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Subspecialties Neuro-ophthalmology, Basic & Translational Research, Education and Training, Practice Management

Another Step Forward

Meet the Author

I’m the George A. Zimmermann Endowed Professor in Multiple Sclerosis and Professor of Clinical Neurology at the University of California in San Francisco (UCSF), US, and I specialize in MS, NMOSD, and related inflammatory disorders of the nervous system. My interest in neuromyelitis optica began during my residency training, when neuromyelitis optica was still considered an aggressive form of multiple sclerosis rather than a distinct disease. I was the global lead investigator for the N-MOmentum trial of inebilizumab.

The search for new and improved methods to both diagnose and treat optical disorders should be unending. This constant pursuit is especially important in the case of rare diseases, which often have limited treatment options and a lack of awareness around symptoms – even among physicians.

Here, I focus on neuromyelitis optica spectrum disorder (NMOSD) – a disease traditionally confused with multiple sclerosis. Certainly, the community has made great progress in understanding NMOSD – and improving therapeutic options. Indeed, clinicians should be aware that three FDA-approved NMOSD treatments are now available and should be initiated shortly after diagnosis. Unfortunately, 40 percent of the US population has a genetic variation that reduces the effectiveness of these therapeutics. Fortunately, this problem may soon be a thing of the past. In data from the phase III N-MOmentum study (presented at Consortium of Multiple Sclerosis Centers), we show that inebilizumab (UPLIZNA) is effective in patients who have this NMOSD genetic variant (1), simplifying the treatment decision-making process for physicians.

Ophthalmologists may be the first physicians to see undiagnosed neuromyelitis optica in patients who present with optic neuritis. In my opinion, all patients who present with their first attack of optic neuritis should be tested for anti-aquaporin-4 antibodies and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies, and should also undergo a brain MRI scan to rule out the typical changes seen in multiple sclerosis. Why? Because optic neuritis can be the first presentation of all three distinct disorders: NMOSD, MOG-associated demyelinating disorder, and MS. And that’s why improving rapid diagnosis to initiate prompt, appropriate treatment is an important focus right now.

Delving deeper

NMOSD is a rare autoimmune disorder that is characterized by bouts of inflammation affecting the central nervous system – specifically, the optic nerves, spinal cord, and brainstem. Auto-antibodies directed against a water channel (aquaporin-4) cause injury to astroglial cell membranes through activation of the complement pathway. As with many other autoimmune diseases, the trigger underlying the breach in self-tolerance that results in the damaging formation of aquaporin-4 antibodies is not understood. Repeat attacks cause inflammation and irreversible damage in affected areas, leading to weakness, numbness, blindness, paralysis, and even death.

Inebilizumab is a B-cell-depleting monotherapy that binds to CD19 proteins on the surface of B-cells. It is FDA-approved specifically for NMOSD based on the N-MOmentum study, a randomized controlled clinical trial that showed a 77-percent reduction in risk of NMOSD attack in aquaporin-4 antibody-positive adults. Treatment with inebilizumab for up to four years allowed more than 80 percent of patients to be attack free. As mentioned above, attacks can cause irreversible damage, so a therapy that reduces or prevents them in the large majority of patients, and over a long term, is central to our treatment goals.

Inebilizumab was not compared directly with current empirically based immune suppressing medications, such as mycophenolate mofetil and azathioprine, or the monoclonal antibody rituximab. Nevertheless, in the N-MOmentum clinical trial, many study participants who experienced attacks despite treatment with these empiric therapies benefited from treatment with inebilizumab.

The genetic variation that reduces the effectiveness of certain monoclonal antibodies, like rituximab, encodes the low-affinity Fc gamma receptor IIIa (FCGR3A). Interestingly, this same genetic variation seems to be associated with more severe neuromyelitis optica – an observation made during the N-MOmentum analysis.

Credit: Image sourced from

Work to do

I am currently conducting several secondary analyses from the N-MOmentum clinical trial that will demonstrate the utility of biomarkers for monitoring disease activity and response to treatment. In addition, the deep investigations into NMOSD that were built into the N-MOmentum trial are allowing us to i) better define clinical attacks, ii) understand the long-term beneficial effects of inebilizumab, and iii) define the role of MRI in both diagnosis and treatment management.

I also see a clear need for comparative efficacy studies for the three FDA-approved treatments: inebilizumab, satralizumab, and eculizumab. Of these three treatments, only inebilizumab showed an effect on NMOSD-related disability; however, whether this is due to pharmacological properties of inebilizumab or to more rigorous clinical trial design needs to be better understood.

Additionally, now that we have three approved treatments, we need to understand the best sequencing of these therapies. Right now, I don’t think it is feasible to conduct more randomized controlled trials in NMOSD, so we will need to turn to observational studies to help address these issues.

Finally, given the central role of anti-aquaporin-4 antibodies in the disease, it may be possible to restore immune tolerance for aquaporin-4; doing so could potentially repair the underlying immune dysregulation in this disease.

If you read nothing else…

Ophthalmologists should take home two key points: 

  1. Optic neuritis can be the first presentation of NMOSD. Order anti-aquaporin-4 antibodies and anti-myelin oligodendrocyte glycoprotein for all patients presenting with optic neuritis.
  2. There are proven treatment options for NMOSD. Promptly refer patients who test seropositive for anti-aquaporin-4 antibodies to neurologists who specialize in inflammatory diseases of the central nervous system so that effective treatments can be promptly started.

To read Friedemann Paul’s article on the importance of NMOSD awareness, click here.

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  1. BAC Cree et al., “Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial,” Lancet, 394, 1352 (2019). PMID: 31495497.
About the Author
Bruce Cree

Professor of Clinical Neurology at the University of California San Francisco Weill Institute for Neurosciences, USA

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