The Importance of Disease-Modifying Therapy Sequencing in Multiple Sclerosis


The neurologist at Cleveland Clinic’s Lou Ruvo Center for Brain Health spoke to the need for data on the proper sequencing strategies for patients with MS who are switching disease-modifying therapies.

Dr Carrie Hersh

Carrie Hersh, DO, MSc, MS neurologist, Cleveland Clinic Lou Ruvo Center for Brain Health

Carrie Hersh, DO, MSc

Recently published data from Carrie Hersh, DO, MSc, neurologist, Cleveland Clinic Lou Ruvo Center for Brain Health, and colleagues suggested that patients with multiple sclerosis (MS) who are switching off of natalizumab have a relatively increased risk of disease activity within 6 months when switching to a moderate efficacy disease-modifying therapy (DMT) compared to switching to a high-efficacy therapy.

Disease activity was sustained at 24 months, yielding greater disability progression for those individuals. The data reveal important, real-world information for clinicians who may be transitioning patients off of natalizumab, particularly those who are switched due to breakthrough disease. Notably, Hersh and colleagues utilized a propensity score model to ensure the groups were comparable.

To find out more about the insights these data offer and what still needs to be done, NeurologyLive spoke with Hersh in an interview.

NeurologyLive: What prompted this study with natalizumab?

Carrie Hersh, DO, MSc: There is a large and rapidly expanding neurotherapeutic landscape in the multiple sclerosis field. While randomized clinical trials are necessary for FDA approval of our DMTs, they are limited in providing relevant information in the real-world clinical setting and are cost-prohibitive for comparative effectiveness studies.

In this particular study, we were interested in exploring DMT sequencing strategies following natalizumab withdrawal. Owing to the vast pharmacopeia available in the MS space, not only understanding DMT performance but answering the question of “what can come next,” if a patient needs to discontinue treatment due to safety or breakthrough disease is important. With natalizumab, the potential risk of PML, for instance, can drive patient and provider decision-making to come off of therapy and try a different DMT. Therefore, determining the efficacy and safety of switching to a particular treatment paradigm (moderate- vs high-efficacy therapy) following natalizumab withdrawal can help inform decision-making in routine practice.

What are the key takeaways for clinicians from these data?

Patients transitioning from natalizumab to another high-efficacy therapy have better inflammatory and disability outcomes compared to those who de-escalate their therapy to a moderate-efficacy DMT.

Patients switching from natalizumab to a moderate-efficacy DMT vs high-efficacy therapy are at a relatively increased risk of disease activity within the first 6 months of discontinuing natalizumab. The increased risk of inflammatory disease activity, predominantly driven by new/active inflammatory lesions, is sustained at 24 months and leads to worse disability in those switching from natalizumab to a moderate-efficacy DMT. Our results also demonstrated that switching to a DMT of at least moderate efficacy following natalizumab discontinuation is effective in reducing the risk of rebound disease when restricting the wash-out period to less than 3 months, particularly when switching to a high-efficacy therapy.

Were any of the data points surprising or unexpected in any way?

There were no overt surprises. It was expected that patients transitioning to a highly effective therapy would have better outcomes compared to those who de-escalated therapy. One could consider the comparable ARR as a little surprising, but relapse evaluation in a retrospective manner is limited. Historically, radiographic markers of new inflammation via brain MRI are more objective compared to assessing clinical relapses, especially in a retrospective cohort where relapses cannot be validated by a central agency or the principal investigator.

How do these data add to the understanding of the use of highly effective DMTs such as natalizumab in MS?

The early use of highly effective therapies in multiple sclerosis is becoming more widespread in the MS field, especially with the treat-to-target goal of “No evidence of disease activity” (NEDA). Therefore, more community and academic neurologists alike are becoming more comfortable with the use of these therapies in their MS populations, including natalizumab. This study highlights the real-world implications of switching from natalizumab [when indicated by the patient or provider] to another DMT, specifically one of moderate- vs high-efficacy. Previous studies demonstrated that patients switching to low-efficacy therapy do not fare as well, and therefore, this treatment paradigm was not assessed in this investigation. Further, there were concerns that the current study would not be well-powered to assess patients switching to low-efficacy therapy because of low sample sizes. Overall, the results from the current study suggest that a high-efficacy therapy should be considered in the appropriate setting when transitioning a patient off of natalizumab, especially when due to breakthrough disease.

Is there a need for more assessments like this in MS for other therapies to understand the proper sequencing strategies?

Yes, there is certainly a need for more studies evaluating DMT sequencing strategies across the spectrum. The current study is limited in that it is a two-center study, so there may be a lower generalizability to the general MS population. However, a larger multi-center study assessing DMT sequencing across these therapies should help further validate our findings. A future study of this caliber to investigate the short- and long-term effects of post-natalizumab sequencing is planned to improve upon the external validity of the current study. Certainly, more work evaluating DMT sequencing following the discontinuation of other therapies, such as B-cell depleting agents that are also used quite widely across the MS community, will help narrow the knowledge gap and expand our understanding of the safety and effectiveness of transitioning patients across treatments.

Transcript edited for clarity.


Hersh CM, Harris H, Conway D, Hua LH. Effect of switching from natalizumab to moderate- vs high-efficacy DMT in clinical practice. Neurology Clin Pract. Published online February 12, 2020, DOI:

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