“A bit thin this year,” said my friend as she left. And I had to agree. No blockbuster news. No big trials. Rather a quiet ECTRIMS this year. The only record was the attendance: 9000 delegates from 70 countries. After due consideration, the committee-of-one has awarded this years’ ACNR ECTRIMS prizes.

ACNR Prize For The Most Motivating Presentation: the skipper of the yacht Sailing Sclerosis

The yacht Sailing Sclerosis sailed from Copenhagen in June to arrive in Boston a few days before the ECTRIMS meeting, crewed entirely by people with multiple sclerosis. The plan is to circumnavigate the world. The skipper, a Neurologist, described how he had been inspired by talking to a man with progressive multiple sclerosis; this blacksmith was depressed because he thought that he would never sail the world in the boat he had built. The Neurologist hit him across the back and told him to get sailing again. (Hopefully the Danish GMC did not hear that bit). The skipper’s reflections on their journey so far were challenging, touching and humble.  They promise to arrive in Barcelona in time for ECTRIMS next year. Well done to Biogen for sponsoring them.

ACNR Prize For The Best Plenary Talk: David Hafler, Yale

David Hafler, one of the rock stars of multiple sclerosis biology, often gives the impression that the only work that is any good comes from his group. That is clearly not correct but annoyingly, it is not completely wrong. The new data he reported at this meeting was that

  • Next generation sequencing of T cells from the periphery and brain of people with multiple sclerosis suggests that the common ancestral founders originates in the periphery, found in cervical lymph nodes (Stern Sci Trans Med 2014). So, Hafler says this proves that multiple sclerosis is triggered in the periphery first and does not arise because of a primary brain problem, like oligodendrocyte death. I am not sure you can be so sure. But the data is impressive.
  • Eating at a fast food restaurant increases the proportion of CD4 T cells that are Th17. Who would have thought! This observation led to the idea that increased salt concentration might drive pathogenic Th17 cells (Kleinewietfeld Nature 2013). Vijay Juchroo identified SGK1 as a salt-sensing kinase which is key to this effect (Nature 2013). New data shows that high salt both reduces the suppressive capacity of regulatory T cells and induces Th17, all induced by SGK.
  • In nearly 40 years of research, no one has been able to differentiate the T cells of people with multiple sclerosis and normal healthy controls. Now, analysing memory CCR6+ T cells from patients with MS, using a novel T cell library technique, it seems that myelin-reactive T cells secrete more IFNg, IL17 and GMCSF, and less IL10, than controls.

ACNR Prize For The Most Obvious Useful Research: Dr Jeffery and the FREEDOMS investigators.

Our brains shrink as we get older. Those with multiple sclerosis have worse brain atrophy. An obvious questions is: does brain atrophy now predict worse disability in the future? This post hoc analysis of the FREEDOMS trial of fingolimod says Yes! The risk of worsening disability (so that you cannot walk unlimited distances, EDSS >4) at four years, is twice as likely if you have high rate of atrophy in the first two years. So, now you know.

The Coveted ACNR Wooden Spoon prize for the Worst Research: Dr Ratzer, from Copenhagen.

This study has all the hallmarks of poor research. Firstly, the researcher attempts to answer a question that has already been flogged to death: steroids have been shown, time and time again, to have no long term effect on inflammation and relapse rate in people with multiple sclerosis. Next, an unsuitable patient population is chosen: people with progressive multiple sclerosis. Thirdly, the number of participants is ridiculously low: n=30. And fourthly, an inscrutable primary outcome measure is used: the level of osteopontin in the CSF. Finally, when the primary outcome measure shows no result, the researcher claims a positive effect from significant tertiary outcome measures: in this case MRI MTR changes. Ummmmm.

ACNR Prize For Confusing Antibody Data: Joint between Dr Ayoglu & Dr Marignier

This is one of our most illustrious prizes, which Dr Bernard Hemmer has won several times. Every year or two, people find a serum autoantibody in people with multiple sclerosis…. which then is not replicated. Dr Ayoglu and colleagues from Stockholm are old hands in this field and presented some really nice work. They had previously shown that multiple sclerosis sera contains autoantibodies to 51 antigens that are not present in healthy control sera, using antigen arrays. They now replicated this in sera from 1000 patients and controls, including controls with autoimmune disease. Their most significant finding was a high proportion of female multiple sclerosis patients have antibodies to anoctamin 2, a calcium-activated chloride channel involved in olfaction and expressed in photoreceptors. There is plenty of work to do to make sense of this discovery, but first we should see if it is replicated.

In passing, Dr Ayoglu pointed out that they had not found antibodies against the potassium channel KIR4.1, adding to the list of studies which have not confirmed Bernard Hemmer’s 2012 NEJM claim that half of multiple sclerosis patients have anti-KIR4.1 antibodies. But, just when we thought that story was dead, Dr Marignier, from Lyon, popped up and showed – using a cell-based assay – poor evidence that some cases of neuromyelitis optica have antibodies against KIR-4.1. Bernard Hemmer, who was chairing the session, explained that his group are now convinced that one explanation for the discrepancy in results is the variable post-translational modification of KIR4.1 in different cell types. Rather unconvincingly, he claimed that ELISAs are better than cell-based assays. So, it looks as though this prize will continue to have many applicants in 2015.

ACNR Genetics Prize: IMSGC (Again)

We have a standing booking for the IMSGC to win this prize. They are – more or less – the only genetic show in town. Phil de Jager presented a joint analysis of “GWAS number 3” and the “MS Chip” giving sample sizes of 35,314 cases and 45,848 controls that now lead to a grand total of 159 variants with genome-wide significance, which still explains less than half of the heritability of the disease. The new pathways identified by this analysis are NK-mediated cytotoxicity and intestinal immune network of IgA production for instance, alongside what we already knew (T cell development, jak-stat activation and lots of T cell thingys). As we have come to expect, the vast majority of the variants are related to immune, mainly T cells, but curiously (because this contradicts David Hafler’s summary of the same work) de Jager claimed that there are some genetic variants which are mainly expressed in brain cells. In another presentation, of the IMSGC’s work on multiple sclerosis in African-Americans, seven new candidates were found of which one, called SMG7, survived a tough replication test; this RNA processing gene is also associated with lupus. This programme of work is a treasure trove for people wanting to understand the pathogenesis of multiple sclerosis.

ACNR Prize for the Most Inappropriately Written-Off Phase 3 Trial: Daclizumab

In truth this was not a good meeting for clinical trials. There was very little that was new or exciting. After the excitement of the last couple of years, I think we are in a cooling-off period. I am – apparently – alone in thinking that the results of the DECIDE trial are reasonably hopeful. Pretty much everyone I spoke to has written off daclizumab because the disability endpoint of this study failed. Daclizumab is an antibody against the IL-2 receptor and has been used in transplantation medicine for some time. It is self-administered SC once monthly and, in this trial, was compared to interferon-beta in 1841 patients. Daclizumab reduced relapse rate and new MRI lesion rate by about 50% but failed to show a significant difference on disability (EDSS changes) confirmed over 3 months. However, it did show a disability difference when confirmed over 6 months, which is traditionally considered the most robust measure of disability change. And I have learnt that phase 3 trials are fragile things, which can generate odd results. So, a sympathetic analyst looks for convergence of other outcome measures. To my mind, daclizumab’s most impressive result was that it significantly reduced brain atrophy compared to that on interferon. There were some skin side effects, but not too much bother otherwise. So, I think daclizumab is probably better than the headline negative result.

ACNR 2014;V14(5):25-26.  First published online 15/9/14