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MS research update - Natalizumab (Tysabri): balancing benefits and risks - 30 December 2013

Summary

This study looked at what factors were associated with a higher level of risk taking. They found that decision making was complex but a higher level of risk was more likely to be accepted by:

  • people on natalizumab compared with those on first line disease modifying drugs
  • those who though that their MS was more severe
  • those with higher scores on neuroticism (defined as a stronger tendency to be tense, anxious and moody)
  • those at highest risk of getting PML (progressive multifocal leukoencephalopathy).
  • those who were JCV positive although at low risk overall of JCV

Someone's relapse rate before treatment or their level of disability, as judged by their EDSS score, did not predict how much risk they were prepared to take.

Background

Risks and benefits

Most things in life involve weighing up the balance of risks and benefits. For example, driving a car has lots of benefits but also carries risks such as the possibility of having an accident. Some people think that the risks outweigh the benefits and decide never to drive. Other people see the balance differently and will drive routinely. Others, such as racing car drivers, will be willing to take a higher than average level of risk perhaps because they experience a thrill and this is a major plus to them although it isn't to most people.

Balancing benefits and risks also takes place when deciding whether to take a particular course of treatment to improve health. Someone will consider the likely benefits but also whether there are risks like side effects. Each individual will have a view on where the balance lies for them.

Estimating risks and benefits only tells you something about the chances of something happening. For example, if one in a hundred people experience dizziness when taking a drug, then 99 people will not feel dizzy. No-one can say who will be the one who does get dizziness.

Natalizumab

Natalizumab, also known as Tysabri, is a disease modifying drug given by intravenous (IV) infusion via a drip once every four weeks. This usually means going into hospital for the day.

The benefits are that it reduces the number of relapses by about two thirds and reduces the rate of disease progression. These benefits have to be weighed up against some relatively minor side effects, including dizziness, vomiting, shivering and joint pain, plus a small risk of getting a serious brain infection called PML (progressive multifocal leukoencephalopathy).

It is possible to assess someone's risk of getting PML using a blood test which detects antibodies to the JCV virus. If someone has not been exposed to the virus, the risk of getting PML is very low. If someone has been exposed, their level of risk will depend on how long they have been treated with natalizumab and whether they had previously taken other immune suppressing drugs.

Because of the risk of PML, natalizumab is only licensed for people who have had two or more disabling relapses in one year (described as rapidly evolving severe relapsing remitting MS) or who have continued to have relapses despite treatment with beta interferon (described as highly active relapsing remitting MS).

How this study was carried out

The participants

114 people with MS on natalizumab treatment were compared with 22 people on first line disease modifying treatments (beta interferon or glatiramer acetate). The researchers recorded age, gender, how long someone had MS, their level of disability using the EDSS scale and the number of relapses per year before beginning treatment.

For the group on natalizumab, the risk of PML was estimated according to the number of doses of drug received, the presence of anti-JCV antibodies and any past history of immunosuppressive treatment. This allowed the group to be split into five sub-groups with different levels of risk of PML.

The assessments

Firstly, the participants were asked two questions about MS:

  • to what extent they thought MS was a severe disease in general (i.e. for people with MS as a whole)
  • to what extent they thought MS was a severe disease in their particular case

They could score anything from 0 (MS is not at all a severe disease) to 10 (MS is the most severe disease you can think of).

Secondly, five personality traits were measured with 12 questions for each one which were then scored. The traits were:

  • neuroticism (a tendency to be tense, anxious and moody)
  • extroversion (directing one's energies and attention outward from oneself)
  • openness (a tendency to be imaginative, curious, insightful and creative)
  • agreeableness (a tendency to be kind, generous, sympathetic and unselfish)
  • responsibility (a willingness to account for one's actions)

Thirdly, five theoretical possibilities were explored, each of which had a different level of risk. Participants were asked if they would continue taking a drug if the chance of a serious side effect was:

  • 1 in two million (very low risk)
  • 1 in 600,000 (low risk)
  • 1 in 5,000 (intermediate risk)
  • 1 in 100 (high risk)
  • 1 in 50 (very high risk)

Participants answered the questions using a scale from 0 (I would not like to continue receiving this drug at all) to 10 (I would like to continue receiving this drug without any doubt). The answers were used to assess how readily someone would accept high or very high risks.

What was found

No differences were found between the treatment groups in their personality traits or how they perceived the severity of MS in general.

A higher level of risk was accepted by:

  • people on natalizumab compared with those on first line disease modifying drugs
  • those who thought that their MS was more severe
  • those with higher scores on neuroticism (i.e. they had a stronger tendency to be tense, anxious and moody)
  • those at highest risk of getting PML
  • those who were JCV positive although at low risk overall of JCV

Someone's relapse rate before treatment or their level of disability, as judged by their EDSS score, did not predict how much risk they were prepared to take.

What does it mean?

The authors concluded that how much someone will accept risk depends on several things, including their personality, but also that they may have adapted to accept a higher risk because of their particular situation (such as being JCV positive).

The group on natalizumab were more willing to accept risks but the authors could not tell if this was because natural risk takers were more willing to go onto natalizumab or whether people on natalizumab became more willing to take risks over time.

Those with more aggressive MS, as judged by their level of disability or their relapse rate, were not greater risk takers. This was a surprise result as the authors predicted that this group would probably have been more likely to try new, more risky therapies, if that meant that the chance to slow down their disease activity was greater too.

The authors concluded that their study shows how complex decision making is in any particular situation.

Tur C, Tintoré M, Vidal-Jordana A, et al.
Risk acceptance in multiple sclerosis patients on natalizumab treatment. 
PLoS One. 2013 Dec 10;8(12)
abstract
Read the full text of this paper

More about decision making

People are being asked to be more involved in decisions about their healthcare. Ideally a decision about what treatment is right for you will be reached by considering the benefits you might expect and any potential associated risks. This includes effects on lifestyle such as when and how a course of treatment is taken. Whilst a neurologist may be an expert in MS, you are the expert in your own MS and how it affects your life; you know your own goals for the treatment and your commitment to stick to the course.

An NHS campaign launched in 2012 recommended three questions to ask your doctor or MS nurse to help you make choices and give you more say in your own healthcare:

Ask 3 Questions

  1. What are my options?
  2. What are the pros and cons of each option?
  3. How do I get support to help me make a decision that is right for me?

Research by topic areas...

Symptoms and symptom management

Veauthier C, Paul F. 
Sleep disorders in multiple sclerosis and their relationship to fatigue.
Sleep Med. 2013 Nov 15. [Epub ahead of print]
abstract

Ahmed A, Simmons Z.
Pseudobulbar affect: prevalence and management.
Ther Clin Risk Manag. 2013;9:483-489. Epub 2013 Nov 29. 
abstract
Read the full text of this paper

Nagaraj K, Taly AB, Gupta A, et al.
Depression and sleep disturbances in patients with multiple sclerosis and correlation with associated fatigue.
J Neurosci Rural Pract. 2013 Oct;4(4):387-91.
abstract
Read the full text of this paper

Coggrave M, Norton C.
Management of faecal incontinence and constipation in adults with central neurological diseases.
Cochrane Database Syst Rev. 2013 Dec [Epub ahead of print]
abstract
Read the full text of this paper

Disease modifying treatments

Maillart E, Louapre C, Lubetzki C, et al.
Fingolimod to treat severe multiple sclerosis after natalizumab-associated progressive multifocal leukoencephalopathy: a valid option? 
Mult Scler. 2013 Dec 23. [Epub ahead of print] 
abstract

Shirani A, Zhao Y, Karim ME, et al.
Investigation of heterogeneity in the association between interferon beta and disability progression in multiple sclerosis: an observational study.
Eur J Neurol. 2013 Dec 18. [Epub ahead of print]
abstract

Coyle PK.
Switching therapies in multiple sclerosis.
CNS Drugs. 2013 Apr;27(4):239-47.
abstract

Drugs in development

Liu J, Wang LN, Zhan S, et al.
Daclizumab for relapsing remitting multiple sclerosis.
Cochrane Database Syst Rev. 2013 Dec [Epub ahead of print]
abstract

Rehabilitation

Yu CH, Mathiowetz V.
Systematic review of occupational therapy-related interventions for people with multiple sclerosis: part 2. Impairment.
Am J Occup Ther. 2014 Jan-Feb;68(1):33-8.
abstract

Yu CH, Mathiowetz V.
Systematic review of occupational therapy-related interventions for people with multiple sclerosis: part 1. Activity and participation.
Am J Occup Ther. 2014 Jan-Feb;68(1):27-32.
abstract

Gacias M, Casaccia P.
Promoting return of function in multiple sclerosis: An integrated approach.
Mult Scler Relat Disord. 2013 Oct 1;2(4).
abstract

Ahmadi A, Arastoo AA, Nikbakht M, et al.
Comparison of the effect of 8 weeks aerobic and yoga training on ambulatory function, fatigue and mood status in MS patients.
Iran Red Crescent Med J. 2013 Jun;15(6):449-54.
abstract
Read the full text of this paper

Assessment tools

Potter K, Cohen ET, Allen DD, et al.
Outcome measures for individuals with multiple sclerosis: recommendations from the American Physical Therapy Association Neurology Section Task Force.
Phys Ther. 2013 Dec 20. [Epub ahead of print]
abstract

Kuspinar A, Finch L, Pickard S, et al.
Using existing data to identify candidate items for a health state classification system in multiple sclerosis.
Qual Life Res. 2013 Dec 15. [Epub ahead of print]
abstract

Paediatric MS

Huppke B, Ellenberger D, Rosewich H, et al.
Clinical presentation of pediatric multiple sclerosis before puberty.
Eur J Neurol. 2013 [Epub ahead of print]
abstract

Psychological aspects

He D, Zhang Y, Dong S, et al.
Pharmacological treatment for memory disorder in multiple sclerosis.
Cochrane Database Syst Rev. 2013 Dec [Epub ahead of print]
abstract
Read the full text of this paper

Pathophysiology

Gamboa OL, Tagliazucchi E, von Wegner F, et al.
Working memory performance of early MS patients correlates inversely with modularity increases in resting state functional connectivity networks.
Neuroimage. 2013 Dec 19. [Epub ahead of print]
abstract

Pregnancy and childbirth

Lu E, Wang BW, Alwan S, et al.
A review of safety-related pregnancy data surrounding the oral disease-modifying drugs for multiple sclerosis.
CNS Drugs. 2013 Dec 17. [Epub ahead of print]
abstract

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