Chronic lesion activity and disability progression in secondary progressive multiple sclerosis

Abstract

Objective: Slowly expanding lesions (SELs), a subgroup of chronic white matter lesions that gradually expand over time, have been shown to predict disability accumulation in primary progressive multiple sclerosis (MS) disease. However, the relationships between SELs, acute lesion activity (ALA), overall chronic lesion activity (CLA) and disability progression are not well understood. In this study, we examined the ASCEND phase III clinical trial, which compared natalizumab with placebo in secondary progressive MS (SPMS).

Methods: Patients with complete imaging datasets between baseline and week 108 (N=600) were analysed for SEL prevalence (the number and volume of SELs), disability progression, ALA (assessed by gadolinium-enhancing lesions and new T2-hyperintense lesions) and CLA (assessed by T1-hypointense lesion volume increase within baseline T2-non-enhancing lesions identified as SELs and non-SELs).

Results: CLA in both SELs and non-SELs was greater in patients with SPMS with confirmed disability progression than in those with no progression. In the complete absence of ALA at baseline and on study, SEL prevalence was significantly lower, while CLA within non-SELs remained associated with disability progression. Natalizumab decreased SEL prevalence and CLA in SELs and non-SELs compared with placebo.

Conclusions: This study shows that CLA in patients with SPMS is decreased but persists in the absence of ALA and is associated with disability progression, highlighting the need for therapeutics targeting all mechanisms of CLA, including smouldering inflammation and neurodegeneration.

Trial registration number: NCT01416181.

Keywords: MRI; MULTIPLE SCLEROSIS.

Conflict of interest statement

Competing interests: VB was an employee of Biogen (Cambridge, Massachusetts, USA) during the completion of the work related to this manuscript and remains a Biogen shareholder. She is now an employee of Agios (Cambridge, Massachusetts, USA), which was not in any way associated with this study. ICG has received fellowship support from Biogen. CE is an employee of NeuroRx Research. DLA has received grants from Biogen, Immunotec and Novartis and consulting fees from Biogen, Celgene, Frequency Therapeutics, Genentech/Roche, Med-Ex Learning, Merck, Novartis, the Population Council, Queens University and Sanofi Aventis and has an ownership interest in NeuroRx. JK, HC, MS, NC, DPB, NF, AG and SB are employees and shareholders of Biogen. LZ and CK were employees of Biogen at the time of these analyses and may hold stock and/or stock options in Biogen. GG has received speaker honoraria and consulting fees from AbbVie, Actelion, Almirall, Atara Bio, Bayer Schering, Biogen, Celgene, FivePrime, GlaxoSmithKline, GW Pharma, Ironwood, Janssen, Merck, Merck KGaA, Novartis, Pfizer, Protein Discovery Laboratories, Sanofi Genzyme, Teva Pharmaceuticals, UCB and Vertex and research support unrelated to this study from Biogen, Ironwood, Merck, Merck KGaA, Novartis, Roche and Takeda.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Association between CLA or whole brain volume loss and composite disability progression in patients with SPMS. Change from baseline to week 108 in T1LV in (A) SELs, (B) non-SELs and (C) CNT2 lesions was significantly associated with composite disability progression in patients with SPMS treated with placebo. No difference in percentage change from baseline to week 108 in (D) whole brain volume was observed in patients with SPMS with composite disability progression compared with those with no progression. Composite progression was confirmed at 24 weeks and end of study on one or more of the EDSS, Timed 25-Foot Walk or 9-Hole Peg Test. In these box-and-whisker representations, the box spans the interquartile range, the median is marked by the horizontal line inside the box and the whiskers are the two lines outside the box that extend to the highest and lowest observations. P values by Van Elteren test; stratified by baseline EDSS Score (≤5.5 or ≥6.0) and baseline T2 lesion volume category based on tertiles (≤6908.79 mm3, >6908.79–18 818.49 mm3 and >18 818.49 mm3). CLA, chronic lesion activity; CNT2, chronic non-enhancing T2; EDSS, Expanded Disability Status Scale; SEL, slowly expanding lesion; SPMS, secondary progressive multiple sclerosis; T1LV, T1-hypointense lesion volume.

Figure 2

Association between CLA and EDSS progression. Increase from baseline to week 108 in T1LV within (A) SELs and (C) CNT2 lesions but not (B) non-SELs was associated with EDSS progression in patients with SPMS treated with placebo. (However, a consistent directional trend was observed in non-SELs.) EDSS progression was confirmed at 24 weeks and end of study. In these box-and-whisker representations, the box spans the interquartile range, the median is marked by the horizontal line inside the box and the whiskers are the two lines outside the box that extend to the highest and lowest observations. P values by Van Elteren test; stratified by baseline EDSS Score (≤5.5 or ≥6.0) and by baseline T2 lesion volume category based on tertiles (≤6908.79 mm3, >6908.79–18 818.49 mm3 and >18 818.49 mm3). CLA, chronic lesion activity; CNT2, chronic non-enhancing T2; EDSS, Expanded Disability Status Scale; SEL, slowly expanding lesion; SPMS, secondary progressive multiple sclerosis; T1LV, T1-hypointense lesion volume.

Figure 3

Association between CLA and 9HPT progression and between CLA and T25FW progression. Change from baseline to week 108 in T1LV within (A) SELs and (C) CNT2 lesions but not (B) non-SELs was associated with 9HPT progression in patients with SPMS treated with placebo. (However, a consistent directional trend was observed in non-SELs.) Change in T1LV from baseline to week 108 within (E) non-SELs and (F) CNT2 lesions but not (D) SELs was associated with T25FW progression in patients with SPMS treated with placebo. (However, a consistent directional trend was observed in SELs.) 9HPT progression and T25FW progression were confirmed at 24 weeks and end of study. In these box-and-whisker representations, the box spans the interquartile range, the median is marked by the horizontal line inside the box and the whiskers are the two lines outside the box that extend to the highest and lowest observations. P values by Van Elteren test; stratified by baseline EDSS Score (≤5.5 or ≥6.0) and by baseline T2 lesion volume category based on tertiles (≤6908.79 mm3, >6908.79–18 818.49 mm3 and >18 818.49 mm3). 9HPT, 9-Hole Peg Test; CLA, chronic lesion activity; CNT2, chronic non-enhancing T2; EDSS, Expanded Disability Status Scale; SEL, slowly expanding lesion; SPMS, secondary progressive multiple sclerosis; T1LV, T1-hypointense lesion volume; T25FW, Timed 25-Foot Walk.

Figure 4

Association between CLA and composite disability progression in the absence of ALA. CLA in (B) non-SELs and (C) CNT2 lesions but not (A) SELs remained associated with composite disability progression in the absence of ALA in patients with SPMS treated with placebo. (However, a consistent directional trend was observed in SELs.) Absence of acute lesion activity was defined as no baseline and postbaseline T1 gadolinium-enhancing and no postbaseline new/enlarging T2 lesions. Composite progression was confirmed at 24 weeks and end of study on one or more of the EDSS, Timed 25-Foot Walk or 9-Hole Peg Test. In these box-and-whisker representations, the box spans the interquartile range, the median is marked by the horizontal line inside the box and the whiskers are the two lines outside the box that extend to the highest and lowest observations. P values by Van Elteren test; stratified by baseline EDSS Score (≤5.5 or ≥6.0) and baseline T2 lesion volume category based on tertiles (≤6908.79 mm3, >6908.79–18 818.49 mm3 and >18 818.49 mm3). ALA, acute lesion activity; CLA, chronic lesion activity; CNT2, chronic non-enhancing T2; EDSS, Expanded Disability Status Scale; SEL, slowly expanding lesion; SPMS, secondary progressive multiple sclerosis; T1LV, T1-hypointense lesion volume.

Figure 5

Prevalence of SELs and frequency distribution of SEL severity in the presence versus absence of ALA. SEL (A) number, (B) absolute volume and (C) relative volume (percentage of baseline non-enhancing T2LV) were greater in patients with SPMS treated with placebo who had ALA compared with those with no ALA. (D) The frequency distribution of patients by range of SEL prevalence indicates that patients with ALA had a greater percentage of their total T2 lesion burden identified as SELs compared with patients with no ALA. In these box-and-whisker representations, the box spans the interquartile range, the median is marked by the horizontal line inside the box and the whiskers are the two lines outside the box that extend to the highest and lowest observations. No acute lesion activity was defined as no baseline or postbaseline Gd+ T1 lesions and no postbaseline new/enlarging T2 lesions in weeks 24, 48, 72, 96 and 108. Acute lesions were defined as baseline Gd+ T1 lesions and postbaseline Gd+ T1 lesions and new/enlarging T2 lesions in weeks 24, 48, 72, 96 and 108. P values by Van Elteren test: stratified by baseline EDSS Score (≤5.5 or ≥6.0) and baseline T2LV category based on tertiles (≤6908.79 mm3, >6908.79–18 818.49 mm3 and >18 818.49 mm3). ALA, acute lesion activity; BL, baseline; EDSS, Expanded Disability Status Scale; Gd+, gadolinium enhancing; SEL, slowly expanding lesion; SPMS, secondary progressive multiple sclerosis; T2LV, T2-hyperintense lesion volume.

Figure 6

Effect of natalizumab on SEL prevalence. Natalizumab reduced the (A) number, (B) absolute volume and (C) relative volume (percentage of baseline non-enhancing T2LV) of SELs in patients with SPMS. Box-and-whisker representations: the box spans the interquartile range, the median is marked by the horizontal line inside the box and the whiskers are the two lines outside the box that extend to the highest and lowest observations. P values by Van Elteren test; stratified by baseline Expanded Disability Status Scale Score (≤5.5 or ≥6.0) and baseline T2LV category based on tertiles (≤6908.79 mm3, >6908.79–18 818.49 mm3 and >18 818.49 mm3). BL, baseline; SEL, slowly expanding lesion; SPMS, secondary progressive multiple sclerosis; T2LV, T2-hyperintense lesion volume; T2w, T2 weighted.

Figure 7

Change in CLA with natalizumab versus placebo. Natalizumab reduced CLA as measured by both (A, B) absolute increase and (C, D) percentage increase in T1LV in SELs and non-SELs compared with placebo in patients with SPMS. Distribution-free quantile confidence limits are displayed. P values by Van Elteren test; stratified by baseline EDSS Score (≤5.5 or ≥6.0) and baseline T2 lesion volume category based on tertiles (≤6908.79 mm3, >6908.79–18 818.49 mm3 and >18 818.49 mm3). BL, baseline; CLA, chronic white matter lesion activity; EDSS, Expanded Disability Status Scale; SPMS, secondary progressive multiple sclerosis; T1LV, T1-hypointense lesion volume.