Refusenik

Barts-MS rose-tinted-odometer: ★★

She is only 24 years of age; a graduate trainee in a marketing company. She has a promising future ahead of her. She lives in London and has a long term partner; they met at University. She knows he is the one for her and they are planning to get engaged in the next 1 to 2 years. Like most graduate trainees they find London expensive and share a house with four other people. She has found lockdown very stressful not because she has had to work from home with four other people, but because she was diagnosed with MS in February last year. 

Despite starting DMF (Tecfidera) in June 2020, she had a very disabling relapse over the Christmas period with lower limb weakness and new-onset bladder symptoms. She has also noted a fine tremor in her right hand. Her latest MRI showed several new lesions and a large lesion in her thoracic spinal cord. Her consultant neurologist has offered her ocrelizumab. However, after doing her own online research including reading The MS-Blog (formerly known as the Barts-MS blog) she has asked to be treated with alemtuzumab. Her consultant has said no and pointed out their centre has virtually stopped using alemtuzumab because as a treatment it is too risky and there are much safer options.

Out of desperation this patient went to see a colleague of mine in private who said of course she can have alemtuzumab and she has now been referred to our centre for treatment. We are now in the process of doing the baseline bloods and will hopefully get this patient treated with her first course of alemtuzumab in the next few weeks. Tragically this poor woman has lost time. What would happen if in the interim she has a further catastrophic spinal cord relapse that leaves her paralysed? Who would be responsible? 

I am beginning to refer to my colleagues who are not prepared to offer and use alemtuzumab and HSCT as the ‘refuseniks’. What they don’t realise is that they are putting themselves and their institutions at risk from legal challenge. How come? When NICE (National Institute of Health and Care Excellence) was created it was done so via an act of parliament. NICE’s primary aim was to get rid of the curse of postcode prescribing and variable access to treatments. Therefore if a therapy has been NICE approved the NHS has a legal obligation to offer people a specific treatment if they are eligible for that treatment. Therefore, in the case above her previous consultant is breaking the law and putting not only him or herself at risk of a legal challenge, but the relevant NHS Trust as well.

In 2021 why are neurologists still so paternalistic? Not allowing patients to choose their own treatment is against one of the central tenets of modern medicine.  In reality, it is not the neurologist or the institution where the neurologist works who are taking a risk when someone is treated with alemtuzumab, it is the patient who is taking the risk. Don’t they understand this? It is getting to the point in time when we are going to have to start naming and shaming these refusenik neurologists. Hopefully, when the national audit figures from blueteq, NHS England’s database of high-cost drugs, is published those centres who are not prescribing alemtuzumab or offering referral for HSCT will be exposed. I am of the opinion that if you are not using alemtuzumab or HSCT in a proportion of your patients with highly active MS then you and your centre are not managing MS the way it should be managed in 2021.

I am sure not all of my neurology colleagues will agree with me; do you?

Conflicts of Interest

Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

Do no harm

Primum non-nocere is a Latin phrase that means “first, do no harm”. 

On the tube this morning I recognised one of our medical students reading Henry Marsh’ book “Do no harm”.  He is a semi-retired neurosurgeon, turned author, who uses his past patients to discuss ethical dilemmas and to criticise the NHS. His book does showcase the life of a surgeon, warts and all.  It is clear that to be a good neurosurgeon you have to be a team player. In surgery, it is critical to get the clinical decision-making correct, i.e. when and when not to operate. Surgery is also a technical speciality above all else; from the age of about 55 a surgeon’s skills deteriorate so it is best to be operated on by someone who is in their prime. In short, if you make the wrong clinical decision and you get things wrong technically then you will get a suboptimal outcome; i.e. you will do harm. 

I remember from very early on in my medical school career being told to do no harm. It is important to understand that this phrase dates back from a bygone era; an era when we hardly had any treatments that worked. 

Wikipedia: It is often said that the exact phrase “First do no harm” is a part of the original Hippocratic oath. Although the phrase does not appear in the AD 245 version of the oath, similar intentions are vowed by, “I will abstain from all intentional wrong-doing and harm”. The phrase “primum non nocere” is believed to date from the 17th century. Another equivalent phrase is found in Epidemics, Book I, of the Hippocratic school: “Practice two things in your dealings with disease: either help or do not harm the patient”. The exact phrase is believed to have originated with the 19th-century English surgeon Thomas Inman. 

In the modern era, we have to walk a tightrope of treating people to prevent future harm from a specific disease, knowing well that a small number of patients will be harmed from the side effects of the treatment. In other words, modern medicine has become a balancing act between the outcome of a population of patients at the expense of a small number of patients with adverse events. 

In the MS space, natalizumab epitomises this dilemma. Natalizumab is one of our most effective DMTs; it is very effective, easy to use and has few adverse events, which are uncommon. Unfortunately, however, in JC virus-positive individuals it may result in PML  a life-threatening infection of the brain. A lot has been done to derisk this complication, but unfortunately, there are still pwMS developing PML as a complication of natalizumab.

One industry analyst said to me that he had no idea why natalizumab was still on the market. He felt it should have been withdrawn after the PML crisis emerged. I said to this individual that he clearly hasn’t seen the impact that natalizumab has on people with MS’ lives. Natalizumab is a truly a transformative drug, which is why I refer to the treatment of MS as being represented by two eras; pre- and post-natalizumab. 

It is clear that pwMS understand that to maximise outcomes for pwMS some individuals have to pay the price of suffering adverse events. This is why it is not surprising that pwMS are prepared to take greater risks than their risk-averse neurologists (see below). I recall working with a rheumatologist who made the point that if he didn’t have a few of his patients dying each year from the complications of his treatment decisions then he was not treating his patients actively enough. The corollary is that a rheumatologist without a body count is being too conservative. 

Could the same analogy be levelled at neurologists? I think yes. I am still seeing far too many pwMS for second or third opinions who are very disabled from watchful waiting, slow escalation or sideways switching when they should have been treated with high efficacy treatments years ago. We really need to change the behaviour of MSologists from being risk-averse to becoming risk-takers. This also means pulling no punches and telling pwMS how bad MS really is and that to maximise your outcome you need to treat the disease effectively early on. 

At Barts-MS we are taking this principle to the extreme with our #AttackMS trial. As always the ideas underpinning this trial are already being adopted by our team so that by the time we get the trial funded and up and running we may not be able to do the study because we would have lost equipoise. 

Wikipedia: Clinical equipoise, also known as the principle of equipoise, provides an ethical basis for medical research that involves assigning patients to different treatment arms of a clinical trial. In short, clinical equipoise means that there is genuine uncertainty in the expert medical community over whether a treatment will be beneficial. 

I would be interested to know the MS Community’s opinions on the #AttackMS trial

Heesen et al. Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists. Mult Scler. 2010 Dec;16(12):1507-12. 

BACKGROUND: Natalizumab is associated with the potentially life-threatening side-effect progressive multifocal leukoencephalopathy (PML). Little is known about patients’ and physicians’ risk estimates and attitudes towards natalizumab treatment.

METHODS: Consecutive natalizumab-treated patients (n = 69) and neurologists (n = 66) in two centres and cooperating private practices received an evidence-based three-page information leaflet about natalizumab-associated PML and an evaluation sheet.

RESULTS: After reading the information, patients were significantly more likely than physicians to intend continuation of natalizumab treatment and willing to accept higher risks of PML: 49% of physicians would stop treatment at a PML risk of 2:10,000 or lower, while only 17% of patients would do so (p < 0.001). This difference could not be explained by risk calculation abilities or lack of understanding. Both groups overestimated natalizumab treatment effects.

CONCLUSION: Patients had a significantly worse perception of multiple sclerosis as a malignant disease. We conclude that patients were willing to accept a higher risk of PML than neurologists. Coherent with their perception of risks and benefits, patients were also more willing to continue treatment. Open information about treatment-related risks is appreciated and might support shared decision making.

CoI: multiple