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CC BY-NC 4.0 · Arch Plast Surg 2022; 49(01): 12-18
DOI: 10.5999/aps.2021.00766
Cosmetic
Review Article

Immunogenicity of botulinum toxin

Syeo Young Wee 
Department of Plastic and Reconstructive Surgery, Soonchunhyang University Gumi Hospital, Gumi, Korea
,
Eun Soo Park 
Department of Plastic and Reconstructive Surgery, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
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Botulinum toxin treatment is the most common non-surgical cosmetic treatment. Although there are many available treatments using botulinum toxin, their effects are temporary and repeated injections are required. These frequent injections can trigger an immunological response. In addition, botulinum toxin acts as an antigen in the body; thus, its effect disappears progressively due to this immunological reaction, which may cause treatment failure. Active botulinum toxin consists of a core neurotoxin and complexing proteins, the exact effects of which remain unclear. However, the complexing proteins are closely related to the immune response and the formation of neutralizing antibodies. Since neutralizing antibodies can lead to treatment failure, their formation should be prevented. Furthermore, various methods of detecting neutralizing antibodies have been used to predict treatment failure.

Keywords

Botulinum toxin - Immunogenicity - Treatment failure


Publication History

Received: 11 April 2021

Accepted: 07 November 2021

Article published online:
02 June 2022

© 2022. The Korean Society of Plastic and Reconstructive Surgeons. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonCommercial License, permitting unrestricted noncommercial use, distribution, and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes. (https://creativecommons.org/licenses/by-nc/4.0/)

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  • REFERENCES

  • 1 Garcia A, Fulton Jr JE. Cosmetic denervation of the muscles of facial expression with botulinum toxin: a dose-response study. Dermatol Surg 1996; 22: 39-43
    PubMedGoogle Scholar
  • 2 Tsui JK. Botulinum toxin as a therapeutic agent. Pharmacol Ther 1996; 72: 13-24
    PubMedGoogle Scholar
  • 3 Nigam PK, Nigam A. Botulinum toxin. Indian J Dermatol 2010; 55: 8-14
    PubMedGoogle Scholar
  • 4 Sellin LC. The pharmacological mechanism of botulism. Trends Pharmacol Sci 1985; 6: 80-2
    Google Scholar
  • 5 Munchau A, Bhatia KP. Uses of botulinum toxin injection in medicine today. BMJ 2000; 320: 161-5
    Google Scholar
  • 6 Jankovic J. Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry 2004; 75: 951-7
    PubMedGoogle Scholar
  • 7 Guida S, Farnetani F, Nistico SP. et al. New trends in botulinum toxin use in dermatology. Dermatol Pract Concept 2018; 8: 277-82
    PubMedGoogle Scholar
  • 8 Harii K, Kawashima M. A double-blind, randomized, placebo-controlled, two-dose comparative study of botulinum toxin type A for treating glabellar lines in Japanese subjects. Aesthetic Plast Surg 2008; 32: 724-30
    PubMedGoogle Scholar
  • 9 Honeck P, Weiss C, Sterry W. et al. Reproducibility of a fourpoint clinical severity score for glabellar frown lines. Br J Dermatol 2003; 149: 306-10
    PubMedGoogle Scholar
  • 10 Carruthers JD, Lowe NJ, Menter MA. et al. Double-blind, placebo-controlled study of the safety and efficacy of botulinum toxin type A for patients with glabellar lines. Plast Reconstr Surg 2003; 112: 1089-98
    PubMedGoogle Scholar
  • 11 Won CH, Lee HM, Lee WS. et al. Efficacy and safety of a novel botulinum toxin type A product for the treatment of moderate to severe glabellar lines: a randomized, double-blind, active-controlled multicenter study. Dermatol Surg 2013; 39 (1 Pt 2): 171-8
    PubMedGoogle Scholar
  • 12 Won CH, Kim HK, Kim BJ. et al. Comparative trial of a novel botulinum neurotoxin type A versus onabotulinumtoxinA in the treatment of glabellar lines: a multicenter, randomized, double-blind, active-controlled study. Int J Dermatol 2015; 54: 227-34
    PubMedGoogle Scholar
  • 13 Scott AB. Botulinum toxin injection of eye muscles to correct strabismus. Trans Am Ophthalmol Soc 1981; 79: 734-70
    PubMedGoogle Scholar
  • 14 Dressler D. Complete secondary botulinum toxin therapy failure in blepharospasm. J Neurol 2000; 247: 809-10
    PubMedGoogle Scholar
  • 15 Scott AB, Kennedy RA, Stubbs HA. Botulinum A toxin injection as a treatment for blepharospasm. Arch Ophthalmol 1985; 103: 347-50
    PubMedGoogle Scholar
  • 16 Frueh BR, Felt DP, Wojno TH. et al. Treatment of blepharospasm with botulinum toxin: a preliminary report. Arch Ophthalmol 1984; 102: 1464-8
    PubMedGoogle Scholar
  • 17 Benecke R. Clinical relevance of botulinum toxin immunogenicity. BioDrugs 2012; 26: e1-9
    PubMedGoogle Scholar
  • 18 Hsieh PF, Chiu HC, Chen KC. et al. Botulinum toxin A for the treatment of overactive bladder. Toxins (Basel) 2016; 8: 59
    PubMedGoogle Scholar
  • 19 Dat A, Chin M, Skinner S. et al. Botulinum toxin therapy for chronic anal fissures: where are we at currently?. ANZ J Surg 2017; 87: E70-3
    PubMedGoogle Scholar
  • 20 Camargo CH, Cattai L, Teive HA. Pain relief in cervical dystonia with botulinum toxin treatment. Toxins (Basel) 2015; 7: 2321-35
    PubMedGoogle Scholar
  • 21 Bhidayasiri R, Truong DD. Evidence for effectiveness of botulinum toxin for hyperhidrosis. J Neural Transm (Vienna) 2008; 115: 641-5
    PubMedGoogle Scholar
  • 22 Ferrante FM, Bearn L, Rothrock R. et al. Evidence against trigger point injection technique for the treatment of cervicothoracic myofascial pain with botulinum toxin type A. Anesthesiology 2005; 103: 377-83
    PubMedGoogle Scholar
  • 23 Inoue K, Fujinaga Y, Watanabe T. et al. Molecular composition of Clostridium botulinum type A progenitor toxins. Infect Immun 1996; 64: 1589-94
    PubMedGoogle Scholar
  • 24 Sharma SK, Singh BR. Immunological properties of Hn-33 purified from type A Clostridium botulinum. J Nat Toxins 2000; 9: 357-62
    Google Scholar
  • 25 Kukreja RV, Singh BR. Comparative role of neurotoxin-associated proteins in the structural stability and endopeptidase activity of botulinum neurotoxin complex types A and E. Biochemistry 2007; 46: 14316-24
    Google Scholar
  • 26 Kwak S, Kang WH, Rhee CH. et al. Comparative pharmacodynamics study of 3 different botulinum toxin type A preparations in mice. Dermatol Surg 2020; 46: e132-8
    PubMedGoogle Scholar
  • 27 Bellows S, Jankovic J. Immunogenicity associated with botulinum toxin treatment. Toxins (Basel) 2019; 11: 491
    CrossrefPubMedGoogle Scholar
  • 28 Dong M, Yeh F, Tepp WH. et al. SV2 is the protein receptor for botulinum neurotoxin A. Science 2006; 312: 592-6
    PubMedGoogle Scholar
  • 29 Pirazzini M, Rossetto O, Eleopra R. et al. Botulinum neurotoxins: biology, pharmacology, and toxicology. Pharmacol Rev 2017; 69: 200-35
    PubMedGoogle Scholar
  • 30 Dressler D, Bigalke H. Immunological aspects of botulinum toxin therapy. Expert Rev Neurother 2017; 17: 487-94
    PubMedGoogle Scholar
  • 31 Stanley EF, Drachman DB. Botulinum toxin blocks quantal but not non-quantal release of ACh at the neuromuscular junction. Brain Res 1983; 261: 172-5
    PubMedGoogle Scholar
  • 32 Kukreja R, Chang TW, Cai S. et al. Immunological characterization of the subunits of type A botulinum neurotoxin and different components of its associated proteins. Toxicon 2009; 53: 616-24
    PubMedGoogle Scholar
  • 33 Naumann M, Boo LM, Ackerman AH. et al. Immunogenicity of botulinum toxins. J Neural Transm (Vienna) 2013; 120: 275-90
    PubMedGoogle Scholar
  • 34 Hasegawa K, Watanabe T, Suzuki T. et al. A novel subunit structure of Clostridium botulinum serotype D toxin complex with three extended arms. J Biol Chem 2007; 282: 24777-83
    PubMedGoogle Scholar
  • 35 Ellenhorn MJ, Barceloux DG. Medical toxicology: diagnosis and treatment of human poisoning. New York: Elsevier; 1988: 1185-7
    Google Scholar
  • 36 Fujinaga Y. Transport of bacterial toxins into target cells: pathways followed by cholera toxin and botulinum progenitor toxin. J Biochem 2006; 140: 155-60
    PubMedGoogle Scholar
  • 37 Park JY, Sunga O, Wanitphakdeedecha R. et al. Neurotoxin impurities: a review of threats to efficacy. Plast Reconstr Surg Glob Open 2020; 8: e2627
    PubMedGoogle Scholar
  • 38 Ravenni R, De Grandis D, Mazza A. Conversion ratio between Dysport and Botox in clinical practice: an overview of available evidence. Neurol Sci 2013; 34: 1043-8
    PubMedGoogle Scholar
  • 39 Carruthers J, Fournier N, Kerscher M. et al. The convergence of medicine and neurotoxins: a focus on botulinum toxin type A and its application in aesthetic medicine: a global, evidence-based botulinum toxin consensus education initiative. Part II: incorporating botulinum toxin into aesthetic clinical practice. Dermatol Surg 2013; 39 (3 Pt 2): 510-25
    PubMedGoogle Scholar
  • 40 Lorenc ZP, Kenkel JM, Fagien S. et al. Consensus panel’s assessment and recommendations on the use of 3 botulinum toxin type A products in facial aesthetics. Aesthet Surg J 2013; 33 (Suppl. 01) 35S-40S
    CrossrefPubMedGoogle Scholar
  • 41 Krebs KM, Lebeda FJ. Comparison of the structural features of botulinum neurotoxin and NTNH, a non-toxic accessory protein of the progenitor complex. Botulinum J 2008; 1: 116-34
    Google Scholar
  • 42 Frevert J. Content of botulinum neurotoxin in Botox®/Vistabel®, Dysport®/Azzalure®, and Xeomin®/Bocouture® . Drugs R D 2010; 10: 67-73
    PubMedGoogle Scholar
  • 43 Kerscher M, Roll S, Becker A. et al. Comparison of the spread of three botulinum toxin type A preparations. Arch Dermatol Res 2012; 304: 155-61
    PubMedGoogle Scholar
  • 44 Frevert J. Pharmaceutical, biological, and clinical properties of botulinum neurotoxin type A products. Drugs R D 2015; 15: 1-9
    PubMedGoogle Scholar
  • 45 Ohishi I, Sugii S, Sakaguchi G. Oral toxicities of Clostridium botulinum toxins in response to molecular size. Infect Immun 1977; 16: 107-9
    PubMedGoogle Scholar
  • 46 Chen F, Kuziemko GM, Stevens RC. Biophysical characterization of the stability of the 150-kilodalton botulinum toxin, the nontoxic component, and the 900-kilodalton botulinum toxin complex species. Infect Immun 1998; 66: 2420-5
    PubMedGoogle Scholar
  • 47 Frevert J, Dressler D. Complexing proteins in botulinum toxin type A drugs: a help or a hindrance?. Biologics 2010; 4: 325-32
    PubMedGoogle Scholar
  • 48 Johnson EA, Bradshaw M. Clostridium botulinum and its neurotoxins: a metabolic and cellular perspective. Toxicon 2001; 39: 1703-22
    PubMedGoogle Scholar
  • 49 Grein S, Mander GJ, Taylor HV. Xeomin® is stable without refrigeration: Complexing proteins are not required for stability of botulinum neurotoxin type A preparations. Toxicon 2008; 51 Suppl 1: 13
    Google Scholar
  • 50 de Almeida AT, De Boulle K. Diffusion characteristics of botulinum neurotoxin products and their clinical significance in cosmetic applications. J Cosmet Laser Ther 2007; 9 Suppl 1: 17-22
    PubMedGoogle Scholar
  • 51 Dodd SL, Rowell BA, Vrabas IS. et al. A comparison of the spread of three formulations of botulinum neurotoxin A as determined by effects on muscle function. Eur J Neurol 1998; 5: 181-6
    Google Scholar
  • 52 Tang-Liu DD, Aoki KR, Dolly JO. et al. Intramuscular injection of 125I-botulinum neurotoxin-complex versus 125Ibotulinum-free neurotoxin: time course of tissue distribution. Toxicon 2003; 42: 461-9
    PubMedGoogle Scholar
  • 53 Frevert J. Xeomin is free from complexing proteins. Toxicon 2009; 54: 697-701
    PubMedGoogle Scholar
  • 54 Pingel J, Nielsen MS, Lauridsen T. et al. Injection of high dose botulinum-toxin A leads to impaired skeletal muscle function and damage of the fibrilar and non-fibrilar structures. Sci Rep 2017; 7: 14746
    PubMedGoogle Scholar
  • 55 Seo MS, Kim YI, Kang KK. et al. Comparison study of the response with botulinum toxin muscle injection in the ICR mice from three different sources. Lab Anim Res 2019; 35: 11
    PubMedGoogle Scholar
  • 56 Wang L, Sun Y, Yang W. et al. Type A botulinum neurotoxin complex proteins differentially modulate host response of neuronal cells. Toxicon 2014; 82: 52-60
    PubMedGoogle Scholar
  • 57 Goschel H, Wohlfarth K, Frevert J. et al. Botulinum A toxin therapy: neutralizing and nonneutralizing antibodies. Therapeutic consequences. Exp Neurol 1997; 147: 96-102
    PubMedGoogle Scholar
  • 58 Sankhla C, Jankovic J, Duane D. Variability of the immunologic and clinical response in dystonic patients immunoresistant to botulinum toxin injections. Mov Disord 1998; 13: 150-4
    PubMedGoogle Scholar
  • 59 Dressler D, Bigalke H. Botulinum toxin antibody type A titres after cessation of botulinum toxin therapy. Mov Disord 2002; 17: 170-3
    PubMedGoogle Scholar
  • 60 Dressler D. Clinical presentation and management of antibody-induced failure of botulinum toxin therapy. Mov Disord 2004; 19 Suppl 8: S92-100
    PubMedGoogle Scholar
  • 61 Kromminga A, Schellekens H. Antibodies against erythropoietin and other protein-based therapeutics: an overview. Ann N Y Acad Sci 2005; 1050: 257-65
    PubMedGoogle Scholar
  • 62 Albrecht P, Jansen A, Lee JI. et al. High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy. Neurology 2019; 92: e48-54
    PubMedGoogle Scholar
  • 63 Naumann M, Carruthers A, Carruthers J. et al. Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX®) across multiple indications. Mov Disord 2010; 25: 2211-8
    PubMedGoogle Scholar
  • 64 Rahman E, Alhitmi HK, Mosahebi A. Immunogenicity to botulinum toxin type A: a systematic review with meta-analysis across therapeutic indications. Aesthet Surg J 2022; 42: 106-20
    PubMedGoogle Scholar
  • 65 Wang C, Sun T, Li H. et al. Hypersensitivity caused by cosmetic injection: systematic review and case report. Aesthetic Plast Surg 2021; 45: 263-72
    PubMedGoogle Scholar
  • 66 Moon IJ, Chang SE, Kim SD. First case of anaphylaxis after botulinum toxin type A injection. Clin Exp Dermatol 2017; 42: 760-2
    PubMedGoogle Scholar
  • 67 Torres S, Hamilton M, Sanches E. et al. Neutralizing antibodies to botulinum neurotoxin type A in aesthetic medicine: five case reports. Clin Cosmet Investig Dermatol 2013; 7: 11-7
    PubMedGoogle Scholar
  • 68 Coleman 3rd WP, Sattler G, Weissenberger P. et al. Safety of incobotulinumtoxinA in the treatment of facial lines: results from a pooled analysis of randomized, prospective, controlled clinical studies. Dermatol Surg 2017; 43 Suppl 3: S293-303
    PubMedGoogle Scholar
  • 69 Atassi MZ. Basic immunological aspects of botulinum toxin therapy. Mov Disord 2004; 19 Suppl 8: S68-84
    PubMedGoogle Scholar
  • 70 Dressler D, Bigalke H, Benecke R. Botulinum toxin type B in antibody-induced botulinum toxin type A therapy failure. J Neurol 2003; 250: 967-9
    PubMedGoogle Scholar
  • 71 Dressler D, Zettl U, Benecke R. et al. Can intravenous immunoglobulin improve antibody-mediated botulinum toxin therapy failure?. Mov Disord 2000; 15: 1279-81
    PubMedGoogle Scholar
  • 72 Hanna PA, Jankovic J. Mouse bioassay versus Western blot assay for botulinum toxin antibodies: correlation with clinical response. Neurology 1998; 50: 1624-9
    PubMedGoogle Scholar
  • 73 Gordon PH, Gooch CL, Greene PE. Extensor digitorum brevis test and resistance to botulinum toxin type A. Muscle Nerve 2002; 26: 828-31
    PubMedGoogle Scholar
  • 74 Dressler D, Bigalke H, Rothwell JC. The sternocleidomastoid test: an in vivo assay to investigate botulinum toxin antibody formation in humans. J Neurol 2000; 247: 630-2
    PubMedGoogle Scholar
  • 75 Voller B, Moraru E, Auff E. et al. Ninhydrin sweat test: a simple method for detecting antibodies neutralizing botulinum toxin type A. Mov Disord 2004; 19: 943-7
    PubMedGoogle Scholar