SUMMIT (Serially Unified Multicenter Multiple Sclerosis Investigation): creating a repository of deeply phenotyped contemporary multiple sclerosis cohorts

Bove, Riley; Chitnis, Tanuja; Cree, Bruce A.C.; Tintoré, Mar; Naegelin, Yvonne; Uitdehaag, Bernard M. J.; Kappos, Ludwig; Khoury, Samia J.; Montalbán, Xavier; Hauser, Stephen L.; Weiner, Howard L.

doi:10.1177/1352458517726657

Cited by 19 publications

(20 citation statements)

References 61 publications

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“…We were not able to identify a statistically significant impact of treatment on long-term disability or brain volume loss; however, this dataset is likely underpowered to detect small treatment effects mediated through reduction of new white matter lesions detected by MRI. 48 Despite these limitations, the characteristics of this dataset are consistent with previously published observations in that MS relapses were associated with new lesions on brain MRI and were associated with increased short-term MS disability. In the clinical trial setting, participants are assessed within a defined window of relapse onset, and relapses are defined by an objective change in EDSS score.…”

Section: Discussionsupporting

confidence: 87%

“…Work is underway to address this issue; we have partnered with other groups who have similar deeply phenotyped long-term datasets for the purpose of increasing statistical power and performing validation studies for these and other observations. 48 Despite these limitations, the characteristics of this dataset are consistent with previously published observations in that MS relapses were associated with new lesions on brain MRI and were associated with increased short-term MS disability. 2,3 The consistency of our findings regarding short-term outcomes lends credence to our longerterm observations.…”

Section: Discussionsupporting

confidence: 87%

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Silent progression in disease activity–free relapsing multiple sclerosis

Cree

Hollenbach

Bove

et al. 2019

Annals of Neurology

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312

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Objective Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow‐up. Notably, “no evidence of disease activity” at 2 years did not predict long‐term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long‐term disability accumulation. Methods Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0–5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA‐DRB1*15:01 as covariates. Results Relapses were associated with a transient increase in disability over 1‐year intervals ( p = 0.012) but not with confirmed disability progression ( p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable ( p < 0.05). Interpretation Long‐term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing–remitting MS. Ann Neurol 2019;85:653–666

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 87%

Silent progression in disease activity–free relapsing multiple sclerosis

Cree

Hollenbach

Bove

et al. 2019

Annals of Neurology

Self Cite

312

208

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“…Patients were recruited in Basel as part of a prospective multicenter study initiated in 2003 (GeneMSA). 9,20,21 In this cohort were included 179 patients with complete sNfL and MRI data, who were recruited at the Neurologic Clinic and Policlinic, University Hospital Basel (Switzerland) between June 2004 and October 2005.…”

Section: Genemsa Cohortmentioning

confidence: 99%

Monitoring of radiologic disease activity by serum neurofilaments in MS

Uher

Schaedelin

Srpová

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo determine whether serum neurofilament light chain (sNfL) levels are associated with recent MRI activity in patients with relapsing-remitting MS (RRMS).MethodsThis observational study included 163 patients (405 samples) with early RRMS from the Study of Early interferon-beta1a (IFN-β1a) Treatment (SET) cohort and 179 patients (664 samples) with more advanced RRMS from the Genome-Wide Association Study of Multiple Sclerosis (GeneMSA) cohort. Based on annual brain MRI, we assessed the ability of sNfL cutoffs to reflect the presence of combined unique active lesions, defined as new/enlarging lesion compared with MRI in the preceding year or contrast-enhancing lesion. The probability of active MRI lesions among patients with different sNfL levels was estimated with generalized estimating equations models.ResultsFrom the sNfL samples ≥90th percentile, 81.6% of the SET (OR = 3.4, 95% CI = 1.8-6.4) and 48.9% of the GeneMSA cohort samples (OR = 2.6, 95% CI = 1.7-3.9) was associated with radiological disease activity on MRI. The sNfL level between the 10th and 30th percentile was reflective of negligible MRI activity: 1.4% (SET) and 6.5% (GeneMSA) of patients developed ≥3 active lesions, 5.8% (SET) and 6.5% (GeneMSA) developed ≥2 active lesions, and 34.8% (SET) and 11.8% (GeneMSA) showed ≥1 active lesion on brain MRI. The sNfL level <10th percentile was associated with even lower MRI activity. Similar results were found in a subgroup of clinically stable patients.ConclusionsLow sNfL levels (≤30th percentile) help identify patients with MS with very low probability of recent radiologic disease activity during the preceding year. This result suggests that in future, sNfL assessment may substitute the need for annual brain MRI monitoring in considerable number (23.1%–36.4%) of visits in clinically stable patients.

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“…Over the past century there has been a disproportionate increase in the rate of MS in young women of childbearing age, moving from near-equal ratios to a 3:1 female:male ratio [ 3 ]. Interestingly, women with MS are more likely to carry the HLA DRB1*1501 risk allele than are men, but otherwise have lower non-HLA genetic risks scores [ 117 ], indicating that interactions of HLA genes and novel exposures may account for some of the increased risk in women. In fact, the increase in the sex ratio parallels increasing westernization and urbanization [ 4 ], sexually specific plasticity in response to changing exposures, including industrialization, sedentarism, and effects of the demographic transition and gender equity on women’s age at menarche and reproductive choices (age at first birth, parity, breastfeeding and exogenous hormone use) [ 118 ].…”

Section: Introductionmentioning

confidence: 99%

Why monkeys do not get multiple sclerosis (spontaneously)

Bove

2018

Evolution, Medicine, and Public Health

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The goal of this review is to apply an evolutionary lens to understanding the origins of multiple sclerosis (MS), integrating three broad observations. First, only humans are known to develop MS spontaneously. Second, humans have evolved large brains, with characteristically large amounts of metabolically costly myelin. This myelin is generated over long periods of neurologic development—and peak MS onset coincides with the end of myelination. Third, over the past century there has been a disproportionate increase in the rate of MS in young women of childbearing age, paralleling increasing westernization and urbanization, indicating sexually specific susceptibility in response to changing exposures. From these three observations about MS, a life history approach leads us to hypothesize that MS arises in humans from disruption of the normal homeostatic mechanisms of myelin production and maintenance, during our uniquely long myelination period. This review will highlight under-explored areas of homeostasis in brain development, that are likely to shed new light on the origins of MS and to raise further questions about the interactions between our ancestral genes and modern environments.

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SUMMIT (Serially Unified Multicenter Multiple Sclerosis Investigation): creating a repository of deeply phenotyped contemporary multiple sclerosis cohorts

Cited by 19 publications

References 61 publications

Silent progression in disease activity–free relapsing multiple sclerosis

Silent progression in disease activity–free relapsing multiple sclerosis

Monitoring of radiologic disease activity by serum neurofilaments in MS

Why monkeys do not get multiple sclerosis (spontaneously)

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