#T4TD Intermittent diarrhoea?

Did you know constipation with intermittent diarrhoea may mean you have faecal impaction? 

The majority of people with MS who have bowel problems suffer from constipation. This occurs because the MS bowel is sluggish due to reduced motility. This can be made worse by anticholinergic drugs that are used for treating urinary frequency and urgency. Over time pwMS may impact their bowels with faeces, which can form a faecolith (faecal stone). Above the hard and impacted faeces or faecolith, the gut bacteria overgrow and liquefy the stool, which is then able to bypass the impaction and cause diarrhoea. 

So if you suffer from chronic constipation and intermittent diarrhoea you need to contact your HCP for help. 

Please note another cause of this problem is cyclical use of laxatives, i.e. you get constipated and then you use laxatives to treat your constipation. The laxatives then cause diarrhoea so you stop taking them. You then become constipated again and the cycle repeats itself. 

To manage MS-related constipation  you really need to:

  1. Optimise your diet by eating lots of fibre.
  2. Don’t dehydrate yourself. Drink plenty of water and don’t equate caffeine and alcoholic beverages as hydrating. Both caffeine and alcohol cause the kidney to make more urine (diuresis) and are in fact dehydrating.
  3. Try and eliminate concomitant medication that exacerbates constipation (anticholinergics and opioids).
  4. Exercise regularly; the anticipation of exercise and exercise stimulates a defaecation reflex.
  5. If you need to use laxatives start with a prokinetic agent that stimulates the bowel to move, for example, senna, and then add-in bulking (e.g. psyllium husks or other fibre substitutes) followed by liquifying agents (lactulose or polyethylene glycol).
  6. Don’t suppress the need to go to the toilet; a lot of people with chronic constipation have learnt bad habits, for example, they don’t like using toilets that are unfamiliar to them. 

#T4TD = Thought for the Day

CoI: none

#T4TD Feeling tired this morning?

Did you know that as many as 1 in 5 people with MS suffer from obstructive sleep apnoea? 

Obstructive sleep apnoea occurs when your breathing stops and starts while you sleep. It typically occurs due to a collapse in the tone of the muscles in your throat. The main symptoms of sleep apnoea include making gasping or choking noises while you sleep, snoring loudly, waking unrefreshed with a muggy feeling as if you have a hangover, feeling very tired during the day and frequently falling asleep in the day.

Sleep apnoea is usually treated with a CPAP (continuous positive airway pressure) mask that you wear while you are asleep. Although sleep apnoea is associated with obesity and getting older it can occur in people who are thin with a normal BMI (body mass index). It is very common in MS and is likely to be due to MS lesions affecting the function of the brainstem.

If you identify with any of these symptoms you need to raise the issue with your HCP so that you can be investigated. Sleep studies to diagnose sleep apnoea can even be done at home using portable devices. 

#T4TD = Thought for the Day

CoI: none

NICE & Siponimod

Here we go again. Most readers will have gathered by now that NICE has not recommended Siponimod for treating active SPMS under the NHS. This is a big disappointment for the MS community in the UK particularly for those patients who have active SPMS or worsening SPMS on a DMT who were hoping to be switched to Siponimod. 

It is clear that some of the assumptions NICE have made about the treatment of MS don’t represent the reality on the ground, in particular, that most people diagnosed with SPMS do not have any disease-modifying treatment. I would argue that the biggest population of potential ‘siponimod-eligible’ patients with SPMS are those smouldering away on existing DMTs. A straw poll of UK MSologits we did in 2014 indicated that most were reluctant to label their patients as having SPMS because of the implications it has for treatment. Most MSologists don’t necessarily stop existing DMTs in patients with worsening disability because they are concerned about the potential for a rebound in inflammatory disease activity. 

NICE Recommendations 

1.1 Siponimod is not recommended, within its marketing authorisation, for treating secondary progressive multiple sclerosis with evidence of active disease (that is, relapses or imaging features of inflammatory activity) in adults. 

1.2 This recommendation is not intended to affect treatment with siponimod that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS healthcare professional consider it appropriate to stop. 

Why the committee made these recommendations 

Interferon beta-1b is the only disease-modifying treatment available for people with active secondary progressive multiple sclerosis. However, few people take it. 

Most people do not have any disease-modifying treatment. Clinical trial results show that siponimod reduces the number of relapses and slows disability progression compared with placebo. It is uncertain how effective siponimod is compared with interferon beta-1b because there is no evidence directly comparing them.

Because of the limited clinical evidence, the cost-effectiveness estimates are uncertain, and none of the analyses reflect the committee’s preferred assumptions. Therefore, siponimod is not recommended.

The idea that MS is three diseases rather one disease is clearly coming back to haunt the field. I think most people working in MS understand that MS is one disease with superimposed inflammation, i.e. relapses and focal MRI activity, determining the clinical phenotype and being the treatment target for licensed anti-inflammatory agents such as siponimod. The question about whether or not focal inflammation drives all pathology has yet to be answered, but based on the early treatment trials of highly-effective agents this seems likely. 

As always we as an MS community are going to have to respond to NICE. But what do we say? I am not sure there is a consensus amongst UK neurologists about how we diagnose and manage SPMS. The following are a series of questions that I think need to be answered when it comes to managing pwMS who are ‘transitioning to’ or have become secondary progressive, which will inform the content and tone of our response to NICE. As always our role as MSologists and MS HCPs is to be patient advocates; I sincerely hope we won’t let you down. 

What components of  ‘disease activity’ do you think should define active SPMS?

What timeframe should be used to define active SPMS?

Do you actively screen for and diagnose SPMS in patients on DMTs?

Do you actively avoid diagnosing SPMS so that you don’t have to stop their DMT?

Do you generally stop DMTs in patients who have transitioned to becoming secondary progressive?

What concerns you when stopping DMTs in patients who have transitioned to becoming secondary progressive?

Do you think it is appropriate to stop DMTs in patients who have transitioned to becoming secondary progressive to see if they become active?

Do you start or switch patients who you have diagnosed as having active SPMS onto interferon-beta-1b according to NHS England’s or other guidelines?

Do you have any patients under your care who have become secondary progressive on DMTs who are now wheelchair-bound (EDSS>6.5)?

CoI: multiple

#T4TD: biohacking

Did you know two lifestyle options, i.e. exercise and diet, are probably the most effective add-on neuroprotective therapies for treating MS? 

Exercise induces long-lasting changes in the brain, which includes upregulation of growth factors and release of endorphins, that are almost certainly neuroprotective. Similarly, diets (caloric restriction, intermittent fasting and low-carbohydrate ketogenic) stimulate metabolic pathways that are both anti-inflammatory and neuroprotective. Why would someone with MS not want to hack their metabolism to derive these benefits? 

CoI: none in relation to this post

#T4TD = Thought for the Day

P.S. Please note that if you are overweight you need to lose weight first to exercise properly. Exercise, without a change in your diet, is not an effective weight-loss strategy.

Live Webinar Tonight 6PM ET! MS and COVID-19: A Webinar Series for Healthcare Providers

Join the National MS Society and the Consortium of MS Centers for a live webinar featuring Gavin Giovannoni, MBBCh, PhD, Chair of Neurology, Blizard Institute Barts and The London School of Medicine and Dentistry and Aaron Miller, MD , Medical Director, Corinne Goldsmith Dickinson Center for Multiple Sclerosis. This webinar will focus on disease modifying therapies and clinical decision-making in the COVID-19 era and will be moderated by Tim Coetzee, PhD the Chief Advocacy, Services and Research Officer for the National MS Society. Submit questions with your registration or during the webinar.If you haven’t registered yet, click here.

Tuesday, June 30th at 6:00 PM ET

https://register.gotowebinar.com/register/351330656592328975

#T4TD – sickness behaviour

This is a first in a new series of ultrashort blog posts called “Thought-4-the-Day” (#T4TD) to make you think about your MS. 

Did you know that MS-related fatigue could be caused by sickness behaviour? 

Sickness behaviour is a coordinated set of adaptive behavioural changes that occur in response to inflammation and/or infection, which includes fatigue or lethargy, depressed mood & motivation, reduced social exploration, loss of appetite, sleepiness, reduced concentration & attention and brain fog.

If you recognise these symptoms you need to ask if your MS is active? Many people with MS notice an improvement in these symptoms when they start effective disease-modifying therapies.

CoI: multiple

#MSCOVID19: COVAX or Coronavirus Ocrelizumab Vaccination Study

Anti-CD20 therapy not only increases your chances of getting COVID-19 but also increases your chances of developing severe COVID-19 and having to be admitted to hospital for treatment. I have argued that the likely mechanism is to be due to anti-CD20 therapies blunting important cross-reactive anti-coronavirus immune response acquired from other community-acquired coronaviruses. If this is correct it means that people with MS (pwMS), and other diseases, on anti-CD20 therapies, will be unlikely to mount protective immune responses to ane effective SARS-CoV-2 vaccine. 

Based on the questions I have been asked on social media and recent COVID-19 related webinars vaccine readiness is clearly playing on the minds of many HCPs and pwMS. To provide some perspective we have recently written a review paper on vaccine readiness to highlight this topic and to how to mitigate this issue. 

It seems likely that pwMS on anti-CD20 therapies are going to have to take a drug holiday to allow peripheral blood B-cell reconstitution before being vaccinated. What I don’t know is whether or not this hypothesis is correct and if correct what level of B-reconstitution will be necessary to allow an adequate vaccine response. I, therefore, propose testing this in a clinical trial where we compare antibody and T-cell responses to the SARS-CoV-2 vaccine when it emerges with different levels of peripheral B-cell reconstitution. The idea will be to vaccinate patients at different time points after early and late (above normal) peripheral blood B-cell reconstitution. I have called this trial the COVAX Study or the “Coronavirus Ocrelizumab VA(X)ccination Study”.

If you are on ocrelizumab would you volunteer to participate in this study?

Baker et al. COVID-19 vaccine-readiness for ocrelizumab and other anti-CD20-depleting therapies in multiple sclerosis and other autoimmune diseases. Authorea. June 23, 2020. DOI: 10.22541/au.159292858.82650822

Although most autoimmune diseases are considered to be CD4 T-cell or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab that is used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities, notably multiple sclerosis, where ofatumumab is in late stage development and ocrelizumab is approved for use. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of multiple sclerosis and COVID-19, it was hypothesised that whilst B-cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B-cell subset inhibition that controls multiple sclerosis and other autoimmunities, would not influence innate and CD8 T-cell responses, which are central to SARS-CoV-2 elimination, nor the hyper-coagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority (mortality rate n=~5/392) of SARS-CoV-2 infected, CD20-depleted people with multiple sclerosis have recovered. However, protective neutralising-antibody and vaccination responses are predicted to be blunted, until naïve B-cells repopulate, based on B-cell repopulation-kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose-interruption to maintain inflammatory disease control in MS and other autoimmune diseases, whilst allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.

CoI: multiple

#MSCOVID19: National Seroprevalence Study

We were hoping to do a UK-wide seroprevalence study in UK residents with MS to see how many had seroconverted to become anti-SARS-CoV-2 antibody positive and to see if there are differences in seroconversion rates between people on different DMTs. Unfortunately, our source of funding has fallen through.

Based on recent insights we would predict that people on ocrelizumab would have lower titres of anti-SARS-CoV-2 antibody titres, be more likely to be seronegative despite a history of COVID-19 and less likely to have neutralizing anti-spike protein RBD (receptor binding domain) antibodies than patients on other DMTs. Answers to these questions are really important for the MS community, have safety implications for pwMS and will address questions around vaccine readiness in the future.

In addition to the cross-sectional analysis, we want to follow the seronegative pwMS over time to study how the COVID-19 pandemic evolves and monitor the development of herd immunity in the MS population. 

To do the first part of this study we need £25,000 to cover the costs of posting out blood spots and doing the initial assay. As this study is time sensitive we need to raise the money ASAP. Applying for grants will take too long. It has been recommended that we crowdfund this project. The question we want to ask you the MS community do you think this study is important enough and are you willing to help raise the money for us?

The results of this study will help the MS community prepare for a vaccine and whether or not the herd immunity strategy is working. 

Please let us know your thoughts. Thank you.

CoI: multiple  

Alemtuzumab Epiphany

Prof G is in a melancholic mood. Why?

This week I am doing video consultations with all the volunteers who participated in the pivotal phase 3 and 10-year extension studies of the alemtuzumab clinical trials. My objectives are three-fold. Firstly, to make sure they are referred back into a routine NHS MS service and are not left floundering without follow-up. Secondly, to complete a few exit EDSS examinations of the last few subjects and thirdly, and most importantly, to thank them for their time and commitment to these trials. 

During my video consultations, it dawned on me that I have never seen a cohort of patients doing so well 10+ years into their MS disease course. The majority are NEDA (no disease activity) fully functional and participating fully in life. Yes, fully in life; married, in civil and other partnerships, working, with families, playing sports, participating in creative activities, volunteering and with very few symptomatic MS problems. Yes, a few of them have thyroid problems, but these are all being managed without a major impact on these patients lives.

I am convinced that some of these trial subjects may actually be cured of having MS. I am witnessing something extraordinary and at the same time something very sad. Why have we, the MS community, not adopted early alemtuzumab treatment as the standard of care? Why wouldn’t you want to take a chance on a treatment that maximises your chances of staying fully functional and may even offer a cure? 

The patients who are not doing so well, unfortunately, got onto alemtuzumab late and therein lies the epiphany; early highly-effective treatment is the only way to realistically slay this beast.  Knowing what I know, if I had MS I would have no hesitation being treated with alemtuzumab or even HSCT.

The tragedy is that the MS community and the regulators have killed alemtuzumab relegating it to a second or in most countries a third or fourth line agent. This is an international tragedy and I am not sure if we will ever get alemtuzumab back to its rightful place as a first-line treatment option for early active MS. 

Alastair Compston, his protege Alasdair Coles and the Cambridge team deserve all the plaudits for getting this innovation to the clinic. However, sometimes this is just not enough to get wide adoption of an extraordinary innovation.

CoI: multiple

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