Is the risk of progressive multifocal leukoencephalopathy the real reason for natalizumab discontinuation in patients with multiple sclerosis?

Abstract

BackgroundProgressive multifocal leukoencephalopathy (PML) is one of the major risks of natalizumab therapy. Despite introduction of the currently employed PML risk stratification algorithm, the incidence of natalizumab-associated PML cases is not decreasing.ObjectivesWe addressed the following questions: How do natalizumab-treated multiple sclerosis patients and their treating physicians assess and deal with PML risk? Is PML risk the real reason for natalizumab discontinuation?Methods699 natalizumab-treated multiple sclerosis patients and 99 physicians were included in this prospective observational study. Questionnaires were completed at 5 different time points. Patients were stratified into 5 subgroups according to the presence of PML risk factors (prior immunosuppression, anti-JCV antibody status, treatment duration). Patients with prior immunosuppression (n = 30, treated by n = 7 physicians) were excluded from analyses, because patient numbers were too small. Patients’ anti-JCV antibody index was not considered because data recruitment ended in 2014. Using Bayesian network and regression analysis, we examined the relationship between different patient- and physician-related factors and patients’ discontinuation of natalizumab.ResultsPatients of all subgroups and physicians assessed the PML risk as low. Overall patient adherence to natalizumab was high (87%). Only 13% of patients discontinued therapy. Natalizumab treatment cessation was associated with different patient- and physician-related factors (physicians’ assessment of general PML risk, number of treated patients per year, natalizumab treatment duration, relapses during the course of study) upon which only physicians’ judgment on treatment continuation, patients’ perception of personal PML risk, and JCV seroconversion showed significant relationships.ConclusionAccording to the currently employed risk stratification algorithm, the objective PML risk probably doesn’t play a dominant role in a patients’ decision to continue or stop natalizumab treatment. The decision-making process is rather guided by subjective views and experiences of patients and treating neurologists. Treating physicians should consider this discrepancy in their advice to improve the risk-benefit-ratio for the individual patient.

Progressive multifocal leukoencephalopathy in Finland: a cross-sectional registry study

“…PML may also ensue from treating multiple sclerosis (MS) with natalizumab, dimethyl fumarate, fingolimod or ocrelizumab [ 3 ]. Of these, the highest risk is associated with natalizumab, the benefits of which patients, neurologists, scientists and the industry may overestimate and PML risk underestimate [ 2 , 9 – 13 ]. In Finland, the use of disease modifying treatments (DMTs) has increased and MS-hospitalizations markedly declined from 2004 to 2014 but the proportion of MS admissions with an infection as the primary diagnosis increased, suggesting a trade-off between benefits and harms [ 14 ].…”

Exploring the Cost Effectiveness of Shared Decision Making for Choosing between Disease-Modifying Drugs for Relapsing-Remitting Multiple Sclerosis in the Netherlands: A State Transition Model

“…[15][16][17]46 Therefore, discontinuation rates were based on real-world data, defined as more than 90 days' interruption in treatment with the chosen DMD measured using pharmacy records. [15][16][17] No data were available for ocrelizumab and alemtuzumab. Discontinuation rates were therefore determined based on the rate of natalizumab, proportionately according to differences found in trial discontinuation rates between 28,40 Mortality risk within each health state was the same for RRMS and SPMS.…”

“…19 Real-world studies in RRMS show that discontinuation rates in the first year after DMD treatment initiation range between 10% and 31%. [15][16][17] Of the people who do persist, only 60% of patients taking injectable or orally administered DMDs were reported to have optimal adherence. 14 Shared decision making is an approach that can help explicitly to integrate informed patient's preferences for treatment options into clinical decisions.…”

“… 13 Third, persistence with and adherence to treatment regimens are suboptimal among many patients. 14 – 17 Treatment persistence refers to “the length of time between initiation and the last dose, which immediately precedes discontinuation,” with discontinuation referring to the patients stopping the medication. 18 With treatment adherence, we refer to the “implementation” component according to the taxonomy by Vrijens et al 18 : “the extent to which a patient’s actual dosing corresponds to the prescribed dosing regimen, from initiation until the last dose.” 19 Real-world studies in RRMS show that discontinuation rates in the first year after DMD treatment initiation range between 10% and 31%.…”

Early diagnosis of progressive multifocal leucoencephalopathy: longitudinal lesion evolution

“…To date, the majority of research has focused on risk stratification with the aim of closely monitoring patients at high risk of developing PML 5–9. In this population, clinicians often prefer to interrupt NTZ therapy rather than address this potentially severe adverse event 10 11. Moreover, NTZ discontinuation is linked to MS pathology resumption, which occurs a few months after the end of the treatment 12.…”