Evolution of NEDA: Q&A With Cleveland Clinic’s Dr Robert Bermel

Each component of NEDA has limitations — for example, measures of brain atrophy may be confounded by various factors, and the correlation between short-term measures of EDSS progression and long-term disability outcomes is unclear.

For many of the estimated 2.5 million people with multiple sclerosis (MS), outcomes have improved substantially in recent decades, as has the efficacy of disease-modifying therapies (DMTs) for MS.1 Whereas treatment previously focused on preventing disability progression and reducing relapse rates, it is increasingly aimed at complete clinical and radiologic disease inactivity.

With the proliferation of more effective therapies, clinicians have expressed concern that traditional, individual outcome measures of treatment response, including annualized relapse rate, lesions shown on magnetic resonance imaging (MRI), and disability progression, may be inadequate to assess overall treatment response. “Composite outcome measures of treatment response that incorporate both clinical and radiologic metrics of disease activity and progression and are potentially more sensitive to the effects of DMTs are now being incorporated into MS clinical trials…,” wrote the authors of a review published in February 2018.2

One such measure is no evidence of disease activity (NEDA), which was initially referred to as “absence of disease activity” and “freedom of disease activity” in a 2009 post-hoc analysis of results from the AFFIRM trial for natalizumab and in studies that followed soon thereafter.3 The 2009 study examined a composite of the following 3 measures in 942 patients with relapsing-remitting MS: no clinical relapse, no increase in disability progression per the Expanded Disability Status Scale, and no new gadolinium-enhancing lesions or new or enlarging T2 lesions.

The results showed that 37% of patients treated with natalizumab achieved freedom from disease activity vs 7% of patients receiving placebo (P <.0001). Subsequent research, such as trials of alemtuzumab, interferon beta-1a, and daclizumab, referred to the composite measure as “disease activity free status.”4-7

The term NEDA first appeared in the literature in 2014 and has since been retermed NEDA-3 to reflect the 3 measures it initially included.8 NEDA-3 has been employed in studies investigating traditional DMTs and in those comparing these agents with novel therapies. In a 3-year trial reported in 2013, treatment with a combination of interferon beta-1a plus glatiramer acetate was associated with an NEDA-3 rate of 33.3%.6 In another study, patients treated with fingolimod had significantly higher rates of NEDA-3 compared with those treated with interferon beta-1a (46% vs 34%, P <.001).9

“NEDA-3 emphasizes the role of inflammatory pathology, reflecting the classical view of MS as a focal disease of the white matter,” according to the recent review. “However, there is growing evidence of diffuse pathology involving both grey and white matter, driven by both inflammatory demyelination and neurodegeneration, that ultimately culminates in brain volume loss.” As such, annualized whole brain volume loss ≤0.4% has been added as a fourth variable.10 The 4-parameter measure is called NEDA-4.

Each component of NEDA has limitations — for example, measures of brain atrophy may be confounded by various factors, and the correlation between short-term measures of Expanded Disability Status Scale progression and long-term disability outcomes is unclear. An additional criticism of NEDA is that “while some constituents may exert proportionally greater influence on longer term MS outcomes, each has equal weight in current NEDA formulations, a potential source of bias,” the review authors reported. “Future iterations of NEDA definitions will almost certainly incorporate novel imaging, blood, and cerebrospinal fluid biomarkers of disease activity and progression, as future research elucidates their place in MS treatment monitoring.”

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To further explore the concept of NEDA, Neurology Advisor spoke with Robert Bermel, MD, MBA, director of the Cleveland Clinic Mellen Center for Multiple Sclerosis.

Neurology Advisor: What is currently known about the potential value of NEDA as a measure of clinical outcome in MS, and what is the main point of debate regarding its use?

Dr Bermel: From large observational studies, evidence suggests that achieving NEDA improves prognosis in MS. In clinical trials with longer term follow-up, patients who achieve NEDA over the first 2 years of therapy tend to remain free of disease activity and have less brain atrophy and better cognitive function. Some neurologists initially believed that NEDA was too strict a standard for disease management and not achievable in many patients, but that is becoming a less relevant argument now that we have higher efficacy DMTs.

There is an emerging belief that we need to actually move in the opposite direction — to increase the standard for MS disease control, especially early in the disease, targeting a more comprehensive measure of disease remission, which might include NEDA components plus other emerging measures such as brain atrophy and serum neurofilament light chain measurement. Therefore, although the specific treatment target may evolve over time as our technology and understanding of the disease improves, treating to target and getting to the target as early in the disease as possible are likely to be common themes in the future.

Neurology Advisor: What are the top takeaways for clinicians?

Dr Bermel: The idea of having a defined treatment target in MS gives healthcare providers and patients a monitoring plan and an appropriate expectation for how to tell whether the medication is working. Especially early in a person’s course with MS, disease activity can be occurring without any corresponding symptoms. Having MRI as part of the NEDA target really emphasizes the importance of checking MRI to monitor for subclinical disease activity and changing therapy if there are new or active MS lesions.

Neurology Advisor: What further research is needed regarding this measure?

Dr Bermel: Many of us believe that there is a window of opportunity early in MS, where controlling the disease early will result in improved long-term outcomes and prevent the development of secondary progressive MS. The updated MS treatment guidelines offer guidance for neurologists on which specific medications to start within MS and what to switch to if there is disease activity, and there is ongoing research to further clarify these topics, including a large clinical trial funded by PCORI and run by the Cleveland Clinic.


  1. Cerqueira JJ, Compston DAS, Geraldes R, et al. Time matters in multiple sclerosis: can early treatment and long-term follow-up ensure everyone benefits from the latest advances in multiple sclerosis? [published online April 4, 2018]. J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp-2017-317509
  2. Lu G, Beadnall HN, Barton J, Hardy TA, Wang C, Barnett MH. The evolution of “no evidence of disease activity” in multiple sclerosis. Mult Scler Relat Disord. 2018;20:231-238.
  3. Havrdova E, Galetta S, Hutchinson M, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009;8(3):254-260.
  4. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1819-1828.
  5. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1829-1839.
  6. Lublin FD, Cofield SS, Cutter GR, et al. Randomized study combining interferon & glatiramer acetate in multiple sclerosis. Ann Neurol. 2013;73(3):327-340.
  7. Havrdova E, Giovannoni G, Stefoski D, et al. Disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with daclizumab high-yield process in the SELECT study. Mult Scler. 2014;20(4):464-470.
  8. Rudick RR, Fisher E, Goodman A, et al. No evident disease activity (NEDA): associations with brain atrophy and functional outcomes in patients from the AFFIRM study. Presented at: CMSC ACTRIMS Cooperative Meeting; May 28-31, 2014; Dallas, TX. Abstract DX03.
  9. Cohen JA, Khatri B, Barkhof F, et al. Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study. J Neurol Neurosurg Psychiatry. 2016;87(5):468-475.
  10. Ghezzi A, Karlsson G, Haering D, et al. Effect of fingolimod on no evidence of disease activity (NEDA-4) and safety in young adult patients with relapsing-remitting multiple sclerosis. Neurology. 2015; 84(14 Suppl):P3.277.