Patients With Multiple Sclerosis Experience a Wearing-Off Effect During Natalizumab Treatment

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older person using walker
More than half of patients with multiple sclerosis experienced a wearing-off effect during treatment with natalizumab.

More than half of patients with multiple sclerosis (MS) experienced a wearing-off effect during treatment with natalizumab, according to study results published in Neurology.

As the major disadvantage of natalizumab is the risk of developing progressive multifocal leukoencephalopathy, many experts extend the intervals between treatment cycles in the hope that minimizing the exposure to the medication would hypothetically reduce the risk for this complication. Conversely, studies have reported that natalizumab-treated patients might have recurrence of their symptoms before their next infusion, pointing to a wearing-off effect.

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The goal of the current study was to explore the prevalence of the wearing-off effect in patients with relapsing-remitting multiple sclerosis (RRMS) and assess the importance of pharmacokinetic/pharmacodynamic measurements and patient characteristics.

The study participants were recruited from the VU University Medical Center in the Netherlands. The researchers focused on adult patients with RRMS who received at least 6 consecutive infusions of natalizumab. The standard treatment interval (SID) was 4 weeks, but there were also patients who received extended interval dosing (EID), with infusions given every 5 to 7 weeks.

The patients were asked to complete 3 questionnaires: the Multiple Sclerosis Impact Scale, the 36-Item Short Form Health Survey, and a questionnaire regarding the patient’s experience of a wearing-off effect either at time of blood sampling or in the past during natalizumab treatment. The participants filled the questionnaires twice: in the hospital just before the infusion, and at home a week after the infusion.

The study enrolled 93 patients, of whom 50 patients (54%) reported the wearing-off effect during natalizumab treatment. Recurrent wearing-off effect at the time of blood sampling was evident in 30 patients (32%).

There was no linear association between natalizumab concentration or α4-integrin saturation with the reporting of a current wearing-off effect. In the SID group (n=62), natalizumab concentration (29.0 vs 19.0 µg/mL, respectively; P =.23) and α4-integrin saturation (75.8%±12.0% vs 72.3±12.8%, respectively; P =.34) were higher in patients without a current wearing-off effect, but the difference was not statistically significant.

The wearing-off effect was more frequent in the SID group compared with the EID group (39% vs 19%, borderline significance; P =.060). Both the natalizumab trough concentration and the α4-integrin saturation were significantly higher in the SID compared with the EID group. The duration of the wearing-off effect in EID patients was comparable with the wearing-off effect of SID patients.

There was no significant difference in age, sex, disease duration, or treatment duration between the groups with and without a current wearing-off effect.

The researchers noted several study limitations, including the cross-sectional design and small sample size.

“The wearing-off effect is a frequently reported phenomenon but does not reflect a nonoptimal pharmacodynamics/kinetic state. We could not identify risk factors predicting the experience of a wearing-off effect and extended treatment intervals do not result in longer duration of the wearing-off effect,” conclude the researchers.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


van Kempen ZLE, Doesburg D, Dekker I, et al. The natalizumab wearing-off effect: end of natalizumab cycle; recurrence of MS symptoms [published online, September 24, 2019]. Neurology. doi:10.1212/WNL.0000000000008357