Hot topic AAN 2023: smoldering MS
The concept of smoldering MS is now mainstream. It is firmly embedded in the MS lexicon and will therefore define future MS research.
I arrived at the American Academy of Neurology (AAN) meeting in Boston on Friday to find that “smoldering MS” is the hot topic. The following banner met me at Logan International Airport, my hotel keycard and sleeve and on many of Boston’s taxis.
Whenever you open the AAN 2023 conference app, it delivers a similar message.
Although a pharmaceutical company is funding the campaign, it tells you something important; the concept of smoldering MS is now mainstream. It is firmly embedded in the MS lexicon and will therefore define future MS research.
Although the focus on smouldering MS is good, many people, including this pharmaceutical company, maybe getting it wrong. They are working on the hypothesis that smoldering inflammation is the primary pathology driving the progressive disease and that suppressing smoldering inflammation will prevent worsening disability. A contrary hypothesis is that smoldering inflammation is occurring in response to what is causing MS. In other words, the smoldering inflammation is the immune system reacting to the cause of MS. If you don’t address the cause of MS, then the stimulus for inflammation will persist.
I have mentioned to you in the past that I think MS is driven by something in the brain and spinal cord, which triggers the inflammatory reaction that we label as MS. I have referred to this as the ‘field hypothesis’ of MS. Some people refer to this as the inside-out hypothesis.
The following observations tell us something is wrong in the field.
Relapses
If you have an MS relapse or attack in one particular area of the brain or spinal cord, you are more likely to have subsequent attacks in this area. I suspect something local, in field, or a specific anatomical area, triggers recurrent attacks in the same site. One explanation is that the area damaged by the initial attack is more likely to trigger autoimmune responses in the future due to the local up-regulation of the so-called second, or danger, costimulatory immune signals.
Another explanation is that something in the field, possibly a virus, triggers relapses. Why do I say this? Firstly, when people with MS (pwMS) were treated in the late 1980s with interferon-gamma, a cytokine or inflammatory mediator that stimulates immune responses, they all had relapses. The exciting thing about these interferon-gamma-induced relapses is that they occurred in sites previously affected by MS. When I discussed this observation with the late Hillel Panitch, the principal investigator on the gamma-interferon trial, he thought that this observation was telling us something fundamental about MS. This insight, in parallel with immunological findings in other disease areas, and led me to formulate my leprosy hypothesis about MS (see below).
A further observation that supports the field hypothesis is the rebound post-natalizumab. This suggests that whilst you keep T and B cells out of the nervous system with natalizumab, the field (brain and spinal cord) becomes more abnormal. When you take your foot off the break by stopping natalizumab and letting the immune cells back in, they detect the abnormal field and run amok, trying to clear up what is causing MS. This happens with IRIS (immune reconstitution inflammatory syndrome) and PML (progressive multifocal leukoencephalopathy). When natalizumab is washed out, the immune system finds the JC virus and tries to clear the virus by initiating an inflammatory process. Rebound post natalizumab is likely a form of IRIS that occurs in response to the virus (EBV), or possibly viruses (EBV and HERVs), that cause MS.
Another critical observation comes from serial MRI studies showing subtle changes in the white matter many weeks or months before a gadolinium-enhancing lesion appears. This suggests that the primary pathology in the nervous system takes weeks or months to trigger a focal inflammatory lesion. The challenge for us all is to find out what this field abnormality is. The best chance we have of doing this is to study the brains of people with MS on natalizumab. To do this, we sadly need pwMS to die whilst on natalizumab treatment and to donate their brain for research to look for viruses. This has already happened in two patients. In both cases, the brain was full of EBV in both the lytic and latent states.
Brain tissue from these two patients who tragically died during fulminating MS relapses following natalizumab withdrawal showed numerous EBV-infected B cells and plasma cells with cytotoxic CD8+ T lymphocytes (CTLs) infiltrating all of the lesions in the white matter. EBV lytically infected cells and granzyme B+ CTLs were observed in actively demyelinating lesions. These cases suggest the rebound post-natalizumab may be in response to EBV-infected B-cells in the brains of people with MS.
Isn’t this another compelling argument that EBV drives MS pathology and disease activity?
A subsequent study from the same laboratory in Rome showed that many CD8 T-cells in the brains of pwMS are EBV-specific targeting EBV proteins from both the latent and lytic phases of the EBV life cycle. This study included post-mortem samples from 12 people with progressive MS.
Despite these studies, the MS community remains sceptical of these results. From my perspective, these studies are congruent with many other observations in the field of MS and are one of the reasons I am convinced that EBV is the cause of MS and is driving the disease.
A big hole in the EBV-infected brain and CD8+ T-cell hypothesis is why patients do so well on natalizumab and why does anti-CD20 therapy prevent rebound post-natalizumab?
If the brain was infected with EBV and you blocked immune surveillance using natalizumab, surely, you would expect some ill effects? We don’t see this happening from a clinical perspective, at least in the short to intermediate term. We see the opposite; pwMS on natalizumab usually have no evident inflammatory disease activity (NEIDA), and many see an improvement in disability. Similarly, brain volume loss approaches the normal range after rebaselining, and fatigue and/or sickness behaviour is improved in pwMS on natalizumab. These observations argue against a direct CNS infection as being the cause of MS? Maybe not. Natalizumab may reduce some components driving smoldering disease, but it does not necessarily stop smoldering MS, which may take many decades to manifest itself. In support of this is the observation that patients who have been on natalizumab for a decade or more often start to notice worsening neurological function, develop progressive MS and are noted to have accelerated brain volume loss. Natalizumab is only a holding measure and not a cure for MS.
Suppose MS is due to EBV-specific CD8+ cytotoxic T-lymphocytes attacking the brain of pwMS. Why does rituximab, a drug that predominantly deletes B-cells, prevent rebound disease activity post-natalizumab? Some have argued that the B-cells must travel to the brain to present antigens to the CD8+ T-cells. I don’t buy this explanation, as other professional antigen-presenting cells in the brains of pwMS can take on this role. Others quote the evidence that T-cells need help from B-cells to cross the blood-brain barrier. Again this does not explain why some carry-over PML cases occur when switching from natalizumab to rituximab (or ocrelizumab) who have developed IRIS (immune reconstitution inflammatory syndrome). In these cases, IRIS-inducing T-cells are trafficking to the brain without circulating B-cells.
The current data and clinical observations generate more questions than they can answer. Still, it does demonstrate that we need to find out if EBV is driving MS from within the CNS or from its effects on the immune system in the periphery. These two scenarios require different treatment approaches. We need to explore both approaches with experiments designed to disprove the hypothesis. This is why we need to explore EBV-specific antiviral agents, therapeutic EBV vaccines, and immunotherapy trials (EBV-specific CTLs and CD19-targeted CAR T-cells) as potential treatments for MS.
Targeting downstream events
The current smoldering MS campaign is an awareness campaign and is not necessarily focusing on one driver of worsening MS beyond NEIDA (no evident disease activity). The campaign is underpinned by the observation that several different mechanisms should be considered when thinking about slowing down or preventing worsening MS. These mechanisms were covered in our paper on smoldering MS, which you can download and read (Giovannoni et al. Smouldering multiple sclerosis: the 'real MS'. Ther Adv Neurol Disord. 2022 Jan 25;15:17562864211066751).
In the current drug development environment, most people are equating smoldering MS to innate immune activation and the hot microglial hypothesis. Why? Because they think they have a class of treatment that works against hot microglia, namely Bruton Kinase inhibitors (BTKi). At the expanding edge of chronic active MS lesions, which we think are slowly expanding and/or paramagnetic rim lesions on MRI, activated microglia appear to be causing demyelination and axonal damage. The current hypothesis being tested is that by inhibiting these microglia using CNS-penetrant BTK inhibitors, we will stop MS from worsening. This is based on the assumption that these hot microglia are dysfunctional and are causing harm. The corollary is that these microglia are not abnormal or dysregulated but are reacting to something abnormal in the tissue. If we could target what is happening in the tissue, the microglia will stop reacting to the signal and stop damaging the tissues at the edge of these lesions. This latter argument is central to the field hypothesis of MS.
Saying this doesn’t mean inhibiting microglia won’t slow down smoldering MS. It may. However, the cause of MS is not being addressed by an approach that targets downstream events. Therefore, it is possible that worsening MS may not be prevented with BTKi but only delayed.
Leprosy hypothesis
According to the Prentice criteria for a surrogate endpoint to be considered as a substitute for the disease (or is the disease), it requires that (1) the baseline measurement of the endpoint is predictive of outcome, (2) changes in the measurement of the endpoint over time is predictive of outcome and (3) changes in the measurement of endpoint in response to therapy is also predictive of outcome (Prentice, 1989). I would add a fourth criterion that (4) the endpoint measurement should predict outcome independent of treatment, i.e. it should behave the same way whether a subject is on placebo or active treatment.
When you apply these four criteria to relapses and/or focal MRI activity (new and/or enlarging T2 lesions or Gd-enhancing lesions), they don’t predict disability outcomes. This is why I state that smoldering MS is the real MS, and the focal inflammatory activity is the immune system’s response to what is causing the disease. Suppressing the immune system’s response to the cause of MS may modify the course of MS, but it does not stop MS from smoldering away.
Why use leprosy as an analogy? Leprosy is an infectious disease caused by a bacterium with a well-defined set of antigens that can be used to interrogate the adaptive immune systems’ responses to antigens. Depending on the immune response, you get a different clinical picture. If you have a brisk inflammatory response, you get tuberculoid leprosy, which presents with inflamed lesions. On the other side of the spectrum, you get lepromatous leprosy, which is more of a smouldering disease with low-grade inflammation. Between these two extremes, you get a grey zone called borderline subtypes. Interestingly people can convert from having lepromatous to tuberculoid leprosy if they shift their immune response to a so-called type 1 immune response driven by interferon-gamma.
I view primary progressive MS as lepromatous MS and relapsing-remitting MS as tuberculoid MS. The SPMS sits in the middle and is borderline MS. Interestingly, gamma interferon seems to have the same effect in MS as in leprosy driving lepromatous MS (PPMS) to become tuberculoid or relapsing MS.
Paper 1 - stereotypical relapses
BACKGROUND AND PURPOSE: MS is a chronic inflammatory disorder of the central nervous system characterized by acute episodes of neurological dysfunction thought to reflect focal areas of demyelination occurring in clinically eloquent areas. These symptomatic relapses are generally considered to be random clinical events occurring without a discernible pattern. The hypothesis that relapses may follow a predetermined sequence and may provide insights into underlying pathological processes were investigated.
METHODS: Employing prospective clinical database data from 1482 MSers who had experienced one or more consecutive relapses were analysed. Using regression analysis, the site and symptom of the index event were compared with those of the first relapse.
RESULTS: It is demonstrated that following disease ignition, subsequent relapses may not be random events but dependent on the characteristics of the index event. All anatomical sites were more likely to be affected in the first relapse if that site had been involved in the index event, with a similar association observed when comparing by symptoms.
CONCLUSION: These findings have importance in understanding the evolution of the disease and predicting individual disease progression and may aid with patient counselling and management.
Paper 2 - case study
Rebound of disease activity in multiple sclerosis patients after natalizumab withdrawal is a potentially life-threatening event. To verify whether highly destructive inflammation after natalizumab withdrawal is associated with Epstein-Barr virus (EBV) reactivation in central nervous system infiltrating B-lineage cells and cytotoxic immunity, we analyzed post-mortem brain tissue from a patient who died during a fulminating MS relapse following natalizumab withdrawal. Numerous EBV infected B cells/plasma cells and CD8+ T cells infiltrated all white matter lesions; the highest frequency of EBV lytically infected cells and granzyme B+ CD8+ T cells was observed in actively demyelinating lesions. These results may encourage switching to B-cell depleting therapy after natalizumab discontinuation.
Paper 3 - case series
Epstein-Barr virus (EBV) is a ubiquitous herpesvirus strongly associated with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). Yet, the mechanisms linking EBV infection to MS pathology are uncertain. Neuropathological and immunological studies suggest that a persistent EBV infection in the CNS could stimulate a CD8 T-cell response aimed at clearing the virus but inadvertently causing CNS injury. Inasmuch as in situ demonstration of EBV-specific CD8 T cells and their effector function is missing, we searched for EBV-specific CD8 T cells in MS brain tissue using the pentamer technique.
Postmortem brain samples from 12 donors with progressive MS and known HLA class I genotype were analyzed. Brain sections were stained with HLA-matched pentamers coupled with immunogenic peptides from EBV-encoded proteins, control virus (cytomegalovirus, influenza A virus) proteins and myelin basic protein. CD8 T cells recognizing proteins expressed in the latent and lytic phases of the EBV life cycle were visualized in white matter lesions and/or meninges of 11/12 MS donors. The fraction (median value) of CD8 T cells recognizing individual EBV epitopes ranged from 0.5 to 2.5% of CNS-infiltrating CD8 T cells. Cytomegalovirus-specific CD8 T cells were detected at a lower frequency (≤0.3%) in brain sections from 4/12 MS donors. CNS-infiltrating EBV-specific CD8 T cells were CD107a-positive, suggesting a cytotoxic phenotype, and stuck to EBV infected cells.
Together with local EBV dysregulation, selective enrichment of EBV-specific CD8 T cells in the MS brain supports the notion that skewed immune responses toward EBV may contribute to inflammation causing CNS injury.
IMPORTANCE: EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas. The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology. Infectious mononucleosis increases the risk of developing MS and immune reactivity toward EBV is higher in persons with MS indicating inadequate control of the virus. Previous studies have suggested that persistent EBV infection in the CNS might stimulate an immunopathological response causing bystander neural cell damage. To verify this, we need to identify the immune “culprits” responsible for the detrimental antiviral response in the CNS. In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus infected cells. This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology.
Paper 4 - Gamma-interferon triggered relapses
We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 microgram), intermediate (30 micrograms), or high (1,000 micrograms) doses of interferon by intravenous infusion twice a week for 4 weeks. Serum levels of gamma interferon were proportional to dose and no interferon was detected in CSF. Seven of the 18 patients had exacerbations during treatment, a significant increase compared with the prestudy exacerbation rate (p less than 0.01). Exacerbations occurred in all three dosage groups and were not precipitated by fever or other dose-dependent side effects. There were significant increases in circulating monocytes bearing class II (HLA-DR) surface antigen, in the proliferative responses of peripheral blood leukocytes, and in natural killer cell activity. These results show that systemic administration of gamma interferon has pronounced effects on cellular immunity in MS and on disease activity within the CNS, suggesting that the attacks induced during treatment were immunologically mediated. Gamma interferon is unsuitable for use as a therapeutic agent in MS. Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells should be investigated as candidates for experimental therapy.
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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 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.
I can see how the MS Research community could be factionalising over this. Let's face it, nobody knows for sure but your field theory is compelling - the way you tell it! I guess an evangelist for the other side could be similarly impassioned. I want to believe you though, Gavin, as a pwPPMS and someone hoping to start a BTKi trial shortly.
Would it be an incorrect reach to say that current DMTs, since they address mostly the acute inflammatory part of MS (relapses and new lesions), but not as much progression, turn RRMS into something mimicking non-active SPMS if NEIDA is achieved?