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Science News: High Prevalence of Neutralizing Antibodies After Long-term Botulinum Neurotoxin Therapy

Submitted by: Bryan X. DeSouza, MD
Edited by: Hristelina Ilieva, MD, PhD

Albrecht P, Jansen A, Lee J, Moll M, Ringelstein M, Rosenthal D, Bigalke H, Aktas O, Hartung H, Hefter H. High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy. Neurology 2019;92:e48-e54. 

Summary: A single center large observational cross-sectional study of 596 patients was performed by Albrecht et al. to determine the prevalence of neutralizing antibodies (NAbs) against botulinum neurotoxin type A (BoNT/A) in long-term BoNT/A treatment for different neurologic indications including hemifacial spasm, blepharospasm, cervical and other dystonias, as well as spasticity. Their study was designed to analyze the probability of remaining NAb negative with the duration of treatment and identifying factors contributing to the induction of NAbs.

At the Heinrich Heine University Neurology clinic, 596 patients were recruited from 2013-2014. The inclusion criteria was as follows: patients were injected for standard indications of dystonia and spasticity and received 4 Botox injections over 1 year. Testing for NAbs was standardized and blinded for binding antibodies and neutralizing antibodies. Data from this cohort was analyzed to determine effects from indications/anatomical sites in 5 subgroups: facial hemispasm (FHS), blepharospasm (BSP), cervical dystonia (CD), other dystonia types (ODT) and spasticity. The effects of the duration of injection therapy and dose level per injection using unified dose units for the different products [abo-BoNT/A (Dysport), ona-BoNT/A (Botox) and inco-BoNT/A (Xeomin)] were also assessed. 
Results: 83 of 596 patients (13.9%) had measurable NAbs. Except for FHS, all other subgroups tested positive for NAbs. Kaplan-Meier analysis was performed, and in all subgroups, the curve declined over time, suggesting a nonlinear increase in conversion to NAb positivity with longer durations of treatment. The curves of the ODT, CD, and spasticity subgroups suggest that patients with these indications and duration of treatment of ≈15 years have a risk of up to 30% to 40% to become NAb positive.
The influence of doses on NAb induction was assessed. Their data shows that the probability of developing NAbs increases with the duration of treatment, is dose-dependent, and is significantly higher in patients having received mean doses of >350 uDU
A stepwise regression analysis was performed. The main influence on NAb induction was the BoNT/A formulation followed by single dose per session (p < 0.01 and p = 0.023, respectively). No additional significant influence was revealed for cumulative lifetime dose, disease entity, or treatment duration.

Comment: Our understanding of the immune system and our ability to manipulate its responses as a therapeutic tool to enhance or suppress immune responses are rapidly evolving. The long term effects of hybridized immunobiologic treatments, reconstitution of the immune system for oncologic therapy and the immunologic responses to medical toxins all have unintended consequences in the neuromuscular system but are poorly understood.

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