Dr. Gordon Broderick
By Gordon Broderick, Ph.D.
Associate Professor, University of Alberta
The news coming out of Norway this week regarding phase II clinical trials for treatment of CFS symptoms with rituximab [1] (marketed as Rituxan) is certainly encouraging. I would add that the apparent success of this approach might not be all that surprising.
As mentioned by the authors, Rituximab is a B-cell suppressor used in the treatment of non-Hodgkin’s lymphoma. Abnormal B cell activity has long been suspected as playing a key role in CFS. As early as 2006, Maes and colleagues [2], in one of several related works, presented evidence of increased IgM antibodies directed specifically at cellular products of oxidative and nitrosative stress. The same year, our work with Dr. Suzanne Vernon and her colleagues also produced evidence of sustained oxidative stress in circulating immune cells based on their gene expression [3].
Figure from Nature Reviews Rheumatology, Taylor and Lindorfer. Rituximab-opsonized B cells are subject to attack and killing by at least three pathways.
The immune system is also the body’s maintenance and clean-up crew, so it is not outlandish to think that a corresponding immune response would be mounted to recycle these cellular products. Coincidentally, Epstein-Barr virus (EBV) among other viral pathogens is a known promoter of oxidative stress [4] and this pathogen alters B cell status through this and other means. Once subjugated, B-lymphocytes also serve as a reservoir for sustained latent infection in EBV.
Consistent with this, evidence of altered status in the B-lymphocytes of CFS patients was found in a study of gene expression conducted by our group [5] in collaboration with the CFIDS Association of America with Dr. Vernon as a co-author. Further work supported by the Association and the National Institutes of Health conducted with Drs. Nancy Klimas and Mary Ann Fletcher of the University of Miami documented immune signaling patterns suggestive of an over-active Th2 or B-cell mediated immune response in a cohort of 50 female CFS patients [6]. Both of these studies were cited in the report published by the Norwegian team.
In a nutshell, these positive clinical trial results are not only welcome but they represent a logical continuation of a line of investigation that has been ongoing. Although significant symptom relief was obtained in a majority of patients (2 out of 3), it is important to note that not all patients were responsive to treatment. This once again highlights the heterogeneous nature of this patient population and the need for better sub-typing. Nonetheless, these remain very encouraging results and they support the next step of investigation, namely that of validation in a set of larger clinical trials.
References:
[1] 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
[2] Maes M, Mihaylova I, Leunis JC. Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. Neuro Endocrinol Lett. 2006 Oct;27(5):615-21.
[3] Broderick G, Craddock RC, Whistler T, Taylor R, Klimas N, Unger ER. Identifying illness parameters in fatiguing syndromes using classical projection methods. Pharmacogenomics. 2006 Apr;7(3):407-19.
[4] Gruhne B, Sompallae R, Marescotti D, Kamranvar SA, Gastaldello S, Masucci MG The Epstein-Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species. Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2313-8.
[5] Aspler AL, Bolshin C, Vernon SD, Broderick G. Evidence of inflammatory immune signaling in chronic fatigue syndrome: A pilot study of gene expression in peripheral blood. Behav Brain Funct. 2008 Sep 26;4:44.
[6] Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun. 2010 Oct;24(7):1209-17.
[Figure shown above, right] Taylor RP and Lindorfer MA. Drug Insight: the mechanism of action of rituximab in autoimmune disease—the immune complex decoy hypothesis. Nature Reviews Rheumatology 3, 86-95 (February 2007) | doi:10.1038/ncprheum0424
Dr. Gordon Broderick is an associate professor of pulmonary medicine in the department of medicine and a member of the faculty of medicine and dentistry at the University of Alberta. He serves as a member of the CFIDS Association’s Scientific Advisory Board.
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It sucks that Dr. Vernon’s and others’ recent application for a comprehensive antibody study was turned down, the one that they applied for when the economic stimulus grant stuff was happening. That seems like it could possibly have been relevant to the Rituximab study. Would that proposal also have identified auto-antibodies? Is there any effort to resurrect the project?
Thanks.
Suzanne resubmitted the application titled, “Identifying Chronic Fatigue Syndrome Subtypes by Detecting Auto-Reactive Antibodies with Antigen Microarrays,” to NIH in July and it has also been submitted to the Department of Defense Congressionally Directed Medical Research Program (CDMRP) Peer Reviewed Medical Research Program (PRMRP). Let’s hope the reviewers know about this study and that they connect its relevance to the proposed project. Keep your fingers and toes crossed, John!
Great news that the application has been re-submitted. I remember being so impressed by the wide range of investigators interested in this subject! As Gordon so aptly noted the Rituximab results “epresent a logical continuation of a line of investigation that has been ongoing”. That’s always encouraging. Good luck with that grant; hopefully the federal government’s slowness will help us here and the committees aren’t done with their reviews. I can’t imagine it would not pass now given the current news.
From your lips to the reviewers’ ears, Cort!
Thank you for noting that NOT EVERYONE RESPONDS. This fact is getting lost in the joy of a good proportion of people showing rigorously documented improvement (a first). Its a great start, but not necessarily a blanket cure. Perhaps most important, it is generating a huge amount of focus, and MONEY for further research.
That’s absolutely true, Marya. It has been interesting to read the recent literature on rituximab in rheumatoid arthritis. There are many similarities in terms of different approaches taken to identify and predict which RA subtypes will be most likely to respond and how to alter dosage, pretreatment (in RA you use methotrexate), frequency of maintenance infusions, etc., to achieve the maximum benefit for the individual patient. It would be so refreshing to see that kind of tenacity and creativity applied to CFS!
Here is info from the Genentech website about RA treatment (http://www.gene.com/gene/products/education/immunology/ra-factsheet.html)
“How Is RA Treated?
• There is no cure for RA. Treatments focus on relieving pain and reducing inflammation, improving overall function and well-being, and slowing joint damage. Treatment may include a combination of drugs, exercise, rest, joint protection and physical and occupational therapy.
• There is a need for multiple treatment options because not all patients respond to all therapies. An estimated 30-40 percent of patients do not adequately respond to some anti-TNF therapies.”
In the third clinical trial of rituximab in RA, these outcomes led to that FDA approval, “51 percent achieved ACR 20, the primary endpoint of the study, versus 18 percent of placebo patients (p<0.0001).” So, while not all patients responded, regulatory “success” can be met with less than perfect results from a clinical trial.
The FDA approval for rituximab carries this designation: “Rituxan® (Rituximab) in combination with methotrexate is indicated for the treatment of adult patients with moderately- to severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.” It’s not designed to be the first treatment for RA, and it’s recognized that it won’t help everyone. It may be helpful to keep that framework in mind as we all learn more about the possibility of this biologic and other immune system therapies being used to treat CFS.
This particular article mentions that Rituximab is a B-cell suppressor used in the treatment of Hodgkin’s lymphoma. Yet elsewhere it’s being reported that it’s used to treat non-Hodgkin’s lymphoma as per the article at http://www.medicinenet.com/script/main/art.asp?articlekey=150773
It seems that treatment strategies are different for each of these conditions so perhaps one of these is simply a misprint. Can you clarify for us which type of lymphoma is the correct one referred to.
Thanks so much.
Thanks, Barbara, for catching that. We’ve corrected it above, since it should read “non-Hodgkin’s lymphoma” for our predominantly US-audience. Here is some information about the cancers for which rituximab (Rituxin) is approved by the FDA (in the US); other countries’ approvals may differ (as in Canada, where Dr. Broderick is located, and Europe):
“In September 2006, the FDA approved two additional uses for Rituxan for patients with CD-20 positive, B-Cell non-Hodgkin’s lymphoma. In February 2010, the FDA approved Rituxan in combination with fludarabine and cyclophosphamide (FC) for people with previously untreated and previously treated CD20-positive chronic lymphocytic leukemia (CLL).” (http://www.gene.com/gene/products/information/oncology/rituxan/)
Rituximab is also used off-label for a host of other conditions and is being in tested in clinical trials for some of these.
I disagree with Gordon that this study by only improving 2/3 of patients health shows this to be a heterogeneous illness. If 2/3 had a specific abnormality that this drug affected and helped the patients that is a fairly large majority of patients that have the same abnormality being corrected.
Also according to Jason lots of people diagnosed using Fukuda so not have CFS but probably MDD or another disorder. So one drug helping most patients I feel actually shows this may be much less of a heterogeneous disorder than some scientists have been predicting. Just some thoughts.
The 2/3 ratio is very encouraging, although it’s important to keep in mind that these were subjects selected by one clinic from patients in one region, so it’s going to take other studies done at other institutions to gain a better understanding of how rituximab can best be used in CFS, and, accordingly how heterogeneous both the illness and the treatment response might be. It’s informative to look at documents like this one, the Consensus Statement for use of rituximab in rheumatoid arthritis (http://ard.bmj.com/content/70/6/909.full.pdf), to anticipate the types of issues that may arise as this research moves forward.
It’s possible you’re confusing Dr. Jason’s statements about case definition. His analyses show that use of the 2005 empiric definition may include people with major depressive disorder. The 1994 Fukuda definition, as was used in the rituximab study to select patients for the clinical trial, excludes individuals with major depressive disorder with melancholic or psychotic features. The Canadian clinical definition excludes people with primary psychiatric disease. Both definitions include individuals with comorbid depressive symptoms.
I would venture that Dr. Broderick’s opinion that M.E. is a heterogeneous illness is a highly educated guess. Attempts to find a biomarker to be used as a diagnostic test have already shown groupings of patterns according to his talk at the state of knowledge. For such an expensive and risky treatment as rituximab, a diagnostic test identifying the M.E. sufferers who would benefit would be extremely useful.
Thanks so very much for the clarification Kim.
Glad it was helpful!
If researchers were to use comprehensive symptom profiles in their studies, would that not be a poolable resource? If one common symptom profile questionnaire was developed and all CFS researchers used it in their studies and then uploaded the results to a central database, wouldn’t that have the potential to describe subgroups purely based on symptoms alone? For example- sudden onset>sore throat>swollen lymph nodes>neurological sequelea (sensitivity to light and/or noise)>relapsing/remitting disease course vs. gradual onset>no sore throat>no swollen lymph nodes>no neurological sequelea (apart from global cognitive dysfunction)>progressive disease course?
Hi John,
We share your vision! After the NIH ME/CFS State of the Knowledge Workshop, a working group with participation from NIH, CDC, several academic centers, private medical practices and the CFIDS Association formed to undertake a project called CASA, for “Collection, Aggregation, Storage and Analysis” of related patient data. In a session at the IACFS/ME conference held last month, Dr. Dennis Mangan introduced the project’s goals:
- To discuss an efficient, systematic and standardized way to collect and analyze data from ME/CFS patients.
- To enable use of these data to inform case definitions, phenotype characteristics, research studies, medical decision making, & delivery of health care.
The REDCap platform (http://project-redcap.org/) discussed by Dr. Italo Biaggioni (Vanderbilt University) at the State of the Knowledge Workshop and other models like the National Database for Autism Research (http://ndar.nih.gov/ndarpublicweb/aboutNDAR.html) would enable this kind of multicenter study to enhance the field. We have used multiple instruments to collect information for the SolveCFS BioBank, have had multiple meetings with REDCap and NDAR, and are working collaboratively to advance broader use and adoption of standardized instruments.
Is anyone taking retuximab for cfs that is not in a study?
Can one get a doctor to prescribe us t
his now?
I would like to try it.
28 years with cfs
Lynn
Hi Lynn,
Drs. Mella and Fluge have repeated the caution that, “Rituximab should not be used to treat CFS/ME outside of clinical studies at present. We also agree that more research is needed.” (Quote from their response to a letter to the PLoS ONE editor at http://bit.ly/sgutnc) There is certainly a lot of off-label use of rituximab documented in the literature for a diverse spectrum of conditions. The term “off label” refers to the fact that in the United States and some other countries, physicians have legal authority to prescribe medications for uses other than those which are approved by regulatory agencies. 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.”
The issue of personal treatment remains a decision between an individual and his/her provider that should be based on the best information available and that person’s particular medical needs and tolerance for risk/benefit, no matter what the medication. Please be sure to read the other posts here about rituximab, including info shared in the comments: http://www.research1st.com/?s=rituximab.
Hi Kim,
So glad Dr Broderick is on board, he is obviously a very caring scientist.
A couple of questions if you don’t mind.. It’s likely to be years before my country takes this on board, especially in terms of cost. I have heard that Rituximab will be out of patent in a couple or so year, will this drive costs down?
Again where I live many ME/FM patients only get an FM diagnosis which complicates things. Do you know if any of the Norway cohort also had co-morbid Fm, and if so would this indicate a response for those symptoms? Hope this makes sense
Thanks in advance
Helen
Hi Helen,
The patients in the study were evaluated for pain and pain scores were included in the assessment, but there isn’t anything reported about how many met criteria for other common comorbid conditions like FM (or POTS, IBS, etc.). Those who improved reported improvement in pain as well as the other symptoms and overall symptoms. You can see the scores in Figure 3 (http://www.plosone.org/article/slideshow.action?uri=info:doi/10.1371/journal.pone.0026358&imageURI=info:doi/10.1371/journal.pone.0026358.g003).
It’s unclear what effect the expiration of the patent protection will have on costs/availability. Rituximab and other monoclonal antibodies are a new generation of therapies that pharmaceutical companies are racing to create “generics” for. So far only India has approved a biosimilar for one of the monoclonal antibodies, but there are many others in various stages of clinical trials and regulatory approval all over the world. This link takes you to a press release, so the information should be considered in that context, but it’s representative of articles in the pharma press about this worldwide race to create biosimilar products: http://www.marketwatch.com/story/multi-therapy-drugs-opportunities-for-generics-biosimilars-2011-11-02.
Hope this is helpful, even though I’m not able to provide straightforward answers to your questions!
I was wondering if one of the patients in the placebo group in the rituximab study improved because of the IV saline that may have unintentionally treated his/her orthostatic intolerance ?
My husband has small cell vasculitis, he has taken methotrexate and is now taking azathioprine … we’ve been reading about rituxin … i wonder if you could give us the names of any rheumatologists w/in a 50 radius of san francisco who specialize in/or have a lot of experience treating vasculitis…thank you very much, sorry we’re so far from alberta.
Hi Betsy,
We don’t maintain a physician referral list. I’ve just googled “vasculitis care in San Francisco” and a number of clinics affiliated with well-known institutions appeared in the results. Good luck finding care for your husband.
appreciate it …
betsy
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