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Neutralizing Antibody and Botulinum Toxin Therapy: A Systematic Review and Meta-analysis

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Abstract

The formation of neutralizing antibodies (NAbs) directed specifically against the active neurotoxin part of the botulinum neurotoxin (BoNT) complex is often cited as a major cause of secondary non-responsiveness (SnR) to treatment. This systematic and meta-analytic review evaluates the frequency of NAbs among patients treated with BoNT therapy for any clinical indication. A comprehensive database search strategy was designed to retrieve relevant clinical data from the published literature up to April 2013. All English-language publications that analyzed NAbs prevalence in more than ten patients were included, regardless of BoNT formulation, assay method, and study design. For the meta-analysis, patients were divided into three categories: secondary non-response (SnR) patients, clinically responding patients and all patients, independently of BoNT responsiveness. The meta-analysis included 61 studies reporting data for 8525 patients; 4972 dystonic patients, 1170 patients with spasticity, 294 patients with urologic indications, 396 patient with hyperhidrosis, 1659 patients with glabellar line, and 34 patients with hypersalivation. Among the “all patients” group NAbs frequency was 20 % for dystonia, 5.9 % for spasticity, and 2.7 % for urologic patients and 1.1 % for other conditions. The prevalence of NAbs was lower (3.5 %) among clinically responding patients and higher in 53.5 % SnR patients. About a half of patients with SnR do not have NAbs. NAbs was high among patients treated with RIMA but it was not associated with clinical non-responsiveness. Meta-analysis of the frequency of NAbs and SnR are limited by the heterogeneity of study design and reported outcomes. Indeed the analysis of several factors that can influence the development of NAbs, i.e., MHC of patients, frequency and site of injection, injection technique, cumulative dose, and toxin denaturation, was not specifically evaluated due to the paucity and heterogeneity of data. The identification of all these missing data should be taken into account in order to improve the methodology of future studies.

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Acknowledgments

The authors thank Anita Chadha-Patel (ACP Clinical Communications funded by Ipsen Pharma) for editorial assistance (English language editing and referencing). Medical editing support was funded by Ipsen Pharma.

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Authors and Affiliations

  1. Clinical Pharmacology Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal

    Margherita Fabbri, Ricardo M. Fernandes & Joaquim J. Ferreira

  2. Dipartimento di Neurologia e Psichiatria, Sapienza Università di Roma, Rome, Italy

    Giorgio Leodori & Carlo Colosimo

  3. Chulalongkorn Center of Excellence on Parkinson’s Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Thai Red Cross Society, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand

    Roongroj Bhidayasiri

  4. Department of Neurology, Geffen School of Medicine at UCLA, Los Angeles, USA

    Roongroj Bhidayasiri

  5. Neurology Service, Institut Clínic de Neurociències (ICN), Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Hospital Clinic of Barcelona, Barcelona, Spain

    Maria Jose Marti

  6. Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal

    Joaquim J. Ferreira

Authors
  1. Margherita Fabbri
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  6. Carlo Colosimo
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  7. Joaquim J. Ferreira
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Correspondence to Joaquim J. Ferreira.

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Authors’ Contributions

Dr. Margherita Fabbri participated in the literature search, data analysis and collection and wrote the first draft of the manuscript. Dr. Giorgio Leodori participated in the literature search, data collection and analysis. Dr. Ricardo Fernandes participated in the statistical and data analysis, figures editing and critical revision. Dr. Roongroj Bhidayasiri participated in the data interpretation and analysis and critical revision. Dr. Maria Jose Marti participated in the data interpretation and analysis and critical revision. Dr. Carlo Colosimo participated in the data interpretation and analysis and critical revision. Dr. Joaquim J Ferreira participated in the manuscript writing, data interpretation and critical revision, supervising the paper.

Conflict of Interest and Financial Disclosures

Dr. Margherita Fabbri: no conflict of interest to report. Stock Ownership in medically related fields: none; Consultancies: none; Advisory Boards: none; Partnership: none; Honoraria to speak: none; Grants: none; Intellectual Property Rights: none; Expert Testimony: none; Employment: Clinic and Pharmacology Unit, Instituto de Medicina Molecular, Lisboa; Contracts: none; Royalties: none; Other: none.

Dr. Giorgio Leodori: no conflict of interest to report. Stock Ownership in medically related fields: none; Consultancies: none; Advisory Boards: none; Partnership: none; Honoraria to speak: none; Grants: none; Intellectual Property Rights: none; Expert Testimony: none; Employment: Dipartimento di Neurologia e Psichiatria, Sapienza Università di Roma; Contracts: none; Royalties: none; Other: none.

Dr. Ricardo M Fernandes: no conflict of interest to report. Stock Ownership in medically related fields: none; Consultancies: none; Advisory Boards: none; Partnership: none; Honoraria to speak: none; Grants: none; Intellectual Property Rights: none; Expert Testimony: none; Employment: Laboratory of Clinical Pharmacology and Therapeutics of Lisbon; Contracts: none; Royalties: none; Other: none.

Prof. Roongroj Bhidayasiri: no conflict of interest to report. Stock Ownership in medically related fields: none; Consultancies: Ipsen Pharmaceuticals, Advisory Boards for Novartis Thailand. Honoraria to speak: GlaxoSmithKline, Novartis, BL Hua, Abbott; Advisory Boards: none; Partnership: none; Grants: Thailand research fund, Ratchadapiseksompot faculty grant and CU-CLUSTER fund of Chulalongkorn University, Intellectual Property Rights: Parkinson’s disease laser cane; Expert Testimony: none; Employment: Chulalongkorn University; Royalties: Blackwell-Wiley, Humana publications; Other: none.

Prof. Maria J. Marti: no conflict of interest to report. Stock Ownership in medically related fields: none. Consultancies: Abvvie, Ipsen and Merz; Advisory Boards: none; Partnership: none; Honoraria to speak: none; Grants: none; Intellectual Property Rights: none; Expert Testimony: none; Employment: Hospital Clinic of Barcelona; Contracts: none; Royalties: none; Other: none.

Dr. Carlo Colosimo: no conflict of interest to report. Stock Ownership in medically related fields: none; Consultancies: Ipsen Pharmaceuticals and Merz; Advisory Boards: none; Partnership: none; Honoraria to speak: UCB, LIMPE; Grants: TEVA; Intellectual Property Rights: none; Expert Testimony: none; Employment: Dipartimento di Neurologia e Psichiatria, Sapienza Università di Roma; Contracts: none; Royalties: Cambridge University Press. Other: none.

Prof. Joaquim J. Ferreira: no conflict of interest to report. Stock Ownership in medically related fields: none; Consultancies: Ipsen, GlaxoSmithKline, Novartis, Teva, Lundbeck, Solvay, Abbott, BIAL, Merck-Serono and Merz; Advisory Boards: none; Partnership: none; Honoraria to speak: BIAL; Grants: GlaxoSmithKline, Grunenthal, Teva, Allergan, Novartis and MSD; Intellectual Property Rights: none; Expert Testimony: none; Employment: Faculty of Medicine, University of Lisbon, Centro Hospitalar Lisboa Norte; Contracts: none; Royalties: none; Other: none.

Funding source

The study had no specific funding but run of search in electronic databases, purchase of reference, and medical editing was supported by Ipsen Pharma, under the direction of the authors. The authors were solely responsible for devising the protocol, interpretation of data, writing the manuscript, and decision to publish and confirm the accuracy of the data and data analysis.

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Fabbri, M., Leodori, G., Fernandes, R.M. et al. Neutralizing Antibody and Botulinum Toxin Therapy: A Systematic Review and Meta-analysis. Neurotox Res 29, 105–117 (2016). https://doi.org/10.1007/s12640-015-9565-5

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  • DOI: https://doi.org/10.1007/s12640-015-9565-5

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