ClinicSpeak: NEDA at 7-years

Has NEDA come of age? #ClinicSpeak #MSBlog #MSResearch

"Good and bad news? The good news is if you go onto a DMT and have NEDA (no evident disease activity) at 2-years it is predictive of a good disability outcome at 7 years (no disease progression). The bad news is that only a minority (8%) of MSers are rendered NEDA at 7-years. The problem with the analysis in this paper is that they did not rebaseline subjects and used the baseline MRI scan as the reference scan. We have now shown across many data sets that DMTs take many months to start working and NEDA rates improve dramatically if you rebaseline using a 6 or 12 month MRI assessment. Disease activity that occurs within the first few months of starting a DMT should not be interpreted as a non-response to the specific DMT. When you look at the survival curves of NEDA in this paper about 50% fail in the first 12 months; therefore, I suspect that the 8% NEDA rate at 7-years will be a lot better if NEDA is redefined using the 12 month scan as the baseline. Some critics would argue that NEDA is too stringent treatment target and we should not aim for it but instead settle for a MEDA (minimal evidence of disease activity). I am against the latter, particularly since we know that a lot of disease activity occurs below the threshold of or current measurement tools and once damage accumulates in MS it tends to be irreversible, i.e. time is brain. In addition, if we have more effective treatments and if the disease is not be controlled on less effective DMTs why wait to offer the patient the option of escalating  to more effective treatments? I envisage some patients saying no as the risks associated with the more effective treatments may be unacceptable, some may want to be extending or starting a family and prefer the DMTs with a good safety profile in pregnancy and others may not accept NEDA as a treatment target. Yes, believe it or not, not all MSers are accepting of NEDA as a treatment target."

"The good news is that neurologists are beginning to move towards NEDA as a treatment target. We are therefore beginning to adopt the approach rheumatologists pioneered for treating rheumatoid arthritis (RA) to MS. I am certain that with this approach we may prevent, or at least delay, the need for canes (EDSS 6.0), chairs (EDSS 7.0) and beds (EDSS 8.0) and at the same time improve quality of life of MSers substantially. A long time before MSers needs a cane they have problems with bladder, bowel and sexual function, fatigue, depression, anxiety and cognitive problems. The real burden of MS at least early on are the hidden symptoms of the disease. May be our focus should be on these instead of our fixation in mobility problems that typically comes on later?"

Epub: Rotstein et al. Evaluation of No Evidence of Disease Activity in a 7-Year Longitudinal Multiple Sclerosis Cohort. JAMA Neurol. 2014 Dec 22.

IMPORTANCE: With multiple and increasingly effective therapies for relapsing forms of multiple sclerosis (MS), disease-free status or no evidence of disease activity (NEDA) has become a treatment goal and a new outcome measure. However, the persistence of NEDA over time and its predictive power for long-term prognosis are unknown.

OBJECTIVE: To investigate NEDA during 7 years as measured by relapses, disability progression, and yearly magnetic resonance imaging (MRI).

DESIGN, SETTING, AND PARTICIPANTS: Patients were selected from the 2200-patient Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) cohort study. Patients were required to have an initial diagnosis of clinically isolated syndrome or relapsing-remitting MS and a minimum of 7 years of prospective follow-up that included yearly brain MRI and biannual clinical visits (nā€‰=ā€‰219). Patients were analyzed independent of disease-modifying therapy. Patients were classified as having early (recent-onset) MS if they were 5 years or less from their first MS symptom at enrollment or otherwise considered to have established MS (>5 years from onset).

MAIN OUTCOMES AND MEASURES: NEDA was defined as a composite that consisted of absence of relapses, no sustained Expanded Disability Status Scale score progression, and no new or enlarging T2 or T1 gadolinium-enhancing lesions on annual MRI. Relapses, progression, and MRI changes were also investigated as individual outcomes.

RESULTS: A total of 99 of 215 patients (46.0%) had NEDA for clinical and MRI measures at 1 year, but only 17 of 216 (7.9%) maintained NEDA status after 7 years. No differences were found in NEDA status between patients with early vs established MS. A dissociation was found between clinical and MRI disease activity. Each year, 30.6% (64 of 209) to 42.9% (93 of 217) of the cohort had evidence of either clinical or MRI disease activity but not both. NEDA at 2 years had a positive predictive value of 78.3% for no progression (Expanded Disability Status Scale score change ā‰¤0.5) at 7 years. Only minor improvement was found in the positive predictive values with additional follow-up of 1 to 3 years.

CONCLUSIONS AND RELEVANCE: NEDA is difficult to sustain long term even with treatment. NEDA status at 2 years may be optimal in terms of prognostic value in the longer term. Our results provide a basis for investigating NEDA as an outcome measure and treatment goal and for evaluating the effect of new MS drugs on NEDA.

CoI: multiple

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