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The effect of disease-modifying therapies on brain volume loss and disability accumulation in multiple sclerosis: a
Alessandro Cagol1,2,3,4, Sabine Schaedelin1,5, Roxanne Pretzsch1,2,3
1Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland.
Background:
Multiple treatments have demonstrated efficacy in preventing brain volume loss (BVL) in randomized controlled trials (RCTs) for multiple sclerosis (MS). However, assessing their relative effectiveness remains challenging due to limited head-to-head comparisons. Additionally, the relationship between treatment effects on BVL and disability accumulation is not established for newer therapies. This study aimed to compare the efficacy of approved disease-modifying therapies (DMTs) in reducing BVL in MS and to investigate the association between treatment effects on BVL and disability accumulation.
Methods:
In this systematic review and network meta-analysis, we included all RCTs enrolling adults with MS that evaluated FDA-approved DMTs and reported BVL outcomes over at least one year. We searched PubMed, Embase, and Cochrane from inception to September 2024. Following PRISMA guidelines, two reviewers independently extracted data on BVL, MRI lesion activity, and disability progression. We conducted a mixed-effects network meta-analysis with placebo as the reference group. Meta-regression analyses examined the association between treatment effects on BVL and disability progression, adjusting for MRI lesion activity.The primary outcome was BVL. Secondary outcomes included MRI lesion accumulation and risk of confirmed disability progression. Effect sizes were reported as the ratio of means (ROM) and hazard ratios (HRs), with 95% confidence intervals (CIs). This study is registered with PROSPERO (CRD420251034936).
Findings:
We included 33 RCTs evaluating 16 DMTs and 26,247 patients. Eight DMTs significantly reduced BVL compared to placebo, including ponesimod (ROM = 0.52; 95%-CI: 0.35-0.77), ofatumumab (ROM = 0.58; 95%-CI: 0.40-0.83), alemtuzumab (ROM = 0.63; 95%-CI: 0.49-0.83), teriflunomide (ROM = 0.71; 95%-CI: 0.52-0.97), ozanimod (ROM = 0.74; 95%-CI: 0.56-0.98), natalizumab (ROM = 0.77; 95%-CI: 0.61-0.96), siponimod (ROM = 0.77; 95%-CI: 0.60-0.98), and fingolimod (ROM = 0.83; 95%-CI: 0.71-0.96). The treatment effect on BVL was associated with the treatment effect on disability accumulation (β = 0.466; p = 0.008), and this association remained significant independently of the treatment effect on MRI activity (β = 0.422; p = 0.005).
Interpretation:
Several DMTs-including newer therapies-significantly reduce BVL, and this effect correlates with reduced disability accumulation. These findings support BVL as a meaningful treatment target in MS.
Funding:
None.
Insights
Eight disease-modifying therapies (DMTs) significantly reduce brain volume loss (BVL) in multiple sclerosis (MS). This reduction in BVL correlates with decreased disability accumulation, supporting BVL as a key treatment target.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) treatments aim to prevent brain volume loss (BVL).
- Head-to-head comparisons of disease-modifying therapies (DMTs) for efficacy are limited.
- The link between BVL reduction and disability progression for newer MS therapies is not well-established.
Purpose of the Study:
- To compare the efficacy of approved DMTs in reducing BVL in MS patients.
- To investigate the association between BVL reduction and disability accumulation with DMT use.
Main Methods:
- Systematic review and network meta-analysis of randomized controlled trials (RCTs) of FDA-approved DMTs in adults with MS.
- Included RCTs reported BVL outcomes over at least one year.
- Network meta-analysis used placebo as the reference; meta-regression examined associations between BVL, disability, and MRI activity.
Main Results:
- 33 RCTs involving 16 DMTs and 26,247 patients were analyzed.
- Eight DMTs significantly reduced BVL compared to placebo: ponesimod, ofatumumab, alemtuzumab, teriflunomide, ozanimod, natalizumab, siponimod, and fingolimod.
- Treatment effect on BVL was significantly associated with reduced disability accumulation, independent of MRI lesion activity.
Conclusions:
- Several DMTs, including newer agents, effectively reduce BVL in MS.
- The reduction in BVL achieved by DMTs correlates with decreased disability accumulation.
- Brain volume loss is a meaningful therapeutic target in the management of MS.
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