A 30,000 foot view of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory, demylinating, neurodegenerative disease of the central nervous system. It is a disease of the immune system going haywire. Most patients have relapsing-remitting MS (RRMS): reversible episodes (days to weeks) of neurological dysfunction that lead to clinical and cognitive deficits. Some, a minority (10-15%), have progressive disease from the onset (Primary Progressive MS) which is a more severe clinical course (PPMS epi). In RRMS, patients experience episodes of symptoms with periods of recovery but in PPMS there are no real symptom-free periods as the patient’s condition steadily declines (Yale MS).

RRMS onset is between 20-35 years and PPMS around 40 with diagnoses made by clinical observation and supported by imaging demonstrating CNS demylination and/or lesions (Filippi 2018). MS is mainly found in people with European ancestry and rarer in other groups. The prevalence is about 2 per 100k in Asia but 1 per 1000 in Western countries, a 50 times higher rate in Western countries (Rosati 2001). The female to male ratio of MS incidence is 3:1, but was previouslt 2:1 about 70 years ago (Koch-Henriksen 2010). It is unclear why women are predominatly affected. Are there environmental triggers that women are exposed to more (e.g., oral contraceptives, childbirth, obesity)? Overall, life expectancy is reduced by 7-14 years but some recent data suggests that it may not actually decrease life expectancy to that level (Scalfari 2013). Because of the nature of the disease, PPMS is associated with higher mortality than RRMS. For many MS patients it is the functional disability (e.g., wheelchair-bound) that impacts their day-to-day and limits their ability to be independent and do the things they wish to do.

Genetics, Environment, MS Risk and Severity Assessment

Genetics and environment contribute towards MS development. We have some understanding of the environmental exposures that increase risk and promote pro-MS states. Large prospective studies following people for years from childhood for evaluating environmental risk factors have not really been conducted. Adolescence is a critical window for MS development, and exposure to environmental triggers during this period increases risk substantially (Olsson 2017). Based on what we do know, being seropositive for EBV (particularly during adolescence), adolescent obesity, smoking, vitamin D level, low sun exposure, and night work are the most important factors (table with odds ratios). Risk of MS with smoking is dose-dependent (Olsson 2017) and I suspect obesity and weight follows the same dose-dependence principle.

What about genetics? MS is polygenic and each genetic hit is associated with a small increase in disease risk. GWAS studies have identified >200 genetic risk variants (Baranzini 2017). Polymorphisms in HLA class I and II genes convey the highest risk of known variations and likely interact with the previously discussed environmental triggers to compound risk potentially nonlinearly (Olsson 2016). Other important variant are genes involved in T cell activation and proliferation (e.g., IL7R, IL2) and components of adaptive and innate immunity (e.g., TNF) (Cotsapas 2018).

A landmark Science paper in 2022 showed that the “risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus; serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion”. EBV is not causative for MS, probably, but is probably the greatest risk factor we know. Given that ~90% of the world has been infected with EBV (source), using this information to stratify risk might be a little difficult. On the whole, we need to also better investigate genetic risk factors and the interaction between MS susceptability genes (e.g., Vitamin D metabolism and HLA genes) with environmental factors.

Given that a patient has MS, we would like to know information about their potential disease trajectory. How quickly might this progress? When might they need a wheelchair, if at all? Understanding prognosis and stratifying patients is important clinically because it allows you to tailor treatment protocols but it also can help the patient make informed decisions about the way in which they want to live their lives. A large-scale GWAS study of ~13k cases and externally validated on ~10k cases began to unravel possible MS severity loci. Key findings include the DYSF-ZNF638 locus that shortened the time required for a walking aid by 4 years while also increasing brainstem and cortical brain tissue pathology (MS severity paper).

Treatments

Ocrelizumab is an anti-CD20 monoclonal antibody (mAb) that specifically targets and kills B cells. It shares a binding epitope with rituximab (another anti-CD20 mAb used in certain heme cancers and conditions like rheumatoid arthtritis). Rituximab is widely used off-label for RRMS (Hauser 2008) and this led to other B cell depletion strategies to treat MS including Ocrelizumab. In summary: Ocrelizumab reduced the relapse rate by 55% relative to Rebif (another MS drug) in RRMS and sustained benefit observed after three years; decreased fatigue relative to placebo in PPMS; reduction in time to clinical disease progression at 12 and 24 months with hazard ratio 0.6 (trial results). Infusion reactions (34% of patients) and serious infections (1.8%) were the most reported adverse side effects. Anti-CD20 drugs are immunosupressive and most infections reported were bacterial that resolved with antibiotics (infection summary). In general, Ocrelizumab helps RRMS patients tremendously and has great outcomes, something that was not possible before. However, the long-term side effects are relatively unknown. When the FDA approved the drug, it required Roche, the manufacturer, to conduct several follow up trials including: a) 10-17 year old with RRMS to determine dosing, safety, and efficacy by 2024; b) prospective five-year study to better understand risk of cancer by 2030; c) prospective five-year study looking into Ocrelizumab exposure pre and post pregnancy by 2029 (FDA doc). While we wait, its important to remember that the clinical trial results outperformed every other MS drug available on the market and reduced the annual relapse rate for patients with relapsing forms of MS by 50 percent. However, it offers only about a 25 percent benefit to patients with a primary-progressive form of the disease (Yale press).

There are other treatment options and a good summary of the available choices can be found at this table. There is a marked lack of ability to treat PPMS amongst existing treatment strategies. In general disease-modifying treatments for RRMS cannot prevent disease worsening in SPMS and PPMS patients (Filippini 2013) - with Ocrelizumab being the first drug which significantly reduced the risk of disability progression compared with placebo in PPMS patients (Montalban 2017). Beyond disease-modifying therapies, we treat relapses with high-dose corticosteroids or plasma-exchange and treat the symptoms of patients as they occur (e.g., botox for spasticity in restricted muscle groups).

Remyelination is one possible treatment strategy explored in larger detail here. No approved biologics are available, but the principle of remyelinating demyelinated regions is the most direct possible solution to MS. It may also be true that permanent axon loss is more likely the irreversible change associated with MS which is made possible and accelerated by demyelination. One avenue of research would be to figure out how to remelinate axons. Maybe by introducing myelinogenic cells into lesioned areas or growth factors that mediate repair of lesions. But, this is a temporary fix since the haywire immune system responsible for the MS will continue marching forwards. Based on our current understanding, true disease-modifying therapies must come from targeting the immune system or components of the immune system present on cells and tissues in the central nervous system.

Early detection and treatment monitoring

As more treatments enter the market, we need to start thinking about tailoring disease-modifying therapies to MS patients. Specifically, can we monitor response to treatment for MS patients and use that information, as we do in cancer treatment, to adjust or switch regimens? Additionally, developing tests to detect MS early is critical so that we can start patients on therapy earlier when the amount of irreversible change is smaller. To do this, we must find noninvasive biomarkers that are preferentially elevated and related to the underlying disease mechanism at hand. Both of these would require a non-invasive monitoring approach and possible candidates include serum protein biomarkers, plasma cell-free DNA, optical coherence tomography (OCT), and MRI (Filippi 2018). Briefly, let us discuss neurofilaments - one protein marker that has been studied with respect to detection and risk stratification of patients with MS. Neurofilaments of the axonal cytoskeleton are released from damaged neurons and axons in neurological disorders and these chains (light, intermediate, and heavy) can be quantified in blood and CSF as a marker of damage (Teunissen 2015 and Norgren 2003). Several studies have demonstrated that levels of light-neurofilament (NfL) in cerebrospinal fluid are higher in individuals with clinically-isolated syndrome (before RRMS but after pre-symptomatic stage) who convert to MS than in individuals who do not convert. Also, higher levels of NfL are associated with greater disability, more frequent relapses, higher numbers of T2-hyperintense and gadolinium-enhancing lesions on MRI and more severe brain atrophy (Siller 2018 , Khalil 2013) , Disanto 2017), , and Disanto 2015). We might monitor NfL levels at baseline and at regular intervals to gauge whether Ocrelizumab is working. We expect that NfL will drop if Ocrelizumab is working because axonal damage starts to decrease. Axonal damage and grey matter pathology (focal lesions, tissue loss, and neuronal abnormalities) are present in MS. NfL is one marker of this. As cells die, they shed DNA and this DNA enters the circulation. We may be able to detect these pieces of DNA to track disease progression and even detect disease. We can draw inspiration from the oncology space (Cristiano 2019 , and Mathios 2021.