- Dig Deeper: A Drug For CFS? Dr. Mella on Rituximab
Norway has never been known for its ME/CFS research but medical breakthroughs aren’t a matter of location; they’re more a function of innovation and attention to detail. Drs. Fluge and Mella apparently have both of these characteristics in spades. A surprising if temporary recovery from CFS that occurred during chemotherapy treatment for cancer caught their eye. Now we know that this has happened many times in the CFS community; the difference, this time, was that it occurred in the presence of two physicians who a) noted it, b) believed in CFS and c) had the determination and ability to carry the project forward in a rather hostile environment.
It wasn’t easy. During an interview in December, Dr. Mella noted that the project was cobbled together using funds they could gather and was done on the side; except for the XMRV finding, CFS researchers have never got much help from the powers that be. The publication of the current paper prompted the Norwegian Directorate of Health, in the first statement of its kind ever from a federal agency, to apologize for the poor treatment that ME patients have received at their hands.
“I think that we have not cared for people with ME to a great enough extent. I think it is correct to say that we have not established proper health care services for these people, and I regret that.”
Hopefully this will be the first of many apologies over the upcoming years for the astounding lack of care and attention given this the many people with this disorder from all quarters.
When last heard, the Fluge/Mella team was trying to cobble enough funds together to do a decent study. With a good immune panel, serology tests for a number of viruses (and XMRV) and MRIs of the brain being done – they did better than decent.
Methods – Half the 30 patients were given placebo and half given the drug and neither patients nor the researchers were aware of who was getting what. Rituximab effectiveness was determined by having the patients assess their symptom levels using a variety of questionnaires including the SF-36 used in many ME/CFS studies 2, 4, 6, 8, 10 and 12 months after treatment. The symptoms assessed were clearly developed for CFS with the patients assessing their fatigue, pain, post-exertional exhaustion and need for rest regularly. For those with positive results all symptom types improved.
Results - As with the first Rituximab study, the results were impressive, with a few patients apparently resolving all their symptoms and others improving significantly, but the effects were also mostly transient, with the symptoms returning after the drug’s effectiveness wore off. The same curious delayed-response pattern seen in the first study – with [/B]symptom improvement occurring 2-7 months after the injections – prevailed in the second.
A Big Hurdle Surmounted – The results mimicked those of the first study, but this study, a placebo-controlled, double-blinded trial (PCDBT) was a different animal entirely. PCDBTs are double-edged swords; they have knocked many a promising finding down and out but they also have the ability to vault a positive finding into the big leagues. It was a double-blinded trial that knocked out the XMRV tests recently and the De Freitas retroviral finding two decades ago, and a similar trial sent Dr. Montoya back to the drawing board for a couple of years to figure out what happened to fantastically successful first herpesvirus antiviral trial results.
An Arrow Pointing at the Heart of ME/CFS?
While the drug wasn’t completely effective in most of those who took it and 40% of patients did not respond, the drug did ‘move’ the disorder significantly, something we haven’t seen since the days of Ampligen. In doing so it not only provided hope for treatment but hope for CFS being seen as a physiological disorder that deserves substantial research support. Dr. Shepherd, medical adviser to the UK ME Association, noted that no drug has been close to this effective in ME/CFS stating,
“It’s the most encouraging drug result so far in the history of this disease. . . Although it’s a small trial, it’s produced dramatic results.” Dr. Shepherd
Dr. Fluge noted it affected all the symptoms of ME/CFS – suggesting that it was impacting a core physiological problem.
“We think it affects all symptoms [of CFS], so it must touch the central pathological mechanism causing the disease,” Dr. Fluge
The biggest impact the study may have, though, may not be the drug itself but the big arrow it’s pointing at the immune system and the research efforts that will surely follow.
Subsets Needed! - The study also highlights the vital need to subset the large and varied group of patients gathered under the CFS banner. Somewhere buried deep in the physiology of the thirty patients in the study lies the answer why one group responded well and the other did not; work toward that answer is under way and it may present the best opportunity yet to break CFS up into its constituent parts.
Most studies now still simply treat people with ME/CFS as if they were all the same, but the Rituximab study rather starkly points out how untrue this is. Dr. Broderick, who appears to have uncovered several immune subsets, highlighted the need, in his commentary on Rituximab, for researchers to more vigorously look for natural groups of ME/CFS patients.
A Great Starting Place – A successful treatment trial is the best of all outcomes. Generally researchers try to pinpoint an abnormality and try to come up with something to fix it, but in this case they’re in a much more enviable position; they know something has worked and now they’re going to attempt to figure out why.
It’s time to learn more about the drug that has excited so many people.
A New Class Of Drug
Developed by IDEC Pharmaceuticals, Rituximab is the first of a new class of drugs called B-cell depleting monoclonal antibodies. Approved by the U.S. Food and Drug Administration in 1997 for B cell non-Hodgkins lymphoma patients, Rituximab has over time expanded its reach greatly, and is now being used to treat or in trial for other cancers such as leukemia and myelomas and autoimmune disorders such as rheumatoid arthritis, autoimmune hemolytic anemia, vasculitis, type 1 diabetes mellitus and Sjogren’s syndrome. (Interestingly the drug became of interest in autoimmune disorders in the same way it did with CFS; a patient with cancer and arthritis had her joint symptoms resolve after taking Rituximab.)
ME/CFS is not the only disorder in which Rituximab may be altering medical viewpoints. Its partial success in multiple sclerosis has re-oriented some researchers away from what was believed to be the putative cause of the disorder (over-active T-cells) to focus more on B-cells.
One of the most heavily studied drugs on the market today, Rituximab is the subject of over 1000 recently completed, recruiting or ongoing clinical trials at the NIH. These weren’t trials that just happened to mention Rituximab….I scrolled through about 500 of them and Rituximab appeared to be the focus of all of them – indicating that this is a very hot drug that is getting a lot of study and interest – just the thing a CFS research community always short on cash needs.
Rituximab is currently co-marketed by Biogen Idec and Genentech in the U.S. and by Roche in Canada (under the trade name Rituxan) and the European Union. Its success opened up a new field of drug development with several more drugs of its type being produced or currently under development.
Rituximab’s Target – B-cells
Rituximab is believed to deplete B-cells in two ways; by recruiting other members of the immune system to attack them and by locking on a receptor on the B-cell that tells the cell to kill itself. B-cells are an integral part of the immune response. Until they are activated, B-cells quietly troll the blood, collecting and digesting molecules called antigens that appear to be suspicious. Once they are digested they place bits of them on MHC molecules for T-cells to inspect. If the T-cells decide those molecules came from a pathogen, they turn around and turn the B-cells on – transforming them into antibody producing machines (‘plasma cells’) that can generate from 100s to thousands of antibodies per second.
These antibodies or immunoglobulins are specifically manufactured to attach to a pathogen and physically stop it from locking onto our cells. The antibodies also alert macrophages to come gobble up the pathogen and they turn on other parts of the immune system. B-cells are key players in the immune response but if they go too far; if they get too zealous, they can mistakenly attack our own cells and overactive B-cell activity has been implicated in many auto-immune disorders.
A Logical Outcome?
Although many were surprised to see a chemotherapeutic/autoimmune drug succeeding in some people with ME/CFS, past research suggests there were good reasons to hope for its success. In a review on the Research1st website, Dr. Broderick stated
“these…results…..represent a logical continuation of a line of investigation that has been ongoing.”
Rituximab’s main target, B-cells, after all, play a major role in the Th2 shift in the immune system that appears to have occurred in CFS. B-cells are also where one of the more intriguing pathogens in ME/CFS live: Epstein-Barr Virus.
B-cells don’t appear to be the end of the story, though with Rituximab. Studies also show that Rituximab can be effective without lowering the level of auto-antibodies that are believed to cause the auto-immune disorders. Indeed, the improvement in ME/CFS and rheumatoid arthritis patients often takes place long after B-cell levels dropped. The fact that many patients relapse long before their B-cells return to normal levels suggests that Rituximab may be affecting other parts of the immune system as well.
While Rituximab is busy destroying B-cells there is also evidence that it may actually be turning on NK cells – which, of course, habitually underperform in CFS. Rituximab also appears to increase production of IL-10 – a key anti-inflammatory cytokine that may be a protective agent in ME/CFS – and reduces levels of the powerful pro-inflammatory cytokine tumor necrosis factor. A review article suggested that Rituximab was able restore Th1/Th2 balance in the immune system. These results suggest Rituximab could be working as an immunodulator helping to re-balance the immune response by turning down the over-activated parts of it and bumping up the under-active ones.
Breaking out of the CFS ‘ghetto’
It takes a big finding to break out of the ‘CFS ghetto’ into the research mainstream where abundant funding is available. XMRV was able to do that in spades but other positive studies often remain ensconced within a small community of researchers and receive scanty follow-up. From all appearances, this small but well-conceived study should be able to break out and gather substantial financial backing for more study. Several ME/CFS researchers and physicians including Dr. Klimas and Dr. Bateman quickly called for NIH Clinical trials to take place.
In fact, because of what has turned out to be some rather prescient efforts, the federal government has the opportunity to jump on the Rituximab finding immediately. In 2009, Dr. Suzanne Vernon, the Research Director of the CFIDS Association of America, got a wide range of investigators from across the US to support a study looking for auto-antibodies in ME/CFS called “Identifying Chronic Fatigue Syndrome Subtypes by Detecting Auto-Reactive Antibodies with Antigen Microarrays,”.
The grant proposal failed to win approval the first time but Dr. Vernon submitted it again in July, to the Department of Defense Congressionally Directed Medical Research Program (CDMRP) Peer Reviewed Medical Research Program (PRMRP). The review process for the CDMRP has just about wound up; whether the Fluge/Mella study results were in time to impact the proposal’s success is unclear but it’s hard to imagine any grant panel not approving that study now. (Update – the study was not approved.)
Another Dead End for XMRV
The Fluge/Mella team looked for XMRV but like other studies, were unable to find it. Dr. Fluge said “We looked as hard as we could for it, by several methods, but the search was negative. We think suggestions it was XMRV [causing CFS] have turned out to be a blind alley, caused by contamination of samples.”
More Studies on the Way from the Fluge/Mella team – Fluge and Mella are already engaged in studies with more frequent infusions of Rituximab in hopes that more intensive use of the drug will elicit a more permanent response. They are also digging into the study participants immune systems to see if they can identify where evidence that an auto-immune process is indeed under way.
ME/CFS Doctors Respond
Dr. Lapp, Dr. Klimas and Dr. Bateman all responded to emails asking their thoughts on the study and the use of Rituximab at the present time in ME/CFS and all responded similarly; they were excited by the results, they were concerned about the ability of many patients to pay for the drug and they all wanted more data, in particular, more studies. Dr. Bateman hoped to help enroll patients in a clinical trial of the drug:
“In short, I think the news is very exciting. I have personally observed the phenomenon of CFS patients improving after chemotherapy. I look forward to and anticipate speedy progress toward a US clinical trial designed specifically to facilitate an FDA indication, should the findings be replicated.My primary goal will be to help enroll well defined patients in such a clinical trial of rituximab, if possible, rather than to start using it for treatment right away. I don’t have enough information yet to know what my position will be on off label use. It will be important to identify our best available biomarkers with which to identify appropriate patients and to assess treatment outcomes.The biggest concerns are cost, appropriate patient selection and understanding the risks in the CFS population.
In a statement to the Norwegian Press, Dr. Klimas emphasized the different ways Rituximab may be working and called for more study into the infections that may be occurring in ME/CFS:
“The recent study of Drs. Øystein Fluge and Olav Mella demonstrating significant improvement in ME/CFS patients treated with the B cell depleting agent Rituximab is a key study for our field. By showing that depleting B cells can cause dramatic improvement, the investigators point the field in the direction of autoimmunity, and autoimmunity caused by an autoantibody.However, there is one other plausible explanation: that the B cells were acting as a reservoir of infection and by depleting the B cell line the viral load can be brought down to the point of suppression by the immune system. Because EBV infection is harbored by B cells, as are several other putative latent viruses that could contribute to illness persistence, I believe both of these theories deserve vigorous scientific pursuit.”
The Early Studies Syndrome : A Cautionary Note
In an email, Dr. Bateman noted that we will need more studies to determine the true extent of Rituximab’s usefulness in the ME/CFS Community. It’s not uncommon for early studies to demonstrate higher rates of efficacy than later studies. Why? The Fukuda definition is so broad that different researchers often look at different types of patients. Researchers also tend to pick patients they think may make their case. When a wider mix of patients are added to the mix in later studies efficacy rates sometimes go down.
Dr. Maes, who has investigated autoimmune processes in ME/CFS, stated he believed there was a significant autoimmune subset in ME/CFS and he has more data to show that, but the percentage may be lower. The word, then, is caution. The study’s strong point was that it was rigorous enough that it seems inconceivable that a good chunk of ME/CFS patients will not benefit, but more studies are needed to figure out how many.
Widespread use of Rituximab is a long ways off as well. In a statement from the Research1st website, Dr. Shepherd cautioned that “We’re still a long way from making this drug more widely available, but if someone wants to mount a UK trial, we’d look at that,” he said.
It will take a while to determine who benefits and how much from Rituximab, far longer than most people with ME/CFS would like, but the current study promises much: a possible treatment path in a very hot area of pharmacological development with more drugs in the pipeline, increased interest in immune research in ME/CFS, and a more serious look at the disorder from all quarters.
Serious Disease – Serious Drug
Rituximab is an expensive drug costing from $6-10,000 a year or more depending on how many times it is infused. Since it will surely take numerous validation trials for insurance companies to pay for Rituximab treatment in CFS the only options at this point appear to be self-pay or to get enrolled in a clinical trial. (Because of the need to take samples throughout the course of their studies, the Fluge/Mella studies are only accepting patients who live in the general area).
Rituximab is coming off patent protection this year and prices should drop signficantly. The manufacturer also offers substantial discounts to people with lower incomes.
Rituximab was originally developed to attack cancer cells and while the Fluge/Mella studies have not uncovered any serious side effects among the ME/CFS patients participating, like many chemotherapeutic drugs it can have serious side effects.
Infection - Rituximab does suppress one part of the immune system – raising the possibility that the immune system will be less able to fight off infection and there is evidence this can occur.
Review papers have reported that, while rare, a variety of serious infections may be associated with Rituximab treatment including hepatitis B, cytomegalovirus, varicella -zoster, herpes simplex, enteroviruses and others. One study that compared infections between Rituximab treated and non-Rituximab treated patients after kidney transplant found that Rituximab treated patients had lower rates of viral infections and higher rates of bacterial infections. About five percent of patients in several trials developed ‘serious’ infections although a broad overview of numerous Rituximab cancer studies did not reveal an incidence of increased infection. Several confounding factors including the use of other immunosuppressant drugs have made it difficult to pin down the role Rituximab plays.
PNL - The increased risk of one rare but life threatening infection called progressive multifocal leucoencephalopathy (PNL) lead the FDA to place a ‘black box’ warning on the drug. PNL is a rapidly progressive and often fatal neurological disorder triggered by the reactivation of the JC Virus (JCV) in the brain. Because of many other confounding factors that may influence the development of PNL, a causal relationship between Rituximab and PNL has not been established.
An overview stated that considering the ‘countless’ number of patients Rituximab has been used in, the ‘complication rate, including the incidence of infectious complications, appears to be low and may not be nearly as significant as other therapies such as long term steroids.” Both the Fluge/Mella paper and Dr. Klimas referred to the seriousness of ME/CFS as reason to quickly proceed with more Rituximab trials.
Many clinicians fail to realize the severity of the illness that has been termed ME/CFS. This is a profoundly ill population, the severity of illness scores are similar to congestive heart failure and severe rheumatic disorders such as rheumatoid arthritis. If a medication like Rituximab is found to be effective in validation studies, the risk/benefit ratio would justify its use in very ill ME/CFS patients. I hope that phase II/III trials can be initiated as soon as possible.Dr. Klimas