The results of research led by scientists at the University of Exeter, and at King’s College London, suggests that young people could be spared from going blind by a new genetic risk tool that could also help predict patients who will progress to multiple sclerosis (MS) earlier, and get treatment started earlier. The study has shown for the first time that combining genetic risk for MS with demographic factors significantly improves MS risk prediction in people presenting with the eye disorder, which is called optic neuritis (ON).

Tasanee Braithwaite, MD, consultant ophthalmologist to the Medical Eye Unit at Guy’s and St Thomas NHS Foundation Trust, and adjunct senior lecturer at King’s College London said, “As a doctor caring for many patients with optic neuritis, I’m excited by the possibility of translating this pilot research into front line clinical care in the near future. Whilst more research is needed, our study provides a strong signal that we could better identify patients at high risk of MS, perhaps enabling these people to have earlier MS treatment in the future. Whereas, if we could better identify people whose optic neuritis is very unlikely to result from MS, we could treat these people urgently to reduce irreversible vision loss and blindness.”

Braithwaite is senior author of the team’s published paper in Nature Communications, titled “Applying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis,” in which they concluded, “This study indicates that a combined model might enhance individual MS risk stratification, paving the way for precision-based ON treatment and earlier MS disease-modifying therapy.”

Optic neuritis (ON) is a condition that affects people of all ages, but especially young adults, usually manifesting in blurred vision and sometimes pain when moving the eyes. “It is a rare but treatable cause of blindness,” the authors wrote. Up to half of people affected in the U.K. eventually go on to develop MS, often many years later. “Optic neuritis (ON) is associated with numerous immune-mediated inflammatory diseases, but 50% patients are ultimately diagnosed with multiple sclerosis (MS),” the researchers continued. Emerging evidence indicates that starting the very effective MS treatments earlier may improve long term health.

Optic neuritis occurs because of swelling in or around the optic nerve. For those individuals with MS-related optic neuritis, the swelling subsides on its own, and vision usually recovers. “In MS-ON, vision usually recovers spontaneously to near-baseline over three months,” the team noted. For many people whose optic neuritis does not result from MS, the optic nerve can be permanently damaged unless high doses of steroids are given quickly, resulting in loss of sight.  “… non-MS ON often requires urgent immunosuppression to preserve vision.”

Steroids can result in harmful side effects. When people first develop optic neuritis, it can be difficult for patients and their doctors to decide whether the possible benefits of steroid outweigh the possible harms, when the likely cause of the optic neuritis is unclear. So, while differentiating MS-ON from non-MS-ON acutely is important for treatment, it is also challenging, Braithwaite and colleagues noted. Identifying whether there is an underlying cause of optic neuritis can be difficult for clinicians, with many important test results taking weeks to return. “There is an unmet clinical need for a tool to improve acute risk stratification, differentiating those at low future MS risk, who may benefit from urgent corticosteroids, from those at high future MS risk, who may benefit from earlier disease-modifying therapy to reduce long-term neurological disability,” the scientists stated.

For their reported study the team analyzed more than 300 common genetic variants linked to developing MS, combining them into a genetic risk score (GRS) that helps clinicians understand an individual’s chance of developing MS. They analyzed data from 500,000 people in the UK Biobank, who shared genetic samples, questionnaires and linked health information from their electronic medical records.

The researchers identified 2,369 UK biobank participants who had MS, and 687 individuals with optic neuritis. Of those, 545 had no identifiable cause for their optic neuritis at the start of the study, and 124 went on to develop MS. Applying the genetic risk score effectively helped separate those individuals at lowest risk from those at high risk, when combined with demographic data. “Using data from the United Kingdom Biobank we showed that combining an MS-genetic risk score (GRS) with demographic risk factors (age, sex) significantly improved MS prediction in undifferentiated ON,” they wrote. “This pioneering investigation establishes a link between an individual’s combined genetic susceptibility, as measured by the MS-GRS encompassing numerous MS-associated loci with common alleles, and the subsequent risk of MS development in those experiencing an initial episode of undifferentiated ON.”

And although the team points out that the MS genetic risk score is not a diagnostic test, their results highlights that it could add one valuable additional piece of information to support doctors and patients to make better decisions. Importantly, the researchers validated their model across two independent cohorts from the U.S. and Finland. “Moreover, we unveil a stratification paradigm for individuals with undifferentiated ON, integrating the MS-GRS, age at ON onset, and sex, which delineates cohorts characterised by varying future MS risks: low (3.6%), intermediate (14.7%), higher (31.6%), and highest (41.2%).”

Co-author Richard Oram, PhD, associate professor at the University of Exeter Medical School, said, “Since the first genome was sequenced three decades ago, we’ve been working towards the promise of being able to use genetics to improve outcomes for individual patients. This research is an excellent example of precision genetic diagnosis in practice.” AS the authors added, “While it has been long-established that ON may be the first presentation of MS, the additional risk stratification outlined in this study could valuably aid management of ON, and greater international consensus on this, in the time-critical window before neuroimaging and serum and cerebrospinal fluid investigations are available.”

The research stemmed from a summer project led by University of Exeter Medicine student, first named author Pavel Loginovič. With funding from the University of Exeter, it expanded into a research collaboration involving academics in Finland and the U.S. Pavel said: “I’m elated to see this paper published, and it’s gratifying that it could have a real impact in moving research forward, ultimately aiming to get people with MS diagnosed and perhaps treated earlier. Leading this analysis while staying on top of my medical studies has been a challenge and an immense opportunity for growth, professional and personal. I’ve enjoyed the academic journey so far, and I’m excited for what’s to come.”

Commenting on the research, Clare Walton, PhD, head of research at the MS Society, who is not one of the named study authors, commented, “Currently, 130,000 people live with MS in the U.K. and one in five will have experienced optic neuritis at the start of their MS journey. This research shows how using genetic scores could be a useful way to predict who will likely continue to an MS diagnosis. “Using immunotherapies in people at high risk of MS could significantly delay the onset of the condition, but these drugs come with side effects. This exciting study opens up the possibility of finding people in which the benefits will outweigh the risks.”

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