Beyond NMOSD: Lessons in Disease Evolution

I recently had the pleasure of attending a roundtable conference on Neuromyelitis Optica Spectrum Disorder (NMOSD), organized by the Guthy-Jackson Charitable Foundation, a leading advocate for NMOSD research. The experience was profoundly inspiring, prompting me to reflect on both the limitations and the immense promise of precision medicine. Hearing the perspectives of world-renowned neurologists and healthcare providers brought a tangible dimension to the scientific research being discussed.

In this article, I share my key takeaways from the conference and expand upon some of the considerations surrounding NMOSD, exploring their relevance to the broader field of precision medicine.

1. The Evolving Landscape of Diseases

NMO (neuromyelitis optica), initially considered a single entity (an extreme variant of multiple sclerosis) has undergone an evolution in classification.

In 2015, criteria were established organizing NMO spectrum disorder (NMOSD) to comprise at least three distinct diseases (Neuromyelitis Optica Spectrum Disorder (NMOSD) - Merck Manual Professional Edition):

• Aquaporin-4 antibody positive (formerly known as NMO antibody positive),
• Myelin oligodendrocyte glycoprotein (MOG) positive (MOGAD),
• Double-antibody negative (patients with this type have clinical neuromyelitis optica spectrum disorder but have neither antibody), with the potential for further subtyping.

In 2023, the field underwent its next step in evolution. The entity termed myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) separated from NMOSD by virtue of having specific diagnostic criteria proposed.

In 2025, the field is expected to update the 2015 NMOSD criteria to address advances in differential diagnosis, clinical features, therapeutic experience and biomarkers. 

This progression of evolution in disease understanding and differential diagnosis reflects a broader trend in medicine where ongoing research leads to the reclassification and refinement of disease definitions, enabling more precise diagnosis and targeted treatment strategies. Examples include subtypes of breast cancer, diabetes, and even autism spectrum disorder.

2. Diagnostic Challenges and the Need for Biomarkers

The absence of definitive diagnostic markers for "double-seronegative" NMOSD, leading to reliance on symptoms, underscores a pervasive challenge in diagnosing many diseases. Conditions such as fibromyalgia, chronic fatigue syndrome, and even some mental health disorders lack clear biomarkers, leading to diagnostic uncertainty and potential misdiagnosis. Developing reliable biomarkers for differential diagnosis, therapeutic response, relapse adjudication and severity, and predictive or regenerative medicine remain critical goals for enhancing diagnostic accuracy and guiding treatment decisions across a spectrum of diseases. The potential misdiagnosis of NMO, NMOSD or MOGAD as MS or lupus highlights the importance of precise diagnostic criteria and the need for continued research into disease-specific biomarkers.

Developing reliable biomarkers for differential diagnosis, therapeutic response, relapse adjudication and severity, and predictive or regenerative medicine remain critical goals for enhancing diagnostic accuracy and guiding treatment decisions across a spectrum of diseases.

3. Closing the Knowledge Gap

The call for improved training and awareness of NMO, NMOSD and MOGAD and related diseases reflects a broader need for continuous medical education across various specialties. Many rare or complex diseases suffer from a lack of recognition and understanding among healthcare professionals, leading to delayed diagnosis and suboptimal treatment. Addressing this knowledge gap requires readily available resources, innovative educational approaches, and the development of comprehensive biomarker panels to aid in diagnosis and treatment selection.

4. Unveiling Comorbidities and Preventing Co-occurring Diseases

The focus on autoimmune comorbidities in NMO, NMOSD and MOGAD highlights the interconnectedness of diseases and the potential for shared underlying mechanisms. Understanding these relationships can lead to the identification of risk factors and the development of proactive interventions to manage or even prevent co-occurring conditions, improving overall patient outcomes.

5. Reassessing Disease Rarity

The evolving understanding of NMO, NMOSD and MOGAD prevalence demonstrates how advances in diagnostic tools and medical knowledge can reshape our perception of disease rarity. This observation is applicable to other conditions, emphasizing the need to re-evaluate assumptions about disease prevalence to ensure adequate resource allocation and research efforts.

6. The Importance of Global Data Exchange

The variability in patient demographics and disease manifestations across different regions highlights the value of worldwide data sharing. This principle applies to all diseases, as global collaboration and data exchange enable the identification of geographic and ethnic variations, facilitating the development of more personalized and effective treatment strategies.

7. From Treatment to Cure

The distinction between treatment and cure in NMO, NMOSD and MOGAD resonates across numerous diseases. While effective treatments exist for many conditions, the ultimate goal remains to find cures that eliminate the disease altogether. This goal underscores the emerging emphasis on antigen-specific immune tolerization in NMO as a model for solving related autoimmune disorders. Continued investment in research and innovative therapeutic approaches is essential for translating scientific discoveries into curative therapies.

8. The Art and Science of Treatment Selection

The challenge of choosing the most appropriate treatment from multiple options is widespread in medicine, even for non-rare diseases. This challenge is amplified in the era of personalized medicine, where tailoring treatment plans based on individual patient characteristics and disease subtypes becomes paramount. Advancements in genomics, biomarker identification, and data analytics are crucial for optimizing treatment selection and improving patient outcomes, especially when dealing with the complexities of small sample sizes and stratified patient populations. The trial-and-error approach highlights the need for better predictive tools to guide treatment decisions and minimize adverse events.

The trial-and-error approach highlights the need for better predictive tools to guide treatment decisions and minimize adverse events.

9. Addressing the Cost of Care

The high cost of maintenance therapeutics to minimize risk of relapse, as exemplified by some NMO treatments, is a significant barrier to equitable access to care for patients worldwide. As an example, the US annual average cost per patient of biologics now FDA approved aquaporin-4 antibody-positive NMO can be $500-700k (The 10 Most Expensive Drugs in the U.S., Period, Drug and administration costs in the commercial market for generalized Myasthenia Gravis pharmaceutical therapies). This issue extends beyond NMO and necessitates ongoing efforts to address drug pricing, promote cost-effective manufacturing, and explore innovative funding models to ensure affordable treatment for all. Understanding the true cost drivers of drug development and production is crucial for developing sustainable solutions.

10. Overcoming Regulatory and Ethical Hurdles:

Disparities in drug approvals and clinical trial regulations between countries present complex challenges. Ensuring ethical research practices, navigating regulatory complexities, and promoting global collaboration are critical for making new treatments accessible to patients worldwide in a timely and responsible manner.

11. Data as the Foundation for AI Advancements:

The importance of high-quality, standardized or harmonized data for AI development applies to all areas of medicine. Robust datasets are essential for training AI algorithms to improve diagnostics, predict disease progression, and identify novel therapeutic targets, ultimately leading to more precise and effective treatments across a wide range of diseases.

In conclusion, I believe the takeaways I gathered from the GJCF roundtable conference offer valuable insights that extend beyond NMO itself. By addressing diagnostic challenges, embracing personalized medicine, promoting global collaboration, and investing in data-driven research, we can continue to push the boundaries of medical knowledge and improve the lives of patients worldwide.

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.