Editors' note: High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy

Abstract

In the article “High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy,” Albrecht et al. investigated the prevalence of neutralizing antibodies (NAbs) against botulinum neurotoxin type A (BoNT/A) in a monocentric, observational cross-sectional study of 596 outpatients treated with BoNT/A over a mean of 5.3 years for different indications and found that 13.9% had measurable NAbs. The probability of developing NAbs increased with the single and cumulative dose of treatment and was associated with the BoNT/A formulation used, leading the authors to recommend avoiding booster injections and reducing the individual injected doses. In response, Dr. Jankovic notes that the authors did not mention other studies that showed a much lower frequency of NAbs, although after shorter periods of observation, and indicates that no data were provided regarding any correlation between the presence of NAbs and clinical response. In this regard, Dr. Jankovic notes that none of the patients in a previous study with blocking antibodies identified by the mouse protection assay (MPA) had any clinical response, suggesting that the MPA may be more clinically meaningful. In their reply, Albrecht et al. postulate that lower rates of NAbs in previous studies may relate to lower sensitivity of the MPA, lower BoNT doses used, and substantially shorter duration of treatment. In contrast to Dr. Jankovic's findings, they report that all their patients with NAbs opted to continue treatment and reported ongoing subjective benefit. Both the authors and Dr. Jankovic agree on the need for novel assays with higher sensitivity and specificity that are (ideally) not animal based. In another response, Mulroy et al. caution that the authors' conclusions may mislead readers into thinking that long-term treatment with frequent or repeated BoNT injections can result in clinical treatment failure. Like Dr. Jankovic, they too highlight the absence of data on clinical effectiveness in this study and note that NAb serostatus did not always correlate with clinical response in previous studies. They also seek to clarify the authors' disclosures, given that the study was funded by Merz Pharmaceuticals, which manufacturers one of the BoNT formulations studied. Replying to these comments, Albrecht et al. argue that there is consensus that the induction of NAbs should be avoided, as they are associated with reduced treatment response in several studies. They acknowledge that they do not have information about NAb induction with treatment intervals shorter than 10 weeks in their study, note the difficulty of comparing treatment efficacy across different indications, and concede that efficacy data were not available for all patients. They also state that pharmaceutical funding had no influence on the interpretation or analysis of their data. This correspondence highlights enduring uncertainty in the field regarding the clinical implications of NAbs as detected by existing animal-based assays. In the special article “Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis,” Rae-Grant et al. reported the findings of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology based on reviewing the evidence on starting, switching, and stopping disease-modifying therapies for clinically isolated syndrome, relapsing-remitting MS, and progressive forms of MS. In response, Dr. Tran, on behalf of Genentech, argues that the report did not make it clear that data on annualized relapse rate reduction and relative risk of in-study disability progression for ocrelizumab (presented along with other therapies in figures 1 and 3) were from direct comparisons with subcutaneous interferon-β-1a 44 μg 3 times weekly in 2 phase 3 randomized, double-blind, double-dummy trials. In response, Dr. Rae-Grant agrees that this information should have been included, but notes that statements in the text of the summary and in a key accompanying table acknowledged the superior efficacy of ocrelizumab compared with interferon- β-1a 3 times weekly. Dr. Rae-Grant also notes that data on subgroup analysis of treatment of highly active MS with ocrelizumab were not available at the time of publication of the systematic review.