KIR4.1 antibodies: A revolution in multiple sclerosis

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

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Rituximab vs Ocrelizumab in multiple sclerosis

Two weeks ago the annual meeting of the ECTRIMS was held in Amsterdam. As usual, several interesting presentations, some of them probably good enough to change the immediate future of MS clinical practice, were presented. Among them, new data regarding the next 3 new oral therapies that probably will be approved when their results are published, laquinimod, teriflunomide and BG-12. These therapies will need a specific review later on. But the focus of this post is on the data of the phase II trial testing Ocrelizumab in MS. Ocrelizumab is a humanized monoclonal antibody targetting the CD20 B-cell marker. It depletes B lymphocytes. It is the molecular and commercial son of Rituximab and the diseases to which is aimed are the same as Rituximab. In fact, what we all expected was that Ocrelizumab improved safety and reduced infussion reactions due to its humanized nature (while Rituximab is chimeric). Rituximab had been tested before in MS with notable success. However, as we explained before, that study did not lead to a phase III trial due to commercial interests. Then its humanized version was tested expecting more safety and tolerability. But it happened that, paradoxically, Ocrelizumab turned out to be less safe. At least, while in Rheumatoid Arthirtis and Lupus Rituximab severe adverse events were very infrequent, their trials with Ocrelizumab were prematurely halted because of several fatal opportunistic infections. In MS the Ocrelizumab phase II trial was continued and, again, a death in the Ocrelizumab arm raised concerns regarding its safety. Now we have additional data regarding both safety and effectiveness. The 96 week results of the phase II trial of Ocrelizumab in MS were presented in ECTRIMS and simultaneously published in Lancet. Effectiveness data are extraordinary. Reduction of 89-96% of the rate of new gadolinium-enhancing lessions and around 80% for

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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

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