Botulinum neurotoxin type A resistance: An emerging problem


Botulinum neurotoxin A (BoNT-A), often referred to as ‘Botox’, is increasingly in cosmetic procedures. However, long-term use and high doses of BoNT-A may lead to immunoresistance, limiting its future therapeutic benefit.


A panel of experts including Dr Mary Dingley, Cosmetic Medicine Centre, Australia, is addressing this emerging issue. They offer guidance to practitioners and promote a culture of open communication with patients about BoNT-A risks, to empower individuals to make a fully informed decision.


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Hello and welcome to Research Pod! Thank you for listening and joining us today. 


Botulinum neurotoxin A, or BoNT-A, is commonly used to treat medical conditions. It’s the ‘proper name’ of ‘Botox’ – and it’s increasingly used in cosmetic procedures. However, long-term use and high doses may lead to immunoresistance. Experts, including Dr Mary Dingley of the Cosmetic Medicine Centre in Australia, address this issue by providing guidance for aesthetic practitioners. 



The bacterium Clostridium botulinum produces a powerful neurotoxin, botulinum neurotoxin A. Most of us know this neurotoxin as ‘Botox’, but this is a popular brand name for BoNT-A. It blocks the nerve signals to the muscle it is injected into; without a signal, the muscle cannot contract. BoNT-A is used to treat muscle conditions such as dystonia, which is repeated and prolonged muscle contraction, and spasticity, which is characterised by increased muscle tone and rigidity, among other disorders. Over the last two decades, its injection has become the most common cosmetic procedure around the world. Originally used to reduce the appearance of facial wrinkles, cosmetic use of BoNT-A has now expanded to include off-label indications such as jawline slimming and body contouring that require significantly higher doses. Intradermal injections of BoNT-A for skin quality improvement are also increasingly popular, adding to the doses used in aesthetics. The effect of the injection is temporary, so repeated injections are required to maintain the desired outcome.  


Emerging evidence shows that repeated injections and higher doses of BoNT-A may provoke the immune system to produce neutralising antibodies called NAbs. A consequence of these antibodies is a reduced or non-existent response to subsequent treatments, resulting in little or no therapeutic benefit. This diminished effect is referred to as a secondary nonresponse, abbreviated as SNR, and can weaken or even prevent future therapeutic benefits for patients. In a key publication, a panel of experts, including Dr Mary Dingley of The Cosmetic Medicine Centre, Australia, assesses the prevalence of this phenomenon in aesthetics. The panel strongly recommends that patients should be fully informed of the risks of neutralising antibody-related SNR. It highlights the importance of acknowledging BoNT-A immunoresistance as a potential complication that may affect future therapeutic use and discusses best practices incorporating clinical, ethical, and biological factors in treatment decision-making to help mitigate the risk of immunoresistance to BoNT-A.  



Several BoNT-A formulations exist and the most widely used are onabotulinumtoxinA, or ONA, abobotulinumtoxinA, or ABO, and incobotulinumtoxinA, or INCO. The first two of these formulations consist of a core neurotoxin and neurotoxin-associated proteins, known as NAPs. INCO consists of the core neurotoxin with no NAPs. It is the core neurotoxin and not the NAPs that bestows therapeutic benefit.  


Upon injection, the NAPs alert the recipient’s immune system to the ‘foreign invader,’ and an immune response is triggered. Special immune cells called dendritic cells recognise NAPs as ‘dangerous’ and boost immunity by offering up these ‘foreign invaders’ to the T-helper immune system cells. These T-helper cells recognise the ‘foreign invader’ and stimulate the production of antibodies by the B-cells. The core neurotoxin, by itself, lacks the ‘danger signals’ required to activate dendritic cells. However, when the core neurotoxin is injected together with NAPs at the same location, there is a risk of core neurotoxin being ‘accidentally’ internalised and presented by activated dendritic cells to T-helper cells, which may lead to the production of neutralising antibodies against the core neurotoxin. This immune response can occur during either therapeutic or aesthetic use of BoNT-A and may be influenced by the following factors: purity of the formulation; an individual’s age when treatments started, which affects the duration of treatment; and the dose and frequency of injections. Dingley recommends that practitioners should carefully consider these aspects in treatment plans and calls for a risk-based approach similar to that suggested for other biologic medications by the US Food and Drug Administration and European Medicines Agency on mitigating adverse immune-related responses associated with therapeutic protein products, as it is equally applicable for BoNT-A use in aesthetic procedures.  



The rate of NAb-associated SNR from therapeutic use of BoNT-A published in systematic reviews and meta-analyses, called SRMAs, is currently estimated at 0.3–27.6% percent.  In aesthetics, there is a common misconception that NAb-related SNR is not an issue due to the lower doses used. However, this ignores the cumulative exposure to BoNT-A over an individual’s lifetime, especially with more patients receiving treatments from a younger age and the increasing popularity of off-label indications employing higher doses. Now, a situation exists in aesthetics where the total dosage of BoNT-A used is not that different from the amounts used in therapeutics, making the risks and consequences of immunogenicity very real. As the real-world extent of NAb-related SNR in aesthetics remains unclear, the panel reviewed available literature on rates of NAb formation and SNR development in aesthetic use of BoNT-A. Systematic reviews and meta-analyses assessing different BoNT-A formulations reported a 0.2–0.4 percent prevalence of NAbs in aesthetics. However, there was a strong consensus that these values were underestimated as they were based on studies not designed to detect NAb formation. The research only studies relatively low-dose on-label indications rather than the higher-dose off-label indications, which constitute a large proportion of real-world BoNT-A use. The studies also had a relatively short follow-up time of 4 to 16 months, whereas NAb formation usually occurs over several years. When case reports and studies were analysed, Dingley and colleagues identified 13 cases of NAb-related SNR, which would have been excluded from SRMAs. Across these 13 cases, the panel found patterns of SNR development following regularly repeated treatments over 2 to 72 months, with all having received ABO or ONA formulations at some point. Notably, there were no reports of NAb formation and SNR in individuals treated only with INCO formulation in aesthetics, a finding mirrored in therapeutic patients. INCO contains only the core neurotoxin needed for therapeutic benefit and no NAPs. Therefore, there is minimal risk of an immune response being launched. This highlights the importance of purity and choice of formulation.  


Despite these apparent lower rates of SNR in aesthetics, the panel warns of the adverse consequences of immunoresistance to BoNT-A treatment. For example, a situation may exist where an individual has undergone extensive aesthetic treatments earlier in life and subsequently develops SNR but then later presents with a medical condition that requires BoNT-A therapy. Therapeutic treatments may then not be as effective or completely ineffective. Such a situation would be detrimental to the patient, significantly impacting their quality of life. There might also be medicolegal implications for the practitioner, especially if the risks of SNR had not been discussed with the individual before treatments commenced. Higher doses and less time between injections to maintain the desired therapeutic effects can signal SNR development. Practitioners are encouraged to recognise these warning signs, test for them, and manage them appropriately. 



There is consensus that despite lower published SNR rates in aesthetics, the true prevalence is most likely higher and will increase with increased aesthetic use of BoNT-A. The development of SNR is a genuine concern that must be addressed. Raising awareness of this issue and its detrimental effects on future therapeutic benefits are needed in the aesthetics world. The experts emphasise the importance of comprehensive clinical assessments but acknowledge the challenge of determining treatment history in aesthetics, where patients attending various clinics and receiving different formulations are commonplace. After obtaining a thorough clinical history, treatment plans should aim to minimise immunoresistance as much as possible. The experts discuss what they call modifiable risk factors, with the choice of formulation being an important consideration for reducing the risk of neutralising antibody formation. They recommend that when the safety and efficacy of formulations are similar, practitioners should consider a highly purified option to lessen the possibility of SNR. Additionally, administering the lowest effective dose at suitable intervals can also help reduce the risk of immunoresistance and is suggested best practice.  



To tackle the growing issue of SNR, Dingley and colleagues advise that a patient-centred approach fostering an environment of open discussion and collaboration with patients is needed, followed by appropriately-tailored treatment plans. The researchers emphasise the importance of better understanding the patients seeking treatment and their reasons for doing so and ensuring that they understand and are aware of risks and treatment choices. For aesthetic BoNT-A use, this refers to the risk of immunogenicity and the choice of available formulations. Core medical ethics principles such as informed consent and patient autonomy must also be applied in aesthetics.  


The task is to bring this crucial issue to the attention of individuals undergoing BoNT-A treatments, the regulators, practitioners, and the wider public. Through raising awareness, we can inform, educate, and adopt best practices to reduce the risk of BoNT-A immunoresistance. 


That’s all for this episode – thanks for listening, and stay subscribed to Research Pod for more of the latest science. See you again soon. 


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