Impact of Standard versus Extended Natalizumab Dosing and Treatment Withdrawal on Relapse, Disability, MRI Activity and Safety in Adults with MS: A Systematic Review and Meta-Analysis
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Background
Natalizumab is a high-efficacy therapy for relapsing-remitting multiple sclerosis (RRMS). Balancing efficacy with the risk of progressive multifocal leukoencephalopathy (PML) is critical. Uncertainty persists regarding the comparative effectiveness of standard interval dosing (SID; every 4 weeks) versus extended interval dosing (EID; every 5-8 weeks) and the outcomes following treatment cessation.
Objectives
To systematically compare the efficacy and safety of natalizumab SID versus EID, and to quantify the absolute risk of relapse and disability progression after treatment cessation in adults with RRMS.
Methods
We conducted a systematic review and meta-analysis (PROSPERO: CRD420251103014) following PRISMA guidelines. We searched MEDLINE, Cochrane Library, ClinicalTrials.gov , and other sources (2015-2025) for randomized controlled trials and observational studies. Primary outcomes were annualized relapse rate (ARR) and disability progression; secondary outcomes included PML incidence and post-cessation relapse. Risk of bias was assessed using Cochrane RoB 2.0 and ROBINS-I. Data were synthesized narratively or via meta-analysis where appropriate, with evidence certainty graded (GRADE).
Results
Twenty-eight studies (3 RCTs, 24 observational studies, 1 case series; n=45,803 participants) were included. Narrative synthesis of ARR (9 studies) showed no consistent difference between SID and EID, with ARR values being very low in both groups. Meta-analysis of PML risk from three studies with events found no significant difference (RR 0.70, 95% CI 0.20–2.54). Disability outcomes were infrequently and heterogeneously reported, precluding meta-analysis. After cessation, the pooled proportion of patients relapsing within 12 months across 4 studies (n=857) was 37.6% (95% CI 34.4–40.9%). The certainty of evidence was low for most outcomes.
Conclusions
EID appears to maintain relapse control comparable to SID. The evidence regarding a reduced PML risk with EID is inconclusive due to imprecision and residual confounding. Cessation carries a high absolute risk of disease reactivation, demanding an immediate transfer to alternate therapy. These data indicate EID as a viable choice for stable individuals, although decisions must be made individually. To definitively estimate PML risk, future research will require uniform outcome definitions as well as bigger, prospective trials.
