Risk Tolerance to MS Therapies Varies


Understanding risk perception and risk tolerance can lead to greater satisfaction with treatment choices and adherence for patients with MS.

Dr Robert Fox

Robert Fox, MD, neurologist and medical director at the Mellen Center for Multiple Sclerosis at Cleveland Clinic

Robert Fox, MD

A recent study determined the tolerance to various risk scenarios associated with current multiple sclerosis therapies and found that risk tolerance differs according to sex, age, disability level, and current disease-modifying therapies (DMTs), which indicates that treatment preferences across these characteristics are also likely to vary.

With the increasing number of DMTs available for treatment of MS, researchers sought to explore risk tolerance to 6 real-world risks associated with current DMTs: skin rash, infection, kidney injury, thyroid injury, liver injury, and progressive multifocal leukoencephalopathy (PML)

“We surveyed over 3000 people living with MS to understand their tolerance to risks associated with MS therapies,” Robert Fox, MD, Vice Chair, Research, Cleveland Clinic Neurological Institute, told NeurologyLive in an interview. “We found that people with MS have varying views regarding the risks they would be willing to take with an MS therapies. Despite this variation, we observed some trends: men, younger individuals, and participants with greater disability reported a higher tolerance. Those currently taking MS therapies — particularly infusion therapies – had a higher risk tolerance. We were surprised that disease duration was not associated with a change in risk tolerance. Similarly, although smoking was expected to be associated with a higher tolerance to risks, we did not find that.”

Individuals with multiple sclerosis from the North American Research Committee on Multiple Sclerosis Registry’s online cohort and the National Multiple Sclerosis Society were invited to complete a survey on tolerance to real-world risks associated with a hypothetical therapy. To be included in the analysis, participants were required to answer questions about their sex, disease duration, Patient Determined Disease Steps, and at least 4—6 of the risk scenario questions.

The survey was completed by 3171 individuals with MS; overall, 79% of the participants were female, 92.5% were white the mean age was 55.1 years, and the mean disease duration was 16.6 years. A majority of the participants, 71.5%, reported lower levels of disability (PDDS score 0—4) and only .3% were reported bedridden (PDDS score 8). It was reported that 53.3% of participants reported current use of DMT with similar 22.21% and 22.9% of participants using oral and injectables, respectively, while only 8.6% were on infusion therapies. Approximately 10% of participants reported no use of DMT for treatment.

To compare risk level according to DMT type, researchers classified DMTs as injectable (daclizumab, glatiramer acetate, interferon beta-1a/1b, peginterferon beta-1a), oral (dimethyl fumarate, fingolimod, laquinimod, teriflunomide) or infusion (alemtuzumab, mitoxantrone, natalizumab).

“Our study has potential applications to regulators as they consider risks related to new MS therapies under review,” Fox concluded. “Regulators have the challenge of comparing efficacy and safety and making decisions about what balance between the two are acceptable to patients. We provide granular data regarding what proportion of people living with MS are tolerant to what level of risk across six different potential complications. Clinicians should recognize that although tolerance to risk is highly variable, there are some trends that can help guide a clinician’s discussion with patients.”

Researchers reported that men, younger individuals, and those with greater disability had a higher tolerance to all risk scenarios.

Male participants reported a high tolerance (1:1000) to all complications except kidney injury (1:50,000) and PML (1:100,000), while for all 6 risk complications, female participants consistently reported 2- to 20-fold lower risk tolerance, reporting a risk tolerance of 1:2000 for both infection and thyroid injury (2-fold lower than male participants) and 1:1,000,000 (20-and 10-fold lower) for both kidney injury and PML.

Tolerance for liver injury, kidney injury, and PML decreased with age but the risk tolerance for injection, skin rash, and thyroid injury were not significantly different across age groups. Older participants (>51 years of age) exhibited lower tolerance to liver, kidney, and PML risks than those <41 years of age.

Additionally, researchers stated that in general risk tolerance increased with disability, and those who reported minimal or no disability (PDDS score 0) had the least tolerance to all risks, and those who reported a PDDS score ≥6 had the highest tolerance to all risks.

Those participants currently taking DMTs exhibited 2- to 10-fold higher tolerance than those not taking any therapy with the risk tolerance to infection, liver injury, and PML significantly higher (P <.0001) in DMT users. Participants on infusion therapies reported the highest tolerance to all 6 risks, while those on injectables reported a lower tolerance.

Overall, study participants exhibited the highest tolerance for infection and thyroid injury (risk tolerance 1:1000 for both) and the least tolerance for kidney injury and PML (1:1,000,000 for both).

Asked about the additional questions this research opens up, Fox explained that they only asked about 1 efficacy scenario (50% reduction in relapse rate and 30% slowing in disability progression), so they are unsure of how this applies to other levels of efficacy. Similarly, there were only 6 complications studied and there are many more that could be considered, too.

The study provides clinicians with an understanding that patient characteristics like sex, age, disability level, and current DMT use are more likely to accept different risks of therapies indicating that treatment preferences across these characteristics are more than likely going to be different.


Fox R,


C, MSW, et al. A survey of risk tolerance to multiple sclerosis therapies. Neurology. 2019;92:1—9.


: 10.1212/WNL.0000000000007245.

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