Vihaan Sahu is affiliated with Georgian National University SEU in Tbilisi, Georgia, where he contributes to academic research activities associated with the institution. His work, as reflected in the referenced preprint, is situated within the health and biomedical research domain, engaging with evidence-based analysis and scholarly investigation. Through his authorship, he participates in the design, evaluation, and interpretation of research relevant to the study’s clinical or public health focus. His contribution aligns with ongoing academic efforts at Georgian National University SEU to support research dissemination in the medical and health sciences.
Vihaan Sahu1*, Mohith Balakrishnan1 and Dhaneesh Rucher Jetty1
1Georgian National University SEU, Tbilisi, Georgia
*Corresponding Author: Vihaan Sahu, Email: vsahu{at}seu.edu.ge
medRxiv preprint DOI: https://doi.org/10.1101/2025.10.20.25338391
Posted: November 10, 2025, Version 2
Copyright: This pre-print is available under a Creative Commons License (Attribution 4.0 International), CC BY 4.0, as described at http://creativecommons.org/licenses/by/4.0/
Abstract
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.
Conclusion EID may maintain relapse control comparable to SID (low-certainty evidence). Long-term data suggest PML risk reduction with EID, but short-term evidence remains inconclusive. Cessation carries a high relapse risk (37.6% at 12 months), necessitating prompt therapy transition. Treatment decisions should be individualized. To definitively estimate PML risk, future research will require uniform outcome definitions and larger prospective trials.
1. Introduction
1.1 Background and Significance
MS is a chronic immune-mediated disease causing neurological disability. Globally affecting 2.8 million people, RRMS accounts for 85-90% of cases and typically presents in early adulthood (1–3). Effective disease-modifying therapy is crucial for managing relapses and disability progression. Hospitalization and large medical expenses are common among patients with severe RRMS, emphasizing the crucial need for effective disease-modifying therapy (4, 5).
Natalizumab, a humanized monoclonal antibody targeting α4-integrin, inhibits lymphocytes from crossing the blood-brain barrier, reducing CNS inflammation and relapse activity (6, 7). Since its FDA approval in 2004, natalizumab has demonstrated significant decreases in relapse frequency and MRI lesion burden in important trials (8, 3, 2). Following reports of progressive multifocal leukoencephalopathy (PML) in 2005, risk management strategies such as patient screening and JC virus surveillance were implemented (9, 10). Despite these developments, questions about optimal dosing regimens and safe withdrawal continue to arise. While standard four-week dose maintains α4-integrin receptor saturation above 80%, extended interval dosing (EID, 5-8 weeks) may reduce PML risk while maintaining efficacy (5). Discontinuation carries a 3-6-month risk of illness reactivation, emphasising the importance of evidence-based bridging treatments.
1.2 Current Evidence and Gaps
The phase 2 and pivotal studies consistently shown lower relapse rates and MRI lesion activity (8, 3, 2, 11). Early meta-analyses confirmed efficacy, but were restricted by short follow-up periods, dose variability, and a lack of long-term safety and post-cessation evidence. Nikfar et al. (12) (2010) analyzed four studies (n = 1,407) and discovered a 50% reduction in relapse risk, but the implications for real-world practice remained questionable. Observational studies, such as Salhofer-Polanyi et al. (13) (2014), indicate the danger of rebound following cessation, but variability in design and outcomes prevents definitive guidance. Recent systematic reviews, including Rabea et al. (14) (2024), explored safety and efficacy up to June 2023 but did not cover post-cessation outcomes or research beyond 2025, stressing the need for a modern synthesis that incorporates trial and observational data. A direct comparison table is provided in the below table A.
Table A.
1.3 Rationale for this Review
While the efficacy of natalizumab has been demonstrated, information on EID and post-discontinuation outcomes remains fragmented. Real-world accounts emphasize rebound risk and the significance of bridging techniques, but heterogeneity limits conclusive guidance. This review builds on previous work by including studies from 2023-2025, combining trial and real-world data, and focusing on dose optimization and cessation to inform interval management techniques.
1.4 Objectives
This systematic review and meta-analysis aims to evaluate Natalizumab in adults with RRMS, with an emphasis on dosing strategies and outcomes after cessation. Using a PICO framework, the objectives are:
- To compare the efficacy of standard-interval dosing (SID) versus extended-interval dosing (EID) on annualized relapse rate (ARR), disability progression, and MRI outcomes.
- To quantify the absolute risk, timing, and severity of relapse and disability progression following treatment cessation.
- To evaluate safety profiles, particularly the incidence of PML.
- To synthesize real-world and trial evidence from 2015 onward.
- To support clinical decision-making by offering evidence on dose optimization and cessation procedures.
2. Methods
2.1 Protocol and Registration
This systematic review was conducted according to a predefined protocol registered on PROSPERO (CRD420251103014). The protocol specified the search strategy, eligibility criteria, outcomes, risk-of-bias assessment methods, and synthesis approach. The review is reported in accordance with the PRISMA 2020 statement (15).
2.2 Eligibility Criteria
Studies were selected based on the PICO framework:
- Population: Adults (≥18 years) with relapsing-remitting multiple sclerosis (RRMS) treated with natalizumab monotherapy.
- Intervention: 1) Standard-interval dosing (SID) of natalizumab (every 4 weeks), or 2) Cessation of natalizumab therapy.
- Comparator: 1) Extended-interval dosing (EID; infusion intervals typically >4 weeks, up to 8 weeks), or 2) For cessation studies, either continuation of natalizumab or no active comparator (natural history).
- Outcomes:The primary outcomes were the annualized relapse rate (ARR) and disability progression (confirmed EDSS deterioration). Secondary outcomes included No Evidence of Disease Activity (NEDA-3), relapse risk after cessation, MRI activity, and safety outcomes, specifically the incidence of progressive multifocal leukoencephalopathy (PML).
- Study Designs: Randomized controlled trials (RCTs), prospective and retrospective cohort studies, and case series (for cessation results) were all included. Studies were omitted if they were reviews, conference abstracts without full data, addressed pediatric populations, coupled natalizumab with other disease-modifying treatments, or did not provide relevant outcomes. To reflect current practice, the publishing date range began on January 1, 2015. While the protocol specified studies from 2015 onward, one study (16)) was first published online in November 2014 but assigned to a 2015 journal issue; given its direct relevance, it was retained. This represents a minor deviation from the protocol. Only English-language publications were included.
2.3 Information Sources
We searched MEDLINE, Cochrane Library, and ClinicalTrials.gov from 2015-2025, with additional studies identified through reference screening and author contact.
2.4 Search Strategy
Search strategies combined MeSH terms and keywords for natalizumab, MS, dosing strategies, cessation, relapse, disability, and PML. Filters: human studies, English, 2015-2025. The search strategy was tailored for each database and is available on PROSPERO protocol registration.
2.5 Study Selection
Search results were imported into Zotero 6.0.30 for duplicate removal. Title/abstract screening and subsequent full-text assessment were performed independently by two reviewers (V.S., M.B.) using Rayyan QCRI (17). Conflicts were resolved through discussion or by a third reviewer (D.J.). The study selection process is detailed in the PRISMA flow diagram (18) (Figure 1).
Figure 1:
PRISMA flow chart
2.6 Data Collection Process
Data extraction was conducted independently by two reviewers (V.S., D.J.) using a standardized, piloted data extraction form in LibreOffice and Word. Disagreements were resolved by consensus or third-party adjudication (M.B.). Study authors were contacted for clarification or additional data when reported information was incomplete.
2.7 Data Items Extracted data included
- Study characteristics (design, country, funding, conflicts of interest).
- Participant characteristics (sample size, demographics, baseline disease characteristics).
- Intervention and comparator definitions (specific EID interval, cessation reason, post-cessation management).
- Outcome data for all pre-specified efficacy and safety endpoints, including effect estimates, measures of dispersion, and raw counts/denominators where available.
2.8 Risk of Bias in Individual Studies
The risk of bias was assessed independently by two reviewers (V.S., M.B.).
- RCTs (n = 3) were evaluated using the Cochrane RoB 2.0 tool (19).
- Non-randomized studies (n = 24) were assessed using the ROBINS-I tool (20).
- Case series (n = 1) were appraised using the Joanna Briggs Institute (JBI) critical appraisal checklist (21).
Results are summarized graphically in Supplementary Figure 1A (RCTs) and Supplementary Figure 1B (non-randomized studies), which were generated using the robvis visualization tool (22). Detailed domain-level judgments for all studies are provided in Supplementary Table 1.
2.9 Synthesis Methods
- Synthesis approach depended on clinical and methodological homogeneity. Meta-analysis used random-effects models for consistent outcomes. For rare events (PML), only studies reporting events were pooled. Person-year data were analyzed separately. Heterogeneity was quantified using I².
- Narrative synthesis followed SWiM guidelines for outcomes with extreme heterogeneity. For ARR, meta-analysis was precluded due to EID definition variability (5-8 weeks), inconsistent reporting (7 calculation methods), and missing data. Median ARR difference was 0.00 (range −0.05 to +0.01).
Sensitivity analyses assessed robustness. Evidence certainty was evaluated using GRADE (24) (Supplementary Table 4).
2.10 Software
We used Zotero, Rayyan QCRI (17), R statistical software (25) with the meta package (26), and LibreOffice/Word for data management and analysis.
3. Results
3.1 Study Selection
Our systematic search identified 1,338 records (1,316 from databases and 22 from trial registries), with an additional 12 records found through citation searching. After removing 297 duplicates, 1,041 titles and abstracts were screened, of which 818 were excluded for irrelevance.
We assessed 223 full texts from databases/registries and 12 from citation searches. Nine full texts (7 database/register, 2 citation) could not be retrieved. Of the remaining 225 reports, 199 (189 database/register and 10 citation) were excluded due to ineligible study design, population, intervention, or outcomes.
Ultimately, 28 studies met inclusion criteria (27 from databases/registries, 1 from citation searching). The PRISMA 2020 flow diagram (18) (Figure 1) summarizes the selection process, and excluded studies are listed in Supplementary Table 2.
3.2 Study Characteristics
The 28 included studies (2015–2025) comprised 3 randomized controlled trials (RCTs), 24 observational studies (prospective and retrospective cohorts), and 1 case series. Across all studies, the total sample size was 45,803 participants, although one large registry (Ryerson et al. (27), n=35,521) heavily influenced this number. Studies were conducted in single-country or multinational settings across Europe, North America, the Middle East, and Australia.
Two primary comparisons were addressed:
- Standard-Interval Dosing (SID) vs Extended-Interval Dosing (EID) of natalizumab, with EID definitions ranging from >5 weeks to 8-week intervals.
- Outcomes after cessation of natalizumab.
The key reported outcomes were annualized relapse rate (ARR), disability progression (EDSS worsening), NEDA-3, PML incidence, and post-cessation outcomes (relapse rates, time to relapse, and EDSS worsening). Funding was disclosed for 22 trials, with 10 getting industrial support, largely from Biogen. Table 1 summarizes the detailed study characteristics, including the baseline demographics.
TABLE 1.Characteristics of Included Studies
3.3 Risk of Bias
RCTs (n=3) were evaluated using ROB 2 (19): two were judged low risk, while one raised some concerns due to deviations from intended interventions.
Non-randomized studies (n=24) were assessed with ROBINS-I (20): 20 had moderate risk and 4 serious risk.
Confounding and missing data were the most common sources of bias. A case series (37) assessed with the JBI checklist was deemed moderate risk. Full risk-of-bias judgments are provided in Supplementary Table 1 and Supplementary Figures 1A and 1B.
3.4 Synthesis of Results
Feasibility of quantitative meta-analysis was pre-assessed for each outcome based on clinical and methodological homogeneity (Supplementary Table 3).
3.4.1 SID vs EID: Efficacy Outcomes (ARR)
Thirteen studies reported ARR, of which 9 provided data suitable for descriptive synthesis. ARR values were consistently low across both dosing strategies (range: 0.0006–0.14).
Based on the direction of point estimates, four studies reported a lower ARR with EID, three reported a lower ARR with SID, and two reported identical or nearly identical ARR between groups.
- The median ARR difference (EID – SID) was 0.000 (range –0.050 to +0.014).
- Pelle 2023 (45) was the only study allowing formal IRR estimation (IRR 0.44; 95% CI 0.16–1.26), showing no significant difference.
Table 3A summarizes ARR outcomes. Meta-analysis was not possible due to heterogeneity in EID definitions, outcome reporting, and lack of raw event data.
Table 3A:ARR Comparison: Study Characteristics and Reported Outcomes
Figure 2.
Annualized Relapse Rate (ARR) Values by Study (Narrative Synthesis).
Figure 3.
Annualized Relapse Rate (ARR) Comparison: SID vs EID across the included studies.
Summary: Both SID and EID maintained very low relapse activity. No strategy consistently outperformed the other.
3.4.2 SID vs EID: Disability Progression and NEDA-3
Heterogeneous outcome definitions and insufficient reporting prevented quantitative synthesis.
- Foley 2022 (34): 24 weeks of reported disability worsening: 92% [SID] vs 90% [EID] progression-free;
- NEDA-3: 163/242 [SID] vs 173/247 [EID].
- Pelle 2023 (45): Unconfirmed EDSS worsening: 13% [SID] versus 11% [EID].
- Riancho 2021 (46): Partial NEDA-3 reporting for EID only. Table 3B presents study-specific outcomes.
Summary: Disability progression and NEDA-3 failure rates were modest across all regimens. The evidence shows equivalency, although comparability was constrained by inconsistent outcome criteria.
Table 3B:Disability Progression and NEDA-3 Outcomes
3.4.3 SID vs EID: Safety Outcome (PML)
Nine studies reported on PML. Given PML typically requires >24 months of natalizumab exposure, we conducted a duration-stratified analysis. The meta-analysis of risk ratio (RR) included three studies reporting PML events, with five additional studies reporting zero events in both arms presented in Table 3C for context (not included in pooled RR calculation).
- Long-term exposure (>24 months): Ryerson et al. 2019 (27) (n=35,521) demonstrated a 94% PML risk reduction with EID (adjusted HR 0.06, 95% CI 0.01–0.44) in JCV-positive patients. Ryerson et al. 2015 (48) person-year analysis (IRR 0.11, 95% CI 0.01–1.99) supported this trend in JCV-positive patients.
- Short-term exposure (<24 months): Butzkueven et al. 2020 (30) (median ∼2 years) reported two PML cases in each group (SID n=210, EID n=236). Foley et al. 2022 (34) (72 weeks) reported one asymptomatic PML case in EID (n=247) and none in SID (n=242).
Primary pooled analysis (3 studies with events): RR 0.70 (95% CI 0.20–2.54), I²=0%. Sensitivity analysis (excluding Foley 2022 asymptomatic case): RR 0.54 (95% CI 0.13–2.17). The pooled estimate was attenuated by inclusion of short-term studies with limited events and variable follow-up. Table 3C summarizes study-level PML data with exposure duration.
Table 3C:PML Incidence in Patients on Standard-Interval Dosing (SID) vs. Extended-Interval Dosing (EID)
Summary: While the pooled analysis showed no significant difference in PML risk (RR 0.70), long-term data from Ryerson et al. (27) demonstrated substantial PML risk reduction with EID (94%) in patients with prolonged exposure. This discrepancy highlights limitations in meta-analyzing rare events without accounting for treatment duration. Ongoing monitoring remains warranted, particularly for long-term users.
Figure 4:
Forest Plot of PML Risk: SID vs EID (Main Analysis).
Supplementary Figure 2: Forest Plot of PML Risk is also provided which includes Sensitivity Analysis Excluding Foley et al. 2022 (34).
3.4.4 Outcomes After Cessation: Relapse and Disability
Four studies (n=857) reported the proportion of patients relapsing within 12 months post-cessation. This was meta-analyzed as a pooled proportion (absolute risk).
- Pooled proportion of patients relapsing: 37.6% (95% CI 34.4–40.9%).
- Heterogeneity: I²=66.1%, largely due to Weinstock-Guttman 2016 (52) (59.3%). Excluding this outlier reduced I² to 0%, with minimal change in pooled estimate (35.2%).
EDSS worsening rates post-cessation were highly variable (19–100%). Excluding the outlier study (González-Suarez et al., 2017 (37), n=4), the weighted mean was 23.1%. Median time to first relapse ranged from 3-9.8 months, clustering within the first 6 months.
Table 3D summarizes cessation outcomes.
Table 3D:Outcomes After Natalizumab Cessation
Summary: Natalizumab cessation was associated with a high absolute risk of relapse (≥1/3 relapsing within 12 months) and frequent EDSS worsening, with most relapses occurring early.
Figure 5.
Forest plot of the proportion of patients relapsing within 12 months after natalizumab cessation (random-effects model).
Figure 6.
Timeline of median/mean time to first relapse across studies reporting this outcome.
Figure 7.
Bar plot of EDSS worsening rates after cessation. The weighted mean excluding the outlier (37) was 23.1%.
3.5 Sensitivity Analyses
Leave-one-out analyses confirmed robustness of pooled results for both PML risk and cessation relapse rates. Exclusion of single studies influenced heterogeneity but not overall interpretation (Supplementary Table 5).
3.6 Reporting Bias
Publication bias could not be formally assessed as each outcome had fewer than 10 studies, insufficient for funnel plots or statistical testing.
3.7 Certainty of Evidence (GRADE)
Certainty of evidence for each outcome is summarized in Supplementary Table 4:
- SID vs EID:
- ARR = Low (risk of bias, inconsistency)
- Disability progression = Very Low (bias, inconsistency, indirectness)
- PML = Low (bias, imprecision)
- NEDA-3 = Low (bias, imprecision, single study)
- utcomes After Cessation:
- Relapse = Low (bias, heterogeneity)
- EDSS worsening = Very Low (bias, inconsistency, imprecision)
The evidence for PML risk reduction was upgraded from Very Low to Low for long-term users (>24mo) based on the large effect size (94% reduction) in Ryerson 2019.
4. Discussion
4.1. Interpreting the Results
This systematic review presents a complete synthesis of evidence comparing standard-interval dosing (SID) with extended-interval dosing (EID) of natalizumab in RRMS, including outcomes after treatment discontinuation. Our analysis includes 28 trials totaling 45,803 participants. The evidence showed significant clinical and methodological variation, which influenced our analytical approach.
The efficacy outcomes for SID vs. EID were similar in direction but varied in reporting. Across nine trials reporting ARR, the median difference (EID – SID) was zero. The point estimates fluctuated, with no clear trend favoring one technique over another. These findings indicate that EID provides relapse control comparable to SID. Similarly, when disability progression and NEDA-3 results were reported, they were modest and similar between groups, despite the limitations of different classifications.
The safety outcomes, specifically PML incidence, were meta-analyzed across the three studies that recorded occurrences. The pooled risk ratio was 0.70 (95% confidence interval: 0.20–2.54). While our point estimate shows that EID may reduce PML risk, the confidence intervals are broad and can account for both clinically significant benefit and harm. The frequency of PML episodes, combined with the observational nature of the evidence, limits the certainty of this discovery. Our pooled PML estimate (RR 0.70) conflicts with Ryerson 2019’s 94% reduction because meta-analysis of rare events is highly sensitive to study duration. When restricted to long-term users (>24mo), EID shows significant PML risk reduction, supporting its use in JCV+ patients with prolonged exposure.
The outcomes upon cessation were evident. The pooled proportion of patients relapsing within 12 months was 37.6%, indicating a substantial absolute risk of illness reactivation following natalizumab withdrawal and emphasizing the importance of proactive transition programs.
4.2. Limitations of the Evidence
Key limitations include predominance of observational studies, heterogeneity precluding meta-analysis for some outcomes, and imprecise PML estimates due to rare events. Residual confounding cannot be excluded.
4.3. Limitations of the Review Procedure
Our review followed PRISMA 2020 guidelines (15). However, several limitations should be acknowledged. The search was restricted to studies published after 2015 and in English, which may have induced bias. Due to heterogeneity in outcome definitions, narrative synthesis was required for the majority of efficacy outcomes.
Finally, the small number of papers for each outcome limited our formal assessment of publication bias. The inclusion of one study from late 2014 (published in 2015) is a minor change from the protocol, stated for transparency.
4.4 Implications for Practice and Research
Clinical implications: For patients with stable RRMS, EID (≤8 weeks) may provide a reasonable balance of efficacy and convenience. However, the choice to lengthen dose intervals should be made on an individual basis. PML risk should not be the primary reason for switching to EID, as the evidence is still equivocal. Our findings highlight the importance of starting alternative therapy as soon as possible for patients who have stopped using natalizumab.
Future research should focus established criteria for EID and outcomes, large prospective registries with adjusted confounders, RCTs powered by clinical outcomes, and comparative efficacy research on post-cessation interventions.
5. Conclusion
This systematic review compiles data from 28 studies on natalizumab dosing and discontinuation in relapsing-remitting multiple sclerosis. It suggests that extended-interval dosing (EID; up to 8 weeks) may maintain relapse control comparable to standard-interval dosing (SID) (low certainty evidence). For PML risk reduction, long- term registry data (Ryerson 2019) suggest potential benefit with EID in patients with prolonged exposure, but short-term evidence remains inconclusive. The discontinuation of natalizumab is associated with a significant absolute risk of disease reactivation, with a pooled 37.6% of patients relapsing within 12 months (low certainty evidence).
In clinical practice, these findings indicate that EID might be considered for stable patients, primarily for convenience reasons, but should not be adopted solely for PML risk reduction given current evidence limitations. The high relapse risk following cessation underscores the critical need for prompt initiation of alternative therapy. Treatment decisions should be individualized, considering patient-specific factors and preferences, and based on ongoing risk-benefit assessment. Future research should focus on prospective studies with consistent outcome definitions, larger sample sizes, and longer follow-up to definitively establish the risk- benefit profile of EID, particularly regarding PML risk reduction.
6. Statements and Declarations
6.1 Competing Interests
The authors declare that they have no competing interests.
6.2 Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
6.3 Ethics Approval and Consent to Participate
Not applicable. This study is a systematic review and meta-analysis of previously published data.
6.4 Consent for Publication
Not applicable.
6.5 Availability of Data and Materials
All data analyzed in this study were obtained from previously published sources. No new datasets were generated or analyzed during the current study.
6.6 Author Contributions
All authors contributed to the conception, study design, data extraction, analysis, interpretation, and drafting of the manuscript. All authors read and approved the final version of the manuscript.
Data Availability
All data analyzed in this study are extracted from previously published studies and are included in the manuscript and Supplementary Files.
Acknowledgments
Not applicable.
Footnotes
- Revised parts, More Novelty clarification, Precision of the Manuscript, Correction in the Reference list.
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