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To the Editor No evidence of disease activity (NEDA) is becoming an important secondary outcome measure in multiple sclerosis (MS) clinical trials. In this context, the article by Rotstein and colleagues,1 demonstrating that NEDA at 2 years has potential prognostic significance, is timely. Interestingly, the authors1 found a dissociation between clinical and magnetic resonance imaging (MRI) disease activity, raising the question of whether the lack of disease progression truly reflects evidence of absence or absence of evidence.
Magnetic resonance imaging disease activity as currently defined in NEDA (new or enlarged T2 bright lesions or gadolinium enhancement) may not incorporate all aspects of MS disease activity and is not sensitive to well pathologically characterized neurodegenerative features present at every disease stage, demonstrable by gray matter lesions and brain and cord atrophy by MRI and manifested clinically with progressive cognitive impairment besides Expanded Disability Status Scale score worsening.2
Much remains to be discovered on the relation between disease activity and progression. Sustained disability progression in the absence of relapses is relatively uncommon in placebo-treated patients with relapsing-remitting MS participating in clinical trials, especially when patients are required to sustain an increase in Expanded Disability Status Scale score for more than 6 months. Therefore, NEDA could be considered an intermediate outcome for gauging response to treatment relatively early in the course of MS. Further studies are required to determine what other measures NEDA should incorporate to better predict more significant long-term outcomes, including development of progressive disease (which is not sharply defined), certain disability milestones, critical degrees of global or regional atrophy, or biomarker(s) reflecting an irreversible shift from an inflammatory to a neurodegenerative process.
No evidence of disease activity may also be difficult to use in the clinic because Expanded Disability Status Scale measurement and other standards are not universally used. Similarly, technical limitations of standard MRI scans in clinical practice render the practice of assessing serial T2 lesion activity as a marker of treatment effect almost useless. For these reasons, the current NEDA definition could not be applied to clinical practice effectively without increasing resources to assess patients in most practices.
Although further research is needed to conclude NEDA is a surrogate measure for complete absence of disease, NEDA clearly could help with the immediate management of patients with MS and in determining when to switch treatment if technical limitations mentioned here are addressed. More importantly, a modified NEDA could allow clinicians to determine which treatment(s) optimally help with long-term management goals such as prevention of clinical progression, brain atrophy, and neurocognitive dysfunction.
Corresponding Author: Jacob A. Sloane, MD, PhD, Multiple Sclerosis Center, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Ks212, Boston, MA, 02115 (firstname.lastname@example.org).
Conflict of Interest Disclosures: Dr Sloane reported receiving personal compensation for consulting and serving on the advisory board of companies or organizations including Roche, Teva Neurosciences, Biogen, and Genzyme. He also reports receiving grant support from Biogen. Dr Kinkel reported receiving personal compensation for consulting and serving on the advisory board of companies including Biogen and Genzyme. No other disclosures were reported.
Funding/Support: Dr Sloane reported receiving personal compensation from MS Cure Fund.
Role of the Funder/Sponsor: MS Cure Fund had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication
Editorial Note: This letter was shown to the corresponding author of the original article, who declined to reply on behalf of the authors.
Sloane JA, Mainero C, Kinkel RP. No Evidence of Disease Activity in Multiple Sclerosis. JAMA Neurol. 2015;72(7):835–836. doi:10.1001/jamaneurol.2015.0587
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