Author: Gavin Giovannoni

We need a national debate about the use of HSCT to treat MS and we need to educate MSers about what to expect. #ClinicSpeak


I received an email from a colleague this week that stated:


“I saw a patient last week that I thought might be worth discussing on the blog. The patient had a self-funded AHSCT in Russia last year after doing badly on an injectable. She went into the transplant with the expectation she would be cured. A year after the transplant she has now developed a spinal cord relapse confirmed on MRI. To complicate matters her lymphocyte count is still around 0.8×10^9/L. She was absolutely devastated when I gave her the MRI results that the HSCT had not worked. It was worse for her than receiving the initial diagnosis of MS. I started my training initially in medical oncology. It reminded me of giving the news to young woman with breast cancer who had just finished six months of adjuvant chemo and at the end of treatment her scan showed new metastatic disease. This is not a situation I’ve encountered before but makes the point that although HSCT is a highly effective DMT, it is not a cure for MS as it is often sold to people travelling abroad to be treated.”

Guillemin et al. Older Age at Multiple Sclerosis Onset Is an Independent Factor of Poor Prognosis: A Population-Based Cohort Study. Neuroepidemiology. 2017 Aug 10;48(3-4):179-187.

It is that time of year when I seem to have time for rumination and reflection. #ThinkSpeak #BrainHealth

Last night I was at dinner with nine of my trainees who have recently left, or are about to, to continue with their career progression (please note progression as it is being used here denotes improvement).

We had some interesting discussion about the changes that are occurring to the practice of medicine and inevitably the conversation came down to AI (artificial intelligence) and algorithmic medicine. One of the other issues we touched on was the stress medics are under and despite knowing about bad behaviours a lot of us still self medicate to reduce stress. Too many medics smoke, drink too much, sleep and exercise too little, have poor diets, etc. If we can’t take control over our own lives how can we expect to give advice to our patients and expect them to take the advice seriously? This conundrum has been pinging around in my head for several years and is one of the motivations behind our #BrainHealth campaign. In response to this problem we are planning to launch a #BrainHealth competition at ECTRIMS in Paris where we will be asking MS centres, Pharma companies and other MS stakeholders to put forward teams of at least 7 people to compete over 100 days to see who which team can collect the most activity points. We hope by making this competitive we will get greater participation and at the same time they will be living examples to pwMS that it can be done. We are also proposing that the teams include pwMS. What do you think? At present we are proposing to use the Virgin Pulse platform to run the competition. Wouldn’t it be nice to see Barts-MS being beaten by a team from Australia?

I don’t think this competition will include diet. So what about diet? What can we do to improve the nation’s and our patients diets? 


I was looking at our dog this morning and thought about how much value he brings to our lives. Because we look after our dog by feeding him well and making sure his comfortable why we wouldn’t we do the same to pets living inside our body? This is when I thought of starting a relationship with my gut microbiome and to start treating it as a pet. If we did this we may be more disciplined about how we feed  it and look after it. After all we are what we eat and our gut microbiome sits at the interface. If we treat our microbiome well, by eating well, it will treat us well.  

Buchan et al. North-South disparities in English mortality 1965–2015: longitudinal population study.  J Epidemiol Community Health 2017;71:928–936.


Background: Social, economic and health disparities between northern and southern England have persisted despite Government policies to reduce them. We examine long-term trends in premature mortality in northern and southern England across age groups, and whether mortality patterns changed after the 2008–2009 Great Recession.


Methods: Population-wide longitudinal (1965–2015) study of mortality in England’s five northernmost versus four southernmost Government Office Regions – halves of overall population. Main outcome measure: directly age-sex adjusted mortality rates; northern excess mortality (percentage excess northern vs southern deaths, age-sex adjusted).


Results: From 1965 to 2010, premature mortality (deaths per 10 000 aged <75 years) declined from 64 to 28 in southern versus 72 to 35 in northern England. From 2010 to 2015 the rate of decline in premature mortality plateaued in northern and southern England. For most age groups, northern excess mortality remained consistent from 1965 to 2015. For 25–34 and 35–44 age groups, however, northern excess mortality increased sharply between 1995 and 2015: from 2.2% (95% CI –3.2% to 7.6%) to 29.3% (95% CI 21.0% to 37.6%); and 3.3% (95% CI –1.0% to 7.6%) to 49.4% (95% CI 42.8% to 55.9%), respectively. This was due to northern mortality increasing (ages 25–34) or plateauing (ages 35–44) from the mid-1990s while southern mortality mainly declined.


Conclusions: England’s northern excess mortality has been consistent among those aged <25 and 45+ for the past five decades but risen alarmingly among those aged 25–44 since the mid-90s, long before the Great Recession. This profound and worsening structural inequality requires more equitable economic, social and health policies, including potential reactions to the England-wide loss of improvement in premature mortality.

It is clear how the MS community feels about ocrelizumab for PPMS #ClinicSpeak #ThinkHand


I have previously discussed the concerns many neurologists have about the risk-benefit ratio of ocrelizumab in PPMS. Ocrelizumab is a much more potent B-cell depleter than Rituximab, i.e. ~10x as potent. A 600-mg dose of ocrelizumab is ~6x more potent than 1,000-mg dose of rituximab. This may explain the efficacy difference between the two monoclonals; particularly if ocrelizumab is targeting the hard to get to meningeal and intrathecal B cells. 


After some of the comments on this blog we ran a survey to poll what pwMS thought about the ocrelizumab results. It is pretty clear that for pwMS ocrelizumab represents a real advance and the beginning of something very important for them. We now have something to build on. Let’s hope we see a large number of new trials exploring other DMTs in more advanced MS. What was once an intractable problem seems tractable. This has to be good news. 


It is interesting that only a minority of the survey respondents support a PPMSer protest. Why? 

Bonenfant et al. Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis? Eur J Neurol. 2016. doi: 10.1111/ene.13181

BACKGROUND AND PURPOSE: The benefits of immunomodulatory treatments in secondary progressive multiple sclerosis (SPMS) are unclear, calling into question their continuation. In the present observational study, we investigated the effect of treatment withdrawal on the clinical course of SPMS.

MS-BASE STUDY

Kister et al. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016 Oct;87(10):1133-7.

BACKGROUND:  Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking.

An in depth look at people with more advanced MS #GuestPost #ThinkHand

Anti-drug antibodies are a major problem in clinical practice and are important for safety and efficacy reasons. #ResearchSpeak #ClinicSpeak #MSBlog

How important are anti-drug antibodies in relation to biological therapies, in particular neutralising antibodies to the monoclonal therapies used to treat MS?

This problem was defined in rheumatology with the monoclonal antibodies targeting TNF-alpha. Infliximab the initial anti-TNF monoclonal is so immunogenic that it has to be used in combination with another immunosuppressive, typically methotrexate or azathioprine, to try and prevent NABs. In comparison, the incidence of NABs on the newer generation anti-TNFs, for example adalimumab, is much lower.

Anti-drug antibodies (ADA), in particular neutralising antibodies (NABs), to the anti-CD20 monoclonals will become increasingly important. In the Swedish study below the incidence of ADAs to rituximab was between 26-37% with some evidence that at least a proportion are neutralizing. The NAb rate to rituximab is known to be in the range of 6-9% compared to 0.2-0.5% for ocrelizumab and ~0% on ofatumumab (Phase 2 trial). We know that NABs are a major problem with biologicals in terms of both efficacy and safety. I would therefore predict that as in other areas, such as the anti-TNF-alphas, NABs will be a major differentiator amongst the anti-CD20s; this won’t be simply for marketing reasons, but it will be driven by efficacy and patient safety concerns. NABs blunt efficacy and are a common cause of treatment failure, and are also responsible for infusion reactions. Just ask any pwMS who has been unfortunate enough to develop anti-natalizumab antibodies.

We also have evidence that NABs are a major problem with alemtuzumab as well. We are setting-up an anti-alemtuzumab antibody assay and will soon be using this assay in clinical practice and will make it available for other groups to use. We hope to extend our panel of NAB testing from anti-natalizumab and anti-alemtuzumab antibodies to include anti-rituximab and anti-ocrelizumab binding and neutralising antibodies. Knowing who has NABs affects clinical practice, in particular patient safety.

Dunn et al. Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies. Mult Scler. 2017 Jul 1:1352458517720044.

BACKGROUND: Rituximab is a chimeric monoclonal anti-CD20 B-cell-depleting antibody increasingly used off-label in multiple sclerosis (MS). The clinical relevance of anti-drug antibodies (ADAs) against rituximab in MS is unknown.

OBJECTIVE: To determine frequency of ADA in relation to B-cell counts, allergic reactions and clinical efficacy in a large cohort of MS-treated patients.

METHODS: Cross-sectional study with collection of serum samples from 339 MS patients immediately before a scheduled rituximab infusion. ADAs were detected using an in-house-validated electrochemiluminescent immunoassay and a commercial enzyme-linked immunosorbent assay (ELISA) to compare methods. Data on patient demographics and clinical outcomes were retrieved from the Swedish MS Registry and patient records.

RESULTS: ADAs were detected in 37% of relapsing-remitting MS and 26% in progressive forms of MS. Presence of ADAs decreased with increasing number of rituximab infusions. There was a significant association between both presence and titres of ADAs and incomplete B-cell depletion, but not with infusion/adverse reactions or clinical outcomes at the group level. Only five patients terminated rituximab during follow-up, four of which were ADA positive.

CONCLUSION: Rituximab treatment is associated with a high degree of ADAs, which correlates with efficacy of B-cell depletion; however, the clinical relevance of ADAs remains uncertain.

CoI: multiple

Are you interested in a MS fellowship at #BartsMS? #GuestPost