Author: Gavin Giovannoni

#ThinkHand – taking telerehabilitation one step further

What does 2019 hold for the various Barts-MS campaigns? 



We are continuing to make the case for our #ThinkHand campaign with several outputs in 2018, which are being used to support our work in this area. I am very proud that ORATORIO-HAND, a phase-3b study of ocrelizumab in PPMS, which will include patients with an EDSS of up to 8.0 and will start recruiting in the first quarter of 2019. The primary outcome in ORATORIO-HAND is the 9-HPT; this in itself is a first and a major milestone for the field of MS. 


In parallel, DrK has been working very hard to get his NIHR funded trial off the ground called CHARIOT-MS. DrK’s perseverance has gotten the study through round 1 of peer-review and we are now waiting to hear whether or not the study will get funded. CHARIOT-MS is a study of oral cladribine in advanced MS will target both SPMS and PPMS up to an EDSS of 8.5 and again the primary outcome will be the 9HPT. 


These two studies are remarkable for several reasons. Firstly, these trials are challenging the dogma that MS is not modifiable beyond EDSS 7.0, secondly, it is shifting the focus away from the lower limbs and EDSS to a new primary outcome the 9-HPT and, finally, it is giving people with advanced MS hope in valuing their hand function and independence. 

As part of our #ThinkHand campaign Alison Thomson, our research designer, in collaboration with the Agency of Design, helped design an upper limb rehabilitation tool called under&over, which we launched at ECTRIMS-2018 in Berlin. We have now been successful in obtaining a grant to test whether or not under&over will work as a rehab tool and are planning a remote web-based study to test it. Again our primary outcome will be stabilisation, or improvement, in the performance of the 9HPT only this time we will be using our cardboard 9HPT. 


Interestingly the telerehabilitation study below showed that remote rehab can work. I see no reason why a web-based rehab programme won’t work either. We will obviously keep you posted on this study, we may even be given permission from the ethics committee to recruit via our blog. 


Would you be interested in helping us design the study and/or participating?



Fjeldstad-Pardo et al. Telerehabilitation in Multiple Sclerosis: Results of a Randomized Feasibility and Efficacy Pilot Study. Int J Telerehabil. 2018 Dec 11;10(2):55-64.


A prospective, randomized, three-arm, evaluator blinded study to demonstrate the feasibility of a telerehabilitation (TR) program in individuals with ambulatory deficits secondary to Multiple Sclerosis (MS) and evaluate its efficacy when compared to conventional on-site physical therapy (PT) was completed. Thirty participants were evaluated at baseline and randomized to one of three groups with intervention lasting 8 weeks: Group 1 (control)- customized unsupervised home-based exercise program (HEP) 5 days a week; Group 2 (TR)- remote PT supervised via audio/visual real-time telecommunication twice weekly; Group 3 (PT)- in-person PT at the medical facility twice weekly. Outcomes included patient reported outcomes (PROs) obtained through questionnaires, and measurements of gait and balance performed with bedside tests and a computerized system. Functional gait assessment improved from baseline in all three groups. There were no significant differences between the TR and the conventional PT groups for a variety of outcome measures. TR is a feasible method to perform PT in persons with MS and has comparable efficacy to conventional in-person PT as measured by patient reported outcomes and objective outcomes of gait and balance.


CoI: The design, development and manufacture of the under&over rehab tool and the follow-on web-based rehab study has been kindly funded by unrestricted grants from F. Hoffmann-La Roche AG.

A new old technology

There is nothing more exciting than a new, but old, technology!

 

A problem we face when making the case for a list of essential medications to treat MS in resource-poor settings is the issue of MS misdiagnosis and the inability to monitor MS disease activity using MRI in these settings. MRI is an expensive innovation and a large number of countries simply don’t have enough MR scanners to go around. How can the small number of pwMS in these countries hijack the scanners for monitoring, when they are needed for diagnostic imaging? In addition, MRI is expensive and often has to be paid for privately. I remember in the early days of MRI this being the case in South Africa; i.e. all the scanners were in the private sector and we had to make a request on a case-by-case basis to get state-funded patients scanned. 

 
With this backdrop, I find the study below very illuminating. They simply analysed CT scans using histogram analysis, which was able to identify pwMS from appropriate controls. Why is this important? CT scanning is widely available, even in resource-poor settings, so being able to use CT to aid in the diagnosis of MS would address at least one of the concerns of our MS Essential Medicines List critics. The question would be logistics, i.e. how easy would it be to implement this sort of analysis in these environments? Maybe it could be done in the cloud using AI tools? Most medical centres, even in resource-poor countries, are now web-enabled. They could simply upload the data and get back a report on the likelihood of the patient having MS. 
 
Please note the reason for doing neuroimaging in the work-up for someone with possible MS is to exclude possible MS mimics. A CT scan goes a long way in doing just this. If you then get back a histogram analysis that makes MS likely, combining this with CSF analysis and other tests you may be able to get the necessary sensitivity and specificity for the diagnosis of MS in these settings. In fact, the ROC (receiver operating curve) analysis in this paper suggests the sensitivity and specificity of the histogram analysis technique are high enough to make this a viable option. 
 
All we need now is an MSologist or neurologist working in a resource-poor setting to take-up the challenge and to test whether or not CT-scanning can be used instead of MRI to make the diagnose of MS. This could transform the diagnostic work-up of people with possible MS in these environments.
 
There is nothing more exciting than a new, but old, technology; i.e. adapting an old technology to address an unmet need in the now. 
 
From: Cauley and Fielden. Tomography 2018 Dec;4(4):194-203.
Cauley and Fielden. A Radiodensity Histogram Study of the Brain in Multiple Sclerosis. Tomography 2018 Dec;4(4):194-203.

Multiple sclerosis (MS) is a progressive neurodegenerative disease, affecting 1 million Americans and 2.5 million people globally. Although the diagnosis is made clinically, imaging plays a major role in diagnosing and monitoring disease progression and treatment response. Magnetic resonance imaging (MRI) has proven sensitive in imaging MS lesions, but the characterization offered by routine clinical MRI remains qualitative and with discrepancies between imaging and clinical findings. We investigated the ability of digital analysis of non-contrast head computed tomography (CT) images to detect global brain changes of MS. All routine diagnostic head CTs obtained on patients with known MS obtained from 1 of 2 scan platforms from 6/1/2011 to 6/1/2015 were reviewed. Head CT images from 54 patients with MS met inclusion criteria. Head CT images were processed and histogram metrics were compared to age- and gender-matchedcontrol subjects from the same CT scanners during the same time interval. Histogram metrics were correlated with plaque burden as seen on MRI studies. Compared with control subjects, patients had increased total brain radiodensity (P < .0001), further characterized as an increased histogram modal radiodensity (P < .0001) with decrease in histogram skewness (P < .0001). Radiodensity decreased with increasing plaque burden. Similar findings were seen in the patients with only mild plaque burden subgroup. Radiodensity is a unique tissue metric that is not measured by other imaging techniques. Our study finds that brain radiodensity histogram metrics highly correlate with MS, even in cases with minimal plaque burden.

 
CoI: none

All I want for Christmas is a cure

How do we know if someone is cured of having MS?



This is a very difficult question that I keep getting asked.


How will we know if we have cured MS?

 Based on what I have said in my recent post ‘Explaining why you get worse despite being NEDA‘ you may be cured of our MS, but still, have progressive disease. The difference between progressive disease, which is due to previous MS damage and that which is due to premature 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, premature ageing is unlikely to stop. In comparison defining a cure in people who are young, with reserve capacity, who have been treated earlier would be a much easier task. 


 I hope you understand that this definition of a cure is incompatible with the terms ‘repair’ and ‘regeneration’. The latter are separate processes that are independent of a so-called biological cure. We clearly need repair and regeneration agents to treat pwMS who have accumulated a significant amount of damage to their nervous systems. In comparison, in pwMS who have been cured of their MS and have not had any significant damage will not need to undergo treatments to repair and/or regenerate their nervous systems.

 Based on our current understanding 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.

 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 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 should be accepted by the wider community; this may be wishful thinking many in the field are saying that we can’t cure MS, therefore, we should not be having this discussion.

 In addition, 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 timeframe. If we had got the autoimmune hypothesis wrong and the IRTs don’t work then I would estimate at least a third should have SPMS at 15 years if our hypothesis is wrong. The problem with 15 years is that it is a long to 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 will change their minds and get them to at least offer IRTs to more of their patients.

 Deep phenotyping: 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 have highly 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 be done quite early on 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? 

So yes, ‘if all you want for Christmas is an MS cure’ it may be staring you in the face.  


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.




 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.

CoI: multiple

More women develop MS than men, why?

Yes, I agree the cause of MS has to explain the changing sex ratio of the disease. 




To prove that MS is caused by a single factor or the interaction of several factors, it has to explain everything we know about the epidemiology of the disease. In terms of EBV being the cause of MS, how does EBV explain why RRMS is becoming more common in women? In comparison, the incidence of PPMS seems to remain constant with an equal number of men and women affected.

One observation that has been noticed across several populations, but not all, is the increasing incidence of MS in women. Why is this occurring? Some of it may be due to the change in smoking prevalence amongst women, which has been increasing relative to males. An outlier here is Iran, which has a sex ratio of F:M of close to 5:1 and is one of the countries where less than 10% of women smoke. I am not convinced that smoking explains the changing sex ratio of MS incidence. 


Some blame cultural factors, for example, the addition of UV blockers in cosmetics over the last 20+ years and other cultural changes causing women to shun sun exposure. 


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

Please note the change is sex ratio is not universal; for example, it has not been noted in Sweden. What the changing sex ratio, or lack of change in some regions, is telling us that it must be driven by environmental factors and hence reversible. What we do know is the changing sex ratio is a proxy for a rising incidence and prevalence of MS. The changing sex ratio is also telling us that MS is preventable, which is why we at Bart-MS are working actively on trying to put in place a platform to do MS prevention studies. #PreventMS is one of our 2019 research priorities. 

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

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

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

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

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




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

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

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

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

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



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

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



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

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

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

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

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

Trojano et al. Geographical Variations in Sex Ratio Trends over Time in Multiple Sclerosis. PLoS One. 2012;7(10):e48078. doi: 10.1371/journal.pone.0048078. Epub 2012 Oct 25

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

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

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

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

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

CoI: multiple

Will 2019 be the year of sequential therapies?

We need to rethink how we want to tackle MS in 2019. Do we need a true induction approach; i.e. sequential therapies? Or will a simple combination therapy approach suffice?



In 2018 I continued to ask the MS community to ditch the term induction therapy (see ECTRIMS2018 slideshow, and Current Opinion review, below). The term ‘induction’ is not a very useful term when describing the mode of action of alemtuzumab, cladribine and HSCT, because it comes with baggage from other disease areas and is often misrepresented.

A lot of people in the field equate the term ‘induction’ with the use of high-efficacy treatment early on in the course of the disease. For example, many Italian neurologists refer to the use of natalizumab as first-line therapy as an induction strategy. Similarly, the use of mitoxantrone before interferon-beta or glatiramer acetate is referred to as an induction strategy in France (see below). The latter is correct, because induction usually means sequential therapies, with two or three phases of treatment. Induction, followed by a consolidation treatment and finally a maintenance therapy.

I have stopped using the term ‘induction’ outside of the context of mitoxantrone followed by maintenance treatment. I now use the term ‘immune-reconstitution therapy’ or ‘IRT’ to describe short intermittent courses of treatment. This is relevant to alemtuzumab, cladribine, monotherapy mitoxantrone and HSCT.

IRTs have many advantages over maintenance therapies, which I have highlighted in the past and cover in detail in my Current Opinion review. The main advantage is that IRTs (1) tend to be on average highly-effective treatments, (2) they only remain in the body for a short period of time, which is a very useful attribute if you are a woman who is thinking about falling pregnant, (3) they induce long-term remission in some patients, which may turn out to be a cure in the future and (4) they frontload risk. Most of the adverse events associated with IRTs occur early in the treatment hence the term frontloading. In comparison with maintenance therapies, the risks accumulate over time. The latter point is not a trivial point; with immunosuppressive drugs, the risks of opportunistic infections and treatment-related malignancies increases with time.

ECTRIMS-2018



However, I predict that based on recent insights we will need to use more sequential and combination therapy strategies to treat MS. We are already doing this without our realising it. I reviewed this in two sequential presentations at this year’s ABN in Birmingham.

ABN 2018



However, we are going to need a more systematic approach if we are going to get sequential and combination therapies right. For example, we need more anti-inflammatory in combination with neuroprotection trials. The latter is happening, but too many neuroprotection trials are still going ahead as monotherapy trials.

Another strategy is antivirals in combination with anti-inflammatories. The latter sound left-field, but we need to do these studies to address the EBV-HERV hypothesis. Something we have been pushing is anti-plasma cell agents on top of anti-inflammatories to scrub the CNS clean of OCBs that may be driving progressive MS. We will hopefully start our first trial in this space this year.

The question we have to ask is how ready is the MS community for adopting induction/sequential and combination therapy strategies to manage MS? Based on recent discussions they are not ready enough.

#ThinkCombination #ThinkSequential

CURRENT OPINION REVIEW


Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol. 2018 Jun;31(3):233-243.

PURPOSE OF REVIEW: The treatment of multiple sclerosis is evolving rapidly with 11 classes of disease-modifying therapies (DMTs). This article provides an overview of a new classification system for DMTs and treatment paradigm for using these DMTs effectively and safely.

RECENT FINDINGS: A summary of research into the use of more active approaches to early and effective treatment of multiple sclerosis with defined treatment targets of no evident disease activity (NEDA). New insights are discussed that is allowing the field to begin to tackle more advanced multiple sclerosis, including people with multiple sclerosis using wheelchairs. However, the need to modify expectations of what can be achieved in more advanced multiple sclerosis are discussed; in particular, the focus on neuronal systems with reserve capacity, for example, upper limb, bulbar and visual function.

SUMMARY: The review describes a new more active way of managing multiple sclerosis and concludes with a call to action in solving the problem of slow adoption of innovations and the global problem of untreated, or undertreated, multiple sclerosis.

A TRUE INDUCTION THERAPY APPROACH

Edan et al. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: a 3-year randomised trial. J Neurol Neurosurg Psychiatry. 2011 Dec;82(12):1344-50.

OBJECTIVES: The long-term impact of interferon-beta-1b (IFN) might be improved by short-term immunosuppression with mitoxantrone (MITOX) in aggressive relapsing-remitting multiple sclerosis (ARMS) patients.

METHODS: In this 3-year clinical and MRI study, 109 ARMS patients (two or more relapses in the previous 12 months and one or more gadolinium (Gd)-enhancing MRI lesion) were randomised into two groups: 54 patients received MITOX monthly (12 mg/m(2); maximum 20 mg) combined with 1 g of methylprednisolone (MP) for 6 months followed by IFN for the last 27 months, and 55 patients received IFN for 3 years combined with 1 g of MP monthly for the first 6 months. The primary endpoint was the time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months.

RESULTS: The time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months was delayed by 18 months in the MITOX group compared with the IFN group (p<0.012). The 3-year risk of worsening disability was reduced by 65% in the MITOX group relative to the IFN group (11.8% vs 33.6%). MITOX patients had a reduced relapse rate by 61.7%, a reduced number of Gd-enhancing lesions at month 9 and a slower accumulation of new T2 lesions at each time point.

CONCLUSIONS: Although there were limitations in this investigator-academic-driven study, the data do suggest that mitoxantrone induction therapy prior to INF beta-1b may have a role in aggressive disease.


Ramtahal et al. Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis. J Neurol. 2006 Sep;253(9):1160-4. Epub 2006 Sep 21.

Background: Mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity.

Objectives and methods: We report our experience utilising Glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with Mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment.

Results: Duration of treatment with Mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased.No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of Mitoxantrone.A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with Mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone, occurring in the two patients who had previously been treated with Glatiramer Acetate. In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of Mitoxantrone, no enhancing lesions were identified on MRI brain scans.

Conclusions: Glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with Mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.



CoI: multiple

What have poppies and fields got to do with the cause of MS?

It took a while for me to truly understand why the poppy is so important to people living in the UK. The poppy is a symbol of remembrance, i.e. to observe and never forget. 



 Why are fields and poppies relevant to MS? 

The study below supports anecdotal clinical evidence of many of my clinical mentors and, now as I have gotten older, my own clinical experience; if you have an MS relapse, or attack, in one particular area of the brain or spinal cord you are more likely to have subsequent attacks in this area. I refer to this as the so-called field effect, i.e. something locally in a specific anatomical area triggers recurrent attacks in the same site. 

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


Another hypothesis, which I favour, is that there is something in the field that triggers relapses. Possibly a virus, like an isolated seed or flower in a field of wheat? Why do I say this? Firstly, when MSers were treated with interferon-gamma, a cytokine that stimulates immune responses, they all had relapses. The interesting thing about these interferon-gamma-induced relapses is that they occurred in sites previously affected by MS. When I discussed this observation with the late Hillel Panitch, who was the principal investigator on the gamma-interferon trial, he thought that this observation was a fundamental observation and was telling us something important about MS. 

Another observation that supports the abnormal field hypothesis is the rebound post-natalizumab. This suggests that whilst you keep T and B cells out of the nervous system with natalizumab the field (brain and spinal cord) becomes more abnormal and when you let these cells back in they detect the abnormal field and run amok trying to clear the field of the offending agent. This is what happens with IRIS (immune reconstitution inflammatory syndrome) and PML. When natalizumab is washed out the immune system finds the JC virus and tries to clear it by initiating an inflammatory process. Some of us think that rebound post natalizumab is simply IRIS in response to the virus that causes MS.

 Another observation comes from serial MRI studies that have shown subtle changes in the white matter many weeks or months before a gadolinium-enhancing lesion appears. This suggests that the primary pathology is something in the nervous system that takes weeks or months to trigger a focal inflammatory lesion. The challenge for us all is to find out what this field abnormality is. I think the best chance we have of doing this is to study the brains of pwMS on natalizumab. To do this we will need someone with MS to die whilst on natalizumab treatment and to donate their brain to a unit with the necessary techniques to look for viruses. I think this will work because the viral load is likely to be higher in the absence of inflammation. This is why it is so important for pwMS to donate their brains for medical research.

If you are interested in more musing about the field hypothesis please read a previous post on the subject.



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

BACKGROUND AND PURPOSE: MS is a chronic inflammatory disorder of the central nervous system characterized by acute episodes of neurological dysfunction thought to reflect focal areas of demyelination occurring in clinically eloquent areas. These symptomatic relapses are generally considered to be random clinical events occurring without discernible pattern. The hypothesis that relapses may follow a predetermined sequence and may provide insights into underlying pathological processes was investigated.

METHODS: Employing prospective clinical database data from 1482 MSers who had experienced one or more consecutive relapses were analysed. Using regression analysis, site and symptom of index event were compared with those of first relapse.

RESULTS: It is demonstrated that following disease ignition subsequent relapses may not be random events but dependent on characteristics of the index event. All anatomical sites were more likely to be affected in the first relapse if that site had been involved in the index event with a similar association observed when comparing by symptoms.

CONCLUSION: These findings have importance in understanding the evolution of the disease and predicting individual disease progression and may aid with patient counselling and management.

Merry Christmas

Christmas is a time for reflection and to spend it with friends and family. 
 
 
#ThinkSocial
 
I went for a long run yesterday that allowed me to reflect on a good year for Barts-MS and for people living with multiple sclerosis (pwMS). We are making unprecedented advances in the treatment of MS. PwMS are being diagnosed earlier, treated earlier and are less disabled than before. We are seeing a drop off in the number of pwMS entering the so-called secondary progressive stage of the disease, i.e. less walking sticks and fewer wheelchairs.
 
Despite these incredible advances, there are a lot of people who have missed the boat and have had their lives turned upside down by MS. We know MS is a very stigmatizing disease and leads to social isolation and loneliness. A  recent study showed that 3 out of 5 pwMS described themselves as being lonely. If you know someone with MS, please pick-up the phone and call them and have a chat. Visit them and/or make arrangements to take them for a walk. Socialise and make them feel loved and wanted. Christmas is a time for sharing and being together. 
 
Twenty-nineteen is going to be the year of thinking social (#ThinkSocial). We are launching several initiatives and research projects exploring how we can ‘maximise’ and ‘expand’ the social capital of pwMS. I am convinced that pwMS who have large social networks do better than pwMS who don’t. 
 
Twas the night
Before Christmas
When all through the house
Not a creature was stirring
Not even a mouse
 
The stockings all hung
By the chimney with care
In hopes
That St. Nicholas
Soon would be there
 
The children were nestled
All safe in their beds
While visions of sugarplums
Danced in their heads
 
And mom in her kerchief
And I in my cap,
Had just settled down
For a long winter’s nap
 
When out on the lawn
There arose such a clatter
I sprang from my bed
To see what was the matter
 
Away to the window
I flew like a flash
Tore open the shutters
And threw up the sash
 
The moon on the breast
Of the new fallen snow
Gave the lustre
Of midday
To object below
 
When what
To my wandering eyes
Should appear
But a miniature sleigh
And eight tiny reindeer
 
With a little ol driver
So lively and quick
I knew in a moment
It must be St. Nick
 
More rapid than eagles
His courses they came
As he whistled
And shouted
And called
Them by name
 
Now dasher
Now dancer
Now prancer
Now vixen
On Comet
On Cupid
On Donder
An Blitzen
 
To the top
Of the porch
To the top
Of the wall
Now dash-away
Dash-away
Dash-away all
 
As dry leaves
Before the wild
Hurricane fly
When they meet
With an obstacle
Mount to the sky
 
So up
To the housetop
The courses
They flew
With a sleigh
Full of toys
And St. Nicholas too
 
And then
In a twinkling
I heard on the roof
The prancing
And pawing
Of each little hoof
 
As I drew in my head
And was turning around
Down the chimney
St. Nicholas
Came with a bound
 
He was dressed
All in fur
From his head
To his foot
And his clothes
Were all tarnished
With ashes and soot
 
A bundle of toys
He had flung
On his back
And he looked
Like a peddler
Just opening
His pack
 
His eyes
How they twinkle
His dimples how merry
His cheeks
Were like roses
His nose like a cherry
 
His drawl little mouth
Was drawn up like a bow
And the beard of his chin
Was a white as the snow
 
The stump of his pipe
He held tight
In his teeth
And the smoke it
Encircled his head
Like a wreath
 
He had a broad face
And a round little belly
That shook when he laughed
Like a bowl full of jelly
 
He was chubby and plump
A right jolly old elf
I laughed when I saw him
In spite of myself
 
A wink of his eye
And a twist of his head
Soon gave me to know
I had nothing to dread
 
He spoke not a word
But went straight
To his work
And filled
All the stockings
Then turned
With a jerk
 
An laying a finger
Along side his nose
An giving a nod
Up the chimney
He rose
 
He sprang
To his sleigh
To his team
Gave a whistle
An away
They all flew
Like the down
Of a thistle
 
But I heard him exclaim
As he drove out of sight
Happy Christmas to all
And to all a good night
 
Hmmm
 
Merry Christmas from Barts-MS!

Natalizumab is unable to stop the shredder

Is the treatment aim of ‘maximising the lifelong brain health of every person with MS’ realistic?


In this study below pwMS stable on natalizumab (one of our most effective DMTs) are still losing brain volume way and above what you would expect for age. Is this premature ageing or is this the slowly expanding chronically active lesion shredding the brain? 


We know that over many years brain volume loss, or brain atrophy, correlates with poor outcome; i.e. cognitive impairment and physical disability. What this study indicates that we clearly need something additional to an anti-inflammatory to treat MS and prevent end-organ damage. What it is telling me is that we are going to need additional add-on treatments to really make a difference for pwMS. What these add-on treatments turn out to be is speculative. At the moment we talk about add-on neuroprotective, remyelinating and neurorestorative therapies when what we may need are antivirals to suppress EBV and HERVs that are driving the slow burn and gradual loss of brain and spinal cord. 

It is clear that unless we normalise brain volume loss in pwMS they will not be able to age normally and nor will be able to ‘maximise‘ their brain health. 

One interpretation of this data is that the focal inflammatory lesion, and relapses, are not MS, but are simply the body’s response to what is really causing the disease. We need to ask the question what is MS and what is driving this accelerated brain volume loss in the absence of focal inflammation? 

Natalizumab continues to make me think about MS and continues to challenge the scientific dogma that MS is simply an organ-specific autoimmune disease. MS is clearly not an organ-specific autoimmune disease; it is a whole lot more complex than that. 


For more information please read my recent blog post ‘explaining why you get worse despite being NEDA‘. 


Koskimäki et al. Gray matter atrophy in multiple sclerosis despite clinical and lesion stability during natalizumab treatment. PLoS One. 2018 Dec 21;13(12):e0209326.

BACKGROUND: Brain volume loss is an important surrogate marker for assessing disability in MS; however, the contribution of gray and white matter to the whole brain volume loss needs further examination in the context of specific MS treatment.


OBJECTIVES:  To examine whole and segmented gray, white, thalamic, and corpus callosum volume loss in stable patients receiving natalizumab for 2-5 years.

METHODS: This was a retrospective study of 20 patients undergoing treatment with natalizumab for 24-68 months. Whole brain volume loss was determined with SIENA. Gray and white matter segmentation was done using FAST. Thalamic and corpus callosum volumes were determined using Freesurfer. T1 relaxation values of chronic hypointense lesions (black holes) were determined using a quantitative, in-house developed method to assess lesion evolution.

RESULTS: Over a mean of 36.6 months, median percent brain volume change (PBVC) was -2.0% (IQR 0.99-2.99). There was decline in gray (p = 0.001) but not white matter (p = 0.6), and thalamic (p = 0.01) but not corpus callosum volume (p = 0.09). Gray matter loss correlated with PBVC (Spearman’s r = 0.64, p = 0.003) but not white matter (Spearman’s r = 0.42, p = 0.07). Age significantly influenced whole brain volume loss (p = 0.010, multivariate regression), but disease duration and baseline T2 lesion volume did not. There was no change in T1 relaxation values of lesions or T2 lesion volume over time. All patients remained clinically stable.

CONCLUSIONS: These results demonstrate that brain volume loss in MS is primarily driven by gray matter changes and may be independent of clinically effective treatment.

CoI: multiple

Have we thrown the baby out with the bath water?

Who are two of the most original and deep thinkers in the field of MS?



Do you want to know about some of the ideas of Thing1 (MD1) and Thing2 (MD2)?


Two of the most original and deep thinkers in the field of MS are my scientific partner David Baker (aka as the MouseDoctor) and Gareth Pryce (aka MouseDoctor2), David’s research assistant. Together they pioneered the field of cannabinoid research in MS. They showed that the CB1 agonist THC, which happens to be the main psychoactive ingredient in cannabis, has both anti-spastic and neuroprotective effects in their animal model of progressive MS. Their work led to the CUPID study below, which unfortunately was negative. Does this mean THC is not neuroprotective in MS? 


No!! Definitely not!

When you look at the design of the CUPID study wearing rose-coloured spectacles and a new worldview shaped by recent insights, which have surfaced in the last 4-5 years, we think the CUPID study was designed to be negative. Why? 
  1. CUPID enrolled too many pwMS who were EDSS 6.0 or 6.5 (78%), i.e. 78% of the trial population had lost too much lower limb function for the EDSS to report out in a reasonable point of time. When you have lost so much lower limb function it is difficult to show a treatment effect, in other words, the therapeutic window had shut. One way around this would have been to look at upper limb function, but this was not included in the CUPID study.
  2. Using the EDSS as the primary outcome; pwMS spend too much time at EDSS 6.0 and 6.5 and hence were less likely to worsen enough during the trial to be informative. This is called the ceiling effect and is a well-described problem with the EDSS.
  3. The study was a fixed-duration study and not an event-driven trial. The two positive trials in progressive MS (ocrelizumab in PPMS (ORATORIO) and siponimod in SPMS (EXPAND)) were both event-driven. In other words, these trials continued until enough progression events happened to give us an answer (please note I am on the steering committee of both these studies and hence I am conflicted).
  4. The CUPID study was a monotherapy trial. We know that THC is not an anti-inflammatory DMT. It should have been combined with an anti-inflammatory. This seems so obvious to us. We have been discussing combination-therapy trials for so long within Barts-MS that we assume the whole field agrees with us. This is not the case. MS-SMART and STAT2 trials were monotherapy neuroprotection trials. At least the ongoing high-dose biotin and opicinumab trials are being done as combination therapy trials. At least Pharma is listening. 
I am not sure if you are aware that in a post-hoc (after the event) analysis of the CUPID trial limiting the analysis to the population with a baseline EDSS < 6.0, THC was shown to significantly delay disease progression on the EDSS. In other words, THC was neuroprotective in this population. We now know that the reason for THC working in this population is based on the length-dependent axonopathy hypothesis. These study subjects had some reserve in their neuronal pathway subserving the legs and hence would report out earlier on the EDDS than the more advanced patients. CUPID would have been positive it had studied a less disabled population.

The great tragedy is that we have thrown out the baby with the bathwater. We think THC is neuroprotective in MS, but because of the trial design, the MS community now thinks it is not. What can we do about it? I propose we do a CUPID-2 study. Only this time it needs to be (1) event-driven, (2) focus on patients with reserve capacity, either EDSS < 6.0 or to use the 9-HPT as the primary outcome and (3) make it a combination therapy trial. 


Do you think the MS community has the appetite to do this? We owe it to people with more advanced MS and we owe it MD1 & MD2; they did all this ground-breaking research on THC and CB1-agonists as potential neuroprotective therapies in MS only to have their lives work destroyed by poor trial design. 




Zajicek et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol. 2013 Sep;12(9):857-865.


BACKGROUND: Laboratory evidence has shown that cannabinoids might have a neuroprotective action. We investigated whether oral dronabinol (Δ(9)-tetrahydrocannabinol) might slow the course of progressive multiple sclerosis.



METHODS: In this multicentre, parallel, randomised, double-blind, placebo-controlled study, we recruited patients aged 18-65 years with primary or secondary progressive multiple sclerosis from 27 UK neurology or rehabilitation departments. Patients were randomly assigned (2:1) to receive dronabinol or placebo for 36 months; randomisation was by stochastic minimisation, using a computer-generated randomisation sequence, balanced according to expanded disability status scale (EDSS) score, centre, and disease type. Maximum dose was 28 mg per day, titrated against bodyweight and adverse effects. Primary outcomes were EDSS score progression (masked assessor, time to progression of ≥1 point from a baseline score of 4·0-5·0 or ≥0·5 points from a baseline score of ≥5·5, confirmed after 6 months) and change from baseline in the physical impact subscale of the 29-item multiple sclerosis impact scale (MSIS-29-PHYS). All patients who received at least one dose of study drug were included in the intention-to-treat analyses. This trial is registered as an International Standard Randomised Controlled Trial (ISRCTN 62942668).


FINDINGS: Of the 498 patients randomly assigned to a treatment group, 329 received at least one dose of dronabinol and 164 received at least one dose of placebo (five did not receive the allocated intervention). 145 patients in the dronabinol group had EDSS score progression (0·24 first progression events per patient-year; crude rate) compared with 73 in the placebo group (0·23 first progression events per patient-year; crude rate); HR for prespecified primary analysis was 0·92 (95% CI 0·68-1·23; p=0·57). Mean yearly change in MSIS-29-PHYS score was 0·62 points (SD 3·29) in the dronabinol group versus 1·03 points (3·74) in the placebo group. Primary analysis with a multilevel model gave an estimated between-group difference (dronabinol-placebo) of -0·9 points (95% CI -2·0 to 0·2). We noted no serious safety concerns (114 [35%] patients in the dronabinol group had at least one serious adverse event, compared with 46 [28%] in the placebo group).


INTERPRETATION: Our results show that dronabinol has no overall effect on the progression of multiple sclerosis in the progressive phase. The findings have implications for the design of future studies of progressive multiple sclerosis, because lower than expected progression rates might have affected our ability to detect clinical change.


FUNDING: UK Medical Research Council, National Institute for Health Research Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society, and Multiple Sclerosis Trust.


CoI: multiple