{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:20:45Z","timestamp":1792092045666,"version":"4.4.0"},"reference-count":89,"publisher":"JMIR Publications Inc.","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JMIR Dermatol"],"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Nonresponse to botulinum toxin type A (BoNT-A) has been reported in both medical and aesthetic applications. Secondary nonresponse (SNR) occurs when BoNT-A is initially effective before failure commences at a later point. Most reported cases involve SNR in aesthetics. Several aspects of this complication remain elusive or controversial.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n We aimed to address unanswered questions regarding the prevalence and etiology of SNR. Additionally, we investigated the immunogenicity of BoNT-A formulations, mainly focusing on the development of neutralizing antibodies that hinder the toxin\u2019s pharmacologic effects. Furthermore, we sought to examine the management strategies for SNR.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n The PubMed and Google Scholar databases were searched from inception for articles on nonresponse to BoNT-A therapy. Articles were evaluated based on their contribution to the field. Expert opinions and panel recommendations regarding management and data gaps were also included in the review.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n There are limited data on SNR prevalence in aesthetic applications compared to therapeutic uses. Trigger factors of SNR include improper handling of BoNT-A; incorrect injection practices; and impurities present in the formulation, such as clostridial complexing proteins that may increase immunogenicity. Other contributing factors include infection; patient characteristics; and treatment parameters that encompass an increased frequency of BoNT-A injections (ie, <3 months apart), higher cumulative dosages, elevated treatment dosages, and booster injections (retreatment within 3 weeks of the initial injection). Neutralizing antibodies developed with first-generation formulations, such as onabotulinumtoxinA and abobotulinumtoxinA that contain clostridial proteins, but not with second-generation BoNT-As, such as incobotulinumtoxinA and daxibotulinumtoxinA, which lack these proteins. Among patients who developed SNR after using first-generation BoNT-A for aesthetic purposes, switching to incobotulinumtoxinA therapy did not result in the development of immune responses. Switching to a protein-free BoNT-A formulation such as incobotulinumtoxinA upon development of SNR has been advocated. To effectively manage SNR, it is crucial to minimize the identified trigger factors.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Nonresponse to BoNT-A is gaining importance in aesthetic treatments. Considering the potential for immunogenicity is essential when selecting a BoNT-A formulation. Preventing SNR is crucial, given the lack of solid data on effective treatments.<\/jats:p>\n <\/jats:sec>","DOI":"10.2196\/69960","type":"journal-article","created":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T12:35:06Z","timestamp":1742042106000},"page":"e69960-e69960","source":"Crossref","is-referenced-by-count":8,"title":["Exploring Nonresponse to Botulinum Toxin in Aesthetics: Narrative Review of Key Trigger Factors and Effective Management Strategies"],"prefix":"10.2196","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5915-4640","authenticated-orcid":false,"given":"George","family":"Kroumpouzos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5788-927X","authenticated-orcid":false,"given":"Fernando","family":"Silikovich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1010","published-online":{"date-parts":[[2025,4,24]]},"reference":[{"issue":"1","key":"R1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.fsc.2006.10.001","article-title":"Botulinum toxin, immunologic considerations with long-term repeated use, with emphasis on cosmetic applications","volume":"15","author":"Borodic","journal-title":"Facial Plast Surg Clin North Am"},{"issue":"4","key":"R2","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1136\/jnnp.65.4.472","article-title":"Outcome of selective ramisectomy for botulinum toxin resistant torticollis","volume":"65","author":"Ford","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"4","key":"R3","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1111\/jocd.12108","article-title":"Clinical resistance to three types of botulinum toxin type A in aesthetic medicine","volume":"13","author":"Stephan","journal-title":"J Cosmet Dermatol"},{"issue":"1","key":"R4","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/s12640-015-9565-5","article-title":"Neutralizing antibody and botulinum toxin therapy: a systematic review and meta-analysis","volume":"29","author":"Fabbri","journal-title":"Neurotox Res"},{"issue":"6","key":"R5","doi-asserted-by":"publisher","DOI":"10.1097\/GOX.0000000000004407","article-title":"Emerging trends in botulinum neurotoxin a resistance: an international multidisciplinary review and consensus","volume":"10","author":"Ho","journal-title":"Plast Reconstr Surg Glob Open"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1524-4725.2010.01710.x","article-title":"Antibody-induced failure of botulinum toxin a therapy in cosmetic indications","volume":"36 Suppl 4","author":"Dressler","journal-title":"Dermatol Surg"},{"issue":"4","key":"R7","doi-asserted-by":"publisher","DOI":"10.1111\/srt.13691","article-title":"Aesthetic doctors\u2019 perception and attitudes toward tolerance in botulinum toxin","volume":"30","author":"Oh","journal-title":"Skin Res Technol"},{"issue":"6","key":"R8","doi-asserted-by":"publisher","DOI":"10.1097\/GOX.0000000000005892","article-title":"Real-world implications of botulinum neurotoxin A immunoresistance for consumers and aesthetic practitioners: insights from ASCEND multidisciplinary panel","volume":"12","author":"Corduff","journal-title":"Plast Reconstr Surg Glob Open"},{"issue":"15","key":"R9","doi-asserted-by":"publisher","first-page":"3878","DOI":"10.1016\/j.molimm.2008.06.031","article-title":"Molecular recognition of botulinum neurotoxin B heavy chain by human antibodies from cervical dystonia patients that develop immunoresistance to toxin treatment","volume":"45","author":"Atassi","journal-title":"Mol Immunol"},{"key":"R10","doi-asserted-by":"crossref","unstructured":"Frevert J Dressler D . 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