Many patients with dystonia or spasticity who receive botulinum neurotoxin type A (BoNT/A) develop neutralizing antibodies (NABs) to the toxin over time, new research shows.
NABs against BoNT/A occur at “surprisingly high rates” during long-term treatment. The incidence was around 14% in the entire cohort of 596 patients but was considerably higher for patients who had been receiving continuous treatment for more than 10 years, Philipp Albrecht, MD, from Heinrich Heine University in Dusseldorf, Germany, told Medscape Medical News.
“The main factors driving the generation of antibodies seem to be the dose and the duration of treatment, suggesting that to avoid antibodies, physicians should try to keep the doses as low as possible,” he said.
The study was published online November 21 in Neurology.
Unique Study Sample
Previous studies on the prevalence of NABs in BoNT-treated patients typically focused on single indications or on patients who had experienced secondary treatment failure. Albrecht and colleagues investigated the prevalence of NABs in patients who had received BoNT/A injections for several different indications and who were still responding to treatment.
The cohort included 408 patients with cervical dystonia, 47 with facial hemispasm, 54 with blepharospasm, 52 with other dystonia, and 33 with spasticity.
Altogether, 83 (14%) of the 596 patients tested positive for NABs. Sixty-four patients with cervical dystonia (16%) developed the antibodies, as did three patients (6%) with blepharospasm, nine (17%) with other dystonia (including Meige syndrome), and five (15%) with spasticity. None of the patients with facial hemispasm developed NABs.
The development of NABs increased over time. A Kaplan-Meier analysis of patients with cervical dystonia, spasticity, and other dystonias revealed that after about 15 years of treatment, the risk of developing NAB was 30% to 40%; for patients with blepharospasm, the risk was about 15%.
According to the results, the probability of developing NABs increases with the duration of treatment, is dose-dependent, and is significantly higher for patients who receive mean doses of >350 uDU compared to those who receive mean doses of <350 uDU (P < .003).
Patients treated with >700 uDU are at the highest risk, the authors say, despite reinjection intervals of 12 to 13 weeks. “Therefore, the dose per injection session should be kept as low as possible to avoid clinically relevant immunization in BoNT/A–treated patients. Therefore, the recent trend of using high doses per session for the treatment of spasticity may come at the cost of higher rates of NAB-positive patients,” they write.
The formulation of the drug also seems to be relevant to NAB induction. Most patients (n = 324) received abo-BoNT/A, 68 received ona-BoNT/A, and 46 received inco-BoNT/A. An additional 158 people received more than one formulation of the drug.
Six percent of the patients who received abo-BoNT/A developed antibodies, as did 7% of those who received ona-BoNT/A. By contrast, none of the patients who received only inco-BoNT/A developed antibodies.
“Our finding that incobotulinumtoxin treatment seems to be associated with less neutralizing antibodies needs to be interpreted with caution, as the follow-up time of our incobotulinumtoxin patients was significantly shorter than for the other two toxins,” Albrecht told Medscape Medical News. “Further studies with longer follow-up times of incobotulinumtoxin-treated patients are needed to further address this point.”
The authors note that the study “adds missing information on the clinically relevant problem of NAB induction in BoNT/A long-term therapy.”
Funding for some of the tests used in the study was provided by a grant from Merz Pharmaceuticals. Dr Albrecht has disclosed no relevant financial relationships.
Neurology. Published online November 21, 2018. Abstract