Dimethyl fumarate treatment in multiple sclerosis: Recent advances in clinical and immunological studies

Abstract

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) in which demyelination and neurodegeneration occurs. The immune system of MS patients is characterized by a dysregulation in the balance between pro- and anti-inflammatory immune cells, whereby both the innate and adaptive immune system are involved. Dimethyl fumarate (DMF) was licensed in 2013 as an oral first-line therapy for relapsing-remitting (RR)MS patients. It has a strong efficacy with neuroprotective and immunomodulatory effects and a favourable benefit-risk profile. However, the effects of DMF on the immune system of MS patients were not clear before entering the market. During the last years, numerous in vitro and ex vivo studies have clarified the working mechanism of DMF in MS. Here, we discuss the pharmacokinetics of DMF and its effect on molecular immune-related pathways, which is further linked to the clinical and immunological effects of DMF treatment. The efficacy and safety of DMF treatment for RRMS is discussed as reported from clinical trials. Further, the immunological effects of DMF treatment in RRMS patients are addressed in more detail, including the distribution and function of immune cells. Taken together, evidence from recent studies points to a multifactorial working mechanism of DMF treatment in MS which leads to a restored immune balance favouring a more tolerogenic or anti-inflammatory immune profile.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) in which infiltrated autoreactive immune cells damage the myelin resulting in a chronic demyelinating and neurodegenerative disease [1]. MS is generally diagnosed in young adults and affects approximately 2.3 million people worldwide [1,2]. Relapsing-remitting (RR) MS is the most common form of the disease that occurs in 80% of all MS patients and shows periods of clinical relapses alternated with periods of remission [1,3]. Different neuroanatomical locations are affected in MS, which results in a wide range of clinical symptoms such as sensory loss, fatigue, widespread weakness, spasticity, blurred vision, depression and cognitive symptoms [1,4,5]. Within 20 years of diagnosis, half of the MS patients need mobility assistance and eventually develop extensive cognitive decline [1]. MS is thought to have a multi-causal character, in which a combination of genetic and environmental risk factors are involved [1,6,7]. Until now, no cure is available. Nonetheless, several disease-modifying treatments exist and the most common treatment strategy is to start with first-line treatments, followed by second line treatments when initial treatment doesn't work [[8], [9], [10]].

The pathogenesis of MS features CNS-directed autoimmune responses that lead to the formation of sclerotic plaques via demyelination, astrocytosis, oligodendrocyte depletion and axonal degeneration [1,11]. Autoreactive CD4⁺ T cells are activated in secondary lymphoid organs via molecular mimicry, bystander effects or cross-reactivity following a failure of tolerance checkpoints [[12], [13], [14], [15]]. These CD4⁺ T cells migrate to the CNS where they are reactivated and produce inflammatory mediators such as cytokines and chemokines [12,16]. The inflammatory mediators attract other immune cells such as B cells, CD8⁺ T cells and macrophages. Together, the infiltrated immune cells cause an inflammatory reaction which leads to demyelinated lesions throughout the CNS [11,15]. Next to this “outside-in” model, the “inside-out” hypothesis states that the pathological processes in MS start in the CNS with the activation and infiltration of autoreactive lymphocytes occurring as a secondary event [16].

The immune system of MS patients is characterized by a dysregulated balance favouring pro-inflammatory responses. T cells have long been thought to be the most important players in MS pathogenesis. Effector memory CD4⁺ T cells can differentiate into T helper 1 (Th) 1 and Th17 cells, which produce pro-inflammatory cytokines including interferon-γ (IFN- γ) or interleukin-17 (IL-17), respectively, and granulocyte macrophage colony-stimulating factor (GM-CSF) [17,18]. CD8⁺ T cells exert cytotoxic functions [19] while central memory CD4⁺ T cells are prevalent in the cerebrospinal fluid of MS patients, provide help for B cell activation and stimulate dendritic cells [15]. More recently, the emergence of B cell depleting treatment has emphasized the importance of B cells in MS pathogenesis [16,20]. Memory B cells, both IgD⁻CD27⁺ class-switched memory (CSM) and IgD⁺CD27⁺ non class-switched memory (NCSM), are involved in MS pathology by antigen presentation, cytokine production and costimulation of T cells [[21], [22], [23]]. Further, IgD⁻CD27⁻ double negative (DN) B cells with pro-inflammatory characteristics were recently described to be abnormally elevated in a proportion of MS patients [24]. For the innate immune system, monocytes act as phagocytes, produce pro-inflammatory factors and reactive oxygen species (ROS) [15]. Natural killer (NK) cells, including CD56^dimCD16⁺ NK cells and CD56^brightCD16^dim NK cells, are involved in the pathogenesis of MS by a disrupted killing activity and a lowered suppression of CD4⁺ T cell proliferation [[25], [26], [27]]. Responses of non-pathological and anti-inflammatory immune cells are underrepresented in MS, which is one of the underlying causes of the immune imbalance observed in MS patients [[28], [29], [30]]. These non-pathological immune cells include naive T and B cells, T helper 2 (Th2) cells, producing IL-4, and regulatory T and B cells (Treg and Breg), producing IL-10.

Dimethyl fumarate (DMF, Tecfidera®, also known as BG-12) was licensed as the first oral first-line therapy for RRMS in 2013. Although it was known that DMF treatment had neuroprotective and immunomodulatory effects [31,32], its multifactorial working mechanism was not fully unravelled at that time. In this review, we describe the molecular, clinical and immunological studies that have contributed to clarifying the mode of action of DMF.