MENACTRIMS Highlights 2022
Flipping the Pyramid Matters
I was quite surprised by how many healthcare professionals (HCPs) from the MENA (Middle East and North Africa) region read MS-Selfie. One neurologist thanked me for teaching her how to manage MS via the MS-Selfie Newsletters. This is remarkable as the MS-Selfie is for people with MS rather than HCPs. It made me think that I may be writing the Newsletters at a level that may be too medical for pwMS. Please let me know if I am or at least ask questions if you don’t understand what I am writing about.
One of the attendees liked my ECTRIMS highlight Newsletter and hoped I would do one at the MENACTRIMS meeting. So here I go and will give it a try.
The be brutally frank, the main themes of the meeting were much the same as ECTRIMS 2022, i.e. (1) flipping the pyramid, (2) smouldering MS & microglia, (3) biomarkers, (4) COVID-19 and (5) EBV. Excluding the science, the main highlight for me was seeing how many women attended the meeting. I was delighted to see that women not only attended in numbers but also presented keynote lectures and research findings and actively engaged in the Q&A and informal discussion sessions. The future is bright in MENA and is tinged with a shade of pink ;-)
Flipping the pyramid
It was clear that Egyptians, like most of the world, are experiencing economic hardship. The Egyptian economy has shrunk, they have high inflation, the Egyptian pound has weakened, and they have been hit by the global energy and food crises. As always, healthcare is a victim of the economy and politics. As a result, access to high-efficacy DMTs seems to be handicapped by financial constraints mainly because the older, less effective DMTs are much cheaper. The payers require pwMS to start on less effective therapies first-line and have these fail them before being escalated to higher efficacy DMTs. This, however, is not the norm in MENA. In the richer Middle Eastern countries, access to higher efficacy therapies did not appear to be constrained, and some neurologists have bought into the concept of flipping the pyramid.
Despite the need for us to be more proactive about treating MS, MENA neurologists have the same concerns as European neurologists; they are concerned that by flipping the pyramid, we will be over-treating pwMS who will eventually turn-out to have benign MS and, therefore, do not need high-efficacy DMTs and the perceived risks associated with these therapies.
Their arguments about over-treating MS can be countered on several fronts. (1) Benign MS is rarely benign MS. When you look at natural history studies, such as those in southern Sweden, after 40-50 years of follow-up, very few (<5%) have benign diseases (low physical disability). It is also very difficult to predict who will have benign disease early in the disease. Benign MS is a retrospective diagnosis; by the time you can say you have benign or non-benign MS, it may be too late to do anything about the course of the disease. DMTs should be considered preventive therapies, i.e. to prevent disability and not to reverse disability. In the current environment, most people with benign MS are those that have had their MS treated early and effectively with DMTs (NEIDA). (2) It is increasingly clear that the maximum benefits of treating MS with high-efficacy DMTs occur early and that the benefits are reduced with time. Yes, time really is brain and/or spinal cord. (3) Finally, with the emergence of natalizumab in JCV-negative patients, cladribine and anti-CD20 therapies (ocrelizumab, ofatumumab & rituximab) the risks of high-efficacy DMTs are not, in fact, that high. All these therapies are highly effective and relatively safe. What HCPs need to do is to remember themselves and to remind pwMS about what untreated or undertreated MS looks like. It is not pretty. Therefore they should let pwMS make their own decisions about flipping the pyramid.
Summary statement: Knowing what we know about MS, it is becoming increasingly hard to justify not offering people with active MS high-efficacy DMTs first-line.
Do you agree or not?
Clearly, this position allows individuals with MS to opt-out of having the pyramid flipped, but at least they have a choice in deciding how they want their MS treated. We have to treat pwMS as individuals, but treating MS could be considered a public health problem. The more pwMS treated with high-efficacy DMTs, the better the outcome for the group. An example of this is the recent comparative data between Sweden and Denmark. In a registry-based retrospective study, 35% of pwMS in Sweden and 8% in Denmark received high-efficacy DMTs first-line and surprise, surprise, the Swedish patients, accrued less disability and had fewer relapses (see Spelman et al., 2021).
Treating MS could be viewed in a similar way to how we use vaccines to prevent infections, i.e. you have to treat as many pwMS as possible with high-efficacy DMTs to prevent disability at a population level, knowing that a small number of people will experience the consequences of serious adverse events from the treatment. In other words, you are putting a minority of pwMS at risk of collateral damage from adverse events to protect the majority of pwMS from unnecessary disability.
In comparison, the approach of maintenance-escalation is delaying access to high-efficacy DMTs and their benefits, which they will at some point require but a point when they are less effective, to protect the minority from serious adverse events.
Who is right, the flippers or the escalators?
In my opinion, the former argument wins hands down. This is why we need to update our “MS Brain Health: Time Matters” policy document to include the latest evidence. I think the update should be called “MS Brain Health: Flipping the Pyramid Matters”. I am not sure this sounds right; suggestions are welcome.
A lot of discussion at MENACTRIMS was about what to do when you identify patients with smouldering MS on DMTs, i.e. patients have NEIDA (no evident inflammatory disease activity), but are still getting worse. Many neurologists suggested escalating DMTs at this point. I commented that we have no idea that escalating patients with smouldering MS who are NEIDA will respond to delayed access to higher efficacy DMTs. This is why we need controlled trials and new treatment strategies to target smouldering MS.
Smouldering MS and microglia
There were numerous talks on smouldering MS. How to define and identify smouldering MS. How to monitor smouldering MS clinically and by using MRI and PET imaging and with other biomarkers, and finally, how to treat it with targeted therapies. We were reminded that BTK inhibitors are the most promising new class of drugs in development. Not only do BTKi target peripheral and central B-cell activation, they also inhibit activated proinflammatory microglia. I made the point that, as a class, they are likely to be potent anti-EBV agents as well.
There were elegant presentations by several different presenters on BTKi, which covered their mode of action, efficacy in phase 2 studies and their unique mode of action due to CNS penetration and ability to downregulate microglial activation. What was not discussed is the ability of BTKi to target EBV-infected B-cells.
You may not be aware that when EBV enters a latency programme, it uses BTKi signalling to bypass pro-survival signals via the B-cell immunoglobulin receptor. The EBV protein that does this is LMP2 (latent membrane protein 2) and substitutes for the B-cell receptor. By inhibiting signalling via BTK, the cells undergo cell death. There is good data on EBV-induced cell survival is inhibited by ibrutinib, a first-generation BTKi. The fact that BTKi are likely to target EBV-infected B-cells excites me and is one of the reasons I have BTKi on my list of potential anti-EBV drugs to be tested in MS. Saying this, I am having a hard time convincing the Pharma companies with BTKi development programmes to look at EBV biology in their trials. Why? I suspect no pharma company wants to take a chance of showing their drug works in MS because it is an EBV antiviral. This insight will lower the bar and open up challenges from competitors.
You may already be aware of my position on microglia. I am not sure if they are innocent bystanders, i.e. making an appropriate response to tissue damage and cleaning up the mess, or they are dysregulated and contributing to the damage in MS. I favour the former position and think that when we treat the causes of MS, i.e. EBV, then the microglial will switch themselves off in due course. This is why showing downregulation of microglial activity on PET imaging with DMTs such as BTKi may represent an anti-EBV effect rather than a microglial effect. I suspect many basic scientists, imaging scientists and pharma scientists will disagree with me. What is your opinion on this?
Biomarkers
There was a rich stream of biomarker talks from an MRI and body fluid perspective. Neurofilament got a lot of airtime, and it looks like it will be widely adopted when the assay becomes available for general use. Despite NFL mainly being a biomarker of acute inflammation, a small signal, at least at a group level, that raised or minimally raised NFL is associated with smouldering MS and poorer disease outcomes. The problem with this insight is that it may be difficult to define a healthy NFL level for individual patients with MS. It is clear that if I had MS, I would want my area under the NFL curve to be as low as possible.
EBV
There was a whole session dedicated to EBV, and MS. Alberto Ascherio reviewed the epidemiological evidence supporting EBV as the cause of MS. Francesca Aliosi then discussed the biology of EBV and MS and presented several alternative hypotheses of how EBV may cause MS. I concluded the session on what needs to be done to prove or disprove the hypothesis that (1) EBV causes MS and (2) drives ongoing MS disease activity. My talk is not new, but it gradually changes slightly whenever I give it. What is clear is that there are at least six paths forwards to test these hypotheses.
Primary prevention at a population level - EBV vaccine to be given at a population level to prevent infectious mononucleosis (IM) and possibly MS and other downstream diseases (other autoimmune diseases and EBV-associated cancers).
Primary prevention in a high-risk population, i.e. first and second-degree relatives of people with MS.
Immunotherapy targeting EBV - therapeutic EBV vaccine(s) to boost immunity to EBV to control infection (latent-lytic cycling).
Immunotherapy targeting EBV - autologous or allogeneic cytotoxic or CAR T-cells targeting EBV to control infection (latent-lytic cycling). For CAR T-cells, this can be EBV or B-cells.
EBV antivirals to treat MS can potentially target either lytic or latent EBV infection in the periphery and/or CNS.
To re-investigate the mode of action of MS DMTs to see if they are working as anti-EBV drugs in MS. I would start with teriflunomide, natalizumab and the IRTs (alemtuzumab, cladribine and AHSCT) as they allow you access to peripheral B-cells. For the anti-CD20 therapies, it is harder as these agents keep B-cells depleted, and hence you can’t access EBV in the periphery.
You can download my presentation from my open-source folder, where I share my slides. You are welcome to hack the presentation and use the slides for your talks.
Egyptians
I want to take this opportunity to thank my hosts for being so kind, enthusiastic and welcoming. Professor Magd Zakaria gave me a string of misketa beads (prayer or worry beads), which had been blessed by a bishop from the Coptic Orthodox Church in Cairo. The reason he gave them to me is that I have had such bad luck over the last two years that by keeping them on me, I will scare away evil spirits, and they will protect me. Such a thoughtful and caring gift. Thank you.
Importance: Treatment strategies for relapsing-remitting multiple sclerosis (RRMS) vary markedly between Denmark and Sweden. The difference in the association of these national strategies with clinical outcomes is unknown.
Objective: To investigate the association of national differences in disease-modifying treatment (DMT) strategies for RRMS with disability outcomes.
Design, setting, and participants: This cohort study used data on 4861 patients from the Danish and Swedish national multiple sclerosis (MS) registries from the date of index DMT initiation (between January 1, 2013, and December 31, 2016) until the last recorded visit at time of data extraction (October 2, 2019).
Exposures: All MS-specific DMTs initiated during the observation period were included in the analysis.
Main outcomes and measures: The primary study outcome was time to 24-week confirmed disability worsening. Secondary outcomes were 24-week confirmed disability improvement, milestone Expanded Disability Status Scale scores of 3 and 4, annualized relapse rate, time to first relapse, and treatment switching. Data were analyzed using inverse probability of treatment weighting-based models using a propensity score to weight and correct the comparison for the imbalance of confounders observed at baseline between the 2 countries.
Results: A total of 2700 patients from the Swedish MS registry (1867 women [69.2%]; mean [SD] age, 36.1 [9.5] years) and 2161 patients from the Danish MS registry (1472 women [68.1%]; mean [SD] age, 37.3 [9.4 years]) started a first DMT between 2013 and 2016, were included in the analysis, and were observed for a mean (SD) of 4.1 (1.5) years. A total of 1994 Danish patients (92.3%) initiated a low to moderately effective DMT (teriflunomide, 907 [42.0%]) and 165 (7.6%) initiated a highly effective DMT, whereas a total of 1769 Swedish patients (65.5%) initiated a low to moderately effective DMT (teriflunomide, 64 [2.4%]) and 931 (34.5%) initiated a highly effective DMT. The Swedish treatment strategy was associated with a 29% reduction in the rate of postbaseline 24-week confirmed disability worsening relative to the Danish treatment strategy (hazard ratio, 0.71; 95% CI, 0.57-0.90; P = .004). The Swedish treatment strategy was also associated with a 24% reduction in the rate of reaching an expanded disability status scale score of 3 (hazard ratio, 0.76; 95% CI, 0.60-0.97; P = .03) and a 25% reduction in the rate of reaching an expanded disability status scale score of 4 (hazard ratio, 0.75; 95% CI, 0.61-0.96; P = .01) relative to Danish patients.
Conclusions and relevance: The findings of this study suggest that there is an association between differences in treatment strategies for RRMS and disability outcomes at a national level. Escalation of treatment efficacy was inferior to using more efficacious DMT as initial treatment.
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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 nor 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 healthcare professional, who will be able to help you.
Another vote for keeping the Newsletters the same.
The alternative for pwMS is generalist non-technical advice which allows clinicians to be gatekeepers. Yes, the newsletters are technical and demand investment in the subject matter to understand them, but are the most accessible route for non-clinicians to grasp what might be going on in their bodies. Also, your newsletters provide a springboard to more technical papers if further research is sought.
As someone with Smouldering PPMS (4th straight MRI showing NEIDA in 2 years), I fully intend to challenge my MS Consultant into finding a solution/ treatment plan to my advancing condition and/or get me onto a trial (BTKi looks promising...). I can honestly say that I wouldn't know or understand enough to challenge my Consultant if your Newsletters didn't exist.
Keep it up Gavin, you're making a difference!
I've said it before, but I think your information level is at the more "medical" end of lay/accessible, but I think that's right where it belongs. There are many other sources that are less technical if people want them, and you are very good about responding to questions.
As for the policy document, I agree "Flipping the Pyramid Matters" is not perfect - it requires extra definitions/context/prior knowledge to be understood! Perhaps something like "start strong" etc.