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  • 1
    In: Annals of Neurology, Wiley, Vol. 80, No. 4 ( 2016-10), p. 499-510
    Abstract: To characterize the accrual of long‐term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (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 Scale (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 2 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% confidence interval [CI] = 7.2–14%) of patients reached an EDSS ≥ 6, and 18.1% (95% CI = 13.5–22.5%) evolved from relapsing MS to secondary progressive MS (SPMS). Interpretation 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. Ann Neurol 2016;80:499–510
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2037912-2
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  • 2
    In: Annals of Neurology, Wiley, Vol. 85, No. 5 ( 2019-05), p. 653-666
    Abstract: 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
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2037912-2
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  • 3
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 51 ( 2019-12-17), p. 25800-25807
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 51 ( 2019-12-17), p. 25800-25807
    Abstract: CD8 + T cells are believed to play an important role in multiple sclerosis (MS), yet their role in MS pathogenesis remains poorly defined. Although myelin proteins are considered potential autoantigenic targets, prior studies of myelin-reactive CD8 + T cells in MS have relied on in vitro stimulation, thereby limiting accurate measurement of their ex vivo precursor frequencies and phenotypes. Peptide:MHC I tetramers were used to identify and validate 5 myelin CD8 + T cell epitopes, including 2 newly described determinants in humans. The validated tetramers were used to measure the ex vivo precursor frequencies and phenotypes of myelin-specific CD8 + T cells in the peripheral blood of untreated MS patients and HLA allele-matched healthy controls. In parallel, CD8 + T cell responses against immunodominant influenza epitopes were also measured. There were no differences in ex vivo frequencies of tetramer-positive myelin-specific CD8 + T cells between MS patients and control subjects. An increased proportion of myelin-specific CD8 + T cells in MS patients exhibited a memory phenotype and expressed CD20 compared to control subjects, while there were no phenotypic differences observed among influenza-specific CD8 + T cells. Longitudinal assessments were also measured in a subset of MS patients subsequently treated with anti-CD20 monoclonal antibody therapy. The proportion of memory and CD20 + CD8 + T cells specific for certain myelin but not influenza epitopes was significantly reduced following anti-CD20 treatment. This study, representing a characterization of unmanipulated myelin-reactive CD8 + T cells in MS, indicates these cells may be attractive targets in MS therapy.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Cold Spring Harbor Laboratory ; 2019
    In:  Cold Spring Harbor Perspectives in Medicine Vol. 9, No. 2 ( 2019-02), p. a032037-
    In: Cold Spring Harbor Perspectives in Medicine, Cold Spring Harbor Laboratory, Vol. 9, No. 2 ( 2019-02), p. a032037-
    Type of Medium: Online Resource
    ISSN: 2157-1422
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2019
    detail.hit.zdb_id: 2628603-8
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