With the introduction of new, more effective drugs for relapsing remitting multiple sclerosis (RRMS), a new treatment goal is emerging. No evidence of disease activity (NEDA), also referred to as freedom from disease activity, represents a high level of treatment effectiveness, as it suggests that the treatment has resulted in a complete remission of MS. However it is not currently known what proportion of patients with MS can be expected to have NEDA over time, this study aimed to follow 219 people with RRMS over a period of seven years to investigate their disease activity.
The participants were assessed with yearly MRI scans and clinical visits every six months at which relapses and EDSS scores were evaluated. NEDA was defined as no relapses, no sustained increase in EDSS score, and no new or enlarging lesions on annual MRI scans.
The study found that after one year 46% of participants had NEDA but at seven years only 8% of participants were NEDA. However it was also found that those participants who showed NEDA at the two year point, had less disability at the seven year point.
The researchers conclude that the ability of NEDA to predict future disability levels needs to be investigated further and NEDA could also be used to evaluate the effectiveness of new MS drugs in trials.
With the introduction of new, more effective drugs for relapsing remitting multiple sclerosis (RRMS), a shift in what to expect from treatment is beginning to develop, from one of partial response, such as reducing the number of relapses, to one of potential remission. A new treatment goal, no evidence of disease activity (NEDA), also referred to as freedom from disease activity, is the aspiration. It represents a high level of treatment effectiveness, as it suggests that the treatment has resulted in a complete remission of the disease. However it is not currently known what proportion of patients with MS can be expected to have NEDA over time and whether disease activity is more often observed as clinical symptoms or lesions on brain scans that may not necessarily result in symptoms. This study aimed to follow a group of people with RRMS over a period of seven years to investigate their disease activity.
How this study was carried out
219 people who had been diagnosed with clinically isolated syndrome (CIS) or RRMS were included in this study. All were aged between 18 and 65 years old, 174 (80%) were female and at the start of the study the average age of participants was 40 years old. The participants were a mixed group, some took no treatments and some were taking a disease modifying therapy, but not for the whole study period. This study looked at a 'real world' situation, so was looking at what happened to the participants over a period and so was not looking at what happened as a result of treatment with a particular drug.
The participants had been assessed over a period of seven years, with yearly MRI scans and clinical visits every six months at which relapses and EDSS scores were evaluated. The researchers used clinical observations and MRI scans to assess if the participants had any evidence of disease activity.
A relapse was defined as the appearance of new symptoms that lasted more than 24 hours were not caused by infection. Progression was defined as an increase of 1 or more in EDSS score that was still apparent at a subsequent assessment. New MRI scan activity was defined as new or enlarging lesions or gadolinium-enhanced lesions visible on a brain or spinal cord MRI.
The authors defined NEDA as no relapses, no sustained increase in EDSS score, and no new or enlarging lesions on annual MRI.
The study found that after one year 46% of participants met the criteria for NEDA, 27.5% of participants were still NEDA at two years and only 8% of participants were NEDA after seven years.
Participants were most likely to show disease activity by having a new lesion being visible on an MRI scan, followed by having a relapse. Increases in EDSS score (indicating disease progression) were the least likely to happen, 57% of participants had no evidence of progression after seven years. The study also found that those participants who showed NEDA at the two year point, had less disability at the seven year point.
The study shows that remaining completely free of disease activity over a long term period is unlikely. However it showed that NEDA status at two years could potentially be used to give a prognosis, as those who were disease free at two years had less disability after seven years. The authors suggest that as the goal of drug therapy in MS is to treat people to prevent disability, it seems logical that treating so there is no evidence of disease activity either clinically or on MRI scans, could be a treatment goal. They conclude that the ability of NEDA to predict future disability levels needs to be investigated further and it could be used to evaluate the effectiveness of new MS drugs in trials.
Rotstein DL, Healy BC, Malik MT , et al.
Evaluation of No Evidence of Disease Activity in a 7-Year Longitudinal Multiple Sclerosis Cohort.
JAMA Neurol. 2014 Dec 22. [Epub ahead of print]
More about no evidence of disease activity (NEDA)
In the past, disease modifying treatments for relapsing remitting MS (RRMS), including the beta interferons and glatiramer acetate, have been evaluated on their ability to reduce relapses. On average these drugs reduce relapses by around one third.
With the introduction of new, more effective drugs, there has been a shift in treatment expectations from one of partial response to one of potential remission. The concept of being 'disease free' has been used for several conditions previously, including cancer and rheumatoid arthritis. With rheumatoid arthritis the aim is to now treat people as soon as possible after diagnosis to prevent a build-up of symptoms, rapidly switching to more effective drugs if there is no response to first line treatments. Increasingly, neurologists are advocating a similarly active approach soon after diagnosis of RRMS.
In MS, no evidence of disease activity is defined by a combination of:
- absence of relapses
- absence of increased disability which lasts more than three months
- absence of MRI evidence of MS activity
The concept of NEDA is still evolving and there is debate over additional measures that could or should be included, such as loss of brain volume, which would indicate loss of nerves. As understanding of what causes MS and the underlying causes of the symptoms experienced increases over time, other measures may be added to monitor the effect treatment has on these.
At the MS Trust conference in 2013, Professor Gavin Giovannoni, a neurologist at Barts and the London School of Medicine and Dentistry, likened MS to an iceberg: there could be lots of disease activity occurring early on and 'beneath the surface', as lesions can occur in the brain and spinal cord, which do not result in symptoms. He suggests adopting an aggressive approach to treating MS early could mean people with RRMS could do better when compared to people who have had less active treatment, resulting in less symptoms and less build-up of disability. You can read more of Prof Giovannoni's thoughts on NEDA on his blog, for example in this post about approaches to treatment and this post comparing the current and potential treatment approaches.
Currently the concept of NEDA is still in its infancy and there are many questions still to be answered, including could an earlier and more active approach to treatment prevent the onset of symptoms and could freedom from disease activity delay or even prevent transition to secondary progressive MS?
It is early days and more research is needed to determine the long-term significance of freedom from disease activity for people with MS but we will provide future updates when there is more to report.