Disability as an outcome in MS clinical trials

Ebers, George C.; Heigenhauser, L.; Däumer, Martin; Lederer, Christian; Noseworthy, John H.

doi:10.1212/01.wnl.0000313034.46883.16

Cited by 163 publications

(128 citation statements)

References 30 publications

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“…Thus, short-term increases in EDSS do not necessarily predict future accumulation of disability in RMS patients over the longer term, a conclusion also reached in a pooled analysis of patients randomized to placebo arms in 31 clinical trials. 48 Because neither clinical nor radiographic features over two years had predictive value, it is not surprising that the combined measure of these variables, NEDA, was also not associated with long-term disability risk. Although this observation must be interpreted with caution because of the relatively small number of NEDA patients in our cohort, another recently published observational study also found that the proportion of patients meeting a NEDA definition declined substantially over time.…”

Section: Discussionmentioning

confidence: 99%

Long‐term evolution of multiple sclerosis disability in the treatment era

Team:

2016

Annals of Neurology

367

167

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Objectives To characterize the accrual of long-term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and MRI data used in clinical trials have long-term prognostic value. Methods This is a prospective study of 517 actively managed MS patients enrolled at a single center. Results More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit. At this last assessment, neurologic disability as measured by the Expanded Disability Status Score (EDSS) was stable or improved compared to baseline in 41% of patients. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first two years had long-term outcomes that were no different from those of the cohort as a whole. 25-OH vitamin D serum levels were inversely associated with short-term MS disease activity; however, these levels had no association with long-term disability. At a median time of 16.8 years after disease onset, 10.7% (95% CI 7.2 to 14%) of patients reached an EDSS ≥6 and 18.1% (95% CI: 13.5 to 22.5%) evolved from relapsing MS (RMS) to secondary progressive MS (SPMS). Interpretations Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies. Notably, the NEDA 2-year endpoint was not a predictor of long-term stability. Finally, the data call into question the utility of annual MRI assessments as a treat-to-target approach for MS care.

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Section: Discussionmentioning

confidence: 99%

Long‐term evolution of multiple sclerosis disability in the treatment era

Team:

2016

Annals of Neurology

367

167

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“…Significant reductions in MRI T2 lesion volume and new lesions were also observed. Notably, this was one of the first trials to employ time to confirmed disability as an outcome [34,35]. Because the EDSS is poorly responsive to changes in the 6-6.5 range, this group also employed a different definition of EDSS change in that range of just 0.5 points, a trend that persists in MS research.…”

Section: Progressive Formsmentioning

confidence: 99%

Interferon Beta and Glatiramer Acetate Therapy

McGraw

Lublin

2013

Neurotherapeutics

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“…[16][17][18] Furthermore, even sustained EDSS progression in research studies may reverse after study completion. 19 enhancing (Gd+) T1-weighted lesions or unequivocally new or enlarging T2-weighted lesions. Although this poll reflected the opinions of a relatively small proportion of the CMSC membership over a short period of time, the results supported the concept that changes to the Lublin-Reingold classification should be considered.…”

Section: Historical Analysis and Critique Of The Lublinreingold Criteriamentioning

confidence: 99%

“…[41][42][43][44][45][46][47][48] In considering the histologic characteristics of classic MS MRI lesions, it is important to recognize that when frequent, sensitive longitudinal (weekly or monthly) 37,49 MRI studies are performed in RRMS patients, almost both relapsing and progressive forms of MS 18,19,31 ; the EDSS is a relatively insensitive barometer of progression; and pseudoprogression may occur, making it difficult to accurately assess stability, worsening, or even mild improvement over the short term. 16,17,19 Progression of cognitive dysfunction is more problematic to clearly document, by either routine clinical or routine imaging metrics. Mild-to-moderate cognitive impairment may not be readily detected even by competent physicians or on EDSS testing, which is insensitive to such changes, [16][17][18] nor can cortical gray matter lesions be easily detected with conventional MRI techniques.…”

Section: Relationship Of Mri To Cns Pathologymentioning

confidence: 99%

“…87,88 Lastly, although most if not all focal Gd+, T2, and T1 hypointense lesions may cause damage to the brain parenchyma, there may be sufficient reserves in neural pathways-with redundancies in critical thresholds of axonal function, or even compensatory mechanisms including plasticity and regeneration (particularly early in the course of MS)-so that new neurologic deficits or progression in disability may not be readily seen. 19,31,89 Ultimately, however, sufficient axonal loss may accumulate over time (albeit at a unique rate in each patient) so that deterioration occurs, even when overt new MRI lesions are not identified. 89 All of the above could decrease MRI lesion conspicuity on conventional scanning and affect the correlation of MRI lesions with clinical phenotypes, relapses, and progression.…”

Section: Relationship Of Mri To Cns Pathologymentioning

confidence: 99%

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Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course

Cook¹,

Dhib‐Jalbut²,

Dowling³

et al. 2012

International Journal of MS Care

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It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS. Int J MS Care. 2012;14:105-114. It was recently suggested by Lincoln et al. 1 that the Lublin-Reingold clinical classification of multiple sclerosis (MS) 2 for the assessment of MS phenotypes and patient evolution over time be modified to include magnetic resonance imaging (MRI). It was recommended that the classification incorporate the "conventional," generally available MRI techniques of gadolinium (Gd) T1-weighted sequences and dual-echo and fluid-attenuated inversion recovery (T2-weighted and FLAIR) images ( course over time and, in turn, more informed clinical trials and a better understanding of appropriate therapies.Prior to the meeting, a survey of members of the CMSC was conducted on the need to modify the Lublin-Reingold classification. Over a 1-week period, 141 responses were received, representing 16% of the CMSC members polled. The results were as follows: A total of 70% of respondents indicated that the LublinReingold classification did not sufficiently distinguish the different forms of MS; 87% felt that the LublinReingold classification did not sufficiently distinguish MS disease activity even within a given category of the disease; and 84% indicated that it would be useful to include certain subclinical indices of disease activity in the clinical classification, such as MRI gadoliniumother MRI modalities that are not currently widely available and other validated biomarkers might be added to the classification in the future.In response to the publication of Lincoln et al., 1 the Consortium of Multiple Sclerosis Centers (CMSC) sponsored an international consensus conference, which was held in Short Hills, New Jersey, from March 5 to 7, 2010. Participating in the conference were 28 invited MS experts from North and South America and Europe who were well versed in clinical trials, the management of MS, biostatistics, neuropathology, neuroimaging, and neuroimmunology. The goal of the meeting was to review the available...

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Disability as an outcome in MS clinical trials

Cited by 163 publications

References 30 publications

Long‐term evolution of multiple sclerosis disability in the treatment era

Long‐term evolution of multiple sclerosis disability in the treatment era

Interferon Beta and Glatiramer Acetate Therapy

Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course

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