A Physician-Completed Digital Tool for Evaluating Disease Progression (Multiple Sclerosis Progression Discussion Tool): Validation Study

Background Defining the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) can be challenging and delayed. A digital tool (MSProDiscuss) was developed to facilitate physician-patient discussion in evaluating early, subtle signs of multiple sclerosis (MS) disease progression representing this transition. Objective This study aimed to determine cut-off values and corresponding sensitivity and specificity for predefined scoring algorithms, with or without including Expanded Disability Status Scale (EDSS) scores, to differentiate between RRMS and SPMS patients and to evaluate psychometric properties. Methods Experienced neurologists completed the tool for patients with confirmed RRMS or SPMS and those suspected to be transitioning to SPMS. In addition to age and EDSS score, each patient’s current disease status (disease activity, symptoms, and its impacts on daily life) was collected while completing the draft tool. Receiver operating characteristic (ROC) curves determined optimal cut-off values (sensitivity and specificity) for the classification of RRMS and SPMS. Results Twenty neurologists completed the draft tool for 198 patients. Mean scores for patients with RRMS (n=89), transitioning to SPMS (n=47), and SPMS (n=62) were 38.1 (SD 12.5), 55.2 (SD 11.1), and 69.6 (SD 12.0), respectively (P<.001, each between-groups comparison). Area under the ROC curve (AUC) including and excluding EDSS were for RRMS (including) AUC 0.91, 95% CI 0.87-0.95, RRMS (excluding) AUC 0.88, 95% CI 0.84-0.93, SPMS (including) AUC 0.91, 95% CI 0.86-0.95, and SPMS (excluding) AUC 0.86, 95% CI 0.81-0.91. In the algorithm with EDSS, the optimal cut-off values were ≤51.6 for RRMS patients (sensitivity=0.83; specificity=0.82) and ≥58.9 for SPMS patients (sensitivity=0.82; specificity=0.84). The optimal cut-offs without EDSS were ≤46.3 and ≥57.8 and resulted in similar high sensitivity and specificity (0.76-0.86). The draft tool showed excellent interrater reliability (intraclass correlation coefficient=.95). Conclusions The MSProDiscuss tool differentiated RRMS patients from SPMS patients with high sensitivity and specificity. In clinical practice, it may be a useful tool to evaluate early, subtle signs of MS disease progression indicating the evolution of RRMS to SPMS. MSProDiscuss will help assess the current level of progression in an individual patient and facilitate a more informed physician-patient discussion.

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Societal costs of primary progressive multiple sclerosis in Australia and the economic impact of a hypothetical disease-modifying treatment that could delay disease progression

Journal of Medical Economics ◽

10.1080/13696998.2021.1872585 ◽

2021 ◽

Vol 24 (1) ◽

pp. 140-149

Author(s):

Laurie J. Brown ◽

Jinjing Li ◽

Matthias Brunner ◽

Martin Snoke ◽

Hai A. La

Keyword(s):

Multiple Sclerosis ◽

Economic Impact ◽

Disease Progression ◽

Progressive Multiple Sclerosis ◽

Primary Progressive Multiple Sclerosis ◽

Societal Costs ◽

Primary Progressive ◽

Delay Disease Progression ◽

Disease Modifying ◽

Disease Modifying Treatment

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N6-Methyladenosine RNA modification in cerebrospinal fluid as a novel potential diagnostic biomarker for progressive multiple sclerosis

Journal of Translational Medicine ◽

10.1186/s12967-021-02981-5 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Fei Ye ◽

Tianzhu Wang ◽

Xiaoxin Wu ◽

Jie Liang ◽

Jiaoxing Li ◽

...

Keyword(s):

Gene Expression ◽

Multiple Sclerosis ◽

Clustering Analysis ◽

Roc Curves ◽

Progressive Multiple Sclerosis ◽

Rna Modification ◽

Diagnostic Model ◽

Consensus Clustering ◽

Rna Methylation ◽

M6a Rna Methylation

Abstract Background Progressive multiple sclerosis (PMS) is an uncommon and severe subtype of MS that worsens gradually and leads to irreversible disabilities in young adults. Currently, there are no applicable or reliable biomarkers to distinguish PMS from relapsing–remitting multiple sclerosis (RRMS). Previous studies have demonstrated that dysfunction of N6-methyladenosine (m6A) RNA modification is relevant to many neurological disorders. Thus, the aim of this study was to explore the diagnostic biomarkers for PMS based on m6A regulatory genes in the cerebrospinal fluid (CSF). Methods Gene expression matrices were downloaded from the ArrayExpress database. Then, we identified differentially expressed m6A regulatory genes between MS and non-MS patients. MS clusters were identified by consensus clustering analysis. Next, we analyzed the correlation between clusters and clinical characteristics. The random forest (RF) algorithm was applied to select key m6A-related genes. The support vector machine (SVM) was then used to construct a diagnostic gene signature. Receiver operating characteristic (ROC) curves were plotted to evaluate the accuracy of the diagnostic model. In addition, CSF samples from MS and non-MS patients were collected and used for external validation, as evaluated by an m6A RNA Methylation Quantification Kit and by real-time quantitative polymerase chain reaction. Results The 13 central m6A RNA methylation regulators were all upregulated in MS patients when compared with non-MS patients. Consensus clustering analysis identified two clusters, both of which were significantly associated with MS subtypes. Next, we divided 61 MS patients into a training set (n = 41) and a test set (n = 20). The RF algorithm identified eight feature genes, and the SVM method was successfully applied to construct a diagnostic model. ROC curves revealed good performance. Finally, the analysis of 11 CSF samples demonstrated that RRMS samples exhibited significantly higher levels of m6A RNA methylation and higher gene expression levels of m6A-related genes than PMS samples. Conclusions The dynamic modification of m6A RNA methylation is involved in the progression of MS and could potentially represent a novel CSF biomarker for diagnosing MS and distinguishing PMS from RRMS in the early stages of the disease.

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Cerebrospinal fluid mtDNA concentration is elevated in multiple sclerosis disease and responds to treatment

Multiple Sclerosis Journal ◽

10.1177/1352458517699874 ◽

2017 ◽

Vol 24 (4) ◽

pp. 472-480 ◽

Cited By ~ 10

Author(s):

Cyra E Leurs ◽

Petar Podlesniy ◽

Ramon Trullas ◽

Lisanne Balk ◽

Martijn D Steenwijk ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Progression ◽

Progressive Multiple Sclerosis ◽

Neurologic Disease ◽

Brain Volumes ◽

Multiple Sclerosis Disease ◽

Relapsing Remitting ◽

Relapsing Remitting Multiple Sclerosis ◽

Digital Polymerase Chain Reaction

Background: Mitochondrial dysfunction is increasingly recognized as an important feature of multiple sclerosis (MS) pathology and may be relevant for clinical disease progression. However, it is unknown whether mitochondrial DNA (mtDNA) levels in the cerebrospinal fluid (CSF) associate with disease progression and therapeutic response. Objectives: To evaluate whether CSF concentrations of mtDNA in MS patients can serve as a marker of ongoing neuropathology and may be helpful to differentiate between MS disease subtypes. To explore the effect of disease-modifying therapies on mtDNA levels in the CSF. Methods: CSF mtDNA was measured using a digital polymerase chain reaction (PCR) CSF mtDNA in two independent MS cohorts. The cohorts included 92 relapsing-remitting multiple sclerosis (RRMS) patients, 40 progressive multiple sclerosis (PMS) patients (27 secondary progressive and 13 primary progressive), 50 various neurologic disease controls, and 5 healthy controls. Results: Patients with PMS showed a significant increase in CSF mtDNA compared to non-inflammatory neurologic disease controls. Patients with higher T2 lesion volumes and lower normalized brain volumes showed increased concentration of mtDNA. Patients treated with fingolimod had significantly lower mtDNA copy levels at follow-up compared to baseline. Conclusion: Our results showed a non-specific elevation of concentration of mtDNA in PMS patients. mtDNA concentrations respond to fingolimod and may be used to monitor biological effect of this treatment.

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Retrospective unbiased plasma lipidomic of progressive multiple sclerosis patients-identifies lipids discriminating those with faster clinical deterioration

Scientific Reports ◽

10.1038/s41598-020-72654-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Mario Amatruda ◽

Maria Petracca ◽

Maureen Wentling ◽

Benjamin Inbar ◽

Kamilah Castro ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Progressive Multiple Sclerosis ◽

Primary Progressive Multiple Sclerosis ◽

Disease Course ◽

Primary Progressive ◽

T2 Lesions ◽

Relapsing Remitting ◽

One Year ◽

Multiple Sclerosis Patients

Abstract The disease course of patients with a confirmed diagnosis of primary progressive multiple sclerosis (PPMS) is uncertain. In an attempt to identify potential signaling pathways involved in the evolution of the disease, we conducted an exploratory unbiased lipidomic analysis of plasma from non-diseased controls (n = 8) and patients with primary progressive MS (PPMS, n = 19) and either a rapid (PPMS-P, n = 9) or slow (PPMS-NP, n = 10) disease course based on worsening disability and/or MRI-visible appearance of new T2 lesions over a one-year-assessment. Partial least squares-discriminant analysis of the MS/MSALL lipidomic dataset, identified lipids driving the clustering of the groups. Among these lipids, sphingomyelin-d18:1/14:0 and mono-hexosylceramide-d18:1/20:0 were differentially abundant in the plasma of PPMS patients compared to controls and their levels correlated with MRI signs of disease progression. Lyso-phosphatidic acid-18:2 (LPA-18:2) was the only lipid with significantly lower abundance in PPMS patients with a rapidly deteriorating disease course, and its levels inversely correlated with the severity of the neurological deficit. Decreased levels of LPA-18:2 were detected in patients with more rapid disease progression, regardless of therapy and these findings were validated in an independent cohort of secondary progressive (SPMS) patients, but not in a third cohorts of relapsing–remitting (RRMS) patients. Collectively, our analysis suggests that sphingomyelin-d18:1/14:0, mono-hexosylceramide-d18:1/20:0, and LPA-18:2 may represent important targets for future studies aimed at understanding disease progression in MS.

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Cytokine Profile in Patients with Progressive Multiple Sclerosis and Its Association with Disease Progression and Disability

Molecular Neurobiology ◽

10.1007/s12035-016-9846-x ◽

2016 ◽

Vol 54 (4) ◽

pp. 2950-2960 ◽

Cited By ~ 25

Author(s):

Ana Paula Kallaur ◽

Sayonara Rangel Oliveira ◽

Andréa Name Colado Simão ◽

Daniela Frizon Alfieri ◽

Tamires Flauzino ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Progressive Multiple Sclerosis ◽

Cytokine Profile

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A qualitative investigation of lay perspectives of diagnosis and self-management strategies employed by people with progressive multiple sclerosis

Health An Interdisciplinary Journal for the Social Study of Health Illness and Medicine ◽

10.1177/1363459316674787 ◽

2016 ◽

Vol 21 (3) ◽

pp. 316-336 ◽

Cited By ~ 9

Author(s):

Julia Frost ◽

Jane Grose ◽

Nicky Britten

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Sense Of Self ◽

Management Strategies ◽

Progressive Multiple Sclerosis ◽

Self Management ◽

Sense Making ◽

Lay Perspectives ◽

Degree Of Certainty ◽

To Come

This article explores how people with progressive multiple sclerosis give meaning to their experiences. It builds upon the self-management literature, which has captured the tension between the desire for retaining normalcy and the increasing burden of self-management associated with chronic disease progression. This repeat interview study is empirically grounded in 28 interviews with 14 people with progressive multiple sclerosis. We identified gender differences in diagnosis-seeking which impacted subsequent sense-making. Male respondents found a diagnosis of multiple sclerosis difficult to come to terms with, and an enduring sense of loss or anger could inhibit further sense-making. A diagnosis of multiple sclerosis was more difficult to obtain for women respondents, and any sense of certainty that diagnosis provided framed their subsequent sense-making strategies. The complex sequelae of multiple sclerosis require that self-management strategies are both contextual and timely, although even the most accomplished self-managers can lose their sense of self with neurodegeneration. Disease progression can be associated with suicidal ideation, suggesting the need for greater dialogue to ensure that people with multiple sclerosis are adequately supported to fulfil their quality of life at all stages of neurodegeneration. These lay perspectives emphasise the articulation of affect rather than the rendering of a medical diagnosis, although diagnosis may provide a degree of certainty in the short term. The ethos of self-management ensures people attempt to retain their sense of ‘normality’ and existent social roles for as long as possible, but this ethos can negate both one’s ability to self-manage and the management of self.

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152 Are neurophysiological parameters an objective measure of disease status and progression in primary progressive multiple sclerosis?

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2011-301993.194 ◽

2012 ◽

Vol 83 (3) ◽

pp. e1.106-e1

Author(s):

J Witherick ◽

N Kane ◽

S Butler ◽

P Walsh ◽

K Blake ◽

...

Keyword(s):

Multiple Sclerosis ◽

Objective Measure ◽

Disease Status ◽

Progressive Multiple Sclerosis ◽

Primary Progressive Multiple Sclerosis ◽

Primary Progressive

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High sensitivity measurement of CRP and disease progression in multiple sclerosis

Neurology ◽

10.1212/01.wnl.0000167129.90918.f5 ◽

2005 ◽

Vol 65 (1) ◽

pp. 153-155 ◽

Cited By ~ 25

Author(s):

M. Soilu-Hanninen ◽

J. O. Koskinen ◽

M. Laaksonen ◽

A. Hanninen ◽

E. -M. Lilius ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

High Sensitivity ◽

Sensitivity Measurement

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Effect of drugs in secondary disease progression in patients with multiple sclerosis

Multiple Sclerosis Journal ◽

10.1191/1352458504ms1030oa ◽

2004 ◽

Vol 10 (3_suppl) ◽

pp. S46-S55 ◽

Cited By ~ 13

Author(s):

Ludwig Kappos

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Progressive Multiple Sclerosis ◽

Positive Effects ◽

Secondary Progressive ◽

The North ◽

Disability Status ◽

Relapsing Remitting ◽

Effect Of Therapy ◽

Almost All

Secondary progressive multiple sclerosis (SPMS) is a form of MS characterized by continuously worsening disability with or without superimposed relapses that occurs after a variable period of relapsing remitting disease and results in limited ambulation for almost all patients. The use of interferon beta (IFN b) for immunomodulation in patients with SPMS has been evaluated in four recent clinical trials: The European multicentre trial on IFN b-1b in SPMS (EUSPMS), the Secondary Progressive Efficacy Trial of Rebif (IFN b-1a) in MS (SPEC TRIMS), the North A merican Study of IFN b-1b in SPMS (NA SPMS), and the Internatio nal MS Secondary Progressive Avonex C linical Trial (IMPAC T). EUSPMS was the only trial to demonstrate a significant positive effect of therapy on disease progression as measured by the expanded disability status scale (EDSS). However, results from all studies demonstrated significant positive effects of treatment on relapse, T2 lesion load, and gadolinium enhancement. Immunomodulation with IFN b has the potential to significantly slow disease progression and improve quality of life for patients with SPMS. While results with monthly IV Ig were disappointing, positive effects on disease progression have been reported with the applicatio n of immunosuppressants, especially Mitoxantrone. The risk-benefit ratio of these cytostatic agents remains controversial. New strategies addressing the important neurodegenerative aspects of the disease are urgently needed.

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