Updated: Apr 6, 2020
If you have a large botulinum toxin practice, you have probably seen patients who do not respond to BOTOX, Dysport, and other brands of BTX-A. Why is this? A November 2018 study published in Neurology found that neutralizing antibodies to therapeutic doses of botulinum toxin increase with long-term treatment. In the past, the longstanding thought had been that such small doses are being used in cosmetics that resistance issues shouldn’t be a concern. However, we are seeing patients who have never had botulinum toxins before who do not respond to injections.
There is still more research to be done, especially in the area of aesthetic medicine, but this recent long-term study has shed light on the subject and is raising awareness that a problem likely exists.
Dosage Found to Affect Neutralizing Antibodies
The 2018 study looked at 596 patients who had been recruited in 2013 and 2014 and who received at least four botulinum toxin injections in a one-year period for therapeutic purposes (non-cosmetic use). Patients were divided into five subgroups based on the neurologic indication for which they received treatment: facial hemispasm, blepharospasm, cervical dystonia, other dystonia, and spasticity. Patients were then split into three different dosage subgroups: 0 to 350 units, 351 to 700 units, and over 700 units. A total of 83 patients – 13.9% – developed antibodies, with those in higher dosage groups at a greater risk.
Do Lower Doses of Botulinum Toxins Cause Antibodies?
Dermatologist and research Dr. Leslie Baumann has performed most, if not all, of the FDA required research trials for the approval of BTX-A for cosmetic use. “In the FDA approval trials, serum samples are sent to look for the development of antibodies to BTX-A in the trials. I don’t recall ever seeing any patient who developed antibodies to BTX-A in a toxin research trial,” Dr. Baumann says. “However, I have about five patients who have slowly developed a resistance to BTX-A in my clinic. We have not done antibody trials on them, but it would be nice if we all compared data to see who else is seeing this.”
Medical Director and Certified Physician Assistant at Baumann Cosmetic Dermatology Ilanit Samuels explains that the BTX-A dosage used for cosmetic use is much lower than the doses used in the Nov 2018 Neurology trial. She states, “The 12 to 30 units of Botox used in the glabellar lines, for example, is much lower than the doses used in the therapeutic trials that showed antibody formation.” Despite this lower dosage, however, Samuels says, “Botulinum toxin resistance is a concern of mine. I have been interested in this because I’ve seen patients come in who have never had injections before and are young, and the toxin doesn’t work on them. They do not have a history of BTX-A vaccination and there is no explanation for their resistance. I have not seen a lot of cases, but it does happen. I also see patients who have been getting injections for many years and start to see that it no longer works for them.”
Does Switching Between BTX-A Brands Increase the Risk of Developing Antibodies?
In a poster presented by Merz called “Decrease in Therapeutic Effect Among Botulinum Toxin Type A Agents: Analysis of the FDA Adverse Event Reporting System Database” at The Aesthetic Meeting in Las Vegas May 2109, they looked at 12,280 patients who had received BTX-A injections. They found the following number of patients who reported decreased efficacy of the BTX-A toxin:
Abobotulinumtoxin A (Dysport) – 9.2% (79/858)
Incobotulinumtoxin A (Xeomin) – 2.2% (15/689)
Onabotulinumtoxin A (Botox) – 11.6% (1,247/10,733)
In their summary, they state that “the percentage of BoNT-A adverse events involving decreased therapeutic response was higher with longer lengths of therapy in the present analysis.” This may explain why the Botox and Dysport numbers were higher, because they have been on the market much longer.
Does Switching Between Botulinum Toxin Brands Increase the Presence of Neutralizing Antibodies?
At this point, there is no data on this. Each form of botulinum toxin has different protein profiles that may play a role in antibody formation. We do not yet know if switching between brands or using more than one brand at a time has any effect.
Botulinum toxin resistance is a real concern for anyone who does not want to lose the ability to treat their wrinkles with BTX-A. There are three main takeaways that medical providers can use to help reduce the chances that patients will develop resistance.
Use the lowest dose possible. Because higher doses seem to be linked with a greater risk of resistance, use the lowest dose needed to get the desired clinical or aesthetic outcome.
Don’t switch from brand to brand if you don’t have to. “What’s really interesting and what was a surprise to me,” says Samuels, “was that a study found that those who switched from company to company had a much higher risk of developing immunogenic responses. So if you’ve started with Botox stick with Botox – don’t hop around between different companies.”
Less frequent injections. Tell your patients that if they don’t have muscle movement, they don’t need another injection yet. While more investigation is needed, current evidence suggests that frequent doses may contribute to antibody formation.
Further investigation is warranted. We do not really know the true incidence of antibody resistance to botulinum toxin A in aesthetic practices. This study focused on therapeutic doses of botulinum toxin, but resistance is a concern in cosmetic dermatology as well.
Have you had experiences with botulinum toxin resistance in smaller doses used for aesthetic purposes? Please connect with me (Dr. Leslie Baumann) via LinkedIn and share your story with me. The more information we have, the better we can address potential resistance issues in the future.
COI: Dr. Baumann performs research trials for Allergan, Galderma, Merz, Evolus and Revance.
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