Immunological Mechanism of Action and Clinical Profile of Disease-Modifying Treatments in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials.

MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis

“…Furthermore, differentiation of human Th17 occurs independently of TGFb (Acosta-Rodriguez et al, 2007;Wilson et al, 2007), and TGFb induces IL-10 expression in autoreactive Th1 cells, promoting a self-regulation mechanism (Huss et al, 2010). IL-10 production has been shown to be impaired in patients with multiple sclerosis (Cao et al, 2015), but positively associated with therapeutic benefit (Du Pasquier et al, 2014). Thus, diminished TGFb signalling would potentially allow encephalitogenic Th1 cells to mediate pathology more robustly due to a lack of inherent regulation.…”

Impact of trial design and patient heterogeneity on the identification of clinically effective therapies for progressive MS

“…The inflammatory drivers of relapses are relatively well understood, which has led to the development of several DMTs highly effective at preventing relapses. 24 In contrast to relapses, progression is generally characterized by diffuse neurodegeneration not obviously associated with specific inflammatory activity, and the underlying mechanisms are less clear. 25 Demyelination itself can cause axons to lose trophic support, and thus induce neurodegeneration, 26 but the lack of translation by highly effective RRMS DMTs suggests that the axonal pathology in PMS may be driven by distinct mechanisms from relapses.…”

Available Pharmacological Options and Symptomatic Treatments of Multiple Sclerosis

“…7 In contrast, no DMT has been observed to have any potential in the management of primary progressive MS yet. 8 However, DMTs mechanism of action is based on the pathophysiological hypothesis of inflammation and immune system attacks on the neurons and myelin sheaths. 9 Therefore, altering the immune system functions would potentially result in a lowered number of invasions on neurons; hence, reducing the disease progression.…”