Early reflections from the EAN 2022

The European Association of Neurology (EAN) meeting is my first face-2-face conference since March 2020.

I am just returning from the 2022 European Neurological Association meeting in Vienna; it is my first face-2-face neurology conference since the COVID-19 lockdown in March 2020. These are some of my early reflections. 

Photo by Waldemar Brandt on Unsplash

Novelty vs. boredom

A very well-known and highly respected colleague said she found the MS content of the meeting boring and derivative, i.e. it was a rehashing of old data with nothing really new. I agree with her to an extent but made the point that there was clearly a seismic shift happening, which was alluded to in many of the presentations I attended and in several offline discussions I had with other attendees. 

It seems as if we have almost cracked dealing with the inflammatory component of MS. In other words, we should be capable with our current therapeutic armamentarium to render pwMS free of inflammatory disease activity; i.e. no relapse or new focal MRI activity. The attention is clearly shifting to smouldering MS. Can we stop people from getting worse despite having NEIDA (no evident inflammatory disease activity)? When challenged she did admit that the BTK inhibitors are offering us a glimpse of what the future of MS management could look like. So it was not so boring then?

Bruton Tyrosine Kinase Inhibitors (BTKi’s)

To me, the dose-dependent impact of evobrutinib on slowly expanding lesions is the most exciting DMT data this year. It is providing us with proof-of-concept data that targeting central pathology with CNS-penetrant small molecules is a viable therapeutic strategy. This is clearly very exciting and supports our ongoing trials of using ixazomib (SIZOMUS study), a CNS penetrant second-generation proteasome inhibitor, and cladribine (CHARIOT study) in more advanced MS. Yes, cladribine is a small molecule and is CNS penetrant and has been shown to reduce the number of IgG oligoclonal bands (OCBs) in the spinal fluid. The OCBs are probably pathogenic in MS and may account for some of the smouldering pathologies we see. So it makes biological sense to use an add-on or dual-action treatment to target this component of MS to prevent or slow down the damage to the end-organ (brain and spinal cord).  

EBV

I was disappointed that there was so little open discussion about EBV being the likely cause of MS and the potential driver of ongoing MS disease activity. I did manage to speak to several senior pharma executives about the hypothesis that BTKIs are working as anti-EBV drugs. Yes, latent EBV infection uses Bruton Tyrosine Kinase to provide a pro-survival signal to the B-cell to stay alive and proliferate to keep the EBV genome replicating. 

Outside of MS, there is reasonable data that BTKi reduces EBV-associated B-cell proliferation. When the early reports emerged that ibrutinib was effective against EBV-associated CNS lymphomas we tried to get the drug into pwMS in a proof of concept study. We failed! The good news is that there are four and potentially five-phase 3 programmes that are underway to develop BTKIs as a treatment for MS. I sincerely hope pharma thinks beyond the simple autoimmune model of MS when developing their products. My suggestion would be to keep the EBV hypothesis centre stage when thinking about BTKi. For this reason, I have suggested testing them as part of an induction-maintenance strategy, i.e. to use an anti-CD20 to deplete B-cell and reduce the EBV viral burden and to then use BTKi’s to suppress further EBV-associated B-cell pathology. This is particularly relevant as I suspect the anti-inflammatory effects of BTKIs based on phase 2 and phase 2 extension studies suggest this class of therapies may not be as effective as anti-CD20 therapies in suppressing MRI and clinical activity. 

Smouldering MS

As part of the ongoing recognition of smouldering MS, there was a big focus on the hidden burden of MS and cognition at the EAN. The impact of MS-associated cognitive impairment on quality of life, employment, safety and adherence to medications were discussed in several sessions. Yes, you can have no physical disability, but be incapacitated by the hidden burden of MS pathology. This is why MS has to be diagnosed and treated early and preferably treated with high-dose DMTs. 

The evidence is now overwhelming that pwMS who start high-efficacy therapy early, in particular as first-line therapy, do better on almost every outcome measure studied. The argument that this comes with excessive risk due to adverse events has been countered by the relatively low adverse events associated with the newer generation of high-efficacy DMTs. I made the point in my satellite symposium that we can now derisk most of these events. It is also important for pwMS to realise that MS is a bad disease and although some of the DMTs can result in life-threatening adverse events these are more than compensated for by the benefit of not getting disabled or at least delaying significant disability far into the future. It was also clear that time is brain. Subjects started on less effective DMTs (interferon-beta or teriflunomide) in the comparator arms of the ocrelizumab and ofatumumab studies never catch up in terms of what is lost. 

Paradigm shift

Another colleague also mentioned to me that he is beginning to see a paradigm shift in the way we think about MS. A paradigm shift tends to happen when there are too many inconsistencies with the current model and there are plenty of inconsistencies and holes in the clinico-radiological definition and autoimmune model we currently have about MS. I couldn’t agree with him more and think our current classification system of relapsing MS vs. progressive MS and active vs. inactive MS is flawed and is in serious need of being updated. Similarly, our diagnostic criteria need to be updated to address presymptomatic MS.  

Silos

COVID-19 has changed things. It is my impression that COVID-19 has sped up the divergence of neurology subspecialties. We seem to have become more siloed. I assume most neurologists with a subspecialty interest spent most of the last 2 years speaking to each other on Zoom with little lateral interaction with colleagues in other fields. Social media scientists call this the echo chamber effect, i.e. groups of people or tribes increasingly listen to the sound of their own voices and ideas and seem somewhat surprised when people outside the echo chamber haven’t heard of them. 

Siloes and echo chambers are a problem

Nobody arrives for a new neurology consultation wearing a label saying ‘I HAVE MS’.  MS is one of the great mimickers in neurology with many unusual presentations, which contribute to misdiagnoses, late diagnosis and delayed access to treatment. Without more interactions between non-MS neurologists, we can’t address this issue. 

Seniors in the MS community are increasingly pushing for the recognition of MS and related disorders to become a recognised sub-speciality and are increasingly stating that patients with MS should be managed in multidisciplinary units by MS experts and not by general neurologists. In rich countries with a high prevalence of MS, this makes sense and is likely to increasingly happen. It already happens in the NHS and some other European countries. However, this shift to super-specialisation ignores the fact that a large number of pwMS are seen by community-based general neurologists who get reimbursed for looking after patients with MS. The financial incentives of private practice result in these neurologists holding onto their patients; referring patients to someone else means less income. 

Continuing medical education

The super-specialisation drive also ignores the fact that a large number of pwMS live in countries with a low prevalence of MS, with too few patients to support centralised MS centres of excellence. For these reasons alone we need to continue to engage with our neurology colleagues, to give them the necessary skills and confidence to manage MS more proactively.  By doing this we will ensure the best outcomes for all pwMS.  This is why I had several meetings about our early plans to set up a new style of continuing medical education to try and address the unmet medical need to disseminate cutting-edge practical knowledge to general neurologists across the world. We are in the process of designing a new type of MS Masterclass for HCPs to learn and manage MS the same way MS is managed as MS units. Please watch out; we will be sharing details with you about this course in the next few months.

Brain Health

In my symposium talk, I congratulated all neurologists on how we as an MS community have shifted the MS curve (bell curve) and it is now clear that long-term MS outcomes have improved dramatically. Saying this we can still do so much better, but we need to move beyond simply targeting relapses and MRI activity and start to focus on the end-organ and smouldering MS. A large focus of the meeting outside of neurology subspecialties was Brain Health and how the EAN and wider neurology community have to focus on improving the brain health of the general population. I should have stood up and pointed out that the MS community came to this realisation quite a long time ago. Our ‘MS Brain Health: Time Matters’ policy initiative maybe 7 years old, but it is still as relevant today as it was 7 years ago. I think we may need to consider updating it to include the new data on flipping the pyramid and the importance of pre-habilitation and lifestyle medicine in improving MS outcomes. The section on MS pathogenesis should also be updated to look at treating beyond focal inflammatory activity and include more information on smouldering MS and end-organ damage as a treatment target. The lifestyle and wellness also need to be updated and have more prominence.

Conclusions

The good thing about attending meetings in person is meeting colleagues and friends, chatting, bouncing around ideas and chewing the cud. For me, it was being exposed to my colleagues and their data from other subspecialties. You would be surprised how exhilarating I found it to hear about the progress in other disease areas.  

I was blown away by how far the dementia neurologists have come with glucagon-like peptide-1 (GLP-1)receptor agonists. Early data from post-hoc analyses from diabetes trials suggest GLP-1 receptor agonists have the potential to delay the onset of dementia or the deterioration in the cognitive loss in patients with minimal cognitive impairment. It is clear these agents have an effect beyond glucose metabolism and are likely to be anti-inflammatory. If these agents work for dementia and possibly Parkinson’s disease as well why won’t they work in MS? Let’s hope the OCTOPUS trial includes a GLP-1 receptor agonist as one of its eight arms in progressive MS. Or maybe one of the Pharma companies with a novel GLP-1 receptor agonist may be tempted to do a phase 2 exploratory biomarker trial in MS? Dare I suggest slowly expanding lesions, brain volume loss and CSF NFL levels as outcome measures?

It was good to attend the EAN meeting. The only thing that was disappointing was the obvious scotoma (blind spot) in the programme about the role that EBV plays in MS. Let’s hope this scotoma, like the acute scotoma that occurs in optic neuritis,  is only temporary. I am still predicting a Black Swan event in MS and the odds of it being due to EBV are increasing rapidly. 

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry or Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.