This week we had the opportunity to read a paper in the New England Journal of Medicine, describing, in my opinion, a breakthrough finding in MS. It’s published by Srivastava and coworkers, from the University of Munich. It describes the presence of antibodies against the KIR4.1 potassium channel in almost 50% of MS patients. Maybe i’m biased because my research is focused in autoantibodies in neuroimmune disorders, but, in my opinion is one of the best papers that has been published in MS in many years for different reasons that i will describe later. However, the impact in the mainstream scientific media and in the community has not been very big so far. It has had a media coverage that is, for example, far behind a recent study describing some allele variants having a small genetic risk of developing MS, being, in my opinion, much less important from the patient care point of view. The study is an example of how research should be conducted. From a very good (and old) hypothesis it develops a set of experiments brilliantly designed to achieve, with success, the goal in a completely unbiased approach. The approach is very similar to what Dr Dalmau and co-workers have been doing with autoimmune encephalitis, but it has some key differences that make the study even better if possible. Briefly, the study starts describing a set of patients that react agains glial components of the central nervous system. Then the authors isolate cell membranes from brain tissue (rat and human). They demonstrate reactivity against those membranes and isolate the proteins to which the antibodies are targetted (being that protein KIR4.1). Then they design another set of experiments to confirm the finding. They use ELISA, flow cytometry and immunocytochemistry to define the specificity of the antibodies and their
It’s been a while since i wrote last post, but NeuroImmunology has been busy with several other projects. It’s been a while too since i decided to write a monographic post about the different oral treatments that are already available or are about to arrive but i postponed it until i had enough time to do it carefully. I will try to clarify the different pros and cons of the oral treatments in general and of each one in particular. It’s also an attempt to organize my ideas about the subject. Until very recently the only disease-modifying treatments available for MS were injected therapies (I say disease-modifying because steroids are only used for relapses and do not modify the course of the disease in the long-term). Interferon and glatiramer acetate (subcutaneous or intramuscular), mitoxantrone (intravenous) and, more recently, natalizumab (intravenous) were the only available options for MS. In some countries people used intravenous immunoglobulins (IVIg), azathioprine (oral) and cyclophosphamide (oral or intravenous) but the evidence for their use in MS is very weak and they were not considered standard treatments for MS. Several major claims and complaints of patients with MS related to the treatment route of administration. Needles, need for portable fridges, problems in the airports and customs, an injection every two days, subcutaneous nodules, risk of infections… So, research on oral therapies was one of the main targets of researchers and companies and one of the things patients are more interested and askabout more often. And oral therapies finally arrived. At this moment there is only one treatment fully available in Europe, fingolimod (Gilenya), four more laquinimod, BG-12 (dimethyl fumarate) teriflunomide and cladribine have completed phase III trials and another one, firategrast, is still on phase II trials but shows promising results. The first and most obvious advantage
MS scientific literature is fascinating. Few neurological (and non-neurological) diseases can compete in number of papers, impact factor and mainstream media attention. However many research projects use classical animal models (experimental allergic encephalmyelitis, EAE) and those animal models have been an enormous source of erroneous extrapolations to MS pathogenesis. Many times the EAE model has been a research target itself and not because the results it could provide truly matched with what we want to know about MS. However, despite the noise that animal models generate, it must be aknowledged that they have evolved into more accurate models and have boosted MS research and knowledge. I like the “from bedside to bench” approach and not the other way round but, sometimes, basic research works initiate breakthrough hypothesis that deserve “bedside” research. I bring up this statement after reading the paper Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination by Kerstin Berer and co-workers and published in Nature in October 2011. The hypothesis is beautiful (but not new) and, although it probably needed a lot of experiments and comprobations, methods are pretty simple. They used a mouse model of spontaneous relapsing remitting MS, in which CD4 T cells constitutively express a T cell receptor that recognizes myelin oligodendrocyte glycoprotein peptides. They start with the observation that this model develops MS in variable proportions depending on the research group using the model. Then they wondered if the way these mice were bred had any influence in encephalomyelitis development and bred them in two different conditions: a conventional pathogen free (or SPF) environment or in a complete germ-free environment. In SPF breeding commensal microbiota can grow and animals are only pathogen-free. In germ-free environment animals don’t have commensal microbiota. The main goal was to see if there were differences in MS
Today New England Journal of Medicine makes public the results of a large clinical trial with more than a thousand patients comparing results of teriflunomide against placebo in MS. Results are not spectacular, but not bad. It decreased a 30% the annualized relapse rate and reduced the rate of disability progression slightly. The best point in favour of teriflunomide is the adverse reactions profile, comparable to that of placebo. That, together with it being oral, makes it a perfect candidate for first-line therapy and likely to be suitable for a combination trial with interferons/glatiramer acetate. Another good point in favour of teriflunomide is that it shows effectiveness in a 2-year trial, which makes results stronger. It’s the third oral treatment showing good results in a phase III trial in MS and, probably, the second one to be approved. Fingolimod is already being used in the USA, and has been approved in Europe, but it scares a little bit and that will play against it when teriflunomide comes out. The third one, cladribine, is at serious risk of being left aside. Moreover, a fourth one, Laquinimod, will be another safe option for first-line therapy in a while although phase III data are still pending. In a few months we’ll have, at least, two oral therapies for MS that will broaden the therapeutic options and will allow to switch patients to safe, tolerable options that, to date, were restricted to painful injected treatments or powerful (but scaring) drugs. Hope teriflunomide approval and commercialization does not take the long, shameful process that Fingolimod is suffering. In February 2010 results were published… and here we still have to give excuses to patients…
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
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.
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.
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
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.
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?