Unraveling treatment response in multiple sclerosis: A clinical and MRI challenge

Claudio Gasperini¹, Luca Prosperini², Mar Tintoré², Maria Pia Sormani², Massimo Filippi², Jordi Rio², Jacqueline Palace², Maria A Rocca², Olga Ciccarelli², Frederik Barkhof², Jaume Sastre-Garriga², Hugo Vrenken², Jette L Frederiksen², Tarek A Yousry², Christian Enzinger², Alex Rovira², Ludwig Kappos², Carlo Pozzilli², Xavier Montalban², Nicola De Stefano²; the MAGNIMS Study Group

Affiliations

¹ From the Department of Neurosciences (C.G., L.P.), San Camillo-Forlanini Hospital, Rome, Italy; Centre d'Esclerosi Multiple de Catalunya (Cemcat), Department of Neurology/Neuroimmunology (M.T., J.R., J.S.-G., X.M.), and Magnetic Resonance Unit, Department of Radiology (A.R.), Hospital Universitari Vall d'Hebron, Universitat Autonoma de Barcelona, Spain; Biostatistics Unit (M.P.S.), Department of Health Sciences, University of Genoa; Neuroimaging Research Unit (M.F., M.A.R.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; Nuffield Department of Clinical Neurosciences (J.P.), West Wing, John Radcliffe Hospital, Oxford; Institutes of Neurology & Healthcare Engineering (O.C., F.B.), University College London (O.C.), UK; Amsterdam Neuroscience and Department of Radiology and Nuclear Medicine (F.B., H.V.), VU University Medical Center, Amsterdam, the Netherlands; Department of Neurology (J.L.F.), Rigshospitalet Glostrup and University of Copenhagen, Denmark; Neuroradiological Academic Unit (T.A.Y.), Institute of Neurology, London, UK; Department of Neurology (C.E.), Medical University of Graz, Austria; Neurologic Clinic and Policlinic, Department of Medicine (L.K.), Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, University of Basel, Switzerland; Department of Neurology and Psychiatry (C.P.), Sapienza University, Rome; and Neurology and Neurometabolic Unit, Department of Neurological and Behavioral Sciences (N.D.S.), University of Siena, Italy. c.gasperini@libero.it.
² From the Department of Neurosciences (C.G., L.P.), San Camillo-Forlanini Hospital, Rome, Italy; Centre d'Esclerosi Multiple de Catalunya (Cemcat), Department of Neurology/Neuroimmunology (M.T., J.R., J.S.-G., X.M.), and Magnetic Resonance Unit, Department of Radiology (A.R.), Hospital Universitari Vall d'Hebron, Universitat Autonoma de Barcelona, Spain; Biostatistics Unit (M.P.S.), Department of Health Sciences, University of Genoa; Neuroimaging Research Unit (M.F., M.A.R.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; Nuffield Department of Clinical Neurosciences (J.P.), West Wing, John Radcliffe Hospital, Oxford; Institutes of Neurology & Healthcare Engineering (O.C., F.B.), University College London (O.C.), UK; Amsterdam Neuroscience and Department of Radiology and Nuclear Medicine (F.B., H.V.), VU University Medical Center, Amsterdam, the Netherlands; Department of Neurology (J.L.F.), Rigshospitalet Glostrup and University of Copenhagen, Denmark; Neuroradiological Academic Unit (T.A.Y.), Institute of Neurology, London, UK; Department of Neurology (C.E.), Medical University of Graz, Austria; Neurologic Clinic and Policlinic, Department of Medicine (L.K.), Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, University of Basel, Switzerland; Department of Neurology and Psychiatry (C.P.), Sapienza University, Rome; and Neurology and Neurometabolic Unit, Department of Neurological and Behavioral Sciences (N.D.S.), University of Siena, Italy.

PMID: 30587516
PMCID: PMC6345120
DOI: 10.1212/WNL.0000000000006810

Review

Unraveling treatment response in multiple sclerosis: A clinical and MRI challenge

Claudio Gasperini et al. Neurology. 2019.

. 2019 Jan 22;92(4):180-192.

doi: 10.1212/WNL.0000000000006810. Epub 2018 Dec 26.

Authors

Affiliations

¹ From the Department of Neurosciences (C.G., L.P.), San Camillo-Forlanini Hospital, Rome, Italy; Centre d'Esclerosi Multiple de Catalunya (Cemcat), Department of Neurology/Neuroimmunology (M.T., J.R., J.S.-G., X.M.), and Magnetic Resonance Unit, Department of Radiology (A.R.), Hospital Universitari Vall d'Hebron, Universitat Autonoma de Barcelona, Spain; Biostatistics Unit (M.P.S.), Department of Health Sciences, University of Genoa; Neuroimaging Research Unit (M.F., M.A.R.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; Nuffield Department of Clinical Neurosciences (J.P.), West Wing, John Radcliffe Hospital, Oxford; Institutes of Neurology & Healthcare Engineering (O.C., F.B.), University College London (O.C.), UK; Amsterdam Neuroscience and Department of Radiology and Nuclear Medicine (F.B., H.V.), VU University Medical Center, Amsterdam, the Netherlands; Department of Neurology (J.L.F.), Rigshospitalet Glostrup and University of Copenhagen, Denmark; Neuroradiological Academic Unit (T.A.Y.), Institute of Neurology, London, UK; Department of Neurology (C.E.), Medical University of Graz, Austria; Neurologic Clinic and Policlinic, Department of Medicine (L.K.), Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, University of Basel, Switzerland; Department of Neurology and Psychiatry (C.P.), Sapienza University, Rome; and Neurology and Neurometabolic Unit, Department of Neurological and Behavioral Sciences (N.D.S.), University of Siena, Italy. c.gasperini@libero.it.
² From the Department of Neurosciences (C.G., L.P.), San Camillo-Forlanini Hospital, Rome, Italy; Centre d'Esclerosi Multiple de Catalunya (Cemcat), Department of Neurology/Neuroimmunology (M.T., J.R., J.S.-G., X.M.), and Magnetic Resonance Unit, Department of Radiology (A.R.), Hospital Universitari Vall d'Hebron, Universitat Autonoma de Barcelona, Spain; Biostatistics Unit (M.P.S.), Department of Health Sciences, University of Genoa; Neuroimaging Research Unit (M.F., M.A.R.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; Nuffield Department of Clinical Neurosciences (J.P.), West Wing, John Radcliffe Hospital, Oxford; Institutes of Neurology & Healthcare Engineering (O.C., F.B.), University College London (O.C.), UK; Amsterdam Neuroscience and Department of Radiology and Nuclear Medicine (F.B., H.V.), VU University Medical Center, Amsterdam, the Netherlands; Department of Neurology (J.L.F.), Rigshospitalet Glostrup and University of Copenhagen, Denmark; Neuroradiological Academic Unit (T.A.Y.), Institute of Neurology, London, UK; Department of Neurology (C.E.), Medical University of Graz, Austria; Neurologic Clinic and Policlinic, Department of Medicine (L.K.), Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, University of Basel, Switzerland; Department of Neurology and Psychiatry (C.P.), Sapienza University, Rome; and Neurology and Neurometabolic Unit, Department of Neurological and Behavioral Sciences (N.D.S.), University of Siena, Italy.

PMID: 30587516
PMCID: PMC6345120
DOI: 10.1212/WNL.0000000000006810

Abstract

Over the last few decades, the improved diagnostic criteria, the wide use of MRI, and the growing availability of effective pharmacologic treatments have led to substantial advances in the management of multiple sclerosis (MS). The importance of early diagnosis and treatment is now well-established, but there is still no consensus on how to define and monitor response to MS treatments. In particular, the clinical relevance of the detection of minimal MRI activity is controversial and recommendations on how to define and monitor treatment response are warranted. An expert panel of the Magnetic Resonance Imaging in MS Study Group analyzed and discussed published studies on treatment response in MS. The evolving concept of no evidence of disease activity and its effect on predicting long-term prognosis was examined, including the option of defining a more realistic target for daily clinical practice: minimal evidence of disease activity. Advantages and disadvantages associated with the use of MRI activity alone and quantitative scoring systems combining on-treatment clinical relapses and MRI active lesions to detect treatment response in the real-world setting were also discussed. While most published studies on this topic involved patients treated with interferon-β, special attention was given to more recent studies providing evidence based on treatment with other and more efficacious oral and injectable drugs. Finally, the panel identified future directions to pursue in this research field.

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Figures

**Figure 1. Definition of the concept of no evidence of disease activity (NEDA)**

**Figure 2. Treatment failure–free survival and disability worsening–free survival**
Treatment failure–free survival (defined as switch to a second-line treatment for lack of efficacy) (A) and disability worsening–free survival (defined as an at least 1-point Expanded Disability Status Scale [EDSS] increase) (B) over 3 years, according to the different combinations of new T2 lesions and relapses during the first year of therapy grouped in a 3-level score, in a cohort of 1,280 patients treated with interferon-β (modified from Sormani et al.¹¹).

**Figure 3. The iceberg of multiple sclerosis phenomena**
Gd = gadolinium; NAGM = normal-appearing grey matter; NAWM = normal-appearing white matter; NO = nitric oxide.

See this image and copyright information in PMC

References

1. Río J, Nos C, Tintoré M, et al. . Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients. Ann Neurol 2006;59:344–352. - PubMed
1. Bermel RA, You X, Foulds P, et al. . Predictors of long-term outcome in multiple sclerosis patients treated with interferon β. Ann Neurol 2013;73:95–103. - PubMed
1. Goodin DS, Traboulsee A, Knappertz V, et al. . Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon β-1b trial in multiple sclerosis. J Neurol Neurosurg Psychiatry 2012;83:282–287. - PubMed
1. Tomassini V, Paolillo A, Russo P, et al. . Predictors of long-term clinical response to interferon beta therapy in relapsing multiple sclerosis. J Neurol 2006;253:287–293. - PubMed
1. Durelli L, Barbero P, Bergui M, et al. . MRI activity and neutralising antibody as predictors of response to interferon beta treatment in multiple sclerosis. J Neurol Neurosurg Psychiatry 2008;79:646–651. - PubMed

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Unraveling treatment response in multiple sclerosis: A clinical and MRI challenge

Affiliations

Unraveling treatment response in multiple sclerosis: A clinical and MRI challenge

Authors

Affiliations

Abstract

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References

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MeSH terms

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Medical