Andrew Gladman explores the current research climate of ME/CFS, discussing how existing research ties into the emerging autoimmune hypothesis.
Throughout the history of ME it is safe to say that understanding of the condition and the research itself has been somewhat fractured at best and lacking significance in many areas. In the last 30 years, following the Lake Tahoe outbreak which piqued the interest of doctors and media, little progress seems to have been made in terms of physiological understanding of the disease processes involved, perhaps due to the stigma of ME as a purely psychological entity which is only in recent years being shaken off.
This struggle clearly speaks to both the complexity of the illness in general and the misunderstanding that many researchers and doctors still have of it to this day. The causal theories proposed range from chronic viral infections, mycotoxins, stress, psychological stress, immune dysfunction and many more; yet none of these have been shown to adequately represent the patient population as a whole or to account for the presented symptoms and varying degrees of disability.
The fractured and inadequate biomedical research to date has left the majority of patients with treatments such as Graded Exercise Therapy (GET) and Cognitive Behavioural Therapy (CBT) as recommended by the National Institute of Health and Care Excellence (NICE). However, the heavily promoted PACE Trial – which endorses these treatments – has itself come in for a large amount of criticism with regard to various aspects of its design, data management and conclusions: and is seen by many patients as being unrepresentative of their own experiences.
This leaves the only other option for patients as specific symptom relief, which many GPs are still unwilling to prescribe; alternative psychological treatments, such as the Lightening Process and Mickel Therapy – coming with a costly price-tag and no guarantee of success; and off-label treatments such as Valcyte or Ampligen, which while of anecdotal benefit to some, are not yet approved for use, and can attract another heavy cost and the risk of quite serious side effects.
A positive change in momentum…
Despite this we do seem to be witnessing a positive change in momentum for ME research and in terms of official recognition that ME has a physiological foundation. In 2011 the Medical Research Council (MRC) announced that more than £1.6m was specifically available for biomedical research into ME/CFS – funds that have now been allocated to specific projects. Alongside this came the establishment of the CFS/ME Expert Group chaired by Prof. Stephen Holgate with the aim of exploring new ways in which to encourage research into ME/CFS; while in America, the Chronic Fatigue Initiative has been pivotal in encouraging collaboration between researchers in many different areas and trying to raise awareness of ME.
Prof. Holgate’s Expert Group has undoubtedly helped with the establishment of multiple initiatives including the UK CFS/ME Research Collaborative (UK CMRC) in April this year, and as a joint charity initiative we have seen the forming of an ME Biobank at University College London – which received a welcome boost from the US National Institutes of Health recently. The annual Invest in ME International ME (ME/CFS) Conference is at the forefront of this momentum change, meaning there are now more opportunities to present and showcase the latest research from new and experienced ME scientists from across the world. Other than something of a misfire in the form of XMRV, the growing research community seems to be going from strength to strength, despite the slow action of other groups such as the US Centres for Disease Control and Prevention (CDC).
Undoubtedly one of the most recognised presences in recent years at the Invest in ME conference has been the Norwegian Doctors Oystein Fluge and Olav Mella. In 2009 Fluge and Mella’s Rituximab pilot study seemed to show major transient improvement for all 3 patients and in doing so attracted quite a lot of attention. A follow up study published in 2011 built upon this, showing further transient improvement rates of 67% in a double-blind placebo controlled study. These results created a clear buzz in the ME community and with data from the maintenance trial of Rituximab presented at the 2013 IiME Conference and due for publication soon – promising positive results gained by extending the treatments over a longer period and aimed at maintaining improvement – it is clear that Rituximab is one of the most positive developments in ME research for decades. Positive, not only as a potential treatment for some, but also as a breakthrough in understanding of the physiological cause of ME: implying as it does that autoimmunity may lie at the root of the illness.
XMRV has taught us not to get carried away before the data is published and reliably replicated, but it’s clear that these studies are incredibly important going forwards – with the potential to change the way researchers and doctors alike approach ME. The importance of these further studies is underlined by the impressive response some of the Norwegian pilot study patients experienced. When asked how they were doing 4 years after the pilot study took place, one of the patients said, “Right now I’m living an active, normal life as a full time student and I really appreciate that the doctors at Haukeland gave me the chance and the health to do what I want in my life, I will never take this lifestyle for granted!” Considering she has received no further Rituximab treatments, it is clear that this drug has a lot of potential!
Autoimmune theory and other research findings…
One important question that the autoimmune theory does raise is how all the other research findings tie in with it. There are numerous researchers currently looking into a plethora of different aspects of ME and it is important to give each one careful consideration. Each area has the potential to represent one piece of a very complex puzzle and only once each is weighed against the others can we discover where each piece goes and indeed whether the piece we are looking at is even a part of the overall puzzle.
For example, Montoya and the Stanford ME/CFS Initiative (Summer 2013 Update), and the projects from Lipkin and Hornig, are looking in detail at the presence and prevalence of pathogen involvement in ME. Given the historical and current causal theories posited by pathogen involvement, many patients and doctors are looking forward to the results once they are published.
It is perhaps difficult to make the initial connection of pathogens to an autoimmune theory and it is of note that many of the pathogens commonly identified or associated with ME are prevalent in similar numbers within the general population. Therefore the question may be why the immune system suddenly starts to respond to them, and becomes a compounding problem for ME patients.
This logically leads to further questions as to whether these pathogens are re-activating and hence require an ongoing immune response or whether the immune system is over-responding to otherwise inert pathogens. Perhaps this could point to an important part of the underlying disease mechanism whereby the immune system is overreacting to the mediators released by the chronic low level pathogens everyone harbours – although as yet these theories are speculative. Another answer could come in the form of dysregulated sensory gating. A recent study in Japan (Health Rising Article by Marco) discusses the possibility of troublesome sensory gating in ME at some length, specifically the potential for this to explain the sensory overload many patients experience. It is interesting to note that this could come as a result of the autoimmune process targeting the neurones of the sensory nervous system – as was originally proposed by Fluge and Mella following their 30 patient trial.
Another researcher undertaking ground-breaking work in the ME field is Professor Julia Newton. Her studies looking into the muscle dysfunction along with the effect of lactic acid upon these muscles and the effect of low blood pressure in ME patients are areas that have not received much research attention in recent times. However both represent intriguing possibilities for physiological problems in ME, possibly even pointing towards the vascular system as a potential autoimmune target bringing with it possible direction for treatment – this is one of the reasons why her results promise to make some very interesting reading. This is one area of research however where the link with autoimmunity would appear to be more subtle – for this reason it is all the more exciting that Professor Newton has been looking into Rituximab herself.
Of all the links between different research areas and the effects of rituximab, Dr. Amolak Bansal’s work into B-cells represents one of the strongest: as would be expected considering the B-cell depleting action of rituximab. Published in March 2013, his research was aimed at intensive B-cell immunophenotyping in order to identify whether there were any consistent B-cell abnormalities in the general ME/CFS population. It is very interesting to note that this study came about as a direct response to positive results shown in rituximab trials – underlining the importance of the rituximab trial in shaping new research directions. Prior to this study the research literature on the topic of B-cells in ME, like many areas of ME research, was inconsistent and sparse. The results of this study however led Dr. Bansal and his team to conclude that there was perhaps a “subtle tendency to autoimmunity.”
Of all the research mentioned, this has the clearest link to the autoimmune theory and its importance is underlined by the desire of Professor Jonathan Edwards and the team at UCL to undertake a similar trial as a preliminary stage of their planned UK rituximab trial – a preliminary trial that thanks to the fundraising efforts of Invest in ME is able to begin in the near future. Professor Edwards, in a recent interview with Phoenix Rising, explained that one of the primary aims of a UK rituximab trial would be to connect the data from the Norwegian study with the B-cell abnormalities Dr. Bansal has reported.
The immune dysfunction hypothesis is nothing new in ME/CFS, being proposed numerous times throughout the history of the disease – certainly the signs have always been there that the problem may stem from the immune system. Many of the drugs patients use off label such as Ampligen and Imunovir act primarily through modulation of the immune system and its aberrant responses, while drugs such as Valcyte act through antiviral properties but still exhibit an immunomodulatory effect. There are many reports of patients improving on these drugs and it’s difficult to not encounter the remnants of the outrage many patients feel towards the denial of Ampligen approval numerous times over the years.
Valcyte itself has been heralded many times by patient subgroups as a treatment that has helped them turn the corner. However a recent study by Kogelnik and Montoya has had disappointing results – perhaps the antiviral properties help a sub-group for whom chronic viral infections are a major factor but these results do not confirm many patients’ beliefs that viruses are to blame. The results simply do not appear as positive as many hoped for. There is the possibility that immunomodulation might explain the improvement in patients for whom the proposed autoimmunity may be the problem, however more research will be required to confirm or deny this. The multi-armed trial involving both Valcyte and rituximab, proposed by Dr. Kogelnik and OMI-MERIT, could be the best way to determine whether Valcyte has a role as an ME treatment.
Future UK Rituximab trials…
Of all the changes Rituximab and the autoimmune theory can and have been making, the most striking is likely the discussion and thought it has provoked among researchers, doctors and patients the world over – influencing the way researchers consider new trials and how patients view the future of ME. Many organisations have taken note of this through public declarations, and the ME Association in the UK have pledged both their interest in this emerging research area and a not insignificant sum towards a UK trial.
Dr. Charles Shepherd has made many comments regarding Rituximab and has partaken in online question-and-answer discussions on the topic. The ME Association issued the following statement early in July for example, “we have consistently maintained that the positive results from the initial case study reports indicate that Rituximab could form a very significant development in finding a drug aimed at treating the underlying disease process in at least a sub-group of people with ME/CFS”. While Dr. Shepherd had this to say regarding the autoimmune hypothesis: “I’m not yet convinced that ME/CFS is what doctors term an autoimmune disease. This is because from what we know so far there is no consistent and robust evidence relating to autoimmunity in ME/CFS that links specific autoantibodies and autoimmune tissue/organ damage or functional change to actual symptoms.”
Dr. Shepherd went on to explain that a “wide range of immune system abnormalities have been reported in ME/CFS. These include the presence of low levels of autoantibodies in some people”, and concludes that “a sub-group of people with ME/CFS have what I think is best described as an autoimmune component”. Dr. Shepherd has also made it clear that the ME Association is very much in favour of supporting a UK rituximab trial proposal from a financial standpoint, provided that such a proposal meets the standard peer review process required by the Ramsay Research Fund.
It is clear then that research into ME seems to have made a positive turn, with more unique directions than ever and many initiatives to help researchers and patients alike. Certainly there is still work to be done in interpreting how evidence such as muscle fatiguability possibly due to excessive lactate build up, Post-Exertional Malaise and mitochondrial dysfunction fit into the puzzle; but now the evidence of physiological abnormalities is mounting, the interpretation and conclusions can begin to be made.
In Rituximab there is not only the offer of a potential treatment even if only for some, but also evidence for an autoimmune causation which could form the central trunk in the tree of ME research for the next few years, and from which all other areas could form the varying branches. The importance of Rituximab research in ME is clear from the comments of researchers, doctors and charities alike. With a phase III multicentre trial now close to being fully funded in Norway and due to commence early next year; plans in place for a smaller replication and exploratory trial at University College London; and early plans for further trials in America at the Open Medical Institute: it is clear that this development is being taken seriously.
It is important to remember that we are still likely dealing with multiple diseases under one larger heading as Prof. Stephen Holgate has outlined on numerous occasions. Rituximab is unlikely to help everyone with ME, however initial trials are incredibly positive and imply that for perhaps a significant sub-group, autoimmunity may be the causal disease mechanism. And it is not beyond the realms of possibility that there may be several different autoimmune conditions under the heading of ME/CFS.
If an autoimmune group can be identified within the larger ME/CFS group in the future, there is a strong possibility that this autoimmune group would be removed from the ME/CFS label and identified as a unique autoimmune entity. This group would likely be given a new name more befitting of the clinical findings. This could benefit those remaining in the ME/CFS group by removing those suffering from an autoimmune disease and allowing more relevant research to continue. Undoubtedly the research going forward has a direction that has been lacking in the past and with this, the potential for new treatments in the near future must surely follow. Who knows where we could be in another 5 years!