Since the first disease-modifying therapy (DMT) for multiple sclerosis (MS) was approved by the FDA in 1993, medications for MS have been developed to slow down the disease. Many have been shown in clinical studies to reduce the frequency of relapse and slow the accumulation of permanent disability.
As early as 2010, MS researchers began to suggest that rather than simply slowing down the disease, a clinical goal of therapy could be “freedom from disease activity.” The idea is that measuring the number of people with MS who can achieve freedom from disease activity could become a better gauge to determine therapeutic effectiveness. The concept is now referred to as “no evidence of disease activity,” or NEDA, for short.
What is NEDA?
While the definition of NEDA is evolving, “no evidence of disease activity” means exactly what is sounds like. A person with MS would show no signs of active disease — but this doesn’t mean that old symptoms or disability would disappear. For NEDA to occur, three conditions need to be met, the combination of which is sometimes called NEDA3.
- No clinical relapses or exacerbations
- No Gd-enhancing (active) lesions and/or no new or newly-enlarging T2 lesions
- No change in the neurological exam or confirmed disability progression
Note that these measures are focused primarily on inflammatory disease activity and do not readily capture other disease consequences, such as neurodegeneration. Researchers have suggested the addition of a fourth measure — brain volume loss— to provide a more comprehensive view of disease activity and progression. This new criteria is called NEDA4.
Why measure brain atrophy?
Brain volume loss (BVL), also called brain atrophy, correlates with disability progression and cognitive decline in people with MS. It can result from lesions in the brain’s grey matter and damage in normal-appearing white and grey matter. Studies have determined that an annual BVL rate of 0.4 percent or more can distinguish between people with MS and healthy individuals who generally experience BVL rates between 0.1 and 0.3 percent each year. To begin to test the theory that NEDA4 provides a more comprehensive assessment of disease activity and progression, researchers have applied the criteria to clinical trial data of different MS therapies (such as fingolimod, peginterferon beta-1a, or other oral therapies). Results suggest that the new four-parameter measure has the potential to capture the impact of therapy on both inflammation and neurodegeneration.
Using NEDA to make treatment decisions
Much of the discussion surrounding NEDA (3 or 4) is among MS researchers and scientists. The concept has not been routinely applied to clinical practice. However, researchers suggest that brain atrophy and cognitive function should be routinely measured and used by neurologists to help patients make more informed treatment choices. The sensitivity of NEDA to detect treatment response and predict future disability may be helpful in deciding when to switch treatments for patients who do not respond to therapy.
NEDA is difficult to maintain over time, but sustained NEDA can predict future lack of disability progression. In a 7-year study, a total of 99 of 215 patients (46 percent) achieved NEDA at year one, but only 7.9 percent maintained NEDA status through year seven. Demonstrating the prognostic power of NEDA, researchers noted that 78.3 percent of patients who still had NEDA status at year two experienced no disability progression by year seven.
This would suggest that using NEDA to make treatment decisions could be helpful in avoiding disability progression. However, there are researchers who point out that NEDA may not be a valid long-term measure because it is not easy to determine whether a patient is “doing well simply because they are not doing badly or because they are taking a particular medication.”
In other words, it might be that NEDA status is more indicative of benign MS than treatment effectiveness.
Disease activity is complex and often hidden
Looking for NEDA, or rather its converse, EDA (evidence of disease activity), demonstrates how MS can be active without causing obvious outward signs. Patients can become confused or frustrated when symptoms, relapses, or disability progression are not represented by changes on MRI scans.
A Norwegian study that examined disease activity in 72 people with relapsing-remitting MS using different treatments found that one year after baseline assessment 54 percent (39/72) of patients were classified as NEDA while 46 percent (33/72) showed EDA. During the follow-up period 14 percent experienced relapses, 15 percent showed disability progression with an EDSS increase ≤1, and 24 percent showed radiological progression compared to baseline MRI. The proportion of patients with different types of evidence of disease activity is illustrated below.
I am struck with how only 15 percent (5/33) of patients who experienced disease activity during the one year follow-up showed both MRI activity AND relapse or disability progression. This is a topic to be discussed further in a future article.
See More Helpful Articles:
Arnold DL, Calabresi PA, et al. Effect of peginterferon beta-1a on MRI measures and achieving no evidence of disease activity: results from a randomized controlled trial in relapsing-remitting multiple sclerosis. BMC Neurol. 2014 Dec 31;14:240. doi: 10.1186/s12883-014-0240-x.
Freedman MS. Are we in need of NEDA? Mult Scler. 2016 Jan;22(1):5-6. doi: 10.1177/1352458515617249. Epub 2015 Nov 9.
Giovannoni G, Turner B, et al. Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult Scler Relat Disord. 2015 Jul;4(4):329-33. doi: 10.1016/j.msard.2015.04.006. Epub 2015 May 8.
Havrdova E, Galetta, Stefoski D, Comi G. Freedom from disease activity in multiple sclerosis. Neurology. 2010 Apr 27;74 Suppl 3:S3-7. doi: 10.1212/WNL.0b013e3181dbb51c.
Kappos L, De Stefano N, et al. Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing-remitting multiple sclerosis. Mult Scler. 2016 Sep;22(10):1297-305. doi: 10.1177/1352458515616701. Epub 2015 Nov 19.
Nixon R, Bergvall N, Tomic D, et al. No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis. Adv Ther. 2014 Nov;31(11):1134-54. doi: 10.1007/s12325-014-0167-z. Epub 2014 Nov 21.
Nygaard GO, Celius EG, et al. A Longitudinal Study of Disability, Cognition and Gray Matter Atrophy in Early Multiple Sclerosis Patients According to Evidence of Disease Activity. PLoS One. 2015 Aug 17;10(8):e0135974. doi: 10.1371/journal.pone.0135974. eCollection 2015.
Rotstein DL, Healy BC, et al. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015 Feb;72(2):152-8. doi: 10.1001/jamaneurol.2014.3537.
Stangel M, Penner IK, et al. Towards the implementation of ‘no evidence of disease activity’ in multiple sclerosis treatment: the multiple sclerosis decision model. Ther Adv Neurol Disord. 2015 Jan;8(1):3-13. doi: 10.1177/1756285614560733.
Ziemssen T, Derfuss T, et al. Optimizing treatment success in multiple sclerosis. J Neurol. 2016 Jun;263(6):1053-65. doi: 10.1007/s00415-015-7986-y. Epub 2015 Dec 24.
Lisa Emrich is a patient advocate, accomplished speaker, author of the award-winning blog Brass and Ivory: Life with MS and RA, and founder of the Carnival of MS Bloggers. Lisa uses her experience to educate patients, raise disease awareness, encourage self-advocacy, and support patient-centered research. Lisa frequently works with non-profit organizations and has brought the patient voice to health care conferences and meetings worldwide. Follow Lisa on Facebook, Twitter, and Pinterest.