Multiple sclerosis and Epstein-Barr virus

Recent developments in the understanding of MS pathogenesis have suggested new avenues for disease-modifying therapy; in particular, the possibility of using antivirals against EBV

Multiple sclerosis (MS) is an autoimmune disease which affects the central nervous system (CNS). It is estimated to affect over 2.8 million people worldwide and Ireland is a high prevalence country with rates >100/100,000 persons.^1,2 Prevalence varies geographically, increasing as one moves north and south from the equator.

According to a recent Irish study of MS incidence, the average age at diagnosis for relapsing remitting MS (RRMS) is 37 years, and it is nearly three times more common in women than men.³

Susceptibility to MS has been associated with a number of factors including environmental, genetic, and epigenetic influences, and the relative impact of each continues to be debated. Of the proposed environmental associations, Epstein-Barr virus (EBV), smoking, obesity, and vitamin D deficiency are the best studied with regard to causality.

While MS generally follows a relapsing remitting pattern, 10 per cent of patients present with primary progressive MS (PPMS). In addition, approximately two-thirds of patients with RRMS may progress to secondary-progressive MS (SPMS) by the age of 75 years, although the time to SPMS is much later than in treated cohorts when compared to older natural history studies. Finally, rarely, patients may present with a fulminant form of MS, characterised by large, tumour-like lesions, known as the Marburg variant.⁴

Pathophysiology

From a pathophysiological point of view, MS is an autoimmune-related neurodegenerative disease characterised by demyelination and axonal transection. A key step in the pathophysiology of MS is the entry of autoreactive immune cells into the CNS, traditionally felt to be an immune-privileged organ. This requires failure of central or peripheral immune tolerance – due to impaired function of T-regulatory cells, or to the autoreactive cells themselves gaining resistance to suppression. Previously, MS was felt to be driven predominantly by autoreactive T-cells, but in recent times the role of B-cells has been increasingly acknowledged, particularly with the development of highly effective B-cell depleting therapeutic agents such as ocrelizumab. Activated microglia also play a key role in pathogenesis. In progressive MS, neurodegeneration is felt to be mediated by pro-inflammatory cytokines produced by these activated microglia, which can lead to neuronal damage via excitotoxicity and production of reactive oxygen species resulting in oxidative injury.⁵

Presentation and diagnosis

Typically, MS presents with focal neurological symptoms, which progress over hours to days, resolve over days to weeks, and occur in the absence of fever or infection. Classical MS syndromes include vision loss and painful eye movements due to an optic neuritis; weakness or sensory symptoms due to a transverse myelitis; diplopia and vertigo due to brainstem lesions; or ataxia due to cerebellar lesions. In addition, in younger patients presenting with trigeminal neuralgia, or in a patient of any age presenting with bilateral trigeminal neuralgia, consideration should be given to a demyelinating lesion of the trigeminal entry zone in the pons. Cognitive and neuropsychiatric presentations have been described, but are less common. The clinical exam findings are characterised by the site of the lesion. A cohort of patients may present with a progressive spastic paraparesis (spasticity and brisk reflexes) rather than a distinct episode, which is supportive of a primary progressive phenotype.⁴

MS is diagnosed based on the McDonald criteria, which have undergone several revisions – the most recent in 2017.⁶ These criteria include clinical and paraclinical markers (MRI, unmatched oligoclonal bands (OCBs) in CSF, and visual evoked responses), and diagnosis is based on being able to demonstrate dissemination in space and time. While dissemination in space can be demonstrated by two distinct clinical episodes, it is more commonly confirmed using MRI, with scans showing more than one T2 lesion in more than two areas of the brain typical for demyelination (juxtacortical/cortical, periventricular, infratentorial or spinal cord). Dissemination in time is determined by two clinical attacks at different time points, or the implication of this by both GAD-enhancing and non-enhancing lesions on MRI, development of new T2 lesions on MRI over time, or by the presence of unmatched OCB in CSF.⁶

Management

Management of MS has focused primarily on targeting the autoimmune response.⁷ As such, the currently available disease-modifying therapies (DMTs) primarily act to prevent relapse and progression of disease due to inflammatory activity. They are generally less efficacious in treating progressive forms of MS, whose pathogenesis involves both inflammatory and neurodegenerative processes. However, some DMTs, including ocrelizumab (approved for PPMS) and siponimod (approved for SPMS) have shown modest but significant benefit in these conditions.⁸

Therapies for RRMS are categorised based on their efficacy in terms of reduction of annual relapse rate (ARR), with the earlier therapies, for example glatiramer acetate and beta interferons, generally reducing ARR by about 30 per cent; the newer oral therapies such as fingolimod and dimethyl fumarate reducing ARR by about 50 per cent; and higher efficacy therapies, such as natalizumab and ocrelizumab, reducing ARR by up to 70 per cent.

Approaches to therapy fall into two categories – early induction with high-efficacy therapy, for example, cladribine, ocrelizumab, or natalizumab, or gradual escalation after starting with a low-efficacy therapy and carefully monitoring for relapse. Two clinical trials are currently underway to compare these two approaches – DELIVER-MS and TREAT-MS – but real-world experience does point to improved outcomes with early initiation of high-efficacy therapies.⁷

Typically, MS presents with focal neurological symptoms, which progress over hours to days, resolve over days to weeks, and occur in the absence of fever or infection

EBV and MS

Recent developments in the understanding of MS pathogenesis have suggested new avenues for disease-modifying therapy; in particular, the possibility of using antivirals against EBV. There has long been speculation about the role of EBV in MS pathophysiology, supported by a number of factors, including that people with MS are almost universally EBV seropositive (99.5 per cent), and negative serology is associated with a much lower risk of MS in both adult and paediatric populations.

Almost immediately after seroconversion the protective effects of seronegative status are lost.

Higher anti-EBNA-1 antibody titres are associated with a seven-fold increase in MS risk, and the presence of latent EBV-infected B-cells in MS demyelinated lesions is seen in some, but not all, pathological studies.

However, proving causation had remained elusive, as EBV is a ubiquitous human lymphotropic herpesvirus – around 94 per cent of the healthy population is infected, while MS remains a relatively rare disease.⁹

Epidemiologists at the Harvard TH Chan School of Public Health overcame these obstacles by testing the hypothesis that MS is caused by EBV in a cohort comprising over 10 million young adults on active duty in the US military – 955 of whom were diagnosed with MS during their period of service.⁹ The US military is made up of roughly 1.3 million people at any one time and each of these is tested for HIV every two years, with the leftover serum then stored in the Department of Defence Serum Repository (DoDSR) in Silver Spring, Maryland, US. In addition, a database with information from all active-duty members including medical, laboratory, and deployment data, is maintained by the defence forces medical team. This allowed researchers to use a nested case-control study design – assessing EBV status in those who developed MS and in a sample of a matched ‘risk set’, a group of on-duty military members who could have hypothetically developed MS at the same time. They recorded EBV status at three time-points, at baseline, last time before being diagnosed with MS and at one point in between.

What the researchers found was that 97 per cent of those who developed MS during follow up had seroconverted to EBV positivity (all before onset of MS), whereas only 57 per cent of those who did not develop MS had seroconverted. Those who were persistently seronegative were 32 times less likely to develop MS than those who seroconverted. This is a momentous turning point, as it clearly points to EBV as a causative factor in MS pathophysiology.⁹

There are a number of theories as to how this might be the case. The first is that molecular mimicry might be at play, with latent and persistent infection providing a chronic source of viral antigenic stimulation. Several EBV antigens are the target of cross-reactive autoantibodies found in MS. Additionally, a study published soon after this paper demonstrated that CSF antibodies from MS patients target residues on EBNA-1 which cross-react with GlialCAM – an adhesion molecule in the CNS. Other theories include the concept that EBV might ‘immortalise’ an autoreactive B-cell clone which should be removed by central or peripheral immune tolerance.¹⁰ Most importantly, this discovery will hopefully lead to a new range of treatments for people with MS.

Currently in trials are a number of vaccines against EBV, such as mRNA-1189 – a vaccine in phase 1 trials by Moderna, which is targeted at four different epitopes on EBV. Its aim is to prevent infectious mononucleosis and to reduce the risk of developing post-transplant EBV-associated malignancy or MS. This is relevant, as patients who have had a symptomatic episode of infectious mononucleosis, as opposed to those who were asymptomatically seropositive, have a 2.3 times increased risk of MS.¹¹

Most recently, scientists from the Queensland Institute of Medical Research (QIMR) Centre for Immunotherapy and Vaccine Development, Berghofer Medical Research Institute in Brisbane, Australia, have developed a polypeptide vaccine which combines 20 CD8+ T-cell epitopes in a beads-on-a-string structure with whole recombinant EBV glycoprotein 350 (gp350) to produce a B-cell response creating neutralising antibodies to prevent initial symptomatic infection, as well as a long-lasting T-cell response to prevent proliferation of latent EBV, which is known to be associated with MS.¹²

Conclusion

In summary, MS is an autoimmune disorder of the CNS, which can present with various focal neurological signs. Classical patterns of MS relapse exist, but other symptoms may be seen. The pathophysiology of MS is becoming more clearly understood, raising the possibility of novel treatments in the coming years.