Effect of treatment with interferon beta-1a on changes in voxel-wise magnetization transfer ratio in normal appearing brain tissue and lesions of patients with relapsing-remitting multiple sclerosis: a 24-week, controlled pilot study

Abstract

Background: This pilot study investigated changes in remyelinating and demyelinating activity in normal appearing brain tissue (NABT) and lesions, by using voxel-wise magnetization transfer ratio (VW-MTR), in patients with relapsing-remitting multiple sclerosis (RRMS) receiving interferon beta-1a 44 mcg subcutaneously (IFN β-1a SC) three times weekly versus healthy controls (HCs) (NCT01085318).

Methods: Increasing (suggestive of remyelination) and decreasing (suggestive of demyelination) VW-MTR changes in NABT and in T2, T1 and gadolinium (Gd)-enhancing lesion volume were measured over 24 weeks in 23 patients treated with IFN β-1a SC and in 15 HCs (where applicable). VW-MTR changes were tested using the Wilcoxon signed-rank or Wilcoxon rank-sum test.

Results: A trend for greater volume of NABT with increasing VW-MTR at 24 weeks was observed for patients versus HCs (median [range] 1206 [0-15278]; 342 [0-951] mm3; p = 0.061). NABT volume with increasing VW-MTR at 12 weeks was significantly greater in patients than in HCs (852 [6-11577]; 360 [0-1755] mm3; p = 0.028). Similar findings were detected for lesion volumes. Two patients with notably high numbers of Gd-enhancing lesions at baseline had a markedly greater volume of tissue with increasing VW-MTR compared with other patients. Volume of NABT tissue with decreasing VW-MTR was significantly greater in patients versus HCs at 24 weeks (942 [0-6141]; 297 [0-852] mm3; p<0.001).

Conclusions: The significant change in NABT volume with increasing VW-MTR at 12 weeks suggests that active remyelination in patients with RRMS may occur during treatment with IFN β-1a SC. Findings from two patients with the highest number of Gd-enhancing lesions at baseline suggest that extensive remyelination in NABT may occur in patients with high disease activity. Tissue volume with decreasing VW-MTR was greater in patients than in HCs, despite treatment, validating the sensitivity of this technique for detecting MS disease activity.

Trial registration: ClinicalTrials.gov NCT01085318.

Conflict of interest statement

Competing Interests: This study was sponsored by EMD Serono, Inc., Rockland, MA, a subsidiary of Merck KGaA, Darmstadt, Germany and by Pfizer, Inc, New York, NY (www.pfizer.com/). B Hayward and F Dangond are employees of EMD Serono, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany. Esther Law and Chris Grantham of Caudex Medical, who assisted in preparing the initial draft of the manuscript, collating the comments of authors and other named contributors, as well as assembling tables and figures, were supported by EMD Serono, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany. Additionally, the authors disclose the following competing interests: R Zivadinov received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Novartis, Bayer and Sanofi-Genzyme for speaking and consultant fees. He also received financial support for research activities from Biogen Idec, Teva Pharmaceuticals, Sanofi-Genzyme, Novartis and EMD Serono. S Markovic-Plese received personal compensation from Genzyme Inc. and EMD Serono for consultant fees. She also received research grants from Biogen Idec, EMD Serono, Genzyme Inc., Teva Pharmaceuticals and Novartis. D Hojnacki has received speaker honoraria and consultant fees from Biogen Idec, Teva Pharmaceuticals, EMD Serono and Pfizer Inc. B Weinstock-Guttman has received honoraria as a speaker and a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Pfizer, Novartis and Acorda, and has also received research funds from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Pfizer, Novartis, Acorda and Cyberonics. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Subject numbers from enrollment to study completion.

HC, healthy control; MRI, magnetic resonance imaging.

Figure 2. Change in VW-MTR in NABT from baseline to 24 weeks.

The figure depicts a comparison between patients and HCs with A) increasing VW-MTR and B) decreasing VW-MTR and difference from baseline within each study group for increasing and decreasing VW-MTR in C) patients and D) HCs. For A) and B), the p value is the difference between patients and HCs from the Wilcoxon rank–sum test; for C) and D), the p-value is the difference from baseline within groups from the Wilcoxon signed–rank test. In the box plots, the bold line represents the median; the boxes represent the middle 50% of data; the top and bottom of the box represent the third and first quartiles; the open circles are outliers. The whisker lines above and below the boxes represent the largest and smallest values that are not considered to be outliers. HC, healthy control; NABT, normal appearing brain tissue; VW-MTR, voxel-wise magnetization transfer ratio.

Figure 3. Change in VW-MTR from baseline to 24 weeks.

Change in A) NABT in patients and in HCs, B) T2-LV, T1-LV and Gd-enhancing lesions in patients only. Gd, gadolinium; HC, healthy control; LV, lesion volume; NABT, normal appearing brain tissue; VW-MTR, voxel-wise magnetization transfer ratio.

Figure 4. Difference from baseline to 24 weeks for increasing and decreasing VW-MTR in T2-LV in patients.

The p-value is for the difference from zero within groups from the Wilcoxon signed–rank test with adjustment. In the box plot, the bold line represents the median; the boxes represent the middle 50% of data; the top and bottom of the box represent the third and first quartiles; the open circles are outliers. The whisker lines above and below the boxes represent the largest and smallest values that are not considered to be outliers. LV, lesion volume; NS, not significant; VW-MTR, voxel-wise magnetization transfer ratio.

Figure 5. Difference from baseline to 24 weeks for increasing and decreasing VW-MTR in T1-LV in patients.

The p-value is for the difference from zero within groups from the Wilcoxon signed–rank test with adjustment. In the box plots, the bold line represents the median; the boxes represent the middle 50% of data; the top and bottom of the box represent the third and first quartiles; the open circles are outliers. The whisker lines above and below the boxes represent the largest and smallest values that are not considered to be outliers. LV, lesion volume; VW-MTR, voxel-wise magnetization transfer ratio.