EDITORIAL
Biomarkers for MS Unpuzzling the progressive multiple sclerosis puzzle
Robert J. Fox, MD
Correspondence to Dr. Fox: [email protected] Neurology® 2014;83:1488–1489
The past 20 years have seen dramatic advances in our understanding and treatment of multiple sclerosis (MS). Diagnostic criteria have been refined, imaging has been applied to both MS diagnosis and longitudinal assessment, and 10 treatments have received US Food and Drug Administration approval, with more on the way. Neurologists can now make an MS diagnosis quickly and accurately. They can apply effective treatments to curtail inflammation, precisely monitor for continued inflammatory disease activity, and change treatments if active disease persists. Treatment paradigms now target no evident disease activity, also called disease activity free status.1 These successes have focused almost exclusively on the early stages of MS—the so-called relapsing-remitting (RRMS) stage of the disease. Progressive MS can either follow the relapsing-remitting stage (and is thus called secondary progressive MS [SPMS]) or develop de novo (called primary progressive MS [PPMS]). Progressive MS presents many challenges for the clinician and researcher alike: the underlying pathophysiology is not known (is it compartmentalized inflammation, or a degenerative disorder independent of inflammation?); no conventional imaging characteristics reliably distinguish between RRMS and progressive MS; no biomarkers (fluid or imaging) have proven utility as a phase II proof of concept outcome metric; and the optimal clinical outcome for phase III trials is unknown.2 A fundamental challenge with progressive MS is differentiating between RRMS and progressive MS. Recent revisions to the MS disease classifications have helped clarify this distinction.3 Disease activity is defined as clinical relapses or active inflammation on MRI (new or enlarging T2 lesions or gadoliniumenhancing lesions). Disease progression is defined as historical or objective clinical progression, independent of clinical relapses. Patients with MS are thus classified on 2 axes: disease activity (active or not active) and disease progression (progressing or not progressing), with the “progressing” classification reserved for those patients with gradual clinical worsening which is independent of relapse activity. These revisions help clinicians recognize that disease activity (i.e., relapses and
new lesions on MRI) can coexist with disease progression (i.e., insidious worsening in walking ability), but leave unknown the underlying pathologic substrates of progressive MS. In this issue of Neurology®, Dickens et al.4 report a study using metabolomics to differentiate RRMS and progressive MS. They used high-resolution proton nuclear magnetic resonance spectroscopy and a specialized multivariate statistical analysis to evaluate metabolites in serum. Using this metabolomics profiling technique and Monte Carlo random assignment modeling, they compared the predictability of patterns of metabolite variation in patients with progressive MS to that in patients with RRMS and controls without MS. Using 2 different datasets, they found that metabolomics could reliably differentiate patients with MS from controls without MS, and (perhaps more importantly) SPMS from RRMS. Serum fatty acids, phosphocholine, N-acetyl species, glucose, and b-hydroxybutyrate were all different in serum of patients with SPMS compared to RRMS. They then used a third, independent dataset to validate the classifications identified in the second dataset, which added confidence to the validity of the biomarker. This study provides at least 2 potential directions for further research in progressive MS. First, the different metabolic profiles point towards potential differences in the pathogenic mechanism of RRMS compared to progressive MS. New pathogenic mechanisms may suggest novel areas to study the underpinnings of progressive MS further and may also point towards new targets for novel therapies. Second, these metabolic profiles may be useful in characterizing clinical patients regarding the progression axis outlined by Lublin et al.3 Early recognition of the progressive phase of MS may better help guide patients regarding prognosis and possibly even be utilized in the inclusion criteria of progressive MS clinical trials. Perhaps not surprisingly, their assay was unable to differentiate PPMS from SPMS, further highlighting the similarities of these 2 MS classifications. This study adds further evidence to the growing recognition that PPMS and SPMS are more similar than they
See page 1492 From the Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, OH. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the author, if any, are provided at the end of the editorial. 1488
© 2014 American Academy of Neurology
are different and perhaps should be considered together as a single disease subset. It is possible that these metabolomics measures may be useful biomarker outcomes in clinical trials, as suggested by the authors, but much more validation is required before that could be entertained. Biomarkers for progressive MS are just one part of the progressive MS puzzle. Additional research needs to focus on benchtop models of progressive MS, high throughput screening methods to identify promising therapies, dynamic biomarkers for phase II trials, robust clinical outcomes for phase III trials, and effective symptom management and rehabilitation paradigms.2 The Progressive MS Alliance (www.progressivemsalliance.org) is a growing international collaborative of MS societies from around the world that is helping focus research efforts on progressive MS through Challenge Grants, Infrastructure Awards, and multicountry Collaborative Network Awards. This global effort will hopefully convert progressive MS into the success story that RRMS has already become.
STUDY FUNDING No targeted funding reported.
DISCLOSURE R. Fox has received personal consulting fees from Biogen Idec, GlaxoSmithKline, MedDay, Novartis, Questcor, Teva, and XenoPort; has served on advisory committees for Biogen Idec and Novartis; and has received research grant funding from Novartis. Go to Neurology.org for full disclosures.
REFERENCES 1. Bevan CJ, Cree BA. Disease activity free status: a new end point for a new era in multiple sclerosis clinical research? JAMA Neurol 2014;71:269–270. 2. Fox RJ, Thompson A, Baker D, et al. Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS. Mult Scler 2012;18: 1534–1540. 3. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014;83:278–286. 4. Dickens AM, Larkin JR, Griffin JL, et al. A type 2 biomarker separates relapsing-remitting from secondary progressive multiple sclerosis. Neurology 2014;83:1492–1499.
Neurology 83
October 21, 2014
1489
Biomarkers for MS: Unpuzzling the progressive multiple sclerosis puzzle Robert J. Fox Neurology 2014;83;1488-1489 Published Online before print September 24, 2014 DOI 10.1212/WNL.0000000000000921 This information is current as of September 24, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/17/1488.full.html
References
This article cites 4 articles, 1 of which you can access for free at: http://www.neurology.org/content/83/17/1488.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Demyelinating disease (CNS) http://www.neurology.org//cgi/collection/all_demyelinating_disease_cn s Multiple sclerosis http://www.neurology.org//cgi/collection/multiple_sclerosis
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Biomarkers for MS Unpuzzling the progressive multiple sclerosis puzzle
Robert J. Fox, MD
Correspondence to Dr. Fox: [email protected] Neurology® 2014;83:1488–1489
The past 20 years have seen dramatic advances in our understanding and treatment of multiple sclerosis (MS). Diagnostic criteria have been refined, imaging has been applied to both MS diagnosis and longitudinal assessment, and 10 treatments have received US Food and Drug Administration approval, with more on the way. Neurologists can now make an MS diagnosis quickly and accurately. They can apply effective treatments to curtail inflammation, precisely monitor for continued inflammatory disease activity, and change treatments if active disease persists. Treatment paradigms now target no evident disease activity, also called disease activity free status.1 These successes have focused almost exclusively on the early stages of MS—the so-called relapsing-remitting (RRMS) stage of the disease. Progressive MS can either follow the relapsing-remitting stage (and is thus called secondary progressive MS [SPMS]) or develop de novo (called primary progressive MS [PPMS]). Progressive MS presents many challenges for the clinician and researcher alike: the underlying pathophysiology is not known (is it compartmentalized inflammation, or a degenerative disorder independent of inflammation?); no conventional imaging characteristics reliably distinguish between RRMS and progressive MS; no biomarkers (fluid or imaging) have proven utility as a phase II proof of concept outcome metric; and the optimal clinical outcome for phase III trials is unknown.2 A fundamental challenge with progressive MS is differentiating between RRMS and progressive MS. Recent revisions to the MS disease classifications have helped clarify this distinction.3 Disease activity is defined as clinical relapses or active inflammation on MRI (new or enlarging T2 lesions or gadoliniumenhancing lesions). Disease progression is defined as historical or objective clinical progression, independent of clinical relapses. Patients with MS are thus classified on 2 axes: disease activity (active or not active) and disease progression (progressing or not progressing), with the “progressing” classification reserved for those patients with gradual clinical worsening which is independent of relapse activity. These revisions help clinicians recognize that disease activity (i.e., relapses and
new lesions on MRI) can coexist with disease progression (i.e., insidious worsening in walking ability), but leave unknown the underlying pathologic substrates of progressive MS. In this issue of Neurology®, Dickens et al.4 report a study using metabolomics to differentiate RRMS and progressive MS. They used high-resolution proton nuclear magnetic resonance spectroscopy and a specialized multivariate statistical analysis to evaluate metabolites in serum. Using this metabolomics profiling technique and Monte Carlo random assignment modeling, they compared the predictability of patterns of metabolite variation in patients with progressive MS to that in patients with RRMS and controls without MS. Using 2 different datasets, they found that metabolomics could reliably differentiate patients with MS from controls without MS, and (perhaps more importantly) SPMS from RRMS. Serum fatty acids, phosphocholine, N-acetyl species, glucose, and b-hydroxybutyrate were all different in serum of patients with SPMS compared to RRMS. They then used a third, independent dataset to validate the classifications identified in the second dataset, which added confidence to the validity of the biomarker. This study provides at least 2 potential directions for further research in progressive MS. First, the different metabolic profiles point towards potential differences in the pathogenic mechanism of RRMS compared to progressive MS. New pathogenic mechanisms may suggest novel areas to study the underpinnings of progressive MS further and may also point towards new targets for novel therapies. Second, these metabolic profiles may be useful in characterizing clinical patients regarding the progression axis outlined by Lublin et al.3 Early recognition of the progressive phase of MS may better help guide patients regarding prognosis and possibly even be utilized in the inclusion criteria of progressive MS clinical trials. Perhaps not surprisingly, their assay was unable to differentiate PPMS from SPMS, further highlighting the similarities of these 2 MS classifications. This study adds further evidence to the growing recognition that PPMS and SPMS are more similar than they
See page 1492 From the Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, OH. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the author, if any, are provided at the end of the editorial. 1488
© 2014 American Academy of Neurology
are different and perhaps should be considered together as a single disease subset. It is possible that these metabolomics measures may be useful biomarker outcomes in clinical trials, as suggested by the authors, but much more validation is required before that could be entertained. Biomarkers for progressive MS are just one part of the progressive MS puzzle. Additional research needs to focus on benchtop models of progressive MS, high throughput screening methods to identify promising therapies, dynamic biomarkers for phase II trials, robust clinical outcomes for phase III trials, and effective symptom management and rehabilitation paradigms.2 The Progressive MS Alliance (www.progressivemsalliance.org) is a growing international collaborative of MS societies from around the world that is helping focus research efforts on progressive MS through Challenge Grants, Infrastructure Awards, and multicountry Collaborative Network Awards. This global effort will hopefully convert progressive MS into the success story that RRMS has already become.
STUDY FUNDING No targeted funding reported.
DISCLOSURE R. Fox has received personal consulting fees from Biogen Idec, GlaxoSmithKline, MedDay, Novartis, Questcor, Teva, and XenoPort; has served on advisory committees for Biogen Idec and Novartis; and has received research grant funding from Novartis. Go to Neurology.org for full disclosures.
REFERENCES 1. Bevan CJ, Cree BA. Disease activity free status: a new end point for a new era in multiple sclerosis clinical research? JAMA Neurol 2014;71:269–270. 2. Fox RJ, Thompson A, Baker D, et al. Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS. Mult Scler 2012;18: 1534–1540. 3. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014;83:278–286. 4. Dickens AM, Larkin JR, Griffin JL, et al. A type 2 biomarker separates relapsing-remitting from secondary progressive multiple sclerosis. Neurology 2014;83:1492–1499.
Neurology 83
October 21, 2014
1489
Biomarkers for MS: Unpuzzling the progressive multiple sclerosis puzzle Robert J. Fox Neurology 2014;83;1488-1489 Published Online before print September 24, 2014 DOI 10.1212/WNL.0000000000000921 This information is current as of September 24, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/17/1488.full.html
References
This article cites 4 articles, 1 of which you can access for free at: http://www.neurology.org/content/83/17/1488.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Demyelinating disease (CNS) http://www.neurology.org//cgi/collection/all_demyelinating_disease_cn s Multiple sclerosis http://www.neurology.org//cgi/collection/multiple_sclerosis
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
