Skill Checkup: Suboptimally Treated Relapsing-Remitting Multiple Sclerosis (RRMS)

Christopher Luzzio, MD


January 26, 2022

According to the 2018 American Academy of Neurology Practice Guidelines on disease-modifying therapies (DMTs) for adults with MS, in cases involving breakthrough disease activity, trying a medication with a different mechanism or efficacy profile may be beneficial. Since the publication of those guidelines, numerous new agents with varying mechanisms of action have been approved by the US Food and Drug Administration and further expanded RRMS treatment options, including siponimod (tablets), cladribine (tablets), diroximel fumarate (delayed-release capsules), ozanimod (capsules), monomethyl fumarate (delayed-release capsules), ofatumumab (injection), and ponesimod (tablets).

The use of injectable therapies has lessened because of the development of alternative DMTs that have greater efficacy. These DMTs include the monoclonal antibodies alemtuzumab, natalizumab, and ocrelizumab and the sphingosine l-phosphate receptor modulator fingolimod. Another monoclonal antibody, ofatumumab, has been shown to be more efficacious than teriflunomide for preventing MS relapses. In this case, given the patient's dislike of self-injectable therapy, an oral drug may be an option to improve adherence. Available oral DMTs for RRMS include fingolimod, teriflunomide, dimethyl fumarate, siponimod, ozanimod, cladribine, and ponesimod. When deciding on the most appropriate course of treatment and the subsequent continuation of therapy, several elements are taken into account with the goal of adherence in mind, such as efficacy and a favorable safety profile. Frequent patient-physician communication is integral in optimizing adherence and desired outcomes.

Replacing interferon beta-1b with a cytokine inhibitor is not a reasonable option. Inhibition of individual cytokines in MS has not proven to be effective or, in the case of daclizumab, safe.

The monoclonal antibody natalizumab as been studied as add-on therapy for individuals with RRMS. One trial showed that adding natalizumab to interferon was more effective than placebo for decreasing relapses and disability progression over 2 years and the numbers of new or enlarging T2 lesions at 1 year. However, natalizumab is associated with safety concerns involving progressive multifocal leukoencephalopathy (PML), and therefore its use is limited. In a recent study, extended interval dosing (ie, any infusion preceded by 10 or fewer infusions in the prior 365 days) was associated with clinically and statistically significantly lower PML risk than standard interval dosing (ie, any infusion preceded by more than 10 infusions in the prior 365 days).

Prompt treatment optimization and a switch of therapy in patients with suboptimal response to or failure of their current MS treatment are important for efficacy. Accumulating data suggest that there is a limited window of opportunity to effectively intervene in RRMS and that appropriately treating early reduces long-term disability. Updated guidelines from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) advocate earlier treatment initiation.


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