The Swedes have investigated how different intensities of initial MS treatments impact long-term physical disability. They compared high-efficacy therapies with standard platform treatments in over 2,500 pwMS to distinguish worsening caused by relapses (relapse-associated worsening, or RAW) from progression that occurs independently of relapses (PIRA). They show that high-efficacy drugs significantly reduced the risk of relapse-associated worsening (RAW) and delayed reaching major disability milestones. However, neither treatment type showed a superior advantage in slowing progression independent of relapse activity (PIRA). This suggests that RAW and PIRA likely stem from different biological processes.

These findings indicate that while modern DMTs excel at controlling inflammation (NEIDA), additional neuroprotective strategies are necessary to halt the disease’s gradual decline associated with SAW. The results of this study advocate for aggressive early intervention (hit-hard-and-early) and the development of therapies that target smouldering processes within the CNS and repair mechanisms.

The findings of this study are not new and are in keeping with other published data. Sadly, however, there are likely too few patients treated with alemtuzumab and cladribine in this cohort and none treated with AHSCT. It is well known that the majority of pwMS on high efficacy treatments in Sweden are on off-label rituximab. I am told that Swedish neurologists now rarely use alemtuzumab, and the uptake of cladribine has also been slow. It would, however, be interesting to see if IRTs (immune reconstitution therapies), in particular alemtuzumab and AHSCT, made a difference in SAW. I say this because alemtuzumab and AHSCT are the most effective treatments we have for MS and have a profound impact on the end-organ in terms of reducing the rate of brain volume loss or brain atrophy. These two treatments do impact SAW, provided they are used early.

It is becoming increasingly difficult to justify a low-efficacy platform DMTs approach when it is clear that pwMS treated with high-efficacy therapies first-line do so much better. Do you agree?

A more interesting question for the next generation of neurologists to answer will be whether an induction-maintenance approach is superior to continued long-term immunosuppression, such as long-term anti-CD20 therapy. I note the Swedes are starting to test rituximab induction followed by cladribine as an exit strategy.

The HIt HArd and hiT Early in Multiple Sclerosis Trial (HiHat) - ClinicalTrials.gov ID NCT07517185, Sponsor Uppsala University

I have been advocating this approach for several years, as it reduces the risks associated with long-term immunosuppression, allows you to recover your naive B-cell population for vaccinations, and, as cladribine is CNS-penetrant, targets CNS-resident B-cells and plasmablasts that are responsible for at least one component of smouldering MS. I have little doubt that this trial will work. Sadly, it is underpowered for efficacy, but who knows if the majority of subjects go into long-term remission, it may affect how both rituximab and cladribine are used in Sweden.

If you are on long-term anti-CD20 therapy, would you consider switching to cladribine? Would you participate in a trial to test the safety and efficacy of anti-CD20 induction followed by an exit via cladribine?

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Guo et al. Long-term disability after initiation of platform versus high-efficacy disease-modifying therapy in relapsing-onset multiple sclerosis. J Neurol. 2026 Apr 1;273(4):240.

Background: Several observational studies have compared high-efficacy and platform disease-modifying therapies (DMTs) with respect to long-term disability in relapsing-onset multiple sclerosis (MS), yet it remains unclear whether observed differences reflect relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), or both.

Methods: We included 2,563 DMT-naïve individuals with relapsing-onset MS enrolled in a population-based study linked to the Swedish MS registry (40 clinics, 2005-2019). The exposure was an initial DMT efficacy class (platform versus high-efficacy therapy), with platform as the reference. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for RAW, PIRA, and time to EDSS 3 and 4. EDSS trajectories were modelled using mixed-effects models. Follow-up started at DMT initiation and was censored at treatment switch, discontinuation, death, drop-out, or study end.

Results: At treatment initiation, 1,987 participants started a platform DMT and 576 a high-efficacy DMT. High-efficacy therapy was associated with a lower risk of RAW (HR 0.60, 95% CI 0.38-0.92), while the risk of PIRA did not differ between treatment groups (HR 1.05, 95% CI 0.79-1.39). Risks of reaching EDSS 3 and EDSS 4 were also lower with high-efficacy DMT (EDSS 3: HR 0.26, 95% CI 0.17-0.38; EDSS 4: HR 0.32, 95% CI 0.18-0.54). EDSS trajectories increased more steeply among participants treated with the platform, with partial convergence toward the high-efficacy group over time.

Conclusions: Our findings suggest that inflammatory and relapse-independent components of MS disability respond differently to current therapies and highlight the need for complementary neuroprotective strategies.

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EBV and MS

Researchers in San Francisco found that people with MS have unusually high numbers of a specific type of immune cell — called CD8+ “killer” T cells — that appear to be reacting to EBV.

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Prof G, I am a post-doc working on the immunology of MS and EBV. There have been several recent publications on EBV and its role in the pathogenesis of multiple sclerosis. I am particularly interested in your take on the following 8 papers. How do you pull the findings of these papers together into a coherent story? I am finding it difficult.

1. Jelcic et al. T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis. Cell Rep Med. 2025 Mar 18;6(3):102027. doi: 10.1016/j.xcrm.2025.102027.

2. Läderach et al. EBV induces CNS homing of B cells, attracting inflammatory T cells. Nature. 2025 Oct;646(8083):171-179. doi: 10.1038/s41586-025-09378-0.

3. Sarkkinen et al. Altered immune landscape of cervical lymph nodes reveals Epstein-Barr virus signature in multiple sclerosis. Sci Immunol. 2025 Feb 21;10(104):eadl3604. doi: 10.1126/sciimmunol.adl3604.

4. Thomas et al. Anoctamin-2-specific T cells link Epstein-Barr virus to multiple sclerosis. Cell. 2026 Jan 22;189(2):585-602.e38. doi: 10.1016/j.cell.2025.12.032.

5. Thomas et al. Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis. Sci Adv. 2023 May 19;9(20):eadg3032.

6. Yasumizu et al. Host Genetic Architecture between Epstein-Barr Virus Activity and Multiple Sclerosis Reveals Shared Pathways. medRxiv [Preprint]. 2025 Dec 15:2025.12.11.25342083. doi: 10.64898/2025.12.11.25342083.

7. Hayashi et al. Antigen specificity of clonally enriched CD8+ T cells in multiple sclerosis. Nat Immunol. 2026 Feb 5. doi: 10.1038/s41590-025-02412-3.

8. Soldan et al. Multiple sclerosis patient-derived spontaneous B cells have distinct EBV and host gene expression profiles in active disease. Nat Microbiol. 2024 Jun;9(6):1540-1554.

NOTE: General Substack newsletters and the microsite are free; only Q&A sessions are restricted to paying subscribers. I can’t run and maintain the MS-Selfie microsite, so I must pay people to assist me. If people want to ask medical questions unrelated to the Newsletters or Podcasts, they either need to become paying subscribers or email (ms-selfie@giovannoni.net) to request a complimentary subscription.

Prof G’s response

Each of these papers is a tour de force in its own right. But you are correct, trying to make sense of them together in one coherent narrative is important.

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Prof G, I am a young neurologist working in MS. I found your reviews of research papers on your previous blog very interesting. As many clinicians and researchers read and follow MS-Selfie, would it be possible to cover more research topics, including basic science? Many thanks.

NOTE: General Substack newsletters and the microsite are free; only Q&A sessions are restricted to paying subscribers. I can’t run and maintain the MS-Selfie microsite, so I must pay people to assist me. If people want to ask medical questions unrelated to the Newsletters or Podcasts, they either need to become paying subscribers or email (ms-selfie@giovannoni.net) to request a complimentary subscription.

Prof G’s response

In response to this email, I am launching a new feature called “Research News” in which I will review papers that have caught my attention over the last week or so. I use several search methods to find research news. None of them is perfect, so I might miss important papers. Let me know if you want me to cover one I have missed.

Unfortunately, these newsletters will be quite highbrow as they are meant to review the science. I would be interested in hearing from readers with MS or family members with MS, whether they like these newsletters. If the feedback is poor, I will drop them.

The following covers the search period from January 28, 2026, to February 4, 2026. I have identified five overarching themes:

1. The prodromal architecture: A network analysis from Scandinavian registries has mapped the pre-MS landscape, identifying psychiatric and metabolic comorbidities up to 15 years prior to diagnosis.

2. Molecular pathogenesis: The elucidation of the CD5-CK2-STAT3 signalling axis in Th17 cells highlights a druggable pathway that decouples pathogenicity from proliferation, offering a potential solution to the safety trade-offs inherent in broad immunosuppression. Concurrently, the metabolic requirements of remyelination have been elucidated through the discovery of the ApoC2 mimetic peptide D6PV, which links lipid metabolism directly to oligodendrocyte maturation.

3. Therapeutics: Clinical trials are under scrutiny, with new data revealing a high prevalence of spin in the reporting of nonsignificant primary outcomes.

4. Biomarkers: The clinical utility of serum neurofilament light chain (sNfL), often touted as a universal biomarker, has been tempered by large-scale meta-regression analyses, suggesting its additive value to standard clinical monitoring is more limited than previously assumed, particularly in unstratified populations. This paper is important for pwMS who have to pay for their sNFL levels outside of their current insurance or healthcare coverage.

5. Remyelination and neuroprotection: Metabolic reprogramming via D6PV, targeting ADGRG1 and RhoA signalling for remyelination, and ageing are discussed in relation to functional recovery in MS.

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In short, none of these claims are supported by the research findings presented in this paper (Willard et al. Combined magnetic resonance imaging and serum analysis reveals distinct multiple sclerosis types. Brain. 2025 Dec 4;148(12):4578-4591). The article introduces a new machine learning model that integrates MRI data with serum neurofilament light chain (sNfL) levels to supposedly categorise MS based on ‘biology’ rather than ‘MS-related symptoms’. The assumption that MS-related symptoms are not biological is incorrect. The fact that humans, and by inference, people with MS, are biological machines means their symptoms are biological.

The Oxford dictionary defines biology as ‘the study of living organisms, divided into many specialised fields that cover their morphology, physiology, anatomy, behaviour, origin, and distribution.’ Symptoms of a disease are hence biological.

The study combined fluid biomarkers (sNFL) with brain imaging, which then identified two distinct disease subtypes: early-sNfL and late-sNfL. The early-sNfL group is characterised by higher levels of inflammatory activity, significant lesion accrual, and faster brain atrophy, whereas the late-sNfL group exhibits more gradual neurodegeneration. The authors claim the multimodal approach, including sNFL, proved superior to MRI-only models in correlating with patient disability and predicting how individuals respond to therapeutic interventions. They claim the findings may provide a prognostic framework to support personalised medicine by identifying more aggressive disease states earlier in the clinical course, which are more likely to predict treatment response.

Limitations

Please note that the authors have identified several limitations and flaws in their study, which can be categorised into issues with the study population, methodology, and challenges related to clinical implementation. The study utilised data drawn from clinical trial cohorts, which means the participants do not fully represent the broader MS population. Due to strict eligibility criteria in the source trials, the study lacks data on underrepresented ethnic groups and patients with co-morbidities. While the model was trained on a cohort including both relapsing–remitting and secondary progressive MS, the external validation was conducted only on a cohort of newly diagnosed patients (early MS). Consequently, the model’s accuracy for late-stage disease remains to be validated.

The external test dataset had a limited range of EDSS scores, which likely contributed to lower correlation coefficients between the model stages and disability measures in the test set than in the training set. Although the study aimed to use unsupervised machine learning, the pipeline was “not entirely unsupervised” because the initial feature selection step relied on correlations with the EDSS. The researchers noted that the decision to narrow the selection to exactly five variables was an “arbitrary decision” guided by the dataset’s size and resources. The SuStaIn algorithm assumes that disease progression follows a “monotonic sequence,” in which subtypes accumulate abnormalities in a fixed order. This assumption facilitates modelling but may limit the model’s sensitivity to fluctuating disease trajectories. In the longitudinal analysis, sNfL levels decreased in untreated control subjects. The authors attribute this to “regression to the mean,” as patients were recruited during active phases of inflammation (a requirement for trial entry), which naturally subsided, complicating the assessment of actual therapeutic effects.

The authors acknowledge that few hospitals currently possess the necessary infrastructure to convert routine MRI scans into the precise quantitative measures required by their model. Quantitative MRI measures are sensitive to differences in scanners and acquisition parameters. While the study used harmonisation (the ComBat algorithm) to mitigate this, such harmonisation poses practical challenges for widespread clinical adoption. The correlations between the model-derived stages and the EDSS were weak. The authors argue this is expected because EDSS is weighted toward motor function, while MRI/sNfL changes often precede clinical symptoms. Still, it highlights a gap between the biological staging and current clinical disability measures. To ensure the model remained accessible for potential clinical translation, the study excluded more advanced imaging modalities (such as myelin-sensitive MRI sequences), which might have provided more comprehensive insights.

I am clearly not on the same page as the authors.

My initial thoughts

The title refers to distinct MS subtypes. Use of the term “distinct" is a misnomer, as some subjects switched from one subtype to the other.

“Given that 7% of patients switched from one subtype to another in the training dataset, and 23% switched in the testing dataset, these subtypes are likely to represent a continuum of underlying pathology.”

The title is therefore misleading and argues against two distinct subtypes of MS.

Please note that the training dataset was derived from a phase 2 Evobrutinib clinical trial conducted between March 2017 and July 2018. The study subjects were selected using well-defined inclusion and exclusion criteria. All trial subjects had to have one or more documented relapses within the 2 years before screening, with either one relapse which occurred within the last year before randomisation or the presence of at least one T1 gadolinium-enhancing lesion within 6 months before randomisation—about a quarter of study subjects had been exposed to DMTs in the past.

Therefore, the cohort used for training and model development had established active MS, as defined by relapses and/or Gd-enhancing lesions on MRI. Another issue is that they were diagnosed using the 2011 McDonald criteria. This creates problems, as subjects with active MS tend to become less active over time due to regression to the mean. In addition, the consequences of having active MS will then unfold over time as part of the natural history of MS. I would be interested to know how the model would have been developed if it included pwMS who did not have active MS as defined by the trial inclusion criteria. I suspect very differently.

Is the model simply measuring baseline MS disease activity, including raised sNFL as an activity marker, and then predicting the consequences of this period of MS disease activity on the end organ, i.e., brain volume loss or end-organ damage? In comparison, those without activity at baseline, i.e. a normal sNFL, will not have the same trajectory in terms of the pathology in the end-organ as measured by MRI, but are likely to regress to the mean in the opposite direction; i.e. have a delayed rise in sNFL as part of the fluctuation in MS disease activity over time. I think any model of MS, a dynamic disease, needs more than a few limited MRI metrics and sNFL to capture its behaviour.

In comparison to the training dataset, the testing dataset was from the phase 3 REFLEX trial that compared two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis or CIS. These subjects were diagnosed using the older 2005 McDonald criteria, were younger and were naive to DMTs. The subjects in this study had CIS rather than established MS. I know that a subsequent analysis of the REFLEX clinical trial population, retrospectively applying the McDonald 2017 MS diagnostic criteria, estimated that about 50% of these subjects would have been classified as having MS. This means that 50% didn’t fulfill the requirements for MS and are more likely to have benign MS. Validating the model developed on established active MS using an early, much younger group of subjects naive to DMTs diagnosed with different diagnostic criteria makes little sense to me, i.e. it is flawed from a scientific perspective, and is likely to introduce bias. For example, the validation using subjects very early in the course of their disease, who were much younger and hence had a greater ability to recover function and repair damage, introduces a biological variable not measured by the model. How does neurological reserve and recovery of function impact the model?

An essential aspect of clinical outcomes and various biomarkers in MS is that they evolve at different rates. In other words, the temporal sequence of how they change over time is out of sequence with each other. I have referred to this phenomenon in the past as lag. Let me give you some examples. Demyelination develops along a specific pathway before loss of function and before a Gd-enhancing lesion is seen. Changes in the magnetisation transfer ratio (MTR) on MRI can occur in normal-appearing white matter (NAWM) several months before an MS lesion becomes visible with Gd-enhancement. This indicates that MTR changes are earlier and more sensitive markers of pre-lesional tissue damage than Gd enhancement. At some point, axonal injury occurs, leading to NFL release. Based on serial sampling studies, we suspect this process may precede the onset of clinical relapse symptoms and the detection of Gd enhancement on MRI. However, these latter processes are likely to cluster into a relatively narrow window that lasts days to weeks. We know that Gd enhancement of a lesion typically lasts 2-3 weeks before resolving, whereas NFL levels remain elevated for months. The latter occurs because of Wallerian degeneration, which takes a long time to unfold: it can take months to clear the debris from transected axons. The proximal axonal degeneration above the lesion may take even longer and play out over years. Similarly, repaired or remyelinated axons may be programmed to die off in the future. We think they are vulnerable to early ageing, energy failure and delayed excitotoxicity. This delayed neurodegeneration may happen over decades. I try to illustrate these time changes in this cartoon that I made more than a decade ago.

The loss of tissue from an acute lesion, i.e., the subsequent atrophy, can take months to years to occur. In optic neuritis and the optic nerve model, atrophy is seen after 3 months and reaches a plateau at about 6 months. Therefore, the inflammation detected now, as evidenced by Gd-enhancing lesions and/or elevated NFL levels, will result in whole-brain or regional atrophy six or more months later. With longer axons than those in the optic nerve, it will take longer than 6 months to reach a plateau. The point I am making is that I don’t know how this model accounts for the lag in changes in these biomarkers. The study utilises five specific MRI-derived measures, three of which are volume measures (limbic cortex, deep grey matter, and parietal cortex volume), all of which are likely to be impacted by lag.

The other two MRI metrics are the total T2 lesion volume and the corpus callosum white matter T1-weighted/T2-weighted ratio. I am aware that the T2 lesion volume changes with time at an individual lesion level in response to treatment. In general, the T2 lesion volume of an acute MS lesion is large and decreases as the Gd-enhancement disappears, i.e., the lesion shrinks in size. Most MRI analyses show a reduction in T2 volumes with treatment. Therefore, this component of the model would be affected by treatment.

The T1-weighted/T2-weighted (T1w/T2w) ratio in the white matter of the corpus callosum changes significantly over time as a function of age. After middle age, the T1w/T2w ratio in the white matter and corpus callosum generally begins to decline. This decrease is thought to be associated with age-related microstructural changes, including myelin degeneration and loss of white matter integrity. How do the significant age differences between the training and validation datasets affect this component of the model?

Therefore, these MRI metrics are not static and change over time. How these dynamic changes affect the model is unknown. The changes may not be that important at a group level. However, I suspect they will create a lot of noise or variability in individual datasets, which may make it difficult to use for decision-making at a patient level.

Summary

A crucial point made by the authors in the discussion is that few centres have the infrastructure to reliably analyse the scans and generate the metrics required as inputs into this model. Therefore, it isn't easy to see how this model will impact precision medicine. In comparison, sNFL and CSF NFL levels are beginning to enter routine clinical practice and are increasingly being used to aid in clinical decision-making. To be blunt, I am not sure how this paper changes my thinking about MS and its management. Our therapeutic strategies remain the same: early, effective treatment is the best way to protect the end organ. Our treatment targets remain no evident inflammatory disease activity (NEIDA) and no evident smouldering disease activity (NESDA), regardless of what proposed subtype of MS you have. We have very effective treatments for NEIDA and less effective treatments for NESDA; it would take a brave neurologist not to treat a person with a low-sNFL phenotype with an anti-inflammatory. Similarly, it would not make sense to ignore smouldering MS in a person with a high sNFL phenotype. The challenge from now on for the MS community is developing treatments for smouldering MS to achieve stable MS and long-term remission regardless of putative subtypes.

Does my response to this paper make sense? I am prepared to answer further questions.

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Paper

Willard et al. Combined magnetic resonance imaging and serum analysis reveals distinct multiple sclerosis types. Brain. 2025 Dec 4;148(12):4578-4591.

Multiple sclerosis (MS) is a highly heterogeneous disease in its clinical manifestation and progression. Predicting individual disease courses is key for aligning treatments with underlying pathobiology. We developed an unsupervised machine learning model integrating MRI-derived measures with serum neurofilament light chain (sNfL) levels to identify biologically informed MS subtypes and stages. Using a training cohort of patients with relapsing-remitting and secondary progressive MS (n = 189), with validation on a newly diagnosed population (n = 445), we discovered two distinct subtypes defined by the timing of sNfL elevation and MRI abnormalities (early- and late-sNfL types). In comparison to MRI-only models, incorporating sNfL with MRI improved correlations of data-derived stages with the Expanded Disability Status Scale in the training (Spearman’s ρ = 0.420 versus MRI-only ρ = 0.231, P = 0.001) and external test sets (ρ = 0.163 for MRI-sNfL, versus ρ = 0.067 for MRI-only). The early-sNfL subtype showed elevated sNfL, corpus callosum injury and early lesion accrual, reflecting more active inflammation and neurodegeneration, whereas the late-sNfL group showed early volume loss in the cortical and deep grey matter volumes, with later sNfL elevation. Cross-sectional subtyping predicted longitudinal radiological activity: the early-sNfL group showed a 144% increased risk of new lesion formation (hazard ratio = 2.44, 95% confidence interval 1.38-4.30, P < 0.005) compared with the late-sNfL group. Baseline subtyping, over time, predicted treatment effect on new lesion formation on the external test set (faster lesion accrual in early-sNfL compared with late-sNfL, P = 0.01), in addition to treatment effects on brain atrophy (early sNfL average percentage brain volume change: -0.41, late-sNfL = -0.31, P = 0.04). Integration of sNfL provides an improved framework in comparison to MRI-only subtyping of MS to stage disease progression and inform prognosis. Our model predicted treatment responsiveness in early, more active disease states. This approach offers a powerful alternative to conventional clinical phenotypes and supports future efforts to refine prognostication and guide personalized therapy in MS.

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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 Queen Mary University of London or 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 healthcare professional, who will be able to help you.

• Increase over at least 6 months of ≥1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is ≤5.5, or ≥0.5 points when the baseline EDSS score is >5.5, or ≥20% from the baseline T25-FW, or ≥20% from the baseline 9-HPT

The previous primary outcome was 6-month Confirmed Disability Progression (CDP), defined as follows:

• Increase of ≥1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is ≤5.5, or an increase of ≥0.5 points when the baseline EDSS score is >5.5

The primary outcome changed from using the EDSS to a composite of the EDSS, T25W and the 9HPT. Wouldn’t it be a tragedy if the trial were positive on the old primary outcome, but negative on the new primary outcome? This may happen because the composite could introduce noise, which would undermine its therapeutic significance. I say this because there is increasing evidence that the T25W is a very noisy outcome measure, fraught with problems. These insights are relatively new and were not widely appreciated when the primary outcome was changed.

While the T25FW is used due to its simplicity, low cost, and speed of administration, it is criticised as a poor or incomplete outcome measure in MS clinical trials. The primary reason for this criticism is that it fails to capture the complexity of walking disability, particularly in terms of endurance, fatigue, and real-world function.

For people with early-stage MS or mild disability (low EDSS scores), the T25FW is often not sensitive enough to detect impairments. In a short 25-foot (7.6-meter) test, pwMS usually “sprint” or compensate momentarily to achieve a normal or near-normal time, masking underlying issues. A pwMS might be losing the ability to walk a mile, but their ability to walk 25 feet remains unchanged. This makes the measure insensitive to early disease progression, causing trials to miss the efficacy of drugs that might be preserving long-term endurance.

Fatigue is one of the most debilitating symptoms of MS, yet the T25FW ignores it almost entirely. The T25FW typically takes less than 10 seconds for a mobile patient. This is not enough time to induce the motor fatigue (progressive slowing down) that characterises MS walking. The T25W measures a patient’s ability to walk to the postbox, but not their ability to walk around a grocery store. A patient might walk the first 100 feet normally but begin dragging their foot (foot drop) or stumbling after 5 minutes. The T25FW misses this entirely.

MS clinical trials aim to improve a pwMS’s quality of life, but a 25-foot sprint correlates poorly with daily activities for many patients. Improving a T25FW time by 0.5 seconds may be statistically significant in a trial, but it may not translate into a meaningful benefit in pwMS’s daily life. Real-world walking requires sustained effort. Measures like the 2-Minute Walk Test (2MWT) or the 6-Minute Walk Test (6MWT) are therefore considered superior because they force the patient to sustain effort, thereby revealing fatigue and balance issues that emerge over distance.

While seemingly standardised, the T25FW is subject to administration variability that can skew trial data. Slight differences in how a HCP encourages a patient (e.g., “walk as fast as you can” vs. “walk quickly but safely”) can significantly alter speed. Because the T25W is only a short burst of effort, it is highly susceptible to a pwMS’s motivation level on that specific day, rather than their physiological limit.

Another example is the recent phase 2 trial of alpha-lipoic acid, which used T25W as its primary outcome (see below). The trial was negative for the primary outcome but positive on MRI metrics that capture smouldering MS very well, i.e. deep grey matter volume. This is a tragedy because it means the chances of taking forward lipoic acid as a treatment for MS are lower due to this negative trial.

So what about the 9HPT? This is a very different sort of outcome measure, as it captures MS worsening or improvement with much greater sensitivity and specificity. It integrates vision, coordination, sensory function, and fine motor coordination into a single outcome measure. Unlike the T25W, it is superior to other outcome measures in detecting change. An example of this is the data from the O’HAND trial, which showed that the 9HPT was superior to that of the EDSS in detecting change across the disability spectrum. It also performed well as part of a composite score with the EDSS.

I suspect that if the PERSEUS trial had focused on the EDSS and 9HPT and excluded the T25W, the study would have been positive. We will have to wait to see the results to see if my prediction is correct.

In my opinion, the MS community needs to discard the T25W as an outcome measure in clinical trials before we throw another baby out with the bathwater.

I hope the scientific concepts in this newsletter make sense to you. You should be aware of how important the design of a clinical trial is to its success or failure. We also need to reflect on past failures and learn from them.

I therefore urge anyone designing trials in progressive MS to discard the T25W as an outcome measure and not include it in a composite outcome measure in MS clinical trials; if you do, you will be disappointed, and many pwMS will feel let down.

Do you have any questions or comments?

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Spain et al. Lipoic Acid for Treatment of Progressive Multiple Sclerosis: A Phase 2 Randomized Clinical Trial. Neurology. 2026 Jan 13;106(1):e214454.

Background and objectives: A pilot trial of the antioxidant lipoic acid (LA) in secondary progressive multiple sclerosis (MS) demonstrated a reduction in the whole-brain atrophy, suggesting neuroprotection. This study determined whether LA preserved walking speed, reduced brain atrophy, and was safe in progressive MS (PMS).

Methods: This phase 2, 24-month, randomized, double-blind, placebo-controlled clinical trial (2018-2023) recruited a convenience sample from 10 US sites, including 5 Veterans Affairs medical centers and 1 Canadian site. Inclusion criteria were as follows: age ≥18 years, primary or secondary PMS, Expanded Disability Status Scale (EDSS) score 3.0-6.5, and relapse-independent disability worsening in the previous 2 years. Exclusion criteria were as follows: confounders of mobility outcomes, LA use in the previous 2 years, and MRI contraindications. Concurrent disease-modifying therapy (DMT) was permitted. Participants were block-randomized by site (1:1) to receive 1,200 mg daily oral LA or placebo. The sample size (n = 118) was powered to detect Timed 25-Foot Walk (primary outcome) speed differences, allowing 25% attrition. Secondary outcomes were brain atrophy, other clinical and patient-reported disabilities, and adverse events. Study visits occurred every 6 months. Laboratory monitoring was increased to every 3 months because of treatment-related proteinuria. Intention-to-treat analysis used linear mixed-effects models.

Results: Participants in the LA (54) and placebo (61) groups were 54.8% female (age 59.1 (SD 8.5) years), with a disease duration of 16.3 (SD 9.7) years and a median EDSS score of 6.0 (interquartile range 4.0-6.0), and 55.7% were on DMT. Groups were matched at baseline. LA participants discontinued from the study more often (37%) than placebo (17%). LA did not slow declines in walking speed (-0.39 ft/sec vs -0.30 ft/sec; -0.08 [-0.33 to 0.17]), nor showed differences in mobility, other clinical, or patient-reported outcomes from placebo. Whole-brain volume seemed stable in LA participants, whereas it trended toward a decrease in placebo, even after accounting for an increased total T2-weighted lesion volume that was greater in the LA group. Deep gray matter volume remained stable in LA participants and decreased in placebo participants. The LA group experienced more proteinuria and fewer suicidal ideation events than the placebo group.

Discussion: LA did not slow decline in walking speed or have other clinical effects different from placebo and was associated with newly described adverse events. Investigating LA mechanisms may help interpretation of volumetric imaging biomarkers in PMS.

Trial registration information: NCT03161028. clinicaltrials.gov/study//NCT03161028, first submission May 18, 2017; first patient enrolled August 17, 2018.

Classification of evidence: This study provides Class II evidence that in people with primary or secondary PMS, oral LA did not improve timed walking speed at 24 months compared with placebo.

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Sanofi has just provided an update on tolebrutinib in primary progressive multiple sclerosis (Paris, December 15, 2025).

The PERSEUS phase 3 study of tolebrutinib in primary progressive multiple sclerosis (PPMS) did not meet its primary endpoint in delaying time to onset of 6-month composite confirmed disability progression compared to placebo. The safety profile of tolebrutinib was consistent with previous studies.

Results from the PERSEUS phase 3 study (clinical study identifier: NCT04458051) showed that tolebrutinib did not meet its primary endpoint in delaying time to 6-month composite confirmed disability progression (cCDP) in participants with primary progressive multiple sclerosis (PPMS). Based on these results, Sanofi will not pursue regulatory registration for PPMS.

“We are disappointed by today’s results; however, we do believe that these results will improve our understanding of the underlying disease biology of multiple sclerosis,” said Houman Ashrafian, Executive Vice President, Head of Research & Development at Sanofi. “We extend our deepest appreciation to the study participants, their families, and healthcare professionals who support our scientific and innovative vision. Our commitment to the multiple sclerosis community remains unchanged, as do our efforts to pursue novel advancements that address existing unmet needs, and we remain confident in the value tolebrutinib can bring to those living with non-relapsing secondary progressive multiple sclerosis.”

Preliminary analysis showed the safety profile was consistent with previous tolebrutinib studies. As previously reported, drug-induced liver injury (DILI) is an identified risk of tolebrutinib. Strict adherence to liver monitoring requirements and prompt management of liver enzyme elevations, are essential to mitigate DILI risk. Full safety and efficacy results will be presented at a forthcoming medical meeting.

Tolebrutinib was provisionally approved in the United Arab Emirates in July 2025 for the treatment of non-relapsing secondary progressive multiple sclerosis and to slow disability accumulation independent of relapse activity in adults. It is currently under regulatory review in the EU and other jurisdictions worldwide. The FDA previously granted Tolebrutinib a breakthrough therapy designation in December 2024.

Prof. G’s initial thoughts

In view of the positive HERCULES non-relapsing SPMS study, these results are unexpected and very disappointing. Do you agree? We will have to examine the results and subgroup analyses to determine whether these findings were driven by the patient population recruited into the study or the failure of the clinical endpoints. The PERSEUS trial recruited pwPPMS in parallel with the fenebrutinib study (FENtrepid). Because the FENtrepid trial compared fenebrutinib with ocrelizumab, an active comparator, people with less active PPMS were more likely to be recruited into the PERSEUS trial. In contrast, those with more active PPMS enrolled in the FENtrepid trial because they were guaranteed a treatment. This may have affected the results. What does this say about the impact of tolebrutinb on smouldering MS? Not much until we see the results, I would be speculating.

What these trial results show is how hard it is to develop MS therapies for smouldering MS. I hope people with PPMS are not too disappointed with these results. At least the O’HAND and FENtrepid studies are positive, so things are evolving for pwPPMS.

Any thoughts or questions?

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I just returned from the annual European Charcot Foundation (ECF) meeting in Italy. This is a small yearly meeting that is predominantly focused on teaching rather than original research. I started the meeting off with a debate. I took the position that MS is progressive in all people with MS. I made the argument that the real MS was smouldering MS and explained that those who had RIS (radiologically isolated syndrome) who did not go on to develop MS were able to cure themselves of having MS. In other words, smouldering MS only happens in people who can’t spontaneously cure themselves of what is causing their disease. I reiterated the point that relapses and focal MRI were simply the immune system’s response to what is causing the disease. I presented my theory that the clinical phenotypes we observe are merely an immunological phenotype, using leprosy as an analogy. Several people didn’t like the leprosy analogy to explain what we see happening in MS.

I also spoke at a sponsored symposium on the past, present and future of MS care, making the point that MS prevention could become a reality and that for people who had MS, we could offer a cure in the future. I based the latter on the EBV driver hypothesis, i.e MS disease activity is being driven by EBV latent-lytic cycling. On the penultimate day, I discussed emerging antiviral strategies targeting EBV for the treatment of MS. I covered the data supporting how I believe AHSCT and alemtuzumab, our most effective DMTs, are working as immunotherapies targeting EBV, specifically as T-cell rejuvenation therapies in combination with EBV autovaccination. For more information on how I think AHSCT and alemtuzumab work, please see: “AHSCT with ATG vs AHSCT with rituximab vs alemtuzumab” (14-Feb-2025).

I spent some time discussing CAR T-cell therapies, emphasising the need to have CNS penetration. When defining a cure for MS, I hypothesised that we would likely have to clear the CNS of pathogenic plasma cells responsible for producing intrathecal (within the meninges) oligoclonal IgG bands, or OCBs. This is why CD19-targeted CAR T-cell therapy may not be sufficient to cure MS. Plasma cells don’t express CD19 and, therefore, will escape deletion with anti-CD19-targeted therapies. A solution to this would be to focus on targeting B-cell maturation antigen (BCMA), which is expressed on plasma cells. This is when a swallow flew into the lecture hall, and instead of it being winter, the lecture theatre was full of sunshine.

Professor Barbara Willekens from Antwerp showed us a video of a young man with advanced progressive MS who had been treated in a first-in-human study of anti-BCMA CAR-T Cell therapy in China. He had an EDSS of 6.5 (two sticks) to 7.0 (wheelchair) as he had started using a wheelchair for outdoor mobility. He underwent CAR T-cell therapy in January 2025, and by October 2025, he was able to run, albeit with some residual spasticity in his lower legs. I estimated, looking at the video, that his EDSS must now be around 3.5-4.0. The audience was so impressed that after the video, the audience spontaneously started clapping, and I must admit I had a tear in my eye.

When someone transitions from almost being confined to a wheelchair to being able to walk and run, we call this the Lazarus effect. The effect is named after the biblical figure Lazarus, who was raised from the dead. In reality, this effect refers to the spontaneous return of signs of life, such as a pulse, after the cessation of cardiopulmonary resuscitation. Also known as autoresuscitation, this occurs within minutes of resuscitation efforts being stopped, with the patient appearing to have “come back to life” after being pronounced dead.

I sincerely hope this one swallow is not the end of this story. I don’t think so. This patient is one of five patients in the small case series below. This study reports the results of the first-in-human study of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in patients with progressive MS (PMS).

The study investigated the safety and efficacy of this CAR-T cell treatment, which is designed to target CNS resident plasma cells, a subset of B cells implicated in central nervous system (CNS) inflammation in PMS. The study found a favourable safety profile, significant depletion of plasma cells in the CNS, and the alleviation of microglial activation in the CNS, suggesting CAR-T therapy holds potential for managing this severe form of MS. The investigators also present detailed single-cell multi-omics analyses to explain the dynamics and mechanism of the CAR-T cells within the patients’ blood, bone marrow, and cerebrospinal fluid.

The study doesn’t overhype the treatment effect, as it was open-label; however, the results are remarkable when considering the EDSS, 9-hole peg test, and timed 25-foot walk results. All patients improved to a greater or lesser extent. I suspect that the patient we saw in the video progressed from an EDSS of 7.0 to 4.5 over 9 months. Let’s hope these results hold up when further randomised trials are completed.

This strategy for treating MS supports my hypothesis that we need to purge the body of EBV-infected B-cells, including those resident in the CNS, and simultaneously remove pathogenic plasma cells from the CNS. The CSF data from these patients show that the kappa free light chains plummet in the CSF, which is a biomarker of antibody production within the CNS. We are using the latter in our SIZOMUS study to investigate the impact of a second-generation proteasome inhibitor (ixazomib) on CNS-resident plasma cells. This CAR T-cell trial gives me confidence that we are on the right track.

I would appreciate your thoughts on these results. Am I overhyping them? Do we need more than 5 swallows to make a summer?

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This study also demonstrates how rapidly Chinese scientists are catching up with us in North America and Europe. When it comes to testing these innovative strategies in MS, they are ahead of the game.

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Qin et al. Anti-BCMA CAR-T therapy in patients with progressive multiple sclerosis. Cell. 2025 Nov 13;188(23):6414-6423.e11.

Progressive multiple sclerosis (PMS), which is characterized by relentless disease progression, lacks effective treatment. While recent studies have highlighted the importance of B cells in driving compartmentalized central nervous system (CNS) inflammation in PMS pathogenesis, current B cell depletion therapies, such as CD20 monoclonal antibodies, face challenges in targeting plasma cells within the CNS. Here, we treated five patients with PMS (one primary PMS and four secondary PMS) with anti-B cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in an ongoing phase 1 clinical trial (ClinicalTrials.gov: NCT04561557). Only grade 1 cytokine release syndrome was observed, and all grade ≥3 cytopenias occurred within 40 days post-infusion in all five patients. Meanwhile, we detected plasma cell depletion in CNS compartments, prolonged expansion and relieved exhaustion of CAR-T cells in the cerebrospinal fluid, and attenuation of microglial activation. These findings provided insights into the potential application of anti-BCMA CAR-T therapy for advancing clinical management of PMS.

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you experience any problems, please consult your healthcare professional, who will be able to assist you.

The essential finding is that EBV reprograms autoreactive B cells in SLE, transforming them into activated antigen-presenting cells (APCs), thereby establishing a potential “driver” of the B cell model that underpins the pathogenesis of SLE.

Patients with SLE exhibited an approximately 25-fold higher proportion of EBV+ve blood B cells compared with healthy controls (HCs). In SLE, EBV+ve B cells are predominantly found within the CD27+CD21low memory B cell subset. This subset of B-cells expresses the transcription factors ZEB2 and TBX21 (T-bet). The EBV+ CD27+ CD21low memory B cells exhibit upregulation of transcriptional programs associated with antigen-presenting cell (APC) function and B-cell activation. Specifically, genes crucial for antigen processing and presentation, including IFI30, TAP2, and PSMB6, were upregulated, indicating an enhanced capacity to process and present autoantigens. This is notable because most EBV latent gene products typically function to reduce the expression of MHC class I and II.

EBV nuclear antigen 2 (EBNA2) is one of the primary mediators responsible for reprogramming EBV-infected B cells, which may play a key role in the pathology. EBNA2 binding sites were found to be enriched at transcription start site (TSS) regions and regulatory elements of genes involved in antigen presentation and activation, including CD27, ZEB2, and TBX21. EBNA2 may also promote the survival, activation, and APC activity of EBV+ve B-cells by engaging host transcriptional coactivators and epigenetic mechanisms, specifically by binding to upstream enhancer elements and increasing chromatin accessibility at key loci (like CD27 and CD70). EBNA2 expression is associated with the latency 3 phase of EBV, which is characterised by increased expression of ZEB2, TBX21, and antigen presentation genes in SLE EBV+ve B-cells.

It is proposed that these EBV-positive B cells function as “driver” B cells by activating other cells necessary for the development of systemic autoimmunity. Recombinant antibodies derived from SLE EBV+ve B-cells, across multiple B-cell subsets, bound HEp-2 cells (44 out of 69 tested) and recognised prototypical SLE nuclear autoantigens (ANAs), such as Sm, dsDNA, Ro52, and histones. Some EBV+ve B cell monoclonal antibodies (mAbs) cross-react with both the viral protein EBNA1 and nuclear antigens, such as Sm. Sm is an important autoantigen in SLE. This supports a model in which EBV infects anti-EBNA1 B cells that exhibit autoimmune cross-reactivity. The presence of these autoreactive clones suggests that EBV infection may promote their survival and activation by overcoming peripheral tolerance checkpoints.

In vitro functional assays demonstrated that SLE EBV+ve B cells serving as APCs (presenting chromatin antigen) were sufficient to activate T peripheral helper (TPH) cells (CD4+PD1hiCXCR5−) and subsequently expand autoreactive EBV−ve DN2 B cells and plasmablasts. This activation potentially fuels the production of ANAs. The EBV−ve B cells within the clonal families showed increased somatic hypermutation (SHM). They encoded mAbs that bound to autoantigens (such as Sm) with higher affinity compared to their EBV+ve clonal family counterparts. This suggests EBV+ve cells initiate the response, enabling affinity maturation in EBV−ve cells, which then secrete high-affinity ANAs.

The proposed mechanistic framework has significant implications for how we perceive EBV’s role in other autoimmune diseases, such as MS, and how treatment strategies may be developed or evolved. These findings clearly provide a rationale for the effectiveness of deep B-cell depletion therapies, such as anti-CD20 and anti-CD19 targeting therapies, including T-cell engagers and engineered CAR-T cells.

The ability of EBV+ve B cells to act as potent APCs—not just antibody producers—explains why profound B cell depletion, such as that achieved by CD19-targeted CAR T cell therapies, might be dramatically effective in refractory SLE. This therapy eliminates both antibody-producing B cells and those functioning as APCs.

The durability of these ultra-deep B cell depletion treatments (like CD19-CAR T cell therapy or anti-BCMA T cell engagers) may be explained by their ability to deplete EBV+ve antinuclear antigen driver B cells successfully. If this can be achieved in the long term, we may be able to cure people of having SLE.

Broader implications for autoimmunity

As you are aware from many of my MS-Selfie newsletters, EBV is epidemiologically associated with SLE, but also MS and several other autoimmune diseases. The proposed framework, where EBV infects and reprograms autoreactive B cells as driver APCs, may play a central role in MS and other EBV-associated autoimmune conditions (Sjögren’s syndrome, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, …).

The study suggests that the development of SLE is tied to EBV infecting B cells that are already autoreactive, which are known to be present in the naïve B cell compartments of patients with autoimmune diseases but not HCs. This suggests that another factor is also required, for example, a genetic predisposition leading to the development of autoreactive B cells, followed by EBV infection and the reprogramming of those specific cells. This research highlights the crucial role of B cells as potent APCs, going beyond their well-known function as autoantibody producers. EBV generates “overdriven” APCs that are capable of breaking immune tolerance and driving systemic autoimmunity.

The question of whether EBV reactivation causes disease flares or merely accompanies the inflammatory B cell differentiation remains unresolved. The study suggests that some lytic-phase EBV gene expression seen in plasmablasts might be a bystander consequence of inflammatory B cell differentiation.

In summary, these findings indicated that EBV is not simply a bystander virus but actively affects pre-existing autoreactivity by converting those autoreactive cells into potent initiators and orchestrators of the systemic autoimmune response in SLE. An analogy would be turbocharging an already volatile engine.

I am aware that this newsletter is quite technical and discusses topics that may be unfamiliar to you. However, in summary, this research suggests that EBV reprograms memory B-cells that present autoreactive antigens to other immune cells, which drives disease activity in SLE. The solution is to purge the body of these EBV-infected cells with treatments targeting EBV, memory B cells, or B cells in general.

If you have any questions, please don’t hesitate to ask.

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Paper

Younis et al. Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus. Sci Transl Med. 2025 Nov 12;17(824):eady0210.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by antinuclear antibodies (ANAs). Epstein-Barr virus (EBV) infection has been epidemiologically associated with SLE, yet its role in pathogenesis remains incompletely defined. Here, we developed an EBV-specific single-cell RNA-sequencing platform and used it to demonstrate that EBV infection reprograms autoreactive antinuclear antigen B cells to drive autoimmunity in SLE. We demonstrated that, in SLE, EBV+ B cells are predominantly CD27+CD21low memory B cells that are present at increased frequencies and express ZEB2, TBX21 (T-bet), and antigen-presenting cell transcriptional pathways. Integrative analysis of chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and RNA polymerase II occupancy data revealed EBV nuclear antigen 2 (EBNA2) binding at the transcriptional start sites and regulatory regions of CD27, ZEB2, and TBX21, as well as the antigen-presenting cell genes demonstrated to be up-regulated in SLE EBV+ B cells. We expressed recombinant antibodies from SLE EBV+ B cells and demonstrated that they bind prototypical SLE nuclear autoantigens, whereas those from healthy individuals do not. We further found that SLE EBV+ B cells can serve as antigen-presenting cells to drive activation of T peripheral helper cells with concomitant activation of related EBV- antinuclear double-negative 2 B cells and plasmablasts. Our results provide a mechanistic basis for EBV being a driver of SLE through infecting and reprogramming nuclear antigen-reactive B cells to become activated antigen-presenting cells with the potential to promote systemic disease-driving autoimmune responses.

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General comments:

At present, large language models, such as Gemini Pro, are very good at doing rapid, detailed searches and producing a summary document with references in about 30-45 minutes. This would take a trained academic like me days, if not weeks, to complete. However, you need to be an expert to weed out the misinformation and inaccurate references in the search. Yes, it makes false claims. In addition, these LLMs have walls or limits to what they can produce, i.e. their training is generally based on information that is accessible on the web and not behind firewalls. Many academic publishers hide content behind firewalls and don’t allow bots to hoover up data behind these walls. In addition, the LLMs at present don’t necessarily go beyond their training material. This is why more specialised LLMs that have access to articles and information behind firewalls are better, for example, SciSpace and OpenEvidence or creating your own LLM by teaching it with resources you define or upload. I do this all the time using Google’s NotebookLM.

Another issue is how to prompt LLMs to give you the most appropriate answers. There is a new science of how to prompt LLMs. For more information on how to prompt LLMs, please read this article from Google.

I note that some, but not all, of you were impressed with the Newsletter that Gemini Pro 2.5 Deep Research produced in response to the prompt: “Is there an alternate theory of multiple sclerosis, other than the autoimmune theory, that posits that Gadolinium-enhancing lesions are actually not the disease but the immune response to what is causing multiple sclerosis?”. Please note I edited this newsletter to make sure I took out the hallucinations, and I culled all the references to make it easier to read. The raw, unedited version was not fit for purpose.

On a superficial level, the review it produced summarised the debate on the "Outside-In" versus the “Inside-Out” models reasonably well, but failed to discuss some pivotal insights from the field that need to be considered, nor did it discuss in any detail what is driving the pathology within the central nervous system (CNS). It only briefly mentioned viruses and spent most of the time discussing oligodendrocyte death and mitochondrial pathology. Surely any thinking person would think of oligodendrocyte death and mitochondrial pathology as being downstream of the cause of MS?

One of Gemini’s scotomas (blind spots) was the lack of mention of a systemic or local toxin driving MS pathology. The two leading contenders are Clostridium perfringens exotoxin and Frederik Gay’s bacterial toxin sphingomyelinase.

Toxins:

Clostridium perfringens is a common inhabitant of the human gut, but certain strains produce potent toxins. The epsilon toxin is a neurotoxin known to cause significant damage to the CNS in animals. Studies have reported a higher prevalence of epsilon toxin-producing strains of Clostridium perfringens in the gut microbiome of individuals with MS compared to healthy controls. Some research has found a higher frequency and/or elevated levels of antibodies against the toxin in MS patients, suggesting a past or ongoing exposure to the toxin. The epsilon toxin is a potent neurotoxin with the ability to cross the blood-brain barrier, which prevents harmful substances from entering the CNS. Once in the CNS, epsilon toxin has been shown in animal studies to target and kill oligodendrocytes selectively.

Sphingomyelinase is an enzyme that breaks down sphingomyelin, a key component of the myelin sheath that insulates nerve fibres. The breakdown product of this reaction is ceramide. High levels of ceramide are known to trigger apoptosis, or programmed cell death. The accumulation of ceramide could lead to the death of oligodendrocytes in the CNS, which are responsible for producing and maintaining myelin. Studies have found increased levels of both sphingomyelinase activity and ceramide within active MS lesions and elevated levels of ceramide in the CSF of pwMS compared to healthy controls. Several bacteria produce sphingomyelinase (e.g., Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus cereus, …). Frederik Gay’s research points to the involvement of a specific bacterial sphingomyelinase as the initiator of the primary lesion of MS, in advance of demyelination, with the bacterial toxin gaining access to the CNS via the mucosa of the paranasal sinuses.

This is why it makes sense to develop therapies to neutralise these toxins to test as DMTs in pwMS. I will do a separate newsletter on the toxin hypothesis of MS later.

Field Hypothesis:

Another Gemini scotoma was stereotypical attacks suggestive of relapse. Did you know that 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 (see paper 1 below). I have in the past referred to this as the so-called field hypothesis, i.e. something locally triggers recurrent attacks in the same site.

What underlies the field effect? One explanation is that the area that is damaged by the initial attack is more likely to trigger autoimmune responses in future as a result of the local up-regulation of so-called second, or danger, costimulatory immune signals. This occurs in response to the factor produced as part of the initial inflammatory event. For T-cells to become activated, they need an antigen-specific signal via the T-cell receptor and an additional signal via co-stimulation.

Another hypothesis, which I favour, is that there is something in the field that triggers relapses. Possibly a virus? Why do I say this? Firstly, when pwMS were treated with interferon-gamma, a cytokine or inflammatory mediator that stimulates immune responses, they all had relapses (paper 2). The interesting 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, who was the principal investigator on the gamma-interferon trial, he thought that this observation was fundamental and was telling us something important about the cause of MS. It was this insight and my discussion with Hillel that led me to formulate my leprosy hypothesis about MS (paper 6).

Another observation that supports the abnormal field hypothesis is the rebound effect after 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 let the immune cells back in, they detect the abnormal field and run amok trying to clear up what is causing MS in the field. This is what 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. Some of us think that rebound post-natalizumab is simply IRIS in response to the virus or viruses that cause MS.

Another observation comes from serial MRI studies that have shown subtle changes in the white matter many weeks or months before a gadolinium-enhancing lesion appears. This suggests that the primary pathology is something in the nervous system that takes weeks or months to trigger a focal inflammatory lesion. The challenge for us all is to find out what this field abnormality is. I think the best chance we have of doing this is to study the brains of people with MS on natalizumab. To do this, we will need someone with MS to die whilst on natalizumab treatment and to donate their brain to a unit with the necessary techniques to look for viruses. In fact, this has happened twice already, and the results are compelling, but seldom discussed by MS researchers.

Brain tissue from two patients who tragically died during a fulminating MS relapse following natalizumab withdrawal showed numerous EBV-infected B cells and plasma cells with infiltrating cytotoxic CD8+ T lymphocytes (CTLs) infiltrating all of the lesions in the white matter (papers 3 & 4). The highest number of EBV lytically infected cells and granzyme B+ CTLs were observed in actively demyelinating lesions. This case suggests the rebound post-natalizumab may be in response to EBV-infected B-cells and plasma cells in the brains of people with MS.

I am aware that two swallows do not make a summer, but could these cases be the smoking gun we are looking for?

Subsequent studies show that a large number of CD8 T-cells in the brains of pwMS are EBV-specific, targeting EBV proteins from both the latent and lytic phase of the EBV life-cycle (paper 5). This study included post-mortem samples from 12 people with progressive MS. A 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 were infected with EBV and you blocked immune surveillance using natalizumab, surely you could expect some ill effects? We don’t see this happening from a clinical perspective, at least in the short to intermediate term. In fact, we know the opposite happens; pwMS on natalizumab usually have no evident inflammatory disease activity (NEIDA) and many of them experience an improvement in disability. After rebaselining brain volume loss on natalizumab, it is close to the normal range, and fatigue and/or sickness behaviour improve. Surely, these observations argue against a direct CNS infection as being the cause of MS? Maybe not. Natalizumab may reduce smouldering MS, but it does not stop smouldering MS, which, in my opinion, is the real MS, and this may take many decades to manifest itself. It is common to see patients who have been on natalizumab for a decade or more with worsening MS and worsening brain volume loss.

Suppose MS is due to EBV-specific CD8+ cytotoxic T-lymphocytes attacking the brain of pwMS. Why does rituximab, a drug that takes out predominantly B-cells, prevent rebound disease activity post-natalizumab? Some have argued that the B-cells are needed to travel to the brain to present antigen to the CD8+ T-cells. I don’t buy this explanation, as there are other professional antigen-presenting cells in the brains of pwMS that can take on this role. Others cite evidence that T-cells require assistance from B-cells to cross the blood-brain barrier. This does not explain why some of the carry-over PML cases from natalizumab to rituximab (or ocrelizumab) have developed IRIS (immune reconstitution inflammatory syndrome). In the latter instances, IRIS-causing T-cells have clearly trafficked to the brain in the absence of circulating B-cells.

So these papers generate more questions than they necessarily answer. Still, it does demonstrate that we need to really 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. However, this should not stop us from exploring both approaches; it is the results of the experiment that disprove the hypothesis. This is why we need to be exploring both EBV-specific antiviral agents and a therapeutic EBV vaccine as potential treatments for MS.

Leprosy hypothesis of MS:

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 system’s 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. The trial of gamma-interferon in MS was stopped because it causes subjects to have relapses. The corollary is that immunosuppressive treatments of relapsing MS suppress relapses but do not stop smouldering or the real MS. In other words, immunosuppressive therapies convert relapsing MS into PPMS. To test the leprosy hypothesis of MS, we would need to know the autoantigen or inciting organism driving MS. Despite decades of research, we have yet to find the MS autoantigen. I doubt we will see an autoantigen, so we should instead focus on the most likely cause of MS, EBV.

For more information on the leprosy hypothesis of MS, please read paper 6 below.

Conclusion

From the few examples discussed above, it is clear that Gemini missed many of the alternative theories of what is driving smouldering MS or the ‘inside-out hypothesis’ of MS. I have only scratched the surface on this topic and will give some additional thoughts on this topic in the future.

However, I am biased! I am firmly in the ‘Inside-Out’ camp and think EBV can explain a lot of the observations above. This is why I am trying to develop, or help develop, with little success, treatments for MS targeting EBV and strategies targeting EBV to prevent MS.

I would like to know what you think of this newsletter compared to the AI-generated one. Do I still have a role? Does MS-Selfie have a future? Do you like these blue-sky type newsletters? Are they too scientific or off-topic for you?

Thanks

Leave a comment

Paper 1 - Stereotypical relapses

Willis et al. Site-specific clinical disease onset in multiple sclerosis. Eur J Neurol. 2014 Sep 8. doi: 10.1111/ene.12564.

Paer 2 - Gamma interferon

Panitch et al. Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet. 1987 Apr 18;1(8538):893-5.

Paper 3 - Case study 1 - lytic EBV infection with natalizumab rebound

Serafini et al. Massive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawal. J Neuroimmunol. 2017 Jun 15;307:14-17.

Paper 4 - Case study 2 - lytic EBV infection with natalizumab rebound

Serafini et al. Epstein-Barr virus-associated immune reconstitution inflammatory syndrome as possible cause of fulminant multiple sclerosis relapse after natalizumab interruption. J Neuroimmunol. 2018 Jun 15;319:9-12.

Paper 5 - Case series

Serafini et al. Epstein-Barr virus-specific CD8 T cells selectively infiltrate the multiple sclerosis brain and interact locally with virus-infected cells: a clue for a virus-driven immunopathological mechanism. J Virol 2019 - DOI: 10.1128/JVI.00980-19.

Paper 6 - Leprosy hypothesis

Giovannoni G. The Yin and Yang of Inflammation in Multiple Sclerosis. In: Hommes OR, editor. Early Indicators Early Treatments, Neuroprotection in Multiple Sclerosis. Milan: Springer Milan; 2004. p. 181-9.

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“Is there an alternate theory of multiple sclerosis, other than the autoimmune theory, that posits that Gadolinium-enhancing lesions are actually not the disease but the immune response to what is causing multiple sclerosis?”

The following is an edited version of the output. Please read it and tell me what is wrong with it; i.e. has Gemini misunderstood the literature, is there something missing, if you could, what would you add to the output? I will then write my own counterargument once we have discussed Gemini’s answer. You can then tell me if I still have a role in this brave new world dominated by information and increasingly by AI-generated slop.

"AI slop" refers to low-quality, generic, and often inaccurate media (text, images, video) produced by artificial intelligence. A lack of effort or expertise characterises this content, flooding the internet with unoriginal and unhelpful material that can be repetitive, verbose, or contain factual errors. The term has a pejorative connotation, similar to "spam," and highlights the problem of AI being used without sufficient human oversight or meaningful input.”

Thank you.

Summary

Multiple Sclerosis (MS) is predominantly understood and managed as a primary autoimmune disease of the central nervous system (CNS). This conventional paradigm, often referred to as the "outside-in" model, posits that an aberrant peripheral immune response triggers an inflammatory attack on myelin and oligodendrocytes, resulting in the characteristic demyelination and neurodegeneration. Within this framework, the appearance of Gadolinium-enhancing (Gd+) lesions on magnetic resonance imaging (MRI) is considered the definitive radiological hallmark of active disease—the direct visualisation of the primary pathogenic event. However, this autoimmune hypothesis, while considered robust, faces significant scientific challenges and does not fully satisfy the rigorous criteria for a classical autoimmune disorder.

In response to these challenges, a compelling alternative aetiological framework has emerged: the "inside-out" hypothesis. This model posits that MS originates not in the immune system, but as a primary degenerative process within the CNS itself. This hypothesis reinterprets Gd+ lesions not as the cause of the disease, but as a visible manifestation of the immune system's secondary response to an underlying, non-inflammatory pathology.

The key points are as follows:

1. The prevailing autoimmune theory of MS is incomplete. Despite its widespread acceptance, it fails to identify a universal autoantigen, is not fully replicated in animal models, and lacks the strong association with other autoimmune conditions that characterise classical autoimmune diseases. These weaknesses necessitate the exploration of alternative models.

2. The "inside-out" hypothesis is supported by a growing body of evidence indicating that significant pathology occurs within the CNS before the arrival of peripheral immune cells. Candidate mechanisms for this primary insult include the premature death of myelin-producing cells (oligodendrocyte apoptosis), a failure of essential cellular logistics within nerve fibres (axonal transport defects), and a fundamental collapse of cellular energy production (mitochondrial dysfunction).

3. This alternative model reframes the interpretation of Gd+ lesions. Rather than representing the primary autoimmune assault, they are viewed as a consequence of the disease—a marker of the inflammatory "cleanup" crew arriving at a site of pre-existing neurodegenerative crisis. This reinterpretation has profound implications for diagnosis and therapeutic strategy, suggesting that the actual target for treatment should be neuroprotection and metabolic support, not solely immunomodulation.

The current dogma: Gadolinium enhancement as a marker of primary autoimmune insult ("Outside-In" model)

The prevailing understanding of MS is rooted in the "outside-in" hypothesis, a framework that defines the disease as an organ-specific, immune-mediated disorder of the central nervous system. This model provides a coherent, albeit incomplete, narrative for the disease's pathogenesis, diagnosis, and treatment, with the Gadolinium-enhancing (Gd+) lesion serving as its central radiological pillar.

The pathophysiological cascade

According to the "outside-in" model, the pathogenic cascade of MS begins in the periphery, outside the CNS. It is hypothesised that in genetically susceptible individuals, an environmental trigger—most notably a viral infection such as Epstein-Barr Virus (EBV)—leads to the activation of autoreactive lymphocytes, specifically T-cells and B-cells, that mistakenly recognise components of CNS myelin as foreign.

These activated immune cells circulate in the bloodstream and migrate to the CNS. A crucial step in this process is the breach of the blood-brain barrier (BBB), a highly selective border that usually protects the brain from systemic inflammation and pathogens. Once across the BBB, these T-cells and B-cells orchestrate a complex inflammatory attack. T-cells release pro-inflammatory chemicals (cytokines) that cause direct damage and recruit other immune cells, such as macrophages, to the site. B-cells can mature into plasma cells that produce antibodies against myelin and also function as potent antigen-presenting cells, further amplifying the T-cell response.

This coordinated assault results in a cascade of pathobiological events: focal lymphocytic infiltration, activation of resident CNS immune cells (microglia), and the hallmark destruction of the myelin sheath (demyelination) and the cells that produce it (oligodendrocytes). While axons are often relatively spared in the initial stages, they are not immune to damage. The inflammatory environment, coupled with the loss of trophic support from myelin, leads to acute axonal injury and, over time, irreversible axonal transection and neuronal loss, which are the primary substrates of permanent neurological disability.

The radiological correlate—the Gd+ Lesion

Within this well-established paradigm, the Gd+ lesion, visualised on T1-weighted MRI scans, is the definitive in vivo biomarker of active, focal inflammation and is interpreted as the direct radiological signature of the primary disease process. Gadolinium-based contrast agents (GBCAs) are large molecules that, under normal physiological conditions, cannot cross the intact BBB. Their appearance within the brain parenchyma on an MRI is therefore unequivocal evidence of a localised BBB breakdown. In the "outside-in" model, this breakdown is a direct consequence of the inflammatory attack. Cytokines released by infiltrating immune cells increase the permeability of the local blood vessels, allowing both the immune cells and the injected gadolinium to leak into the CNS tissue. The gadolinium accumulates in the area of acute inflammation, causing a shortening of the T1 relaxation time and appearing as a bright (hyperintense) signal on T1-weighted images. This enhancement is a transient phenomenon, typically lasting 2-6 weeks, after which the inflammation subsides and the BBB begins to repair itself, causing the enhancement to fade.

The clinical utility of Gd+ lesions is deeply embedded in the diagnosis and management of MS. A Gd+ lesion is considered a reliable marker of a new or reactivating MS plaque, signifying acute disease activity at the time of the scan. Its presence is often correlated with clinical relapses, although many enhancing lesions can be clinically silent, depending on their location and size. The detection of Gd+ lesions is a cornerstone of the McDonald diagnostic criteria, the international standard for diagnosing MS. The presence of a Gd+ lesion on a baseline MRI scan can fulfil the criterion for "dissemination in time," allowing for a definitive diagnosis of MS even after a single clinical event (a clinically isolated syndrome) by demonstrating that pathological processes are ongoing.

Furthermore, the count and volume of Gd+ lesions are critical endpoints in clinical trials for disease-modifying therapies (DMTs). The efficacy of a new drug is often measured by its ability to reduce or eliminate the formation of new Gd+ lesions. In clinical practice, the appearance of new Gd+ lesions in a patient on therapy is considered a sign of breakthrough disease activity. It usually prompts a switch to a more potent medication. The evolution of these lesions is also tracked over time. An acute Gd+ lesion typically leaves behind a permanent, non-enhancing scar visible as a hyperintense area on T2-weighted or FLAIR sequences. In cases of severe tissue destruction, the lesion may evolve into a T1-hypointense "black hole," which signifies axonal loss and gliosis and is associated with worse long-term disability.

The entire clinical and research framework for MS is thus built upon the foundational assumption that Gd+ enhancement is a direct and reliable proxy for the primary disease process. The logic is straightforward: if the disease is a primary inflammatory attack, and Gd+ enhancement visualises this attack, then stopping the formation of Gd+ lesions is equivalent to halting the disease. This rationale has successfully guided the development of a large arsenal of anti-inflammatory and immunomodulatory DMTs. The success of these therapies in reducing relapses and Gd+ lesion formation has, in turn, created a powerful feedback loop, reinforcing the validity of both the "outside-in" model and the interpretation of the Gd+ lesion as its primary radiological manifestation. This makes it exceptionally difficult to consider alternative interpretations without questioning the very foundations of modern MS care.

Foundational cracks: a critical appraisal of the autoimmune hypothesis

While the "outside-in" model presents a compelling narrative and has led to effective treatments for the inflammatory aspects of MS, the classification of MS as a classical autoimmune disease is built on a foundation with significant and persistent cracks. A rigorous examination of the evidence reveals that MS fails to meet several key criteria that define canonical autoimmune disorders, suggesting that the role of the immune system, while undeniably central, may be more complex than that of a primary, unprovoked aggressor.

Failure to meet Witebsky's postulates for autoimmunity

Decades of intensive research have yielded a wealth of information about the immune-mediated nature of MS. Yet, the evidence remains circumstantial when held against the established criteria for defining an autoimmune disease.

The missing autoantigen

A fundamental criterion for any given autoimmune disease is the identification of a precise autoantigen—a specific self-molecule targeted by the immune system—that is present in all patients with the disease. In myasthenia gravis, this is the acetylcholine receptor; in neuromyelitis optica (NMO), it is the aquaporin-4 water channel. Despite exhaustive efforts to identify a similar target in MS, focusing on myelin components like myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG), as well as various lipids and gangliosides, no single, confirmed autoantigen has been universally identified in all MS patients. This absence of a specific target is a significant departure from the classical autoimmune model.

Ambiguous animal models

The primary animal model for MS, Experimental Autoimmune Encephalomyelitis (EAE), is induced by immunising animals with myelin antigens, which then triggers a CNS-directed immune attack. While EAE has been invaluable for studying the mechanisms of neuroinflammation, it has limitations as a model for a spontaneous human disease. Critically, the disease process in EAE can be induced by multiple different myelin antigens, with no single antigen proving superior or uniquely causative. Furthermore, attempts to passively transfer the disease to healthy animals by administering autoantibodies or autoreactive T cells from people with MS have produced conflicting and inconsistent results, failing to definitively prove a single, transferable pathogenic agent, as would be expected in a classic autoimmune disorder.

Lack of specificity in autoreactive cells

While it is true that patients with MS often have a higher frequency of T-cells that react to myelin antigens compared to healthy controls, particularly during relapses, this finding is not specific to the disease. Autoreactive T-cells capable of recognising myelin components can also be readily isolated from the blood of healthy individuals who show no signs of MS. Their mere presence, therefore, is not sufficient to prove causality. It suggests that the control of these potentially pathogenic cells, rather than their existence, is the critical factor, and that in MS, this control mechanism may fail.

Weak association with other autoimmune diseases

Patients with a confirmed autoimmune disease often have an increased risk of developing other autoimmune conditions. However, extensive, population-based cohort studies have generally failed to demonstrate a strong association between MS and the broader spectrum of autoimmune diseases. While some case reports exist, and a weak association with thyroid disease has been noted, MS does not typically cluster with conditions like systemic lupus erythematosus or Sjögren's syndrome in the way that these diseases cluster with each other. This again contrasts sharply with a disease like NMO, which has a clear autoimmune signature.

These persistent discrepancies between MS and classical autoimmune diseases do not negate the critical role of the immune system in MS pathology. The presence of perivascular inflammatory infiltrates, oligoclonal bands in the cerebrospinal fluid, and the apparent efficacy of immunomodulatory therapies all confirm that MS is an immune-mediated disease. However, the failure to satisfy these core criteria strongly suggests that the immune response may not be the primary, instigating event. If the immune system is not the unprovoked aggressor, then it must be reacting to something. This line of reasoning logically leads to the hypothesis that the autoimmune phenomena observed in MS are, in fact, a secondary response to a primary pathological process occurring within the CNS itself. This conceptual shift is the gateway to the "inside-out" hypothesis.

A paradigm shift: the "Inside-Out" hypothesis of MS

The "inside-out" hypothesis represents a fundamental re-conceptualisation of MS pathogenesis. It challenges the primacy of the immune system in the disease's origin and instead proposes that MS is initiated by an intrinsic, degenerative process within the central nervous system. In this model, the well-documented inflammation and autoimmune phenomena are not the cause of the disease, but rather a secondary, albeit highly consequential, reaction to this primary CNS cytodegeneration. This paradigm shift inverts the established causal relationship: degeneration precedes and provokes inflammation, rather than the other way around.

This alternative view presents a potential explanation for one of the significant paradoxes in MS clinical care: the disconnect between inflammation and disease worsening. Current disease-modifying therapies are remarkably effective at suppressing the inflammatory attacks that characterise relapsing-remitting MS (RRMS). Yet, they have a much more modest impact on the relentless accumulation of disability seen in advanced forms of the disease. The "inside-out" model suggests this is because these therapies target the secondary inflammatory response, leaving the underlying primary degenerative driver largely untouched. To frame the stark differences between the two competing paradigms, the following table provides a direct comparison.

Candidate mechanisms for the primary insult

The "inside-out" hypothesis is not a single theory but a framework that encompasses several potential mechanisms for the initial, non-inflammatory CNS injury. Research has converged on three particularly compelling candidates, which are not mutually exclusive and may interact to drive the disease process.

1. Primary oligodendrogliopathy (oligodendrocyte death)

There is substantial pathological evidence to suggest that the death of oligodendrocytes—the sole myelin-producing cells of the CNS—can be a very early event in MS lesion formation, occurring even before the mass infiltration of peripheral immune cells. Studies of early MS lesions have identified oligodendrocytes undergoing programmed cell death (apoptosis) in so-called "pre-phagocytic" areas, where there is microglial activation but a conspicuous absence of the T-cell and B-cell infiltrates that characterise a classic inflammatory lesion. In this scenario, an unknown stressor—perhaps metabolic, toxic, or viral—triggers apoptosis in vulnerable oligodendrocytes. The death of these cells leads to the destabilisation and subsequent breakdown of the myelin sheaths they support. This disintegration of myelin releases a host of proteins and lipids that are normally sequestered from the immune system. This release of cellular debris acts as a powerful danger signal, attracting and activating microglia and, eventually, the peripheral immune system to the site to clear the damage, thereby initiating the secondary inflammatory cascade. This model is supported by novel experimental systems where inducing apoptosis specifically in oligodendrocytes is sufficient to trigger rapid demyelination and a robust local microglial response, all in the absence of a primary autoimmune trigger.

2. Primary axonopathy (axonal dysfunction)

For many years, axonal damage in MS was considered a late and secondary consequence of inflammatory demyelination. However, it is now clear that axonal injury is an early and pervasive feature of the disease. The "inside-out" model posits that this axonal pathology may not be secondary at all, but rather a primary driver of the disease process. A key line of evidence comes from studies of axonal transport, the intricate logistical system that moves essential cargoes, such as mitochondria, proteins, and vesicles, along the length of the axon. In animal models of MS, profound defects in axonal transport have been shown to occur very early, preceding structural signs of axonal degeneration and even overt demyelination.

This suggests a primary metabolic or structural failure within the axon itself. Such a failure can initiate a devastating vicious cycle. Impaired transport of mitochondria starves the axon of adenosine triphosphate (ATP), the energy currency of the cell. This energy deficit is particularly damaging for axons, which have enormous energy demands to maintain ion gradients and propagate nerve impulses. This demand increases exponentially when the insulating myelin sheath is lost. The lack of ATP further cripples the energy-dependent molecular motors responsible for axonal transport, leading to a downward spiral of energy failure, accumulation of toxic protein aggregates, and eventual axonal degeneration. The debris from this degenerating axon would then, like the debris from a dying oligodendrocyte, trigger a secondary inflammatory response.

3. Mitochondrial dysfunction

A more fundamental "inside-out" trigger, potentially underlying both oligodendrogliopathy and axonopathy, is mitochondrial dysfunction. Mitochondria are the powerhouses of the cell, and the CNS, with its incredibly high metabolic rate, is exquisitely sensitive to any disruption in their function. A wealth of evidence points to widespread mitochondrial pathology in MS. Post-mortem studies of MS brain tissue and analyses of animal models reveal mitochondrial respiratory chain deficiencies, abnormalities in mitochondrial structure and transport, and a significant reduction in energy production capacity in both neurons and glial cells.

This systemic energy failure within the CNS could be the primary insult that initiates the entire pathogenic cascade. A deficit in ATP production can directly lead to the axonal transport failures described above. Dysfunctional mitochondria also produce an excess of damaging reactive oxygen species (ROS) and lead to dysregulation of intracellular calcium levels, both of which are potent triggers for apoptosis in oligodendrocytes. Therefore, a primary mitochondrial defect could simultaneously precipitate both oligodendrocyte death and axonal dysfunction, creating a perfect storm of cellular degeneration that culminates in a robust secondary inflammatory response. Recent research has highlighted explicitly that a reduction in mitochondrial activity in the cerebellum is a key contributor to the death of Purkinje cells, which are crucial for motor control, directly linking mitochondrial failure to the clinical symptoms of MS.

Reinterpreting the evidence: the Gd-enhancing kesion in the "Inside-Out" Context

The "inside-out" hypothesis does not dispute the physiological reality that a Gd-enhancing lesion represents: a focal area of acute inflammation and blood-brain barrier disruption. Instead, it radically redefines the lesion's meaning and significance within the broader narrative of the disease. In this context, the Gd+ lesion is transformed from the inciting incident into a secondary, reactive phenomenon—a late-stage marker of an underlying degenerative crisis that has already been unfolding silently.

According to the "inside-out" model, the appearance of a Gd+ lesion signifies the point at which a primary, smouldering neurodegenerative process—be it oligodendrocyte death, axonal failure, or mitochondrial collapse—reaches a critical threshold. At this point, the amount of cellular death and the accumulation of myelin and axonal debris become substantial enough to trigger a full-blown inflammatory response from the CNS's resident immune cells (microglia) and, subsequently, the peripheral immune system. This inflammatory response, while likely intended to be a reparative "cleanup" operation, is itself damaging and is responsible for the acute BBB breakdown that allows gadolinium to enter the tissue.

This sequence of events—degeneration followed by inflammation—is supported by several lines of evidence:

• Animal models: The Cuprizone Autoimmune Encephalitis (CAE) model provides compelling experimental support. In this model, mice are first treated with cuprizone, a toxin that induces a subtle myelin perturbation and oligodendrocyte injury without causing overt demyelination or inflammation. Only after this primary, non-inflammatory insult is established is an immune challenge administered. This challenge then precipitates a robust inflammatory demyelination, complete with BBB breakdown and Gd+ enhancement on MRI. This model elegantly demonstrates that a primary CNS pathology can precede and directly cause a secondary inflammatory event that is radiologically identical to a classic MS lesion.

• Human neuropathology: Pathological examination of human MS brain tissue has revealed the existence of "pre-active lesions." These are areas characterised by clusters of activated microglia and evidence of early myelin damage and axonal injury. Still, crucially, they lack the significant infiltration of T-cells and B-cells from the periphery. These pre-active lesions are thought to represent the initial stage of lesion formation. This "inside-out" degenerative process has not yet triggered the full-scale adaptive immune response that would lead to Gd+ enhancement. They provide a pathological snapshot of the disease process before the arrival of the inflammatory cavalry.

Radiological evidence supporting a neurodegeneration-first model

While the Gd+ lesion is the most dramatic radiological finding, other, more subtle MRI features lend support to the idea of a primary, widespread degenerative process.

• Normal-appearing white matter (NAWM): Proponents of the "inside-out" model emphasise that the focal lesions visible on conventional MRI are not the whole story. Using advanced, quantitative MRI techniques, researchers have demonstrated subtle but widespread pathological changes throughout the so-called "normal-appearing" white matter of MS patients—areas that are distant from any focal inflammatory lesions. These changes in NAWM suggest a diffuse, global CNS pathology, a slow-burning degenerative process that affects the entire brain. From this perspective, the focal Gd+ lesions are merely the "tip of the iceberg," representing localised hotspots where this underlying degenerative process has flared up to a degree that necessitates a visible inflammatory response. This helps to explain the well-known clinico-radiological paradox, where patients can accumulate significant disability over time even in the absence of new Gd+ lesions, as the disability is driven by the "smouldering" degeneration occurring in the NAWM.

• Central vein sign: The observation that the vast majority of MS lesions are perivenular, meaning they form around a small central vein, is a key radiological feature. This "central vein sign" is compatible with both pathogenic models. In the "outside-in" view, the vein is the portal of entry through which autoreactive immune cells leave the bloodstream and enter the brain. In the "inside-out" view, the perivenular space, which is part of the brain's glymphatic waste clearance system, could be where metabolic byproducts and cellular debris from a primary degenerative process accumulate. This accumulation of "danger signals" in the perivenular space would then trigger a localised inflammatory response, explaining why the lesions form in this specific anatomical location.

• Re-evaluating clinical practice: In recent years, there has been a significant clinical and regulatory debate regarding the necessity of routine gadolinium administration for monitoring MS patients, driven by concerns about long-term gadolinium deposition in the brain. Many experts now advocate for a reduced-gadolinium or gadolinium-free monitoring strategy, focusing instead on the appearance of new or enlarging lesions on T2-weighted sequences. T2 lesions represent the permanent "footprint" or scar left by a pathological event, reflecting cumulative tissue damage and demyelination. This clinical shift, whether intentional or not, aligns with the "inside-out" perspective. It implicitly prioritises the measurement of irreversible tissue destruction (T2 lesions) over the measurement of the transient inflammatory response (Gd+ lesions), acknowledging that it is the former, not the latter, that is the ultimate driver of long-term disability.

In summary, the "inside-out" model does not change what a Gd+ lesion is—it remains a sign of inflammation and BBB breakdown. However, it fundamentally changes what a Gd+ lesion means. It is no longer the fire itself, but rather the smoke signalling a pre-existing, and arguably more critical, degenerative fire burning silently within the CNS.

A broader view: survey of other aetiological theories and contributing factors

While the "outside-in" versus "inside-out" debate forms the central axis of current thinking on MS pathogenesis, several other theories and risk factors contribute to a more complete, albeit complex, picture. These factors often do not stand as independent theories but can be integrated as potential triggers or modulators within either of the two main paradigms.

The infectious hypothesis: trigger or cause?

The link between viral infection and MS is one of the most robust findings in the field of epidemiology. The Epstein-Barr virus (EBV), the cause of infectious mononucleosis, has emerged as the leading candidate. A large body of evidence now indicates that EBV infection is an essential prerequisite for the development of MS; the disease is exceedingly rare in individuals who have never been infected with the virus.

However, the precise role of EBV remains a subject of intense investigation and debate.

• As an "Outside-In" trigger: EBV could initiate the disease via "molecular mimicry." In this scenario, the immune system mounts a normal response to the virus, but some components of EBV bear a structural resemblance to proteins in CNS myelin. This could lead to cross-reactivity, where T-cells and B-cells primed to attack the virus mistakenly target the myelin sheath, initiating the autoimmune cascade.

• As an "Inside-Out" contributor: Alternatively, EBV establishes a lifelong latent infection, primarily within B-cells. It is plausible that these latently infected B-cells, which can reside within the CNS, contribute to a primary "inside-out" process over many years. The presence of the virus could induce chronic cellular stress, alter B-cell function, or periodically reactivate, contributing to a pro-inflammatory microenvironment that could eventually trigger neurodegeneration.

Other infectious agents, such as human herpesvirus-6 (HHV-6), have also been implicated, though the evidence is less compelling than for EBV.

The vascular hypothesis: the rise and fall of CCSVI

For a period, a vascular theory of MS gained significant public attention. The theory of Chronic Cerebrospinal Venous Insufficiency (CCSVI), proposed by Dr. Paolo Zamboni, hypothesised that MS was caused by impaired venous drainage from the CNS due to stenoses (narrowings) in the jugular and azygos veins. This venous obstruction was thought to cause blood to reflux back into the brain, leading to perivenular iron deposition, which in turn triggered a secondary inflammatory response and demyelination. The proposed treatment was a vascular procedure called "liberation therapy," an angioplasty to open the narrowed veins. The scientific community has largely refuted the CCSVI hypothesis. Subsequent, more rigorous, blinded, and larger-scale studies failed to replicate the initial findings. These studies found that the proposed venous abnormalities were not more common in people with MS than in healthy controls or individuals with other neurological diseases. Randomised controlled clinical trials of the "liberation therapy" demonstrated no clinical benefit for MS patients and, in some instances, were associated with serious adverse events, including venous thrombosis and stent migration. CCSVI is no longer considered a credible cause of MS.

The metabolic and environmental milieu

A range of environmental and lifestyle factors are known to modulate the risk of developing MS and influence its course. These factors likely contribute to either immune dysregulation (favouring an "outside-in" process) or CNS vulnerability (favouring an "inside-out" process).

• Vitamin D deficiency: A low level of vitamin D, often linked to reduced sun exposure in higher latitudes, is one of the most well-established environmental risk factors for MS. Vitamin D has known immunomodulatory effects, and its deficiency may predispose individuals to autoimmune responses. It may also play a direct role in CNS health and repair, meaning its absence could increase the brain's vulnerability to a primary degenerative insult.

• Metabolic factors: Obesity, particularly in childhood and adolescence, and cigarette smoking are strongly linked to an increased risk of developing MS and to a more rapid disease progression. Both factors promote a state of chronic, low-grade systemic inflammation and oxidative stress, which could lower the threshold for either a peripheral autoimmune attack or an intrinsic CNS degenerative process to take hold.

• Faulty lipid metabolism: An intriguing, though less mainstream, theory posits that MS may be a primary metabolic disorder of faulty lipid metabolism. Since myelin is composed predominantly of lipids, a systemic defect in lipid processing could lead to the production of unstable myelin, making it prone to spontaneous breakdown and subsequent inflammatory scavenging. This theory frames MS as being more analogous to a metabolic disease like atherosclerosis than to a classical autoimmune disease.

These contributing factors underscore the complexity of MS aetiology, suggesting that the disease arises from a complex interplay between genetic predisposition, environmental exposures, and lifestyle, which together create the conditions for either a primary autoimmune or a primary neurodegenerative process to unfold.

Future directions: toward a unified model

The intense debate between the "outside-in" and "inside-out" paradigms of MS should not be viewed as a zero-sum contest in which one theory must wholly vanquish the other. Instead, the accumulated evidence points toward a more nuanced and complex reality. Reconciling these two models may be the key to understanding the disease and developing more effective, personalised treatments.

Reconciling the paradigms

A unified model would propose that both "outside-in" and "inside-out" mechanisms are valid, with their relative contributions varying between patients and over the course of the disease in a single patient.

• Relapsing-Remitting MS (RRMS): The most common form of the disease at onset, RRMS is characterised by discrete inflammatory attacks (relapses) followed by periods of recovery (remission). This clinical picture, with its dramatic, Gd-enhancing inflammatory lesions and strong response to immunomodulatory therapies, aligns well with the "outside-in" model. In these patients, a primary dysregulation of the peripheral immune system may indeed be the dominant driver of disease activity in the early stages.

• Primary Progressive MS (PPMS): A smaller subset of patients experiences a progressive accumulation of disability from the very onset of the disease, without clear relapses. PPMS is characterised by less focal inflammation on MRI and a notoriously poor response to most anti-inflammatory DMTs. This form of the disease may represent a purer manifestation of the
  "inside-out" model, where a primary, relentless neurodegenerative process is the main driver, with inflammation playing a more subdued, secondary role.

• Secondary Progressive MS (SPMS): Many patients who begin with RRMS eventually transition to a secondary progressive course, where disability accrues steadily, independent of relapses. This transition could represent the point at which an initially "outside-in" inflammatory process triggers a self-sustaining "inside-out" neurodegenerative cascade. Chronic inflammation and repeated insults to the CNS may exhaust its metabolic and repair capacity, initiating a primary degenerative process that becomes uncoupled from peripheral immune attacks and is therefore refractory to standard immunomodulatory treatments.

Implications for research and therapeutics

Accepting this heterogeneous model of MS has implications for the future of research and clinical care. The central challenge shifts from identifying a single cause to developing tools that can dissect the dominant pathogenic pathway in an individual patient.

• Implications for research: The field must move beyond Gd+ lesions as the sole biomarker of disease activity. The research focus must expand to include the development and validation of biomarkers capable of detecting and quantifying the primary "inside-out" processes. This includes:

• Advanced neuroimaging: Utilising quantitative MRI techniques to measure subtle changes in normal-appearing white and grey matter, which may reflect the underlying degenerative process.

• Metabolic and molecular markers: Developing blood or cerebrospinal fluid tests for markers of mitochondrial stress, axonal injury (such as neurofilament light chain, sNfL), and oligodendrocyte damage.

• Refined animal models: Employing a combination of animal models—both traditional EAE ("outside-in") and toxin-induced models like cuprizone ("inside-out")—to test therapies that target different aspects of the disease process.

• Implications for therapeutics: The "inside-out" paradigm necessitates a fundamental shift in therapeutic strategy, particularly for progressive MS. While immunomodulation will continue to be an important tool for controlling the inflammatory component of the disease, it is clearly insufficient for halting disease progression. The ultimate goal must be to develop and deploy a new class of drugs that target the primary degenerative process itself. The therapeutic pipeline must prioritise:

• Neuroprotective agents: Drugs that can shield axons and neurons from metabolic stress, oxidative damage, and excitotoxicity.

• Mitochondrial support: Therapies aimed at boosting mitochondrial function and energy production within CNS cells.

• Remyelinating agents: Compounds that can promote the differentiation of oligodendrocyte precursor cells and enhance the natural process of myelin repair, which is known to be inefficient in MS.

Conclusions

The "inside-out" framework, which posits a primary neurodegeneration that secondarily elicits an immune response, provides a compelling explanation for the shortcomings of the conventional autoimmune model and the clinical realities of progressive MS. Viewing the Gd+ lesion as a consequence rather than a cause challenges the very foundations of MS diagnosis and treatment. This paradigm shift provides a crucial conceptual roadmap for future research and, most importantly, for the development of innovative neuroprotective and reparative therapies that hold the promise of finally halting the relentless degenerative process that underpins long-term disability in MS.

Questions to you, the reader

Has Gemini misunderstood the literature? Is there something missing? If you could, what would you add to the output?

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If you have questions unrelated to the newsletters or podcasts, please email them to ms-selfie@giovannoni.net. Prof. G will try to answer them as quickly as possible.

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Firstly, it uses the outcome conversion to progressive MS as if this is a well-defined and separate entity. MS is one disease, and in the majority of people with MS, progression of MS, or as I prefer, worsening MS, is present from the beginning of the disease. Smouldering disease activity can even be detected in people with asymptomatic MS.

Yes, the term progressive MS should be banned. Progressive typically means an increase or improvement. In the context of MS progression, or progressive, is a misnomer. It is also a very stigmatising term. Please be aware that not everyone with MS necessarily has smouldering MS. I suspect some pwMS can spontaneously clear whatever is causing the disease and never go on to develop gradual worsening of the disease. Similarly, some pwMS treated with immune reconstitution therapies (IRTs) seem to go into long-term remission with no evidence of smouldering disease activity (NESDA).

There is no concrete evidence that someone with a label of SPMS or PPMS differs from someone with RRMS based on biology. Yes, people with so-called progressive MS tend to be older and have lost more reserve capacity, hence they can’t compensate for any ongoing damage that is occurring. Still, their disease is as modifiable as someone with less disability. The difference is that the treatment effect, or expectation of a treatment effect, from the DMT is lower. The reason for this is that our current treatments prevent or slow down future damage and are not neurorestorative therapies. Saying this pwMS do have the ability to recover function, but this is likely to be due to endogenous repair mechanisms that are allowed to kick into action when MS-related inflammation is suppressed. We even see sustained improvement in disability in people with relatively advanced MS. For example, in the HERCULES tolebrutinib trial, subjects with advanced SPMS on tolebrutinib were more likely to improve compared to subjects randomised to placebo. The sad thing is that the regulators are likely to entrench the clinical phenotypes and only license tolebrutinib for SPMS and not for pwMS with other labels, hence denying them an effective treatment for smouldering disease.

The other aspect of this meta-analysis is that it shows markers of damage predict damage. This is not surprising. We have known for decades that in MS worsening begets worsening. The problem I have is that almost all the markers of damage are not used in routine clinical practice and, therefore, are a theoretical construct. How many of you know what your spinal fluid GFAP and CHI3L1 levels are? How many of you are having regular serum NFL levels measured? Similarly, are you having annual spinal cord MRI scans to detect new or expanding spinal cord lesions? Does your centre tell you that you have paramagnetic iron rim or slowly expanding lesions on MRI? Do you have annual brain volume measurements and annual OCT to measure how thick your retinal nerve fibre layers are? All these factors are associated with a poor prognosis.

The question you will have is whether or not knowing this information will change your treatment. In the NHS, we have stringent criteria for escalating treatment, and none of the requirements are based on body fluid biomarkers. To change treatment, you have to have new inflammatory activity (relapses or new or enlarging MRI lesions) and worsening disability. The latter is to access spinonimod for SPMS or ocrelizumab for PPMS. In our centre, we do act on raised CSF NFL levels; we treat this as biochemical evidence of ongoing inflammation or a biochemical relapse.

The problem with the prediction of worsening MS is that it is probably not worth looking for it unless you can do something about it. The other issue we have in the field of MS is that most people don’t view treating MS as a preventive therapy, i.e. we treat MS to prevent future disability. Once you have disability, we can’t turn back the clock. This is why ‘Time Matters’ - time is brain and spinal cord. The best time to prevent disability is early on in the disease course. Treat early and treat effectively. And flip the pyramid. There is now overwhelming evidence that pwMS treated first-line with the most effective DMTs do better on average. Therefore, all recently diagnosed pwMS should have the option of a high efficacy DMT and should be educated to make their own decisions about whether to choose a high efficacy DMT or not. Do you agree?

How many of you would want to know your prognosis, i.e. your chances of worsening MS? If yes, in what format would you like the information to be in? Would you also want access to new biomarkers of damage? Or would you prefer not to know this information?

I think having a prognostic calculator at baseline may help focus the mind of both the person with the disease and their treating neurologist. However, the calculator needs to be pragmatic and include factors that are measured and accessible from routine clinical practice. Knowing if you are in a good, intermediate or poor prognostic group may help decision-making. Maybe I am wrong.

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Finally, do you want more research-related MS-Selfie newsletters? I don’t want to overload you with emails.

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Paper

Solís-Tarazona et al. A systematic review and meta-analysis of real-world data predictors for conversion to progressive multiple sclerosis. Mult Scler Relat Disord. In Press 2025.

Background: Available fluid biomarkers, neuroimaging techniques, and clinical assessments may enhance the prediction of conversion to secondary progressive multiple sclerosis (SPMS).

Objectives: To identify robust real-world predictors of MS progression in the literature.

Methods: A systematic review was conducted in EMBASE. A total of 20,338 MS patients from 64 eligible studies were included. A p-value meta-analysis and a tipping point analysis were performed to assess associations with MS progression and EDSS.

Results: Among CSF biomarkers, GFAP (p = 6.2 × 10⁻¹⁰) and CHI3L1 (p = 1.7 × 10⁻¹¹) demonstrated consistent aggregated associations with disease progression. In serum, NfL (p = 2.5 × 10⁻13) and GFAP (p = 1.4 × 10-8) showed a strong association with concurrent EDSS and disease progression. Spinal cord lesions (p = 9.4 × 10⁻¹¹) and iron rim lesions (p = 4 × 10⁻⁶) were the strongest radiological predictors. Among clinical assessment tools, significant associations were found with concurrent EDSS, but the prediction of progression was limited.

Conclusion: Fluid biomarkers, particularly CSF GFAP, CHI3L1, and serum NfL, along with spinal cord lesions and iron rim lesions on MRI, provide consistent evidence for predicting MS progression. There is a need for harmonized and accessible outcome measures in real-world datasets.

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How important is this study and how does it fit in with the EBV hypothesis of MS?

There is little scientific debate about the potential for infections and vaccines to trigger autoimmune diseases such as MS. The most likely mechanism underlying this phenomenon is antigen-specific molecular mimicry. However, the time from exposure to EBV and the clinical onset of MS is rather long for molecular mimicry.

Arguably, the most well-documented infectious agent to trigger autoimmunity is group A beta-haemolytic streptococcus (GAS) or Streptococcus pyogenes. It is the established cause of acute rheumatic fever, Sydenham’s chorea, glomerulonephritis, arthritis, vasculitis, and paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A characteristic of GAS-associated autoimmune diseases is the close timing between infection and the onset of disease. In subjects with acute post-streptococcal autoimmune disease, there is usually microbiological evidence of recent or current infection, i.e. there is serological evidence of recent infection in the form of a raised anti-streptolysin (ASO), anti-DNAse B or anti-hyaluronidase antibody titres, or the organism can be cultured or detected from samples taken from the throat or skin.

A similar close temporal relationship between exposure to the triggering antigen and disease onset is observed with vaccine- and enteric infection-triggered Guillain-Barré syndrome, a type of neuropathy. Similarly, the temporal association between the AS03 adjuvanted AH1N1 influenza vaccine and narcolepsy is less than six months. Yes, narcolepsy is considered an autoimmune disease.

In comparison, the long lag time between EBV seroconversion or EBV-associated infectious mononucleosis (IM), the first exposure to EBV, and the clinical onset of MS is estimated to be approximately 8 years. This long lag time would support the argument that molecular mimicry is not the mechanism by which EBV causes MS. This new study’s findings provide a counterargument to this, i.e. MS has an asymptomatic or prodromal phase that could be as long as 15 years.

The problem is overinterpretation and reverse causation, i.e. could sickness behaviour as defined by increased healthcare utilisation, noted in this prodromal period, increase one’s risk of getting MS instead. Could chronic stress from sickness behaviour create an environment where, if one gets exposed to EBV, it makes it more likely that one gets MS? The obvious question is, do people who develop infectious mononucleosis (IM) or symptomatic EBV infection also have a prodrome? The answer is yes. The same group have data on this that has yet to be published. So I think teh prodromal sickness behaviour as defined by this study sets the scene for EBV to trigger MS, and that it does mean that MS has a prodrome of 15 years.

Defining MS as a biological disease rather than using the standard clinicoradiological definition of MS will potentially allow the diagnosis of MS to be made in the asymptomatic phase and will shorten the lag phase between the initial exposure to EBV and disease onset. This will also allow us to dissect the sequence of events and answer the causation reverse-causation question.

However, what constitutes a biological definition of MS is, at present, a moot point and requires further study. Some investigators support the hypothesis that immunological endophenotyping may enable the diagnosis of pre-MS relatively soon after primary EBV exposure. A recent study has shown that after IM, raised antibody titres to an EBV epitope in EBNA-1 (EBNA-1^381-452-peptide) predict at-risk individuals who will subsequently go on to develop MS (see paper two below). Notably, the significantly elevated anti-EBNA-1^381-452-specific IgG titres could be identified as early as nine months after EBV-seroconversion and a median of 5.4 years before MS diagnosis. This group has also shown that these raised antibodies precede the increase of blood neurofilament light chain levels that are thought to represent the biological onset of MS, because they are raised before symptom onset. This study’s finding needs to be reproduced, but it implies that subclinical disease processes that underlie MS may start quite soon after IM.

I am convinced that EBV drives MS disease activity, similar to how GAS infection drives attacks of rheumatic fever. The first attack of MS is asymptomatic in the vast majority of people destined to develop clinically definite MS and likely occurs quite soon after primary EBV exposure. MS only manifests later when a subsequent attack or lesion forms in a clinically eloquent pathway. This explains why most people destined to develop MS have pre-existing multiple white matter lesions on their baseline brain MRI when presenting with their first clinical attack. EBV differs from GAS because it establishes a latent infection that intermittently reactivates asymptomatically. It is this intermittent asymptomatic reactivation of EBV (latent-lytic cycling) that likely drives MS disease activity. This is why we need to test EBV antivirals and EBV-targeted immunotherapies in MS and, at the same time, try to prevent MS by EBV vaccination.

I would be interested to know if any of you recall being unwell in the decade or so before you developed clinically apparent MS.

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Paper 1

Ruiz-Algueró et al. Health Care Use Before Multiple Sclerosis Symptom Onset. JAMA Netw Open. 2025 Aug 1;8(8):e2524635.

Importance: Health care use increases before multiple sclerosis (MS) onset. However, most studies have focused on the 5 to 10 years preceding the first demyelinating disease code from administrative data. Few studies have examined patterns before clinically determined MS symptom onset from clinical records.

Objective: To examine health care use 25 years before MS symptom onset in a clinical cohort from British Columbia, Canada.

Design, setting, and participants: This matched cohort study accessed data prospectively collected from January 1991 to September 2018. All data were released mid-2024 for analysis. The study was conducted in British Columbia using publicly funded universal health insurance data. Patients with MS were identified from MS clinic records and matched with up to 5 individuals randomly selected without replacement from the general population by sex, birth year, socioeconomic status, and postal code of residency.

Main outcomes and measures: Linked clinical and administrative data were used to compare physician visit rates 25 years before MS onset using adjusted negative binomial models and 15 years before MS onset by International Classification of Diseases, Ninth Revision (ICD-9) chapter and physician specialty.

Results: A total of 2038 patients with MS (mean [SD] age at symptom onset, 37.9 [10.9] years; 1508 female [74.0%]) and 10 182 matched individuals were included. All-cause physician visit rate ratios (RRs) for patients with MS were consistently elevated from 14 years before onset (adjusted RR [ARR], 1.19; 95% CI, 1.07-1.33), peaking the year before MS onset (ARR, 1.28; 95% CI, 1.21-1.35). The RRs for ill-defined symptoms and signs were consistently elevated 15 years before onset, exceeding 1.15 and peaking at 1.37 (95% CI, 1.19-1.56) the year before MS onset. Mental health-related RRs from 14 years before onset were significant (excluding years 7, 5, and 4), with RRs in the 3 years before MS onset ranging from 1.30 (95% CI, 1.05-1.58) to 1.38 (95% CI, 1.12-1.68). Sensory, musculoskeletal, and nervous system RRs were elevated 8, 5, and 4 years before onset, respectively, with, for example, a peak of 2.42 (95% CI, 1.90-3.07) for nervous system concerns the year before MS onset. By physician specialty, general practice visit RRs were significantly elevated in each of the 15 years before MS onset, reaching 1.23 (95% CI, 1.17-1.30) in the year before onset. Psychiatry visit RRs were elevated 12 years before onset (2.59; 95% CI, 1.23-5.47). Neurology and ophthalmology RRs were significantly higher up to 8 to 9 years before onset, peaking the year before MS onset at 5.46 (95% CI, 4.30-6.93) for neurology and 1.64 (95% CI, 1.30-2.08) for ophthalmology.

Conclusions and relevance: In this matched cohort study of people with and without MS, health care use was higher among patients with MS 14 to 15 years before MS symptom onset, suggesting that MS may have started earlier than previously thought. Mental health and psychiatric issues along with ill-defined signs and symptoms might be among the earliest features of the prodromal period preceding nervous system-related and neurologic visits by 7 to 11 years.

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Paper 2

Vietzen et al. Early identification of individuals at risk for multiple sclerosis by quantification of EBNA-1381-452-specific antibody titers. Nat Commun. 2025 Jul 14;16(1):6416.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease. Epstein-Barr virus (EBV) encodes for the EBNA-1381-452 region that induces autoreactive antibody responses, which are likely critically involved in MS pathogenesis. Here we investigate whether these EBNA-1381-452-specific antibodies can serve as a biomarker to identify at-risk individuals for MS. We quantify EBNA-1381-452-specific antibody titers from 324 relapsing-remitting MS patients and 324 matched controls in longitudinal follow-up plasma samples, starting from the individual's EBV-seroconversion. In MS patients, significantly elevated EBNA-1381-452-specific IgG titers are identified that are increased already as early as nine months after EBV-seroconversion (OR:5.7; 95% CI: 4.1-8.1; P < 0.0001) and a median 5.4 years prior to MS diagnosis. Especially, the presence of continuously high EBNA-1381-452-specific antibody titers is associated with a more rapid MS diagnosis after EBV-seroconversion (P < 0.0001). Thus, the quantification of EBNA-1381-452-specific IgG antibody levels may provide a prognostic biomarker to determine the individual's risk for the diagnosis of MS.

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or 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 healthcare professional, who will be able to help you.

Many of the issues for T1DM prevention are similar to those for MS, but the main difference is that we have probably found the cause of MS and hence will potentially start primordial prevention studies earlier in MS than they will in T1DM. However, regarding secondary prevention, we are slightly ahead of T1DM. We can identify people with radiologically isolated syndrome (RIS), soon-to-be defined asymptomatic MS, albeit serendipitously at present, and then treat them to prevent them from developing clinically definite MS. However, many healthcare systems don't cover the costs of treating patients with RIS. Saying this, the vast majority of patients referred to me with RIS when interrogated clinically have clinical signs that they are not aware of, which allows them to label them as having MS.

T1DM has the advantage over MS in that it has better prediction tests, i.e., autoantibodies that can predict the development of T1DM in the near future. In addition, it now has a licensed treatment that delays the onset of T1DM in high-risk antibody-positive people—the drug teplizumab works by targeting T cells through antibodies against CD3 on T-cells. At present, this therapy is not covered by the NHS, but paediatric endocrinologists have started treating high-risk patients before NICE has approved the drug.

The downside for the field of T1DM is that diabetologists are very good at managing the disease. Patients on closed-loop systems that function as an artificial pancreas are likely to live almost ‘normal’ lives despite the costs and the not-so-insignificant hassle of living with an artificial pancreas. These excellent metabolic outcomes change the risk-benefit balance of potentially high-risk preventive therapies. However, I am not so sure about these arguments. Having an artificial pancreas with all the paraphernalia of glucose sensors and insulin pumps, and the costs of living a lifetime with T1DM, is not something I would want in comparison to a potential early high-risk immunotherapy to prevent the disease. People with T1DM also have mental health issues associated with having the disease, and many other hidden symptoms that are not highlighted. Although arguably not as bad as MS, T1DM is a stigmatising disease and reduces quality of life. I think using effective insulin replacement therapy as an argument against secondary prevention in T1DM is a poor and flawed position.

People with relapse-onset MS are lucky in that they have a sentinel event or events, i.e. an attack or relapses, that should allow a timely and relatively early diagnosis before too much irreversible end-organ damage has occurred. The same cannot be said for people with primary progressive MS (PPMS) who present when they have lost a lot of function. In comparison, the vast majority of people with T1DM present with end-organ damage, which is end-stage, and the only treatment option is insulin replacement therapy and rarely pancreatic islet transplantation. The challenge for the T1DM field is implementing population screening to diagnose T1DM before the loss of the end-organ.

Population screening raises many ethical issues about identifying people without treatment. We in the field of MS are in a catch-22. We have two licensed MS DMTs, dimethyl fumarate and teriflunomide, that have been shown to delay patients with RIS from developing clinically-definite MS. However, these trials were small and have not resulted in a label change for these DMTs. Hopefully, changing the definition of MS by reclassifying RIS as MS, albeit asymptomatic MS, will allow us to start treatment earlier. The funding of DMTs for asymptomatic MS will be a battle. Still, we may convince funders of the merits of treating asymptomatic MS as both DMF and teriflunomide are now generic and relatively cheap. At the same time, I would argue for further RIS trials to generate additional evidence for better and more pragmatic DMTs, particularly cladribine. Cladribine, in my opinion, would be the best therapy for asymptomatic MS as it is a short course, relatively safe, well tolerated and has better efficacy than teriflunomide and DMF. Do you agree? I think it will be hard to convince people with asymptomatic MS to remain on a tablet lifelong when they have not had any obvious symptoms of MS.

The T1DM field has taken the route of initially focusing on high-risk individuals, i.e family members of people with T1DM. It is now expanding to the general population with new antibody screening assays in development. I was impressed to see them developing point-of-care lateral flow tests for autoantibody screening. Sadly, we in the MS field are far from having screening tests that are reliable and validated. Even using genetic testing with polygenic risk scores (PRS) will not be sufficient to identify those who will develop MS with sufficiently high sensitivity and specificity. The area under the receiver operating curve for an MS PRS of less than 0.8 makes it unsuitable for MS prediction.

The downside of focusing on high-risk individuals is that, from a preventative perspective, it will prevent only a small proportion of people from developing MS. The reasons for this are that only a minority of people who develop MS can be classified as being high-risk before they develop MS. For example, only one in seven people with MS has a positive family history of MS. The majority of people who develop MS are, in fact, at low or moderate risk of developing MS and will not get through screening with our current tools. I favour targeting the general population for MS prevention to cast a wide net. I covered this in my recent talk at the Nobel MS symposium in Stockholm, which you can watch or review the slides.

My advice for the T1DM community from an MS is the following:

1. Adopt your new biological definition of T1DM to diagnose asymptomatic disease as early as possible, i.e. double auto-antibody positivity should be classified as T1DM.

2. Develop and validate markers of early pancreatic end-organ damage

   1. This may require focusing on exocrine pancreatic function, which appears to precede the loss of endocrine function

   2. Relying on endocrine stress testing with C-peptide curves after an oral glucose tolerance test may be too late in the evolution of T1DM. By the time you have a compromised area under the C-peptide curve, i.e., metabolic dysfunction, it is probably too late to modify the course of the disease substantially. We need to define and diagnose T1DM before this stage of the disease. The message here should be ‘time is pancreas’.

   3. Develop and validate an easy-to-do stress test of exocrine pancreatic function, which may be affected earlier than endocrine function. This could be matched by structural evidence of pancreatic damage, i.e., volume loss.

3. Define a T1DM cure (e.g. loss of antibody positivity)

   1. More work needs to be done on high-risk individuals with spontaneous cures, i.e. loss of autoantibodies. Do these people have evidence of regeneration of the pancreas? Is pancreatic end-organ damage reversible?

   2. Defining a treatment-related cure will allow the field to treat a target in early disease prevention.

4. Focus on prevention

   1. Primary prevention, for example, helps develop a multivalent enterovirus vaccine. Enterovirus infections are considered the most likely trigger of T1DM. Will a pan-enterovirus vaccine reduce the incidence of T1DM? I was impressed to notice that rotavirus vaccination reduces the incidence of T1DM by about 10%. I was told that SARS-CoV-2 infection increases the risk of getting T1DM by about 5-fold. In response, the UK is conducting a COVID-19 vaccine study on high-risk individuals to see if it can prevent the development of T1DM-associated autoantibodies.

   2. Paediatric and adult T1DM incidence registers need to be established. These are essential for observational studies to see if an intervention reduces the incidence of T1DM. We need to have one for MS in England. Scotland is the only home country to have an MS incidence register.

   3. Secondary prevention trials of disease-modifying therapies in presymptomatic T1DM with little end-organ damage, such as anti-CD40, anti-CD40L, anti-CD20, anti-CD3, cladribine, etc., will require the field to set up a platform study similar to those in place for oncology trials. This will allow multiple potential DMTs to be tested in parallel.

5. Develop adult T1DM secondary prevention models, e.g., stiff-person syndrome (SPS), an adult model of T1DM. At diagnosis, a third of people with stiff-person syndrome already have T1DM, and another third will develop T1DM in the next few years. Treating SPS with novel immunotherapies will allow one to study the effect of these treatments on T1DM evolution and provide a clue that they may work in children with early T1DM.

6. Work on finding the cause: “What is necessary for the development of T1DM?” This will allow the field to focus on one factor to prevent T1DM, similar to our focus on EBV as a prevention target to prevent MS.

You can view and download my slides from this meeting here. You are welcome to use them and hack them as you feel appropriate.

As a thought experiment would you trade in MS for having T1DM or would you stick with the autoimmune disease you know already?

I want to thank Parth Narendran for inviting me. It is good to see that we are not the only disease area with many miles to go before we sleep.

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or 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 healthcare professional, who will be able to help you.

The first three days are closed to invited delegates. I will speak on day four, Thursday, 5th June, the open day, which is open to the public and people with MS. The open day is about the treatments of MS and the future. When I was invited to speak, I was given a blank sheet. I have decided to focus on my current research interest in MS prevention and the role of EBV in the pathogenesis of MS. I have entitled my talk ‘Infectious mononucleosis - a pragmatic target for preventing multiple sclerosis’.

On arriving at the symposium, a colleague from Italy said that funding for MS research is drying up because of the impact of biosimilars on the field. He implied that development pipelines are drying up because big pharma does not think there is any money to make out of the future treatment of MS. He implied that the MS community is satisfied that the efficacy of anti-CD20 therapy is sufficient to manage MS. Clearly, I disagreed. What about smouldering MS? I told him we need a CNS penetrant approach to stop smouldering MS.

I then gave him a thought experiment to consider. What will happen to the field of MS if fenebrutinib proves to be a superior therapy to ocrelizumab in primary progressive MS? Will that change the field, i.e., move it from anti-CD20 to focus on CNS mechanisms? He may be satisfied with NEIDA (no evident inflammatory disease activity) as a treatment target. We also have to switch off smouldering MS, and our attention should shift to NESDA (no evident smouldering disease activity) and beyond. Do you agree?

A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Ocrelizumab in Adult Participants With Primary Progressive Multiple Sclerosis (FENtrepid) (ClinicalTrials.gov ID NCT04544449)

I am getting more bullish about fenebrutinib, and I am now giving fenebrutinib about a 60% (range 40-80%) chance of being superior to ocrelizumab in treating primary progressive MS. This is based on tolebrutinib results in non-relapsing SPMS, fenebrutinib CNS penetration data and its anti-inflammatory effects seen on the phase 2 extension trial and the fact that BTKi are pan anti-EBV drugs targeting latent EBV infection.

Thinking beyond BTKIs, what about CD19-targeted CAR T-cell therapies, EBV antivirals, and EBV immunotherapies? The MS community should take a philosophical approach to its thinking. I would start by defining and getting consensus on defining an MS cure. We can then look for cures, whether spontaneous or secondary to MS treatment. My focus will be on EBV and MS prevention, but then I am biased.

The good thing about meetings like this is the time for thinking and reflection. When I have the time, I will update you and record my talk so you can hear about IM and MS prevention.

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or 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 healthcare professional, who will be able to help you.

Today's press release shows that vidofludimus, an inhibitor of dihydroorotate dehydrogenase (DHODH), reduced 24-week confirmed disability worsening (CDW) by 20% compared to placebo and 30% in subjects with primary progressive MS (PPMS)> Please note these are relative risk reductions we will need to see the results for the absolute reduction and the number needed to treat to prevent one CDW. Significantly, in the subpopulation without Gd-enhancing lesions at baseline, 24-week CDW was reduced by 29% compared to placebo. The impact of vidofludimus on the annualised rate of per cent brain volume change was relatively modest, i.e. 5% better than placebo. However, it did impact thalamic volume, i.e. it reduced some end-organ damage. Annualised thalamic volume loss was reduced by 20% in the vidofludimus group compared to placebo. The total volume of new or enlarging T2 lesions showed a substantial difference between vidofludimus calcium and placebo over time, with vidofludimus calcium decreasing and placebo increasing the volumes; the mean per cent change was -0.22% for vidofludimus and +2.97% for placebo at month 24. Importantly, no new safety signals were identified with vidofludimus.

Vidofludimus has a similar mode of action to teriflunomide. As these results are relatively modest compared to other high-efficacy DMTs and tolebrutinib, the first BTK inhibitor to report out in non-relapsing MS, many will say there is no place for teriflunomide me-too in the MS therapeutic landscape. I disagree.

Firstly, vidofludimus has fewer off-target effects than teriflunomide, i.e. it is better tolerated with less liver toxicity. It also has at least two other modes of action. It has been shown to activate Nurr1, which may be neuroprotective. Whether vidofludimus gets into the central nervous system to activate Nurr1 is a moot point and needs further work. The third mode of action is its antiviral effects, particularly its impact on EBV (see abstract link below).

Vidofludimus is high on my list of anti-EBV antiviral agents to treat MS. We now need to show that it works via an EBV mechanism. I sincerely hope Immunic, the company developing the drug, will invest in finding this out. I have many ideas on how to look at EBV biology in vidofludimus-treated pwMS.

Vidofludimus is one of the agents on my list of maintenance therapies after an induction therapy. It would now be my go-to agent for testing in the iTeri study, which would have to be now called the iVido study.

Do you find these results exciting? Or is there no place for a teriflunomide me-too in the MS therapeutic landscape? Would you participate in the iVido study?

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Marschall M, Peelen E, Müller R, et al. IMU-838, a small molecule DHODH inhibitor in phase 2 clinical trial for multiple sclerosis, shows potent anti-EBV activity in cell-culture-based systems: potential additional benefits in multiple sclerosis treatment. ECTRIMS. 2021. ePoster P372. Multiple Sclerosis Journal. 2021;27(2_suppl):134-740.

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We have known for some time that brain aging is accelerated in MS and that it is associated with worse physical and cognitive disability and more significant change in disability over time. I have always included brain ageing as one of the drivers of smouldering MS. I suspect brain age is an integrator at the level of the end-organ of all the damage that accumulates over time.

Erin Beck from Mount Sinai (New York) gave an excellent presentation on using MRI to determine brain age. She showed that accelerated brain ageing is more pronounced in early MS. She reviewed the evidence that accelerated brain aging is associated with physical and cognitive disability and a more significant change in disability over time. Of interest is that she uses an AI method to analyse the MRI of the brain that generates a single metric to represent brain age. On average, people with MS have a brain age that is approximately 10 years older than their chronological age.

She presented evidence that focal (lesions) and diffuse (smouldering) brain damage contribute to brain ageing. She implied that brain age could be used prognostically and potentially as a biomarker of a treatment response in MS. If a particular MS therapy works, it should slow down the premature accelerated brain ageing that is seen in MS. Or even better, can we reverse the brain age signature with neurorestorative therapies?

In parallel, a fascinating paper (see paper below) has just been published, showing an increase in somatic single-nucleotide variants (sSNVs) in neurons from MS lesions compared to normal-appearing MS and control tissues. These sSNVs are somatic mutations in the DNA of individual neurons that are not present in the so-called inherited germline DNA. The investigators found an increase of ~44 mutations per year in neurons from chronic MS lesions, which is 2.5 times faster than in neurons from normal-appearing MS and control tissues. A signature analysis of the mutations suggested that the mutations were age-associated and probably due to neuroinflammation.

These two pieces of evidence support other findings that inflammation harms you and causes premature ageing, which targets the brain in the case of MS. We need proof that treating MS early and effectively stops or prevents premature ageing. I suspect the data using MRI brain age is already out there. We only need several pharmaceutical companies to analyse the trajectory of MRI brain ageing in the subjects in their clinical trials. I would predict that subjects randomised to highly effective DMTs would do better than subjects randomised to placebo or lower efficacy DMTs.

As brain age can be relatively easily measured using MRI and AI, would you want to know the age of your brain relative to your chronological age? If you are 40 years old and your brain age comes back as 52, i.e. 12 years older than your chronological age, how would you use this knowledge?

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Abstract 1

E. Beck. MRI Assessment of Biological Age in MS. S2.1. ACTRIMS 2025

There is a complex interplay between aging and most aspects of MS pathology that are visualized on MRI, including focal lesion formation, chronic inflammation, and repair, as well as more diffuse structural changes. MS may potentiate age-related changes in the immune and central nervous systems, leading to accelerated aging and increased chronic inflammation, decreased repair, and increased diffuse myelin and neuro-axonal damage with age, ultimately resulting in more rapidly progressive disability. In young people, new focal inflammatory demyelination in both the white and gray matter is more common, but new lesions are more likely to repair and less likely to demonstrate chronic inflammation than in older people. To better understand how aging and MS interact to yield more diffuse structural changes in the brain, we use large MRI datasets of healthy individuals and both statistical and deep learning-based techniques to model changes in individual structural measures, including brain volume and cortical curvedness, as well as brain age, a more global measure derived directly from T1-weighted MRI, over the human lifespan. These models allow us to begin to untangle MS vs age-related changes in the brain and determine how brain aging influences the disease course. We find that brain aging is accelerated in MS, with more pronounced acceleration in early disease. Accelerated brain aging is in turn associated with worse physical and cognitive disability and greater change in disability over time. A better understanding of how both focal and diffuse central nervous system damage is both caused by and may contribute to aging is important for predicting outcomes in MS and targeting treatments toward aging-related processes, which may be important drivers of disability progression.

Article

Motyer et al. Neuronal somatic mutations are increased in multiple sclerosis lesions. Nature Neuroscience (2025); Published: 04 March 2025.

Neuroinflammation underpins neurodegeneration and clinical progression in multiple sclerosis (MS), but knowledge of processes linking these disease mechanisms remains incomplete. Here we investigated somatic single-nucleotide variants (sSNVs) in the genomes of 106 single neurons from post-mortem brain tissue of ten MS cases and 16 controls to determine whether somatic mutagenesis is involved. We observed an increase of 43.9 sSNVs per year in neurons from chronic MS lesions, a 2.5 times faster rate than in neurons from normal-appearing MS and control tissues. This difference was equivalent to 1,291 excess sSNVs in lesion neurons at 70 years of age compared to controls. We performed mutational signature analysis to investigate mechanisms underlying neuronal sSNVs and identified a signature characteristic of lesions with a strong, age-associated contribution to sSNV counts. This research suggests that neuroinflammation is mutagenic in the MS brain, potentially contributing to disease progression.

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or 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 healthcare professional, who will be able to help you.

1. The MS field is fixated on effector mechanisms and measuring damage. Many talks and posters discussed how the immune system causes damage to the nervous system and how we measure the damage using immune markers, body fluid markers, electrophysiology, OCT (optical adherence tomography), MRI and PET imaging, clinical outcomes, or AI (machine and deep learning). However, I was disappointed that nobody mentioned neurological stress testing to measure resilience or reserve.
   

2. There was little discussion on what I call proximal events that lead to someone developing MS in the first place. There are two talks on EBV and MS. Dalia Rotstein (Toronto, Canada) extended the EBV prodrome to IM (infectious mononucleosis) itself, showing that IM triggers sickness behavior and excess healthcare utilisation. Could MS begin at the time of IM? This needs some deep thought but is a novel and intriguing concept. I will come back to this topic in future.
   
   Another presentation using longitudinally collected samples implied that systemic EBV reactivation occurs in the three-month window before a relapse occurs (Abstract 1). The study did not report actual viral detection, only the B-cell gene transcription signature in response to EBV products. The presentation was very data-heavy, and I would need to digest the paper when it comes out before drawing premature conclusions. Another study showed that EBV-specific CD8+ cells are enriched in the spinal fluid of patients with MS (Abstract 2). This would imply that EBV is active in the CNS of pwMS, and the immune system responds to lytic EBV CNS infection. This data would be compatible with other EBV data and argues for testing CNS-penetrant EBV antivirals in MS.

   

3. There were excellent talks on the biology of myelination and remyelination and their complexity. The question I ask is, is remyelination a problem in MS? If you switch off the disease, for example, with alemtuzumab or AHSCT, patients remyelinate and recover function spontaneously. Indeed, the real issue is using their treatments early. Trying to remyelinate a damaged nervous system without curing someone of having MS is foolhardy. If the autoimmune target in MS is myelin or the oligodendrocyte, the cell that makes myelin, repairing these two components will invite further attacks on their integrity. It is like doing a kidney transplant in someone with an autoimmune kidney disease. In many autoimmune diseases of the kidney, the disease reoccurs in the transplanted kidney.
   
   This is why remyelination therapies in isolation will not work. Similarly, targeting remyelination therapies a long time after the event, i.e. after the loss of neurons and axons, won’t work either. You need a surviving neuron and demyelinated axon to remyelinate it successfully. This is why remyelination and neurorestorative therapies are so many decades away. There are too many issues to overcome, the biggest being poor phase 3 trial design and the need to include the physiological stimulus to promote repair (rehabilitation) as part of the trial design.
   

4. Another highlight was the role of microglia in MS pathology. Using new technologies, it is clear that the microglial response is very complicated. Microglia are mediators of damage and repair. So it will be a yin and yang. As paramagnetic rim lesions or PRLs are due to activated microglia, this topic will probably be the year's MS hot topic. It was great to see data from the relapsing and progressive tolebrutinib studies showing that the more PRLs you have, the worse your prognosis. Tolebrutinib is associated with a better outcome in subjects with PRLs, implying that this is how it probably works. Whether this treatment response is due to its effect on microglia or EBV is a moot point. I argue that the BTK inhibitors are working via EBV mechanisms and not necessarily via microglia. This post-hoc analysis tells us that tolebrutinib has a bioactive mechanism of action targeting CNS mechanisms. These results offer real hope for slowing down and preventing further damage in those with smouldering MS and possibly how to identify high-risk subjects (PRL+) who are more likely to respond to the treatment. I suspect these results will increase the need for detecting and monitoring for PRLs in routine clinical practice. Would you want to know how many PRLs you have in your brain?

   

   
   
   Several talks discussed smouldering MS or at least referred to it. This included many posters and research presentations. It is clear that the term has now become sticky, as a large proportion of the MS community refers to the phenomenon of PIRA (progression independent of relapse activity) as smouldering MS.

There was no overt discussion on MS prevention at this meeting. I hope this becomes a significant focus in future meetings. If you have any questions about ACTRIMS, please feel free to ask.

Abstract 1

King et al. A Pre-Relapse Immune Signature Implicates EBV Reactivation in Multiple Sclerosis Attacks. ACTRIMS 2025, CE1.2.

Background: Despite the efficacy of B-cell depletion therapies, relapsing-remitting multiple sclerosis (MS) remains a complex disease with ambiguity surrounding the cell and molecular mechanisms that cause relapses. Single-cell RNA sequencing (scRNA-seq) of clinical specimens provides a systematic framework for documenting cells and pathways in human diseases.

Objectives: The aims of this study are to 1. catalogue peripheral immune cells before, during, and after relapse, 2. reveal the earliest molecular mechanisms in the ontogeny of a relapse, and 3. identify and validate novel blood-based biomarkers of relapse.

Methods: We applied single cell RNA-sequencing (scRNA-seq) to 30 clinical blood samples from 6 RRMS patients and 6 age/sex matched healthy controls. Samples were drawn within 90 days before relapse, or during relapse, and paired with remission samples. A robust mixed-effects model was utilized to identify perturbed cell types and transcriptomic features associated with relapses. Cell-specific molecular features were characterized with minimal-bias signature-scoring and surface marker imputation. A set of prioritized, predictive biomarkers were derived from whole genome-sequencing, single cell gene expression, and imputed surface proteins. Finally, 309 bulk RNA-sequencing libraries of FACS-sorted CD3+, CD14+, and CD19+ cells were constructed from 71 additional MS patients at timepoints pre- and post-relapse to validate relapse features in an expanded cohort of patients.

Results: We observe a pre-relapse, pro-inflammatory transcriptional signature in MS patients up to 87 days prior to relapse. This signature, localized primarily within B cells, plasmacytoid dendritic cells (pDCs) and monocytes, is consistent with host response to reactivation (and lytic replication) of Epstein-Barr virus (EBV). The pre-relapse signature is attenuated in active relapse samples, which instead exhibit aberrant type 2 classical dendritic cell (cDC2) and CD8+ cytotoxic T cell features. The MS relapse-specific signatures are greater in magnitude than inter-patient heterogeneity observed in healthy controls.

Conclusions: Our data implicate a monocyte/dendritic cell response to EBV reactivation in B cells as one of the earliest events in the development of relapses in MS. The multi-omic cellular atlas offers a wealth of new blood-based biomarkers predictive of disease activity. Several of these pre-relapse mechanisms are potentially targetable with new and existing therapies, offering hope for more specific, personalized treatments for MS patients.

Abstract 2

Ashida et al. Expansion of EBV-Specific Cytotoxic CD8 T Cells in CSF: Implication for Intrathecal EBV Infection in Multiple Sclerosis. ACTRIMS 2025 V367.

Background: Multiple sclerosis (MS) is an immune-mediated CNS demyelinating disease. Epstein-Barr virus (EBV) has been implicated as a risk factor of MS. B cells, the target of EBV infection, play a critical role in MS disease mechanisms, along with the clonal expansion of CD8 T cells. However, how CD8 T cells respond to EBV-infected B cells in MS remains unclear.

Objectives: This study aimed to investigate the expanded subpopulation of CSF CD8 T cells linked to EBV-infected B cells in MS.

Methods: We performed bulk RNA sequencing (RNA-seq) of prospectively acquired cerebrospinal fluids (CSF) cell samples derived from 348 MS and 164 controls. We generated TCR repertoire library and performed weighted gene co-expression network analysis (WGCNA). We validated the major findings using cellular indexing of transcriptomes and epitopes (CITE-seq) data on CSF CD8 T cells from 13 MS patients and 5 controls and combined these with publicly available single cell RNA-seq data from MS CSF. An in vitro system using patient-matched peripheral blood mononuclear cells and lymphoblastoid cell lines (CSF-LCL) generated from CSF B cells assessed CD8 T cell responses to EBV-infected B cells.

Results: In CSF bulk RNA-seq, MS patients exhibited higher TCR clonality and specificity to EBV lytic proteins compared to controls. TCRs from MS patients showed greater clustering coefficient (i.e. TCR similarity) in complementarity-determining regions 3 (CDR3), particularly those predicted to target EBV antigens. Importantly, TCR clustering coefficient was associated with the expression of cytotoxic CD8 module genes in WGCNA, such as CD8A, GZMH, GZMK, and NKG7 and with interferon signaling module. scRNA-seq revealed a subpopulation of GZMK+GZMH+ double positive (DP) CD8 T cells expressing genes related to identified cytotoxicity and interferon signaling modules. These DP CD8 T cells had significantly higher predicted specificity for EBV proteins than other CD8 cells. In vitro PBMC co-culture with CSF-LCLs expanded autologous DP CD8 T cells, while these CD8 T cells exhibited some cytotoxicity to CSF-LCL.

Conclusions: Our study shows significant expansion of EBV-specific cytotoxic DP CD8 T cells in MS CSF, providing indirect evidence for the intrathecal EBV infection in MS.

Abstract 3

Oh et al. Paramagnetic Rim Lesions as a Prognostic and Predictive Biomarker in the Tolebrutinib Phase 3 Trials for Disability Outcomes. ACTRIMS 2025 LB1.1.

Background: Tolebrutinib is a brain-penetrant Bruton’s tyrosine kinase inhibitor (BTKi) that, in phase 3 pivotal trials, led to a 31% and 29% reduction in disability accumulation relative to placebo and teriflunomide in nrSPMS and RMS, respectively. MRI paramagnetic rim lesions (PRLs) are chronic active lesions associated with inflammation, demyelination, and axonal transection in the white matter and are correlated with disability accumulation and resistant to currently approved therapies. Because BTKi can modulate neuroinflammation driven by disease-associated microglia and B cells, we asked, in a post-hoc analysis, whether PRLs were associated with response to tolebrutinib.

Objectives: To evaluate PRLs observed at baseline as a prognostic and predictive biomarker for disability accumulation and treatment response in HERCULES and GEMINI.

Methods: HERCULES (NCT04411641), GEMINI 1 (NCT04410978), and GEMINI 2 (NCT04410991) were phase 3, double-blind trials of 60 mg tolebrutinib once daily. In HERCULES, participants were randomized 2:1 to receive tolebrutinib or placebo. In GEMINI, participants were randomized 1:1 to receive tolebrutinib or teriflunomide (14 mg once daily), each with matching placebo. 437 (39%) of the 1131 HERCULES participants and 631 (34%) of the 1873 GEMINI participants were from sites with imaging capabilities allowing evaluation of PRLs. Following prior studies, we analyzed the effect of tolebrutinib on time to onset of 6-month confirmed disability worsening (6-mo CDW) in participants with 0, 1-3, or ≥4 PRLs at baseline. PRLs were manually identified on SWI images generated from 3D-gradient echo phase images (6 echoes ranging from 4.9 to 41 ms, 0.8-mm isotropic resolution).

Results: Across both trials, 653 participants (61%) had PRLs, consistent with data from observational studies with high-sensitivity MRI sequences. In HERCULES, the proportion of participants with 0, 1-3, or ≥4 PRLs at baseline was 40%, 36%, and 24%, respectively, with similar proportions in GEMINI. In both HERCULES and GEMINI, the risk of 6-mo CDW increased as a function of baseline PRLs in the placebo and teriflunomide comparator groups, respectively. In HERCULES, tolebrutinib appeared to mitigate the risk of 6-mo CDW with greater effect in participants with more baseline PRLs, reducing the risk by 54% in participants with ≥4 PRLs. In GEMINI, a similar risk mitigation was observed with a 46% and 49% risk reduction in participants with 1-3 and ≥4 PRLs, respectively. In tolebrutinib-treated participants with PRLs in both HERCULES and GEMINI, the risk of 6-mo CDW was numerically similar to the corresponding risk in participants without PRLs.

Conclusions: This post-hoc analysis suggests that the impact of tolebrutinib treatment may be greater in those with higher number of PRLs, consistent with the CNS bioactive mechanism of action of tolebrutinib.

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or 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 healthcare professional, who will be able to help you.

The biggest question from this data is how does childhood and adolescent obesity increase one’s risk of getting MS? Several Mendelian randomisation studies suggest that the genetic variants leading to obesity are associated with MS risk. Hence, obesity is in the causal pathway.

Others posit that obesity leads to a state of chronic inflammation and acts as a non-specific pro-inflammatory signal that reduces your threshold of developing MS and other autoimmune diseases. Obesity is associated with changes in the gut microbiome, which can also lead to inflammation. Obesity is also related to hormonal changes and reduced vitamin D levels. Low vitamin D is a risk factor for developing MS. Finally, obesity changes immune functions. These changes may tip the balance in favour of autoimmunity.

I have investigated diet and autoimmunity. It was clear that since humans made sugar a commodity and our sugar intake increased, so did obesity and autoimmunity. This is why anyone thinking about MS prevention should engage in public health policies to reduce childhood and adolescent obesity. Sugar taxes and other initiatives to reduce processed carbohydrate consumption are part of MS prevention.

Please be aware that obesity still requires EBV. If you remove EBV from the equation, obesity is not a risk for developing MS. EBV is necessary but insufficient for someone to develop MS, which is why I am so focused on EBV as a target for MS prevention.

How many of you were chubby as children or were overweight or obese as adolescents? Please be aware that the majority of people who develop MS will not have been obese as children or adolescents. All the data shows is that obesity increases your risk.

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What should you do with this information? If you have MS and have children or adolescents who are overweight, you should try and get them to lose weight to lower their risk of developing MS.

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Paper 1

Hagman et al. Pediatric obesity and the risk of multiple sclerosis: a nationwide prospective cohort study. Int J Obes (Lond). 2025 Jan 30. doi: 10.1038/s41366-025-01727-3.

Background: Emerging evidence implies a link between high pediatric body mass index (BMI) and an increased risk of multiple sclerosis (MS). However, previous research suggests this association is only present for adolescent obesity and not childhood obesity. The present study aimed to assess the association between pediatric obesity and risk of developing MS, and to investigate if degree of obesity and age at obesity treatment initiation affects the risk. In a subgroup, response to obesity treatment on MS risk was assessed.

Methods: In this cohort study, patients aged 2-19 years from the Swedish Childhood Obesity Treatment Register (BORIS), and matched individuals from the general population were followed prospectively. MS was identified through the National Patient Register. Hazard ratios (HR) adjusted for parental MS were calculated.

Results: The study included 21,652 individuals with pediatric obesity and 102,187 general population comparators. The median age at follow-up was 21 (Q1, Q3 18, 25) years. The adjusted HR (95% CI) for developing MS in the pediatric obesity cohort was 2.28 (1.45-3.58). In stratified analyses, obesity class I was not associated with MS, HR = 1.34 (0.64-2.81), while the association between obesity class II and MS was strengthened, HR = 3.42 (1.89-6.19). MS was associated with both childhood obesity, HR = 3.16 (1.12-8.87), and adolescent obesity, HR = 2.12 (1.28-3.51). A decrease in BMI SDS was not associated with lower likelihood of MS, HR = 1.09 (0.92-1.29) per 0.25 BMI SDS unit decrease.

Conclusions: Both childhood and adolescent obesity are associated with an increased risk of MS. Moreover, a dose-response relationship between the degree of obesity and the risk of future MS was indicated, while response to pediatric obesity treatment did not affect the association, highlighting the importance of preventing high degree of obesity early in life.

Paper 2

Pakpoor et al. Estimated and projected burden of multiple sclerosis attributable to smoking and childhood and adolescent high body-mass index: a comparative risk assessment. Int J Epidemiol. 2021 Jan 23;49(6):2051-2057.

Background: Smoking and childhood and adolescent high body-mass index (BMI) are leading lifestyle-related risk factors of global premature morbidity and mortality, and have been associated with an increased risk of developing multiple sclerosis (MS). This study aims to estimate and project the proportion of MS incidence that could be prevented with elimination of these risk factors.

Methods: Prevalence estimates of high BMI during childhood/adolescence and smoking in early adulthood, and relative risks of MS, were obtained from published literature. A time-lag of 10 years was assumed between smoking in early adulthood and MS incidence, and a time-lag of 20 years was assumed between childhood/adolescent high BMI and MS incidence. The MS population attributable fractions (PAFs) of smoking and high BMI were estimated as individual and combined risk factors, by age, country and sex in 2015, 2025 and 2035 where feasible.

Results: The combined estimated PAFs for smoking and high BMI in 2015 were 14, 11, 12 and 12% for the UK, USA, Russia and Australia in a conservative estimate, and 21, 20, 19 and 16% in an independent estimate, respectively. Estimates for smoking are declining over time, whereas estimates for high early life BMI are rising. The PAF for high early life BMI is highest in the USA and is estimated to increase to 14% by 2035.

Conclusions: Assuming causality, there is the potential to substantially reduce MS incidence with the elimination of lifestyle-related modifiable risk factors, which are the target of global public health prevention strategies.

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or 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 healthcare professional, who will be able to help you.

To prove that MS is caused by a single factor or the interaction of several factors, we must explain everything we know about the disease's epidemiology. If EBV is the cause of MS, how does EBV explain why relapsing-remitting MS (RRMS) is becoming more common in women? In comparison, the incidence of primary progressive MS (PPMS) remains constant, with an equal number of men and women affected.

Please note that the change in sex ratio is not universal; for example, it has not been noted in Sweden. Another outlier here is Iran, where the sex ratio of F:M was very high and has subsequently come down. In 2006, the F:M sex ratio was 3:1, which is very high, and it has since decreased to 2.2:1 in 2017. The ratio ascended from 2006 to 2010, increasing from 3.1 to a peak of 3.5, respectively, and a descending pattern from 2010 to 2017, decreasing from 3.5 to 2.2.

Some commentators suggest the changing sex ratio is due to the change in smoking prevalence amongst women, which has been increasing relative to males since the end of the Second World War. However, Iran is also an outlier here as less than 10% of Iranian women smoke compared to more than 30% of Iranian men. I am, therefore, unconvinced that smoking explains the changing sex ratio of MS incidence and why is the sex ratio of pwPPMS not changed?

Some blame cultural factors, such as the addition of UV blockers in cosmetics over the last twenty-plus years and other cultural changes that have caused women to shun sun exposure, resulting in women more likely to become vitamin D deficient.

Others have suggested the use of oral contraceptive pills (OCP) or a change in the work environment. However, the change in sex ratio appears to go back to the beginning of the 20th century, so it predates the change in the work environment associated with World War II or the introduction of the OCP in the ’60s.

The changing sex ratio, or lack of change in some regions, or the dynamic changes in countries such as Iran tell us that it must be driven by environmental factors and, hence, reversible. The changing sex ratio has also been used as a proxy for a rising incidence of MS.

I don’t have the answer to this MS mystery. If any of you have any ideas, please let me know. What I do know is that MS is much more common in women, and hence, it could badged as a pink-ribbon disease.

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Relevant papers

Orton et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 2006 Nov;5(11):932-6.

BACKGROUND: Incidence of multiple sclerosis is thought to be increasing, but this notion has been difficult to substantiate. In a longitudinal population-based dataset of patients with multiple sclerosis obtained over more than three decades, we did not show a difference in time to diagnosis by sex. We reasoned that if a sex-specific change in incidence was occurring, the female to male sex ratio would serve as a surrogate of incidence change.

METHODS: Since environmental risk factors seem to act early in life, we calculated sex ratios by birth year in 27 074 Canadian patients with multiple sclerosis identified as part of a longitudinal population-based dataset.

FINDINGS: The female to male sex ratio by year of birth has been increasing for at least 50 years and now exceeds 3.2:1 in Canada. Year of birth was a significant predictor for sex ratio (p<0.0001, chi(2)=124.4; rank correlation r=0.84).

INTERPRETATION: The substantial increase in the female to male sex ratio in Canada seems to result from a disproportional increase in the incidence of multiple sclerosis in women. This rapid change must have environmental origins even if it is associated with a gene-environment interaction, and implies that a large proportion of multiple sclerosis cases may be preventable in situ. Although the reasons why the incidence of the disease is increasing are unknown, there are major implications for health-care provision because the lifetime costs of multiple sclerosis exceed pound1 million per case in the UK

Kamali et al. Increasing Incidence and Male to Female Sex Ratio of Multiple Sclerosis in Tehran, Iran: A Population-Based Study. Iran J Public Health. 2022 May;51(5):1193-1194.

Amongst 11152 multiple sclerosis patients who were evaluated from 2006 to 2017, there was a significant reduction (P-value=0.01) in female to male ratio over the time from 3:1 in 2006 into 2.2:1 in 2017. This ratio changes demonstrated an ascending pattern from 2006 to 2010 (3.1 to 3.5, respectively), and also a descending pattern from 2010 to 2017 (3.5 to 2.2, respectively). Consequently there were significant changes in the female to male ratio by passing the time, with respect to the Pearson correlation coefficient (Pearson=−0.69, P=0.01).

Ramagopalan et al. Sex ratio of multiple sclerosis and clinical phenotype. Eur J Neurol. 2010;17(4):634-7. Epub 2009 Nov 24.

BACKGROUND AND PURPOSE: In a longitudinal population-based dataset of patients with multiple sclerosis (MS), we have previously observed a substantial increase in the female to male sex ratio in Canada over the last 50 years. Here, we aimed to determine whether this change in sex ratio is related to the clinical course of MS.

METHODS: We calculated sex ratios by birth year in 11 868 patients with relapsing-remitting (RR) MS and 2825 patients with primary progressive (PP) MS identified as part of the Canadian Collaborative Project on the Genetic Susceptibility to MS.

RESULTS: Year of birth was a significant predictor for sex ratio in RR MS (P < 0.0001, chi(2) = 21.2; Spearman’s rank correlation r = 0.67), but not for PP MS (P = 0.44, chi(2) = 0.6; Spearman’s rank correlation r = 0.11).

CONCLUSIONS: An increase in the number of female RR MS patients over time accounts for the increasing sex ratio of MS.

Kampman et al. Sex ratio of multiple sclerosis in persons born from 1930 to 1979 and its relation to latitude in Norway.J Neurol. 2013 Jan 6.

A remarkable increase in female to male ratio of multiple sclerosis (MS) is recognised in high incidence areas. Norway is a high-risk area for MS, spanning latitudes 58-71°N. We studied whether the sex ratio has changed over time and whether it differs by clinical phenotype or by latitude. Population-based epidemiological data and data from the Norwegian MS Registry on patients born from 1930 to 1979 were combined in this study. Place of birth was retrieved from the Norwegian Population Registry and information on clinical subtypes was obtained from the Norwegian MS Registry. The female to male ratio ranged from 1.7 to 2.7 (median 2.0) in 5,469 patients born in Norway and increased slightly by 5-year blocks of year of birth (p = 0.043). The sex ratio was 2.6:1 in 825 patients born 1970-1979, which is significantly higher than in those born 1930-1969 (p < 0.001). In patients with relapsing-remitting onset, the sex ratio was 2.4:1, while it was 1.1:1 in those with primary progressive disease. The sex ratio did not differ between the south, the middle and the north of the country. The overall sex ratio of MS is strongly determined by cases with relapsing-remitting onset. We did not observe the remarkable increase in sex ratios of MS reported from other high-risk areas. The high sex ratio in the youngest birth cohorts may change as an increasing proportion of cases in this age group is being diagnosed. Sex ratio was not associated with latitude.

Boström et al. Sex ratio of multiple sclerosis in the National Swedish MS Register (SMSreg). Mult Scler. 2012 Jun

Background: Sex ratio in multiple sclerosis has been reported from several geographical areas. The disease is more common in women. In Europe, the female-to-male ratio varies from 1.1 to 3.4. A recent study from Canada has reported a significant increase, with time, in female-to-male ratio in multiple sclerosis over the last 100 years.

Objective: The aim of this study was to analyse any change in sex ratio in multiple sclerosis in the Swedish population.

Methods: Data from the Swedish MS Register and data from the Swedish National Statistics Office were used to estimate sex ratio by year of birth and year of onset.

Results: In the analysis of sex ratio by year of birth there were 8834 patients (6271 women and 2563 men) born between 1931 and 1985. The mean women-to-men ratio was 2.62. No clear trend was noted for the women-to-men ratio by year of birth (Spearman’s rho = 0.345, p = 0.298, n = 11). The number of patients analysed by year of onset was 9098 during the time period 1946 until 2005. The mean women-to-men ratio was 2.57. No significant change in women-to-men ratio (Spearman’s rho = -0.007, p = 0.983, n = 12) with time was observed.

Conclusion: There is no evidence for an increasing women-to-men ratio with time amongst Swedish multiple sclerosis patients.

Trojano et al. Geographical Variations in Sex Ratio Trends over Time in Multiple Sclerosis. PLoS One. 2012;7(10):e48078.

BACKGROUND: A female/male (F/M) ratio increase over time in multiple sclerosis (MS) patients was demonstrated in many countries around the world. So far, a direct comparison of sex ratio time-trends among MS populations from different geographical areas was not carried out.

OBJECTIVE: In this paper we assessed and compared sex ratio trends, over a 60-year span, in MS populations belonging to different latitudinal areas.

METHODS: Data of a cohort of 15,996 (F = 11,290; M = 4,706) definite MS with birth years ranging from 1930 to 1989 were extracted from the international MSBase registry and the New Zealand MS database. Gender ratios were calculated by six decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the respective national registries of births.

RESULTS: Adjusted sex ratios showed a significant increase from the first to the last decade in the whole MS sample (from 2.35 to 2.73; p = 0.03) and in the subgroups belonging to the areas between 83° N and 45° N (from 1.93 to 4.55; p<0.0001) and between 45° N to 35° N (from 1.46 to 2.30; p<0.05) latitude, while a sex ratio stability over time was found in the subgroup from areas between 12° S and 55° S latitude. The sex ratio increase mainly affected relapsing-remitting (RR) MS.

CONCLUSIONS: Our results confirm a general sex ratio increase over time in RRMS and also demonstrate a latitudinal gradient of this increase. These findings add useful information for planning case-control studies aimed to explore sex-related factors responsible for MS development.

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MS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want to ask questions unrelated to the Newsletters or Podcasts. If you can’t afford to become a paying subscriber, please email a request for a complimentary subscription (ms-selfie@giovannoni.net).

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Important Links

📋 MS-Selfie microsite

💰 Donations to MS-Selfie

👈 Prof. G’s Backstory and CV

💾 Prof. G’s MS Blog Archive

❓ Conflicts of Interest

🦋 BlueSky Social

🔗 LinkedIn

🖋 Medium

General Disclaimer

Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or 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 healthcare professional, who will be able to help you.