Development of a Sensitive Outcome for Economical Drug Screening for Progressive Multiple Sclerosis Treatment

Kósa, Péter; Ghazali, Danish; Tanigawa, Makoto; Barbour, Chris; Cortese, Irene; Kelley, William N.; Snyder, Blake; Ohayon, Joan; Fenton, Kaylan; Lehky, Tanya; Wu, Tianxia; Greenwood, Mark C.; Nair, Govind; Bielekova, Bibiana

doi:10.3389/fneur.2016.00131

Cited by 49 publications

(87 citation statements)

References 34 publications

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“…MSFC is a continuous scale that takes considerable investment of resources to perform; therefore, it is rarely administered outside of clinical trials. Most importantly, MSFC sensitivity to measure yearly disability progression in MS cohorts does not meaningfully outperform EDSS6, 14.…”

Section: Discussionmentioning

confidence: 90%

“…One of the validated advantages of CombiWISE over EDSS is its increased sensitivity in detecting individualized disability progression6 in 1–2 years. While linear regression slopes derived from cross‐sectional data demonstrated the higher dynamic range of NeurEx in comparison to both EDSS and CombiWISE, only a longitudinal cohort can correctly estimate accuracy of individualized progression measurements.…”

Section: Resultsmentioning

confidence: 99%

“…CombiWISE6, a continuous, statistical learning‐optimized scale that combines SNRS, EDSS, 25FW, and nondominant hand 9HPT, has excellent sensitivity; CombiWISE outperformed 57 clinical, electrophysiological and imaging outcomes6 in detecting yearly MS disability progression. Nevertheless, CombiWISE does not eliminate the problem of cumbersome acquisition, even though a public website allows its automatic computation: https://bielekovalab.shinyapps.io/msdss/.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is unclear if expert‐defined scales are optimal. Additionally, inter‐rater differences stemming from ambiguous algorithms lower scales’ utility6.…”

Section: Introductionmentioning

confidence: 99%

“…As an alternative to expert‐based clinical scales, Combinatorial Weight‐Adjusted Disability Scale (CombiWISE6) was developed using statistical learning. Although CombiWISE outperformed 57 clinical, imaging, and electrophysiological outcomes in a power analysis, its development was restricted to existing clinical scales and their cumbersome acquisition limits CombiWISE's broad clinical use.…”

Section: Introductionmentioning

confidence: 99%

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NeurEx: digitalized neurological examination offers a novel high‐resolution disability scale

Kósa

Barbour

Wichman

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo develop a sensitive neurological disability scale for broad utilization in clinical practice.MethodsWe employed advances of mobile computing to develop an iPad‐based App for convenient documentation of the neurological examination into a secure, cloud‐linked database. We included features present in four traditional neuroimmunological disability scales and codified their automatic computation. By combining spatial distribution of the neurological deficit with quantitative or semiquantitative rating of its severity we developed a new summary score (called NeurEx; ranging from 0 to 1349 with minimal measurable change of 0.25) and compared its performance with clinician‐ and App‐computed traditional clinical scales.ResultsIn the cross‐sectional comparison of 906 neurological examinations, the variance between App‐computed and clinician‐scored disability scales was comparable to the variance between rating of the identical neurological examination by multiple sclerosis (MS)‐trained clinicians. By eliminating rating ambiguity, App‐computed scales achieved greater accuracy in measuring disability progression over time (n = 191 patients studied over 880.6 patient‐years). The NeurEx score had no apparent ceiling effect and more than 200‐fold higher sensitivity for detecting a measurable yearly disability progression (i.e., median progression slope of 8.13 relative to minimum detectable change of 0.25) than Expanded Disability Status Scale (EDSS) with a median yearly progression slope of 0.071 that is lower than the minimal measurable change on EDSS of 0.5.InterpretationNeurEx can be used as a highly sensitive outcome measure in neuroimmunology. The App can be easily modified for use in other areas of neurology and it can bridge private practice practitioners to academic centers in multicenter research studies.

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Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…However, it is unclear if expert‐defined scales are optimal. Additionally, inter‐rater differences stemming from ambiguous algorithms lower scales’ utility6.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NeurEx: digitalized neurological examination offers a novel high‐resolution disability scale

Kósa

Barbour

Wichman

et al. 2018

Ann Clin Transl Neurol

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Pharmacodynamic effects of daclizumab in the intrathecal compartment

Komori

Kósa

Stein

et al. 2017

Ann Clin Transl Neurol

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ObjectiveIt was previously demonstrated that daclizumab therapy normalizes cellular cerebrospinal fluid (CSF) abnormalities typical of multiple sclerosis (MS) in the majority of treated patients. However, CSF cells represent only the mobile portion of intrathecal immune responses. Therefore, we asked whether daclizumab also reverses compartmentalized inflammation and if not, whether residual inflammation correlates with clinical response to the drug.MethodsForty MS patients treated with an intravenous or subcutaneous injection of daclizumab were followed for up to 16 years in two open‐label clinical trials. MRI contrast‐enhancing lesions (CELs), clinical scales, and CSF biomarkers quantified residual disease.ResultsRapid decreases in CELs, sustained throughout the observation period, were observed with daclizumab treatment. Daclizumab therapy induced modest but statistically significant (P < 0.0001) decreases in CSF levels of T‐cell activation marker CD27 and IgG index. Interleukin 2 (IL‐2) CSF levels increased from baseline levels during treatment, consistent with reduced IL‐2 consumption by T cells, as a consequence of daclizumab's saturation of high‐affinity IL‐2 receptors. CSF levels of IL‐12p40, chitinase‐3‐like protein‐1 (CHI3L1), chemokine C‐X‐C motif ligand 13, and neurofilament light chain (NFL) were also significantly reduced by daclizumab. Among them, inhibition of CHI3L1 correlated with inhibition of NFL and with lack of disease progression.InterpretationThese observations confirm daclizumab's direct pharmacodynamics effects on immune cells within central nervous system tissues and identify inhibition of CSF biomarkers of myeloid lineage as a stronger determinant of reduction in clinical MS activity than inhibition of biomarkers of adaptive immunity.

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Pharmacotherapy in Secondary Progressive Multiple Sclerosis: An Overview

2018

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Multiple sclerosis is an immune-mediated inflammatory disease of the central nervous system characterised by demyelination, neuroaxonal loss and a heterogeneous clinical course. Multiple sclerosis presents with different phenotypes, most commonly a relapsing-remitting course and, less frequently, a progressive accumulation of disability from disease onset (primary progressive multiple sclerosis). The majority of people with relapsing-remitting multiple sclerosis, after a variable time, switch to a stage characterised by gradual neurological worsening known as secondary progressive multiple sclerosis. We have a limited understanding of the mechanisms underlying multiple sclerosis, and it is believed that multiple genetic, environmental and endogenous factors are elements driving inflammation and ultimately neurodegeneration. Axonal loss and grey matter damage have been regarded as amongst the leading causes of irreversible neurological disability in the progressive stages. There are over a dozen disease-modifying therapies currently licenced for relapsing-remitting multiple sclerosis, but none of these has provided evidence of effectiveness in secondary progressive multiple sclerosis. Recently, there has been some early modest success with siponimod in secondary progressive multiple sclerosis and ocrelizumab in primary progressive multiple sclerosis. Finding treatments to delay or prevent the courses of secondary progressive multiple sclerosis is an unmet and essential goal of the research in multiple sclerosis. In this review, we discuss new findings regarding drugs with immunomodulatory, neuroprotective or regenerative properties and possible treatment strategies for secondary progressive multiple sclerosis. We examine the field broadly to include trials where participants have progressive or relapsing phenotypes. We summarise the most relevant results from newer investigations from phase II and III randomised controlled trials over the past decade, with particular attention to the last 5 years.

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Development of a Sensitive Outcome for Economical Drug Screening for Progressive Multiple Sclerosis Treatment

Cited by 49 publications

References 34 publications

NeurEx: digitalized neurological examination offers a novel high‐resolution disability scale

NeurEx: digitalized neurological examination offers a novel high‐resolution disability scale

Pharmacodynamic effects of daclizumab in the intrathecal compartment

Pharmacotherapy in Secondary Progressive Multiple Sclerosis: An Overview

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