- Chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis: a reasonable approach.
Chronic cerebrospinal venous insufficiency is a novel hypothesis, proposed for the first time by Dr Paolo Zamboni, to try to explain the elusive cause of multiple sclerosis (MS). Briefly, this hypothesis proposes that the autoimmune attack against oligodendrocytes and the demyelination process, hallmarks of MS pathology, are caused by an excessive deposition of iron around small veins in the brain. This hypothesis is proposed after having found that venous blood flow may be altered in MS patients and, attending to Dr Zamboni’s studies, that yugular and azigos veins show an increased frequency of stenosis compared to normal controls. This hypothesis has never been accepted for a number of reasons but what matters most to me are the consequences of the disregard with which the neurological community has received this hypothesis.
Nature Journal has recently published a paper about the power of social networks to movilize patients and its potential to divert funding to studies or procedures demanded by patients. The example to illustrate the power of social networks is Zamboni’s CCSVI. In Canada, the attention paid by the mainstream media to this condition and to Dr Zamboni has turned into many patients claiming for the treatment of their vein stenoses, a procedure called, not randomly, “the liberation procedure”. But not always new healers deserve and receive attention by the media. But the context with this story is perfect…for both mainstream media and patients.
Dr Zamboni’s wife suffers MS. He is a vascular surgeon, attending to his Pubmed profile, a reputed one in the field of varicose veins surgery, but he has now focused on trying to help his wife (and others) studying MS from his vascular surgeon perspective. That means he is an outsider. Someone not familiar for the “MS stablishment”. He proposes a radically different approach in a pretty frequent and severe disease with huge pharma and national funding agencies investments, a growing number of neurologists, radiologists, biologists, immunologists, etc dedicated to it and an exponential increase in its research. And proposes a “liberation procedure” to something that nowadays has no cure… The perfect context for swindlers, mainstream media misunderstood headings, pharmaconspiracy theories, personal heroisms and the perfect environment for politicians. And that’s what we have… patients rallying for something not properly studied under the certainty that all the people involved in MS care, funding, research or market have something to hide in order to keep their positions and privileges.
Zamboni proposes an etiologic pathway that presents many unsolved questions with current evidences: it does not clarify the role of HLA genetics, the Epstein-Barr virus issues, the distance-to-the-equator gradient, the early involvement in many patients of the optic nerve, the oligoclonal bands at the beginning of the disease, the selective attack to oligodendrocytes (and not to astrocytes, neurons, microglia…) and many more. But we may assume that it’s a valid hypothesis. Then Zamboni should clarify in large epidemiologic studies what he sees in small ones, he should also answer scientifically to those who have published against his theory , he would have to integrate his findings to those that already have been accepted in MS pathogenesis theories, his findings would need to be validated in a different cohort and, after that, design one or more trials clearly showing the benefits of his procedure. That is the only approach possible. Until then, being so sorry for patients, what he does should be considered iatrogenesis.
Alternative hypotheses, those that challenge a paradigm, a stablished way of thinking and doing things in any science field usually are either believed or mocked. Believed is the appropriate word because when an hypothesis leaves the field of speculation to become a truth, an absolute, peer-reviewed, well-stablished, replicated truth is neither mocked nor believed anymore. Is just a fact. Something to include in guidelines and textbooks.
Science history is full of left aside hypothesis, dead-end streets and beautiful, logic, coherent explanations never demonstrated. And that’s why science is so often unbearably slow. The process, to be fair and, at last, useful, needs to be that slow. That’s something science journalists with big sounding headings and patients with big problems don’t understand sometimes.
Before the internet era it was quite easy to condemn to oblivion those ideas that did not fit the stablished standards. Those ideas wrongly left aside because they challenged the stablished ones were always able to arise and finally prevail. The misleading, wrong or even malicious ideas were properly forgotten. But now anyone with a favorable context (such as Zamboni’s) can spread challenging ideas, regardless of being true, untrue, good or fatal. Before, we had leaders in opinion, academic hierarchies. Now we have trends and impact factors. Now,unvalidated (but revolutionary and “liberative”) proposals are available to anyone. More, they may be, though incorrect or insufficient, published in good science journals because they increase their impact factors (remember the chronic fatigue syndrome issue in Science). Experts and academy have several problems when spreading ideas, mostly with the revolutionary ones or those that challenge the ideas of the stablished experts. They are not well organized, are not fully open and don’t communicate with their patient communities properly. That means that general public, people, patients, etc, without any filter, are scientifically abandoned in the internet to the will of those with powerful and attractive (but false) ideas or to those with personal or monetary interests but bold and shameless enough to mobilize patients’ organizations and appear on TV selling their own thing.
So, in my opinion, we need to get two conclusions from the CCSVI experience (an others, the most important the mumps-measles-rubella vaccine controversy, that lead to disease outbreaks). First, that we, doctors, need to communicate better not only in private but also in those places where people go to gather information by themselves (internet, media, etc). If not, others will and that’s not desirable for neither us nor patients. And second, the only way to get treatments approved is the (unfortunately damn slow) way of science and more science. An example: check how long took to natalizumab to get approved… So, Zamboni, keep working that hard and shut our mouths up.
- Progressive multifocal leukoencephalopahy and Rituximab
In a previous post we discussed the shameful oblivion in which Rituximab has been left apart because of its patent expiry date. Just this week a new paper on Archives of Neurology deepens our disappointment. Besides the great efficacy of Rituximab, maybe comparable to that of Natalizumab (or even better as seen in their phase II trials), now we know that the most scaring side effect of multiple sclerosis new drugs, the progressive multifocal leukoencephalopathy (PML), occurs much less frequently (in a similar disease, rheumatoid arthritis) than in Natalizumab.
Despite this new paper is a case series, with several limitations, i think the neuroimmunological community should think about leaving aside a powerful drug which, moreover, will be soon free of patent. A shameful story, re-visited.
- Fingolimod, two years view
The last issue of the Lancet Neurology journal, has published the extension phase study of the TRANSFORMS trial. Briefly, the TRANSFORMS trial was a randomized controlled trial comparing i.m. interferon beta 1a versus two different doses of fingolimod (0.5mg and 1.25mg). Its results were published on New England Journal of Medicine on February 2010, together with FREEDOMS, a Fingolimod versus placebo trial and CLARITY, a cladribine versus placebo trial. It showed a better perfomance than interferon in annualized relapse rate, with a concerning profile of side effects and some red flags, such as the risk of developing skin neoplasms or herpetic infections. Despite that, the overall performance in that study led to its approval by the FDA and EMEA but, while its being commercialized already in the US, it’s still on its way to the pharmacy in Europe.
In the controlled phase of the trial relapse rate with fingolimod was about a 50% lower than with interferon, and 80% o f patients remained free of relapse with fingolimod while only 63% of them were free of relapse with interferon in the first year of the study. Those were quite good results. There were also good results in MRI parameters. However there were no differences in disability outcomes, in one hand probably because the EDSS is not that a precise measure and in the other hand because overall relapse rates were pretty low. Significant side effects were present in the fingolimod arm, mostly on the high those arm, being the most concerning ones two deaths of herpes virus infections (one varicella zoster and one herpes simplex encephalitis). Another intriguing fact was the higher incidence of skin neoplasms (basal cell carcinomas and in-situ melanomas) in the fingolimod arms. Also heart conduction blocks and macular oedema were more frequent on patients taking fingolimod.
With this background, an extension phase of the trial was started, switching all patients previoulsy on interferon to one of the two doses of fingolimod. It must be said that, the extension phase of the study was not blinded anymore. This extension phase does not add very much to the initial findings but confirms the good efficacy results shown on the first year and clearly demonstrates a reduction on relapse rate in the group of patients treated with fingolimod compared to their first year on the study, when they were on interferon. The reduction on relapse rate was abut 30% compared to that on the first year when patients were on interferon.
Side effects looked pretty similar to those on the first year, also more frequent on the high dose arm, but probably with a slight decrease in the percentage of patients suffering severe adverse events, including death and skin neoplasms.
The data on this extension study, though not new and probably biased by the unblinded uncontrolled nature of the study, provide additional support for Fingolimod as a strong, more effective and, most importantly, oral alternative to current conventional treatments. However, its safety issues make us wonder if it could be better, and even more tolerable, having a monthly iv treatment far more powerful, specific and, attending to the trials (and not post-commercialization surveillance studies, still lacking in fingolimod) almost as safe, called Natalizumab.
- The shameful story of Rituximab in Multiple Sclerosis
Two weeks ago a few collegues from Spain and I attended the 3rd Preceptorship Program in MS at Steven Hauser’s department in UCSF. The scientific program and the overall quality of the course were outstanding. We had the opportunity to hear and ask those that have been ahead of MS research in the last years (Oksenberg, Goodin, Cree, Baranzini and, of course, Hauser). We heard beautiful stories of genetics, Vitamin D, EB virus, in vivo imaging and, what matters most at last, new treatments. It really was an extraordinary experience. But this is not the topic i wanted to talk about…
One of the treatment stories was one we heard before in 2010 ISNI meeting in Sitges (SPAIN), the one about Rituximab and MS. Apart from the commercial history of Idec, Biogen, Genentech and so on, the important thing is that it all ended up in an phase II clinical trial. A revolutionary clinical trial.
It was revolutionary because it challenged the “MS-is-(for-sure)-a-T-cell-mediated-disease” dogma showing that a B cell therapy was able to achieve unbelivable results in MS. But most importantly it was revolutionary because it got a striking 91% reduction in new enhancing lessions compared to placebo and, despite being a phase II trial, achieved a 50% reduction in relapse rates compared to placebo in less than a year. These are Natalizumab-level results, but with a quite safer profile than Natalizumab. At least, the experience with other diseases yields a progressive multifocal leukoencephalopathy (PML) rate much lower to that of Natalizumab. Just 6 reumathoid arthritis (in which Rituximab is used routinely) patients have suffered PML over more than 120000 patients treated despite RA patients having used much more frequently concomitant immunessuppresants than MS patients do usually.
The results achieved in the study deserved a NEJM paper and, for sure, a phase III trial. But that won’t happen. At least not in the short term.
It turns out that Rituximab patent expires in the US in 2015. This means that, by the time the phase III is over, the patent will be over too. So, no profit then in doing such an investment. To surpass this inconvenience Genentech invented a new drug, antiCD20 as well, but humanized (Rituximab is chimeric), called Ocrelizumab, and started the whole process again. Then, obviously, we got a phase II trial with ocrelizumab in MS. Results have not been published yet but have been presented at 2010 ECTRIMS meeting and show,as expected, an almost equal efficacy profile to that of rituximab. But a patient died on the ocrelizumab arm from an unexpected “systemic inflammatory syndrome”. That could be chance and still hope larger studies to be assured… but it was not chance. Several rheumatoid arthritis trials with ocrelizumab have been terminated because “the overall benefit to risk profile of ocrelizumab was not favorable in RA” what it really means that 7 patients died unexpectedly in the high ocrelizumab dose arms of the trials.
So, what have we now? Rituximab, an extraordinarily effective therapy, used for quite a long time now, pretty safe but that will never be approved for MS if phase III trials are not performed (and phase III trials are not planned to be performed) because that drug has become unprofitable. On the other hand we have an equally effective therapy, tested in phase II trials, to date showing a pretty less safe profile (to the point of having been stopped in other diseases) but potentially profitable if the company overcomes the safety issues. Guess wich one will be approved in a few years.
This is terrible. We don’t have so many choices to give our patients to throw away the best ones or have to wait several more years. But it’s terrible not only for MS patients… Rituximab has been tested in small case series of myasthenia gravis, neuromyelitis optica, NMDAR encephalitis, Lambert Eaton myasthenic syndrome, CIDP, anti-MAG neuropathy… diseases that, if MS may not have rituximab phase III trials, they won’t for sure. And, in those case series, it has shown pretty good results that need to be confirmed in order to be approved and used routinely. If a bad commercial decision halts rituximab development or commercialization for all those diseases, MS included, it will be the most shameful story in neuroimmunology. So, if not big pharma, a consortium of neuroimmunology departments should perform that expected phase III trial and bring rituximab back to neuroimmunology therapy.
If, in the meantime, ocrelizumab, ofatumumab or any other treatment can be developed and results positive it will be welcomed, but not a single effective drug should be left behind.
- Fingolimod approved!
First, the good news, a week ago the EMEA informed positively for Gilenya (Fingolimod) approval. This will expand the spectrum of therapeutic options for patients with multiple sclerosis and will fulfill the long desired availability of oral drugs for that chronic disease.
The bad news are that only selected patients will have access to this new drug and will not need to inject anything. Candidate pantients will be those that do not respond to a complete “a full and adequate” course of Interferon beta or those with high activity at the begining of the disease. This indication copies that of the Tysabri and restricts quite a bit the number of candidate patients. It is quite surprising that EMEA had not reserved a third indication for those that have cutaneous or systemic side effects wih current treatments, mostly when the great advantages that fingolimod pills add are comfort in administration and tolerance, and not efficacy that only slightly overtakes that of interferons. On one hand we may have an alternative for those patients with increased activity in which we think natalizumab may be too much but in the other hand this can delay natalizumab start in those patients who really deserve it.
Anyway, Gilenya approval is good news for the Neuroimmunology community and hope we can have it available the sooner to treat MS.
For details, find attached the EMEA report.
- Plasmapheresis guidelines for NeuroImmune disorders
AAN evidence based reviews don’t add anything new to what we probably know (or should know) or suspect about a treatment or intervention, but it’s always useful to have all data summarized to avoid the whole process of revision by oneself.
In the last issue of Neurology journal we’ll find an evidence-based review about the use of plasmapheresis in neurological disorders. Not any surprise in GBS and CIDP being the diseases with a better level of evidence in plasmapheresis efficacy. Not anything to question, but just highlight a (small) paradox… One of the main mechanisms of action of plasmapheresis is pathogenic antibody removal, then, how can a well known antibody mediated disease like myasthenia have less evidence than those diseases in which cellular immunity is considered more important, such as MS or CIDP?
- The exorcist girl explained…
Though its first description was published in Annals of Neurology in 2005, we started to pay atention to NMDA receptor autoimmune encephalitis in 2007, when several more cases and the pathogenic antibodies were described. It was difficult to believe that it could be possible to discover a new disease well into the twenty first century. It was not that a diagostic marker, a rare onset of a known disease or a particular clinical feature were described. It was the description of a disease, like in the Charcot days, but adding the diagnostic test, the pathogenic mechanism and the (almost) miraculous treatment.
This happened just three years ago… After three years of intense publishing, meetings and deserved attention to Dr Dalmau (and co-workers) it turned out that this disease was not that uncommon. Hundreds of cases arose when nobody had been aware of these patients. Most of them may still have an “idiopathic” adjective at their diagnosis field in the discharge report or may have died while their doctors still wonder what could that be.
Some may think that chance always plays a role when such discoveries are made, but in this case an entire life devoted to the study of immunlogic mechanisms of paraneoplastic diseases was the key to success. It’s not just a discovery, it’s a great amount of lab and clinic work. It could have been just another interesting case report but it was the description, not only of a syndrome, but of the basic immunopathology of it as well. More, it was the stablisment of a consistent model of approach to the study of neuro-immune diseases, starting with patients sera to follow with murine models and not the other way. A model that has in anti-NMDAR encephalitis its best example but that has contributed to the description of other auto-antibodies causing treatable encephalitis, such as GABAb, or the re-explanation of the true ethiologic factors that cause diseases previously attributed to antibodies against potassium channels, such as those caused by LGI1 and CASPR2 antiboides.
Now, having shaken the Neuroimmunology stablishment by getting far more attention in immunological issues than MS neuroimmunologists get, it seems, as it is reflected in the last Lancet Neurology paper, that they are trying to explain the physiopathology of the bizarre collection of symptoms the anti-NMDAR encephalitis shows. This will be a different adventure we also will eagerly follow not only because of its interest but because it’ll be another step towards the end of magical explanations of human behaviour. The end of exorcist girls… and the arousal of neurological awareness about a (most of the times) treatable disease that can be, otherwise, devastating.
- Here we go!
Taking a look around the internet, trying to find a blog/podcast/newsfeed/whatever, to discuss, learn and update about neuroimmunology i found almost nothing and decided to create this blog with that purpose.
There may not be many neuroimmunologists out there but i think it’ll be enough if a few gather round this blog and comment what will come in the science and clinical practice of our field.
So, anybody interested is welcome to provide information or even write posts, and every one out there is invited to join the discussion (if any).