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April 10, 2018; 90 (15) Article

Fingolimod effect on gray matter, thalamus, and white matter in patients with multiple sclerosis

Laura Gaetano, Dieter A. Häring, Ernst-Wilhelm Radue, Nicole Mueller-Lenke, Avinash Thakur, Davorka Tomic, Ludwig Kappos, Till Sprenger
First published March 14, 2018, DOI: https://doi.org/10.1212/WNL.0000000000005292
Laura Gaetano
From the Medical Image Analysis Centre (L.G., E.-W.R., N.M.-L., T.S.), University Hospital Basel; Neurologic Clinic and Policlinic (L.G., L.K., T.S.), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel; Novartis Pharma AG (D.A.H., D.T.), Basel, Switzerland; Novartis Healthcare Pvt Ltd (A.T.), Hyderabad, India; and Department of Neurology (T.S.), DKD HELIOS Klinik Wiesbaden, Germany.
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Dieter A. Häring
From the Medical Image Analysis Centre (L.G., E.-W.R., N.M.-L., T.S.), University Hospital Basel; Neurologic Clinic and Policlinic (L.G., L.K., T.S.), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel; Novartis Pharma AG (D.A.H., D.T.), Basel, Switzerland; Novartis Healthcare Pvt Ltd (A.T.), Hyderabad, India; and Department of Neurology (T.S.), DKD HELIOS Klinik Wiesbaden, Germany.
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Ernst-Wilhelm Radue
From the Medical Image Analysis Centre (L.G., E.-W.R., N.M.-L., T.S.), University Hospital Basel; Neurologic Clinic and Policlinic (L.G., L.K., T.S.), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel; Novartis Pharma AG (D.A.H., D.T.), Basel, Switzerland; Novartis Healthcare Pvt Ltd (A.T.), Hyderabad, India; and Department of Neurology (T.S.), DKD HELIOS Klinik Wiesbaden, Germany.
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Nicole Mueller-Lenke
From the Medical Image Analysis Centre (L.G., E.-W.R., N.M.-L., T.S.), University Hospital Basel; Neurologic Clinic and Policlinic (L.G., L.K., T.S.), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel; Novartis Pharma AG (D.A.H., D.T.), Basel, Switzerland; Novartis Healthcare Pvt Ltd (A.T.), Hyderabad, India; and Department of Neurology (T.S.), DKD HELIOS Klinik Wiesbaden, Germany.
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Avinash Thakur
From the Medical Image Analysis Centre (L.G., E.-W.R., N.M.-L., T.S.), University Hospital Basel; Neurologic Clinic and Policlinic (L.G., L.K., T.S.), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel; Novartis Pharma AG (D.A.H., D.T.), Basel, Switzerland; Novartis Healthcare Pvt Ltd (A.T.), Hyderabad, India; and Department of Neurology (T.S.), DKD HELIOS Klinik Wiesbaden, Germany.
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Davorka Tomic
From the Medical Image Analysis Centre (L.G., E.-W.R., N.M.-L., T.S.), University Hospital Basel; Neurologic Clinic and Policlinic (L.G., L.K., T.S.), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel; Novartis Pharma AG (D.A.H., D.T.), Basel, Switzerland; Novartis Healthcare Pvt Ltd (A.T.), Hyderabad, India; and Department of Neurology (T.S.), DKD HELIOS Klinik Wiesbaden, Germany.
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Ludwig Kappos
From the Medical Image Analysis Centre (L.G., E.-W.R., N.M.-L., T.S.), University Hospital Basel; Neurologic Clinic and Policlinic (L.G., L.K., T.S.), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel; Novartis Pharma AG (D.A.H., D.T.), Basel, Switzerland; Novartis Healthcare Pvt Ltd (A.T.), Hyderabad, India; and Department of Neurology (T.S.), DKD HELIOS Klinik Wiesbaden, Germany.
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Till Sprenger
From the Medical Image Analysis Centre (L.G., E.-W.R., N.M.-L., T.S.), University Hospital Basel; Neurologic Clinic and Policlinic (L.G., L.K., T.S.), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel; Novartis Pharma AG (D.A.H., D.T.), Basel, Switzerland; Novartis Healthcare Pvt Ltd (A.T.), Hyderabad, India; and Department of Neurology (T.S.), DKD HELIOS Klinik Wiesbaden, Germany.
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Citation
Fingolimod effect on gray matter, thalamus, and white matter in patients with multiple sclerosis
Laura Gaetano, Dieter A. Häring, Ernst-Wilhelm Radue, Nicole Mueller-Lenke, Avinash Thakur, Davorka Tomic, Ludwig Kappos, Till Sprenger
Neurology Apr 2018, 90 (15) e1324-e1332; DOI: 10.1212/WNL.0000000000005292

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Abstract

Objective To study the effect of fingolimod on deep gray matter (dGM), thalamus, cortical GM (cGM), white matter (WM), and ventricular volume (VV) in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods Data were pooled from 2 phase III studies. A total of 2,064 of 2,355 (88%) contributed to the analysis: fingolimod 0.5 mg n = 783, fingolimod 1.25 mg n = 799, or placebo n = 773. Percentage change from baseline in dGM and thalamic volumes was evaluated with FMRIB’s Integrated Registration & Segmentation Tool; WM, cGM, and VV were evaluated with structural image evaluation using normalization of atrophy cross-sectional version (SIENAX) at months 12 and 24.

Results At baseline, compound brain volume (brain volume in the z block [BVz] = cGM + dGM + WM) correlated with SIENAX-normalized brain volume (r = 0.938, p < 0.001); percentage change from baseline in BVz over 2 years correlated with structural image evaluation using normalization of atrophy percentage brain volume change (r = 0.713, p < 0.001). For placebo, volume reductions were most pronounced in cGM, and relative changes from baseline were strongest in dGM. Over 24 months, there were significant reductions with fingolimod vs placebo for dGM (0.5 mg −14.5%, p = 0.017; 1.25 mg −26.6%, p < 0.01) and thalamus (0.5 mg −26.1%, p = 0.006; 1.25 mg −49.7%, p < 0.001). Reduction of cGM volume loss was not significant. Significantly less WM loss and VV enlargement were seen with fingolimod vs placebo (all p < 0.001). A high T2 lesion volume at baseline predicted on-study cGM, dGM, and thalamic volume loss (p < 0.0001) but not WM loss. Patients taking placebo with high dGM (hazard ratio [HR] 0.54, p = 0.0323) or thalamic (HR 0.58, p = 0.0663) volume at baseline were less likely to show future disability worsening.

Conclusions Fingolimod significantly reduced dGM volume loss (including thalamus) vs placebo in patients with RRMS. Reducing dGM and thalamic volume loss might improve long-term outcome.

Glossary

BVL=
brain volume loss;
BVz=
brain volume in the z block;
cGM=
cortical gray matter;
dGM=
deep gray matter;
FIRST=
FMRIB’s Integrated Registration & Segmentation Tool;
FREEDOMS=
FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis;
Gd=
gadolinium;
GM=
gray matter;
MS=
multiple sclerosis;
RRMS=
relapsing-remitting multiple sclerosis;
SIENA=
structural image evaluation using normalization of atrophy;
SIENAX=
structural image evaluation using normalization of atrophy cross-sectional version;
WBV=
whole brain volume;
WM=
white matter

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 677

  • Received April 12, 2017.
  • Accepted in final form January 16, 2018.
  • © 2018 American Academy of Neurology
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