Introductory Chapter: State-of-the-Art Developments in Multiple Sclerosis

1. Introduction

Multiple sclerosis (MS) is an immune-mediated, progressive neurological disease with a heterogeneous course of illness. The symptoms can vary from person-to-person and can include problems with balance, vision, movements of limbs and sensation, cognitive deficits, gait difficulties and bladder dysfunction [1]. According to the World Health Organisation Atlas of MS report in 2020, 2.8 million people were reported to be living with MS worldwide, which is about 1 in 3000 people [1]. MS is nearly twice as more common in females (69%) as compared to males (31%); the majority of diagnosis are made between the ages of 20 and 50 years, although MS also occurs in young children and older adults [1]. More recently, Epstein-Barr virus (EBV) has emerged as an important link in epidemiological studies with patients infected with EBV having a higher risk of developing MS [2]. Smoking and diet also play a significant role in MS. A recent UK biobank study of nearly 8000 people showed that cessation of smoking was related to reduced deterioration in motor function and mobility in MS [3]. A diet that avoids processed foods, gluten, lectins and casein, and a diet that contains low-saturated fats were also found to be helpful in reducing fatigue in MS patients [4].

MS pathogenesis is considered to be autoimmune in nature and myelin proteins have been studied in detail and used to induce MS-like disease features in animal models, termed as experimental autoimmune encephalomyelitis. Some of the other key pathological features include neuroinflammation, breakdown of blood-brain barrier and gliosis. Both innate and adaptive immune systems play a role in MS disease pathogenesis [5]. Taking forward the recent finding of higher risk with EBV infection, a mechanistic link has been found that could possibly explain the role of EBV. Molecular mimicry¹ between a transcription factor of EBV, termed as EBV nuclear antigen 1 (EBNA1), and CNS glial cell adhesion molecule (GlialCAM), was demonstrated. Immunisation with EBNA1 in mouse model of MS was found to exacerbate the disease. The same study also found that MS patients had prevalence of anti-EBNA1 and anti-GlialCAM antibodies [6]. Latest research on myelin regeneration in a zebra fish model found that some oligodendrocytes (cells that produce myelin) survive demyelination in MS and go on to produce aberrant and mistargeted new myelin, as compared to new oligodendrocytes that are produced after demyelination [7].

Clinically, there are four different types of MS, namely: (i) relapsing-remitting MS (RRMS), which is the most common type that is characterised by exacerbations of illness followed by partial or complete recovery; (ii) primary progressive MS (PPMS) characterised by progressive worsening of neurological function or disability from the onset of illness; (iii) secondary progressive MS (SPMS) characterised by initial relapsing-remitting course followed by progressive increase in neurological function or disability; and (iv) clinically isolated syndrome (CIS) characterised by monophasic or first episode of neurological dysfunction associated with demyelination and inflammation in the central nervous system (CNS) occurring in a patient not known to have MS [8]. Treatment involves a multi-disciplinary approach due to the varying symptoms that occur in MS. Hence, different professionals are involved such as neurologist, specialist nurse, physiotherapist, occupational therapist, urologist, rehabilitation specialists in a multi-pronged approach to manage MS. The mainstay of medical management is oral and monoclonal antibody therapies called as disease modifying therapies (DMTs).

2. Latest in DMT research

DMTs are available to MS patients in oral, injection and infusion forms. Mechanism of action for DMTs includes immunomodulation or immunosuppression affecting lymphocyte number, lymphocyte proliferation, lymphocyte trafficking or cytokine production (Figure 1) [9]. Thus, DMTs reduce neuroinflammation in CNS, and prevent relapses and new lesion formation. For RRMS, there are over a dozen DMTs that have been licenced for use; for PPMS, ocrelizumab, which is a monoclonal antibody against CD20 antigen expressed on B cells, has been recently licenced for use; for CIS, preparations of interferon beta, which reduce secretion of proinflammatory cytokines, and T cell trafficking in CNS or glatiramer acetate, which stimulates myelin protein and T cell modulation, are used [9, 10]. Some of the other DMTs used in MS treatment are natalizumab (monoclonal antibody, α4 integrin receptor antagonist that reduces T cell and leucocyte migration across blood-brain barrier); cladribine (anti-metabolite that causes depletion in T and B cells), teriflunomide (inhibitor of pyrimidine synthesis that causes reduction in lymphocytes), etc. [9, 10]. Specific mechanisms of action are poorly understood and DMTs are associated with a range of unwanted side effects and safety concerns that require regular and robust monitoring. Some mild side effects include flu-like symptoms or gastrointestinal tract upset; however, serious side effects include cardiac arrhythmias, malignancy and liver damage [9].

Figure 1.

Mechanism of action for DMTs in MS. These include immunomodulation by suppression of lymphocyte numbers, modulating lymphocyte proliferation and trafficking and production of cytokines. Adapted from [9]. Abbreviations: DMT: Disease-modifying treatment; MS: Multiple sclerosis.

3. Latest in stem cell transplantation therapies in MS

Autologous haematopoietic stem cell transplantation (aHSCT) is a newer type of treatment for MS. Guidelines recommend that aHSCT is offered to those patients with highly active RRMS where DMTs have been ineffective [11, 12]. In short, the first step in aHSCT involves chemotherapy and growth factor such as granulocyte colony-stimulating factor so that stem cells move from bone marrow into blood stream from where the stem cells are harvested and then frozen. Following this, chemotherapy is done so that the immune system is ablated or ‘wiped out’. Next, the harvested stem cells are infused into the patient, for reconstitution of the immune system (Figure 2). The entire process of preparation, harvesting and reconditioning of immune system can take 3–4 months, which then requires long-term follow-up clinically [13, 14]. A Phase 3 randomised controlled trial comparing aHSCT with older DMTs showed that aHSCT is effective in RRMS [15] but there are no studies comparing efficacy of aHSCT with newer DMTs [13]. Another type of stem cell transplantation technique that is also finding ground in MS is called autologous mesenchymal stem cell transplantation (AMSCT). MSCs are non-haematopoietic stromal stem cells found in the bone marrow. Phase 2 randomised controlled clinical trials against placebo have found AMSCT to be safe in MS patients [16] and also to be beneficial in PPMS by improving cognition and reducing relapses [17].

Figure 2.

Flow diagram to show process of aHSCT treatment in MS. A patient with MS first undergoes chemotherapy and growth factor infusion so that stem cells move from bone marrow into the blood stream. Then, stem cells are harvested and frozen for later use. Next, chemotherapy is done to ablate the existing aberrant immune system of patient with MS, following which the harvested stem cells are infused back into the patient. Abbreviation: aHSCT: Autologous haematopoietic stem cell transplantation; MS: Multiple sclerosis.

4. Latest research on neuroimaging and biomarkers in MS

Magnetic resonance imaging (MRI) is the mainstay of diagnosing MS radiologically. Gadolinium is a key marker used to study and phenotype MS, and it acts as a marker for neuroinflammatory lesions and blood-brain barrier breakdown. It also aids in the diagnostic process to some extent by helping in monitoring disease progression or efficacy of treatment [18]. Although conventional MRIs are useful in qualitative information, quantitative MRIs (QMRI; which involve disentangling the source of signal variation in images and use mathematical or computational modelling) are being increasingly useful in MS clinics and research. QMRI is more specific for studying and differentiating between grey and white matter MS lesions and for detecting the extent of myelin and axonal damage [19]. Recently, unsupervised machine-based learning has been developed to identify MS subtypes. Dataset for over 6000 MS patients were used in a study, in which MS was sub-typed into cortex-led, normal appearing white matter-led and lesion led. Clinical correlation showed that patients with lesion-led MS had the highest risk of disability and relapse rate. Patients in this subtype also showed increased response to treatment [20].

Discovering effective molecular biomarkers is also an extensive area for on-going research. There is good evidence to suggest that early detection and treatment of MS has a better prognosis [21]. Thus, the quest is to find markers that are found in the early stages of illness, or even perhaps in the preceding stage of appearance of clinical features in MS. At present, CSF analysis for IgG index and oligoclonal bands are used in supporting a diagnosis of MS [22, 23]. Other known CSF biomarkers include neurofilament light chain [24], chemokine CXC motif ligand 13 (CCL13) [25], osteopontin [26] and matrix metallopeptidase 9 [27]. Progress is also being made in identifying serum markers. A recent study found two proteins, oncostatin M and hepatocyte growth factor, to be associated with MS in comparison with healthy controls [28]. The same study also found that plasma CCL20 and CCL11 were associated with MS disease duration and progression [28].

5. Perspectives

MS is a disease with a complex heterogeneity in clinical presentation, neuroinflammatory lesions, imaging and treatment response. This leads to challenges in various stages of MS disease pathogenesis, for example in the initial diagnostic stage of varying symptomatology and neuroimaging, as well as in identifying appropriate treatment with DMTs. For MS patients, the degree of disability and prognosis varies and is difficult to predict. All of these throw up opportunities for research in MS, such as identifying and classifying MS lesions, predicting response to therapy, improving neuroimaging accuracy and its usefulness in predicting outcome, biomarkers for early detection and for detecting response to treatment. This introductory chapter, and indeed the entire book, is intended to stimulate interest in these areas of MS research and to serve as a good starting point to ensure readers can get maximum benefit from reading the upcoming chapters. Several such wonderful areas of research are covered in this book, which range from biomarkers, genetic and lifestyle factors affecting MS, to imaging techniques and innate immune mechanisms in MS. We hope you find this book a useful tool in enhancing your knowledge and understanding of MS, as well as to stimulate your interest in the different spheres of MS research.