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

BackgroundNatalizumab is a high-efficacy therapy for RRMS. While EID may reduce PML risk, critical gaps persist in understanding post-cessation outcomes, posing urgent clinical challenges for neurologists discontinuing treatment. ObjectivesTo compare efficacy/safety of natalizumab SID vs. EID and quantify relapse/disability risk after cessation in adults with RRMS. MethodsWe conducted a systematic review/meta-analysis (PROSPERO: CRD420251103014) following PRISMA guidelines. We searched MEDLINE, Cochrane Library, ClinicalTrials.gov, and other sources (2015-2025) for RCTs and observational studies. Primary outcomes: ARR and disability progression; secondary: 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, with evidence certainty graded (GRADE). ResultsTwenty-eight studies (n=45,803) were included. The key finding was a substantial 41.7% (95% CI 30.8-53.6%) pooled relapse risk within 12 months of cessation (4 studies, n=857) using a random-effects model. Sensitivity analysis excluding the outlier study (Weinstock-Guttman 2016) showed a relapse risk of 36.9% (95% CI 33.7-40.3%). Narrative synthesis of ARR (9 studies) showed no consistent SID vs. EID difference (median difference 0.00). Meta-analysis of PML risk (3 studies) found no significant difference (RR 0.70, 95% CI 0.20-2.54). Disability outcomes were too heterogeneous for meta-analysis. Evidence certainty was low for most outcomes. ConclusionThis review demonstrates a substantial 41.7% relapse risk within 12 months of natalizumab cessation, representing the most critical clinical implication. While EID may maintain efficacy comparable to SID, the high withdrawal relapse rate necessitates prompt therapy transition and patient counseling. Treatment decisions must encompass the entire continuum from initiation to discontinuation.