Safety of Newer Disease Modifying Therapies in Multiple Sclerosis

Abstract

In the past decade, the therapeutic arsenal for multiple sclerosis has expanded greatly. Newer more potent disease modifying therapies (DMTs) with varying mechanisms of actions are increasingly used early in the disease course. These newer DMTs include oral therapies (teriflunomide, dimethyl fumarate, fingolimod, siponimod, ozanimod, and cladribine) and infusion therapies (natalizumab, alemtuzumab, and ocrelizumab), and are associated with better control of disease activity and long-term outcomes in patients with MS compared to older injectable therapies (interferon beta and glatiramer acetate). However, they are associated with safety concerns and subsequent monitoring requirements. Adverse events are initially observed in phase 2 and 3 clinical trials, and further long-term data are collected in phase 3 extension studies, case series, and post-marketing reports, which highlight the need to periodically re-evaluate and adjust monitoring strategies to optimize treatment safety in an individualized approach.

Therapy Switches in Fingolimod-Treated Patients with Multiple Sclerosis: Long-Term Experience from the German MS Registry

“…If disease activity is present despite (selective) immunosuppressive therapy, a rapid switch to more effective DMDs, such as monoclonal antibodies (e.g., natalizumab or ocrelizumab), represents an appropriate option. Nevertheless, switching to monoclonal antibodies should be weighed on an individual basis, as the selectivity and high efficacy are also offset by the risk of severe adverse drug events [ 47 ]. For example, PML in patients on natalizumab and eventual respiratory tract infections in those on ocrelizumab should be considered when switching to a new treatment [ 47 ], as adverse drug events were the second most frequent reason for therapy changes (35.1%) in our study.…”

Superoxide Dismutase-1 Intracellular Content in T Lymphocytes Associates with Increased Regulatory T Cell Level in Multiple Sclerosis Subjects Undergoing Immune-Modulating Treatment

“…Low intracellular SOD-1 level in T lymphocytes characterized MS-RR subjects treated with fingolimod ( Figure 1 ). Such a feature is conceivable with the ability of the drug to trap lymphocytes inside secondary lymphoid organs [ 25 , 26 , 27 ], likely inhibiting SOD-1 induction, usually associated with antigen-dependent T-cell activation [ 11 ]. This mechanism, likely hampering the recognition of neural antigens by pathological T cells, might underlie the lack of SOD-1 increase that we observed in MS subjects undergoing effective fingolimod treatment.…”

“…A wide array of immune-modulating treatment options has been described for MS, but the molecular mechanisms underlying their ability to shape the deranged immune response in the central nervous system (CNS) is not completely understood [ 25 , 26 , 27 ]. In this regard, the main therapeutic approaches for MS are represented by: IFN β 1b, described to mediate attenuation of immune cell functions inside the CNS; glatimer acetate, a mixture of polypeptides able to exert immune suppression; teriflunomide, an inhibitor of dihydroorotate-dehydrogenase, a key mitochondrial enzyme involved in the de novo synthesis of pyrimidines in rapidly proliferating cells such as lymphocytes; dimethyl fumarate, able to mediate T H 1/T H 2 shift as well as to act on endogenous cellular antioxidative pathways involving the Nrf2 transcription factor; cladribine, a purine analogue acting as immune suppressor; and fingolimod, a structural analogue of sphingosine which is able to modulate sphingosine 1 phosphate receptor in immune and brain cells [ 25 , 26 , 27 ].…”

COVID-19 Vaccine intent in appalachian patients with multiple sclerosis

“…United States Census Bureau. 2010 ) Due to the common notion that older MS therapies such as interferons and glatiramer acetate are “safer” due to their well-established long-term safety profiles and monitoring strategies, ( Jalkh et al, 2020 ) we also grouped participants by their disease-modifying therapy (DMT) types. DMT was categorized as older, newer, and none.…”

“…( Marrie et al, 2021 ) Some newer DMTs (excluding interferons and glatiramer acetate) are also thought to be associated with safety concerns due to their long lasting immunosuppressive and immunomodulatory effects and require monitoring for infectious diseases. ( Jalkh et al, 2020 ) It is therefore important to know and understand the vaccine intent of this population. In this study, we conducted a cross-sectional survey aimed to determine COVID-19 vaccine intent in Appalachian PwMS and to examine factors associated with vaccine hesitancy.…”