time I wrote, there were two more studies pending, both open label and without a control group. One of those is still ongoing. The other has been completed. It found an improvement in self-reported fatigue scores in 64% of patients. It took an average of 23 weeks to see improvement. 14 patients had a “major response” lasting an average of 105 weeks; 4 had a “moderate response” lasting 69 weeks. 18 of the 28 subjects were the same individuals who had participated in the 2008 randomized study. Adverse events included two allergic reactions, two episodes of neutropenia, and eight transient symptom flares. One major responder dropped out after 32 months when he experienced a full relapse. Since there was no control group, it’s hard to judge what these results mean.

By the time that study was published, July 2015, the researchers had embarked on a randomized, double-blind, placebo-controlled study, and they were also conducting a small open-label study on patients with very severe symptoms. Two out of their four severe patients had experienced “a slight beneficial effect” but they had classified all four as non-responders. They warned that the treatment is experimental and they said:

We do not encourage the use of rituximab for ME/CFS outside of approved clinical trials, and this is especially important for the group with very severe disease.

All the Rituximab/CFS research has been done by a single group of researchers in Norway. I find that a bit worrisome. Their results will be more convincing if they can be replicated elsewhere.

A totally disabled patient

Whitney Dafoe was a world-traveling photojournalist until 2009 when he started to develop crushing fatigue, dizziness, GI problems, joint pain, and weight loss (down to 115 pounds on a 6 foot 3 inch frame). According to a news article his disease has now progressed to where he can no longer talk, read, eat solid food, or use the Internet, and rarely gets out of bed. Dr. Kogelnik was the one who made the diagnosis of CFS. Whitney’s father, Ronald Davis, is a researcher affiliated with Kogelnik; the research seems to be mainly focused on identifying possible biomarkers for CFS and looking for an etiology.

Whitney is featured in a video that also features Dr. Kogelnik and his Open Medicine Institute. He posts as “Whit” on the Phoenix Rising forum. In December 2012 he was able to write an articulate, coherent post. He apparently was started on rituximab by Dr. Kogelnik in January 2013 and rapidly went downhill. By April he posted “Can’t read much now…”

In September he posted a disjointed message saying he was worse since starting rituximab, and complaining of throat swelling, apnea, and sleeplessness. He says “CFS also wrse[sic]. I can’t talk. Can’t type/text enough to communicate. Haven’t had a conversation with someone in 8 months…”

By November 2013 he was no longer able to post for himself. He had his caretaker post “I am now 99.99% bedridden and can’t go to a dentist. I have serious sleep apnea that wakes me up in the night unable to breathe, and seriously disturbing my sleep…” According to more recent posts, he can’t tolerate his sister being in the room or even his partner who used to lift him from bed to stretcher; the only people who can care for him are his parents.

I want to stress again that I don’t have all the facts, but I can’t help but wonder if this unfortunate young man might have developed cognitive and other neurologic problems due to PML triggered by the rituximab. If nothing else, I think we can assume that the rituximab didn’t help him. He thinks it made him worse, and he may be right.

Comments on Kogelnik from other patients

The following are quotations from posts on the Phoenix Rising forum and I want to stress that the information in them is unverified. On the other hand, I have no reason to doubt their veracity. Please take them with the grain of salt that they deserve. Note: ME stands for myalgic encephalomyelitis, an alternate name for CFS that some people feel is more appropriate.

I am surprised they haven’t published a retrospective chart review of all ME/CFS patients they’ve treated with rituximab at this clinic. I suspect this hasn’t happened because the outcomes with this treatment are abysmal in the real world outside of the Norwegian trials and no one would be prepared to hand over $40k once they saw the numbers.

I do not believe it is a research study and it is offered to anyone that they feel is a good candidate (who is then informed of all the potential risks.)… they are charging $40k for a treatment whose efficacy has not been adequately established in ME/CFS and they have not published their outcomes despite having treated an unknown number of patients with RTX. Even a small case series would be useful so people can have some peer-reviewed information before parting with 40 grand.

the reason I started this thread is because no where on PR or anywhere else I searched could I find one single person who went to OMI and got Ritux and had a significant recovery or remission. Everyone failed or only had a short response. It could be that most of these people don’t know of or aren’t active on any ME forums like PR, but it just seemed weird to me because 67% is an impressive efficacy rate and I would’ve expected to see more.

I am a health care professional, and he attempted to push me into studies I was not interested in after risks discussed. One of drugs carried risks of death with weird virus causing movement disorder. Side effect RARE – but no thanks! Clearly he had ego involved in wanting to publish this. Does not respect the importance of patient’s role in making decisions within the context of informed consent.

Conclusion: Rituximab for CFS is, at best, experimental

The evidence that rituximab may be an effective treatment for CFS is preliminary. It must be considered an experimental treatment at this point. I can only speculate about what Dr. Kogelnik is doing, because he has not been very forthcoming with information. In interviews he talks about organizing trials, but so far he mainly seems to be trying to collect better information on CFS patients rather than putting rituximab to a fair test. He has published nothing on rituximab; PubMed lists only two studies he did on valganciclovir. I searched for his name on clinicaltrials.gov and all I found was a study on vitamin D. If he is indeed treating patients outside of clinical trials, I think that’s a very bad idea. Rituximab is a very dangerous drug: its side effects can be fatal. I don’t know for sure if Whitney was harmed by the drug; but if he wasn’t, it’s only a matter of time until someone is harmed. I hope patients will carefully consider the risks and the preliminary state of the evidence before they spend a lot of money ($40,000?) on a therapeutic trial of rituximab. I understand the desperation and the wish to try “anything” that might relieve their suffering, but clinical trials are the only way to find out if this treatment really works. If patients are treated outside of clinical trials, their experience doesn’t help advance the scientific knowledge needed to help other patients.

I hope the advice of the Norwegian researchers will be heeded: not to use rituximab outside of approved clinical trials, especially on patients with very severe disease.