My trip to Lucerne and the Charcot Project

A few weeks ago I was invited to give a lecture at the annual Swiss MS Society meeting on 'The Charcot Project' and the rationale behind using anti-viral drugs to treat MS.

As promised my slides from the meeting; they should be self-explanatory:

The Charcot Project is an initiative that Professor Gold and I launched about 5 years ago to tackle MS from a different perspective; a perspective that MS is caused by a virus and to tackle MS we need to start doing treatment trials using anti-virals. The two leading viral contenders are EBV and HERVs.  If you have any queries about the slides please feel free to ask. 

In this presentation, I stress the point that I have made several times before that MRI activity (new Gd-enhancing lesions) and relapses are not MS, the disease. If they were the disease they would predict MS outcomes whether or not you are on a DMT. The data indicates they only predict outcomes when you are on a DMT. Based on Prentice criteria of what constitutes a surrogate end-point for a disease both relapses and MRI activity fail. 

I then review the observation that changes occur weeks to months in the white matter before a new focal lesion occurs. This would indicate something is happening in the brain of pwMS prior to inflammation ('Field Hypothesis'). This may explain the Prineas lesion, i.e. oligodendrocyte apoptosis without overt inflammation. The million dollar question is what is killing the oligodendrocyte? 

I then review the epidemiology evidence supporting EBV and possibly HERVs as the viral aetiology of MS. I complete the lecture with some experiments that need to be done to prove that EBV is the cause of MS. Simple? I wish! Trying to get funding for studying the viral cause of MS is very difficult and slow, but we will get there, eventually. 

ProfG    

How easy is it to design an algorithm to sequence DMTs?

Last week DrK and I joined an esteemed panel of academic neurologists (all male, unfortunately*) to discuss issues around the sequencing of DMTs.

*We need more women on platforms such this and other MS-related committees. The gender divide is very large in the field of MS. It is very embarrassing to me as a father and husband; my daughters and my wife are card-carrying feminists and every bit as capable as their male peers.  

The following is my presentation that many of you requested. You can download it from SlideShare.

Sequencing of DMTs is a very hot topic and increasingly relevant to how we select DMTs today. What factors do we need to consider when choosing DMTs to make sure it is safe to transition patients onto in the future? 

When making a choice of DMT have you asked your neurologist what drug x does do your future DMT choices? This is something that is becoming increasingly important when selecting DMTs. 

Please stop to think and to ask questions. 

Getting it right the first time is more important than you realise. 

Sequencing workshop treatment algorithm from Gavin Giovannoni

ProfG    

Comorbidties and smoking, what can we do about them?

The elephant in the room is comorbidities such as hypertension, diabetes, obesity, metabolic syndrome and smoking. How can we get pwMS to take their general health seriously? 

In the study below physical comorbidity was not only associated with disability but with each additional comorbidity, there was a mean increase in the EDSS score of 0.18. By optimising your general health you will reduce your chances of getting worse. 

When last have you been to your family doctor, or GP, to have your blood pressure, weight, blood sugar and lipids checked? If you haven't had these done in the last 12 months you should go and get them done. 

Are you still a smoker? If yes, you need to read the second paper below that shows smoking reduces the effectiveness of interferon-beta. I wouldn't be surprised if this observation extends to other DMTs. We know that pwMS who smoke do worse than non-smokers. So if you want to improve your outcome you need to stop smoking. Please note you don't have to necessarily give up your nicotine habit. You can get your daily fix of nicotine from several other safer options (gum, skin patches, tablets, e-cigarettes, etc.). 

COMORBIDITIES

Zhang et al. Effects of physical comorbidities on disability progression in multiple sclerosis. Neurology. 2018 Jan 3. pii: 10.1212/WNL.0000000000004885.

OBJECTIVE: To examine the association between physical comorbidities and disability progression in multiple sclerosis (MS).

METHODS: We conducted a retrospective cohort study using linked health administrative and clinical databases in 2 Canadian provinces. Participants included adults with incident MS between 1990 and 2010 who entered the cohort at their MS symptom onset date. Comorbidity status was identified with validated algorithms for health administrative data and was measured during the 1 year before study entry and throughout the study period. The outcome was the Expanded Disability Status Scale (EDSS) score as recorded at each clinic visit. We used generalized estimating equations to examine the association between physical comorbidities and EDSS scores over time, adjusting for sex, age, cohort entry year, use of disease-modifying drugs, disease course, and socioeconomic status. Meta-analyses were used to estimate overall effects across the 2 provinces.

RESULTS: We identified 3,166 individuals with incident MS. Physical comorbidity was associated with disability; with each additional comorbidity, there was a mean increase in the EDSS score of 0.18 (95% confidence interval [CI] 0.09-0.28). Among specific comorbidities, the presence of ischemic heart disease (IHD) or epilepsy was associated with higher EDSS scores (IHD 0.31, 95% CI 0.01-0.61; epilepsy 0.68, 95% CI 0.11-1.26).

CONCLUSIONS: Physical comorbidities are associated with an apparent increase in MS disability progression. Appropriate management of comorbidities needs to be determined to optimize outcomes.

SMOKING

Petersen et al. Smoking affects the interferon beta treatment response in multiple sclerosis. Neurology. 2018 Jan 17. pii: 10.1212/WNL.0000000000004949.

OBJECTIVE: To investigate whether smoking in patients with relapsing-remitting multiple sclerosis (RRMS) treated with interferon beta (IFN-β) is associated with the relapse rate and whether there is an interaction between smoking and human leukocyte antigen (HLA)-DRB1*15:01, HLA-A*02:01, and the N-acetyltransferase-1 (NAT1) variant rs7388368A.

METHODS: DNA from 834 IFN-β-treated patients with RRMS from the Danish Multiple Sclerosis Biobank was extracted for genotyping. Information about relapses from 2 years before the start of treatment to either the end of treatment or the last follow-up visit was obtained from the Danish Multiple Sclerosis Treatment Register. Smoking information came from a comprehensive questionnaire.

RESULTS: We found that the relapse rate in patients with RRMS during IFN-β treatment was higher in smokers compared to nonsmokers, with an incidence rate ratio (IRR) of 1.20 (95% confidence interval [CI] 1.021-1.416, p = 0.027) and with an IRR increase of 27% per pack of cigarettes per day (IRR 1.27, 95% CI 1.056-1.537, p = 0.012). We found no association or interaction with HLA and the NAT1 variant.

CONCLUSION: In this observational cohort study, we found that smoking is associated with increased relapse activity in patients with RRMS treated with IFN-β, but we found no association or interaction with HLA or the NAT1 variant.

ProfG    

What is causing the MS pandemic?

Is it not the time to do something about the obesity pandemic? What has obesity got to do with MS? 

The latest data from Canada indicates that the prevalence and incidence of MS continues to increase; this is a trend across the world. Importantly, Canada may have just surpassed Scotland as the highest prevalence region of the world. Why is this happening? Why has MS become a pandemic? Is there anything we can do about this?

MS and other autoimmune diseases were very uncommon 150+ years ago. Our genetics haven't changed and therefore there must be an environmental factor driving the increased incidence. Could it be the macroenvironment (climate, latitude, etc.) or the microenvironment (diet, smoking, exercise, etc.)? Many of the migration and genetic studies, particularly from Canada, would argue against the microenvironment being responsible. However, I am not so sure. 

Well known non-genetic risk factors for developing MS are EBV infection, particularly late infection, low vD levels or sunlight exposure and smoking. More recent factors that have emerged are child obesity and organic solvent exposure. 

I am particularly interested in obesity, which seems to be a real risk factor as it is supported by two Mendelian randomization studies. These show that those who are genetically predisposed to being obese have a  higher risk of getting MS. What is it about obesity that raises your risk of getting MS? Is it because adipose tissue is pro-inflammatory and stimulates autoimmunity secondarily? Could adipose tissue soak up circulating vD as it is a fat-soluble vitamin and lower vD levels? Or could obesity be the smoking gun and represent something in our diets that have triggered the epidemic? These are only a few of the hypotheses floating about amongst academic who think MS is a preventable disease. 

As always these observations are associations and not causal. To prove obesity is in the causal pathway will be a gargantuan task. But linking obesity to an increasing incidence of MS and other autoimmune diseases may help public health officials and politician do something about the obesity pandemic that threatens the planet. 

Multiple sclerosis: Prevalence and impact. The Daily, Wednesday, January 17, 2018.

Estimates from individual provinces suggest that the prevalence of multiple sclerosis (MS) among Canadians may be one of the highest in the world. A new study released today in the publication Health Reports provides information on the impact MS has on people's lives, such as mobility, pain, sleep and cognition. About two-thirds of those diagnosed reported that their lives were affected moderately, quite a bit, or extremely by MS. Although 57% of people with MS could walk without aid, almost one-third (31%) required a wheelchair, a mechanical aid such as a cane or walker, or the help of another person, and 12% could not walk at all. Just over half (53%) were usually pain-free, with the rest reporting pain that prevented a few activities (21%) or some/most activities (25%). Close to two-thirds (62%) experienced difficulty getting a good night's sleep. Half (50%) of people whose only neurological condition was MS had difficulty remembering most things and/or thinking and solving problems. MS can be limiting in other ways. Close to one-third reported that it had prevented them from driving (30%), or compromised their educational opportunities (32%). More than half (58%) experienced at least some limitations in job opportunities. As well, 43% reported that MS had a negative impact on their social interactions, such as feeling left out, embarrassed, or that others felt uncomfortable around them or avoided them. This study also provides the most recent national prevalence estimates of MS. An estimated 93,500 Canadians living in private households and 3,800 in long-term care institutions reported a diagnosis of MS. At 290 cases per 100,000 in the household population, prevalence exceeded that in many other countries and was higher than reported in earlier Canadian studies. Women are two to three times more likely than men to have MS (2.6 women reported MS for every man with the condition). Unlike neurological disorders such as dementia and Parkinson's disease that tend to develop at older ages, MS is more prevalent in younger adults. MS was diagnosed between the ages of 20 and 49 for 82% of those with the disorder.

Mokry et al. Obesity and Multiple Sclerosis: A Mendelian Randomization Study. PLoS Med. 2016 Jun 28;13(6):e1002053.

BACKGROUND: Observational studies have reported an association between obesity, as measured by elevated body mass index (BMI), in early adulthood and risk of multiple sclerosis (MS). However, bias potentially introduced by confounding and reverse causation may have influenced these findings. Therefore, we elected to perform Mendelian randomization (MR) analyses to evaluate whether genetically increased BMI is associated with an increased risk of MS.

METHODS AND FINDINGS: Employing a two-sample MR approach, we used summary statistics from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and the International MS Genetics Consortium (IMSGC), the largest genome-wide association studies for BMI and MS, respectively (GIANT: n = 322,105; IMSGC: n = 14,498 cases and 24,091 controls). Seventy single nucleotide polymorphisms (SNPs) were genome-wide significant (p < 5 x 10-8) for BMI in GIANT (n = 322,105) and were investigated for their association with MS risk in the IMSGC. The effect of each SNP on MS was weighted by its effect on BMI, and estimates were pooled to provide a summary measure for the effect of increased BMI upon risk of MS. Our results suggest that increased BMI influences MS susceptibility, where a 1 standard deviation increase in genetically determined BMI (kg/m2) increased odds of MS by 41% (odds ratio [OR]: 1.41, 95% CI 1.20-1.66, p = 2.7 x 10-5, I2 = 0%, 95% CI 0-29). Sensitivity analyses, including MR-Egger regression, and the weighted median approach provided no evidence of pleiotropic effects. The main study limitations are that, while these sensitivity analyses reduce the possibility that pleiotropy influenced our results, residual pleiotropy is difficult to exclude entirely.

CONCLUSION: Genetically elevated BMI is associated with risk of MS, providing evidence for a causal role for obesity in MS etiology. While obesity has been associated with many late-life outcomes, these findings suggest an important consequence of childhood and/or early adulthood obesity.

Gianfrancesco et al. Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility. Am J Epidemiol. 2017 Feb 1;185(3):162-171.

Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelianrandomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.

ProfG    

Is HSCT for everyone, or not?

The HSCT zealots would want you to believe that HSCT is the solution to MS and that we the neurologists are preventing you from accessing this curative treatment. Are they correct? Or do we need evidence from randomised trials?

I saw a patient for a third opinion late last year. She was in her mid-20s and had just failed alemtuzumab with a severe spinal cord relapse 19 months into her 2-year alemtuzumab treatment protocol. The question is what do we do now? She had previously failed interferon-beta and hence fulfilled our criteria for HSCT. When I mentioned to her that the risk of premature ovarian failure (early menopause) was over 40% with aHSCT and that she would need to freeze down eggs if she wanted to optimise her chances of having children in the future she answered an emphatic no. HSCT as a treatment option was too risky for her. This risk was not around the infectious complications, but fertility. 

Please note HSCT is not for everyone based on personal circumstances. This patient then opted for natalizumab treatment as her JCV serostatus was negative. I think the latter is a very wise choice given her wish to start a family in the future. 

I have commented extensively in the past on HSCT (both non-myeloablative and myeloablative) and I would urge you to reread my earlier post after the BBC Panorama programme on the topic. 

A large number of the HSCT zealots seem to ignore the fact that HSCT does not result in a cure in many pwMS treated with HSCT and that there is an issue of HSCT-related mortality. The latter is often conveniently ignored. 

The recent study by Sullivan and colleagues quote a 6% mortality rate at 6 years in patients with severe scleroderma treated with myeloablative HSCT compared to 0% in the standard cyclophosphamide group. One could argue that mortality rates are higher in this population than in people with MS. I suspect that this may be correct, but in the Murao et al. HSCT MS meta-analysis paper there were 37 deaths, out of 281 HSCT treated patients with MS or a 13% mortality rate, from any cause (treatment-related or not); 8 deaths or 2.8% were reported within 100 days from transplant and were considered transplant-related mortality. These figures are probably within the same range as those reported for other autoimmune diseases treated with HSCT. Are you prepared to take these risks? Not all pwMS are and we need to respect their decisions. 

How effective is HSCT? In the scleroderma study below the so called event-free survival rate at 54 months was 79% in the transplantation group compared to 50% in the cyclophosphamide group. What about MS? In the metanalysis below the 5-year probability of progression-free survival as assessed by the EDSS score was 46%. Is this better than alemtuzumab, natalizumab, ocrelizumab, rituximab or cladribine? Let's generate the evidence from head-2-head studies and find out. 

The main message from this post is that HSCT is not that safe; HSCT has many short-term complications including a relatively high mortality and although its efficacy is high it is not necessarily higher than currently licensed DMTs. So don't believe everything the HSCT zealots tell you or ask them to show you the data. 

Please note that we at Barts-MS do offer HSCT as a treatment option, but patients have to fulfil the criteria as set by the London MS-AHSCT Collaborative Group. We are not denying people with MS access to this treatment option. 

Sullivan et al. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. 

N Engl J Med. 2018 Jan 4;378(1):35-47.

BACKGROUND: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma.

METHODS: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score.

RESULTS: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. 

CONCLUSIONS: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

Muraro et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. 2017 Apr 1;74(4):459-469. 

IMPORTANCE: Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis(MS) that fail to respond to standard therapies.

OBJECTIVE: To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort.

DESIGN, SETTING, AND PARTICIPANTS: Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.

EXPOSURES: Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen.

MAIN OUTCOMES AND MEASURES: The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models.

RESULTS: Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).

CONCLUSIONS AND RELEVANCE: In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.

ProfG    

Walking the talk, but too slowly: one #MSBrainAttack too many

How quickly should we treat MS? As soon as possible. 

I made the case on behalf of DrK last month for a natalizumab Brain Attack Trial? I now have a personal clinical anecdote why we should not delay things any longer.

I saw a new referral in my MS clinic about 6 weeks ago. She was from an ethnic minority (red flag) with highly-active disease. Her imaging was very active but slightly atypical; she had a confluent lesion around the aqueduct that has been described in anti-aquaporin-4 positive patients with NMO spectrum disorder. I, therefore, delayed making the diagnosis to repeat her imaging, do a lumbar puncture and check her anti-AQU-4 results. As this, all occurred over the Christmas period it took 6 weeks for her to come back to me with all the results. In this period she has gone onto to have a very disabling brainstem attack. All her tests are back and confirm the original diagnosis of MS. If only I had started her on natalizumab whilst I was doing all the tests we would probably have prevented her having this attack. 

She is now coming into hospital as an urgent admission for a course of intravenous steroids and to be started on natalizumab. Please note we have decided to start natalizumab without knowing her JCV serostatus. If she is JCV-ve we will leave her on natalizumab and if she comes back JCV+ve we will then decide on what DMT to transition her onto after a 12 month period of treatment. 

What this patient illustrates is that MS activity tends to be clustered. A powerful predictor of a relapse is a recent relapse. The case for putting patients with possible early active MS at risk from having to wait is well illustrated in this example. Why don't we to treat all patients like this with natalizumab to protect their brains and spinal cords while we complete their diagnostic work-up? This is analogous to treating stroke.

Why natalizumab? (1) It is one of our most effective DMTs, (2) it works very quickly, (3) it is given as an IV infusion, hence there is no problem with adherence and (4) it is very safe for up to 12 months. (5) It is also relatively safe in pregnancy. During this 12 month period, the neurologist and the patient can then decide what strategy they want to pursue in the long-term. This could be to continue natalizumab long-term or to switch to another DMT, or in the case of an alternative diagnosis the drug can be stopped.

To make the Brain Attack Trial a reality we need the EMA to license natalizumab as a 1st-line treatment. This will probably require data. Hence we are proposing that Biogen sponsor a 'Brain Attack Trial'. This would become even more important if you can derisk the PML problem associated with natalizumab. Imagine if we can reduce the risk of PML to zero? Who wouldn't want to start on natalizumab as a first-line therapy? Natalizumab will become the one and only platform therapy. The problem with this is that Biogen has other DMTs in the MS space and the Brain Attack Trial will potentially result in natalizumab cannibalizing their other DMT market. How bold is Biogen?

ProfG    

ECTRIMS2017 Is Here! What do you want us to report on?

The Programme (UK)/Program (US) is online (CLICK HERE) The abstracts are now live

Come and see us at the Google Hangout 15.45-16.45 Central European Summer Time = GMT + 2 h) with NDG and ProfB your hosts to answer your questions and to report on what's "Hot" and What's "Not"....OK, they won't waste their time, and your time, with the what's not :-).

If you miss the Hangout some of us can be found on the ClinicSpeak and DigestingScience stands.