Causes – Prof G's MS Blog Archive

#ECTRIMS2021: EBV as a therapeutic target; another Lazarus effect?

Barts-MS rose-tinted-odometer: ★★★★★★
(6-stars calls for a bright orange Thursday, #FFA500)

As you are aware by now I am one of the people in the field of MS who thinks EBV is the cause of MS. My position is essentially based on epidemiological evidence and causal inference. At the moment I honestly don’t know how EBV causes MS, but one hypothesis is that ongoing EBV infection in the CNS or in a peripheral compartment drives MS disease activity. EBV resides in memory B-cells and memory B-cell appears to be the main target of all effective MS disease-modifying therapies.

The question is can we simply treat MS by targeting EBV and not using a sledgehammer; i.e. depleting all B-cells (anti-CD20) or taking out the memory B-cell with non-selective immune reconstitution therapies (IRTs), e.g. AHSCT or alemtuzumab? One way to do this is to use anti-EBV drugs or cellular therapies targeting EBV infected cells.

This is why one of my highlights at this meeting is Atara Bio’s phase-1 MRI data on using anti-EBV HLA-matched cytotoxic T-lymphocytes as a treatment for progressive MS. Study subjects who had sustained improvement in the EDSS showed a significant increase or improvement in their brain MTR (magnetization transfer ratio) at 12 months compared to baseline. MTR is an MRI marker of tissue integrity and is thought to represent tissue repair and remyelination. The important point for me is the MTR is an objective measure done using software and is blinded to the clinical information or treatment allocation. Having an objective measure on MRI that correlates with a relatively subjective clinical measure improves my confidence that what we are seeing may be real.

The other remarkable observation in this study is by how much some of the responders in this study improved. EDSS scores improved by well over one EDSS point with one patient improving by as much 2.5 points, i.e. from an EDSS of 5.5 to 3.0. Two other subjects went from EDSS 6.0 to 4.5; from needing a walking stick to walk 100m to be able to walk between 300m and 499m unassisted and without taking a rest. Outside of relapses, these sorts of EDSS improvements don’t happen in people with established progressive MS. This is almost as impressive as the Lazarus effect we see rarely in patients treated with steroids or plasma exchange for a relapse. The Lazarus effect describes those patients who go from EDSS 7.0+ (bed-bound) to getting up and walking within hours to days of being treated.

Note: Lazarus of Bethany, also known as Saint Lazarus, or Lazarus of the Four Days, venerated in the Eastern Orthodox Church as Righteous Lazarus, the Four-Days Dead, is the subject of a prominent sign of Jesus in the Gospel of John, in which Jesus restores him to life four days after his death (source Wikipedia).

The following are heat map tables from the poster in the patients who improved and those who didn’t improve. Green being an improvement and red is no improvement. Even in the so-called non-responders, some study subjects improved.

The good news is Atara’s product is now in phase 2 as part of a blinded study and if it clears this hurdle a large phase 3 programme is planned. Prior to this data emerging my odds of this strategy working in MS would have been way below 50%; actually in the order of 2-5%. Now with objective MTR data correlating with such dramatic clinical improvements, my predictions have soared to now being above 50%, i.e. in the order of 50-67%.

Pender et al. Updated open-label extension clinical data and new magnetization transfer ratio imaging data from a Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive multiple sclerosis. ECTRIMS 2021, P368.

Introduction: Mounting evidence suggests Epstein-Barr virus (EBV) is a necessary risk factor for development of multiple sclerosis (MS) [Abrahamyan et al. JNNP 2020]. Early experience with autologous EBV-specific T-cell therapy proved safe and may offer clinical benefit [Pender MP et al. JCI Insight 2018; Ioannides ZA et al. Front Neurol 2021].

Objectives/aims: Evaluate the safety and potential efficacy of ATA188 in adults with progressive MS in an ongoing open-label extension (OLE) study, including an imaging biomarker: magnetization transfer ratio (MTR).

Methods: In part 1 of this 2-part Phase I/II study, 4 cohorts received escalating doses of ATA188. Patients (pts) were followed for 1 year and could participate in a 4-year OLE. Sustained disability improvement (SDI; including expanded disability status scale [EDSS] and timed 25-foot walk), as well as safety, were measured [Pender MP et al. EAN 2020]. As a biomarker of improvement, change from baseline in MTR, an exploratory endpoint, was assessed.

Results: 25 pts received ≥1 dose of ATA188 and were followed for up to 33 mos (m). No grade >3 adverse events (AE), dose-limiting toxicities, cytokine release syndrome, graft vs host disease, or infusion-related reactions were observed. 2 treatment-emergent serious AEs were previously reported (muscle spasticity [grade 2; not treatment related]; MS relapse [grade 3; possibly treatment related]) and, as of April 2021, 1 was reported in the OLE (fall; grade 2; not treatment related). Efficacy was evaluated in 24 pts in the initial 12m period and, as of April 2021, in 18 pts in the OLE followed for up to 33m. 9 pts met SDI criteria either in the initial 12m period (n=7) or in the OLE (n=2); of these, 7 had sustained EDSS improvement. Of the 8 pts that achieved SDI and entered the OLE, 7 maintained SDI at all subsequent timepoints. Pts with sustained EDSS improvement (vs those without) had greater increases in MTR signal (in unenhancing T2 lesions and normal-appearing brain tissue) at 12m.

Conclusions: Preliminary data indicate ATA188 is well tolerated. Sustained EDSS improvement drove SDI in most pts, and in all but 1 pt, SDI was maintained at all subsequent timepoints. As a biomarker associated with disability, pts with sustained EDSS improvement (vs those without) showed greater increases in MTR signal at 12m, which may be suggestive of remyelination. The Phase 2 portion of this study, EMBOLD (NCT03283826), is ongoing and currently enrolling.

The following is Atara’s press release if you want more information.

ATA188-ECTRIMS2021-PR_FINAL

Please note that I am a consultant to Atara and sit on their EBV/MS advisory board and advise them on their clinical development programme.

Conflicts of Interest

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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 the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

Curing MS

Barts-MS rose-tinted-odometer: ★★★★★

I have been asked many times if we can cure someone who has MS. I have tried to explain what an MS cure may look like many times on this blog and have actually published articles defending the definition.

I explained in a previous post that you may be cured of your MS, but still, have worsening or progressive disease. The difference between progressive disease, which is due to previous MS damage and ageing is that the former should burn out, i.e. after a period of time, your worsening disability should eventually stop or flat-line. In comparison, MS-induced premature ageing is unlikely to stop. In comparison defining a cure in people who are young, with reserve capacity, who have been treated earlier is a much easier task.

From a biological perspective you can be cured but still have neurological deficits from previous damage, which need to be targeted with so-called ‘repair’ and ‘neuroregenerative’ therapies. These are separate processes and are independent of a so-called biological cure.

Based on our current understanding of MS a cure can only really occur in relation to IRTs (immune reconstitution therapies; e.g. alemtuzumab, cladribine & HSCT), i.e. treatments that are given as short courses that address the underlying ‘cause’ of MS. Maintenance treatments that need to be given continuously can’t cure MS, because when you stop the treatment MS disease activity tends to return and in some cases, particularly with anti-trafficking agents (natalizumab and fingolimod), to a greater extent than before, which we call MS rebound.

For arguments sake let’s say we have treated a group of pwMS early in the course of their disease with an IRT and they have gone into long-term remission with no evident disease activity (NEDA). How long should we wait before declaring a victory over their MS; 10, 15, 20 or 25 years? In the past, we have proposed defining a cure as NEDA at 15 years post-treatment as a starting point (see our MSARD Editorial below). Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a standard end-point that could potentially be accepted by the wider MS community. However, this may be wishful thinking many in the field are saying that we can’t cure MS, therefore, we should not even be having this discussion. Do you agree?

The average time to the onset of secondary progressive MS is ~14-15 years so one would expect to see a significant proportion of people manifesting with SPMS in this 15-year timeframe. If we have gotten the autoimmune hypothesis wrong and IRTs don’t work then I would estimate at least a third of treated subjects should have SPMS at 15 years. The problem with 15 years is that it is a long wait if you have MS. Many pwMS want to know ‘now’ if an IRT offers a cure, therefore we need data to convince the naysayers to support the ‘cure hypothesis’. Hopefully, convincing data, such as the HSCT data below, will change their minds and get them to at least offer IRTs to more of their patients.

In the past, I have proposed a deep phenotyping project to look at pwMS who are NEDA-2 post-IRT to see if we can find any evidence of ongoing inflammatory, or neurodegenerative, MS disease activity. I proposed interrogating them in detail and comparing them to a similar cohort of pwMS who are being treated with maintenance DMTs. Deep phenotyping is simply a term that refers to the interrogation of the CNS to see if the IRT has stopped ongoing damage and protected reserve capacity.

The study that has come closest to reaching this 15-year time point is the Canadian myeloablative HSCT cohort (see below). Mark Freedman, the principal investigator, has told me that all of these patients remain NEDA-2 (no relapses or MRI activity) although some have worsened in relation to their disability, which may be a result of previous damage and not ongoing MS disease activity. However, the most impressive observation is that this cohort of patients, who all had very active MS prior to HSCT, has ‘normalised’ their rate of brain volume loss or atrophy after an initial precipitous drop in brain volume due to pseudoatrophy and/or chemotherapy-induced neurotoxicity. Mark Freedman has also said that about a third of these patients, who have had lumbar punctures, have lost their OCBs (personal communication). However, the spinal fluid analyses have all been done quite early after HSCT hence we don’t know how many subjects who have reached 10 years of follow-up or more have persistent OCBs. Wouldn’t this be an interesting fact to know?

When the 10-year lumbar puncture and spinal fluid analysis was done in a group of Polish subjects treated with intravenous cladribine, 50% had lost their spinal fluid oligoclonal IgG bands (OCBs) at 10 years and this group of OCB-negative patients tended to have stable disease compared to those who hadn’t lost their OCBs. This is why we are doing the SIZOMUS (Ixazomib) and the DODO (high-dose ocrelizumab) studies to try and scrub the CNS clean of pathogenic B-cells and plasma cells that may be driving low-grade smouldering MS. Exciting? You bet! These two studies are one of the reasons I get up in the morning, look at myself in the mirror and say nobody can say Barts-MS isn’t doing innovative MS research.

The question I am now asking myself is switching a definition of a cure to a biological one a better strategy? This is a new line of thinking that has been brewing in my head for the last 12 months or so. If EBV is the cause of MS can we simply put pwMS into remission and clear them of EBV? This is why I want to do the iTeri and similar studies, i.e. to give an IRT and follow it with a drug that prevents EBV reactivation (antiviral) or scrubs B-cells of EBV (EBNA-1 antagonists).

I am sure many cynics will be saying no not Prof G thinking aloud. Yes, I am thinking aloud. If only a minority of pwMS treated with IRTs go into long-term remission why can we increase the proportion by using the induction-maintenance approach that targets the cause of MS? What do you think?

If you agree with this strategy I am going to need help to get the iTeri concept study funded.

DEFINING A CURE:

Banwell et al. Editors’ welcome and a working definition for a multiple sclerosis cure. Multiple Sclerosis and Related Disorders. 2013; 2(2):65-67.

…. Defining a cure in MS is a difficult task. How long should we wait before declaring a victory; 15, 20 or 25 years? Oncologists have back-tracked on this issue and instead of a cure they now prefer to use the term NEDD, or no evidence of detectable disease, at a specific time-point knowing full well that a limited number of subjects will relapse and present with recurrent disease after this point. We propose using the term NEDA, or no evident disease-activity, at 15 years as a starting point for defining a cure. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a usual endpoint. In addition, the median time to the onset of secondary progressive MS is ~10-11 years (Kremenchutzky, Rice et al. 2006) and is well within the 15-year time window of our proposed definition of a cure. At present NEDA is defined using a composite of a) no relapses, or b) no EDSS progression, or c) no MRI activity (new or enlarging T2 lesions or no Gd-enhancing lesions) (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). This description is currently based on data that is routinely collected in contemporary clinical trials (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). The definition of NEDA will evolve with technological innovations and clinical practice, and in the future, it will almost certainly include MSer-related outcomes, grey matter disease activity, an index of brain atrophy and hopefully a CSF biomarker profile…..

References:

Giovannoni, G., S. Cook, et al. (2011). “Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis.” Lancet Neurol 10(4): 329-337.

Havrdova, E., S. Galetta, et al. (2009). “Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study.” Lancet Neurol 8(3): 254-260

Kremenchutzky, M., G. P. Rice, et al. (2006). “The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease.” Brain 129(Pt 3): 584-594.

THE CURE #1?

Atkins et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016 Aug 6;388(10044):576-85.

BACKGROUND: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.

METHODS: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.

FINDINGS: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no GdGd-enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.

INTERPRETATION: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease’s aggressive nature.

THE CURE #2?

Rejdak et al. Cladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study. Mult Scler Relat Disord. 2019 Jan;27:117-120.

Background: There has been long-term interest in cladribine as a drug for the treatment of MS. The current study focused on the effect of cladribine on oligoclonal bands (OCB) expression in the CSF in relapsing-remitting MS (RRMS) patients observed over 10 years.

Methods: 29 treatment-naive subjects with RRMS were prospectively enrolled and received induction therapy with subcutaneous parenteral cladribine (at a cumulative dose of 1.8 mg/kg; divided into 6 courses every 5 weeks given for 4-6 days, depending on patients’ body weight). Selected patients received maintenance doses in the follow-up period.

Results: Isoelectric focusing revealed that 55% of patients did not have OCB in CSF after cladribine treatment as compared to baseline testing when 100% of patients were positive for OCB. There were no significant differences in Expanded Disability Status Scale scores at baseline and at the end of treatment cycle between OCB-positive vs. OCB-negative subgroups. At the last follow-up, OCB-negative patients had lower disability compared to OCB-positive patients (p = 0.03).

Conclusion: Cladribine-induced immune reconstitution leads to long lasting suppression of intrathecal humoral response, which might be an additional mechanism that enhances the therapeutic effect on disease progression in RRMS patients.

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On being EBV-negative and having MS

Barts-MS rose-tinted-odometer: ★★★★★

I have been diagnosed with MS and I am Epstein Barr Virus (EBV) negative. Therefore, EBV is not the cause of MS. Correct? I wish it was that simple.

Firstly, no laboratory test is 100% sensitive and specific. In other words, some people who have negative standard EBV serology may still have the virus, i.e. a false negative result, and some people who have a positive result may not have the virus a so-called false-positive result. A very sensitive assay is one that limits the number of false-negative results, i.e. gets the result correct almost all the time. A very specific assay limits the number of false-positive results and excludes those with infection or disease. Do these terms give you a sense of deja vu? The COVID-19 lab tests have made them part of the public lexicon.

In this study below we checked out two commercial EBV serology assays and as expected they were not perfect. So yes you can be EBV-antibody negative and still have EBV.

Dobson et al. Comparison of two commercial ELISA systems for evaluating anti-EBNA1 IgG titers. J Med Virol. 2013 Jan;85(1):128-31.

High IgG titers against the Epstein-Barr virus nuclear antigen, EBNA-1, have been strongly correlated with the risk of developing multiple sclerosis. ELISAs are used frequently to measure EBNA-1 titers, however concerns remain regarding the accuracy of results. Ordering absolute results into rank quintiles for analysis may be preferable. Using 120 serum samples, two commercially available ELISAs (produced by DiaSorin and VirionSerion) were compared, both in terms of absolute results and rank quintiles. The positive predictive value of the VirionSerion ELISA was 99.1% when compared to the DiaSorin ELISA, however, the negative predictive value was 64.3%. Sensitivity and specificity were acceptable at 95.5% and 90.0%, respectively. There was poor correlation between absolute results, R(2) = 0.49; and the kappa coefficient for rank quintiles was low at 0.23. Although sensitivity and specificity appear adequate, the poor negative predictive value and kappa coefficient are of major concern. Care must be taken when selecting assays for experimental use.

In a meta-analysis of EBV and MS, we showed that when you use the immunofluorescence assay, which although being very labour intensive is considered the gold standard for diagnosing MS 100% of pwMS were EBV-positive. Interesting? Then on the flip side being EBV immunofluorescence negative was the most powerful predictor of not getting MS. These and other findings are part of the evidence that convinced me decades ago that EBV is the cause of MS.

Pakpoor et al. The risk of developing multiple sclerosis in individuals seronegative for Epstein-Barr virus: a meta-analysis. Mult Scler. 2013 Feb;19(2):162-6.

Background: Epstein-Barr virus (EBV) infection is widely considered to be a risk factor for multiple sclerosis (MS). A previous meta-analysis estimated an odds ratio (OR) for MS in individuals seronegative for EBV of 0.06. Given the potential importance of this finding, we aimed to establish a more precise OR for adult and paediatric onset MS in EBV seronegative individuals.

Methods: PubMed and EMBASE searches were undertaken to identify studies investigating the association between MS and EBV. Twenty-two adult and three paediatric studies were included. ORs were calculated using a fixed effects model. A sub-group analysis based on the method of EBV detection was performed.

Results: The OR for developing adult MS in EBV seronegatives was 0.18 (95% confidence interval (CI) 0.13-0.26)) and for paediatric MS was 0.18 (95% CI 0.11-0.30). Sub-group analysis on EBV detection method showed that studies which used immunofluoresence generated an OR=0.07 (95% CI 0.03-0.16); for those that used enzyme-linked immunosorbent assay (ELISA) OR=0.33 (95% CI 0.22-0.50) and for studies which used ELISA and immunofluoresence OR=0.00 (95% CI 0-0.43).

Conclusion: The sensitivity and specificity of the assay used to measure EBV antibody titres have an influence on the association between MS and EBV. Looking at studies where two independent methods are used and therefore are likely to be the most robust, EBV appears to be present in 100% of MS patients. This has implications for future studies of EBV in MS. MS patients without EBV infection, if they truly exist, should be studied in more detail.

Now, what about the diagnosis of MS?

In the study below approximately 1 in 5 people diagnosed with MS don’t have MS. This figure is much higher than in previous studies. I usually quote a large Danish post-mortem study that suggests only 1 in 20 people with MS (pwMS) are misdiagnosed. It is important to realise that there is no one test that can be done to diagnose MS. MS is diagnosed by combining a set of clinical and MRI findings, electric or neurophysiological investigations and laboratory tests. If these tests fulfil a set of so-called MS diagnostic criteria the Healthcare professional (HCP) or neurologist makes a diagnosis of MS.

The underlying principle of making a diagnosis of MS is showing dissemination of lesions in space and time and excluding other possible diagnoses that can mimic MS. The diagnostic criteria have evolved over time from being based purely on clinical finding to the more recent criteria that include evoked potentials, spinal fluid analysis and MRI to help confirm dissemination in time and space.

Dissemination in time means two attacks or MS lesions occurring at least 30 days apart. Dissemination in space means lesions occurring in different locations, for example, the optic nerve and spinal cord.

The electrical or neurophysiological tests are called evoked potential (EPs) and test electrical conduction in a particular neuronal pathway. They can be useful to show the effects of lesions in pathways that are not evident on neurological examination or seen on MRI. The EPs can also show slow electrical conduction which is one of the hallmarks of diseases that affect myelin, the insulation of nerves that are responsible for speeding up electrical conduction.

The laboratory tests are typically done to exclude other diseases that can mimic MS. One test that is useful in helping to make the diagnosis of MS is examining the spinal fluid for the presence of oligoclonal immunoglobulin G or IgG bands (OCBs), which are the fingerprint of a specific type of immune activation within the central nervous system (CNS).

The OCB fingerprint is relatively specific for the diagnosis of MS in the correct clinical context. Please note OCBs can are found in infections of the nervous system and other autoimmune diseases, therefore, the presence of OCBs are not diagnostic on their own.

Please note being EBV seropositive is currently not part of the diagnosis of MS so you can be diagnosed with MS and still be EBV-negative. What we don’t know is whether or not EBV-negative MS is biological MS, i.e. the same disease as EBV-positive MS. This is something I have been wanting to study for a long time.

I have spent some time explaining this all to you as we neurologists get the diagnosis wrong approximately 5% of the time and if this paper below is correct maybe in even a higher number of patients. In other words, at least 1 in 20 people who have a diagnosis of MS in life don’t have MS when their brains are studied at postmortem.

Why is getting the correct diagnosis of MS so important? Firstly, some of the treatments for MS have life-threatening complications; you don’t want to expose people without MS to these complications. Some diseases that mimic MS can be made worse by MS DMTs. This latter is particularly relevant for NMO or neuromyelitis optic. Patients with NMO misdiagnosed as having MS get worse on many of the MS DMTs. Finally, a diagnosis of MS has many psychological, social, financial and economic implications for people. Just having a diagnosis of MS, even if you turn out to have benign MS in the future, has implications for the person concerned. For example, it may affect your life choices and may impact your ability to get insurance cover to name to obvious examples. I would, therefore, advise you to make sure you have MS and not an MS mimic.

The most common MS mimics:

The evolving definition of MS based on diagnostic criteria:

Clinical criteria only:

Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552-68.

Clinical, EPs and CSF analysis:

Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31.

Clinical, EPs, CSF analysis and MRI:

What the evolving definition of MS tells us is that the diagnosis and hence the disease MS as we currently define it is a moving target. In other words, someone 10 years ago who do not fulfil the diagnosis of MS, i.e. didn’t have the disease, maybe diagnosed today as having MS. How can this be? This is why I would prefer to use a biological definition of MS. Yes, I am currently working on a paper that sets out the principles for redefining MS as a biological disease.

So what then do I do at the moment if I have MS and I am EBV negative? Until we prove EBV is the cause of MS and include EBV in the diagnosis I don’t think knowing if you are EBV positive or negative makes any difference to the diagnosis of MS and its management.

However, I would like to challenge the status quo. Can we really continue to ignore the evidence linking EBV to MS? Don’t we owe it the next generation of pwMS to act on this information ASAP? Is anyone prepared to donate several million dollars to a consortium to EBV treatment and prevention trials in MS, i.e. the Charcot Project?

Kaisey et al. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord. 2019 May;30:51-56.

BACKGROUND: Multiple Sclerosis (MS) specialists routinely evaluate misdiagnosed patients, or patients incorrectly assigned a diagnosis of MS. Misdiagnosis has significant implications for patient morbidity and healthcare costs, yet its contemporary incidence is unknown. We examined the incidence of MS misdiagnosis in new patients referred to two academic MS referral centers, their most common alternate diagnoses, and factors associated with misdiagnosis.

METHODS: Demographic data, comorbidities, neurological examination findings, radiographic and laboratory results, a determination of 2010 McDonald Criteria fulfillment, and final diagnoses were collected from all new patient evaluations completed at the Cedars-Sinai Medical Center and the University of California, Los Angeles MS clinics over twelve months.

RESULTS: Of the 241 new patients referred with an established diagnosis of MS, 17% at Cedars-Sinai and 19% at UCLA were identified as having been misdiagnosed. The most common alternative diagnoses were migraine (16%), radiologically isolated syndrome (9%), spondylopathy (7%), and neuropathy (7%). Clinical syndromes and radiographic findings atypical for MS were both associated with misdiagnosis. The misdiagnosed group received approximately 110 patient-years of unnecessary MS disease-modifying therapy.

CONCLUSION: MS misdiagnosis is common; in our combined cohort, almost 1 in 5 patients who carried an established diagnosis of MS did not fulfill contemporary McDonald Criteria and had a more likely alternate diagnosis.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Epidemic

Barts-MS rose-tinted-odometer: ★

Do you live in Scotland? Thes latest MS incidence (new cases) and prevalence (all cases) figures from the Scottish Highlands should make Scottish public health officials shiver.

In the Scottish Highlands, there are now over 18 people diagnosed with MS every year per 100,000 population with a total of 376 people with MS per 100,000 population. These figures may be artificially low as a lot of people born in the highlands may move away, for example to University or to work, and don’t get counted or included in these figures.

This is one of the highest, if not the highest, MS incidence rates in the world and about 30% higher than the figure from about a decade ago. This would indicate that we are still living through an MS epidemic and something needs to be done about it as urgently as possible.

What can be done? If MS is preventable the Scots should be setting-up and testing various MS prevention strategies to see if they can lower the incidence or at least stop its continual rise. This may be an opportune time to look into vitamin D prevention trials and campaigns to get first and second degree relatives to sign-up for more targeted MS prevention studies.

Francisco Javier Carod-Artal. The epidemiology of multiple sclerosis in the Scottish Highlands: Prevalence, incidence and time to confirmed diagnosis and treatment initiation. Mult Scler Relat Disord. 2020 Nov 28;47:102657.

Introduction: Although multiple sclerosis (MS) is frequent in the northern hemisphere, there have not been recent epidemiological studies in the Scottish Highlands about MS.

Objectives: To get updated data regarding MS prevalence, incidence and mortality in the Highlands. Time between symptom onset and MS diagnosis was also evaluated in incident MS cases and the pattern of use of disease-modifying therapies (DMTs) was analysed.

Methods: Study population was people with MS under the care of the Highland Health and Social Care Partnership. The catchment area included North area (Wick, Thurso, Brora, Invergordon), Center (Inverness, Aviemore, Nairn, Fort William), and West coast (Ullapool, Skye). Data were obtained from the MS database at Raigmore hospital (prevalence, midyear 2017) and the prospective hospital-register based study (diagnosis) that was carried out over a 12-month period, in 2016. The 2010 McDonald criteria for diagnosis of new MS cases were used. Crude prevalence and incidence and 95% confidence interval (CI) were calculated for the MS adult onset population, and data was standardised to the European standard population 2013; cause-specific mortality rate was analysed. Pattern of use of DMTs during the first year of diagnosis was also registered.

Results: 745 patients were registered in the MS database. 75.4% (562 cases) were females, and female/male ratio was 3:1. Mean age of population was 54.1 ± 14.1 years (range: 15-95 years). Mean number of years since diagnosis was 8.5 ± 4.6 years. Estimated prevalence for the population aged 15 and older was 376 cases per 100,000 inhabitants (95% CI: 354-399). 36 incident MS cases were registered in 2016 (88.8% females; mean age 40.4 ± 12.1 years). Annual incidence in Highlands was 18.2 per 100,000 inhabitants (95% CI: 14-24). The mean period of time from symptom onset to diagnosis was 38.8 ± 43.2 months. 47.2% (17/36) did not take any DMT during the first year after the diagnosis.

Conclusion: Prevalence and incidence of MS in the Scottish Highlands is high. Although the gap period between symptom onset and diagnosis is moderate, a significant proportion of recently diagnosed MS patients were not keen to start a DMT the first year after the diagnosis.

Crowdfunding: Are you a supporter of Prof G’s ‘Bed-to-5km Challenge’ in support of MS research?

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#BlackSwan: anecdotal evidence we can’t ignore

Barts-MS rose-tinted-odometer: ★★★★★

What is a black swan event?

“The black swan theory or theory of black swan events is a metaphor that describes an event that comes as a surprise, has a major effect, and is often inappropriately rationalised after the fact with the benefit of hindsight”. (Source Wikipedia)

The case study below is another example of a mounting number of case studies of patients with MS being treated with antivirals, with activity against EBV, doing well. We now need to do properly powered randomised controlled trials to test the EBV causation of MS hypothesis definitively.

Prof. Julian Gold and I launched the Charcot Project in 2012 to investigate the viral aeitology of MS. We tried on numerous occasions to get trials funded to test this hypothesis and have failed. We managed to test one anti-retroviral in a small proof-of-concept study, which was negative. Since then we have managed to get funding to see if famciclovir is capable of suppressing EBV shedding in the saliva. This study should have been completed by now, but we had to delay its start because of the COVID-19 pandemic.

We have also managed to show that teriflunomide is anti-EBV in that it reduces EBV viral shedding in the saliva of people with MS. I suspect this is a very relevant an important observation and underpins the iTeri study, i.e. to use a B-cell depleting agent as induction therapy and teriflunomide or related compound as a maintenance therapy to prevent EBV reinfecting B-cells during the B-cell reconstitution phase.

Life is short and I started working on EBV as a cause of MS way back in 2005 and feel like I am treading water. The evidence that EBV is the cause of MS is so overwhelming that we really can’t afford to ignore it any longer. What we need is a substantial investment from the major funding agencies, MS charities, wealthy philanthropists and Pharmaceutical companies with antiviral drugs in their portfolio to prove (or disprove) that EBV is the cause of MS.

When you apply Bradford-Hill’s causation theory to EBV being the cause of MS there is only one criterion out of nine that still needs to be ticked and that is experimental evidence. What we need are therapeutic interventional trials targeting EBV to complete the proof.

Torkildsen et al. Tenofovir as a treatment option for multiple sclerosis. Mult Scler Relat Disord 2020 Oct 7;46:102569. doi: 10.1016/j.msard.2020.102569.

Some antiretroviral medications are also inhibitors of EBV. We describe a patient with highly active MS who was infected with HIV and started HIV-treatment containing tenofovir alafenamide (TAF), a potent inhibitor of EBV lytic reactivation. Her MS was in complete remission during this treatment, and she had new radiological disease activity again after switching to tenofovir disoproxil fumarate, an HIV drug with less potent activity against EBV replication. Based on the recently detected mechanism of TDF and TAF, we suggest that further studies on these drugs in MS are warranted.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

A false sense of security?

Just catching up with my reading. Whilst I was away on holiday the ASCLEPIOS I and II trials was published in the New England Journal of Medicine.

There is little doubt that ofatumumab is superior to teriflunomide when it comes to suppressing focal inflammation, i.e. relapses, MRI activity and peripheral blood neurofilament levels. However, ofatumumab’s effectiveness against teriflunomide on the real MS (delaying disability progression and reducing the relative loss of brain volume) is less impressive. Is this just another example of a dissociation between the anti-inflammatory effects of an anti-CD20 therapy and its impact on the end-organ as measured using brain volume loss or is it telling us something about teriflunomide and the cause of MS?

Image from supplementary material N Engl J Med 2020; 383:546-557.

It is clear, at least to me, that MS the disease is not due to focal inflammation. Based on the Prentice criteria for disease surrogates, both relapse and focal MRI activity don’t predict disability outcomes in natural history studies and placebo arms of clinical trials. If focal inflammation was MS then relapses and focal MRI activity would predict outcome whether or not you are on a DMT. The point I making here may be a philosophical one, but it a critically important one. In comparison, sustained or confirmed disability progression has to be MS and is based on the pathological correlates that define MS (demyelination, neuroaxonal loss and gliosis).

So why does ofatumumab do so poorly on these metrics relative to teriflunomide, when you would expect it do better? I think teriflunomide is the outlier and this opinion is based on several observations.

Teriflunomide has effects on disability progression that are way and above what you expect from its impact on relapses and focal MRI activity; i.e. both teriflunomide phase 3 placebo-controlled trials were positive on disability progression, despite a moderate reduction in relapse rate (~33% vs. placebo).

Teriflunomide also has a significant and unexpected effect on brain volume loss compared to placebo, which again is out of proportion to its anti-inflammatory effects.

Teriflunomide is more effective when used 2nd and 3rd line. Teri is the only DMT to show the latter and this observation was seen in both phase 3 studies, which makes it likely to be a real, and a very important, finding.

Finally, teriflunomide is a broad-spectrum antiviral agent, which may be part of its mode of action in MS. Could teriflunomide be targeting the viral cause of MS independent of its effects on the immune system’s response to that virus? Could it be an anti-EBV agent? Although teriflunomide’s antiviral mode of action needs more study, I suspect this is the reason why teriflunomide is the outlier that disproves the dogma.

Despite these observations, I suspect the MS community is going to propel ofatumumab to blockbuster status within the first 12 months of its launch. However, I want to reiterate that I think anti-CD20 therapies are lulling us into a false sense of security, i.e. because anti-CD20 therapies are so good at suppressing relapses and focal MRI activity we think we have sorted out the treatment of MS. However, when you look carefully at the end-organ of pwMS on anti-CD20 it is clear that their brains are still being shredded by smouldering MS. It is clear to me that we need to go way and beyond ofatumumab and anti-CD20 therapies to target whatever is causing smouldering MS. This is why we need to think combination therapies and find an add-on therapy, possibly an antiviral, that normalises brain volume loss in people with MS who are rendered free of focal inflammatory activity.

Hauser et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med 2020; 383:546-557.

BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.

METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.

RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, −0.11; 95% confidence interval [CI], −0.16 to −0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, −0.15; 95% CI, −0.20 to −0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P=0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P=0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P=0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups.

CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231).

CoI: multiple

Not COVID-19: obesity and MS

Are you sick and tired of hearing about COVID-19 and MS? How about something completely different; the destigmatization of obesity?

Finally, the medical community or at least a part of it are making amends for the half-century or more of treating obesity as a disorder of self-control. The joint internal consensus statement for ending the stigma of obesity is long overdue (see article and box below).

Even when I have done factual posts about childhood and adolescent obesity as a risk factor for developing MS I have been criticised by commentators for fat-shaming. I am not. All I am doing is quoting the evidence that childhood/adolescent obesity is associated with an increased risk of developing MS and may in fact be in the causal pathway that leads to developing MS.

What the consensus statement below is finally acknowledging is the irrefutable evidence that obesity is a disorder of metabolism; an endocrine disorder that leads to patients increasing the amount of energy they store as fat. Finally, the dogma that obesity is due to the excess consumption of calories and/or the reduced expenditure of calories is finally being put to rest as not being the root cause of obesity.

A simplified way of explaining the mechanisms that lead to obesity is that your metabolism gets hijacked by a hormonal imbalance that results in energy be hoarded away in your adipose tissue and it not being released for consumption by the remainder of the body. This triggers the brain to think that you are starving and sets off a behavioural response to seek more food or calories. In other words, the metabolic state associated with obesity causes hunger and the food-seeking behaviour associated with it and not the other way around.

The sad thing is that we the medical profession have known about this insight for centuries, but we decided to forget or ignore the metabolic research underpinning obesity being a metabolic disease in the 70’s and 80’s when we were hoodwinked by dodgy science and fake news. Yes, the high saturated-fat heart hypothesis of cardiovascular disease is to blame. The conspiracy underpinning the change in the dietary guidelines that have caused the global obesity pandemic has been well highlighted by investigative journalists in several extremely well-crafted exposes. The tragedy is as the population replaced saturated fat in our diets with polyunsaturated fats and carbohydrates, in particular, processed and ultra-processed carbohydrates, we created a metabolic storm that has resulted in an epidemic of obesity, diabetes, hypertension, fatty liver and the other ills associated the metabolic syndrome.

Shifting the focus sway from obesity as a result of an individual’s lack of self-discipline to it being a metabolic disease driven primarily by diet will allow us to tackle the epidemic, i.e. to flatten the curve and hopefully chop off its tail to steal a COVID-19 analogy.

The metabolic cause of obesity is rather quite simple; it is driven predominantly by raised insulin levels or hyperinsulinaemia. High blood sugar or glucose levels stimulate the pancreas to produce insulin. The insulin works to reduce blood glucose levels by signalling to the liver and muscles to make glycogen (short-term glucose storage) and to the liver and adipose tissues to make fat. Whilst insulin levels are high the adipose tissue is unable to release fat as an energy source and so the adipose tissue continues to take-up glucose to convert into fat. As glucose levels drop it triggers a counter-regulatory hormonal response that causes you to become hungry and you then seek out sugary foods. This then starts a vicious cycle that results in insulin levels being raised most of the day, instead of only being raised for a few hours after a meal. This hyperinsulinaemia eventually causes the liver and muscles to become resistant to insulin’s action, but less so in adipocytes particularly the adipocytes around the abdomen and internal organs. The latter causes the so-called centripetal and visceral obesity that is typical of insulin resistance.

The only way to break this vicious metabolic cycle is to try and lower your insulin levels as much as possible. This is why low carbohydrate or ketogenic diets work so well at correcting the metabolic syndrome (hyperinsulinaemia) and result in loss of weight. The good thing about keeping insulin levels low is that the body gets used to a new normal or steady-state glucose level that is driven by another metabolic process called gluconeogenesis (glucose from protein), which does not trigger the counter-regulatory hormonal response that makes you feel hungry. In addition, the ketones your body produce, particularly β-hydroxybutyrate, is known to suppress appetite and explains why people on ketogenic diets don’t feel the same levels of hunger as people on high carbohydrate diets.

If you have MS having high levels of circulating β-hydroxybutyrate maybe be good for your MS. β-hydroxybutyrate activates the hydroxycarboxylic acid receptor 2 (HCA2), which is also known as niacin receptor 1 (NIACR1) and GPR109A. This is the same receptor that fumaric acid works on. I suspect that ketosis works at a cellular level in the same way that dimethyl fumarate (DMF) and diroximel fumarate work, which are both licensed MS disease-modifying therapies (DMTs). By binding to the HCA2 receptor β-hydroxybutyrate stimulates a transcription factor called NRF2 and downregulates NFKappa-B the master regulator of inflammation. The NRF2 mechanism of ketosis almost certainly overlaps with what has been described in animals with intermittent fasting and the drug metformin to promote the rejuvenation of oligodendrocyte precursors, remyelination and recovery of function.

Despite criticism from dietary zealots the evidence that low-carbohydrate/ketogenic diets are bad for you is very weak. In fact, I would argue that from an evolutionary perspective man was first a low-carbohydrate species and only acquired the sophisticated carbohydrate metabolic response to fatten up for winter when fruits and grains are plentiful at the end of summer. We were never meant to metabolise carbohydrates 24/7 365 days a year. Feast and famine was the norm, which is how our primate cousins live in the wild.

Although we need controlled evidence before promoting low-carbohydrate/ketogenic diets as a treatment for MS and for MS prevention there is no reason why pwMS can’t try these dites improve their metabolic health. If I had MS I would not hesitate to hack my metabolism with either a low-carbohydrate/ketogenic diet or intermittent fasting, but not caloric restriction. The scientific case for using these former diets as an adjunct to other MS therapies is simply too compelling to ignore.

Rubino et al. Nat Med 2020 Apr;26(4):485-497.

Rubino et al. Joint International Consensus Statement for Ending Stigma of Obesity. Nat Med 2020 Apr;26(4):485-497.

People with obesity commonly face a pervasive, resilient form of social stigma. They are often subject to discrimination in the workplace as well as in educational and healthcare settings. Research indicates that weight stigma can cause physical and psychological harm, and that affected individuals are less likely to receive adequate care. For these reasons, weight stigma damages health, undermines human and social rights, and is unacceptable in modern societies. To inform healthcare professionals, policymakers, and the public about this issue, a multidisciplinary group of international experts, including representatives of scientific organizations, reviewed available evidence on the causes and harms of weight stigma and, using a modified Delphi process, developed a joint consensus statement with recommendations to eliminate weight bias. Academic institutions, professional organizations, media, public-health authorities, and governments should encourage education about weight stigma to facilitate a new public narrative about obesity, coherent with modern scientific knowledge.

CoI: multiple

HSCT is shifting the Bell curve

Barts-MS rose-tinted-odometer ★ ★ ★

The good news is that the use of autologous HSCT to treat autoimmune diseases rose (by 19%) in the European Bone Marrow Transplant registry in 2018. Importantly, this rise was predominantly due to HSCT treatment for multiple sclerosis. This would indicate that at least at the very right of the bell curve there is increasing use of a more aggressive approach to treating MS. If this indicates that the bell curve has shifted to the right it means that more pwMS are being treated with highly effective treatments and I suspect that many are getting onto these as first-line therapies.

What will this mean at a population level? I suspect that over time the prognosis of MS will improve and an increasing number of patients treated with IRTs (cladribine, alemtuzumab and HSCT) will be rendered free of detectable disease in the longterm. If and whether we will be able to claim that a proportion of these pwMS are cured of having MS will depend on the MS community coming up with a widely accepted definition of what an MS cure looks like.

How IRTs actually work will remain a moot point. Immunologists will claim that they deplete pathogenic autoimmune T and B lymphocytes and reset regulatory immunological networks. Proponents of the EBV hypothesis will claim they all work by targeting pathogenic memory B cells that harbour EBV. Sorting out these competing theories will really require targeted EBV studies, the sort that has been developed by Atara Bio. Another strategy will be using anti-viral agents active against EBV; this will include both existing and new anti-EBV therapies.

If I have to bet on the outcome I would favour the EBV hypothesis. There are simply too many holes in the autoimmune theory of MS and the epidemiology backing EBV as the cause of MS is now so overwhelming that the wider MS community is finally getting behind EBV vaccination as a possible preventive strategy. I hope you agree.

Passweg et al. and the European Society for Blood and Marrow Transplantation (EBMT). The EBMT activity survey on hematopoietic-cell transplantation and cellular therapy 2018: CAR-T’s come into focus. Bone Marrow Transplant. 2020 Feb 17.

Hematopoietic-cell transplantation (HCT) is widely used for acquired and congenital disorders of the hematopoietic system. Number of transplants performed in Europe and associated countries continues to rise with 47,468 HCT in 42,901 patients [19,630 allogeneic (41%) and 27,838 autologous (59%)] reported by 701 centers in 50 countries in 2018. Main indications were myeloid malignancies 10,679 (25%; 97% allogeneic), lymphoid malignancies 27,318 (64%; 20% allogeneic), solid tumors 1625 (4%; 2.9% allogeneic), and nonmalignant disorders 3063 (7%; 81% allogeneic). This year’s analysis focuses on cellular therapies with the marked growth in CAR T-cell therapies from 151 in 2017 to 301 patients reported in 2018. Other cellular therapy numbers show less significant changes. Important trends in HCT include a 49% increase in allogeneic HCT for chronic phase CML (although transplant numbers remain low) and a 24% increase in aplastic anemia. In autologous HCT, there is an ongoing increase in autoimmune diseases (by 19%), predominantly due to activity in multiple sclerosis. This annual report reflects current activity and highlights important trends, useful for health care planning.

CoI: multiple

Black Swan?

Is this the black swan I have been looking for?

We need to be able to explain smouldering MS and why pwMS get worse despite having no evident disease activity (NEDA) on DMTs. One of the hypotheses is that something is occurring within the brains and spinal cords of pwMS. I have referred to this in the past as the field hypothesis and have suggested that it could be due to an active virus within the brains of pwMS. I have always made the point that the two viruses with most of the evidence behind them are EBV and HERVs, particularly HERV-W.

This study below strongly suggests that the HERV-W envelope protein may be driving smouldering MS. It would be interesting if the ENV protein is found in SELs (slowly expanding lesions). This study supports our Charcot Project and the urgent need to formally test HAART (highly active antiretroviral therapies) in MS. Our INSPIRE trial, which was negative, was not HAART as it only tested one anti-retroviral and integrase inhibitor.

Do you have the appetite for another push at getting funding for an add-on HAART trial in MS? The case for doing it is compelling both from an epidemiological and basic science perspective.

LET’S DO IT!

Kremer et al. pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis. Proc Natl Acad Sci U S A. 2019 Jun 18

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.

Japan epicentre of an Asian MS epidemic

I am about to return from a short MS meeting in Tokyo. This was my first exposure to Japan and Japanese culture. It is everything and more than I expected.

I am beginning to get a sense of what ikigai means. Ikigai translates ‘to a reason for being, encompassing joy, a sense of purpose and meaning and a feeling of well-being’. Ikigai derives from iki, meaning life and kai, meaning the realisation of hopes and expectations.

I first learnt about ikigai from the ‘Blue Zones’, a book by Dan Buettner, on the secrets of the world’s ‘happiest places’, where people are super-agers. One of the blue zones is Okinawa, a subtropical Japanese island to the South of Japan. Some of the philosophy underpinning happiness and super-ageing is cultural and is specific to the Japanese culture.

The lessons of the blue zones are applicable to our Brain Health initiative and I would urge you to read the book. Who knows it may change the way you want to live your life regardless of whether or not you have MS.

It is clear that MS is a problem in Japan and the incidence and prevalence is rising. Why? Japan is now one of the epicentres of the global MS epidemic; i.e. an area of the world where MS has gone from a low to a medium incidence area, similar to Iran, and will quite soon become a high incidence area. The clue to this is the rapidly increasing sex ratio of females to males that is now over 3:1.

As an MS community, we need to study these epicentres to see if we can pin down the cause of MS and put in place robust prevention trials. Japan has rapidly westernised and the Japanese neurologists I spoke to think this is the reason why the incidence of MS is increasing in Japan. Not sure I buy this at face value. What is it about the Western lifestyle that is causing MS? Could it be childhood obesity? Processed carbohydrate/sugar consumption? Smoking? Change in the epidemiology of EBV infection; a different strain, later infection, more infectious mononucleosis? Less sunshine and lower vitamin D levels?

It is interesting that Japanese neurologists think MS is more benign in Japan than elsewhere. I am not sure why they think this. All the evidence I saw this weekend points to Japanese MS being identical to Western European MS. Unfortunately for Japanese MSers, they have access to fewer DMTs and there are only two highly effective DMTs licensed in Japan, i.e. fingolimod and natalizumab. There is also a much higher JCV seroprevalence rate in Japan of close to 80% with a higher proportion of people with a high anti-JCV index. This makes the risk of PML potentially much higher in Japan. For example, there have been 4 cases of non-carryover PML on fingolimod, which equates to a PML rate of about 1 in 1,000 to 1,500 per fingolimod-treated MSer. This is an order of magnitude higher than the non-carryover PML rate on fingolimod outside of Japan and clearly needs further study.

Another factor is the reluctance of Japanese neurologists to use off-label treatments, for example, subcutaneous cladribine and rituximab. The reasons for this are multiple but mainly relate to lack of reimbursement and cultural factors. It was also clear that the Japanese neurologist, similar to British neurologists, are quite conservative and prefer a step-care approach. The Japanese are particularly concerned that because of their ancestry they may respond differently to DMTs, which have been tried and tested in other populations. In other words, they need data on the safety and efficacy of specific DMTs in their own Japanese MS population. To get a drug licensed in Japan Pharma has to trials in Japan.

As a result of the JCV problem extended interval dosing of natalizumab, also referred to as EID, and PML surveillance (3-monthly MRI monitoring) is very important for natalizumab-treated Japanese MSers. In fact, Japan is the one country that the derisking of PML for natalizumab is critical. Until other high-efficacy DMT arrive the Japanese are going to have to make do with fingolimod and natalizumab. In comparison, we are spoilt for choice in the UK and other high-income countries; we have forgotten what it was like to manage MS before the avalanche of new DMTs.

I have uploaded my slides from Japan on my slideshare site; you are welcome to download them and repurpose the slides for your own uses. I presented our #AttackMS study as a way to illustrate how important time matters in MS. I am not sure the Japanese neurologists agreed with such an active approach to treating MS. Do you?

Houzen et al. Consistent increase in the prevalence and female ratio of multiple sclerosis over 15 years in northern Japan. Eur J Neurol. 2018 Feb;25(2):334-339.

BACKGROUND AND PURPOSE: The prevalence of multiple sclerosis (MS) is considered to be lower in East Asia than in Western countries. An increasing trend has been reported globally for the prevalence of MS. We investigated the changes in the prevalence and clinical characteristics of MS in the Tokachi province of Hokkaido, northern Japan from 2001 to 2016.

METHODS: Prevalence was determined on 31 March 2016. Data-processing sheets were collected from all MS-related institutions in Tokachi province. We applied Poser’s diagnostic criteria for MS as used in our previous three studies. Cases of neuromyelitis optica spectrum disorders were excluded.

RESULTS: In 2016, the crude MS prevalence was 18.6/100 000 (95% confidence interval, 14.3-23.8) in northern Japan. Over the last 15 years, the prevalence of MS in the same area was 8.1, 12.6 and 16.2 in 2001, 2006 and 2011, respectively. The female:male ratio was 3.57, which increased from 2.63 in 2001. The ratios of primary progressive, relapsing-remitting and secondary progressive MS types were 2%, 84% and 14%, respectively.

CONCLUSION: Our results demonstrated a consistent increase in MS prevalence among the northern Japanese population, particularly in females, and relatively lower rates of progressive MS in northern Japan than in Western countries.

CoI: multiple