Oh, my thyroid!

Barts-MS rose-tinted-odometer: ★★★ (mid-summer orangey-yellow #f5bd1f)

As you are aware if you choose to be treated with the most effective IRTs (immune reconstitution therapies) you stand a relatively high chance of developing a second autoantibody-mediated autoimmune disease, with thyroid disease being the most common. For example, the cumulative incidence of second autoimmune diseases post-alemtuzumab is ~45%. In other words, if you want a potential cure from MS with these treatments you need to be prepared to get a second autoimmune disease. 

At present secondary autoimmunity seems to be more common post-alemtuzumab when compared to AHSCT and we haven’t seen this complication with cladribine, but I suspect there will be isolated cases. The true incidence of these autoantibody-mediated problems post-AHSCT is not known, but is clearly an issue and I am beginning to wonder why we don’t put in place the same monthly blood and urine monitoring post-AHSCT as we do post-alemtuzumab. 

By far the commonest is autoimmune thyroid disease with about 20% of males and 40% of females with MS being treated with alemtuzumab developing autoimmune thyroid disease. The type of autoimmune thyroid disease post-IRT is not quite the same as standard Grave’s disease. It tends to be more brittle with frequent fluctuations and even remissions. The reason for this is that post-IRT Grave’s disease tends to have stimulatory antibodies against the thyrotropin receptor, which activates the thyroid gland  to produce thyroid hormone. These anti- thyrotropin receptor antibodies don’t seem to damage the thyroid gland in the same way as other anti-thyroid gland antibodies. Despite this many patients end up with hypothyroidism and need to go onto thyroxine or thyroid replacement therapy. 

NOTE: “ Levothyroxine is best taken on an empty stomach 30 minutes before food, and not to be taken with caffeine. This is not commonly taught and may be a cause for poor response—so worth sharing”. Simon Hodes. Investigating hypothyroidism: how to take levothyroxine.BMJ 2021;373:n1463

The following figure and review paper is worth reading if you are more interested in the diagnosis and management of thyroid problems post IRTs. 

a) Hyperthyroidism/thyrotoxicosis. b) Hypothyroidism. TSH, thyroid-stimulating hormone; TRAb, thyrotropin receptor autoantibodies; FT4, free-thyroxine; FT3, free-triiodothyronine; GD, Graves’ disease; ATD, antithyroid drug; RAI, radioiodine; TPOAb, autoantibodies to thyroid peroxidase; LT4, levothyroxine. Image from Eur Thyroid J.

Muller et al. 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy. Eur Thyroid J. 2019 Jul;8(4):173-185.

Thyroid dysfunction (TD) frequently occurs as an autoimmune complication of immune reconstitution therapy (IRT), especially in individuals with multiple sclerosis treated with alemtuzumab, a pan-lymphocyte depleting drug with subsequent recovery of immune cell numbers. Less frequently, TD is triggered by highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV), or patients undergoing bone-marrow/hematopoietic-stem-cell transplantation (BMT/HSCT). In both alemtuzumab-induced TD and HIV/HAART patients, the commonest disorder is Graves’ disease (GD), followed by hypothyroidism and thyroiditis; Graves’ orbitopathy is observed in some GD patients. On the contrary, GD is rare post-BMT/HSCT, where hypothyroidism predominates probably as a consequence of the associated radiation damage. In alemtuzumab-induced TD, the autoantibodies against the thyrotropin receptor (TRAb) play a major role, and 2 main aspects distinguish this condition from the spontaneous form: (1) up to 20% of GD cases exhibit a fluctuating course, with alternating phases of hyper- and hypothyroidism, due to the coexistence of TRAb with stimulating and blocking function; (2) TRAb are also positive in about 70% of hypothyroid patients, with blocking TRAb responsible for nearly half of the cases. The present guidelines will provide up-to-date recommendations and suggestions dedicated to all phases of IRT-induced TD: (1) screening before IRT (recommendations 1-3); (2) monitoring during/after IRT (recommendations 4-7); (3) management of TD post-IRT (recommendations 8-17). The clinical management of IRT-induced TD, and in particular GD, can be challenging. In these guidelines, we propose a summary algorithm which has particular utility for nonspecialist physicians and which is tailored toward management of alemtuzumab-induced TD. However, we recommend prompt referral to specialist endocrinology services following diagnosis of any IRT-induced TD diagnosis, and in particular for pregnant women and those considering pregnancy.

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CURE-3

Barts-MS rose-tinted-odometer: ★★★★★ (still seeing red, despite Summer having finally arrived)

I am considering retraining as a medical philosopher. The thinking of the MS research community is riddled with fundamental errors that could be sorted out by applying basic philosophical principles. One example is the diagnostic tautology we are wedded to in how we define MS as a disease. Another relates to the classification of categorical MS disease states. Defining an MS cure, etc. I am also being criticised for supporting two conflicting, juxtaposed theories about the potential cause of MS. How can I ‘believe’ MS is caused by EBV and at the same time talk about IRTs (immune reconstitution therapies) potentially curing MS as an autoimmune disease.

The reality is that scientists are not religious and don’t hold beliefs. Scientists put forward hypotheses, which are then tested and refined. Over time hypotheses get rejected and/or evolve and if the experimental evidence becomes overwhelming they enter the canon of human knowledge as facts. In comparison, beliefs are immutable and cannot be challenged. Therefore, I don’t believe EBV is the cause of MS and I don’t believe MS is an autoimmune disease. I hypothesise that EBV is the cause of MS, I hypothesise that MS is an autoimmune disease and I hypothesise that these two theories are not mutually exclusive, i.e. MS can be caused by EBV and still be an autoimmune disease. In other words, EBV is the driver of autoimmunity and by removing EBV from the MS causal pathway you prevent or cure MS. 

To prevent EBV infection we are exploring doing an EBV vaccine trial in people at high risk of MS and then following them to see if they go on to develop MS or not. This experimental paradigm is well-rehearsed and relatively easy to understand. 

What is not easy to understand is how EBV causes MS. One theory is that EBV simply provides autoreactive B-cells and T-cells with a survival advantage and as a result, they persist, expand in numbers and become dysregulated, which tips over into autoimmunity that becomes self-perpetuating. How EBV does this is not known. One mechanism that I have proposed is that because EBV infection causes B-cells and T-cells to hyperproliferative, i.e. go through many cell divisions, they acquire so-called somatic mutations in their genomes that sets the stage for autoimmunity.

There is mounting evidence in MS that the majority of pwMS have somatic (in the body and not in the germline) mutations in T-cells and B-cells (see studies below). These mutations could provide these cells or clones with a survival advantage, based on simple Darwinian selection principles, which explains why they persist and expand in number. Think of these cells as being like a kind of benign tumour. The important thing is that these cells can be killed using aggressive immunodepletion strategies such as AHSCT or alemtuzumab treatment. 

Another thing to remember is that it may not be one but several somatic mutations that are required to trigger autoimmunity. So if you purge the downstream autoimmune clones, but leave the upstream driver clones behind, they may have the potential to acquire new mutations and hence reactivate autoimmunity in the future. This could explain why some people who go into long-term remission after HSCT or alemtuzumab treatment breakthrough many years later with recurrent MS disease activity. 

The two studies below show that pwMS harbour many somatic mutations in their circulating B-cells and T-cells. These data not only underpin the hypotheses presented above, but also support the hypotheses that MS is an autoimmune disease triggered by EBV and that it can be cured by an immune reconstitution therapy. 

So I won’t be deterred by my campaign to define what an MS cure looks like so that we can look for it and claim it as a victory in the management of this awful disease

Yes, I am a big supporter of the hypothesis that MS is a curable disease and this position is absolutely compatible with my positions on the role of EBV and autoimmunity in causing MS. Do you disagree?

The great tragedy is that if IRTs cure MS in a proportion of pwMS, why are we not using IRTs more widely? Now that is the big story that can be told another day.  

Our current approach to treating MS. Photo by Luis Villasmil on Unsplash

van Horebeek et al.  A robust pipeline with high replication rate for detection of somatic variants in the adaptive immune system as a source of common genetic variation in autoimmune disease. Hum Mol Genet. 2019 Apr 15;28(8):1369-1380.

The role of somatic variants in diseases beyond cancer is increasingly being recognized, with potential roles in autoinflammatory and autoimmune diseases. However, as mutation rates and allele fractions are lower, studies in these diseases are substantially less tolerant of false positives, and bio-informatics algorithms require high replication rates. We developed a pipeline combining two variant callers, MuTect2 and VarScan2, with technical filtering and prioritization. Our pipeline detects somatic variants with allele fractions as low as 0.5% and achieves a replication rate of >55%. Validation in an independent data set demonstrates excellent performance (sensitivity > 57%, specificity > 98%, replication rate > 80%). We applied this pipeline to the autoimmune disease multiple sclerosis (MS) as a proof-of-principle. We demonstrate that 60% of MS patients carry 2-10 exonic somatic variants in their peripheral blood T and B cells, with the vast majority (80%) occurring in T cells and variants persisting over time. Synonymous variants significantly co-occur with non-synonymous variants. Systematic characterization indicates somatic variants are enriched for being novel or very rare in public databases of germline variants and trend towards being more damaging and conserved, as reflected by higher phred-scaled combined annotation-dependent depletion (CADD) and genomic evolutionary rate profiling (GERP) scores. Our pipeline and proof-of-principle now warrant further investigation of common somatic genetic variation on top of inherited genetic variation in the context of autoimmune disease, where it may offer subtle survival advantages to immune cells and contribute to the capacity of these cells to participate in the autoimmune reaction.

Valori et al. A novel class of somatic mutations in blood detected preferentially in CD8+ cells. Clin Immunol. 2017 Feb;175:75-81.

Somatic mutations have a central role in cancer but their role in other diseases such as autoimmune disorders is poorly understood. Earlier work has provided indirect evidence of rare somatic mutations in autoreactive T-lymphocytes in multiple sclerosis (MS) patients but such mutations have not been identified thus far. We analysed somatic mutations in blood in 16 patients with relapsing MS and 4 with other neurological autoimmune disease. To facilitate the detection of somatic mutations CD4+, CD8+, CD19+ and CD4-/CD8-/CD19- cell subpopulations were separated. We performed next-generation DNA sequencing targeting 986 immune-related genes. Somatic mutations were called by comparing the sequence data of each cell subpopulation to other subpopulations of the same patient and validated by amplicon sequencing. We found non-synonymous somatic mutations in 12 (60%) patients (10 MS, 1 myasthenia gravis, 1 narcolepsy). There were 27 mutations, all different and mostly novel (67%). They were discovered at subpopulation-wise allelic fractions of 0.2%-4.6% (median 0.95%). Multiple mutations were found in 8 patients. The mutations were enriched in CD8+ cells (85% of mutations). In follow-up after a median time of 2.3years, 96% of the mutations were still detectable. These results unravel a novel class of persistent somatic mutations, many of which were in genes that may play a role in autoimmunity (ATM, BTK, CD46, CD180, CLIP2, HMMR, IKFZF3, ITGB3, KIR3DL2, MAPK10, CD56/NCAM1, RBM6, RORA, RPA1 and STAT3). Whether some of this class of mutations plays a role in disease is currently unclear, but these results define an interesting hitherto unknown research target for future studies.

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Am I cured?

Barts-MS rose-tinted-odometer: ★★★★★ (seeing purple; a Sunday morning purple)

Could you imagine if we made the treatment target in MS a cure? This is a very contentious issue; however, based on the current dogma that MS is an autoimmune disease driven by rogue autoreactive cells we should have the ability to either purge these cells from the body or imprison them via tolerance mechanisms indefinitely. Do you agree? 

After being taken to task on using the C-word (see blog post 19-May-21) I am relieved that you readers condone the use of the word. This means we can now hopefully refine the definition of an MS cure, look to see if any pwMS treated with immune reconstitution therapies (IRTs) fulfil the definition of an MS cure. Please be aware that an MS cure doesn’t mean the restoration of lost neurological function; you can be cured of further autoimmune attacks on the nervous system, but the damage that is already done won’t necessarily be repaired as part of the cure. This is why we need to at least offer IRTs as early as possible in the course of the disease, which is why we need to have the option of using IRTs first-line. I hope this makes sense.

Forms response chart. Question title: Do you think it is appropriate to use the word CURE in the context of treating multiple sclerosis?. Number of responses: 170 responses.

Forms response chart. Question title: Do you think discussing an MS CURE is raising false hopes?. Number of responses: 170 responses.

Forms response chart. Question title: Do you think the term LONG-TERM REMISSION is a better term than CURE to describe the concept of MS going away and never coming back?. Number of responses: 170 responses.

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Survey Disclaimer: No personal identifiers will be collected as part of these surveys unless otherwise stated. By completing these surveys you are consenting to the data you provide being analysed by Professor Giovannoni and his collaborators. Results of these surveys will be presented on this blog and maybe submitted for publication.

Tickled pink

Barts-MS rose-tinted-odometer: ★★★ (seeing pink; tickled pink)

Thank you for completing yesterday’s poll. It is quite clear that you, our blog readers, want us to prioritise the following changes to the way we prescribe DMTs in the NHS. The most important priority is for pwMS to access immune reconstitution therapies (alemtuzumab, cladribine and HSCT) early as 1st-line therapies for active MS. Please note if you have rapidly evolving severe MS (RES) you can be treated with alemtuzumab and cladribine first-line, but outside of this very small group of patients, we can’t prescribe IRTs first-line. For more information on RES vs. active MS classification system and its implications for some pwMS, I would recommend you read ‘Watchful Waiting 2‘.

The next priority is access to natalizumab, a very high efficacy therapy, as 1st-line therapy for active MS. At the moment the only agent that covers this broad bracket is ocrelizumab. My reading into this is that if you don’t have RES but just active MS, you would like more choice and not simply have one high-efficacy option first-line. 

The third priority relates to treating advanced or progressive MS, i.e. getting rid of the stopping criteria when people with MS reach EDSS 7.0 (wheelchair) and liberalise the prescribing of ocrelizumab and siponimod for primary progressive and secondary progressive MS, respectively. My interpretation of the latter is that you want to challenge the active vs. inactive progressive MS dichotomy

Finally, treating asymptomatic MS and liberalising the use of platform therapies and fingolimod is not a priority. This worries me because as we move into an area of testing and exploring the induction-maintenance paradigm we need to be able to use platform therapies 2nd- and 3rd-line. I have made the point before that pwMS are not going to be able to remain on anti-CD20 therapies indefinitely because of the potential risks; for example, as your immunoglobulin levels drop and serious infections increase the benefit-risk balance changes. Therefore, we are going to need to test de-escalation approaches to derisk anti-CD20 and other chronic immunosuppressive treatments. This is the rationale of the iTeri study that I have proposed doing; i.e. induction with ocrelizumab or rituximab followed by maintenance with teriflunomide. 

I would be interested to know if you are surprised by the poll’s findings? 

I wonder if the Australian neurologists chuckle when they read this sort of blog post? They have no restrictions on how they treat MS and can use any DMT, including AHSCT, as they and their patients see fit. If only the NHS would allow us to practice in this way 🙁

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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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Curing MS

How close are we to offering some people with MS a cure?

I am speaking at the Imperial College Neuroscience Society this morning on ‘how close we are to curing MS’. I think we are very close; in fact some of the longterm follow-up data of IRT (immune reconstitution therapies), in particular, alemtuzumab, non-myeloablative HSCT and myeloablative HSCT looks very promising. I suspect that when we complete our long-term follow-up of cladribine -treated patients we will find a similar story.

If you want to have any chance of potentially curing yourself of MS you have to be treated early, as early as possible, with an IRT preferably with one of the big guns. The problem you will have is finding a neurologist who agrees with this treatment strategy.

Are IRTs ahead of their time?

I am beginning to think that immune reconstitution therapies or IRTs are ahead of their time. Many neurologists, people with MS (pwMS), payers – particularly fee-for-service insurance companies – and the regulators are unable to get their heads around how these agents work. In addition, a few recent review articles, written by colleagues, cast doubt on this treatment strategy and the terminology we use. 

IRTs are the only treatments that are addressing the cause of MS and hence have the potential to cure MS. We will know in the near future how many pwMS in very long-term remission post -alemtuzumab, -HSCT or -cladribine are truly MS free. This information is critical to convince a sceptical field of the value of these treatments.

The mortality associated with HSCT makes people shudder. Although the risk of dying from one of the complications of HSCT is quoted as being between one of 1 in 333 (0.3%) to 1 in 50 (2%) many pwMS are taking this risk in the UK or abroad. Despite HSCT being a viable treatment option for pwMS in England and now Scotland many UK MSologists don’t routinely put this option on the table when discussing switching treatments with their patients who are failing other high-efficacy therapies. Why?

Even going to the easy-to-use, easy-to-monitor, oral cladribine option we are seeing slow adoption. Why? I am now convinced HCPs don’t understand IRTs, in particular, the concepts of frontloading of risk and long-term remission.

The study below shows that patients failing alemtuzumab in year one after the first course of five infusions, do very well after receiving their second course. Despite these patients having more active disease and early breakthrough activity, they do very well longterm with high chances of being rendered NEDA and experiencing disability improvement and having brain volume loss that slows markedly – into the normal range – after year 2.

DMTs are about protecting the end-organ or brain and keeping it as healthy as possible so that pwMS can live a normal life as possible and have the necessary reserve to deal with ageing when it sets in.  Is this message difficulty to communicate? Knowing this brain volume data why wouldn’t we want to at least offer an IRT to all our patients with active disease and I mean first, second or third line? It is clear the sooner you are treated with an IRT the better you do. 

I am now planning to do a series of online lectures on IRTs to explain why they should be so appealing as a treatment strategy for pwMS. Would you be interested in watching? 

I also have a vested interest in getting IRTs adopted. We want to use them as induction agents in more advanced MS to be followed by maintenance therapies that target the processes within the brain and spinal cord to address smouldering MS. 

Van Wijmeersch et al. Efficacy of alemtuzumab over 6 years in relapsing-remitting multiple sclerosis patients who relapsed between courses 1 and 2: Post hoc analysis of the CARE-MS studies. Mult Scler. 2019 Nov 1:1352458519881759

BACKGROUND: Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen.

OBJECTIVE: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers).

METHODS: Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension.

RESULTS: Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%).

CONCLUSION: Early relapsers’ outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit.

CLINICALTRIALS.GOV REGISTRATION NUMBERS: CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553.

CoI: multiple

Yellow Fever Vaccine Alert

In the past, I have made the claim that vaccinations, including vaccination with live attenuated viruses such as yellow fever, are relatively safe post-IRTs (immune reconstitution therapies) such as alemtuzumab, cladribine and HSCT.

I even have two Alemtuzumabers on my books who have both had yellow fever vaccines before travelling to Ecuador and the Galapagos Islands. who I frequently mention in talks who had no problems with the vaccine. I will have to retract that advice. HCPs have just been sent the following warning from the MHRA (Medicines and Healthcare products Regulatory Agency).

Yellow fever vaccine (Stamaril) and fatal adverse reactions: extreme caution needed in people who may be immunosuppressed and those 60 years and older

“We have recently received 2 reports of fatal adverse reactions to the yellow fever vaccine (Stamaril). Due to an increased risk of life-threatening reactions, the vaccine must not be given to anyone with a medical history of thymus dysfunction or who is immunosuppressed. In addition, extreme caution must be used and a careful risk assessment conducted before vaccination of people aged 60 years and older due to a substantially increased risk of such adverse reactions in this age group.”

This is particularly relevant to Alemtuzumabers in that there is recent data that has been presented that it damages the thymus. If you are HCP who works with MSers please read the advice on the MHRA’s website.