Introduction
Botox is the most frequent non-surgical cosmetic treatment performed worldwide. Even Though various treatments are performed by using botox injections, their effect is temporary and requires repeated injections. Frequently injecting botulinum toxin into the body may trigger immunological reactions. The repeated use of botulinum toxin may also act as an antigen within the body, causing the injection to be less effective and resulting in treatment failure. Hence, it is important to analyze the cause and overcome them to gain better treatment outcomes.
What Is Botulinum Toxin?
Botulinum toxin is the most poisonous neurotoxin produced by Clostridium botulinum. The toxicity affects nerves and causes muscle weakening. The cosmetic form of botulinum toxin is referred to as Botox. The injections can improve appearance by relaxing muscles responsible for wrinkles. Active botulinum toxin contains a neurotoxin and complexing protein. The complex proteins are responsible for initiating the immune response and formation of neutralizing antibodies. Neutralizing antibodies can cause treatment failure. Hence, their generation must be prevented.
What Are the Types of Botulinum Toxins?
Botulinum toxin is classified into eight serotypes A, B, C1, C2, D, E, F, and G, based on immunological characteristics. Serotypes A and B are commercialized for clinical use.
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Botulinum Toxin Type A: It is the most commonly used product that is approved for cosmetic and clinical purposes. The three most frequently used botulinum toxin type A products are onabotulinum Toxin A (Botox), abobotulinumtoxin-A (Dysport), and incobotulinum toxin A (Xeomin).
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Botulinum Toxin Type B: The only available product with this serotype is rimabotulinumtoxin B. The product is currently not approved for cosmetic purposes due to limited research.
How Does Botulinum Toxin Work?
Botulinum toxin works in four areas of the nervous system. The neuromuscular junction, autonomic ganglia, postganglionic parasympathetic nerve (involuntary muscle function) endings, and sympathetic nerve (voluntary muscle function) endings are the area of action for the toxin. The botox injection interrupts the transmission of alpha motor neurons at the neuromuscular junction leading to the weakening of muscles. In addition, the toxin also prevents the secretion of acetylcholine from parasympathetic and cholinergic postganglionic sympathetic neurons. Therefore, they form an apt method for treating overactive smooth muscles and abnormally active glands.
Hence, the botulinum toxin has gained a wider acceptance for cosmetic and medical purposes. The cosmetic application of botulinum toxin is to treat glabellar frown lines (vertical lines that appear between eyebrows), crow’s feet (wrinkles near the corner of the eye), and transverse lines of the forehead. The medical application of the toxin is for treating strabismus (crossed eye), blepharospasm (eye twitching), movement disorders, urological disorders, dermatological disorders, and pain treatment of myofascial pain syndrome (deep aching pain in muscles). Chronic diseases of the muscle are treated with botulinum injections. The effects last for three months, and the individuals require repeat injections resulting in tolerance build-up or treatment failure.
What Is the Immunogenicity of Botulinum Toxin?
The immunogenicity of botulinum toxins is dependent on complex proteins and neutralizing antibodies.
The Immune Response Related to Complex Proteins
Complex proteins are responsible for protecting and stabilizing neurotoxins. Earlier, it was determined that complex proteins protect the botulinum toxin in the gastrointestinal tract by inducing protease resistance. However, the opinion was negated when botulinum toxin type A did not require oral administration. The complex protein was said to induce the stabilization of biological activity during the pre-use period of neurotoxin and facilitate muscle binding after use. Studies found that incobotulinum toxin A was stable even without complex proteins. The complex protein was said to be large, which caused limitations in the diffusion of complex protein from the target tissue. The studies showed no significant difference in injection spread among different preparations.
The key role of complex protein is immunostimulation by stimulating the immune cells. Studies have suggested that complex proteins are linked to the interleukin-6 pathway and stimulate an immune response by inducing the secretion of inflammatory cytokines (signaling protein that controls inflammation). After injection of botulinum toxin, there is an increase in transforming growth factor beta 1, inflammation-related marker, and interleukin-6. In addition, botulinum toxins containing complex protein act on lymphoblasts and fibroblasts along with neurons to release multiple inflammatory cytokines.
Generation of Neutralizing Antibodies
Immunogenicity is described as antibody formation by protein products. The proteins present in botulinum toxin present as antigens, inducing an immune response resulting in the formation of antibodies. Antibodies that can block the function of botulinum toxin are known as neutralizing or blocking antibodies. Their action is specific to neurotoxins. If the antibodies do not produce clinically relevant effects, they are known as on-neutralizing antibodies. The effect is limited to complex proteins.
Immunogenicity is directly related to the number of proteins. A high amount of protein in botulinum toxin increases the generation of neutralizing antibodies. Therefore, it can be concluded that the presence of complex proteins increases antigenic protein, causing antibody formation and treatment failure.
Other Factors
The dose of injection, injection interval, cumulative dose, number of injections, history of previous injections, and formulation of botulinum toxin may affect the immunogenicity of the toxin. These factors are referred to as treatment-related causes for inducing immune responses. They are known to be responsible for generating neutralizing antibodies. Among botulinum type A toxin abobotulinumtoxin was responsible for producing more neutralizing antibodies compared to others.
What Are the Side Effects of Botulinum Toxin?
After botulinum injection, the patient may be unsatisfied with outcomes causing partial or complete treatment failure. The treatment failure is categorized as primary and secondary. Primary failure is described as less than 25 percent treatment response even after increasing the dose or application o 2 to 3 injection trials. It can be caused by low sensitivity to toxins, misdiagnosis, insufficient dose, incorrect injecting technique, or injecting into other muscles. Secondary failure occurs when the injection is effective during the first application but fails to induce a response with subsequent applications. It indicates a poor prognosis. The presence of immunogenic protein and neutralizing antibodies are important determinants for treatment failure.
Hypersensitivity may develop after botox injection. A combination of complex proteins and gelatin that is used as a solvent in toxic preparation may form a protein that induces a hypersensitivity reaction. In a few patients, immunoglobulin E-mediated immune reactions were reported.
How to Overcome Treatment Failure?
To overcome treatment failure, attempts were made to replace serotypes of toxin with other types, but they had limited effect. When individuals resistant to type A toxin were injected with type B, the patients showed temporary improvement but later experienced treatment failure. Using two different serotypes could cause cross-reactivity and immune resistance. Plasmapheresis (a procedure that separates blood components) or intravenous immunoglobulin could neutralize antibodies but involve high cost and risk.
Recent studies have suggested the use of products with low antigen occurrence to minimize neutralizing antibody generation. The injection must be administered at a low dose, and additional doses must be avoided. The injection can be administered at intervals of three months.
Conclusion
The use of botulinum toxin has revolutionized cosmetic and therapeutic procedures. The procedure is non-surgical and may require repeated application due to temporary effects. The toxin contains neurotoxic and complex proteins as ingredients. The complex protein may act as an antigen to initiate an immune response leading to treatment failure. Preventing antibody formation can mitigate the risk of treatment failure.
