By K. Kimberly McCleary, President & CEO
Drs. Fluge and Mella
A study published on Oct. 19, 2011, in PLoS ONE reports on results of a double-blind, placebo-controlled trial of the drug rituximab in CFS. A team of researchers at two institutions in Bergen, Norway, led by Drs. Øystein Fluge and Olav Mella, first observed marked recovery in a CFS patient who was treated for Hodgkin’s disease with cytotoxic chemotherapy. They followed that with a small study of rituximab, a monoclonal antibody treatment approved by the Food and Drug Administration (FDA) for five conditions: non-Hodgkin’s lymphoma (NHL); chronic lymphocytic leukemia; rheumatoid arthritis; Wegener’s granulomatosis; and microscopic polyangiitis. Rituximab (also known as Rituxan) is administered intervenously (IV) during an overnight hospital stay for monitoring according to established protocols.
In the first case series, three CFS patients were treated with rituximab on an open-label basis, meaning that the physicians and the patients knew they were administering/receiving the drug. All three patients experienced significant improvement; two of them responded within three months and the third had a delayed response, occuring 5 1/2 - 9 months after treatment. This experience led the investigators to hypothesize that B cells of the immune system might play a significant role in CFS. Rituximab works by killing B cells that have a marker called CD20 on their surface and is used to rid the body of these cells that are overactive, too great in number or dysfunctional. A new population of healthy B cells is produced by the body’s stem cells. The positive results of this small open label trial led Drs. Fluge and Mella to conduct the larger study with a more rigorous design to test the effects of the drug compared to a placebo not expected to have therapeutic benefit.
Anne Kathrine Olsen Karlsen was the first ME patient Drs. Mella and Fluge treated with rituximab. (Photo: TV2 Norway)
Thirty patients meeting the 1994 Fukuda definition for CFS were enrolled in the study. Patients were between 18-65 years of age; 80 percent were female and duration of illness ranged from 8 months to 18 years. 21 of the 30 had defined or possible infectious onset of their illness, including mononucleosis, gastroenteritis, respiratory or urinary infection or other unspecified viral infection. Subjects were carefully screened for active infections with several viruses because rituximab carries a risk of reactivating viruses when it depletes B cells needed to mount a healthy immune response, especially if faced with a viral infection. All subjects were tested using multiple assays for XMRV and MLV infection; no evidence was found. 21 of the subjects rated themselves as “stable” before the trial began; two were “improving” and seven were worsening. After the trial, the investigators compared all 30 patients’ symptoms to the Canadian clinical definition for ME/CFS. All but two met these criteria as well as the broader Fukuda criteria.
At random, half of the patients were assigned to treatment and half were assigned to receive placebo by the pharmacy, although neither the physicians, the nursing staff, nor the patients knew which individuals were receiving which infusion until after the study was completed. This is what is meant by the term “double-blinded, placebo-controlled” trial, a “gold standard” design used to minimize bias of either the physician or the patient.
Figures from the PLoS ONE paper showing fatigue scores for both groups
Each subject in the study was evaluated closely using standardized symptom instruments before the study (baseline), and at 2, 4, 6, 8, 10 and 12 months after intervention. Immune system measurements were also taken. Each subject received two IVs, given two weeks apart. Patients who received rituximab were given 500 mg/m2. Saline was used for the placebo in this study. It is unclear whether the researchers were aware that IV-saline has been used in CFS to treat orthostatic intolerance-associated symptoms with some benefit, although its long-term use can be challenging due to the potential for infection.
There were no major adverse effects reported during the study. Minor effects were noted, but none led to withdrawal from the study. Two individuals did drop out, one due to pregnancy and another to pursue an alternative therapy. Both were in the group receiving placebo, although neither knew this at the time they withdrew.
Based on the analysis of results after the investigators were “unblinded” to which subjects received treatment and placebo, there was major response for at least six weeks in 9 of 15 patients who received rituximab, compared to one who received saline. There was one more person in each group who had moderate improvement. Overall, two-thirds of the Rituximab-treated group met the criteria for lasting improvement compared to 12 percent of the placebo group. This is a statistically significant result. Only one of the responders in the rituximab group showed an “early” response pattern, while the other nine started to improve 3-7 months after treatment. The responders in the rituximab group experienced an mean duration of improvement for 25 weeks. Two patients in the rituximab group and one in the placebo group have had “lasting major responses for all CFS-related symptoms without signs of relapse, 32, 30 and 23 months after intervention, respectively.” One of the individuals who responded to placebo was also one of the two subjects who did not fulfill Canadian criteria for ME/CFS. It is possible that both the responders to the saline placebo had orthostatic intolerance; however, this was not assessed or reported in the paper.
There do not appear to be substantial differing characteristics between the responders in the rituximab group and those who did not respond. There were no apparent differences in immune testing at baseline or after treatment. There was no difference in the modest adverse events reported between the responders and the non-responders. The investigators have started a new open-label trial of Rituximab with the two initial infusions given two weeks apart and then followed with maintenance infusions at 3, 6, 10 and 15 months. This study took more than three years to complete.
The authors state that the results support the concept of CFS as an autoimmune disease. They are working to identify the target for the autoimmune process. They assert that results of their study and the measures taken “support the assumption that CFS is not primarily a mental health disorder.” Additionally, they comment that the delayed response to B-cell depletion with rituximab is “difficult to explain from a viral elimination mechanism” and that the pattern is more consistent with “gradual elimination of an autoantibody, perhaps by preferential elimination of short-lived pre-plasma cells.” They recognize that their research requires follow-up with larger studies and that the suggested mechanism may apply to specific subsets of CFS patients. While there are risks associated with rituximab treatment, the authors argue, “the persistent and often devastating symptoms of CFS and the very low quality of life in many sufferers justify the use of Rituximab in carefully evaluated CFS patients.”
The results of this study showing that two infusions of rituximab may provide durable relief from CFS are extremely encouraging. The most exciting news from the study is the possibility of disease-modifying treatment for at least some people with CFS. This study also provides support for other possible approaches to repair immune abnormalities that have been identified in CFS patients. The application of a therapy approved for two types of cancer and rheumatoid arthritis validates the seriousness of the illness and demonstrates the large unmet need for effective treatment. We hope that its promising results will spur new investment from pharma, academic and government research institutions to meet this huge need. We congratulate the team in Bergen, Norway, for pioneering this approach, for the exciting results they have produced and the hope they have generated.
Elene Naeverlid got CFS at age 16. She is one of the responders in the study. (Photo: der Spiegel Online)
We will continue to provide news about this study and will provide additional perspective and updates about its impact on the direction of research for CFS.
Media coverage of this study:
Press release by PLoS ONE (Oct. 19, 2011)
“Chronic fatigue syndrome eased by cancer drug,” by Andy Coghlan at New Scientist magazine (Oct. 19, 2011)
“Norweigan research breakthrough can solve CFS mystery,” TV2 in Norway (English translation) (Oct. 19, 2011)
“Elene cured of ME,” TV2 in Norway (English translation) (Oct. 19, 2011)
“American professor applauds research results,” TV2 in Norway (English translation) (Oct. 19, 2011)
“Cancer drug can help the chronically exhausted,” by Nina Weber at der Spiegel Online (English Translation) (Oct. 20, 2011)
“Cancer drug may also treat CFS,” by Brenda Goodman at WebMD (Oct. 20, 2011)
“Possible cause found for CFS,” News 10 (Rochester, NY) (Oct. 20, 2011)
“Hilft rituximab bei chronischem Erschöpfungssyndrom?” (Can Rituximab help CFS?) aerzteblatt.de (Germany) (Oct. 20, 2011)
“Anne was sick with ME,” TV2 in Norway (English translation) (Oct. 20, 2011)
“Will find the world’s first ME test,” TV2 in Norway (English translation) (Oct. 20, 2011)
“Rituximab proven to treat ME/CFS,” staff writer at Pharmaceutical Business Review (Oct. 21, 2011)
“ME sufferer ‘Gunnar’ was not believed, was admitted to psychiatric (ward),” TV2 in Norway (English translation) (Oct. 21, 2011)
“Hope for CFS/ME patients,” Kavlifondet (a Norweigan charitable trust supporting the research)
“B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome,” Medical News Today (Oct. 21, 2011)
“Anne Kathrine put the cancer doctors on the trail of ME treatment,” TV2 in Norway (English translation) (Oct. 22, 2011)
More stories from TV2 listed in “Media Blitz by Norway’s TV2,” by Kim McCleary at Research1st.com (Oct. 23, 2011)
“Immune system defect may cause ME,” by James Gallagher, BBC News (Oct. 24, 2011)
“Cancer drug ‘key to treating chronic fatigue’ as experts say syndrome may be caused by defective immune system,” by Claire Bates, U.K. Daily Mail (Oct. 24, 2011)
“CFS: Study supports autoimmune disease theory,” by Katie Moisse, ABC News (Oct. 24, 2011) (Note: video is from an earlier broadcast and doesn’t correspond to written report)
“Rituximab may also treat chronic fatigue syndrome,” by Brenda Goodman for Medscape (Oct. 24, 2011) (free registration required)
“Could a defective immune system cause ME?” by Jessica Laurence for AOL UK (Oct. 24, 2011)
“Immune system defect may be behind CFS,” The Pioneer (English daily newspaper published in India) (Oct. 24, 2011)
“CFS study supports autoimmune disease theory,” by Joshua Cohan, ABC News Radio (Oct. 24, 2011)
“Defective immune system causes chronic fatigue,” by Amber on Tue Pinxteren, gezondheid.blog.nl in Netherlands (English translation) (Oct. 25, 2011)
“Treatment for CFS developed from cancer drug rituximab,” ActiveQuote.com (Health insurance news for U.K.) (Oct. 25, 2011)
“Health insurance news: ME could be caused by immune system defect,” USayCompare.com (Health insurance news for U.K.) (Oct. 25, 2011)
“CFS — A treatable autoimmune disease,” by Matthew Edlund, M.D., for AOL Healthy Living and Huffington Post (Oct. 26, 2011)
“Norweigan group targets CFS via B-cell depletion,” by Cormac Sheridan for BioWorld International (subscription only) (Oct. 26, 2011)
“Rituximab in CFS: More research is needed,” by Drs. Jos WM van der Meer, Andrew Lloyd, Matthew Buckland, Alistar Miller, Dedra Buchwald and Brian Angus to the editor of PLoS ONE (Oct. 27, 2011)
“Rituxan: Re-energizing CFS,” by Michael J. Haas, Science-Business eXchange (subscription only, from Nature.com) (Oct. 27, 2011)
“Chronic fatigue syndrome treated by cancer drug,” by Chris Amos for AuthorityEmpire.com (Oct. 30, 2011)
“Solving the CFS riddle,” by Jens Helleland Adnanes for HealthCanal.com (Oct. 31, 2011)
“Medical breakthrough in ME/CFS treatment — radical improvement with cancer treatment,” Bergen Teknologioverforing (BTO, the Haukeland University Hospital’s technology transfer arm)
“Surgeon honored for best idea,” by Stine Grahamar, Bergens Tidende (Nov. 18, 2011)
List of media coverage compiled by PLoS ONE: http://bit.ly/qe6GOB
For additional information, please read “Observations on Rituximab’s Early Success,” by Gordon Broderick, Ph.D., and “Rituximab Basics with Dr. John Sweetenham” at Research1st.com. More news coverage and global impact described in these follow-up stories: http://www.research1st.com/2011/10/23/media-blitz/ and http://www.research1st.com/2011/11/03/ftdo/
Reference:
Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, et al. (2011) Benefit from B-lymphocyte depletion using the anti-CD20 antibody Rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS ONE 6(10): e26358. doi:10.1371/journal.pone.0026358
K. Kimberly McCleary has served as the Association’s chief staff executive since 1991.
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What a hopeful article. I pray that this is our answer!
Well done and thankyou for this promising and interesting research!
Can anyone tell me if lazer therapy applied to the cns could be possible, because it can be used for gallstones to break them up, and maybe it could kill off any viruses too. Gammarays have been used on cancer tumors too. Just wondering, thanks.
Love to see this research tried here in the US to see if similar results can be achieved. I’m sure there will be no lack of volunteers to sign up for the trial.
Very interesting. Let’s hope it’s the beginning of a cascade of good news.
Thanks for your analysis of the Norwegian study, it is always easier to get a grip on new developments after reading CAA’s reviews! Much appreciated.
And the research sounds really interesting, let’s hope there’s much more to come.
CAA Thank you for the easy access in finding the Story.
Research moving forward, This is stellar news for our patient population.Even if it only works for a subset.
This sounds like a significant study overall. I would like to have seen more mentioned about the adverse side effects, short and long term risks – i.e., types of effects, duration, etc. The only disconcerting portion of this piece was unfortunately the phrasing of the authors’ statement that the results “support the assumption that CFS is not primarily a mental health disorder.” Who drew the conclusion that CFS IS a mental health disorder? This statement I found particularly ignorant and insensitive, not to mention offensive. Let anyone, anywhere live with this illness one day, one week, let alone month after month and year after year and draw this “mental health disorder” conclusion. These words would not be uttered in the same sentence with CFS.
This is an exciting study with exciting results. My hat is off to the researchers and the time, money and skill invested in finding treatment for this debilitating disease. Thank you.
Hi Sharon — the full text of the article is available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0026358. Here is the section on Adverse Events:
“There were no serious adverse events or major toxicity. The complaints during infusion or the following day were mild and also reported by the placebo patients (five in the Rituximab group and four in the Placebo group). Two patients in each group reported slight worsening of CFS the first two months after intervention (Table 5). Two patients in the Rituximab group reported feeling uneasy and sleepless from 2–7 and 6–8 months, respectively, synchronous with a clear clinical response. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening from two months after intervention, in both preceding a clinical response of CFS. One patient in the Rituximab group had a five years history of major CFS symptoms, and reported some lower back pain and episodes of balanitis from 5–7 months, synchronous with improvement of his CFS-related muscle pain and headache and with improving fatigue and cognitive function. His low back pain disappeared, and after the 12 month study period his CFS symptoms have resolved further and he is at present back in full-time work 30 months after intervention.”
In spite of the reality of the illness experienced by those must live with it, there continues to be some debate (although steadily diminishing) that CFS may be a mental health disorder. It’s likely the authors included that statement in hopes of setting aside those lingering questions.
Kim,
Thank you for your reply, I very much appreciate it. Forgive the delay, I’ve experienced a setback and have not been at the computer. Time spent on these types of activities takes a toll, much the way physical exertion does. Yes, I am acquainted with the unfortunate perception by many in the medical field that CFS is something other than a physical disease process. When I first fell ill, I was hospitalized as I could barely move, talk, think. Hospital docs at first thought perhaps it was MS, MG, many things; after countless tests, I was released with the diagnosis “self limiting virus, fatigue”. I had to seek out an integrative physician to take this illness seriously and treat it accordingly. The truth is that losing one’s ability to function, sleep, work, drive a car, take care of the bare necessities of living can and naturally does contribute to a huge sense of anxiety, and other symptoms that could be construed as something other than a physical disease process. The sensitivity on my part, I believe, may be shared by many, relative to a dismissive attitude by otherwise competent medical personnel. The more light that can be shed on this punishing illness, the better. This study is impressive. How is this information disseminated to the medical community; is there an effective way to accomplish this?
Lars, no worries. I appreciate your input.
Kelly, thank you very much for your comments.
Patience is something I only believed I practiced well before! Certainly we want the finest studies done by the most capable researchers and methods developed for treatment which are safe. In this process, patience is not optional, yet at times it can be challenging to maintain a patient outlook when one’s life is slipping further and further away.
To everyone, in whatever part of the world, who is determined to pinpoint the cause(s) of this illness, and to find a cure, I cannot say in mere words in any comment section the depth of appreciation I feel. Thank you to all.
Hi Sharon,
The study authors have emphasized that these are still “early days” in this research. From the WebMD article published on Thursday, “Despite the positive results of the study, researchers stressed that it was far too early for people with chronic fatigue to seek treatment with rituximab. ‘For the time being, this is a clinical trial. It is not for routine use. We need at least one more large study, partly here and partly somewhere else, to confirm the results,’ Mella says.”
In the meantime, the WebMD article will help start to inform physicians and the broader public about this approach to treatment and will, possibly, help open their minds to the severity and reality of the illness. Here’s a link if you haven’t seen the article yet: “Cancer drug may also treat CFS,” by Brenda Goodman (http://www.webmd.com/chronic-fatigue-syndrome/news/20111020/cancer-drug-may-also-treat-chronic-fatigue-syndrome) Hopefully media coverage will continue building.
We share your determination to be impatiently patient and to accelerate the pace of top-quality research like this that points to new possibilities for ending the pain, disability, stigma and isolation of CFS. That is, quite simply, why we have narrowed our focus to research focused on objective diagnostics and effective treatments. Thank you for your words of encouragement and support.
It IS offensive to hear ppl talk about CFS in the same sentence as a mental health issue. Unfortunately, I’ve found that more docs in Europe believe this than in the US, and as these docs are from Norway, perhaps they are making this statement to improve European false assumptions about CFS. Certainly there is no excuse for docs to believe this, but it still persists. So I’m okay with the statement bc it’s further educating people (who, admittedly, should’ve known better).
This is excactly the case. In Norway there have been load voices arguing that ME is a mental illness or mental weaknes in the person – and ME-pasients have got litle to no help at all. So thats why they strongly emphazise this point. I was all in tears hearing this doctors explaining on national news about how they belive this drug works and why – just mindblowing!
And even more so this weekend – “Norway’s Directorate of Health apologises for treatment of ME patients” http://www.euro-me.org/news-Q42011-003.htm
Fantastic! An actual apology? We’d never get that in the US. VERY encouraging. Thanks for the link!
I answered another post as well, just like to add that last spring there was a study on Norwegian doctors/health workers that found that 52% of them belived ME/CFS to be a mental weakness in the person/mental illness.
And the media have also painted the picture of ME/CFS more or less as hypocondriac – mainly talking about Lightning Process, or as if ME/CFS was a stress related illness that happens to mentally weak people….
I love this doctors for making a point of their findings absolutely excludes that mentall illness can be the cause of ME/CFS! I was all in tears
and you probably guessed that I’m Norwegian 
I agree with you on all points. Those who called CFS a mental issue probably were professional medical people long since out of school before CFS became a buzzword. They never heard of it in school. They treated me with antidepressants to help me cope with the fatigue. Many times I drove over a mountainous highway to work with different levels of DUI.
Sharon,
Thanks for your comment about mental disease. I suppose this disease could drive us all crazy.
It is so wonderful to have research that we can be hopeful about.
Thank God!
Pauline
Thank you for this article. It’s so hard to put any hope in yet another discovery, though I must admit this sounds very hopeful.
Would you please answer two questions I have regarding this?
1) How might this relate, if at all, to Ampligen?
2) What’s your best speculation as to when this might be available in the U.S.?
Thank you for all you do to help make sense of this disease!
Hi Christine,
Ampligen is a very different compound than Rituximab although both are administered by IV and both act on the immune system. Ampligen requires infusions 2-3 times each week and its benefits diminish after the drug is stopped, although the length of residual benefit varies. Hemispherx has reported many times that results of the latest Ampligen study are forthcoming.
Rituximab is available in the U.S. and is approved for 5 diseases. It and other biologics have been used “off-label” to treat lupus, psoriasis, inflammatory bowel disease, uveitis, asthma, diabetes, congestive cardiac failure and multiple sclerosis. The physicians who conducted the CFS study reported above have cautioned that it’s too soon to advise CFS patients to try the drug. From the WebMD article, “Despite the positive results of the study, researchers stressed that it was far too early for people with chronic fatigue to seek treatment with rituximab. ‘For the time being, this is a clinical trial. It is not for routine use. We need at least one more large study, partly here and partly somewhere else, to confirm the results,’ Mella says.”
Thank you so much for your immediate, and very helpful response!
great news! thanks for writing on this.
although, and perhaps i will just have to look further, there is no mention of WHICH symptoms the patients had and which ones subsided. it seems that many times i am interested in news about a study or treatment or even a general story on CFIDS, it turns out that the CFS the people profiled have is not like mine. i guess i am wondering what subset of CFS folks might be helped by this treatment. those of us with mainly neurologic probs, and post-exertinal malaise of course, but no fevers, sore throats, swollen lymph nodes, aching muscles or serious fatigue? those with POTS? i’m just happy about this story but still wondering…
Hi Amy,
The full text version the paper includes all the symptom instruments they used during the trial. Basically they tracked fatigue, pain, cognitions, other symptoms and “overall CFS” symptoms. They seemed to track together in those who improved and those who didn’t. In other words, when one symptom changed, so did the others. Figure 3 shows the symptom patterns for each of the 10 Rituximab “responders.” (Try this link: http://www.plosone.org/article/showImageLarge.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0026358.g003) They didn’t report any testing for orthostatic intolerance or exercise testing. Hope that answers your questions.
Sharon:
Sharon. With all respect I really think you`re over-hyping this statement “CFS is not primarily a mental health disorder”
Who wrote that? Mella?
What (Mella & co) actually did say in Norwegian TV2 was that it is definitely time to realize that this disease have it`s roots in the immune system, and that B-cells play a central role in the disease mechanism, either direct or indirect. (It`s simply too early to conclude that B-cells are the root for this disease, because more investigation are needed)
But the clue, woow, that was pretty strong. 2/3 of the responders of Rituximab explored huge improvments in _every_ symptoms of the disease!
It`s also important to remember that this study had only 2 injections, with 2 weeks apart. A bigger study is underway where they plans to increase the medication – through more frequent injections. This study shows that autoimmunity is the case for M.E. (or cfids/cfs)
Prof. Mella also said that the need for further investigation is needed and this study definitely proved that something is very wrong with the white blood-cells (immune -system)
I`m not sure where exactly you read this statement that upset you a little Sharon. No matters where you have heard or read it from. I have listen to Professor Mella and dr. Fluge, at Norwegian TV channels, and they are so convinced about this disease have its roots in, yes exactly – the immune -system!
And these guys are extremly serious in their works!
PS! Did you note that professor in neurology Harald Nyland was involved in this paper. That is a real seal of approval for this paper, and he is the most renowned neurologist in Norway.
Best regards
Lars (Norwegian)
Hi Lars,
The comment appears in the full text of the paper. Thanks for the additional information and affirmation of this team’s commitment to carrying these results forward. Let’s be kind to one another. New information can be challenging to process, especially after the dynamic circumstances of the past several months. I hope you’ll continue to share information from Norway with our readers around the world. Thanks!
Hi Kim
I have to say its so much information about this study, and i obviously missed this part.But this is not a big issue really.
To me, is no doubt that this research team have touched something substantial in relation to the disease mechanism. Agree with you Kim, that last several mounts have been a major stress for many with subsequent disappointments. And sufferers of this horrible disease need to be to be kind to each other. I really apologies if anyone felt my post was not in that category, it was not my intention.
I think that the study expressed cautiously and virtually, probably approaching the reality, that there is still a great numbers of physicians that still doubts about the facts, that this disease clearly have its root in the biomedical part of the medicine. (but more research are needed)
Here are som translations relation to what was said in “Good Morning Norway” on TV2, of October 20. 2011. Elene, Mella and Fluge were the guests.
Here is what i feel was of particularly interest.
Elene Naeverlid got CFS at age of 15/16. She had typical symptoms including fevers, and sweats, and several to moderat affected, with compleatly lack of energy. (she used 8 years to fulfilled her high school) She become sick since she was affected by an infection back in 2001.
She is one of the responders of the first study of only 3 M.E patians, when pilotstudy started. (Every 3 had major improvements of rituximab)
When Eline got her first 2 injections, symptoms start reduce within 4 months, until symptoms were gone and she got her life back. Than the medication worked for 5 (or 6 months) and symptoms went back unfortunately.
At this point she regret that she had been part of the pilot study, because she felt it so horrible when she was healthy and then symptoms went back. She got another injection and same situation happened, about 4 – 5 months later symptoms disappeared, and she got her life back once again. Now, 3 years later she is healthy, and she got her last injections with rituximab in February 2011. (maintenance treatment 8 months ago and still no symptoms have appeared so far)
Mella and Fluge were discussed why not the 1/3 of the rituximab group did not improved. And it can be many reasons for that, like the doses (too small, maybe need for more often injections) of the medications, or the fact that this non-responders could have other parts of the immune system that were attacked. And also that other medication could make improvement for those who did not respondend for rituximab.
The need for a diagnostic tool:
Again this is a very important task, and the team feels that the answer for this key should be found in tools developing a system that captures autoimmunity. (Like in RA, Lupus or other autoimmune diseases)
Thank you
Lars
Thanks, Lars, for bringing us this information about Elene’s experience. (I included her picture from der Spiegel in the article above.) To me, one of the most exciting things is that 2/3 of the Rituximab group had a significant response, and that group was selected using only the 1994 case definition (+ no active infections and some past medication exclusions). The protocol was a “one-size-fits-all” approach, as it has to be in the double-blind study design. What that means to me is that there is tremendous opportunity to improve upon this early success, through better subsetting on the patient selection, monitoring of physical parameters, and enhanced understanding of the dosing schedule that will be gained through the open label label study now underway. It also seems worthwhile to understand the two responders in the placebo group who experienced improvement after two saline infusions. Dr. David Bell (Lyndonville, NY) has used saline infusions to help his patients who have low blood volume and/or orthostatic intolerance. There may be some patients for whom this intervention alone would provide therapeutic benefit — not just a placebo effect! We can learn a tremendous amount from this study.
It’s also encouraging that there were no serious adverse events and few side effects in the Rituximab group. All drugs and biologics carry risks and this is a potent therapy, for sure. But there is some hesitation to test medications in CFS patients because there are many treatments that CFS patients seem not to tolerate, even at below-standard doses. The reports of adverse events after Rituximab therapy need to be considered in the context in which the treatment is used. For instance, in Europe it is not the first line therapy in rheumatoid arthritis, so patients have to first be treated with TNF inhibitors and fail to improve on those. When Rituximab is given, it is given with methotrexate. The side effects and adverse events reported could be resulting from all those factors combined. In cancer treatment, patients may have had a series of other therapies (surgery, chemotherapy, radiation) before they are given Rituximab. So searching the internet for “Rituximab + side effects” can produce some worrisome results. It appears from what is reported in the PLoS ONE study that the group of 30 CFS patients were relatively treatment-naive and this may have resulted in less side effects overall. Another important thing to keep in mind overall.
Please continue to share news from Norway with us!
Very promising. If it can convince many that this is indeed the physical somatic illness that it is — that too will be huge contribution. Thank you to the researchers!! CFids Association – keep us posted!
We will! We have two more pieces about the study under way and we’ll continue to bring more information about this approach, follow-up studies, etc.
Promising research for sure. I’d also like to see replication done elsewhere and hope for a high quality study in the USA.
According to the registry at clinicaltrials.gov, there are two more trials underway at Haukeland University Hospital, but they are both open label trials, rather than double blind RCTs which are the ‘gold standard’ so to speak.
Hi Andrew,
The team in Norway is using the open label study to learn more about the dose-response to understand how to better select responders and sustain the benefits that were seen in 2/3 of the Rituximab group, but for most tapered off. The next double-blind will benefit from this enhanced look at the timing of initial doses and schedule for maintenance doses. You might be interested in this Consensus Statement for use of Rituximab in rheumatoid arthritis: http://ard.bmj.com/content/70/6/909.full.pdf. There is a lot to learn about this therapy and how its action in CFS might be different from the other conditions for which it’s been approved, and those in which it has been used off label. Nature Reviews Rheumatology has published many articles in the past two years that are very informative.
@ Sharon asked about side effects and as noted in the study, this particular group of patients did not experience any severe side effects. However there are risks. Serious adverse events, which can cause death and disability, include:
Severe infusion reactions
Cardiac arrest
Tumor lysis syndrome, causing acute renal failure
Infections
Hepatitis B reactivation
Other viral infections
Progressive multifocal leukoencephalopathy (PML)
Immune toxicity, with depletion of B cells in 70% to 80% of lymphoma patients
Pulmonary toxicity
A small number of patients with systemic lupus erythematosus have died in the context of being treated with rituximab. In some cases, reactivation of latent JC virus (a common virus that can cause progressive multifocal leukoencephalopathy) occurred in the brains of these patients. There has also been at least one case of a patient with rheumatoid arthritis who developed PML in the context of treatment with rituximab. JC virus reactivation (resulting in PML) in an immunosuppressed person commonly results in death or severe brain damage.
Rituximab has been reported as a possible cofactor in a chronic Hepatitis E infection in a person with lymphoma. Hepatitis E infection is normally an acute infection, suggesting the drug in combination with lymphoma may have weakened the body’s immune response to the virus.
Remember there are relative risk and absolute risk measures. Absolute risk is the probability that a specified event will occur in a specified population, in contrast to the relative risk of the event. Relative risk is the ratio of the risk of disease among those exposed to a risk factor to the risk among those not exposed.
That said, based on its safety and effectiveness in clinical trials, rituximab was approved by the U.S. Food and Drug Administration in 1997 to treat B-cell non-Hodgkin lymphomas resistant to other chemotherapy regimens.
Thanks, Kelly. This is important information to share. There are many articles in the literature about evaluating the safety of these biologic approaches and how to prevent the infections and other adverse events that can occur following depletion of B cells. (e.g., “Safety of biologic therapy in rheumatoid arthritis” by Robert S. Woodrick & Eric M. Ruderman, Nature Reviews Rheumatology, Oct. 11, 2011).
However, it’s also important to keep in mind that the adverse events in other diseases may result from a combination of factors. I’ll copy a comment I made in response to Lars (above) along these lines:
It’s also encouraging that there were no serious adverse events and few side effects in the Rituximab group. All drugs and biologics carry risks and this is a potent therapy, for sure. But there is some hesitation to test medications in CFS patients because there are many treatments that CFS patients seem not to tolerate, even at below-standard doses. The reports of adverse events after Rituximab therapy need to be considered in the context in which the treatment is used. For instance, in Europe it is not the first line therapy in rheumatoid arthritis, so patients have to first be treated with TNF inhibitors and fail to improve on those. When Rituximab is given, it is given with methotrexate. The side effects and adverse events reported could be resulting from all those factors combined. In cancer treatment, patients may have had a series of other therapies (surgery, chemotherapy, radiation) before they are given Rituximab. So searching the internet for “Rituximab + side effects” can produce some worrisome results. It appears from what is reported in the PLoS ONE study that the group of 30 CFS patients were relatively treatment-naive and this may have resulted in less side effects overall. Another important thing to keep in mind overall.
I recall this same situation when valgancyclovir (Valcyte) was first being proposed/tested for use in CFS. The side effect profile was very intense and it alarmed some people to think that this drug was suitable for CFS. At one meeting I attended, it was explained that the drug had been used as a “last resort” in very late state HIV disease or after organ transplant, so the adverse events needed to be viewed in that context. I try to keep that experience in mind as each new therapeutic possibility arises.
After more than ten years of suffering, I really hope this is the beginning of the end!
Kim or Lars,
Given the ethical considerations of withholding successful treatment from a given population when it is known to reduce harm, (According to FDA or other similar regulatory groups’ protocols), and assuming that larger clinical trials support these current findings, is there any anticipation of the investigators to modify future studies to be either no control, short term placebo, or strictly dosing studies? I realize this question is premature given that this is still in phase 2 clinical trials, but the drug has been approved for several other treatments, and although I am hesitant to add any fuel to the already (understandably) impatient patient population, I am curious. Thank you all! Claudia
Hi Claudia,
The team is conducting two open label studies now. One will evaluate 30 CFS patients (defined as meeting 1994 Fukuda criteria + listed exclusions) using this intervention protocol: Two infusions of Rituximab 500 mg/m2 (max 1000 mg) given two weeks apart, followed by maintenance Rituximab infusions 500 mg/m2 (max 1000 mg) at 3, 6, 10, and 15 months. (See http://clinicaltrials.gov/ct2/show/NCT01156909?term=Rituximab+AND+chronic+fatigue+syndrome&rank=2)
The second is an open label trial of 5 patients with very severe CFS (defined as meeting 1994 Fukuda criteria and meeting WHO performance status III or IV, no comorbid depression, plus listed exclusions) with this protocol: Two infusions of Rituximab 500 mg/m2 (max 1000 mg) given two weeks apart, followed by maintenance Rituximab infusions 500 mg/m2 (max 1000 mg) at 3, 6, 10, and 15 months. For up to 5 patients in the study, standard plasma exchange (one plasma volume, up to 5 treatments, during 1-2 weeks) will be performed 2-3 weeks prior to start of Rituximab therapy. (See http://clinicaltrials.gov/ct2/show/NCT01156922?term=Rituximab+AND+chronic+fatigue+syndrome&rank=1).
The study authors have emphasized that these are still “early days” in this research. From the WebMD article (see link above), “Despite the positive results of the study, researchers stressed that it was far too early for people with chronic fatigue to seek treatment with rituximab. ‘For the time being, this is a clinical trial. It is not for routine use. We need at least one more large study, partly here and partly somewhere else, to confirm the results,’ Mella says.”
I hope this addresses your question.
Yes Kim, Thanks for the info and the links!
Thanks for the information on the current studies!
I found this quite interesting. Many of us have those fatty tumors (lipomas) that are also associated with Dercum’s Disease which has a known immune system genesis. Perhaps CFIDS patients may develop a mild version of Dercum’s as a consequence of the same sort of immune system imbalance. I would like to see someone poke around for a connection between the two conditions. I just have a gut feeling about this.
FACTS ABOUT THE ME/CFS STUDY (Mella and Fluge)
Facts about ME study that offers hope to millions of people.
The study is the first of its kind and provides new hope for treatment of ME/CFS patients.
A patient with ME /Chronic Fatigue Syndrome developed lymphoma in 2001. During chemotherapy the patient experienced a dramatic improvement of all ME/CFS symptoms after six to seven weeks into treatment. Three months after cancer treatment was completed began ME/CFS symptoms to return.
The patient appealed repeatedly to the physician Fluge with questions about what improvements could result. This was the thought process of doctors Fluge and Prof. Mella to understand the mechanisms behind ME/CFS.
Pilot Study
(Elene, pictured above in the article was one of the three.)
This led then to a so-called pilot study with three patients who were treated with the antibody Rituximab. Also, these patients experienced an improvement of symptoms, but like the first patient was temporary.
The results of the pilot study was still convincing enought that cancer doctors at Haukeland University Hospital had approved a larger study with many more ME/CFS patients. This time, doctors hypothesized that B-cell depletion was an important mechanism.
http://www.tv2.no/nyheter/innenriks/helse/fakta-om-mestudien-som-gir-haap-til-millioner-av-mennesker-3519496.html
WILL DEVELOP THE WORLD`S FIRST ME/CFIDS TEST:
With financial support from the Kavli Foundation hope ME-scientists in Bergen to find biological traces of the disease. The hope is to find the world’s first ME/CFS-test.
Wednesday night revealed the TV 2 that the Norwegian researchers Olav Mella and Øystein Fluge has had a breakthrough that may solve the riddle of ME/CFS. Later that evening, it was also known that cancer doctors will now receive support from the Kavli Foundation. The scientists have signed a contract, or cooperative agreement with the Foundation, and grant will go to lab research, not clinical studies.
- Lab research is very important for us to find a biomarker. In this way we may distinguish those patients who will have the effect,and those who will not have the effect of the medicine, says Professor Fluge to TV 2
If scientists can find a biomarker, it might cause you can take a test that can tell whether you have ME/CFIDS or not.
http://www.tv2.no/nyheter/innenriks/vil-finne-verdens-foerste-metest-3615684.html
Lars
What a discussion! I have learned quite a bit here.
I’m not holding my breath, not until vast studies are done, and CFIDS sufferers are helped en masse, without severe side effects.
In my optimistic view that all scientific breakthroughs will help us in the long run, even if Rituximab does not work or is not suitable for all people with this disease, at least the findings will help to bolster the case that this is a real physical disease with real symptoms — and it will help to quell the naysayers, or as I like to call them, the CFIDS-deniers.
And in that light, it may help people with medical help, insurance, disability benefits and may cause more doctors, friends, family and employers to be more understanding.
It will surely bolster our situation to the world, including the media, which I believe all of the discussion around XMRV, true or not, helped to do also. It brought this disease out of the closet, and into the public sphere. And it can’t be hidden back in the closet now.
I have my own trepidations about this or any drug. I am one of those people described above who has had terrible reactions to medications, bad ones. And I still can’t use a lot of medications for allergies due to my own body’s reactions, or I have to use 1/3 of the recommended dosages, or just not bother.
So while I’m interested, I’ll [im]patiently wait to hear the news.
I think whatever happens that more knowledge and findings will tell the medical community that this is a real disease with organic causes and debilitating symptoms. And that the isolation forced upon us by this disease is not a choice. None of us want to retreat from other people, life’s activities, work, even fun!
Great information. Thanks.
I think they requested other countries to carry out clinical trials, too. I hope we can get that rolling.
Do they plan on carry out clinical trials for fibromyalgia ?
Hi Julie,
I have not seen anything about studies of rituximab in fibromyalgia in the news reports or listings of trials on clinicaltrials.gov.
This is great news. What I want to know is where can I have this drug prescribed NOW. Mininal side effects and a 67% success rate! After 7 years of my life being at half speed I am ready to take some risks.
If this can’t be prescribed in the US, where can I go to have it administered?
Brent,
Please see the comments above regarding side effects/adverse events.
Rituximab is approved in the U.S. for five indications:
•Rituxan (Rituximab) received U.S. Food and Drug Administration approval in November 1997 for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin’s lymphoma (NHL).
•In April 2001, a supplemental Biologics License Application was approved for Rituxan for these additional uses: retreatment of patients with Rituxan who have relapsed following initial Rituxan therapy, use of eight weekly doses (compared to original four) per course of treatment, treatment of patients with bulky disease (lesions > 10 cm).
•In February 2006, the FDA approved Rituxan for the first-line treatment of diffuse large B-cell, CD20-positive, non-Hodgkin’s lymphoma (DLBCL- a type of NHL) in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens.
•Also in February 2006, the FDA approved Rituxan in combination with methotrexate for the treatment of moderately- to severely-active rheumatoid arthritis in patients who have had an inadequate response to one or more TNF antagonist therapies.
•Additionally, in February 2010 Rituxan was approved in combination with fludarabine and cyclophosphamide (FC) for people with previously untreated and previously treated CD20-positive chronic lymphocytic leukemia (CLL).
In the United States and some other countries, physicians have legal authority to prescribe medications for off-label use. From wikipedia, “once a drug has been approved for sale for one purpose, physicians are free to prescribe it for any other purpose that in their professional judgment is both safe and effective, and are not limited to official, FDA-approved indications. This off-label prescribing is most commonly done with older, generic medications that have found new uses but have not had the formal (and often costly) applications and studies required by the FDA to formally approve the drug for these new indications. However, there is usually extensive medical literature to support the off-label use.”
Rituximab is an intravenous therapy that must be administered in a hospital or clinic setting, as Drs. Mella and Fluge did in the CFS study. It is prescribed most often by oncologists and rheumatologists experienced in its use in cancer and rheumatoid arthritis. There are several publications about off-label use of rituximab in other autoimmune and inflammatory disorders. Here’s a 2010 article about off-label use as documented in an insurance database, showing 25% of patients receiving rituximab were provided the therapy for indications other than those approved by FDA. (Van Allen et al, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3051865/?tool=pubmed)
Hope this information addresses your question.
I have been thinking about the few placebos who saw some improvement. The first thought is maybe they benefited from the increased volume. However, saline infusions would have a more immediate affect, say within a week. As Dr. Bell says, the CFS patient’s body tends to readjust and bring down the volume again.
If the people are not seeing improvement for months after the two infusions, I don’t think the increased volume is causing the affect.
Hi Tina,
There are other physicians who are surprised that the effects of saline in a small subset of CFS patients are more durable than they would expect, but it’s hard to know without more testing for orthostatic intolerance at baseline. The data for the placebo responders is in Figures S4 at the end of the paper: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0026358. It looks like for one of the placebo responders, improvement began within 4 weeks and for the other, it took 6 weeks.
Dr. Italo Biaggioni is conducting a clinical trial of saline (and other therapies) in CFS + postural orthostatic tachycardia syndrome (POTS) at Vanderbilt University. See: http://clinicaltrials.gov/ct2/show/NCT00580619?term=chronic+fatigue+syndrome+%2B+saline&rank=1 Maybe that will help de-mystify the response seen in two of the placebo-treated patients in the Fluge study.
Eight years ago I had chemo for breast cancer and this was one time I actually felt well. It was so remarkable I called Dr.Lapp to tell him about it. Sorry to say the wellness only lasted a week and then went slowly back down,this only occcured for the first two cycles of chemo and then no more but I relished every day,hour and minute of being my old self!
I have another cancer and will experience a masectomy with reconstruction and then another helping of chemo cocktails, hope for those few days of wellness again.
Hi Kim, Would these questions be for you or for your CFIDS doc representative? That was an interesting exchange to date here. I have a question about active infections and the use of Rituximab. My understanding is that most people with ME/CFS, when assessed with the best infection testing methods, do have active infections at times or all the time, of some sort: ie HHV6 A or B, EBV, Enteroviruses, etc. What are the chances of finding 30 ME/CFS patients to be negative for all relevant infections (I noticed it was just serology testing mentioned in the study which can miss a lot of infections if I understand correctly). It seems they may have still had hard-to-find and diagnose infections in the trial.
Would the rest of us be ruled out of a Rituximab Trial if these showed up, and would that make a difference in the subset that responds or the risks?
Second, My other query is: would the B cells that appear targeted with Rituximab be at all the same B cells that are involved in the autoimmune disease, Celiac Disease, which many of us also have with ME/CFS? Could there be a relationship and would Rituximab treat one illness if you had the other? Perhaps the genetic glitch in DQ2 and DQ8 in celiac disease are related to the genetic glitch reported by Dr. Peterson in Stockholm as DQ3 with the two others I now forget.
I always want to find someone who knows the science and immunology of CFS and ask them to compare it to the immune knowledge of Celiac Disease because the overlap of the illnesses is so common. Do you know who I can ask this of. Maybe one could help understand the other.
Thanks for all the work and please pass this on to whomever can best answer them.
Valerie
“The most exciting news from the study is the possibility of disease-modifying treatment for at least some people with CFS.”
I smiled as I now know that there is indeed some hope when it comes to our health. With all the improvements and addition to the world of medicine, to Plastic Surgery and even Oncology, along with the other Specializations, it’s indeed very lightening that slowly but surely, there’ll be a cure/treatment, or atleast they’re trying to find out about it.
What I’m wondering now is how can this be of effect to those with something in relevance to CFS?
Regards,
Mark
Thank you for giving me hope. I have been suffering with CFIDS for 20 years.
Pauline
can i sign in as volunteer for research rituximab, please?
CVS is destructing my life for 15 years now.
can i sign in as volunteer for research rituximab?
CVS(in dutch) is destructing my life for 15 years now.
please give me a reaction and adress where i can sign inn.
thank you!
Hi Herma,
Here is a link to the post about the phase II open-label study from clinicaltrials.gov: http://clinicaltrials.gov/ct2/show/record/NCT01156922?term=chronic+fatigue+syndrome&intr=%22Rituximab%22&rank=1