Understanding MS

Multiple sclerosis

MS is an autoimmune disease characterised by inflammation and damage to the central nervous system (CNS). Common MS symptoms include impairments to cognition, walking, and balance; bladder or bowel dysfunction; abnormal tiredness; or visual disturbances¹. The symptoms of MS are caused by peripherally driven inflammation and neurodegeneration of the CNS^2-5.

MS is characterised by four disease courses or phenotypes^6,7:

• clinically isolated syndrome (CIS)
• relapsing-remitting MS (RRMS)
• secondary progressive MS (SPMS)
• primary-progressive MS (PPMS)

The course of the disease is indicated by evidence of progression, active disease and relapses, and the extent and nature of disability⁷. PPMS differs in important ways from RRMS and SPMS, discussed below, and can be considered apart from relapsing forms of the disease⁶.

The onset of MS is typically marked by CIS, which is the first episode of neurological symptoms caused by inflammation or demyelination in the CNS. CIS, which must persist for at least 24 hours, does not yet satisfy diagnostic criteria for MS as people who experience CIS may or may not develop MS⁸. RRMS, however can develop from CIS^3,4,6.

Approximately 85% of people with MS are initially diagnosed with RRMS⁸. RRMS is characterised by clearly defined episodes of new or increasing neurologic symptoms (‘relapses’, ‘exacerbations’), followed by periods of partial or complete recovery (‘remissions’)⁶. RRMS can be characterised as ‘active’ (with relapses and/or evidence of new magnetic resonance imaging [MRI] activity over a period of time) or ‘not active’, and ‘worsening’ (a confirmed increase in disability following a relapse), or ‘not worsening’⁶.

SPMS follows an initial relapsing-remitting course. Some people with RRMS transition to a secondary progressive course, which shows progressive worsening of neurologic function (accumulation of disability) over time. SPMS can be characterised as ‘active’ (with relapses and/or evidence of new MRI activity during a period of time) or ‘not active’, and ‘with progression’ (evidence of disability accumulation over time, with or without relapses or new MRI activity), or ‘without progression’⁷.

A standardised definition of SPMS has not been developed. Assessments that consider other manifestations of MS disability are required. Clinical tools are being developed for establishing a standardised assessment based on patient-physician discussions of clinical history⁹.

Following 6–10 years from MS onset, approximately 25%–40% of people with RRMS have progressed to SPMS, with a median time to transition ranging from 10 to 23 years^10–13

PPMS is characterised by worsening neurologic function from symptom onset, without early relapses or remissions. PPMS can be described as ‘active’ (with an occasional relapse and/or evidence of new MRI activity over time), or ‘not active’, and ‘with progression’ or ‘without progression’⁶.

PPMS differs in important ways from relapsing forms of MS (RRMS, SPMS):

• People with PPMS tend to have fewer brain lesions than people with RRMS or SPMS
• Brain lesions in people with PPMS may contain fewer inflammatory cells
• People with PPMS may exhibit more lesions in the spinal cord than in the brain
• The average age of onset is approximately 10 years later in PPMS than RRMS or SPMS
• People with PPMS commonly have more difficulty walking and remaining in the workforce than people with RRMS or SPMS

Approximately 15% of people with MS are diagnosed with PPMS⁸.

Overview of MS epidemiology

In 2020, approximately 2.8 million people worldwide had MS (Figure 1)^14,15.

Figure 1. Number of people with multiple sclerosis per 100,000 worldwide, 2020 (Adapted¹⁴). MS, multiple sclerosis.

Onset of MS commonly occurs between the ages of 20–40⁴. MS affects more women than men: 69% of people with MS are women, 31% are men¹⁴.

The prevalence of familial MS is approximately 11.8%¹⁶. Environmental and lifestyle risk factors include Epstein-Barr virus (EBV) infection in adolescence and early adulthood, tobacco exposure through active or passive smoking, low levels of vitamin D, a lack of sun exposure, and obesity during adolescence^4,14.

Every 5 minutes, someone, somewhere in the world, is diagnosed with MS¹⁴

Unmet needs

There are common unmet needs in people living with MS, and for HCPs treating MS (Table 1)^17-22.

Table 1. Unmet needs in people with MS and healthcare professionals (Adapted^17-22). HCP, healthcare professional; MS, multiple sclerosis.

Potential actions to help address some of these unmet needs in both people and HCPs could include^17-22:

• Improve the quality of all interactions between HCPs and their patients
• Collaborate to form ‘joint’ local education, communication, and patient-engagement initiatives
• Motivate people to self-manage their MS
• Optimise consultation time
• Understand and optimally manage ‘hidden’ disease symptoms
• Improve benefit versus risk communication as related to MS therapies
• Provide accurate, clear information about MS in an accessible format
• Share new knowledge and information about MS with multidisciplinary team members, HCPs, and patients

Greater use of patient-centred educational resources before, during, and after consultations to improve understanding and communication of MS, is essential²²

By bridging unmet needs, patients are better equipped to make informed decisions with HCPs, as part of a multidisciplinary, individualised disease management approach^7,23,24.

Introduction

Multiple sclerosis (MS) is an immune-mediated disease, caused by peripherally driven inflammation and neurodegeneration of the central nervous system (CNS)^2-5.

As MS progresses, lesions in the CNS and the brain indicate advancement from neuroinflammation to neurodegeneration, leading to irreversible neuroaxonal degeneration, demyelination, and cumulative disability, diminishing mobility, cognitive decline, and loss of independence^2-5.

MS disease phenotypes comprise clinically isolated syndrome (CIS), relapsing remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS)^6,7. Approximately 85% of people with MS are diagnosed with RRMS⁸. As described in the previous section, PPMS differs from relapsing MS phenotypes (RRMS, SPMS) in important ways. Almost 15% of people with MS are diagnosed with PPMS⁶.

Follow the link to learn some of the important differences between PPMS and relapsing forms of MS

The development of relapsing forms of MS, excluding PPMS, is shown in Figure 2²⁵.

Figure 2. Evolution of relapsing forms of multiple sclerosis – RRMS, SPMS (Adapted^26-30). CIS, clinically isolated syndrome; CNS, central nervous system; GM, grey matter; MRI, magnetic resonance imaging; MS, multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; WM, white matter.

Referral timing and pathways

People who report symptoms that might be MS-related should be referred to a neurologist as early as possible³¹. The aspirational goal for referral is 5 days³¹.

A patient ought to receive follow-up evaluations every 6 months and, minimally, once per year³¹. During these evaluations, people are assessed for treatment efficacy, MS progression, and if they are living a ‘brain-healthy’ lifestyle³¹. Healthcare professionals (HCPs) should also probe at follow-up for unmet patient needs³².

Early diagnosis

Even with improved diagnostic tools and criteria, diagnosis delays are common in people with MS (Figure 3)³³. Psychiatric manifestations may mask early symptoms of MS and can be associated with delays in diagnosis³⁴.

Figure 3. Delayed diagnosis of multiple sclerosis (Adapted³³). MRI, magnetic resonance imaging.

Referral to a neurologist is advised at the earliest signs of MS symptoms^31,33. Early diagnosis and intervention may slow the progression of MS, and benefit long-term patient outcomes.

Diagnoses that present similarly to MS include vasculitis, HIV infection, Lyme disease, thyroid dysfunction, and several nutritional deficiencies³⁵. Typical findings consistent with a diagnosis of MS include T2 (and T1 post gadolinium) hyperintense periventricular lesions, known as Dawson fingers³⁶. Spinal cord lesions are usually longitudinally oriented; their length does not extend beyond 1 or 2 spinal segments, and their width does not extend more than half the diameter of the cord³⁶. The McDonald criteria states that the key requirements for MS diagnosis are dissemination in time, damage to the CNS at different dates, and dissemination in space, damage to different parts the CNS. It uses MRI evidence to test these criteria and suggest an MRI scan should be carried out where MS diagnosis could be a possibility³⁷.

Conventional neuroimaging can miss or underestimate CNS damage. White matter can appear normal on a conventional MRI scan, while higher-resolution testing not available as part of routine clinical care, and/or immunohistochemical techniques, can identify widespread axonal damage indicating disease activity that may or may not be associated with clinical symptoms³⁸. There is an unmet need for information and support at neurology clinics for people with MS, particularly at the time of diagnosis³⁹.

While an early diagnosis is important, avoiding misdiagnosis, due to diverse clinical presentations of MS, and tests with high sensitivity, but limited specificity, should also be considered⁴⁰.

Biomarkers

Dozens of biomarkers are currently being evaluated to improve diagnostic accuracy and to monitor disease activity that relates to MRI pathology^41-43. In addition, many potential markers are being evaluated on their usefulness as prognostic for conversion from CIS to MS and for disability progression⁴².

Table 2 shows the classification and clinical uses of biomarkers for MS⁴⁴.

Serum neurofilament light chain (sNfL) is a component of neurofilament found in the neuronal cytoplasm. When an axon is damaged, cytoskeletal proteins, including neurofilaments, are released into the extracellular space and subsequently into the CSF and the blood⁴⁵. It is important to note that changes in sNfL can highlight neurodegeneration, and is not specific to MS⁴⁶.

• In people with RMS, sNfL levels are correlated with neuroinflammatory and neurodegenerative activity^41,45,47
• Baseline sNfL levels are associated with T2 lesion volume, and Gd+ lesions as early as the first demyelinating event⁴⁸
• Higher concentrations of sNfL in people with CIS and RMS are related to higher MRI lesion load and higher disability scores⁴⁹

Glial fibrillary acidic protein (GFAP) is an astrocyte-specific skeletal protein that is encoded by the GFAP gene in humans. GFAP is released into CSF and blood upon activation or glial cell damage⁵⁰.

GFAP is a candidate serum biomarker to assess disease severity in progressive forms of MS, particularly in combination with NfL^51,52.

In the EXPAND HET trial, GFAP was retrospectively analysed as an exploratory biomarker^53,54:

• High baseline GFAP levels were significantly associated with high Expanded Disability Status Scale (EDSS), low Symbol Digit Modalities Test (SDMT) score, presence of Gd+ lesions, and a high T2 lesion volume at baseline
• Siponimod reduced GFAP levels from baseline to EOS by 1.2%, compared to 9.2% increase in placebo group

Progress is being made to identify diagnostic or prognostic biomarkers for MS. Advances in biomarker identification and validation could improve treatments, reduce relapses and delay disease progression⁴⁴.

Early intervention

Early intervention can maximise the chances of altering the course of MS before the disease progresses further, even if the disease minimally impacts the patient’s functioning^33,55-57.

Delayed treatment of MS is associated with worsening disease course and poorer response to treatments³¹

Starting treatment early (<2 years after diagnosis) is associated with a 40% reduction in risk of progression in people who had a first event of MS, or clinically isolated syndrome (CIS)²⁵.

Early initiation of high-efficacy therapies (HETs) can be accompanied by other appropriate steps to help preserve brain tissue and optimise brain health early in the disease course, including exercise, meditation, music therapy, social engagement, smoking cessation, weight loss, and control of comorbidities^33,58,59. These steps may improve the chances of altering the MS course before further relapses or disability progression occur³³.

In a cohort analysis of 592 people from the UK with MS who were prescribed pharmacological treatment, long-term outcomes were more favourable with early intensive therapy versus starting on first-line moderate-efficacy treatment⁶⁰.

There is increasing evidence that initiating HET early in MS may more effectively manage MS, and therefore may be a good choice to prevent irreversible progression, especially in people with forms of RRMS at risk of early and rapid advancement of disability^{43,55,56,61-63}.

In addition, analytical models have shown that early treatment of MS is cost-effective for the health care provider and society, as well as slowing MS progression⁶⁴.

Immunoglobulins in MS

Immunoglobulins (Igs), also termed antibodies, function as part of the healthy immune system to destroy bacteria and viruses (Figure 4)⁶⁵.

In MS, however, excessive amounts of IgG and IgM antibodies in the CSF, as measured using an oligoclonal band (OCB) assay, are associated with inflammation and active lesions^66-68. Often used as a marker of inflammation in the diagnosis of MS⁴³, the presence of oligoclonal IgG bands in the CSF are seen in up to 95% of people with MS⁶⁶.

Immune-modulating HETs target the immune system to reduce the autoimmune reaction in MS⁶⁹. The question of the impact of these medications, in particular B-cell depleting treatments, on the ability of people with MS to elicit a suitable immune response to infections and post-vaccination is relevant in the time of the COVID pandemic⁷⁰. Evidence continues to emerge on the impact of B-cell depleting anti-CD20 therapies on IgG and IgM serum levels, with data indicating varying levels of reduction over time for the available treatments^70,71.

Figure 4. Immunoglobulins (Adapted⁶⁵). Ig, immunoglobulin.

Holistic patient care

The optimal holistic patient care plan is management by specialists and HCPs with expertise in treating people with MS⁷².

MS specialists, primarily neurologists and MS nurses, will be most familiar with symptoms and MS progression, and are best positioned to manage the treatment options for people⁷², which may include pharmacological and/or non-pharmacological treatments.

Other stakeholders who may play a critical role in supporting patient needs include psychologists, physiotherapists, case workers, social workers, and community support groups⁷².

Together, these MS care units can provide seamless and efficient care across the continuum of MS⁷². This communication and trust between HCPs and people with MS, can help identify invisible symptoms and ultimately improve quality of life⁷³.

Education for people with MS is critical for adherence with care plans, and is associated with improved satisfaction and better adherence to treatment²². In some people with MS, however, education alone may be insufficient to improve outcomes. For example, physician referral to an exercise program is twice as effective as simply providing written information from Physical Activity Guidelines to adults with MS⁷⁴.