“What we did in the paper was to try to identify these 4 symptoms and to provide some rationale for particular knowledge gaps that still exist. There are particular questions that we wanted scientists and clinicians to think about, so that we could move the field forward, at least in these 4 symptoms to start with.”

Multiple sclerosis (MS) organizations across the world, together making up the International Progressive MS Alliance, have published a paper that calls for action in the field of progressive MS to prioritize certain areas of research. The groups aimed to identify and bring to attention important issues in progressive MS that need more research and funding.

First author Kathy Zackowski, PhD, OTR, senior director, patient management, care, and rehabilitation research, National MS Society, and colleagues, isolated 4 symptoms that they believe need to be targeted in progressive MS research: fatigue, pain, mobility and upper extremity impairment, and cognitive impairment. They stressed the fact that research in these symptoms is mostly done in relapsing MS as opposed to progressive MS.

 spoke with Zackowski to learn more about strategies to forward research in progressive MS and this call to action. She shared her hopes that the paper will prompt thought and push clinicians and researchers toward further advancements.

Zackowski KM, Freeman J, Brichetto G, et al. Prioritizing progressive MS rehabilitation research: A call from the International Progressive MS Alliance. 

. Published online March 15, 2021. doi: 10.1177/1352458521999970

Videos

The senior director of patient management, care, and rehabilitation research at the National MS Society discussed her recently published paper that called for progressive MS research. 

Improving Progressive MS Research: Kathy Zackowski, PhD, OTR

A recent publication by the International Progressive MS Alliance, consisting of multiple sclerosis (MS) agencies across the world, has 

called for action in the field of progressive MS

. The alliance has called on the research community expand on progressive MS research as well as organizations to devote more funding to its care.

The National MS Society is one such member organization of the alliance, and first author Kathy Zackowski, PhD, OTR, senior director, patient management, care and rehabilitation research, and colleagues outlined current issues with progressive MS research in the paper, published in the Multiple Sclerosis Journal. The authors of the paper isolated 4 symptoms that they believe need to be targeted in progressive MS research: fatigue, pain, mobility and upper extremity impairment, and cognitive impairment. They stressed the increased burden of these symptoms on people with progressive MS compared to those with relapsing MS.

 spoke with Zackowski to learn more about the need for progressive MS research and the current dearth of inquiry in this area. She discussed the lack of studies including progressive MS and the imbalance of treatments between relapsing-remitting MS and progressive MS.

What prompted the call to action for progressive MS research?

 Over 2.5 million people worldwide are affected by MS and 15% of these people are diagnosed with primary progressive MS. Eighty percent of people with relapsing-remitting MS will transition to secondary progressive MS. Treating MS has grown substantially. There's a growing number of disease-modifying therapies (DMTs), which is kind of the primary medical therapy that people with MS get. And these DMTs primarily treat relapsing remitting and secondary progressive MS, there's really only 1 approved for primary progressive MS. People with progressive MS have very few treatment options. 

The clinical consequences of having progressive MS are really varied and cumulative. They range from kind of mild sensory or visual changes to more profound cognitive and motor impairments. We know that in addition to the individual effects from the progression of the disease, there are also broad far-reaching results. MS can impact a person's job, stress to their family, add to financial strain associated with medical care. Yet, the weight of evidence is focused on symptom management that comes overwhelmingly from studies that are predominantly or even solely involving people with relapsing-remitting MS.

What is the state of research in progressive MS compared to relapsing MS?

This paper evolved because we understood that there's a lack of studies among people with progressive MS. And that creates a big challenge for clinicians and researchers in the field to evaluate symptomatic treatment in progressive MS. Back in 2018, the Progressive Alliance convened a scientific congress in Toronto, Canada, that focused on symptom management and rehabilitation in progressive MS. This was attended by scientists, industry members, and people affected by MS. It was meant to provide an avenue to share evidence supporting interventions specific to progressive MS. What we found is that the existing evidence was broad. So, there are some studies, but they were small and didn't really have sufficient depth and quality to meet the needs of people with progressive MS. We addressed cognitive rehab, the importance of exercise, motor learning, brain stimulation, fatigue interventions. But how do you tailor this to progressive MS? That was completely unanswered. 

It became clear that we need faster and more efficient progress in the field. So, a big challenge for rehabilitation versus taking a medication or getting a shot is that it's complicated. It requires an expert to provide the intervention and then it requires a lot of effort from the person receiving it, and it's usually on a continuous basis—a few times a week, or even once a day. All these factors make it much more complicated to study as well as to provide. So, the call to action was really to target research efforts aimed at optimizing rehabilitation with the goal of improving quality of life for people with progressive MS, given that there isn't sufficient research being done. This affects how clinicians can even provide treatment to people with progressive MS. Ultimately, things need to move faster, and hopefully this paper is the start to that.

Zackowski KM, Freeman J, Brichetto G, et al. Prioritizing progressive MS rehabilitation research: A call from the International Progressive MS Alliance. Mult Scler J. Published online March 15, 2021. doi:10.1177/1352458521999970

Articles

Kathy Zackowski, PhD, OTR, senior director of patient management, care, and rehabilitation research at the National MS Society discussed her team’s call to action for research. 

The Remaining Necessities for Future Progressive MS Research

evaluating anakinra (NCT04025554) and tolebrutinib

 on 7-Tesla magnetic resonance imaging (MRI) paramagnetic rim lesions (PRL) in progressive multiple sclerosis (MS) are currently underway as part of a new phase 2a clinical trial paradigm.

 The studies were virtually presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021 by Jemima Akinsanya, DO, Neuroimmunology Clinical Fellow, National Institutes of Health.

Anakinra is a recombinant human interleukin-1 receptor antagonist that was approved by the FDA for the treatment of rheumatoid arthritis and neonatal-onset multisystem inflammatory disease in 2001.

 Tolebrutinib is an investigational, orally available, brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor.

 spoke with senior author Daniel Reich, MD, PhD, senior investigator, National Institutes of Neurological Disorders and Stroke, to learn more about the unique mechanisms of anakinra and tolebrutinib. He discussed future studies he would like to see conducted with the treatments.

Could you provide some background on tolebrutinib and anakinra?

: The big unmet need, from a clinical point of view, is to address progressive MS, for which we don't really have great therapeutic options. A lot of people are working hard to try to understand the mechanisms that drive progressive MS. One of the mechanisms that seems to really be important is chronic inflammation that never really resolves in the brain—we know we can stop the acute inflammation with now around 20 disease-modifying therapies. The chronic inflammation is driven probably both by lymphocytes, T and B cells, which really drive the acute inflammation, but also by the innate immune cells, and particularly the innate immune cells of the brain microglia. So, we've been thinking about which therapies might modulate the activation of those cells, and the mechanisms they use to damage brain tissue. 

Anakinra is a soluble recombinant antagonist of the IL-1 receptor. IL-1 is a cytokine that's heavily involved in innate inflammation, and that we know is present in these areas of chronic inflammation in the MS brain. Anakinra has never, to our knowledge, been trialed in MS, and it can, unlike some of the antibodies against the IL-1 receptor, get into the brain. Tolebrutinib, on the other hand, is an investigational, unapproved drug. It's an inhibitor of Bruton tyrosine kinase (BTK) for which there are approved drugs. But tolebrutinib is able to enter the brain, and again, BTK is involved not just in signaling mechanisms within B cells, but also in innate immune cells like microglia and macrophages. So, this may have a double hit that it works both on acute and chronic inflammation. That's the thinking behind the choice of these 2 drugs.

What further research are you working on or would you like to see conducted?

The field has gotten so good at finding new therapies to block new relapses. But we are in our infancy in finding these kinds of treatments, and particularly in small, efficient trial designs that can be done like the ones we are trying to do. So, I'd like to see more research into trial design. And then there's deeper research into the biology. I'm particularly excited about some of the new tools in the genomic space for understanding cellular and molecular pathology and relating that to the imaging. One of the big efforts in our lab is to really go in and try to understand the cellular diversity. That is, the dozens of different kinds of cells present in in these lesions—and we're beginning to unravel that. That work is turning up new targets that we didn't necessarily expect, and we may find that some of those molecular targets might be amenable to treatment with repurposed medications that we know very well. Anakinra is an example of that, although it's injectable. There may be other targets that play unexpected roles in these lesions or maybe we will find molecular and cellular targets that are shared between MS and other neurological or non-neurological diseases.

There's tremendous interest now in the immune and inflammatory component of Alzheimer disease (AD). I think with the uncertain results of the anti-amyloid therapies, people are really turning their attention to the role that microglia play well. Microglia are exactly the cells that are activated and proliferated at the edge of these chronic active lesions. We already know that some of the proteins that are turned up in the microglia in AD are the same ones that are turned up in the inflammatory MS lesions. I see a sense of shared purpose here that will allow us to transcend our little categories [and saying] “I work on MS and they work on AD.” No, we have to really understand the ways in which brain tissue could be damaged. There probably aren’t an infinite number of ways, and they're probably shared across diseases. I think it's a tremendously exciting time to be able to open up this field and for new researchers at the beginning of their career to go into this. I think there's a lot we're going to learn in the next few years.

Transcript edited for clarity. For more coverage of ACTRIMS Forum 2021, 

1. Akinsanya J, Absinta M, Dargah-zade N, et al. Toward the use of paramagnetic rim lesions in proof-of-concept clinical trials for treating chronic inflammation in multiple sclerosis. Presented at ACTRIMS Annual Forum; February 25-27, 2021. Poster P126.
2. Kineret® (anakinra) for injection, for subcutaneous use. FDA. 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103950s5136lbl.pdf

Daniel Reich, MD, PhD, senior investigator at the National Institutes of Neurological Disorders and Stroke, spoke about his investigations into the role of microglia in progressive MS. 

Targeting Chronic Inflammation in Progressive MS

Central nervous system (CNS) demyelination persists in prolonged follow-up despite tumor necrosis factor alpha inhibitor (TNFαi) treatment discontinuation, according to a recent retrospective analysis cohort of individuals with neurologic dysfunction.

These findings were presented virtually at the 

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021

, February 25-27, by Spencer K. Hutto, MD, clinical fellow, Advanced General and Autoimmune Neurology, Massachusetts General Hospital. Hutto and colleagues found that more than half of the patients (n = 12; 57%) had new disease activity over time. Clinical relapse was experienced by 48% (n = 10), with a median of 41 months to first relapse (range, 12-80). Magnetic resonance imaging (MRI) lesion accrual was experienced by 47% (n = 10), with a median of 28 months to new lesion or lesions (range, 3-139).

 spoke with Hutto to learn more about the associations between TNFαi inhibitors and CNS demyelination. He also stressed the importance of continuing long-term follow up of patients after treatment discontinuation.

 Could you give some background on TNFαi inhibitors and CNS demyelination?

 TNFαi inhibitors are very commonly used agents. In fact, they're some of the most commonly used biologics in medicine these days. That's an important thing to understand. So, we've known about this association since 1999, when there was a study that showed patients with MS that were treated with TNFαi inhibitors had increased numbers of relapses, and since that time, the use of TNF inhibitors has exploded in rheumatology for treatment of things like rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Since then, there have been tons of reports of demyelinating events in association with TNFαi inhibitors. I think the main problem though is figuring out are these drugs provoking or initiating CNS demyelination or a CNS demyelinating disease? Or are they just unmasking en masse in people who would have otherwise developed it later on?

Could you give a brief overview of your study? 

We studied 21 patients across the Mass General Brigham system here in Boston, who clearly had a demyelinating event in association with using one of these TNFαi inhibitors. Presently, there are five in use and our patients suffered events in association with adalimumab, etanercept, and infliximab. We took a very careful look at how they did clinically over the course of a long period of follow up, in terms of, actual attacks and clinical relapses, but also their MRIs and ancillary testing. So, we looked at their blood work and also their CSF, and also the prevalence of MS risk factors in that population. Those factors include tobacco use, vitamin D deficiency, obesity and personal family history of MS. What we found in these patients is that the median duration of a demyelinating event occurred at 11 months of using the TNF alpha inhibitor and in general, patients presented very similar to what they might with MS. Visible visual dysfunction was actually the most common and weakness and sensory loss were also common. CSF was abnormal in most patients. Most patients had the TNF alpha inhibitors discontinued at onset because of any possible associations.

One important thing to note, because there's such confusion about whether or not it's the TNF inhibitors versus an actual unmasking of disease, is that despite stopping the drug, about half of our patients went on to develop new MRI lesions later, and about 40% suffer clinical relapses later on. Recurrent events continued at a high rate in those patients who continued the drug or were re-challenged with the drug later, but even in those patients who had, you know, no prior events concerning for an MS attack, who stopped the TNF alpha inhibitor immediately, and were not started on an MS disease modifying therapy, and I think that's the most clinically applicable subgroup in patients they also went on to have a relatively high rate of relapses as well. 

Most patients suffered this new activity within the first 2 to 3 years. So, we think our study informs how long patients should be followed for after as opposed to just stopping the treatment and assuming that the issue is kind of laid to rest. It's important to follow these patients for a prolonged period of time. In conclusion, we saw that the CNS demyelinating events occurring in association with TNF alpha inhibitors are kind of indistinguishable from what we see with MS normally. MS is not necessarily monophasic and can relapse, so it’s very important to follow patients closely in the future. Finally, I would like to say that I think that CNS demyelinating events in association with these drugs are very rare, and I want people to understand that they shouldn't be afraid to use them if their healthcare team feels they're necessary.

Transcript edited for clarity. For more coverage of ACTRIMS Forum 2021, click 

Hutto SK, Rice DR, Mateen FJ. Long-term outcomes of CNS demyelination associated with exposure to TNFa Inhibitors: A Retrospective cohort analysis. Presented at ACTRIMS Annual Forum; February 25-27, 2021. Abstract P165

Spencer Hutto, MD, a fellow of autoimmune neurology at Massachusetts General Hospital, discussed his team’s investigation into demyelinating events after the use of TNFαi inhibitors. 

TNFαi Inhibitors and CNS Demyelination

Therapeutic Advances in Neurological Disorders 

characterized humoral immunity in patients with multiple sclerosis (MS) who have received mRNA-COVID-19 vaccines and were treated with high-efficacy disease-modifying therapies (DMT) and found that cladribine (Mavenclad; EMD Serono) was the only DMT observed to not impair humoral response.

Lead author Anat Achiron, MD, PhD, professor of neurology, Sackler School of Medicine, Tel-Aviv University, and colleagues evaluated the BNT162b2-COVID-19 (Pfizer-BioNTech) vaccine in 125 adults with multiple sclerosis (MS) to provide evidence-based guidelines to the MS community regarding the magnitude of protective humoral immunity in patients treated with high-efficacy DMTs.

Protective humoral immunity was demonstrated in 46 of 47 (97.9%) of healthy subjects (n = 47) and untreated patients with MS (n = 32). All patients (100%) treated with cladribine (n = 23) developed a high level of antibodies post-COVID-19 vaccination (

<.0001). Notably, cladribine was the only DMT with a 100% protective humoral immunity rate.

"Bringing Mavenclad-treated patients into a state where they can live their lives as normally as possible during a global pandemic is of utmost importance to us.” Danny Bar-Zohar, MD, Global Head, Development, Merck KGaA, said in a statement.

 “Beyond the convenient oral dosing schedule, proven efficacy, and well-characterized safety profile of MAVENCLAD, newly generated data now show encouraging initial evidence for these patients’ ability to generate adequate antibody response to COVID-19 vaccination, which is so important for patients.”

Active MRIs Pre-Pregnancy Predict Postpartum Relapse in MS

The same was not observed for the other DMTs evaluated in the study. Patients treated with fingolimod (n = 26; Gilenya; Novartis) showed no development of a post-vaccination humoral response. Only 1 of 26 patients (3.8%) had an antibody response that, although attenuated, was above the cut-off value for a positive response (

The study authors noted that the failure to develop antibody response in patients treated with fingolimod could be related to the low lymphocyte count in the majority of patients. In total, 38.5% (10 of 26) had a lymphocyte count below 500 cells/mm3, and an additional 50% (13 of 26) had lymphocyte count between 500 and 1000 cells/mm3.

Among 44 patients treated with ocrelizumab (Ocrevus; Genentech), 10 (22.7%) demonstrated a protective antibody titer (

<.0001). Additionally, 42 of 44 (95.5%) patients had lymphocyte counts above 1000 cells/mm3, indicating that the failure to develop humoral response was not related to absolute lymphocyte count.

Achiron et al wrote, “For ocrelizumab-treated patients, the failure to mount appropriate [immunoglobulin G] immune response was regardless of the absolute lymphocyte counts that were in the normal range, or to the time-interval from the last ocrelizumab treatment dose that was from 3.1 to 8.9 months, suggesting the need to postpone the next dosing to enable an effective post-vaccination humoral response.”

After the last treatment DMT dose, development of a protective SARS-CoV-2 antibody titer was as early as 4.4 months in the cladribine group. In comparison, the majority (34 of 44; 77.3%) of patients treated with ocrelizumab did not develop a protective SARS-CoV-2 antibody titer when vaccinated up to 8.9 months after the last treatment dose. Notably, those that did develop protective antibody response were vaccinated between 3.7 and 6.4 months after the last treatment dose.

Of 125 COVID-19 MS vaccinees, 76 (60.8%) were relapsing-remitting, 24 (19.2%) primary-progressive, 18 (14.4%) secondary progressive, 4 (3.2%) clinically isolated syndrome, and 3 (2.4%) patients with radiologically isolated syndrome. 

1. Achiron A, Mandel M, Dreyer-Alster S, et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. 

. Published online April 22, 2021. doi: 10.1177/17562864211012835

2. EMD Serono announces new data strengthening evidence for continued safe and effective Mavenclad use during the COVID-19 pandemic. News release. April 23, 2021. Accessed April 29, 2021. 

https://www.businesswire.com/news/home/20210423005353/en/EMD-Serono-Announces-New-Data-Strengthening-Evidence-for-Continued-Safe-and-Effective-MAVENCLAD%C2%AE-Use-During-the-COVID-19-Pandemic

Cladribine, which was represented in the highest proportion of patients developing protective SARS-CoV-2 antibody response among other DMTs, had humoral response findings independent of lymphocyte count. 

Advances in Multiple Sclerosis

Improving Progressive MS Research: Kathy Zackowski, PhD, OTR

The Remaining Necessities for Future Progressive MS Research

Targeting Chronic Inflammation in Progressive MS

TNFαi Inhibitors and CNS Demyelination

Humoral Immune Response to COVID-19 Vaccine Identified Among MS DMTs