Title | Antibody Development in Patients Treated Long-Term With OnabotulinumtoxinA for Benign Essential Blepharospasm and Hemifacial Spasm |
Creator | Craig N. Czyz, DO; John A. Burns, MD; Reece E. Bergstrom, DO |
Affiliation | Division of Ophthalmology (CNC, RB), Section Oculofacial Plastic and Reconstructive Surgery, Ohio University/Ohio Health Doctor's Hospital, Columbus, Ohio; and Department of Ophthalmology (CNC, JAB), Oral and Maxillofacial Surgery, Grant Medical Center, Columbus, Ohio. |
Abstract | Report the development of onabotulinumtoxin-A neutralizing antibodies in patients treated consecutively for 20 years or longer for benign essential blepharospasm (BEB), hemifacial spasm (HFS), and Meige Syndrome. |
Subject | Benign Essential Blepharospasm; Hemifacial Spasm; Meige Syndrome |
OCR Text | Show Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Antibody Development in Patients Treated Long-Term With OnabotulinumtoxinA for Benign Essential Blepharospasm and Hemifacial Spasm Craig N. Czyz, DO, John A. Burns, MD, Reece E. Bergstrom, DO Background: Report the development of onabotulinumtoxinA neutralizing antibodies in patients treated consecutively for 20 years or longer for benign essential blepharospasm (BEB), hemifacial spasm (HFS), and Meige Syndrome. Methods: Prospective, randomized, cross-sectional study of 12 randomly selected patients from a single clinical practice that have been treated consecutively for 20 or more years with onabotulinumtoxinA for BEB, HFS, or Meige Syndrome. Serum samples were collected from each subject and analyzed for neutralizing antibody formation using the Mouse Protection Assay. Results: None of the tested patients (0%) displayed neutralizing antibodies to onabotulinumtoxinA. The mean duration of treatment was 27.5 years (range 22.1–34.1, SD 3.1, 95% confidence interval 25.45–29.50). Nine of the patients had a diagnosis of BEB, 2 HFS, and one Meige. Eleven of the 12 patients were women. There was no statistically significant difference in treatment dosage or interval over the course of treatment. Conclusions: The data support previous studies showing low incidence of antibody formation for botulinum A toxins with this subset of long-term treated patients. The results also provide further evidence for studies that have suggested increased onabotulinumtoxinA treatment volumes and/or decreased intervals between treatments are not due to neutralizing antibody formation and secondary nonresponse, but rather study designs that do not consider the titration phase of initial treatments. This study is specific to long-term treated patients, and the results cannot be generalized to patients naive to treatment. Journal of Neuro-Ophthalmology 2021;41:e684–e687 doi: 10.1097/WNO.0000000000001171 © 2021 by North American Neuro-Ophthalmology Society Division of Ophthalmology (CNC, RB), Section Oculofacial Plastic and Reconstructive Surgery, Ohio University/Ohio Health Doctor’s Hospital, Columbus, Ohio; and Department of Ophthalmology (CNC, JAB), Oral and Maxillofacial Surgery, Grant Medical Center, Columbus, Ohio. The authors report no conflicts of interest. Address correspondence to Craig N. Czyz, DO, Division of Ophthalmology, Section Oculofacial Plastic Surgery, Ohio University/ OhioHealth, 1100 Oregon Avenue, Columbus, OH 43201; E-mail: dsp4000@aol.com e684 A n issue with many protein-based therapeutics is immunogenicity. Immunogenicity is the ability of a molecule or substance, such as protein, to provoke an immune response and ultimately elicit antibody formation. Secondary nonresponse occurs when a previously effective treatment no longer produces clinical results. A primary cause of secondary non-response is neutralization by antibodies, although subjective patient expectations and placebo effect are also potential causes (1). Development of antibodies and subsequent secondary nonresponse is seen is many therapeutic drugs (2). Because many commercially available botulinum neurotoxin (BoNT) preparations contain nonhuman proteins, they may act as antigens and elicit antibody formation when injected into a patient creating secondary nonresponse effects (3). There are 2 types of antibodies involved with BoNT immunogenicity: neutralizing (nAb), that bind to the heavy chain of the core BoNT; and non-neutralizing, that bind to the epitope on all regions of the core BoNT (3). If sufficient amounts of antibodies develop, biological activity of the BoNT can be inhibited reducing clinical response. The development of nAb have been shown to be directly proportional to protein load (4–7). However, the presence of nAb does not directly correlate to reduced clinical response of therapy (3). Multiple studies have been published pertaining to the efficacy and safety of BoNT treatment for various neuromuscular disorders (8,9). Studies that focus on the use of onabotulinumtoxinA (Botox, Allergan, Irvine, CA) for treatment of benign essential blepharospasm (BEB), hemifacial spam (HFS), and Meige Syndrome have suggested long-term usage can results in decreased clinical efficacy requiring more frequent injections and/or increased dosage volumes (5,10). Additional studies have suggested that larger dose volumes demonstrated development of nAb, and titrating the dose makes antibody production improbable (5,9). These findings were called into question by a Czyz et al: J Neuro-Ophthalmol 2021; 41: e684-e687 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution study that found no change in dosage interval or volume in patients treated long-term with onabotulinumtoxinA (10). The authors suggested the perceived change in dosage interval and volume was because of study design and data analysis errors, in that researchers did not account for the titration phase of initial treatment. The presence of BoNT antibodies can be determined using various laboratory methods, with the gold standard being Mouse Protection Assay (MPA). Briefly, MPA tests for nAb by determining the ability of sera to prevent the death of mice given a lethal dose of BoNT. There are other types of assays, such as in vitro analyses using enzymelinked immunosorbent assays (ELISA, Western blots, and radioimmunoprecipitation assays), that can provide quantitative estimates of the binding antibody titer against the core neurotoxin. These assays fail to distinguish between neutralizing and non-neutralizing antibodies (11). They are only able to detect antibodies that bind to the core BoNT, which may not lead to a reduced clinical efficacy. The immunogenicity rates reported in literature for all types botulinum A toxin (BoNT/A) products are minimal. However, following individuals with longer continuous treatment periods would help clinicians understand the rates at which patients are likely to develop nAb and secondary nonresponse over time. Previous studies have tested only secondary nonresponders or those who initially were successful with treatment, but later became resistant. This patient series investigates the development of onabotulinumtoxinA antibodies and their effects on clinical response in BEB, HFS, and Meige Syndrome patients treated consecutively for 20 years or longer. selection from a single practice. All patients receiving onabotulinumtoxinA treatment for 20 years or longer for BEB, HFS, or Meige, with a minimum of one treatment per year, were assigned a number in the database. A random number generator was then used to produce 12 values. The randomly generated numbers were then matched to patients in the database and they were invited to participate in the study by the principle investigator. All 12 of the originally selected patients met the inclusion criteria and agreed to participate following review of written informed consent. Serum samples were then collected from each subject and analyzed by an independent laboratory using the MPA protocol as described previously (12). Statistical analysis was conducted with SPSS 20 (IBM Corporation, Somers, NY). It was determined that the use of multiple comparison correction was not required for the data set before analysis. Scaled data were compared using an independent samples t test. All statistical testing was 2-tailed and conducted at the 0.05 alpha level. RESULTS Twelve patients’ serum samples were successfully tested using the MPA method (Table 1). None of the tested patients (0%) displayed neutralizing antibodies to onabotulinumtoxinA. The mean duration of treatment was 27.5 years (SD 3.1, 95% confidence interval [CI] 25.45– 29.50) with a range of 22.1–34.1 years. Treatment duration by BoNT/A formulation was 5.5 years (SD 3.2, 95% CI 3.44–7.47) for 79-11 and 22.0 years (SD 0.04, 95% CI 21.99–22.04) for BCB 2024. Nine of the patients had a diagnosis of BEB, 2 HFS, and one Meige. Eleven of the 12 patients were women. The average BoNT/A dose for the first 5 treatments (fourth–ninth), following the titration phase (first–third), was 75 units (SD 24) vs. the average dose at the last 5 treatments of 71 (SD 26), resulting in a nonstatistically METHODS The study was approved by an institutional review board and written informed consent was obtained from all participants. Patients were recruited by random database TABLE 1. Patient demographics, neurotoxin formulation, treatment duration, and serum assay results Duration of Treatment, yr Botox Formulation Patient ID Gender Diagnosis 79-11 BCB 2024 Total MPA Result 1 2 3 4 5 6 7 8 9 10 11 12 Female Female Female Female Male Female Female Female Female Female Female Female BEB HFS BEB BEB BEB BEB HFS BEB BEB Meige BEB BEB 2.0 8.1 5.0 3.1 4.1 6.0 8.0 4.0 7.0 12.1 0.1 6.0 22.0 22.0 22.0 22.0 22.0 22.0 22.1 22.0 22.1 22.0 22.0 22.0 24.0 30.1 27.0 25.1 26.1 28.0 30.1 26.0 29.1 34.1 22.1 28.0 Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Czyz et al: J Neuro-Ophthalmol 2021; 41: e684-e687 (2) (2) (2) (2) (2) (2) (2) (2) (2) (2) (2) (2) e685 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution significant mean difference of 24 units (SD 12, 95% CI 230 to 21, P = 0.7365) over the course of treatment. The average duration between treatments for the first 5 treatments (fourth–ninth) was 108 days (SD 37) vs. the average duration for the last 5 treatments of 135 days (SD 53). This produced a mean difference in treatment duration of 27 days (SD 22, 95% CI 218 to 73, P = 0.2239) that was not statistically significant. DISCUSSION All of the randomly sampled patients, who had been receiving onabotulinumtoxinA continuously for 22 years or longer, were negative for the presence of antibodies. Furthermore, none of the participants had clinical signs of secondary nonresponse or required dose volume increases or reduced injection intervals following the initial titration phase. The results suggest the development of BoNT/A antibodies do not appear as the result of dose exposure over time. These results further support the findings of studies that have shown no decrease in treatment interval or increase in treatment volume for patients treated for 10 years or longer with BoNT/A for BEB, HFS, or Meige (9,10). The volume increases required for sustained clinical effectiveness as reported in other studies may be because of not accounting for the titration phase of treatment in data analysis, rather than development of nonresponsiveness via the development of antibodies. There is no standard BoNT/ A dosing volume for BEB, HFS, or Meige Syndrome patients; therefore, most clinicians will start at a lower dosing point to avoid unwanted effects. As the dose is titrated over the next 1–3 injections cycles for maximal clinical response, the dose volume increase or treatment interval can be statistically misinterpreted as nonresponse. The negative MPA testing results support previous findings that overall immunogenicity is low and secondary nonresponse is unlikely because of dosing volume and interval. A study of secondary nonresponders to BoNT products showed that less than half (44.5%) of patients tested positive for neutralizing antibodies (13). Multiple studies suggest that failure of treatment or secondary nonresponse has a higher likelihood because of the lack of titrating response, technical issues such as inadequate dosing, and/or failure to identify proper injection sites, that relate to the perceived increase in dosing rather than development of neutralizing antibodies or true secondary nonresponse (9,10). This study is specific to long-term BoNT/A treated patients, and the results cannot be generalized to patients naive to treatment. It is likely that certain individuals develop antibodies to BoNT/A resulting in decreased clinical response earlier in the treatment phase. Decreasing time between treatments or increasing dosing volume may not alter clinical response. Thus, these patients would not be contained in this sample population as they would have e686 stopped receiving treatment long before the 20-year time point. To reiterate, the purpose of this report is not to comment on the overall immunogenicity of BoNT, rather it is to provide additional evidence supporting previous studies that postulated increased treatment dosage or decreased interval do not equate to increased immunogenicity. Those individuals that develop antibodies will likely do so early in the treatment cycle, not in the later phases. This series of patients provides data to support the theory that increased dosage volumes and/or decreased treatment intervals as shown in other studies may be because of study design, rather than an increased immune response to BoNT via formation of nAb and secondary nonresponse. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: C. N. Czyz and J. A. Burns; b. Acquisition of data: C. N. Czyz; c. Analysis and interpretation of data: C. N. Czyz. Category 2: a. Drafting the manuscript: R. Bergstrom and C. N. Czyz; b. Revising it for intellectual content: C. N. Czyz and J. A. Burns. Category 3: a. Final approval of the completed manuscript: C. N. Czyz. REFERENCES 1. Benecke R. Clinical relevance of botulinum toxin immunogenicity. BioDrugs. 2012;26:e1–e9. 2. Wolbink GJ, Vis M, Lems W, Voskuyl AE, de Groot E, Nurmohamed MT, Stapel S, Tak PP, Aarden L, Dijkmans B. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:711–715. 3. Naumann M, Boo LM, Ackerman AH, Gallagher CJ. Immunogenicity of botulinum toxins. J Neural Transm (Vienna). 2013;120:275–290. 4. Borodic G, Johnson E, Goodnough M, Schantz E. Botulinum toxin therapy, immunologic resistance, and problems with available materials. Neurology. 1996;46:26–29. 5. 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Date | 2021-12 |
Language | eng |
Format | application/pdf |
Type | Text |
Publication Type | Journal Article |
Source | Journal of Neuro-Ophthalmology, December 2021, Volume 41, Issue 4 |
Collection | Neuro-Ophthalmology Virtual Education Library: Journal of Neuro-Ophthalmology Archives: https://novel.utah.edu/jno/ |
Publisher | Lippincott, Williams & Wilkins |
Holding Institution | Spencer S. Eccles Health Sciences Library, University of Utah |
Rights Management | © North American Neuro-Ophthalmology Society |
ARK | ark:/87278/s6h1excn |
Setname | ehsl_novel_jno |
ID | 2116209 |
Reference URL | https://collections.lib.utah.edu/ark:/87278/s6h1excn |