The Future of NMOSD Research: Standardizing Relapse, Advancing Acute Care, and Moving Beyond Broad Immunosuppression

Neuromyelitis optica spectrum disorder (NMOSD) is a severe, relapse-driven autoimmune disease in which early and effective treatment can dramatically alter long-term disability. As FDA-approved therapies have reduced relapse risk to historically low levels, the field now faces a new challenge: refining trial methodology, optimizing long-term outcomes, and pushing beyond relapse prevention alone.

In this 5-part panel series, Shamik Bhattacharyya, MD, Anne M. Finucane Endowed Chair in Neurology and Associate Professor of Neurology at Harvard Medical School, and Philippe-Antoine Bilodeau, MD, of the Division of Neuroimmunology at Mass General Brigham and Instructor in Neurology at Harvard Medical School, analyze their comparative effectiveness study published in Neurology and discuss its broader implications. Drawing from real-world data and decades of clinical experience, they explore how the NMOSD treatment landscape continues to evolve—and where the field must go next.

In this closing discussion, the focus shifts toward the future. The panel addresses the importance of transparent and standardized relapse definitions, the need for prospective comparative effectiveness trials, and emerging frontiers in acute attack management, symptomatic therapy, immune tolerance strategies, and novel cellular approaches such as CAR T-cell therapy. Together, they outline a vision for NMOSD research that prioritizes both methodological rigor and meaningful reductions in long-term disability.

Edited Transcript

Philippe-Antoine Bilodeau, MD:

Regarding the issue of standardizing relapse definitions, I think the most important principle is transparency. That is true in research more broadly: be very explicit about the definition you used and clearly state it in the methods section.

In many papers, you will see something like, “a relapse was defined as new neurologic signs and symptoms lasting more than 24 hours.” From clinical practice, we know that could encompass many different scenarios. It could be worsening pain, a new headache, or something more clearly inflammatory. So it is important to be precise about how relapse is defined.

In our study, we also performed sensitivity analyses to evaluate whether differences in relapse definitions affected the outcomes. That was essentially a way to ensure that our findings were not driven solely by how we defined relapse. Similarly, when using methods such as inverse probability treatment weighting for causal inference, it is important to clearly state what variables were included in the model, why they were chosen, and why others were not.

As for the future, the next step is a clinical trial. This was a retrospective study. We applied rigorous methods to generate insight into comparative effectiveness and safety, but ultimately, a prospective comparative effectiveness trial is needed. We are currently leading such an effort through the Sumaira Foundation and Mass General Brigham—the BEST NMOSD trial—which is expected to launch in the coming months.

Shamik Bhattacharyya, MD:

To add to that, much of the field has focused on immunotherapy trials. However, patients’ lived experiences are also shaped by pain, spasticity, bladder dysfunction, and other symptoms common in NMOSD. A missing piece in our treatment landscape is symptomatic therapy trials—how do we improve quality of life after a relapse has already occurred?

There has traditionally been less enthusiasm for these types of trials, but they are critically important. Another area where multiple sclerosis has been ahead is in remyelination trials. Although none have yet succeeded, at least there have been attempts. In NMOSD, we have not meaningfully explored how to reverse disability once a severe attack has occurred. Most patients present after a significant event, and even if we prevent future attacks, they may remain paraplegic or blind. We need to consider whether we can develop therapies that meaningfully improve existing disability.

Philippe-Antoine Bilodeau, MD:

Another frontier is acute treatment trials. There are really two additional directions for the field. One is developing tolerizing therapies—teaching the immune system to stop reacting to aquaporin-4. The other is determining how to limit disability from the first attack.

The field has been very successful in developing relapse-prevention therapies. Many patients on newer treatments rarely relapse. But the damage from the initial attack can still be profound. Some patients remain blind or wheelchair-bound from their first episode of longitudinally extensive transverse myelitis.

We need to explore whether early use of therapies such as B-cell–depleting agents, complement inhibitors, IL-6 receptor blockers, or even neonatal Fc receptor antagonists during the acute attack could limit early damage. That may represent the next frontier in reducing disability.

And when discussing autoimmune diseases, it is difficult not to mention CAR T-cell therapy—chimeric antigen receptor–engineered T cells designed to deplete specific immune targets. Clinical trials are being planned in NMOSD to target B cells with CAR T-cell approaches. These strategies may allow for deeper tissue depletion of pathogenic B cells and potentially more durable outcomes.

At present, much of what we do could be described as broadly immunosuppressive. The immune system reacts to a single antigen—aquaporin-4—and we suppress large portions of the immune system to stop that reaction. The ultimate goal is greater selectivity: abolishing reactivity against the specific antigenic target while preserving normal immune function. That is the long-term vision not only for NMOSD, but for autoimmune disease as a whole.