Risk-Benefit Analysis Helps Determine Multiple Sclerosis Therapy

woman patient doctor
woman patient doctor
Despite an elevated risk of PML, treatment with natalizumab results in slower disease progression than other treatments.

A new study published in Neurology1 suggests that natalizumab (NTZ) has the “highest benefit” compared with other multiple sclerosis (MS) disease-modifying drugs when measured across a complete risk-benefit framework.

NTZ and fingolimod (FGL) are among the newer drugs to have shown greater efficacy than previous generations of MS therapies, including gold standard treatments like interferon beta 1a and glatiramer acetate (GA).2 These benefits, however, are at the cost of serious, life-threatening adverse effects, most notably progressive multifocal leukoencephalopathy (PML), a rare, often fatal viral infection of the brain.2

The current study was designed to compare efficacy against projected risk of PML for 3 commonly used MS agents: NTZ, FGL, and GA. The investigators used a Markov state transition model to design a retrospective head-to-head comparison of the 3 study drugs. Efficacy was evaluated by disease worsening over a 30-year period, quantified by changes in Expanded Disability Status Scale (EDSS) scores. Outcomes from disease progression were measured against potential outcomes from PML (using annual probability risk calculations), including death and disability.

Despite high mortality risks posed by PML, NTZ was predicted to offer greater “net benefit” compared with both FGL and GA in patients without prior immunosuppression, largely due to its impact on slowing disease progression. In sensitivity analyses, NTZ consistently conferred maximum increases in quality-adjusted life years (QALYs) over 30 years for high, medium, and low risks of PML, as well as across the full range of changes in EDSS scores and their associated mortality rates.

Mortality with NTZ was highest in patients with high PML risk in the first 4 years of treatment and in patients with medium PML risk in the first 13 years of treatment, resulting in a modest reduction of 1.03 QALYs over 30 years. This trend reversed in favor of NTZ with increasing years of treatment. The investigators noted that their presumption of a stable PML risk in the study most likely resulted in overestimating early risk and underestimating later risk.

In a hypothetical model of a 30-year-old woman with relapsing remitting MS with a high risk of PML, NTZ was associated with a predicted increase of 15.06 QALYs, compared with 13.99 for FGL and 12.71 for GA over 30 years. It also showed a longer time to severe disability (measured as EDSS >6 or the need for walking assistance) with NTZ compared with FGL and GA (22.7 years vs 17.0 and 12.4 years, respectively). After 20 years of NTZ treatment, the risk profile for the hypothetical patient showed a 16% improvement in QALYs, accompanied by a 15% future risk of PML and a 22% risk of mortality from all causes.

The risk-benefit analysis model provides a practical decision-making tool for patients and physicians to select an MS agent that most suits the patient’s disease state and comfort with risk profiles.

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  1. Bargiela D, Bianchi MT, Westover MB, et al. Selection of first-line therapy in multiple sclerosis using risk-benefit decision analysis [published online January 13, 2017]. Neurology. doi: 10.1212/WNL.0000000000003612
  2. Filippini G, Del Giovane C, Vacchi L, et al. Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2013;6:CD008933.