Abstract| Volume 37, 101565, January 2020

“No Evidence of Disease Activity”: Is it An Aspirational Therapeutic Goal in MS?

      Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disease of the brain and spinal cord that leads to demyelination and neurodegeneration. The diagnosis is based on the integration of the clinical presentation and paraclinical markers with the most important being the magnetic resonance imaging (MRI). The clinical, radiological and underlying pathology of MS is highly heterogeneous, therefore the effectiveness of disease-modifying treatments (DMT) differs in patients. As multiple therapies are becoming available, there is a lower threshold to accept any disease activity or worsening and the importance to create a surrogate marker to evaluate the efficacy of the DMT is rising. The model of “No evidence of disease activity” (NEDA) has been used as an outcome measure for treatment response. It is based on the absence of disease activity, which is defined, by the absence of clinical relapses, disability progression on EDSS, and radiological activity. Our aim was to extensively review the literature about the concept of NEDA and its different variants. We also reviewed the importance of its use as a surrogate marker to assess the efficacy of different DMTs.
      A search of multiple electronic databases was done in March 2019 including PubMed, MEDLINE and Cochrane Library. The keywords used in our search were “Multiple Sclerosis” AND “No evidence of disease activity” AND “MRI” and as a result we retrieved 413 articles. Duplicates, articles not written in English and those not including MS patients or investigating NEDA were excluded. Articles were screened by title then by abstract and 98 remained. Data was extracted from the articles including the details on participant characteristics, methods, outcomes, and results.
      Although NEDA-3 combines important clinical and radiological aspects of MS, it is limited by its sensitivity to inflammatory stages. In addition to NEDA-3 components, NEDA-4 assesses brain volume loss. Among the reviewed papers, 55% evaluated NEDA-3 while only 26% addressed both NEDA-3 with-4, and 17% of the articles discussed the addition of other outcome measures. The majority of studies highlighted the importance of NEDA-3 as an outcome measure for disease progression prediction, while some emphasized the importance of having additional markers for disease activity. Three studies suggested that NEDA-4 had a more comprehensive view of inflammatory and degenerative activities when used as outcome measure. However, one study failed to report any predictive value. “No Evidence of Progression or Active Disease” (NEPAD) has also been defined as an outcome measure by adding the 9-hole peg test and 25-foot walk test to NEDA-3 components. It even had a more comprehensive and clinically meaningful endpoint in primary progressive MS (PPMS) patients.
      The definition of NEDA should be constantly revised as the inclusion of new parameters might give better understanding to the underlying pathology of the disease. Biomarkers such as CSF and serum neurofilament, OCT and/or neuropsychiatric testing should be further investigated about their potential to improve measurement of disability progression. Furthermore, additional studies should be done to investigate the time a patient is in NEDA as it may be an important prognostic factor.