Introduction

Resistance to botulinum toxin (BT) type A (BTA) which leads to reduced treatment effectiveness, is becoming a concern in aesthetics. Resistance has been noted even with low BTA doses. However, several aspects of this complication remain elusive or controversial. Primary genetic resistance to BT is a phenomenon where individuals exhibit an innate insensitivity to the toxin upon initial exposure, without prior treatments or antibody development. Most reported cases involve secondary resistance while primary resistance is extremely uncommon.¹

Prevalence

There are sparse data regarding the prevalence of BT resistance. In a recent survey among 673 Korean aesthetic providers, 53.9% reported experiencing BT resistance. Of those, 59% indicated the resistance rate as <1% and 36% as approximately 1-25%.² Nevertheless, the prevalence of resistance is likely underreported as many providers are unaware of it and may solely increase the BTA dose injected at sessions following a partial response.

Etiology

Primary resistance can be attributed to genetic variations that affect the toxin's target molecules (receptors) or its mechanisms of action (mutations of genes encoding transport and cleavage proteins).^3-5 Primary resistance has been attributed to pre-existing BT antibodies, possibly due to prior immunization against botulism.

Secondary resistance to BT is believed to be due to the development of neutralizing antibodies (NABs) that hinder the pharmacological effects of BT.⁶ This immune response can be influenced by epigenetic changes affecting the expression of genes involved in immune function, including those encoding for proteins interacting with BT.^3,7 Impurities in the BT formulation, such as bacterial complexing proteins, inactivated toxin, flagellin, and DNA contaminants, are thought to increase immunogenicity.⁸ Retrospective studies suggest an association between higher protein exposure and increased risk of antibody formation.^9,10 The precise mechanisms leading to resistance are still unknown, as the pure 150-KDa neurotoxin itself has low immunogenicity, without any known associated pattern recognition receptors or toll-like receptors on dendritic cells. Park et al. suggested that when adjuvants in the BT formulation are injected alongside the 150-KDa neurotoxin, they can activate dendritic cells that may internalize the neurotoxin and present it to T helper lymphocytes resulting in NAB formation.⁸ It is uncertain whether NABs naturally dissipate over time, and as a result, it is unclear whether reinjection should be attempted after a prolonged period.⁶ Existing assays cannot distinguish between NABs and non-neutralizing antibodies. Limitations in the antibody testing may contribute to an underestimate of the prevalence of resistance to BT.

Alternate explanations for resistance to BT include muscle injection fibrosis, BT receptor downregulation, worsening of dynamic line depths, and interactions with drugs like aminoglycosides and quinolones.¹ It's worth noting that lack of clinical response may also stem from inadequate treatment, such as improper injection techniques or product reconstitution.⁴ In such cases, antibody testing is unhelpful.

Factors involved

While toxin purity is a crucial factor in resistance development, other factors have been implicated. The increased frequency of BTA injections (i.e., <3 months apart) is an essential trigger factor.⁶ Other factors implicated include high treatment dosage, cumulative dosage, booster injections (re-treatment within 3 weeks of the initial injection), and the patient’s immune responsiveness.^1,8 Intradermal, rather than intramuscular, injections are thought to carry a higher risk of developing BTA resistance possibly because the dermis is highly populated with antigen-presenting dendritic cells.² COVID stimulates the immune system and may increase the risk of mounting an immune response against BTA.¹¹

Preventive measures

Several authors have advocated using a highly purified toxin that demonstrates the least immunogenicity, such as incobotulinumtoxinA.^6,8 Most experts recommend using the smallest BTA dose that achieves the desired clinical effect, avoiding booster injections, and waiting at least 3 months between treatments.^2,6 Regarding maximum dose, 56.5% of aesthetic providers responded that BTA dose should be limited to <100 units per day, and 97.3% reported using <300 units in total.² Such total doses are unlikely for wrinkle reduction but are possible with some off-label indications such as muscle size reduction. In body indications, higher doses of BTA are injected, thus increasing a patient’s exposure to foreign proteins and their risk of NAB formation. Consequently, it is advisable to use a highly purified BTA when treating body indications. Other authors recommend using toxins that offer improved longevity for cosmetic results, such as daxibotulinumtoxinA-lanm. Patients with prior complete or partial BTA failure to onabotulinumtoxinA may benefit from anti-CGRP monoclonal antibody preventive therapy.¹²

Management

Switching to a highly purified toxin once resistance is noted has been advocated.⁸ Anecdotally, many authors would switch to incobotulinumtoxinA for partial resistance. For complete resistance, many experts advise offering a 2-2.5-year-holiday, then resuming with a highly purified toxin at a large dose. Measuring NABs may help determine the length of the holiday period. This author has successfully used a short course of prednisone or immunomodulator (i.e., methotrexate) immediately before BTA injection to mitigate an immune response leading to decreased BTA efficacy. For cervical dystonia, switching to a different botulinum toxin serotype, such as type B (rimabotulinumtoxinB), has been attempted and found to be beneficial.¹³ However, injecting such an off-label toxin in aesthetics presents challenges, including a suboptimal longevity or adverse effects.

References
1. Stephan F, Habre M, Tomb R. Clinical resistance to three types of botulinum toxin type A in aesthetic medicine. J Cosmet Dermatol. 2014;13(4):346-348.
2. Oh SM, Kim HM, Ahn TH, Park MS, Ree YS, Park ES. Aesthetic doctors' perception and attitudes toward tolerance in botulinum toxin. Skin Res Technol. 2024;30(4):e413691.
3. Dingley M. Botulinum neurotoxin type A resistance: An emerging problem [internet]. Available from: https://researchoutreach.org/articles/botulinum-neurotoxin-type-a-resistance-emerging-problem.
4. Frevert J, Dressler D. Clinical relevance of immunoresistance to botulinum therapy [internet]. In: Botulinum Toxin Therapy Manual for Dystonia and Spasticity. Intech; 2016. Available from: http://dx.doi.org/10.5772/64566.
5. Carr WW, Jain N, Sublett JW. Immunogenicity of botulinum toxin formulations: potential therapeutic implications. Adv Ther 2021;38:5046–5064.
6. Torres S, Hamilton M, Sanches E, Starovatova P, Gubanova E, Reshetnikova T. Neutralizing antibodies to botulinum neurotoxin type A in aesthetic medicine: five case reports. Clin Cosmet Investig Dermatol. 2013;7:11-17.
7. Dobryansky M, Korsh J, Shen AE, Aliano K. Botulinum toxin type A and B primary resistance. Aesthet Surg J. 2015;35(2):NP28-NP30.
8. Park JY, Corduff N, Frevert J, Wanitphakdeedecha R, Chao YYY. Immunogenicity associated with aesthetic Botulinumtoxin A: A survey of Asia-Pacific physicians' experiences and recommendations. Plast Reconstr Surg Glob Open. 2022;10(4):e4217.
9. Greene P, Fahn S, Diamond B. Development of resistance to botulinum toxin type A in patients with torticollis. Mov Disord. 1994;9:213–217.
10. Jankovic J, Schwartz K. Response and immunoresistance to botulinum toxin injections. Neurology. 1995;45:1743–1746.
11. Mehta D, Wildman H. Botox resistance and COVID-19 vaccines: Is type B Botox a viable solution? J Cosmet Dermatol. 2024;23(2):368-369.
12. Alpuente A, Gallardo VJ, Caronna E, Torres-Ferrús M, Pozo-Rosich P. Partial and nonresponders to onabotulinumtoxinA can benefit from anti-CGRP monoclonal antibodies preventive treatment: A real-world evidence study. Eur J Neurol. 2021;28(7):2378-2382.
13. Hefter H, Samadzadeh S, Moll M. Transient improvement after switch to low doses of RimabotulinumtoxinB in patients resistant to AbobotulinumtoxinA. Toxins (Basel). 2020;12(11):677.