Efficacy and Safety of Extended-interval Dosing of Natalizumab in Multiple Sclerosis: A Systematic Review and Meta-analysis With Subgroup Evaluation
Bara Hammadeh1, Sadeen Eid2, Mohammed Alnajjar2, Issam Abu-Issa2, Mohammed Alhallaq3, Mustafa Ghazi2, Ahmed Badr4, Mays Shawawrah5
1Al-Balqa' Applied University, 2Jordan University of Science and Technology, 3Mansoura University, 4Department of General Surgery, Hamad Medical Corporation, 5Kingston Health Sciences Centre
Objective:
This meta-analysis and systematic review will compare EID and SID in major clinical and radiological outcomes, with particular emphasis placed on the effects of various dosing intervals. 
Background:
Natalizumab is an effective drug of relapsing-remitting multiple sclerosis (RRMS) but has a risk of progressive multifocal leukoencephalopathy (PML). Extended interval dosing (EID) has been suggested to help alleviate this risk with lowered annual drug exposure, but its relative effectiveness and safety compared to conventional interval dosing (SID) needs to be thoroughly evaluated.  
Design/Methods:

The systematic search was performed according to the PRISMA guidelines and included databases containing studies comparing EID (5-12 weeks) to SID (4 weeks) of natalizumab in MS patients. Relapse, disability progression (with the EDSS), radiological activity (Gadolinium-enhancing and T2 lesions) and PML data were mined. The possibility of bias was evaluated with the help of the ROB 2 and ROBINS-I tools. Random- or fixed-effects models were used to conduct meta-analyses based on the heterogeneity (I2 statistic), and the results were presented in the form of risk ratios (RR) or mean differences (MD). 

Results:

Twenty-five studies were included. Disability progression (MD -0.09, 95% CI: -0.46 to 0.29), PML incidence (RR 1.03, 95% CI: 0.29 to 3.60), and the risk of new T2 lesions (RR 1.24, 95% CI: 0.96 to 1.61) did not have significant differences between EID and SID. EID was linked with statistically significant decrease in risk of clinical relapse (RR 0.91, 95% CI: 0.83 to 1.00). Subgroup analysis demonstrated that shorter EID periods (5-8 weeks) have superior radiological control in comparison with longer ones (>8 weeks), which shows that efficacy is interval-dependent. 

Conclusions:

EID natalizumab has the same efficacy and safety profile as SID with the possibility for reduced risk relapse. 6-week dosing interval might have an optimal balance between efficacy-safety. 

10.1212/WNL.0000000000213175
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