clinical topic updates

Newer Disease-Modifying Therapies for Relapsing Forms of Multiple Sclerosis

by Malcolm H. Gottesman, MD


An increased understanding of the pathophysiology of multiple sclerosis (MS) has led to the development and recent US Food and Drug Administration approvals of several disease-modifying therapies (DMTs) for relapsing-remitting MS. Having these additional options provides clinicians and patients with greater flexibility when making treatment decisions.

Expert Commentary

Malcolm H. Gottesman, MD

Chief Emeritus, Division of Neurology
Winthrop Comprehensive MS Care Center, NYU Langone Hospital
Professor, Department of Neurology
NYU Long Island School of Medicine
Mineola, NY

". . . the anti-inflammatory landscape is fairly well covered with our available therapies, and what we currently need is a paradigm shift toward agents that would promote remyelination and prevent neurodegeneration.”

Malcolm H. Gottesman, MD

The newly approved DMTs, in general, are high-efficacy drugs that should be used primarily in younger patients with newly diagnosed relapsing-remitting MS and active disease. I follow a de-escalation paradigm, giving the more potent DMTs initially and then switching to less potent drugs as needed as the patient gets older. The newer DMTs are difficult to compare because they have not been around for very long and they have not been studied under the same conditions. That said, each novel approach is associated with its own unique profile.

For CD20-directed B-cell–depleting therapy, contraindications include active hepatitis B virus infection, and there are precautions regarding the risk of infection. The B-cell depleters are excellent drugs, but I think that COVID-19 has resulted in many changes, some of which relate to vaccine efficacy. The antibody response to vaccines such as those for COVID-19 or boosters may be attenuated in patients receiving these agents. Ocrelizumab is given every 6 months, which may allow some time for B-cell reconstitution. If you are giving monthly injections of a drug such as ofatumumab, which is a great convenience because patients can administer the agent at home, there is less opportunity for reconstitution, and patients may fail to achieve an effective immune response with COVID-19 boosters.

It appears that natalizumab does not interfere very much with vaccines, unlike the B-cell–depleting agents. Unfortunately, COVID-19 booster shots may become necessary, and I am not as enthusiastic about the B-cell depleters as I used to be, for that reason. The sphingosine-1-phosphate inhibitors are taken orally. They are not quite as potent clinically as natalizumab and the B-cell depleters, and they have the potential for cardiac side effects, but I have been impressed by them.

Taking a broad view, the anti-inflammatory landscape is fairly well covered with our available therapies, and what we currently need is a paradigm shift toward agents that would promote remyelination and prevent neurodegeneration. The best we can do is to shut down MS with whatever it takes as soon as it is diagnosed. This can be done safely and for extended periods, and I have observed the benefits of this approach. If you stop the disease process definitively and rapidly, many patients with MS will do extremely well, much better than in the past. You cannot delay treatment, as the first few years are critical. If a patient develops new lesions, for example, that is bad news because new lesions sow the seeds for neurodegeneration. Once there is a fair amount of demyelination, I think that patients are in trouble no matter what you do in terms of shutting off inflammation.


Bosanac T, Hughes RO, Engber T, et al. Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy. Brain. 2021 May 8;awab184. doi:10.1093/brain/awab184

Bross M, Hackett M, Bernitsas E. Approved and emerging disease modifying therapies on neurodegeneration in multiple sclerosis. Int J Mol Sci. 2020;21(12):4312. doi:10.3390/ijms21124312

Faissner S, Gold R. Oral therapies for multiple sclerosis. Cold Spring Harb Perspect Med. 2019;9(1):a032011. doi:10.1101/cshperspect.a032011

Lassiter G, Melancon C, Rooney T, et al. Ozanimod to treat relapsing forms of multiple sclerosis: a comprehensive review of disease, drug efficacy and side effects. Neurol Int. 2020;12(3):89-108. doi:10.3390/neurolint12030016

McAlpine LS, Fesharaki-Zadeh A, Spudich S. Coronavirus disease 2019 and neurodegenerative disease: what will the future bring? Curr Opin Psychiatry. 2021;34(2):177-185. doi:10.1097/YCO.0000000000000688

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