Evolution of Visual Outcomes in Clinical Trials for Multiple Sclerosis Disease-Modifying Therapies

From the Section Editor: In March 2018, the Journal of Neuro-Ophthalmology (JNO) launched its inaugural "Disease of the Year" section, featuring multiple sclerosis (MS). Beginning from a "Bench" perspective, Meltzner and colleagues presented an elegant overview of the pathogenic mechanisms believed to underpin central nervous system (CNS) injury in MS. To complement these efforts, Backner and Levin highlighted how the afferent visual pathway, as a putative model of CNS inflammation, can be interrogated with measures of structure and function to capture clinical and sub-clinical evidence disease activity in MS patients. Building on these concepts in this issue of the JNO, Nolan et al summarize how visual outcomes have been employed as outcome measures in MS clinical trials. In addition, Burton and Freedman advance us closer to the "Bedside" arena of clinical care, by surveying the rapidly changing therapeutic landscape, and providing a framework for escalating treatments in MS patients. In the Bench-to-Bedside section of this issue of the JNO, Cree provides a historical account of the how treatment paradigms have evolved over the years, to the modern era in which immunosuppressive agents have taken center stage. Specific emphasis is given to ocrelizumab, which targets CD2O B lymphocytes, as promising new treatment for relapsing remitting and progressive MS patients. Probstel and Hauser broaden the discussion around ocrelizumab by reviewing the role of B-cell depleting agents in the treatment of MS. In their review, they also discuss the development of related biomarkers that may be used to monitor treatment response, as our understanding of MS care continues to advance. Background: The visual pathways are increasingly recognized as an ideal model to study neurodegeneration in multiple sclerosis (MS). Low-contrast letter acuity (LCLA) and optical coherence tomography (OCT) are validated measures of function and structure in MS. In fact, LCLA was the topic of a recent review by the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) to qualify this visual measure as a primary or secondary clinical trial endpoint with the Food and Drug Administration (FDA) and other regulatory agencies. This review focuses on the use of LCLA and OCT measures as outcomes in clinical trials to date of MS disease-modifying therapies. Methods: A Pubmed search using the specific key words "optical coherence tomography," "low-contrast letter acuity," "multiple sclerosis," and "clinical trials" was performed. An additional search on the clinicaltrials.gov website with the same key words was used to find registered clinical trials of MS therapies that included these visual outcome measures. Results: As demonstrated by multiple clinical trials, LCLA and OCT measures are sensitive to treatment effects in MS. LCLA has been used in many clinical trials to date, and findings suggest that 7 letters of LCLA at the 2.5% contrast level are meaningful change. Few clinical trials using the benefits of OCT have been performed, although results of observational studies have solidified the ability of OCT to assess change in retinal structure. Continued accrual of clinical trial and observational data is needed to validate the use of OCT in clinical trials, but preliminary work suggests that an intereye difference in retinal nerve fiber layer thickness of 5–6 μm is a clinically meaningful threshold that identifies an optic nerve lesion in MS. Conclusions: Visual impairment represents a significant component of overall disability in MS. LCLA and OCT enhance the detection of visual pathway injury and can be used as measures of axonal and neuronal integrity. Continued investigation is ongoing to further incorporate these vision-based assessments into clinical trials of MS therapies.

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