Moving to NeuroImmunology Club

It’s been a while since i worte the last post here. Many subjects should have been discussed and others updated but several things, one of them being the Twitter time sink, prevented more frequent updates on the blog.

The second thing that happened is that i am moving the blog. The new one will no longer be just a blog but a NeuroImmunology Club instead. A place where not only posts are written but where neuroimunology discussion happens. The new site contains all previous posts and comments and is located at . Two additional features have been added to the blog:

  1. Forums for discussion
  2. RSS feed (Paper Club) to share the papers that i find most interesting for the NeuroImmunology Club. Every week a summary post with the papers added to the feed will be published. So far i am the only one adding papers to the feed but if anybody else wants to participate i’ll be glad to add another RSS feed and create a bundle of neuroimmunology papers.

This site will still be available but won’t be updated anymore so, if you want to keep updated in NeuroImmunology, please change your feed to

Narcolepsy: welcome to neuroimmunology!

A recent report in Science Traslational Medicine (1) has deserved a lot of attention by mainstream media. Headlines referred to it as the confirmation that narcolepsy is an autoimmune disease. Narcolepsy is an interesting disease both clinically (sleep attacks, cataplexy, sleep paralysis, visual hallucinations during early sleep and awakening…) and pathophysiologically. Current knowledge points at a selective death or damage in the neurons of the anterior part of the hypothalamus responsible of orexin production. Orexin (or hypocretin) is a secreted proteic neurotransmitter that regulates awakeness and apettite and whose levels in CSF are significantly lower in patients with narcolepsy than in controls. As usual, the exact cause of narcolepsy is unknown, although recent studies suggest that an autoimmune response, probably triggered by an environmental factor (let’s say, a virus), is the key process in its development (2).The paper by De la Herrán-Arita and colleagues reports an interesting, well-performed study that, contrary to what mainstream media say, does not demonstrate that narcolepsy is an autoimmune disease. But we’ll come to that later.

The autoimmune hypothesis of narcolepsy is not new at all. Among the genes that have been associated to narcolepsy, most play important roles in the immune system (3). The strongest association was found with the HLA-DQB1*0602 allele, which more than 95% of the narcolepsy patients carry. But other genes, related to the immune system have also been implicated (4). However, as in any other complex disease, genes don’t explain everything. What the HLA system does is to present antigens (the targets of an immune response, regardless of it is against a pathogen or an autoimmune one) to T cells (lymphocytes) and T cells are the ones enabled to kill a cell carrying that antigen or to call other cells so they are the ones killing the antigenic cell.  One of the main functions of HLA is to present viral particles to these lymphocytes. However, in many autoimmune diseases, the viral particles can have some similarities in structure with endogenous proteins and, thus, the immune system can divert the immune response to a self protein. Once the autoimmune response is set is usually very difficult to get rid of those autoreactive lymphocytes.

So, following this paradigm, it has been found an increase in the incidence of narcolepsy in two situations: the H1N1 influenza outburst and the H1N1 influenza vaccination campaing (5), meaning that one of the environmental triggers of narcolepsy are influenza-virus. In other reports it was described that Streptococci were the environmental trigger (6). What De la Herrán-Arita and co-workers demonstrate is, first, that some orexin pepetides bind to DQ0602 and that CD4 (helper) T cells secrete inflammatory cytokines (interferon) when incubated with orexin peptides bound to DQ0602. Second they demonstrate that patients with an increase in CD4 T cells reactivity against orexin also have a (slightly) increased reactivity against H1N1 influenza virus peptides. Finally, when those patients were vaccinated with Pandemrix (H1N1 vaccine), the number of orexin-reacting cells increased significantly. This summarizes a tremendous amount of work and a beautiful paper. In my opinion, however, a couple of clarifications have to be made with regard to the “this paper demonstrates that narcolepsy is an autoimmune disease” statement. To be honest, those extraordinary claims are not mentioned by the authors. Mainstream media are te ones concluding so strongly about the study findings. In fact, most of the clarifications have already been mentioned by the authors in the discussion, but i think some of them are worth to be highlighted because are useful for other “autoimmune diseases”.

– First, the finding of a specific immune response does not mean that the cause of a disease is autoimmune. Immune responses against self antigens are present in degenerative, infectious, toxic and genetic disorders as a way to clear debris from a damaged tissue, as a stochastic phenomenon or as a secondary immune reaction not causing damage by itself. So describing immune mechanisms does not imply autoimmune disease. A true autoimmune disease has to fulfill the Koch postulates that, so far, narcolpesy does not.

Linking with the previous point is interesting to note that narcolepsy patients react more strongly than controls against two orexin peptides, but there are several other orexin peptides to which patients and controls react exactly the same and to the same extent patients do against the two narcolepsy-specific peptides. Moreover siblings and monzigotic twins of narcolepsy patients that do not have the disease (but that share the HLA DQ0602) do not show increased reactivity against the orexin peptides. That can be due to key differences in the T cell receptor repertoire between patients and controls but then the important fact is neither the HLA nor the virus, but the T cell receptor (that is the one recognizing the peptide bound to the HLA). In that sense a recent paper by the same group has refined the genetic association studies and found that TCR beta chain is also a genetic risk factor for narcolepsy (4).

– Second, CD4 T cells are key cells in an immune response but do not cause damage to the tissue because they are not meant to cause damage, just help others do it. The ones that usually cause damage are B cells or CD8 T cells. CD8 T cells recognize HLA class I, which has not been found to be a risk factor in narcolepsy. B cells secrete antibodies but autoantibodies have not been found in all patients with narcolepsy. If that were the case, as in other autoimmune diseases such as myasthenia gravis or rheumatoid arthritis, they could be a great diagnostic tool and, so far, they are not. However, some years ago, another group not only described that TRIB2 antibodies (7) are present in a significant proportion of narcolepsy patients with cataplexy but that the innoculation of those antibodies to rodents led to hypersomnia, cognitive disturbances and cataplexy and, importantly, to orexin-secreting neurons loss  in those same animals (8). The demonstration that passive transfer of IgG determines narcolepsy is a much more solid proof that it is in fact an autoimmune disease that the paper we are currently reviewing.

Linking with that it arises, to me, a big question. Considering that CD4 T cells have been found to react against orexin peptides, the logical move is to try to demonstrate anti-orexin antibodies. I bet the authors tested them and did not find them (but this is just what i would have done and maybe they did not). Which is then the mechanism through which that CD4 T cell leads to selective orexin-neuron damage? It might be that after an acute immune response, when all orexin-secreting neurons are dead, the antibodies dissappear but, still, big knowledge gap there…

To sum-up… Scientific reports in mainstream media, and this is not the authors fault, usually not only overclaim when reporting new findings but also, very importantly, tend to forget the scientific context of the finding and condemn previous findings to oblivion. The study by De la Herrán-Arita is an important study and deserves credit for it but,

It’s not the first study to suggest that narcolepsy is autoimmune. Several others have suggested that before from different perspectives: epidemiological, clinical and pathophysiological.

It does not demonstrate that it is an autoimmune disease (that still needs some work to be demonstrated) and other studies demonstrate that with more compelling evidence. I believe narcolepsy is, indeed, autoimmune, but claiming that it with this study is overclaiming.

It does not link the disease with the Pandemrix vaccine or with the influenza virus. That was demonstrated before with epidemiological studies. What the study does is to provide evidence of a possible molecular mimicry link between orexin and H1N1 influenza.

Finally, for the record, the aim of this post is just to clarify, just as authors do in the discussion, the mainstream media overclaims, not to criticize an otherwise interesting study.

So, regardless of this particular study, evidence in favor of narcolepsy being an autoimmune disease is compelling and, thus, efforts to try to treat it as such (and not only the symptoms), need to be started. Narcolepsy might be another neuroimmune disease with potential disease-modifying treatment and neuroimmunologists should  be implicated.


1: De la Herrán-Arita AK et al, CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy. Sci Transl Med. 2013 Dec 18;5(216):216ra176.
2: Singh AK, Mahlios J, Mignot E. Genetic association, seasonal infections and autoimmune basis of narcolepsy. J Autoimmun. 2013 Jun;43:26-31.
3: Tafti M, et al, DQB1 Locus Alone Explains Most of the Risk and Protection in Narcolepsy with Cataplexy in Europe. Sleep.
2014 Jan 1;37(1):19-25.
4: Han F et al Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic. PLoS Genet. 2013 Oct;9(10):e1003880
5: Dauvilliers Y, et al Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain. 2013 Aug;136(Pt 8):2486-96.
6: Aran A, et al Elevated anti-streptococcal antibodies in patients with recent narcolepsy
Sleep. 2009 Aug;32(8):979-83.
7: Cvetkovic-Lopes V, et al Elevated Tribbles homolog 2-specific antibody levels
in narcolepsy patients.
J Clin Invest. 2010 Mar;120(3):713-9.
8: Katzav A, et al Passive transfer of narcolepsy: anti-TRIB2 autoantibody positive patient IgG causes hypothalamic orexin neuron loss and sleep attacks in mice. J Autoimmun. 2013 Sep;45:24-30.

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 frequency and confirm the results in two different series of cases, testing ¡almost 400 patients!. Then they map the epitope of the protein that is being targetted and design immune competition experiments to further support the specificity of the finding and finally develop in vivo experiments with murine models to confirm that patients’ immunoglobulins bind to that protein and determine loss of the protein and complement fixation (one of the ways how antibodies cause damage). Awesome.

But, why is the discovery of those KIR4.1 antibodies so important? I’ll try to summarize my reasons…

First, for historical reasons. The quest for antibodies in MS has been a research topic for many years. Patients have IgG oligoclonal bands in the CSF and B cells in CSF and brain tissue. And, as we have explained before, a trial with Rituximab, that depletes B cells, the cells producing antibodies, has been very successful in phase II trials. So, as in many other diseases, autoantibodies were thought to play a role. However, animal models, biased towards a T-cell paradigm of MS and a huge body of literature describing antibodies against myelin proteins and other proteins, precluded, in my opinion, an unbiased search for new antibody reactivities. To the point that many researchers thought that there was not a unique antibody but many differnt antibodies depending on the patient. This paper opens a new era in MS research. So, first reason why this paper is important is because it changes a decades-long paradigm and many things in MS research, from animal models to patient classification for trials will have to take those antibodies in account.

The second important reason is because, although not right now, it will have important influence in patient care:

1. Diagnostic criteria will have to incorporate these antibodies and probably set a “seropositive” and “seronegative” category. And this is very important because primary progressive MS patients have antibodies in a similar proportion to RRMS and secondary progressive patients. So maybe we should start classifying patients not depending on clinical features but on serological status.

2. Clinical trials and, thus, treatments, will have to be assaied depending on the presence of these antibodies. Maybe patients with antibodies respond better to Rituximab than those that don’t have them. But, more importantly… we know that patients with primary and secondary progressive MS don’t respond to immune therapies very well (not to say at all). But, what if those with antibodies do respond to antibody-depleting therapies? For example, the OLYMPUS trial, testing Rituximab efficacy in primary progressive MS, failed in finding effectiveness in PPMS patients. But, it detected a subgroup of patients, those with more “active lessions”, in which it could be useful. What if we re-classify patients not by MRI status but by antibody status? Is rituximab then clearly effective?

3.Those antibodies, for sure, will help defining clinical-immunological correlations and prognostic subgroups. I’m mostly thinking about a first neurologic episode, for example. If a patient has an optic neuritis but negative antibodies, has the same risk of developing MS than a patient with positive antibodies? That is applicable to response to therapy subgroups, to severity subgroups and antibody titers, etc.

4. If 50% of patients have KIR4.1 antibodies maybe the other half is “a different thing”…the same way we have myasthenia with anti-AChR, MusK and LRP4 antibodies and they have different clinical features and response to therapies, it can happen the same with MS. Now, having a 50% rate of positivity for KIR4.1 many more scientists will believe that the other half have also autoantibodies against something else and that can help being more accurate in diagnosis and management.

5. Maybe now we can understand some unexplained things in MS…. is KIR 4.1, a potassium channel, responsible for the variation in symptoms depending on temperature (Uhthoff’s phenomenon) in MS? How does fampridine exert its function improving some symptoms in MS if it blocks potassium channels? Is the increased frequency of uveitis intermedia (pars planitis) in MS a general autoimmune association or it derives from the fact that KIR4.1 is expressed in the Müller glia of the retina? And so on…

All these things will have to be addressed in studies designed specifically for solving those dilemmas but, in summary, we will see a lot of changes in MS research and care derived from this study. It’s going to become one of the most cited papers in MS and very likely it will improve a lot what we know of that disease and will rescue B-cell depleting therapies in favor of all patients. Or, at least, in favor of those with antibodies against KIR4.1. Congratulations to Dr Srivastava and co-workers because they have found something very interesting for those like me who like neuroimmunology and, more importantly, something that helps in clarifying MS pathogenesis and, that, in the end, will improve care.

Pills for multiple sclerosis

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 of oral therapies is that they overcome the annoying need of injections. That adds one important thing, the adherence to treatment, that was far from optimal with injectable standard therapies (interferon and glatiramer acetate), will probably improve substantially. However, being less annoying does not mean that they are free of adverse events. Some patients tend to think that oral therapies are “less strong” than injected ones. In this case, specially with some of the above-mentioned treatments, is not true at all and that has to be taken in account when deciding which treatment use for each patient. It’s not the same having an aggressive MS than a “benign” one. Regarding adherence and tolerance one important thing is that some treatments, despite being oral, will have also immediate side effects: skin rashes, diarrhea, hair thinning or loss… that may not be important overall but can be for some patients. In some cases the balance of effectiveness/side effects might balance in favor of intravenous therapies. For example, the benefit of receiving natalizumab might outweight the need of visiting once a month the hospital if that prevents relapses, need for steroids, etc. The best thing of the new scenario is that the options increase significantly and so are the chances of finding the appropriate treatment for every patient in terms of both effectivenes and safety.

So, let’s start:


Fingolimod is currently available in the US and Europe. We’ve wrote about it before. Is quite effective, clearly better than interferon and glatiramer acetate but, in my opinion, the safety profile, despite not being very bad, raises some concerns.

Profile: Fingolimod is a sphingosine-1 phosphate receptor (SP1R) inhibitor. SP1R function is necessary for lymphocytes to leave the lymph nodes. Fingolimod, then, exerts its function by preventing the egress of pathogenic lymphocytes from lymph nodes. In that way, autoreactive lymphocytes can not get into the central nervous system and attack the myelin. The standard treatment regimen is a 0.5mg pill daily.

Effectiveness: Annualized relapse rate showed a 50% reduction in comparison to placebo and a 40% when compared to interferon beta 1a (intramuscular). Despite that benefit in relapse rate, disability progression only showed a modest reduction with fingolimod when compared to placebo and there was no difference compared to interferon.

Safety: As a consequence of lymphocyte sequestration in the lymph node, there’s an important peripheral lymphopenia. Risk of severe infections is higher in fingolimod (as it is with all immunosuppressive drugs). In the pase 3 trials there were 2 deaths that could be related to the treatment. One was an herpes simplex encephalitis and the other one a varicella-zoster systemic infection. Both deaths occurred with the higher doses (1.25 mg), but none with the dose that has been approved (0.5 mg) and now, varicella serologies are routinely performed before starting treatment. Other important side effects to take in account are cardiovascular events. Fingolimod can cause bradycardia, so the first dose has to be administered monitored in the hospital. It’s not recommended to use fingolimod in patients with known cardiopathies or arrythmias or under treatment with drugs that can cause bradycardia (such as beta-blockers or calcium antagonists). One post-commercialization death is probably related with this side effect of the drug. Other side effects that can be concerning but that are carefully monitored are skin neoplasms (basal-cell carcinomas) and macular edema (which was also more frequent in the higher doses and not with the approved dose).

Conclusion: Fingolimod is a powerful oral therapy but the safety issues can make it less desirable than some other oral treatments that are to come. If MS is very aggressive patients and doctors will tend to prescribe monoclonal therapies with a better efficacy (natalizumab, rituximab/ocrelizumab, alemtuzumab…). And for patients with a milder MS the safety issues can be an important pitfall.


Phase III trial testing cladribine in multiple sclerosis were published in the New England Journal of Medicine the same day that fingolimod results were reported. Despite a similar effectiveness compared to fingolimod, the increased frequency of neoplasms, severe infections and deaths compared to placebo, led to negative reports of FDA and EMEA and was not approved.

Profile: Cladribine is a chemotherapeutic drug that is used in a rare leukemia. It’s a purine analog, so it interferes in DNA synthesis. Usually cells can metabolize it easily, but not blood cells, so it acts as a cytotoxic drug in those cells. The treatment regimen consists of 4 doses monthly (aproximately) for 4 months and two more doses at weeks 48 and 52.

Effectiveness: Very similar to fingolimod. A decrease of 50% in annualized relapse rate and a slight decrease in the rate of disability progression compared to placebo.

Safety: There were 4 deaths in the cladribine group and two in the placebo group, although none of them seem to be related to the treatment. However, the rate of infections and, more importantly, the rate of neoplasms of any kind was higher among cladribine-treated patients. These facts, added to the duration of the effect (lasts for months), that prevents a quick withdrawal if any serious adverse reaction appears, were determinant in its rejection as a standard therapy in MS.


Two phase III trials have been developed to test teriflunomide in MS. The TEMSO trial, comparing it with placebo, resulted positive, with a good safety profile. However, when comparing teriflunomide with interferon, despite a better safety and tolerance with teriflunomide, there was no difference in effectiveness. Nevertheless applications for approval have been filed and awaiting decision. Teriflunomide is administered once daily.

Profile: Teriflunomide is the active metabolite of leflunomide, a drug used since the late nineties in rheumatoid arthritis. It acts halting the division of rapidly growing cells, including inflammatory cells.

Effectiveness: The effectiveness of teriflunomide is a step lower than fingolimod and cladribine. It decreases the relapse rate approximately a 30% and the disability progression between a 21% and a 29% depending on the dose. Those results, that are in the range of interferon effectiveness, are dissapointing when compared with other treatments such as fingolimod or natalizumab.

Safety: The main advantage of teriflunomide compared to currently available treatments is the safety and tolerability profile. With an important add-on: it has been used (leflunomide) in rheumatoid arthritis and the experience is huge (around 2 million patients-year exposed). In the trials there were no deaths and the rate of serious adverse events was similar to that of placebo. Diarrhea and hair thinning or loss were the only adverse events that were more frequent in teriflunomide than in placebo. However those adverse events did not lead to discontinuation. In rheumatoid arthritis patients leflunomide caused two progressive multifocal leukoencepaholopathies  (but the rate is extremely low).


Laquinimod, as teriflunomide, is also a step below fingolimod and cladribine. However, again, its safety profile makes it appropriate for patients with low disease activity with a good risk-benefit balance. It has a surprisingly good performance on disability considering the por results in relapse rate reduction. Results of the ALLEGRO phase III trial were recently reported in the New England Journal of Medicine. It’s administered once daily.

Profile: Laquinimod is a quinoline derivative that acts reducing inflammatory infiltrates in the central nervous system and decreasing demyelination and axonal loss.

Effectiveness: Despite a very modest decrease (23%) in relapse rates compared to placebo, surprisingly disability progression was almost a 30% lower than for placebo. Usually the performance on relapses (related to inflammatory attacks) is much better than on disability (related to stablished neuronal loss). This is not the case, what has led to several studies to assess the “neuroprotective effect” of laquinimod. So, despite a dissapointing effect on relapses, the overall effectiveness in disability is similar to that of interferon, fingolimod and other “more powerful” drugs.

Safety: As in teriflunomide, no deaths occurred with laquinimod and the rate of severe adverse events was similar to placebo. Among the frequent adverse events, abdominal and back pain were significantly higher in the laqinimod group. However, overall tolerance was good.

Dimethyl Fumarate (or BG-12)

Phase III trials with fumarate have not been published yet but the results from the DEFINE trial have been reported in the last ECTRIMS meeting. It yields a very good effectiveness (in the range of fingolimod) with an also good safety profile. It’s curently under review by FDA and EMEA. The only important disadvantage is that it needs to be taken twice or three times a day, influencing adherence and, then, effectiveness.

Profile: BG-12 is a immunomodulatory drug that has been tested in psoriasis. Its mechanism of action is not understood but it decreases the levels of some inflammatory cells and cytokines in animal models. It has been suggested that it acts in both, inflammatory lessions and preventing axonal/neuronal loss. It’s administered daily, twice or thrice.

Effectiveness: The annualized relapse rate and the risk of relapse is around 50% lower compared to placebo. It also decreased disability progression by 38%.

Safety: No deaths, serious adverse events, infections or neoplasms were reported. The most frequent adverse events in the fumarate group were flushing and gastrointestinal symptoms, which were higher the first month of treatment and then decreased.


Firategrast has been studied only in a phase II trial. However, the good results of that trial and the features of the molecule make it an interesting treatment that deserves attention.

Profile: Firategrast is a small molecule that inhibits the alpha4 intergins. This is the same molecular target of natalizumab, but natalizumab is a monoclonal antibody, with a half-life of 11-12 days, while firategrast half-life is around 4 hours. This is important if a serious adverse event appears because it allows a faster reaction to prevent further progression of the adverse event. It’s administered twice a day.

Effectiveness: Phase II trials usually are not powered to detect differences in clinical parameters and so, no significant differences were detected when compared to placebo. It decreased significantly the rate of gadolinium-enhancing lessions (meaning the rate of new inflammatory lessions in the MRI) by 50% (in the high dose group). A trend towards lower relapse rates in the firategrast group was found but those differences were not statistically significant.

Safety: Firategrast was well tolerated and no significant adverse events were reported comparing with placebo.

So, in summary, a handful of new oral therapies (and another handful of parenteral therapies) is about to come. With the important advantage of improving the tolerability of the treatments, keeping, in the worst case, the effectiveness of the traditional therapies. Moreover, the appearence of this variety will improve the individualization of care. Patients with low disease activity could benefit from teriflunomide or laquinimod, patients with higher activity could use fingolimod or BG-12…patients not tolerating or responding to one of them can switch to another one or to one of the old treatments…. and combination therapies can be used to increase the options when suboptimal responses are achieved. And that’s only for the oral therapies… if we add the highly effective alemtuzumab, natalizumab, rituximab, ocrelizumab… the therapy of MS is experiencing an exponential progress that benefits first and most importantly MS patients, except those with progressive forms. Hope the research efforts on progressive forms can lead soon to a similar variety in therapies for them too.

Does multiple sclerosis start from the gut?

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 rates between both groups. And eureka!: none of the animals bred in germ-free environment developed EAE while 80% of SPF-bred animals developed EAE at 30 days. Moreover, when germ-free animals were recolonized with microbiota developed EAE at the same rate and frequency as SPF-bred animals. The study then describes a number of immunological tests to confirm that the observation is due only to the breeding variable and not to factors related to the nature of the model or to complete T cell anergy due to germ-free conditions.

The main conclusion is that non-pathogenic bacterial microbiota may contribute to MS development. Or, more accurately, that autoreactive lymphocytes are necessary, but not sufficient, condition to develop MS. However, again, EAE is not MS, and human nature is much more varied and genetic discordant than lab mice. But taking in account that we know that genetic causes are not sufficient to develop MS and environmental factors play a decissive role, further research and, importantly, further colaboration, for example, between the MS genetics research consortium ( International MS Genetics Consortium) and microbiome research consortium (The Human Microbiome Project) is needed to explore in humans what this beautiful and simple study reports in mice.

Fingolimod unexpected death

A few days ago we had access to this alert in Medscape. An MS patient, that had completed the 6-hour vigilance period after the first dose of fingolimod, died unexpectedly the next day.  We don’t know much about it and we should wait until this case is resolved and an official report released. We only know that the patient was already taking beta-blockers and calcium channel antagonists, with bradycardia among their side effects. However, it re-inforces my view that Fingolimod safety has to be carefully followed-up.
Anyway, one important message is that an oral treatment, a pill, does not necessarily have to be safer than a biological treatment. It may be easier to take for patients but not necessarily innocuous.

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 relapses…  As expected, those results were similar to the ones obtained with Rituximab. In every other context those data will be enough to develop a phase III trial and probably get approval when completed. If we did not have Rituximab i would be pussing for Ocrelizumab phase III trial, but i can’t knowing what we know: A woman died (out of 200 patients). In the supplementary material of the The Lancet paper there is a detailed description of what happened. Infection was not detected and this patient had been stung by a wasp days before. But this patient has to be added to those of the RA and lupus trials and not be neglected.

We have then, a very good therapy, pretty safe and with a huge use experience, Rituximab. We have a very good therapy, not so safe or, at least, that raises serious concerns about some safety issues, some of them leading to patients’ deaths and that has not been used in clinical practice yet. What should we do? I think that if we, neurologists, have any trace of common sense, we should push for a phase III trial on Rituximab, convince Roche and Biogen of getting rid of Ocrelizumab (their losses can be still higher if they keep pushing that option) and persuade them that they have a nice therapy, that probably no other company will challenge on the short term and will give them profits for sure. In my opinion that is the best way of saving governments and companies money, accelerating the approval of a new therapy for aggressive MS and avoiding unknown risks. The alternative should be a public or privately funded (through foundations or patients’ associations) alternative trial to overcome the commercial criteria in drug development.

What do you think?


Interferons, get out!

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…

What’s going on disimmune peripheral neuropathies

Last June NeuroImmunology attended the 2011 Biennial meeting of the Peripheral Nerve Society in the Bolger Center, Potomac (MD).

We were obviously interested in disimmune disorders but, we must recognize that, probably, breakthrough, surprising and interesting works were outside our field. Genetic and acquired neuropathies sessions showed, in our oppinion, a higher level than disimmune neuropathies ones.

However, the whole meeting was pretty interesting and some useful conclusions made us think that past work may be starting to give results. I have several comments and remarks regarding disimmune neuropathies:

For me, the first and most important conclussion is the desperate need we have in knowing a lot more of disimmune neuropathies pathogenesis:

  • Guillain-Barré syndrome studies are focused almost exclusively in antiganglioside antibodies (which, to date, are the best and more solid research line in these disorders) and don’t seem to point in any other direction, cause or mechanism. However, the ambitious GBS multicentric database projected by Dr Jacobs’ group will, for sure, help in performing other kind of studies, genetic, pathologic and immunopathogenic. We hope we can move on antiganglioside antibodies and see beyond. Dr Huizinga, from Dr Jacobs group, presented their job on dendrictic cell role in GBS pathogenesis and molecules implicated in dendritic cell priming of B cells. It seems that new, non-antiganglioside, works are arising. Regarding antiganglioside antibodies, all posters presented by Dr Willison and Yuki groups were also remarkable.
  • CIDP is, by far, the less known of all disimmune neuropathies. We still debate if auto-antibodies or T cells are the effectors. Immunopathogenic studies are scarce, weak and based in imperfect models (modified from multiple sclerosis ones, like experimental autoimmune neuritis – EAN- ). The most remarkable work in CIDP and related diseases was presentation by Gerd Meyer zu Horste, from Dr Kieseier’s lab, showing a new model of CIDP obtained knocking out ICAM-1 in NOD mice. Apart from this job, Dr Kieseier’s group is the only one that consistently publishes in CIDP basic immunology, and that was evident in the number of presentations in the meeting. In the same direction of disease models, Dr Figlia, from Angelo Quattrini group presented a beautiful conference about a model of demyelinating neuropathy caused in mice by an spontaneous mutation on dystroglycan. Although pathological features resembled those of a CIDP it pops up the question if that would fit better with an inherited cause of neuropathy, taking in account that dystroglycan is a necessary element of the extracellular matrix and has nothing to do with immune system (as far as i know). Anyway, beautiful work. Neurofascin was proposed by Dr Pollard group, as a novel antigen for GBS and CIDP. However, antigens detected by ELISA always raise the question if those antigens, detected in their denaturalized situation would be detected as well in conformational, natural situations and, thus, could be pathogenic. But, again, nice stuff to work on.
  • Nothing remarkably new was presented in multifocal motor neuropathy and paraproteinemic neuropathies pathogenesis. In anti-MAG neuropathy i liked a work, by an Argentinian group (Dr Lopez and co-workers) on the protective role of MAG for motor neurons.

The other main conclusion i reached in the meeting was that the former (knowing better the mechanisms) should lead to better, more specific therapies. We are blindly trying whatever is being tested succesfully in other diseases and still have not any alternative therapy likely to become a standard treatment in the future, IVIG and steroids aside. We’ve tried Rituximab, Alemtuzumab, Natalizumab… but except the isolated case in which Natalizumab was used, nothing specifically chosen on an immunopathogenic basis. We still are eagerly waiting for a trial with Eculizumab in GBS

However, among all the IVIg and Rituximab noise, i found an interesting poster regarding therapy. A trial in rats comparing efficacy of a recombinant IgG-Fc compound that could substitute the scarce and expensive IVIg courses. It demonstrated to be as effective as conventional IVIg in EAN Lewis rats. We hope this could be the first step to a novel therapy that could avoid the need of donors that we have now with conventional IVIg.

In conclusion, although several good presentations were worth the trip, we got home the idea that more knowledge of mechanisms and more lab work is desperately needed to move forward in disimmune neuropathies. Unless we prefer to stay stuck to decades-old theories and treatments.

All the abstracts of the meeting can be found online here

Extraordinary claims…

… require extraordinary evidence. That is the heading of a “Message from the Editor” in Annals of Neurology published online in April 2011. It comments on a paper demonstrating the absence of retroviral particles in CSF of patients with chronic fatigue syndrome while criticizes the role of publishers (and researchers)  paying (too much) attention to breakthrough discoveries while they don’t care much about those same discoveries when they fail to be replicated. It also points out the role of mainstream media and the internet in amplifying these “extraordinary claims” and highlight the need of humble statements and careful replication before attracting mainstream media focus on those claims. They, as we did, compare the case with that of the CCSVI (the other way, though) and remember us the necessary slowness of science: ” […] as journal editors we have a responsibility to do everything possible to insure that data appearing in our pages will stand the test of time.”

The only thing i don’t like in that necessary message is that it will remain within the limits of Annals of Neurology readers. That is the battle clinicians and researchers need to win. The one outside the official means. If we fail to convey this message out of our limits we will lose the battle against bad, harmful, attractive science. So the scientific community has to grow public but grow around our own environments, both our clinics and, more importantly, our communities.