Letter to the Editor
Botulinum Toxin Type A and B Primary Resistance
Aesthetic Surgery Journal 2015, Vol 35(2) NP28–NP30 © 2015 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: [email protected] DOI: 10.1093/asj/sju027 www.aestheticsurgeryjournal.com
Michael Dobryansky, MD, FACS; Jessica Korsh, MS; Allison E. Shen, BA; and Kristen Aliano, MD
In this paper, we review factors affecting BT type A primary resistance and postulate whether genetics may play a role. We also investigate the advantages and disadvantages of using off-label botulinum toxin type B for type A–resistant patients. We performed a retrospective chart review of two patients treated by a single surgeon who exhibited botulinum toxin A primary resistance. Lastly, we also performed a review of the literature for publications regarding BT primary resistance or therapy failure.
CASE REPORTS Patient 1 is a 44-year-old Russian female from Moscow. Prior to attempting treatment with BT type B, the patient received Restylane (Valeant Pharmaceuticals International Inc., Bridgewater, NJ) and Xeomin (incobotulinumtoxinA, Merz Aesthetics, Greensboro, NC) to the face. She had also received Botox and Dysport (abobotulinumtoxinA, Ipsen Biopharmaceuticals Inc., Basking Ridge, NJ) prior to presentation. Initially, improper injection technique was considered as the cause of treatment failure and no attempts were made to draw her blood looking for antibodies. Following primary BT type A treatment failure, the patient then successfully underwent treatment with BT type B and was happy with the results. Repeated administration four months after the initial successful treatment produced a Dr Dobryansky is a plastic surgeon, Ms Korsh and Ms Shen are research assistants, and Dr Aliano is a research fellow at a private plastic surgery practice in Garden City, NY. Corresponding Author: Michael Dobryansky, MD, FACS, Long Island Plastic Surgical Group, 999 Franklin Ave, Suite 300, Garden City, NY 11530, USA. E-mail: [email protected]
Downloaded from http://asj.oxfordjournals.org/ by guest on October 6, 2015
Botulinum toxin (BT) has become increasingly employed for its cosmetic indications and as a treatment for conditions with muscle hyperactivity due to its ability to inhibit acetylcholine release at the neuromuscular junction. Conditions it is indicated for include movement disorders (spasticity, cervical dystonia), urological disorders (overactive bladder), dermatological conditions (axillary hyperhidrosis), and cosmetic applications.1 BT does not represent a cure for the aforementioned conditions, rather it provides transient relief of symptoms; thus, patients may require numerous treatments, typically every few months. Naïve BT consists of a 150 kD neurotoxin with a complex of up to 6 other non-clostridial proteins, such as hemagglutinins.1 BT has 7 immunologically distinct serotypes, of which types A and B are two. The various serotypes work through distinct mechanisms to inhibit a set of proteins, the SNARE complex, thus causing a flaccid paralysis of the target muscle.2 Differences between BT formulations can include the bacterial strain from which it was produced, the manufacturing process, and the amount and type of excipients.1 Various reasons are implicated in the causation of BT primary resistance and therapy failure. Upon BT type A therapy failure, use of BT type B can be implemented. Indications for Botox (onabotulinumtoxinA) include temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity, and moderate to severe lateral canthal lines associated with orbicularis oculi activity in adult patients (Botox, Allergan, Inc., Irvine, CA). MyoBloc (rimabotulinumtoxinB, Solstice Neurosciences, Louisville, KY) is indicated for the treatment of cervical dystonia in adults and has been approved by the Food and Drug Administration (FDA) for this since 1999.
Dobryansky et al
partial effect. The patient reported a significantly higher pain level from BT type B administration as compared to BT type A, and decided against continuing any BT treatments in the future. Patient 2 is a 45-year-old Russian female who also displayed primary therapy failure with BT type A. It is not believed that she was exposed to any botulinum-spoiled canned food. No attempts were made to draw her blood looking for antibodies. She then received partially-successful treatment with BT type B following primary BT type A treatment failure. She also reported more pain from BT type B administration and similarly decided against continuing any BT treatments in the future.
DISCUSSION
preexisting BT antibodies (AB), chronic exposure to BT in childhood botulinum, cross-reaction of other AB (tetanus toxin AB), and abnormalities of BT acceptors; however, there is no evidence confirming these speculations. Use of BT type B can be implemented upon BT type A primary or secondary therapy failure. BT type B has been shown to produce more local and systemic anticholinergic adverse effects than BT type A. These include dryness of the mouth, accommodative dysfunction, conjunctival irritation, reduced sweating, dysphagia, heartburn, constipation, bladder voiding difficulties, and dryness of nasal mucosa.8 Additionally, seldom mentioned in the literature is the fact that BT type B injection is very painful. This is consistent with a previous report in the literature indicating that BT type B injection is more painful than BT type A. Dutton et al.2 also report that the severity of local pain is greatly reduced, though not eliminated, by diluting the toxin in a 1:1 ratio with preserved saline. Therefore, a significant disadvantage to using MyoBloc in the treatment of type A resistance is the extreme discomfort patients experience during the injection. Previous studies have investigated the efficacy of BT type B treatment in patients with secondary therapy failure to BT type A in non-cosmetic applications.9 These studies indicate that, although BT type B may be initially effective in some patients with BT type A secondary therapy failure, these result are likely transient. Dressler et al.9 reported that 86% of patients in their study developed BT type B therapy failure after 5 applications, which could not be overcome by doubling the dose. Opinions vary as to the clinical significance of AB production in BT type A therapy, and the relationship between the presence of ABs and treatment success is unclear. AB production in BT type A therapy results when the immune system identifies the toxin and/or its composite proteins (which are present in preparations of Botox and Dysport, but not Xeomin) as foreign substances; in response to studies suggesting that lower protein loads might minimize immune response, producers of BT type A have sought to reduce protein levels accordingly.10 Some researchers have suggested that Xeomin has less immunogenic potential than other BT type A therapies, but it is worth noting that AB production is less than 1% for both Botox and Dysport.4 For BT type A, reports in the literature vary as to whether or not a relationship between AB production and BT therapy success exists, and results may depend on study design and treatment indication.1,11,12 Barnes and colleagues reported that 25 out of 36 patients who were BT type A resistant had no ABs to the type A toxin or toxin complex. Barnes et al.11 report that none of their subjects who did respond to BT type B therapy had ABs to the type B toxin or the type B toxin complex. Each BT serotype has a unique functional binding site; therefore, ABs to one serotype should not affect response to another serotype.2 Dutton and colleagues2 reported a
Downloaded from http://asj.oxfordjournals.org/ by guest on October 6, 2015
To our knowledge, this is one of the first studies investigating BT type A primary therapy failure in cosmetic applications and, thereafter, the efficacy of MyoBloc. All three FDA-approved products for BT type A therapy are tolerated reasonably well by patients. No serious adverse events were reported in Botox® clinical trials.3 Likewise, while in one study regarding the use of Dysport to treat glabellar lines 66% of patients reported experiencing mild or moderate adverse events, the treatment was not thought to be responsible for the vast majority of these events.3 Data for Xeomin is less abundant, as it is the most recently approved product for BT type A therapy, yet the most common adverse effects reported in clinical trials were headaches and nasopharyngitis.4 Adverse effects do not necessarily constitute failure, however; BT therapy can be deemed a failure when the patient, physician, or both are not satisfied with the intended treatment outcome.5 BT therapy failure is classified as primary or secondary. Primary therapy failure occurs following the first application, whereas secondary therapy failure treatment is initially successful before failure commences at a later point. One report in the literature indicates primary resistance for BT type A occurring at a rate of 6.25% (3/16 patients) in non-cosmetic applications.6 Secondary therapy failure to BT type A in non-cosmetic applications occurs in approximately 5-10% of patients with non-cosmetic applications.7 Furthermore, therapy failure can be partial or complete. Primary therapy failure may result from an inappropriate diagnosis for a condition that can be partially affected or treated with BT therapy. Examples of inappropriate diagnoses are congenital ptosis, myasthenia gravis, eyelid opening apraxia, and eyelid dehiscences in presumed blepharospasm. Further inappropriate diagnoses include antecollis and various forms of spasmodic torticollis (cervical dystonia).5 Additional causes of primary therapy failure include target muscle selection, BT dosing, and reduced BT potency due to improper handling during storage and transport.5 Proposed causes of primary therapy failure include
NP29
Aesthetic Surgery Journal 35(2)
NP30
CONCLUSION To our knowledge this is one of the first studies investigating primary BT resistance in cosmetic applications. Furthermore, we investigated the possibility of genetic influences on BT resistance; however, there is no evidence in the literature to support this. Approved treatment options for patients who are BT type A resistant are limited. While BT type B may be efficacious during the initial courses of treatment, patients may require more frequent treatments or become unresponsive to BT type B treatment as well.
REFERENCES 1. 2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Funding The authors received no financial support for the research, authorship, and publication of this article.
Disclosures The authors declare no potential conflicts of interest with respect to the research, authorship, and publication of this article.
13.
Benecke R. Clinical Relevance of Botulinum Toxin Immunogenicity. BioDrugs. 2012;26(2):1-9. Dutton JJ, White JJ, Richard MJ. Myobloc for the treatment of benign essential blepharospasm in patients refractory to botox. Ophthal Plast Reconstr Surg. 2006;22(3):173-177. Lorenc ZP, Kenkel JM, Fagien S, et al. A review of onabotulinumtoxinA (Botox). Aesthet Surg J. 2013;33 (Suppl 1):9s-12s. Lorenc ZP, Kenkel JM, Fagien S, et al. IncobotulinumtoxinA in clinical literature. Aesthet Surg J. 2013;33(Suppl 1): 23s-34s. Dressler D. Clinical presentation and management of antibody-induced failure of botulinum toxin therapy. Mov Disord. 2004;19(Suppl 8):S92-S100. Ford B, Louis ED, Greene P, Fahn S. Outcome of selective ramisectomy for botulinum toxin resistant torticollis. J Neurol Neurosurg Psychiatry. 1998;65(4):472-478. Kessler KR, Benecke R. The EBD test-a clinical test for the detection of antibodies to botulinum toxin type A. Mov Disord. 1997;12(1):95-99. Dressler D, Eleopra R. Clinical use of non-A botulinum toxins: botulinum toxin type B. Neurotox Res. 2006;9 (2-3):121-125. Dressler D, Bigalke H, Benecke R. Botulinum toxin type B in antibody-induced botulinum toxin type A therapy failure. J Neurol. 2003;250(8):967-969. Lorenc ZP, Kenkel JM, Fagien S, et al. IncobotulinumtoxinA (Xeomin): background, mechanism of action, and manufacturing. Aesthet Surg J. 2013;33(Suppl 1):18s-22s. Barnes MP, Best D, Kidd L, et al. The use of botulinum toxin type-B in the treatment of patients who have become unresponsive to botulinum toxin type-A - initial experiences. Eur J Neurol. 2005;12(12):947-955. Lange O, Bigalke H, Dengler R, Wegner F, deGroot M, Wohlfarth K. Neutralizing antibodies and secondary therapy failure after treatment with botulinum toxin type A: much ado about nothing? Clin Neuropharmacol. 2009;32(4):213-218. Berman B, Seeberger L, Kumar R. Long-term safety, efficacy, dosing, and development of resistance with botulinum toxin type B in cervical dystonia. Mov Disord. 2005;20(2):233-237.
Downloaded from http://asj.oxfordjournals.org/ by guest on October 6, 2015
12.5% primary failure rate with BT type B in patients with BT type A therapy failure. Barnes et al.11 reported a failure rate for MyoBloc of approximately 64% (36/56 patients) in non-cosmetics indications following BT type A failure. Dutton et al.2 reported that the treatment duration for BT type B appears to be less than that for BT type A, averaging about 7. 3 weeks. Barnes and colleagues11 recommend trying increasing doses of BT type B before confirming treatment failure. Patients may develop secondary treatment failure to BT type B because MyoBloc has a higher antigenic load than Botox, which may cause a more rapid development of blocking ABs.5 It has been postulated that ABs to BT type A may facilitate therapy failure for BT type B.2,13 The preparation conversion ratios between BT types must be addressed in order to compare therapeutic results due to differences in their potencies.8 The proposed conversion ratio for Botox and MyoBloc use at the neuromuscular junction is 1:40, and for use at the autonomic synapses may be 1:20.8
Botulinum Toxin Type A and B Primary Resistance
Aesthetic Surgery Journal 2015, Vol 35(2) NP28–NP30 © 2015 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: [email protected] DOI: 10.1093/asj/sju027 www.aestheticsurgeryjournal.com
Michael Dobryansky, MD, FACS; Jessica Korsh, MS; Allison E. Shen, BA; and Kristen Aliano, MD
In this paper, we review factors affecting BT type A primary resistance and postulate whether genetics may play a role. We also investigate the advantages and disadvantages of using off-label botulinum toxin type B for type A–resistant patients. We performed a retrospective chart review of two patients treated by a single surgeon who exhibited botulinum toxin A primary resistance. Lastly, we also performed a review of the literature for publications regarding BT primary resistance or therapy failure.
CASE REPORTS Patient 1 is a 44-year-old Russian female from Moscow. Prior to attempting treatment with BT type B, the patient received Restylane (Valeant Pharmaceuticals International Inc., Bridgewater, NJ) and Xeomin (incobotulinumtoxinA, Merz Aesthetics, Greensboro, NC) to the face. She had also received Botox and Dysport (abobotulinumtoxinA, Ipsen Biopharmaceuticals Inc., Basking Ridge, NJ) prior to presentation. Initially, improper injection technique was considered as the cause of treatment failure and no attempts were made to draw her blood looking for antibodies. Following primary BT type A treatment failure, the patient then successfully underwent treatment with BT type B and was happy with the results. Repeated administration four months after the initial successful treatment produced a Dr Dobryansky is a plastic surgeon, Ms Korsh and Ms Shen are research assistants, and Dr Aliano is a research fellow at a private plastic surgery practice in Garden City, NY. Corresponding Author: Michael Dobryansky, MD, FACS, Long Island Plastic Surgical Group, 999 Franklin Ave, Suite 300, Garden City, NY 11530, USA. E-mail: [email protected]
Downloaded from http://asj.oxfordjournals.org/ by guest on October 6, 2015
Botulinum toxin (BT) has become increasingly employed for its cosmetic indications and as a treatment for conditions with muscle hyperactivity due to its ability to inhibit acetylcholine release at the neuromuscular junction. Conditions it is indicated for include movement disorders (spasticity, cervical dystonia), urological disorders (overactive bladder), dermatological conditions (axillary hyperhidrosis), and cosmetic applications.1 BT does not represent a cure for the aforementioned conditions, rather it provides transient relief of symptoms; thus, patients may require numerous treatments, typically every few months. Naïve BT consists of a 150 kD neurotoxin with a complex of up to 6 other non-clostridial proteins, such as hemagglutinins.1 BT has 7 immunologically distinct serotypes, of which types A and B are two. The various serotypes work through distinct mechanisms to inhibit a set of proteins, the SNARE complex, thus causing a flaccid paralysis of the target muscle.2 Differences between BT formulations can include the bacterial strain from which it was produced, the manufacturing process, and the amount and type of excipients.1 Various reasons are implicated in the causation of BT primary resistance and therapy failure. Upon BT type A therapy failure, use of BT type B can be implemented. Indications for Botox (onabotulinumtoxinA) include temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity, and moderate to severe lateral canthal lines associated with orbicularis oculi activity in adult patients (Botox, Allergan, Inc., Irvine, CA). MyoBloc (rimabotulinumtoxinB, Solstice Neurosciences, Louisville, KY) is indicated for the treatment of cervical dystonia in adults and has been approved by the Food and Drug Administration (FDA) for this since 1999.
Dobryansky et al
partial effect. The patient reported a significantly higher pain level from BT type B administration as compared to BT type A, and decided against continuing any BT treatments in the future. Patient 2 is a 45-year-old Russian female who also displayed primary therapy failure with BT type A. It is not believed that she was exposed to any botulinum-spoiled canned food. No attempts were made to draw her blood looking for antibodies. She then received partially-successful treatment with BT type B following primary BT type A treatment failure. She also reported more pain from BT type B administration and similarly decided against continuing any BT treatments in the future.
DISCUSSION
preexisting BT antibodies (AB), chronic exposure to BT in childhood botulinum, cross-reaction of other AB (tetanus toxin AB), and abnormalities of BT acceptors; however, there is no evidence confirming these speculations. Use of BT type B can be implemented upon BT type A primary or secondary therapy failure. BT type B has been shown to produce more local and systemic anticholinergic adverse effects than BT type A. These include dryness of the mouth, accommodative dysfunction, conjunctival irritation, reduced sweating, dysphagia, heartburn, constipation, bladder voiding difficulties, and dryness of nasal mucosa.8 Additionally, seldom mentioned in the literature is the fact that BT type B injection is very painful. This is consistent with a previous report in the literature indicating that BT type B injection is more painful than BT type A. Dutton et al.2 also report that the severity of local pain is greatly reduced, though not eliminated, by diluting the toxin in a 1:1 ratio with preserved saline. Therefore, a significant disadvantage to using MyoBloc in the treatment of type A resistance is the extreme discomfort patients experience during the injection. Previous studies have investigated the efficacy of BT type B treatment in patients with secondary therapy failure to BT type A in non-cosmetic applications.9 These studies indicate that, although BT type B may be initially effective in some patients with BT type A secondary therapy failure, these result are likely transient. Dressler et al.9 reported that 86% of patients in their study developed BT type B therapy failure after 5 applications, which could not be overcome by doubling the dose. Opinions vary as to the clinical significance of AB production in BT type A therapy, and the relationship between the presence of ABs and treatment success is unclear. AB production in BT type A therapy results when the immune system identifies the toxin and/or its composite proteins (which are present in preparations of Botox and Dysport, but not Xeomin) as foreign substances; in response to studies suggesting that lower protein loads might minimize immune response, producers of BT type A have sought to reduce protein levels accordingly.10 Some researchers have suggested that Xeomin has less immunogenic potential than other BT type A therapies, but it is worth noting that AB production is less than 1% for both Botox and Dysport.4 For BT type A, reports in the literature vary as to whether or not a relationship between AB production and BT therapy success exists, and results may depend on study design and treatment indication.1,11,12 Barnes and colleagues reported that 25 out of 36 patients who were BT type A resistant had no ABs to the type A toxin or toxin complex. Barnes et al.11 report that none of their subjects who did respond to BT type B therapy had ABs to the type B toxin or the type B toxin complex. Each BT serotype has a unique functional binding site; therefore, ABs to one serotype should not affect response to another serotype.2 Dutton and colleagues2 reported a
Downloaded from http://asj.oxfordjournals.org/ by guest on October 6, 2015
To our knowledge, this is one of the first studies investigating BT type A primary therapy failure in cosmetic applications and, thereafter, the efficacy of MyoBloc. All three FDA-approved products for BT type A therapy are tolerated reasonably well by patients. No serious adverse events were reported in Botox® clinical trials.3 Likewise, while in one study regarding the use of Dysport to treat glabellar lines 66% of patients reported experiencing mild or moderate adverse events, the treatment was not thought to be responsible for the vast majority of these events.3 Data for Xeomin is less abundant, as it is the most recently approved product for BT type A therapy, yet the most common adverse effects reported in clinical trials were headaches and nasopharyngitis.4 Adverse effects do not necessarily constitute failure, however; BT therapy can be deemed a failure when the patient, physician, or both are not satisfied with the intended treatment outcome.5 BT therapy failure is classified as primary or secondary. Primary therapy failure occurs following the first application, whereas secondary therapy failure treatment is initially successful before failure commences at a later point. One report in the literature indicates primary resistance for BT type A occurring at a rate of 6.25% (3/16 patients) in non-cosmetic applications.6 Secondary therapy failure to BT type A in non-cosmetic applications occurs in approximately 5-10% of patients with non-cosmetic applications.7 Furthermore, therapy failure can be partial or complete. Primary therapy failure may result from an inappropriate diagnosis for a condition that can be partially affected or treated with BT therapy. Examples of inappropriate diagnoses are congenital ptosis, myasthenia gravis, eyelid opening apraxia, and eyelid dehiscences in presumed blepharospasm. Further inappropriate diagnoses include antecollis and various forms of spasmodic torticollis (cervical dystonia).5 Additional causes of primary therapy failure include target muscle selection, BT dosing, and reduced BT potency due to improper handling during storage and transport.5 Proposed causes of primary therapy failure include
NP29
Aesthetic Surgery Journal 35(2)
NP30
CONCLUSION To our knowledge this is one of the first studies investigating primary BT resistance in cosmetic applications. Furthermore, we investigated the possibility of genetic influences on BT resistance; however, there is no evidence in the literature to support this. Approved treatment options for patients who are BT type A resistant are limited. While BT type B may be efficacious during the initial courses of treatment, patients may require more frequent treatments or become unresponsive to BT type B treatment as well.
REFERENCES 1. 2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Funding The authors received no financial support for the research, authorship, and publication of this article.
Disclosures The authors declare no potential conflicts of interest with respect to the research, authorship, and publication of this article.
13.
Benecke R. Clinical Relevance of Botulinum Toxin Immunogenicity. BioDrugs. 2012;26(2):1-9. Dutton JJ, White JJ, Richard MJ. Myobloc for the treatment of benign essential blepharospasm in patients refractory to botox. Ophthal Plast Reconstr Surg. 2006;22(3):173-177. Lorenc ZP, Kenkel JM, Fagien S, et al. A review of onabotulinumtoxinA (Botox). Aesthet Surg J. 2013;33 (Suppl 1):9s-12s. Lorenc ZP, Kenkel JM, Fagien S, et al. IncobotulinumtoxinA in clinical literature. Aesthet Surg J. 2013;33(Suppl 1): 23s-34s. Dressler D. Clinical presentation and management of antibody-induced failure of botulinum toxin therapy. Mov Disord. 2004;19(Suppl 8):S92-S100. Ford B, Louis ED, Greene P, Fahn S. Outcome of selective ramisectomy for botulinum toxin resistant torticollis. J Neurol Neurosurg Psychiatry. 1998;65(4):472-478. Kessler KR, Benecke R. The EBD test-a clinical test for the detection of antibodies to botulinum toxin type A. Mov Disord. 1997;12(1):95-99. Dressler D, Eleopra R. Clinical use of non-A botulinum toxins: botulinum toxin type B. Neurotox Res. 2006;9 (2-3):121-125. Dressler D, Bigalke H, Benecke R. Botulinum toxin type B in antibody-induced botulinum toxin type A therapy failure. J Neurol. 2003;250(8):967-969. Lorenc ZP, Kenkel JM, Fagien S, et al. IncobotulinumtoxinA (Xeomin): background, mechanism of action, and manufacturing. Aesthet Surg J. 2013;33(Suppl 1):18s-22s. Barnes MP, Best D, Kidd L, et al. The use of botulinum toxin type-B in the treatment of patients who have become unresponsive to botulinum toxin type-A - initial experiences. Eur J Neurol. 2005;12(12):947-955. Lange O, Bigalke H, Dengler R, Wegner F, deGroot M, Wohlfarth K. Neutralizing antibodies and secondary therapy failure after treatment with botulinum toxin type A: much ado about nothing? Clin Neuropharmacol. 2009;32(4):213-218. Berman B, Seeberger L, Kumar R. Long-term safety, efficacy, dosing, and development of resistance with botulinum toxin type B in cervical dystonia. Mov Disord. 2005;20(2):233-237.
Downloaded from http://asj.oxfordjournals.org/ by guest on October 6, 2015
12.5% primary failure rate with BT type B in patients with BT type A therapy failure. Barnes et al.11 reported a failure rate for MyoBloc of approximately 64% (36/56 patients) in non-cosmetics indications following BT type A failure. Dutton et al.2 reported that the treatment duration for BT type B appears to be less than that for BT type A, averaging about 7. 3 weeks. Barnes and colleagues11 recommend trying increasing doses of BT type B before confirming treatment failure. Patients may develop secondary treatment failure to BT type B because MyoBloc has a higher antigenic load than Botox, which may cause a more rapid development of blocking ABs.5 It has been postulated that ABs to BT type A may facilitate therapy failure for BT type B.2,13 The preparation conversion ratios between BT types must be addressed in order to compare therapeutic results due to differences in their potencies.8 The proposed conversion ratio for Botox and MyoBloc use at the neuromuscular junction is 1:40, and for use at the autonomic synapses may be 1:20.8
