#MSCOVID19 webinar have you registered?

This week I am participating in a debate on how to manage patients with MS on DMTs during the COVID-19 pandemic. Rather than a didactic lecture, I am going to debate several issues with Dr Kerstin Hellwig in relation to two case scenarios (see below), which will highlight the evolving complexities of how to manage MS during these troubling times. If you haven’t registered yet please do so ASAP as places are limited.

Case 1: A 36-year old male has been on ocrelizumab for 2 years; this is his second DMT after having previously received interferon β-1a. He was due his 6th dose of ocrelizumab in March 2020 but this has been postponed indefinitely by his MS centre.

Do you agree with this decision?

What are his chances of getting severe COVID-19 with B-cell depletion?

What about secondary bacterial infections in the event he does get COVID-19?

When will it be safe to resume ocrelizumab treatment?

He is worried that on ocrelizumab therapy he will be unable to show response to an anti-SARS CoV-2 vaccine? Is this a factor to consider when reviewing his treatment?

Would you consider switching his treatment to allow him to be ‘vaccine-ready’ and if yes to what therapy would you switch?

Case 2: A 28-year old woman with highly active RRMS. Previously suffered relapses on dimethyl fumarate in the past. She was treated with oral cladribine in June and July 2019. She is due her second course in late June and July 2020. She had been told be her treating neurologist that she should delay her next course of treatment until after the COVID-19 pandemic is over.

Do you agree with this decision?

How effective is one course of oral cladribine and will it be sufficient to protect her during the current pandemic?

If she received her 2nd year of oral cladribine should she be shielded and for how long?

Could measuring her lymphocyte counts assist in management of this patients?

What is a safe lymphocyte count?

Would delaying her second course of oral cladribine affect her ability to be vaccinated with an anti-SARS-CoV-2 vaccine in the next 12-24 months?

CoI: multiple

Wiped-out and you?

Do you relate to this list of facts in relation to MS-fatigue?

  1. The most common spontaneously reported symptom for pwMS is fatigue.
  2. PwMS use the words “tired,” “exhausted,” “wiped out,” and having “little or no energy” to describe their fatigue. 
  3. More patients rated fatigue as their “most troubling symptom” compared with other MS-related symptoms. 
  4. Half of the people living with MS report feeling constantly fatigued and more than 90% reported experiencing fatigue at least daily. 
  5. The top three most frequently reported negative impacts of fatigue were social functioning, emotional well-being, and cognitive functioning. 
  6. PwMS describe themselves as “homebodies,” as fatigue limited their social interactions with friends and family and impacted the types of activities they could participate in. 
  7. PwMS attribute their inability to think clearly or focus for long periods of time to their fatigue. 
  8. PwMS report experiencing depression and anxiety because of their fatigue, which would often have further negative effects on their relationships with friends and family. 

Although this list comes from a new qualitative study on MS-related fatigue (see below) they are not new insights.

As fatigue is a reasonably well-defined problem in MS we should be asking ourselves why haven’t we cracked it and have effective treatments to manage it?

I think we can crack-it but we have to acknowledge that MS fatigue relates to (1) active inflammation and (2) the consequences of the damage that inflammation causes. If we acknowledge this then we are half-way towards treating and preventing MS-related fatigue, i.e. treating MS early (before too much damage occurs) and effectively (NEDA and beyond). 

The following is what we know about MS-related fatigue.

Inflammation in the brain causes fatigue. This is due to inflammatory mediators or cytokines, in particular, interleukin-1 (IL-1) and TNF-alpha, which trigger sickness behaviour. Sickness behaviour is the behavioural response we have to inflammation, which forces us to rest and sleep so that our body can recover. This is what happens to you when you get a viral infection; in fact many of the pwMS I look after describe their fatigue as being similar to the fatigue they experience when they get flu. Sickness behaviour from an evolutionary perspective is well conserved and occurs in most animals. This type of fatigue needs to be managed by switching off ongoing inflammation in the brain. This is why so many pwMS who go onto highly-effective DMTs come back saying ‘I feel so much better, my fatigue and/or brain fog has cleared’. Do you relate to this? This is why recent-onset fatigue that can’t be explained by other factors (see below) may indicate MS disease activity. At present fatigue on its own does not constitute a relapse, but there are some of us who would disagree; particularly if we investigate more deeply we often find subclinical/MRI or biomarker (neurofilament) evidence of relapse in these patients.

Another cause of fatigue is the exercise-related conduction block. This is when pwMS notice their legs getting weaker with exercise. We think this is due to demyelinated, or remyelinated axons, failing to conduct electrical impulses when they become exhausted. Exercise-induced fatigue is probably the same as temperature-related fatigue; a rise in body temperature also causes vulnerable axons to block and stop conducting. To deal with this type of fatigue we need therapies to promote remyelination and to increase conduction. These types of fatigue are treated by rest, cooling and possibly drugs such as fampridine that improve conduction. At the heart of this type of fatigue is localised energy failure.

The other cause of fatigue is neural plasticity. When the brain is damaged by MS other areas are co-opted to help take over, or supplement, the function of the damaged area. In other words, it takes more brainpower to complete the same task that normal people do. This type of fatigue usually manifests as mental fatigue and is why pwMS have difficulty concentrating for prolonged periods of time. At present we have no specific treatment for this type of fatigue except to prevent it by treating MS early and effectively. Some patients find amantadine and modafinil helpful. In short, preventing the loss of brainpower, or damage, in the first place should prevent this type of fatigue.

Fatigue can also be related to so-called co-morbidities, or other diseases, that are related to MS. The big co-morbidities that cause fatigue, which need to be screened for are:

  • Infection – we all get tired when we have infections; it triggers sickness behaviour 
  • An underactive thyroid gland or hypothyroidism – hypothyroidism is commoner in pwMS 
  • Poor sleep hygiene and/or sleep disorders – if you are not sleeping well you feel tired in the morning 
  • Obesity – when you are overweight it takes more energy to perform physical tasks 
  • Depression and anxiety; fatigue is a common symptom of depression and anxiety and unless this is screened for and treated in persists.  
  • Side effects of drugs; in particular drugs that cause sedation and from DMTs. Anticholinergics and anti-spasticity drugs are sedating and blunt cognition and may worsen MS-related fatigue. Specific side effects, for example, the flu-like side effects from interferon-beta may make fatigue worse. 
  • Excessive alcohol consumption; although classified as drug alcohol causes and exacerbates MS-related fatigue in several ways, most notably by causing poor sleep hygiene and exacerbating depression.
  • Deconditioning; deconditioning is simply the term we use for being unfit. If you are unfit, performing a demanding physical task makes you tired. Deconditioning is treated with exercise, which paradoxically can reduce fatigue. 
  • Poor nutrition; some pwMS are anorexic and eat very poorly and hence have little energy as a result of this. Although this is quite rare I look after a few pwMS with this problem. Similarly, overnutrition may have the same effect. Some of the hormones your gut produce cause you to feel tired and want to sleep; i.e. the so-called siesta effect. Reducing the size of your meals and changing your eating behaviour may improve post-prandial (after eating fatigue). I have a few patients who avoid eating lunch for this reason. Too much fast-sugar (high-glycaemic index) raises insulin levels that cause post-prandial insomnia or food coma. Going onto a low carbohydrate diet helps this type of fatigue.

It is apparent from this discussion that fatigue in MS is more complex than you realise and needs a systematic approach to be treated and managed correctly. So be careful, or at least wary, when your neurologist simply wants to reach for the prescription pad to get you out of the consultation room as quickly as possible. Like other MS-related problems, an holistic and systematic approach is needed to manage and treat MS-related fatigue correctly. 

On a positive note, you should also be able to use the information in this post to help formulate a fatigue self-management plan and prepare yourself to ask the really challenging questions when you next see your MS team. 

I would be interested to know if any of you have any stories to relate with us about your attempts to self-manage your fatigue, particularly during lock-down. 

Penner et al. Exploring the Impact of Fatigue in Progressive Multiple Sclerosis: A Mixed-Methods Analysis. Mult Scler Relat Disord 2020 May 27;43:102207.

Background: Patient-focused literature on fatigue in progressive forms of multiple sclerosis (MS) is sparse. This study aimed to explore progressive MS patients’ experiences of fatigue.

Methods: Adult patients in the United States with primary progressive MS (n=21) and secondary progressive MS (n=23), recruited from research panels, completed the following PRO measures: Patient Global Impression of Severity (Fatigue) (PGI-F); Fatigue Scale of Motor and Cognitive Functions (FSMC); Modified Fatigue Impact Scale (MFIS); Patient Health Questionnaire, two-item version (PHQ-2); and Patient Determined Disease Steps (PDDS). Patients subsequently participated in a 45-minute semistructured telephone interview and were asked to describe their MS symptoms and to comment on how MS affected their day-to-day lives. More detailed questions followed on the nature of their fatigue, including symptoms, impacts, frequency, and bothersomeness.

Results: Patients’ mean age was 52.5 years, mean time since diagnosis was 14.7 years, and 81.8% were female. 79.5% of patients were unemployed and/or receiving disability benefits. Of all spontaneously reported MS symptoms, fatigue was the most common (n=38, 86.4%), followed by ambulation problems (n=31, 70.5%) and muscle weakness (n=25, 56.8%). Patients used the words “tired,” “exhausted,” “wiped out,” and having “little or no energy” to describe their fatigue. More patients rated fatigue as their “most troubling symptom” (n=17, 38.6%) compared with other MS-related symptoms. Half of patients reported feeling constantly fatigued, and more than 90% reported experiencing fatigue at least daily. The top three most frequently reported negative impacts of fatigue were social functioning, emotional well-being, and cognitive functioning (all >80%). Patients described themselves as “homebodies,” as fatigue limited their social interactions with friends and family and impacted the types of activities they could participate in. Patients attributed their inability to think clearly or focus for long periods of time to their fatigue. Patients also reported experiencing depression and anxiety because of their fatigue, which would often have further negative effects on their relationships with friends and family. On the fatigue PRO measures, mean (standard deviation) scores were 75.2 (14.7) on the FSMC and 55.0 (15.2) on the MFIS. Most participants scored in the “high” fatigue category on the FSMC (84.1%) and above the clinically significant fatigue threshold (86.4%). MFIS and FSMC total scores correlated with PGI-F (polyserial correlations r=0.74 and r=0.62, both p<0.01) and PHQ-2 (r=0.56 and r=0.57, both p<0.01), but not with PDDS (r=0.09 and r=0.02, both p>0.05).

Conclusions: Fatigue is a common, troublesome, and disabling symptom which has a profound impact on patients’ daily lives, as evidenced by qualitative analyses and high scores on established fatigue measures observed in this sample. These findings provide insights into the burden of fatigue and can inform its measurement in both clinical and research settings. Treatments that improve the symptoms of fatigue or prevent exacerbations are needed for patients with progressive MS.

CoI: multiple

no patient should be left behind

As America burns and the #BlackLivesMatter campaign goes global and spreads to the UK people of colour have been asking white people to say something. The quote Megan Markle “….. the only wrong thing to say is to say nothing”.  At the same time, my eldest daughter is adamant that keyboard activism is wrong; “it easy to type and post something to social media”, she says “but it much is harder to something proactive and sincere”. As a secondary school teacher in a state comprehensive school in South London where a lot of her students have social problems and come from a BAME (black, Asian and minority ethnic) background, she has the moral high ground.

This discussion reminds me of a stinging criticism we at Barts-MS had from a person who was then working in a very senior position for one of the MS charities in the UK. She said that Barts-MS pandered to the rich, white, educated, middle-class person with MS, who came to our centre to get what they wanted and that we were neglecting our local population of patients who were much more needy. She claimed we had an unconscious bias against BAME (black, Asian and minority ethnic) patients with MS. This was a stinging attack on our MS service. 

I am acutely aware of unconscious bias in healthcare and her criticism hurt. For example, a very prestigious neurorehabilitation centre refused to publish an audit in the early naughties, which showed that people from upper-income groups (socioeconomic classes 1 & 2) were massively overrepresented in their unit compared to patients from lower socioeconomic classes. How and why unconscious biases creep into healthcare are well studied and understood, but to be accused of it yourself was sobering.

To counter the criticism against Barts-MS, which serves the most diverse population in London and arguably in the UK, we decided to do an audit of the patients on disease-modifying therapies in our centre. We argued that if we did have unconscious biases that favoured the well-educated and rich white middle classes they would more likely to be on higher efficacy DMTs than the less well educated, poorer local patients under our care. We felt somewhat vindicated when we showed that within our service socioeconomic class did not predict a person’s likelihood of being on any particular tier of DMT. In other words, if you get into our service regardless of who you are we will treat you the same. 

The exercise of doing this audit also triggered a deep desire in me to find out more about the social determinants of health (SDoH) and how they impact on MS outcomes. I have spent the better part of 5 years studying the SDoH, which has led to our #ThinkSocial campaign, our social capital research projects and for a SDoH workstream to be a part of our Raising-The-Bar initiative. Our motto is ‘no patient should be left behind’ and we mean it when we say it. 

In fact, I may have developed a conscious bias in favour of BAME patients with MS. As BAME patients with MS  have a worse prognosis they are often given a worse prognostic profile, which results in us steering them towards higher efficacy therapies. The patient I described yesterday, who I am now fast-tracking through diagnostic tests despite the COVID-19 restrictions on our service, is being driven by the fact that he comes from a BAME background. I am now questioning myself if this patient happened to be white would he be getting the same treatment approach from me? I sincerely hope so. 

Saúl Reyes et al. Socioeconomic Status and Disease-Modifying Therapy Prescribing Patterns in People With Multiple Sclerosis. Mult Scler Relat Disord. 2020 Feb 24;41:102024.

Aims: To examine the association between socioeconomic status (SES) and disease-modifying therapy (DMT) prescribing patterns in people with relapsing-remitting multiple sclerosis (pwRRMS).

Methods: A cross-sectional analysis was conducted among pwRRMS treated with a DMT in the neuroinflammation service at The Royal London Hospital (Barts Health NHS Trust). Study data were collected between July and September 2017. SES was determined by patient income and education extracted from the English Index of Multiple Deprivation. Based on their efficacy, DMTs were categorized as moderate efficacy (Glatiramer Acetate and Beta-Interferons), high efficacy (Cladribine, Fingolimod and Dimethyl Fumarate) and very-high efficacy therapies (Natalizumab and Alemtuzumab). Multinomial logistic regressions were performed for univariate and multivariate models to assess differences between SES and DMT prescribing patterns.

Results: Treatment consisted of moderate efficacy (n = 76, 12%), high efficacy (n = 325, 51.3%) and very-high efficacy therapies (n = 232, 36.7%). Medians for income and education deciles were 4 (IQR 3-7) and 6 (IQR 4-8), respectively. After multinomial logistic regression analysis, patient income was not associated with increased odds of being treated with high efficacy (OR, 0.92; 95% CI, 0.82-1.04; p = 0.177) or very-high efficacy DMTs (OR, 0.95; 95% CI, 0.85-1.06; p = 0.371). Similarly, patient education was not associated with being treated with high efficacy (OR, 0.91; 95% CI, 0.80-1.03; p = 0.139) or very-high efficacy therapies (OR, 0.92; 95% CI, 0.81-1.04; p = 0.188).

Conclusions: SES was not predictive of DMT prescribing patterns in pwRRMS. Whilst this appears reassuring within this universal health care setting, the same methodology needs to be applied to other MS services for comparison. Data could then be further interrogated to explore potential socioeconomic inequities in DMT prescribing patterns across the UK.

CoI: multiple

#MSCOVID19: new normal

Will we ever get back to managing MS proactively or is this the new normal?

I saw a new patient with probable MS via video consultation this week. He was from a BAME background and I could sense that he has very active MS despite only having had two relatively mild attacks in the last 14 months; an episode of transient diplopia lasting a few days and a mild sensory relapse lasting just shy of two weeks. An MRI done two and a half years ago when he presented with optic neuritis was abnormal. At the moment he is fully functional without any physical disability apart from some persistent fatigue. 

Without being able to do a physical examination of this patient (I need to know if there are subtle motor and cerebellar signs), arrange an MRI and do a semi-urgent lumbar puncture to confirm the diagnosis and check neurofilament levels, I can’t do an accurate prognostic profile. If he has definite MS (diagnosis to be confirmed) he would only be eligible for platform therapies and ocrelizumab. But as ocrelizumab is an irreversible treatment I want to be confident of the diagnosis. In addition, I want to be able to offer this patient other options and not only one highly-effective therapy. 

What should I do? Well, I have had to tell a sort-of-a-porky and book a Gd-enhanced MRI claiming it is urgent when in reality a diagnostic/prognostic MRI for multiple sclerosis is not a neurological emergency. If this patient has to wait prerequisite 3-4 months, or possibly longer, for us to complete the diagnostic workup because of the COVID-19-induced changes to our MS service there is high likelihood of him having a catastrophic relapse and ending up disabled. ‘Time is Brain’ is how I justified asking for an urgent MRI to myself. 

Managing MS during the COVID-19 pandemic is clearly suboptimal and people with MS or possible MS are getting a raw deal. I suspect the same is happening across other specialities. I know it is happening in oncology, I saw it with my own eyes on the medical wards. 

Have you seen what is install for the NHS post-COVID-19? The following graph is from a recently launched online ‘NHS Waiting List Estimation Tool’, which shows you the backlog in terms of outpatient appointments that are waiting for the NHS post-COVID-19.  People are talking about COVID-19 burnout amongst NHS staff, it is going to be much worse post-COVID-19 when we have to try and clear the backlog created by the reconfiguration of the NHS to deal with COVID-19. 

Medbelle NHS Waiting List Estimation Tool

If any of you have had bad experiences, delays in diagnosis, monitoring or treatment please let us know. I shudder to think about how much brain will be lost due to the change in the way we manage MS induced by COVID-19. I sincerely hope this does not become the new normal.

CoI: multiple

#MSCOVID19: antibody positive

Would knowing that you were anti-SARS-CoV-2 antibody-positive change your behaviour? 

The WHO and other public health agencies are trying to play down the importance of having antibodies to SARS-CoV-2 saying they don’t yet have the data to say these antibodies protect you from reinfection. Yes and no. No in that we don’t have data yet in relation to SARS-CoV-2, but YES in relation to other viral infections. 

If you have been infected with SARS-CoV-2, either asymptomatically or symptomatically (COVID-19), and have developed an antibody response (IgM and/or IgG) to the viral proteins then you are likely to be protected from reinfection in the short (months) and intermediated (years) term. We know from other coronavirus infections that these antibody levels wane with time and the protection is lost, which is why we can get repeated infections with other common coronaviruses. I suspect the same may happen with SARS-CoV-2 as well; in other words, immunity may not be life long. 

It is also clear that people who have asymptomatic and mild infections have lower antibody levels than people with severe infections and hence their immunity may be less effective and less longlasting. It also seems that having antibodies to other coronaviruses, i.e. previous coronavirus infections, may protect from getting severe COVID-19. The latter implies that some of these antibodies may be cross-protective. 

A lot of effort is going into the testing of convalescent plasma from COVID-19 patients, which contains anti-SARS-CoV-2 antibodies, as a treatment in severe COVID-19. The preliminary results are looking promising. In addition, many academic laboratories and pharma companies are trying to develop commercial neutralizing monoclonal anti-SARS-CoV-2 antibodies as a treatment to prevent and treat COVID-19. 

All of this evidence, and basic immunology, suggests that having anti-SARS-CoV-2 antibodies is likely to indicate that you will be immune to reinfection in the short to intermediate-term and even if you were reinfected you would get an asymptomatic or mild infection. The whole premise of herd immunity is built on these assumptions, which is why the WHO and public health officials should get off the fence. 

But why are they sitting on the fence? I suspect it has to do with behavioural psychology. They don’t want to see antibody-positive people relaxing their guard and acting normally, i.e. no social distancing, no handwashing, no masks, etc. They would set a bad example for people who are antibody negative. 

But knowing what I know about virology and immunology if I was antibody-positive it would be a great relief to me and my family. I would be at low risk of getting COVID-19, I could see patients face-2-face without putting them at risk and I could reassure my family that I am not going to infect them. I could even potentially visit and help vulnerable people living near me without fear of infecting them. It is for these reasons that I had my blood taken yesterday to find out if I have had SARS-CoV-2 infection or COVID-19. If antibody-positive then that severe flu-like illness I had over Christmas could have been the sentinel event. There is increasing evidence that SARS-CoV-2 was already circulating in London in December and I was unwell for 3 weeks with many symptoms compatible with COVID-19. If it was that event I could have been infected by patients or staff whilst working on the general medical wards. If on the other hand, if I was antibody negative then I will remain super vigilant and may not cancel my life insurance policy just yet.

Long et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nature Medicine (2020), Published: 29 April 2020.

We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT–PCR results and for the identification of asymptomatic infections.

CoI: none

#MSCOVID19: loss of smell

As you are aware that about 30% of people with COVID-19 present with loss of smell (anosmia) and/or loss of taste (ageusia). The loss of smell happens because the coronavirus damages the nerve endings in the olfactory epithelium in the nose. The good news is that it looks like most people recover their sense of smell and taste, but the recovery can take many months. At present we don’t know how many affected people don’t recover smell. 

As MS affects smell and taste pathways within the brain it is likely that pwMS are a greater risk of developing abnormal smell and taste function with COVID-19 and may also take longer to recover function. This will need to be studied in the MS population to see if these assumptions or hypotheses are correct.

We do know that losing smell and taste affects your quality of life and is often associated with depression. Is there anything you can do to address this problem? Smell specialists recommend smell training, which can be self-administered. Two very good web resources are run by the UK charities Fifth Sense and Abscent. To start smell training you will need to create your own smell kit; this web resource from Abscent is self-explanatory. 

I am interested to know if any of you who have COVID-19 are suffering from a persistent loss of smell and taste and how has it affected your life? Please let us know if smell training makes a difference. 

Lapostolle et al. Clinical Features of 1487 COVID-19 Patients With Outpatient Management in the Greater Paris: The COVID-call Study. Intern Emerg Med 2020 May 30. doi: 10.1007/s11739-020-02379-z. 

Clinical features of COVID-19 have been mostly described in hospitalized patients with and without ICU admission. Yet, up to 80% of patients are managed in an outpatient setting. This population is poorly documented. In France, health authorities recommend outpatient management of patients presenting mild-to-moderate COVID-19 symptoms. The aim of this study was to describe their clinical characteristics. The study took place in an emergency medical dispatching center located in the Greater Paris region. Patients included in this survey met confirmed COVID-19 infection criteria according to the WHO definition. We investigated clinical features and classified symptoms as general, digestive, ear-nose-throat, thoracic symptoms, and eye disease. Patients were included between March 24 and April 6 2020. 1487 patients included: 700 (47%) males and 752 (51%) females, with a median age of 44 (32-57) years. In addition to dry cough and fever reported in more than 90% of cases, the most common symptoms were general symptoms: body aches/myalgia (N = 845; 57%), headache (N = 824; 55%), and asthenia (N = 886; 60%); shortness of breath (N = 479; 32%) and ear-nose-throat symptoms such as anosmia (N = 415; 28%) and ageusia (N = 422; 28%). Chest pain was reported in 320 (21%) cases and hemoptysis in 41 (3%) cases. The main difference between male and female patients was an increased prevalence of ear-nose-throat symptoms as well as diarrhea, chest pains, and headaches in female patients. General symptoms and ear-nose-throat symptoms were predominant in COVID-19 patients presenting mild-to-moderate symptoms. Shortness of breath and chest pain were remarkably frequent.

CoI: none in relation to this post

#MSCOVID19: New UK Government guidelines

Dare you disagree with Government guidelines? The following are excerpts of the new guidelines posted last night on the Government’s website. Unfortunately, people on ‘immunosuppression therapies sufficient to significantly increase the risk of infection’ are still on the list with no justification of what this risk should be. Based on the experience emerging from pwMS getting COVID-19 on MS disease-modifying therapies (DMTs) this statement is incorrect. On balance pwMS on DMTs don’t appear to be at increased risk of getting COVID-19, severe COVID-19 or dying from COVID-19. In terms of dying from COVID-19, the same risk factors playing out in the general population appear to be playing out in pwMS, i.e. older age, comorbidities and disability. Advanced disability is linked to age; pwMS who are disabled tend to be older.

The good news is that shielding is now less intense and people who are shielding can at least go out and meet with people albeit at a distance. This will be good news for many people. Please be aware that this virus does not appear to be spread outdoors unless you are in close contact with people.

Guidance on shielding and protecting people who are clinically extremely vulnerable from COVID-19 (Updated 31 May 2020)

Clinically extremely vulnerable groups

Expert doctors in England have identified specific medical conditions that, based on what we know about the virus so far, place some people at greatest risk of severe illness from coronavirus. Disease severity, history or treatment levels will also affect who is in this group.

Clinically extremely vulnerable people may include:

  1. Solid organ transplant recipients.
  2. People with specific cancers:
    • people with cancer who are undergoing active chemotherapy
    • people with lung cancer who are undergoing radical radiotherapy
    • people with cancers of the blood or bone marrow such as leukaemia, lymphoma or myeloma who are at any stage of treatment
    • people having immunotherapy or other continuing antibody treatments for cancer
    • people having other targeted cancer treatments which can affect the immune system, such as protein kinase inhibitors or PARP inhibitors
    • people who have had bone marrow or stem cell transplants in the last 6 months, or who are still taking immunosuppression drugs
  3. People with severe respiratory conditions including all cystic fibrosis, severe asthma and severe chronic obstructive pulmonary disease (COPD).
  4. People with rare diseases that significantly increase the risk of infections (such as severe combined immunodeficiency (SCID), homozygous sickle cell).
  5. People on immunosuppression therapies sufficient to significantly increase risk of infection.
  6. Women who are pregnant with significant heart disease, congenital or acquired.
  7. Other people have also been classed as clinically extremely vulnerable, based on clinical judgement and an assessment of their needs. GPs and hospital clinicians have been provided with guidance to support these decisions.

More information about who has been classed as clinically extremely vulnerable is available on the NHS Digital website.

If you’re still concerned, you should discuss your concerns with your GP or hospital clinician.

Staying at home and shielding

People classed as clinically extremely vulnerable are advised to take additional action to prevent themselves from coming into contact with the virus. If you’re clinically extremely vulnerable, you’re strongly advised to stay at home as much as possible and keep visits outside to a minimum (for instance once per day).

This is called ‘shielding’ and the advice is now updated:

  1. If you wish to spend time outdoors (though not in other buildings, households, or enclosed spaces) you should take extra care to minimise contact with others by keeping 2 metres apart.
  2. If you choose to spend time outdoors, this can be with members of your own household. If you live alone, you can spend time outdoors with one person from another household (ideally the same person each time).
  3. You should stay alert when leaving home: washing your hands regularly, maintaining social distance and avoiding gatherings of any size.
  4. You should not attend any gatherings, including gatherings of friends and families in private spaces, for example, parties, weddings and religious services.
  5. You should strictly avoid contact with anyone who is displaying symptoms of COVID-19 (a new continuous cough, a high temperature, or a loss of, or change in, your sense of taste or smell).

The Government is currently advising people to shield until 30 June 2020 and is regularly monitoring this position.

For full details please refer to the Government’s website.

CoI: multiple

Don’t mention the C-word

Don’t mention the C-word as it raises unnecessarily high expectations is what many of my colleagues say. I don’t agree with them. Showing we have cured, or not cured, MS is how we will ultimately test the hypothesis that MS is an autoimmune disease. 

People with MS (pwMS) want a cure. However, even if we have an MS cure in hand we may not prevent or reverse progressive disease.  Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or inflammation sets up processes that result in delayed worsening. The acute inflammatory MS lesion also damages axons and neurons but they manage to remain functioning albeit in a vulnerable state. However, this damage primes these axons and nerves to die off in the future. I like to call this delayed post-inflammatory neurodegeneration.

The mechanisms that result in delayed neurodegeneration of nerves or smouldering MS are many and include innate immunity (hot microglia), energy deficits (mitochondrial dysfunction), excitotoxicity (calcium overload), free radicals (oxygen and nitrogen radicals), premature ageing, intrathecal plasma cell production of pathogenic autoantibodies, persistent viral infection, etc.

Clearly, anti-inflammatory drugs that prevent new lesion formation, such as natalizumab, alemtuzumab and ocrelizumab, will not be able to prevent the delayed neurodegeneration from previous inflammatory lesions. What has happened in the past has happened; i.e. the water under the bridge analogy. So if you have relapsing MS and have had a lot of inflammatory activity in the past that have damaged many nerve fibres, even if you go onto a highly effective DMT that renders you NEDA, it is not going to prevent the ongoing loss of nerve fibres that are primed to die off from previous inflammation in the future. This is why did the PROXIMUS trial and are promoting the OXO trial; add-on neuroprotective drug to try and modify the primed but delayed die-off of neurons and axons in the future.

What protects you from entering the “clinically-apparent” secondary progressive phase of the disease is your reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I suspect that pwMS, who have been treated with highly-effective DMTs and who have now become secondary progressive, had a low reserve capacity and a large number of damaged nerve fibres that had been primed to die off. In other words, they were treated with DMTs too late to prevent SPMS in the vanguard pathway (the neuronal pathway with the most damage). This is why I keep pushing the message ‘early effective treatment’ is the only way to prevent secondary progressive MS. 

The same processes happen in PPMS the only difference is pwPPMS don’t have the earlier relapses that bring them to the attention of the medical profession in the initial stages of the disease. 

There are two conclusions to be drawn from these observations; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, and (2) we need additional add-on neuroprotective, remyelinating and neurorestorative therapies to target the delayed neurodegenerative processes referred to above. 

In addition to this, we need to avoid and/or reverse any other factors that prematurely age the nervous system. The ageing hypothesis of progressive MS is a major factor that underpins our Brain Health campaign, which targets non-specific factors that have been associated with more rapid progression in MS (smoking, co-morbidities, lack of exercise, infections, etc.). Common to all these factors is that they reduce your reserve and hence bring forward and speed up progressive MS.

So unless you are rendered NEDA early in the course of your disease it may not prevent you from entering the progressive phase of the disease, i.e. it will not be the panacea you want. In addition, our licensed DMTs don’t kill long-lived plasma cells that continue to make intrathecal (within the CNS) antibodies that may drive progressive MS. The exceptions may be natalizumab and cladribine. 

There are several reports of pwMS on natalizumab losing their OCBs (oligoclonal bands or antibody bands). It now emerges that plasma cells live in a ‘niche’ or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this proves to be the case natalizumab may still have the edge on the other DMTs in this regard.

A recent report from Poland showed that about 50% of pwMS treated with intravenous cladribine more than 10-years ago had lost their oligoclonal IgG bands and were more likely to be stable than the those who have not lost their OCBs. There is old and new data emerging suggesting that the immunoglobulin is present in the cerebrospinal fluid of pwMS is toxic to oligodendrocytes (cells that make myelin) and can stimulate microglia. Just maybe the immunoglobulins are responsible for the slowly expanding lesions (SELs) or the subpial grey matter lesions that are such an important part of progressive MS

To target plasma cells, which are long-lived, we will need add-on therapies. This is high on our list of priorities and we are starting the SIZOMUS trial, COVID-19 permitting, to test a therapy for myeloma (malignant plasma cells) in MS. We are also looking at the effects of cladribine in a similar way (CLADRI–PLUS and CLAD-B studies) and we also want to look at the impact of very early treatment of MS with natalizumab as well (ATTACK-MS study). We also have a longish list of other potential therapies we would like to try as well, but we need help with this, i.e. funding, colleagues to share the workload and potential Pharma interest to give us access to some of the compounds we have identified as potentially promising. 

Our challenge and objective are to scrub the MS brain free of B-cells and plasma cells!

Some people don’t buy into this hypothesis, but it is also supported by the observation that pwMS who receive higher doses of ocrelizumab do better than those receiving lower doses. I think that this may be related to more CNS penetration of ocrelizumab and is why I have proposed that Roche do a double-dose or DODO study. In relation to the DODO study, it is not necessarily about giving double-dose ocrelizumab indefinitely, but only early on as induction therapy and then to explore post-induction safer maintenance therapies (BTKi or teriflunomide). Please see the iTeri and iBruT studies in the slide show below. I can’t stress how important these observations are and they have made me question whether or not we have optimised the dose of both ocrelizumab and rituximab and other emerging anti-CD20 therapies. 

 

So yes, we may be able to cure you of MS with IRTs but you may not realise it depending on when in your course you are treated. So as you can see we as an MS community have a lot still to do when it comes to improving disease outcomes of people with MS and yes we need to mention the C-word. We need to define what a cure means and how to look for it so that we can declare victory or not. 

CoI: multiple

PS there is quite a lot chatter going on Twitter in relation to this post.

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HAPPY WORLD MS DAY!

Today is World MS Day 2020 and its theme is ‘connections’. 

MS Connections are about building community connection, self-connection and connections to quality care. The event is coordinated by the MSIF, who want to challenge social barriers that leave pwMS feeling lonely and socially isolated. Together, they are advocating for better services and are celebrating support networks. Another action the championing of self-care. 

For some of you, these objectives may look very soft and fluffy, when all you want is hard science, innovation and new treatments to prevent, stop, reverse and cure MS. However, if you been in the field for decades you realise that science happens slowly and incrementally and even when it does deliver real groundbreaking innovations and results, the field is often not ready to adopt them. Why? Social scientists know the answers to this, which is why I spend more time nowadays reading the social sciences than I do reading the sciences.  

For example, the biggest class of innovations to hit the field of MS during my career are the immune reconstitution therapies (IRTs), i.e. alemtuzumab, cladribine and HSCT. Many pwMS who have been treated with IRTs are now in longterm remission and have potentially been cured of their MS.  Yes, these individuals may live out their lives with no further attacks. The rate of adoption of IRTs is depressingly low and with COVID-19 and its fallout, they are being abandoned as treatment options by many HCPs. 

I think we as a field are making a big mistake by abandoning IRTs. As a class, IRTs have to be the answer to how we will treat MS in the future. I envisage using IRTs as true induction therapies and following them with targeted maintenance treatments (e.g. antivirals) and add-on remyelination and neurorestorative therapies in the future. IRTs are the gateway to really changing the lives of pwMS, yet we seem to be abandoning them.

Please note I personally think anti-CD20 therapies should be used as IRTs; i..e. two years of treatment with a high-dose followed by maintenance therapy. This will also make anti-CD20 therapies safer as a class; their Achille’s heel will always be longterm safety.

Back to World MS Day. The objectives of #MSConnections reminds me of our #ThinkSocial campaign, which is to focus on the social determinants of health (SDoH) and how they impact on MS outcomes. 

What are the SDoH?

The SDoH are life-enhancing resources, such as food supply, housing, economic and social relationships, transportation, education and health care, whose distribution across populations effectively determines length and quality of life. As MS is such a disabling disease with poor quality of life it is likely to impact on the SDoH, which in turn will have a negative feedback and make MS outcomes worse. This vicious cycle has to be broken if we want to optimise MS outcomes; i.e. when applying the philosophy of marginal gains we can’t ignore the SDoH when managing someone with MS. 

The Swedish study below, which I often quote, is an example of how having MS reduces your earnings. Interestingly, the reduction in earnings even begins before MS diagnosis and clearly increases thereafter. I suspect some people who have prodromal MS have difficulty working, which impacts on the average outcome or earnings. Besides sickness absence and disability pension, educational level and type of occupation are influential determinants of earnings in pwMS. In other words, inequality plays a role in determining your earnings once you have MS. Are you surprised? I am not.

Very few HCPs routinely screen for the SDoH during consultations. I think we are making a mistake by not. The following is a shortlist of some of the SDoH that may impact on MS outcomes:

1. Level of education and health literacy
2. Poverty (absolute or relative)
3. Employment / unemployment
4. Access to social services (personal independent payments, etc.)
5. Home environment (heating, cleanliness, amenities, etc.)
6. Local environment (safety, green spaces, amenities, etc.)
7. Food poverty (absolute or relative)
8. Transport (access and costs)
9. Childcare (access and costs)
10. Social isolation (social networks, access to the internet, mobile phone, data, etc.)
11. Lifestyle factors (sedentary vs. active, smoking, alcohol and other addictions)
12. Need to be looked after by a child (childcarer) or ageing parents or other family members (aged carers)
13. Cognitive impairment and hidden psychiatric comorbidities (depression and anxiety)
14. Physical and emotional abuse

How do we address these issues during a consultation without upsetting pwMS by being too overbearing? Some solutions to improving or at least addressing the SDoH could include:

1. Provide information about IT solutions to help pwMS.
2. A high-risk register of patients within the MS service; patients on this list would need to be seen and contacted more frequently, ideally on pre-planned and regular basis.
3. Selective home visit programme. 
4. Making sure patients know that they can get hospital transport so they don’t go out of pocket or reimburse their travel costs. 
5. Convert were possible physical face-2-face visits with telemedicine options (COVID-19 has turbocharged this change).
6. To do a complex needs assessment similar to what is done in other disease areas to identify high-risk or vulnerable patients.
7. Encourage the government to waive prescription costs for pwMS and other disabilities.
8. Encourage the government to create a healthy food voucher system for pwMS and other disabilities.
9. Encourage the government to improve social services for pwMS and other disabilities.
10. Engage pwMS and include them in your service; for example, using an MS Health Champions model.
11. Explore social prescribing to increase social capital.
12. Enrol all patients into a lifestyle and wellness programme.

On World MS Day do you have any suggestions we can add to the list? I co-chair the SDoH workstream on our Raising the bar initiative so any workable ideas may get implemented in the NHS or as part of social services. 

Wiberg et al. Earnings among people with multiple sclerosis compared to references, in total and by educational level and type of occupation: a population-based cohort study at different points in time. BMJ Open. 2019 Jul 11;9(7):e024836. 

OBJECTIVES: To investigate earnings among people with multiple sclerosis (PwMS) before and after MS diagnosis compared with people without MS, and if identified differences were associated with educational levels and types of occupations. Furthermore, to assess the proportions on sickness absence (SA) and disability pension (DP) in both groups.

DESIGN: Population-based longitudinal cohort study, 10 years before until 5 years after MS diagnosis.

SETTING: Working-age population using microdata linked from nationwide Swedish registers.

PARTICIPANTS: Residents in Sweden in 2004 aged 30-54 years with MS diagnosed in 2003-2006 (n=2553), and references without MS (n=7584) randomly selected by stratified matching.

OUTCOME MEASURES: Quartiles of earnings were calculated for each study year prior to and following the MS diagnosis. Mean earnings, by educational level and type of occupation, before and after diagnosis were compared using t-tests. Tobit regressions investigated the associations of earnings with individual characteristics. The proportions on SA and/or DP, by educational level and type of occupation, for the diagnosis year and 5 years later were compared. 

RESULTS: Differences in earnings between PwMS and references were observed beginning 1 year before diagnosis, and increased thereafter. PwMS had lower mean earnings for the diagnosis year (difference=SEK 28 000, p<0.05), and 5 years after diagnosis, this difference had more than doubled (p<0.05). These differences remained after including educational level and type of occupation. Overall, the earnings of PwMS with university education and/or more qualified occupations were most like their reference peers. The proportions on SA and DP were higher among PwMS than the references.

CONCLUSIONS: The results suggest that the PwMS’ earnings are lower than the references’ beginning shortly before MS diagnosis, with this gap increasing thereafter. Besides SA and DP, the results indicate that educational level and type of occupation are influential determinants of the large heterogeneity of PwMS’ earnings.

CoI: multiple

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