By K. Kimberly McCleary, President & CEO
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.
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.
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.
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)
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)
by Nina Weber at der Spiegel Online (English Translation) (Oct. 20, 2011)
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)
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)
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)
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)
by Chris Amos for AuthorityEmpire.com (Oct. 30, 2011)
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/
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.