Улучшения в множественном склерозе.

Introduction

Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS), and its prevalence is increasing globally.
1
It is a major cause of disability in young people and a source of significant healthcare burden.
1

MS was first defined as a disease in 1868 by Charcot and shown to be due to CNS demyelination, astrogliosis and axonal degeneration through careful histopathological studies later in the 19th and 20th centuries.
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Over the past three decades, the diagnosis and management of MS have undergone a transformation. Better understanding of pathogenetic mechanisms has informed innovative therapeutic strategies, largely driven by the advent of disease‐modifying monoclonal antibodies. With significant advancements in controlling the inflammatory elements of MS, focus is shifting to investigating and treating the progressive, degenerative aspects of the disease. Moreover, as the evidence for an aetiological role of Epstein Barr virus (EBV) infection strengthens, the preventive potential of vaccination is being explored.
3

Epidemiology

The epidemiology of MS is changing. Its prevalence is rising, and globally, in 2020, an estimated 2.8 million people were living with the disease.
1
In 2021, 131.12 Australians per 100 000 people had MS, up from 103.7 per 100 000 in 2017.
4
High‐prevalence regions, such as Denmark and Scotland, have reported a threefold rise in prevalence, and incidence has doubled.
1
The median age of diagnosis is 32 years, and women are affected 2–5 years earlier than men.
1
Late‐onset MS, defined as symptom onset after 50 years, is also increasing and accounted for 12% of cases in a recent Swedish registry study.
5
Overall, the average age of the MS population is rising, with peak‐age prevalence estimated in the sixth decade of life.
1
The trajectory of the disease is also changing, as earlier diagnosis and treatment advancements delay disability milestones and improve survival.
6

Substantial geographical variations in MS prevalence have long been studied and still exist, with the highest frequency of the disease found in Northern Europe and North America.
1
The lowest frequency is in South East Asia and Africa, where the incidence is only 0.4 per 100 000 compared to 6.8 in Europe.
7
However, regions with historically low prevalence are recently reporting higher rates of MS. In Northern Japan, the prevalence of MS has risen from 8.6 to 22.4 per 100 000 over two decades.
8
This, like in other regions of the world, appears to be a genuine increase in the frequency of the disease shown by rising incidence rates.
1

Globally, the female‐to‐male ratio is 3:1, though this varies by region, ranging from 2.1:1 in Turkey to 5:1 in Malaysia.
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,
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,
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In Australia, the sex ratio has markedly increased in recent decades. In Newcastle, New South Wales, female prevalence increased by 371.4% between 1981 and 2021, whereas the increase in men was 220.4%, such that the sex ratio shifted from 1.4 to 3.3.
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This has led to speculation that a female‐specific environmental trigger may be pertinent to the pathogenesis of the disease.
12

Risk factors

Environmental factors

The aetiology of MS remains unknown. Environmental factors have a profound effect on risk and play a greater role than genetics.
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People carry the risk of the region they lived in until approximately 15 years of age, and those who migrate before adolescence acquire the risk of their new locale,
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indicating an exposure in early life is instrumental. A recent Canadian study found that the proportion of life spent in Canada was directly related to risk of developing MS in immigrants from low‐prevalence regions.
15

A latitudinal gradient in MS prevalence has long been established, increasing with distance from the equator.
14
This effect varies globally and is absent or at least diminished in some regions.
16
A clear latitudinal gradient remains in Australia and New Zealand, and the risk of MS is three times higher in Tasmania than in Queensland, with an increase of 3% per degree of latitude.
17
This latitudinal gradient prompted investigation into the immune effects of vitamin D and UVB radiation. Certainly, a correlation between low vitamin D levels and increased MS prevalence has been demonstrated, and vitamin D has immunomodulatory properties that may attenuate autoimmune activity.
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Several randomised controlled trials have failed to demonstrate a benefit from vitamin D supplementation on MS clinical outcomes.
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However, the recent ‘D‐lay MS’ study, the largest therapeutic trial of vitamin D in MS, found a relative risk reduction in disease activity of 34% in people with clinically isolated syndromes (demyelinating conditions characterised by a singular clinical event that are a precursor to MS).
19
It may be that an impaired response to or low levels of vitamin D impacts disease biology early in its course.

The strongest demonstrable aetiological factor in the genesis of MS is infection with the EBV. The risk of MS is extremely low among EBV seronegative individuals, and it is widely considered a prerequisite for developing the disease.
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Over 99% of MS patients have evidence of past EBV infection compared to 95% of the general population.
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A study of 10 million young adults in the US military found MS risk increased 32‐fold after EBV infection.
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Moreover, serum neurofilament, a biomarker of neuroaxonal injury, increased after EBV seroconversion. The age of exposure and EBV antibody titre are also important, as is a history of symptomatic infectious mononucleosis.
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MS risk increases when primary EBV infection occurs after the age of 10 years, and individuals with high antibody titres have a higher relative risk of the disease.
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The mechanism by which EBV contributes to MS has not been proven. Infected autoreactive naïve B cells are thought to present antigens that are structurally similar to myelin.
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The importance of age of infection may relate to stage of thymic maturation and timing of autoreactive T‐cell negative selection.
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,
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Other important environmental factors include smoking and obesity. Smoking increases risk in a dose‐dependent manner and increases the risk of developing secondary progressive disease.
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The association between obesity and MS risk is particularly evident in young females, with a linear relationship between BMI and MS risk at the ages of 10 and 20 years.
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Genetic factors

More than 200 genes have been associated with MS, the vast majority of which are within the major histocompatibility complex region.
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,
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Still, it is not a hereditary disease, and no single variant is sufficient to cause MS.
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,
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The genetic variants associated with MS implicate both adaptive and innate immune cells in the pathogenesis of the disease, particularly T‐helper‐cell differentiation.
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Genetic factors are estimated to account for 30% of overall disease risk, and each variant increases total risk in an additive manner.
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,
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The risk to a first degree relative is 2.77%, compared to a 0.3% population risk.
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The percentage of concordance for monozygotic twins is approximately 25%–30%, compared to 3%–5% for dizygotic twins.
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HLA‐DRB1*15.01 is found on the short arm of chromosome 6 and is the single strongest genetic risk factor, conferring a threefold increase.
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Of interest, vitamin D has been shown to alter HLA‐DR antigen expression and antigen presentation.
30

Pathophysiology

MS is commonly regarded as an autoimmune disease; however, its precise pathogenesis remains unclear, and current evidence does not fully support its classification as a typical autoimmune disorder.
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Although immune‐mediated mechanisms play a central role in MS pathophysiology, and intrathecal antibody production occurs, a specific antigen target has not been identified.
31

The disease is characterised by CNS inflammation and degeneration, with either predominating at different stages. The clinical subtypes of primary progressive MS (PPMS), relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) were first conceived in 1996 and are determined by the degree of inflammatory versus degenerative activity.
32
As our understanding of MS disease mechanisms evolves, we recognise that patients lie somewhere on a continuum between the two throughout the course of their disease, and this binary classification of disease subtypes may become rudimentary. Historical data indicate that 85%–90% of patients present with RRMS and 10%–15% with PPMS.
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Of the RRMS group, 80% developed SPMS within 10–20 years, though this figure is falling due to earlier diagnosis and treatment.
34

Demyelination is the hallmark of MS, but it is not a myelin‐specific disease. Axons, neurons and glial cells are also targeted. Focal inflammatory disease is characterised by demyelinating lesions and axonal loss. Figure  1 demonstrates the histopathology of an early lesion (reproduced from Prineas et al ., 2021).
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This process is driven by autoreactive T cells, B cells and proinflammatory cytokines that stimulate microglial cells and astrocytes, resulting in antibody production and breakdown of the blood‐brain barrier.
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Although autoreactive T‐cells were long held to be the key driver of this inflammatory activity, the efficacy of B‐cell‐depleting treatment shifted the focus to B cells, which are now recognised to be integral.
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They contribute to disease through antigen presentation, antibody and cytokine production, and the formation of meningeal follicle‐like structures.
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These follicles lead to a sustained compartmentalised humoral immune response within the CNS and are associated with faster disease progression.
37

Reproduced from Prineas et al . 2021.
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“Exceptionally early lesions in exceptionally early multiple sclerosis. The lesion at the far right showed, at high magnification, pyknotic oligodendrocytes and pale but intact myelin. The large lesion on the left showed commencing loss of myelin in the presence of numerous early phagocytes and monocytes. Unidentified large IgG + mononuclear cells were present throughout the section (A) Luxol fast blue‐PAS, (B) CD45, (A and B) × 2.5”.

Focal inflammatory lesions cause relapses that manifest with subacute onset focal neurological deficits, and relapse‐associated worsening occurs more frequently early in the disease course.
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Smouldering disease refers to chronic pathobiological processes that occur beyond acute inflammation and can manifest radiologically as chronic active lesions that slowly expand over years.
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,
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This occurs due to chronic microglial and astrocytic activation within the CNS and contributes to brain and cord atrophy.
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It may be clinically silent or manifest with slow and subtle disability increase, often referred to as progression independent of relapse activity (PIRA). This is argued by some to be the primary process driving neurodegeneration in MS, and PIRA accounts for half of disability‐worsening events in RRMS.
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The implications of this for disease monitoring and therapeutics are under continued investigation, as current methods of surveillance are inadequate for quantifying smouldering activity.

Neurodegenerative processes occur gradually over years and causes cortical degeneration, neuronal injury and global atrophy.
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They occur due to persisting microglial and innate immune mediators, mitochondrial damage causing energy deficits and antibody‐mediated damage.
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Moreover, age‐related neurodegenerative processes are accelerated.
4

Clinical features

Classical presentations include optic neuritis, acute myelitis, brainstem and cerebellar syndromes. Optic neuritis in MS is typically unilateral and characterised by gradual‐onset monocular visual loss, ocular pain and dyschromatopsia.
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Myelitis is most often partial and manifests with sensory or motor deficits of the limbs and may cause a truncal sensory level. Sphincter dysfunction, particularly urinary retention, can also occur. Lhermitte's phenomenon is an electrical sensation migrating down the back upon neck flexion. It is associated with cervical cord lesions and affects up to 41% of MS patients.
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Internuclear ophthalmoplegia is a typical brainstem syndrome that presents with diplopia.
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Other signs of a brainstem syndrome include facial numbness or weakness, dysarthria and vertigo.
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Non‐specific MS symptoms may include fatigue, which affects over 75% of people,
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and cognitive dysfunction. These are often poorly captured during routine clinical surveillance but are recognised to correlate with underlying disease activity.
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Moreover, they can occur years before classical MS symptoms appear, reflecting an under‐recognised prodromal disease phase.
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Worsening of neurological symptoms under heat stress, referred to as Uhthoff's phenomenon, can occur from environmental heat, fevers and exercise.

Diagnosis and monitoring

MS lacks a confirmatory diagnostic test and is a diagnosis of exclusion. Clinico‐radiological features are relied upon to define the disease. First developed in 2001, the diagnostic McDonald criteria have undergone several revisions, with the latest occurring in 2024 and awaiting publication.
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MRI head and spine in combination with clinical history are used to demonstrate dissemination of disease in space (DIS) and time (DIT), though other supportive criteria can be used for diagnosis.

To fulfil DIS criteria, lesions must be demonstrated in two characteristic topographies. To improve sensitivity, the latest revision includes a fifth topography, the optic nerve, in addition to cortical/juxtacortical, periventricular, infratentorial and spinal cord.
47
In those presenting with symptoms typical of MS but without DIT, the presence of lesions in four or five topographies is enough to diagnose MS. If a symptomatic patient has lesions in only one topography, MS can be diagnosed if there are six central vein signs (CVSs) or paramagnetic rim lesions (PRLs) (see ‘Radiology’ section), plus DIT or cerebrospinal fluid (CSF) oligoclonal bands (OCBs).
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OCBs that are restricted to the CSF indicate intrathecal antibody production, though they are not specific to MS. Eighty per cent of MS patients have CSF OCBs at first attack, and it is estimated that 90% are OCB positive at some point.
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CSF kappa free light chains (κ‐FLC) have similar diagnostic accuracy to OCBs and can be used in their place in the latest diagnostic criteria.
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,
48

Radiologically isolated syndrome (RIS) refers to asymptomatic patients with incidental characteristic MS lesions on MRI. Fifty‐one per cent of people with RIS will develop MS after 10 years,
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and it has long been debated whether, or when, these patients should commence disease‐modifying therapy (DMT). An important revision to the 2024 McDonald criteria is that asymptomatic patients can now be diagnosed with MS.

Patients with RIS who have DIS and DIT, or DIS and OCBs, or DIS and ≥ 6 CVS, now meet MS diagnostic criteria.
47

Radiology

MRI of the head and spine is the imaging standard in MS diagnosis and surveillance. The five characteristic topographies for MS lesions are shown in Figure  2 . It is important to recognise that these are not specific to MS; various CNS diseases can present with similar findings. The differentials for white matter lesions are broad and include vasculitis, chronic microvascular ischaemia, collagen vascular diseases such as lupus, neuromyelitis optica spectrum disorder and acute disseminated encephalomyelitis.

Sagittal and Axial T2 FLAIR lesions in characteristic periventricular distribution with perpendicular/perivenular orientation (A, B), juxtacortical white matter lesions (C – red arrows), infratentorial brain stem and cerebellum (D), right optic nerve (E – yellow arrow), spinal cord (F – green arrows).

The typical periventricular white matter lesions of MS are ovoid, touch the ventricular surface and radiate from it in a perpendicular orientation.
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Characteristic spinal MS lesions are short segment (<2 vertebral bodies) and eccentrically located.
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Optic nerve lesions are typically unilateral, short and anterior.

White matter plaques are evident on T2 and FLAIR imaging. T1‐weighted imaging may show focal hypointensities within lesions, so‐called black‐holes (Fig.  3A ), which represent axonal loss and gliosis.
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In the acute phase, T1 post‐contrast enhancement of lesions occurs and typically forms an incomplete ring at the lesion's periphery (Fig.  3B ) and can persist for 1–2 months. T2* sequences can demonstrate central veins within MS lesions (Fig.  3C ), a sensitive and specific finding incorporated into the diagnostic criteria.
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PRL (Fig.  3C ) are also evident on susceptibility weighted imaging in 35%–60% of patients.
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These are formed by iron‐laden macrophages, which signify smouldering inflammation and can predict worse clinical outcomes.
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Non‐contrast Axial T1 with focal hypointense “black holes” (A – blue arrows). Post‐contrast Axial T1 with incomplete ring of enhancement (B – yellow arrow). Axial SWI (T2*) and magnified image shows lesion with a “central vein sign” (green arrow) and “paramagnetic rim lesion” (red arrows) (C).

MRI has several limitations, and the absence of new or enhancing lesions does not exclude inflammatory activity. Lesions of the cortex and deep grey nuclei are not well demonstrated on standard sequences, although improvements have been made with the use of double inversion recovery, phase‐sensitive inversion recovery and the introduction of 7 T MRI.
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Without volumetric analysis, subtle progression of atrophy and slowly expanding lesions often go undetected. Although not yet incorporated into clinical practice on a large scale, volumetrics is increasingly utilised in MS research.

Treatment

There remains no cure for MS. There are three aspects to treatment: symptom management, relapse management and modifying therapy.

Symptomatic management

A comprehensive multidisciplinary approach to symptom management is key in caring for people with MS. Symptoms vary greatly between patients depending on lesion location and disease duration. Pharmacological measures such as amantadine, naltrexone and modafinil are frequently employed for treatment of fatigue, albeit with limited evidence. Spasticity affects over 80% of MS patients at some point in their disease course.
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Baclofen, gabapentin, tizanidine and intramuscular botulinum toxin injections can provide benefit. Cannabinoids are increasingly prescribed to treat spasticity and neuropathic pain and a 2020 Cochrane review found they probably increase the number of people who report ‘very much’ or ‘much’ improvement in health status compared with placebo.
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Hypertonic bladder (overactive bladder syndrome) is a frequent autonomic complication that is treated with anti‐cholinergic medications, selective beta‐adrenergic receptor agonists and sometimes botulinum toxin and sacral nerve stimulators. Constipation is common and should be treated in routine fashion, although the serotonin agonist prucalopride may have a particular place in severely affected patients.
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Other frequently reported symptoms that are difficult to treat are brain fog, cognitive impairment and sexual dysfunction.

Relapse management

A relapse is defined as a new neurological symptom attributable to MS lasting more than a day, associated with an objective clinical or imaging finding and without fever or systemic illness.
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The latter features differentiate a true relapse from a ‘pseudo‐relapse’, wherein physical stress from intercurrent illness or pyrexia (Uhthoff's phenomenon) can result in transient recrudescence of neurological symptoms.

The strategy for treating relapses remains largely unchanged and a pulse of high‐dose intravenous corticosteroids over 3–5 days is standard of care.
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In severe or refractory relapses, this may be combined with or followed by plasmapheresis. Evidence to support the use of intravenous immunoglobulin is lacking, and this is not routinely given.

DMT

DMTs are immune modulators that reduce MS activity, aiming to achieve ‘no evidence of disease activity’ (‘NEDA’). Meeting three parameter NEDA criteria (NEDA‐3) requires (i) no clinical relapse, (ii) no disability progression and (iii) no new or enlarging lesions on MRI.
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This has been expanded in the research setting to NEDA‐4 and even NEDA‐5, including brain volume loss and serum neurofilament light (NfL) as additional criteria.
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With the MS treatment paradigm shifting over the last decade from an escalation strategy to an induction strategy, improvements in disability milestones continue.
34

Historically, lower‐efficacy lower‐risk DMTs were favoured as first line; however, this has been shown to result in worse outcomes.
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Using high‐efficacy treatment within 2 years of disease onset is associated with less disability after 6 years and commencing high‐ versus moderate‐efficacy therapy leads to NEDA‐3 rates of 52% versus 19% after 2 years.
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As a result, using a high‐efficacy DMT as first‐line therapy is generally considered standard practice in Australia, and in 2022, moderate‐ to high‐efficacy DMTs accounted for 75% of all prescriptions, an increase from 54% in 2013.
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A detailed review of each DMT is outside the scope of this article, and a summary of RRMS DMT efficacy is presented in Table  1 .

Table 1 Efficacy of disease‐modifying therapies approved for relapsing remitting MS in Australia DMT Mechanism of action Efficacy Relapse relative risk reduction in pivotal studies Natalizumab Anti‐alpha4 integrin mAb High 68% versus placebo Ocrelizumab Anti‐CD20 mAb High 46%–47% versus interferon beta Ofatumumab Anti‐CD20 mAb High 50.5%–58.5% versus teriflunomide Alemtuzumab Anti‐CD52 mAb High 49.4%–54.9% versus interferon beta Cladribine Deoxyadenosine analogue Moderate 57.6% versus placebo Fingolimod Sphingosine‐1‐phosphate receptor modulator Moderate 48%–55% versus placebo Dimethyl fumarate NrF2 inhibitor Moderate 44%–53% versus placebo Teriflunomide
Mitochondrial
dihydro‐orotate dehydrogenase inhibitor
Low 31.5%–36% versus placebo Interferon beta Alters cytokine balance Low 32%–34% versus placebo Glatiramer Anti‐inflammatory Low 29% versus placebo

Efficacy of disease‐modifying therapies approved for relapsing remitting MS in Australia

Mitochondrial

dihydro‐orotate dehydrogenase inhibitor

B‐cell therapies are currently the most widely used DMTs in Australia.
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They are monoclonal antibodies (mAbs) that target the CD20 antigen and cause B‐cell depletion.
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B‐cell depletion is assumed to suppress the inflammatory component of MS by reducing antigen presentation to autoreactive T cells as well as proinflammatory cytokines. The anti‐CD20 mAbs substantially reduce relapse rates, and 10‐year data for ocrelizumab found 92% of RRMS patients did not require a walking aid.
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However, their effect on progressive disease mechanisms is modest.
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This may partly relate to insufficient CNS penetration, where a compartmentalised humoral response persists within meningeal B‐cell follicles, resulting in smouldering inflammation and neurodegeneration.
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Immune reconstitution therapy involves chemotherapeutic ablation of the immune system, which, after reconstitution, restores immune tolerance with the potential for long‐term disease remission. The first immune‐reconstituting therapy developed for MS was alemtuzumab, an anti‐CD52 monoclonal antibody. Although 75% of RRMS patients showed no disability worsening after 5 years, secondary autoimmune complications of alemtuzumab can be severe, and even life threatening.
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These safety concerns have greatly reduced its use since the availability of B‐cell therapy.

Autologous haemopoietic stem cell transplantation (AHSCT)

An alternative method of immune reconstitution is AHSCT. With improved safety in recent years, it is increasingly offered to RRMS patients with ongoing inflammatory activity despite a high‐efficacy DMT and in exceptional cases as first‐line therapy.
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Best outcomes have been shown in younger patients with early RRMS and high inflammatory activity. Relapse‐free survival across four large cohort studies was 80% at year 5, and progression‐free survival ranged from 63% to 95% at year 4.
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Moreover, retrospective comparative studies have shown possible superior effectiveness over alemtuzumab with a two‐ to three‐fold reduction in secondary autoimmunity.
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The role of AHSCT in PPMS and SPMS is less established, with limited data and a lack of published randomised trials. A recent observational study of progressive MS patients with low relapse activity treated with AHSCT did not demonstrate reduction in disability progression.
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Future directions

Novel biomarkers

Acknowledging the contribution to disease from smouldering inflammation, the need for additional biomarkers in MS has become more important than ever. A blood‐based biomarker of CNS inflammation has the potential to transform treatment monitoring and prognostication. To date, serum NfL (sNfL) has shown the most promise as a non‐invasive, cost‐effective measure.
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Neurofilaments are an important structural element of myelinated axons, with the NfL being the most useful of the three subunits.
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Their levels in CSF and serum rise when neuronal and axonal damage occurs. This has been demonstrated in several neurodegenerative diseases, including Alzheimer's dementia and motor neurone disease.
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In MS, sNfL levels correlate with neuronal loss and focal inflammatory lesions.
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Moreover, switching to higher‐efficacy MS treatment is associated with lower sNfL concentrations, highlighting its potential in therapeutic monitoring.
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Widespread translation of sNfL into clinical practice is yet to occur, and some hurdles remain, particularly regarding the confounding effects of other neurological and non‐neurological comorbidities. Nonetheless, it will likely prove a helpful adjunct to monitoring disease on an individual level.

A second serum biomarker of interest is glial fibrillary acidic protein (GFAP). It is a protein derived from astrocytes after CNS injury and has been shown to correlate with PIRA and long‐term MS disease progression rather than relapse activity.
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,
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Patients with high GFAP have poorer outcomes even after treatment with high‐efficacy DMTs, highlighting a group with a need for novel therapeutic strategies.
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Bruton tyrosine kinase (BTK) inhibitors

BTK inhibitors are an established treatment for B‐cell malignancies and a second generation of drugs is under investigation in MS. BTK is expressed by B cells and myeloid cells and inhibition suppresses adaptive and innate immune mechanisms.
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As they act in the periphery and the CNS, they may show more promise in disrupting the central mechanisms responsible for progressive disease.
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Phase III results in RRMS have been disappointing, with both evobrutinib and tolebrutinib failing to meet their primary endpoint when compared to teriflunomide.
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,
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However, tolebrutinib was found to reduce 6‐month confirmed disability progression by 31% compared to placebo in non‐relapsing SPMS and to induce disability improvement in 10%.
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These results suggest that this drug class has a greater impact on smouldering disease and chronic active lesions than acute, focal inflammatory activity.

CAR T‐cell therapy

Chimeric antigen receptor (CAR) T‐cell therapy has proven revolutionary in the treatment of haematological malignancies, and its potential in autoimmune disease is now being explored. Described as a living drug, CAR T cells are made by re‐engineering patient T cells in the laboratory to produce surface receptors that recognise and bind to specific antigens.
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It is hoped that the superior CNS penetration of CAR T cells will translate to more effective depletion of meningeal B‐cell follicles than anti‐CD20 mAbs.
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A CD19 CAR T‐cell product is currently under investigation and in small numbers demonstrated CSF CAR T‐cell expansion without problematic neurotoxicity.
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Frexalimab

Frexalimab targets the CD40‐CD40L costimulatory pathway, which regulates adaptive and innate immune mechanisms.
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A precise role in MS pathogenesis has not been established; however, people with progressive MS have high levels of CD40L expression on activated T cells, which broadly correlates with patient EDSS.
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Of note, EBV infection stimulates CD40L/CD40 signalling and induces B‐cell expression of CD40L,
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which may increase the capacity for EBV‐infected B cells to present autoantigens to T cells. As an anti‐CD40L mAb, frexalimab inhibits binding to CD40, thereby disrupting T‐cell‐mediated immune responses. In a phase II trial of RRMS, the annualised relapse rate was only 0.04 after 48 weeks of treatment.
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Phase III randomised controlled trials in both relapsing and progressive disease are in progress.

EBV vaccination

Given the weight of evidence supporting a pathogenic role of EBV infection in MS, the potential for MS prevention with EBV vaccination is being explored. Development of a safe and effective vaccine has proven challenging, and prevention of EBV infection in human studies is yet to be achieved.
3
Nonetheless, an Australian research group last year demonstrated potent and durable immune protection against EBV in pre‐clinical models and future studies are awaited.
3

Conclusion

Advancements in MS research in the 21st century have had a major impact on real‐world patient outcomes. However, a deeper understanding of disease aetiology is needed to explain the rising prevalence and shifting epidemiology globally. Highly effective therapy for progressive disease is lacking, and the outcomes of several active phase III trials are eagerly anticipated.

Acknowledgements

Karen Thomas, MS nurse practitioner, Royal North Shore Hospital. Open access publishing facilitated by The University of Sydney, as part of the Wiley ‐ The University of Sydney agreement via the Council of Australian University Librarians.

Funding: None.

Conflict of interest: None.

References