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IncobotulinumtoxinA for the Treatment of Glabella and Forehead Dynamic Lines: A Real-Life Longitudinal Case Series

Authors da Cunha ALG , Vasconcelos R , Di Sessa D, Sampaio G, Ramalhoto P, Zampieri BF, Deus BS, Vasconcelos S, Bellote T, Carvalho J, Petrone G, Figueredo V, Limongi Moreira G 

Received 2 December 2022

Accepted for publication 11 March 2023

Published 22 March 2023 Volume 2023:16 Pages 697—704

DOI https://doi.org/10.2147/CCID.S391709

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Jeffrey Weinberg



Ana Lucia Gonzaga da Cunha,1 Rossana Vasconcelos,2 David Di Sessa,3 Gabriel Sampaio,4 Pitila Ramalhoto,5 Bruno F Zampieri,6 Bárbara S Deus,7 Suyan Vasconcelos,8 Talitha Bellote,9 Juiano Carvalho,10 Giseli Petrone,5 Vinicius Figueredo,11 Gustavo Limongi Moreira3

1Clínica Skinline, Santo André, SP, Brazil; 2Nomina Clinica Médica De Cirurgia Plástica, Dermatologia e Oncologia, São Paulo, SP, Brazil; 3DSL Clínica Médica, São Paulo, SP, Brazil; 4Host Clínica, São Paulo, SP, Brazil; 5Private Clinic, Rio de Janeiro, RJ, Brazil; 6Hospital Alemão Oswaldo Cruz, São Paulo, SP, Brazil; 7Clinica Avatié, São Paulo, SP, Brazil; 8Clinica Splendore, Aracaju, SE, Brazil; 9Instituto La Beautè, Curitiba, PR, Brazil; 10Private Clinic, São Paulo, SP, Brazil; 11Host Clinica, São Paulo, SP, Brazil

Correspondence: Gustavo Limongi Moreira, DSL Clínica Médica, Rua Pamplona 145 / 1717, Jardim Paulista, Sao Paulo, SP, 01405-900, Brazil, Email [email protected]

Background: There is substantial interpersonal variation in the patterns of muscular contraction that substantiates the use of personalized points of application and dosages in clinical practice to achieve optimal results. Nevertheless, there has been no real-life therapeutic series with botulinum toxin for aesthetic treatment of the face in which the subjects were systematically followed to assess its long-term benefit.
Purpose: To assess the performance and length of the treatment of glabellar and forehead lines with IncobotulinumtoxinA in a real-life setting.
Patients and Methods: We enrolled 20 adults with indications for the treatment of upper facial dynamic lines (glabella and forehead) with botulinum toxin. The protocols of injection points were personalized by the injectors. The participants were photographed under maximum facial contraction before the application (D0) and after 15, 90, 120, and 180 days. The photos were randomly assessed by two blinded experienced raters to consensually grade the dynamic lines according to the Merz Aesthetics Scales (MAS). Efficacy was defined as the reduction in the MAS score.
Results: At D15, 18 (90%; 95% CI: 80%– 100%) participants reached the zero score, or a 2-point reduction on the MAS score from the forehead and 16 (80%; 95% CI: 65– 90%) reached that reduction for the glabella. These values from D90 were 14 (70%; 95% CI: 55– 85%) for both sites. At D120, these values were 11 (55%; 95% CI: 35– 75%) and 8 (40%; 95% CI: 25– 55%) for the forehead and glabella. At D180, 10 (50%; 95% CI: 30– 70%) participants presented a MAS score for forehead or glabella dynamic lines lower than the score assessed at D0.
Conclusion: As much as 70% of the patients sustained a reduction of scores after 120 days of the treatment for dynamic glabellar and forehead lines. Half of the patients evidenced prolonged benefit at 180 days.

Keywords: incobotulinumtoxinA, botulinum toxin, injection technique, ONE21, dynamic wrinkles, upper face, Xeomin

Introduction

Facial aging is a complex process that involves genetic, behavioral, and environmental factors. It comprises the loss of volume in fat compartments, sagging as well as skin dyschromia, alteration in texture, radiance, patterns of facial mimic, and dynamic wrinkles, which result from repeated muscle activity.1–3 These elements substantiate the use of combined procedures for facial rejuvenation.

Neurotoxins (as botulinum toxin A) are the gold standard treatment for dynamic wrinkles of the upper face. Nevertheless, despite procedure safety and satisfactory results, the comparative performance of different brands provides heterogeneous results, which can be due to different dosages, points of injection, dilution, the severity of the wrinkles, protocols of outcomes, and follow-up.4–6

Randomized controlled trials for the assessment of the efficacy of botulinum toxin utilize standardized dosages and points of injection to increase the internal validity of the study. Nevertheless, the variation of muscles used in the contraction of the face, as well as their intensity, can demand an individualized regimen of treatment to maximize the results.7–9

Despite the expert recommendations, in clinical practice, the protocols of aesthetic use of botulinum toxin (eg, dosages and points of injection) vary highly between countries, the assessment of injectors, and the patient’s demands.10–12 Actually, pragmatic and real-life studies offer the best evidence of the effectiveness of a treatment, measuring the extent to which an intervention does what is intended in routine circumstances.13

To date, there have been no real-life therapeutic series with botulinum toxin for aesthetic treatment of the face in which the subjects were systematically followed to assess its long-term benefit. This study aimed to assess the performance and length of the benefit treatment of glabellar and forehead lines with INCO in a real-life setting.

Patients and Methods

This prospective, evaluator-blinded, longitudinal real-life study enrolled 20 adult participants, who were indicated for treatment for upper facial dynamic lines (glabella and forehead) with botulinum toxin, in ten medical offices in Brazil from January 2021 to March 2022.

Inclusion criteria were age ranged between 30 and 50 years old, in accordance to follow-up by 180 days without other facial procedures, female-to-male inclusion rate of 3:1, without systemic comorbidities, breastfeeding, or pregnancy. Exclusion criteria were rosacea, facial acne, facial scars, facial dyschromias, dark circles, suntanning, severe skin laxity, obese, and autoimmune diseases.

The assessment and protocols of injection points and dosages were personalized by the injectors, according to their routine use and individual perception of adjustment needed at two weeks. Botulinum toxin was the only facial procedure the patients were subjected during the follow-up period.

The vials of 100U of incobotulinumtoxinA (INCO, Xeomin®/Bocouture®, Merz Pharmaceuticals GmbH) were reconstituted in 1 or 2 mL of sterile saline solution shortly before the treatments.

The participants were photographed under maximum facial contraction before the application (D0) and after 15, 90, 120, and 180 days (D15, D90, D120, D180). The photos were randomly assessed by two blinded experienced raters to consensually grade the severity of dynamic lines according to the Merz Aesthetics Scales (MAS), a 5-point scale in which the scores range from 0 (no lines) to 4 (very severe lines).14

The main outcomes were any reduction of the MAS score and its reduction by 2 points from baseline (D0), or MAS = 0 if MAS = 1 at D0, assessed at D15, D90, and D120. Secondary outcomes were MAS scores at D180 lower than D0 and adverse events, as well as the association with MAS reduction at D180 according to age, INCO dosage, and MAS at D0.

The 95% confidence intervals (95% CI) were calculated for the percentiles of MAS reductions through bootstrapping (5000 resamples).15 The change in the MAS assessment before and after treatment was analyzed by Generalized Estimated Equations, and the multiple comparisons were corrected by the Šidák procedure.16,17 Correlations between the dose used to treat each region and MAS severity were explored by Spearman’s (rho) rank correlation.18 The reduction of MAS at D180 in comparison with D0 was explored by a multivariate binary logistic regression model according to age, phototype, and MAS score at D0, and the effect size was represented by the odds ratio (OR).19

A posteriori sensitivity analysis was performed through the assessment of the female subjects of the sample.20

Data were analyzed using IBM SPSS v25 software. Significance was set as a p-value ≤0.05.21

The sample size was preliminarily estimated to detect up to 70% of participants with a reduction of MAS score by 2 points from baseline (D0), or MAS = 0 if MAS = 1 at D0, at D90. Considering a standard error of 20%, alpha = 0.05 and power = 0.80, resulting in 20 treatments.22

The study complies with the Declaration of Helsinki. It was approved by the Research Ethics Committee of the Faculdade de Medicina de Botucatu, UNESP (Botucatu, São Paulo, Brazil), with approval no. 4.767.103, and all the participants gave written consent for data and image publication.

Results

The main demographic and clinical data of the participants are presented in Table 1. Ages ranged from 31 to 50 years old, there was a predominance of women (80%), and most baseline MAS scores for dynamic lines were severe and very severe. The range of units of INCO used to treat the forehead was 7 to 44, and glabella was 17 to 35 (Supplementary Table); however, these doses were not correlated with the previous MAS severity (rho < 0.4; p > 0.085).

Table 1 Main Demographic and Clinical Data of the Participants (n = 20)

The follow-ups of the participants are disclosed in the Figures 1–3. According to the consensual blind assessment (Figures 4 and 5), the MAS scores from the forehead and glabella dynamic lines at D15, D90, and D120 were lower than their values at D0 (p < 0.01). The reduction of at least 1-point MAS scores from forehead dynamic lines was achieved in 90%, 85%, 70% of participants at D15, D90, and D120, respectively. For the glabellar lines, the MAS reduction was 85%, 95%, 80%, at D15, D90, and D120, respectively (Figures 6 and 7).

Figure 1 Sequential visits (previous to 180 days) from a participant who received 23 units of IncobotulinumtoxinA on the glabella. Photos under maximum contraction.

Figure 2 Sequential visits (previous to 180 days) from a participant who received 22 units of IncobotulinumtoxinA on the forehead. Photos under maximum contraction.

Figure 3 Sequential visits (previous to 180 days) from a participant who received 44 units of IncobotulinumtoxinA on the forehead. Photos under maximum contraction.

Figure 4 MAS scores of dynamic lines of the forehead at D0, D15, D90, D120, and D180 (n = 20).

Figure 5 MAS scores of dynamic lines of the glabella at D0, D15, D90, D120, and D180 (n = 20).

Figure 6 Percent (95% CI) of participants with any improvement in forehead MAS dynamic lines severity, according to the visits (n = 20).

Figure 7 Percent (95% CI) of participants with any improvement in glabellar MAS dynamic lines severity, according to the visits (n = 20).

At D15, 18 (90%; 95% CI: 80–100%) participants have reached zero or a 2-point reduction on MAS score from the forehead and 16 (80%; 95% CI: 65–90%) for the glabella. These values from D90 were 14 (70%; 95% CI: 55–85%) for both sites. At D120, these values were 11 (55%; 95% CI: 35–75%) and 8 (40%; 95% CI: 25–55%) for the forehead and glabella, respectively.

At D180, 10 (50%; 95% CI: 30–70%) participants presented a MAS score for forehead or glabella dynamic lines lower than the assessed at D0. The long-term reduction of MAS scores for the glabella was not associated with age (p > 0.07) or dose of INCO (p > 0.43); however, the more intense MAS score at D0, the greater the chance of long-term improvement at the forehead (OR = 3.8; p < 0.01) and glabella (OR = 3.9; p = 0.02). There were no adverse effects from the treatments assessed at D15.

In the sensitivity analysis, only the 18 women were analyzed, and the results are quite comparable to the whole sample. The MAS reduction in forehead dynamic lines was achieved in 89%, 89%, 72%, and 50% of the participants at D15, D90, D120, and D180, respectively. The reduction for glabellar dynamic lines was achieved in 89%, 100%, 83%, and 50% of the participants at D15, D90, D120, and D180, respectively.

Discussion

This case series brings real-life data regarding the treatment of forehead and dynamic glabella lines with INCO. By tailoring the treatment of these regions according to the individualized needs, we demonstrated sustained benefits for up to 70% of the participants after 120 days, despite a wide variation in dosage and points of application.

Real-life data from aesthetic treatments incorporates pragmatic results that can differ from the outcomes achieved in standardized procedures from randomized controlled trials because the results are influenced by the assistant assessment, the treatment regimen, and patient demands. Nevertheless, these results are more reliable regarding the expected effectiveness in clinical practice, when the aesthetic procedures are personalized. Furthermore, the individualization of the assessment for the treatment of upper face dynamic wrinkles with INCO can result in better outcomes than the homogeneous approach for all patients and can potentially decrease the rate of adverse effects.23,24

There has been a lack of blinded comparative (head-to-head) studies, with homogeneous outcomes, on assessing long-term effects of botulinum toxin A among brands and different techniques.5

In a standardized injection protocol of abobotulinumtoxin A in 22 Brazilian patients, the evaluator-blinded 120 days of any improvement for forehead and glabellar lines, at maximum contraction, was evidenced in 70.4% and 83.9% of the subjects, respectively. For the 180-days follow-up, the reduction of contraction scores for forehead and glabellar lines was sustained at 22.2% and 35.5% of the subjects, respectively.25 These results are quite parallel with the demonstrated in this case series.

Another Brazilian series with 110 subjects reported the results of the treatment of the upper face with a standardized dosage of Lanzhou botulinum toxin type A. The investigators perceived any improvement after 120 days in 37% of the subjects. Interestingly, the perception of long-term improvement after 180 days was higher by the patients (50%) than by the investigator (20%).26

A multicenter trial that enrolled 300 subjects treated with a standardized dose of abobotulinumtoxinA for glabellar dynamic lines resulted in 60% of the subjects with any reduction on contraction scores at D120, and 31% of the subjects evidenced only mild lines at maximum contraction at D120.27 A meta-analysis that polled the data from four trials, with 523 onabotulinumtoxinA-treated subjects with a standard dosage on glabella, resulted in 50% of the subjects with any reduction of contraction scales after 120 days of the treatments.28 In a multicenter trial with the standardized injection protocol of onabotulinumtoxinA in 203 patients from United States, the evaluator-blinded 120 days’ improvement (mild lines at maximum contraction) for glabellar lines were evidenced in 26.2% of the subjects.29 Nevertheless, only head-to-head trials can compare and adequately explore the different brands in their long-term performance.

Our results showed that the patients with more severe dynamic lines have a greater long-term benefit, but not those who were injected with a greater dosage. As long as INCO promotes a definitive blockade in neuromuscular transmission, this result suggests that the number of points of application decided on the basis of the assessment of muscle contraction and the dosage of injection can result in better long-term results. It means that the right assessment and application technique are paramount for the success of the treatment and that the characteristics of INCO allow individualized approaches and future new technique development.30

The aesthetic treatment of the upper face with botulinum toxin A promotes an overall improvement in skin and facial appearance. The long-term benefit can be due to the decrease of the muscle contraction, which leads to its mass reduction and a lower strength in its recovery. This phenomenon can be more pronounced in the more severe cases.31 A behavioral conditioning of lower muscle contraction to perform face expressions cannot be excluded, as the greater positive reinforcement following botulinum toxin A treatment should occur in the more severe cases.32,33

This study has limitations for being neither randomized nor controlled, as well as it was underpowered for the analysis of subgroups regarding age, gender and skin phototype. Nevertheless, these limitations do not hinder the assessment of pragmatic results regarding the INCO performance for the treatment of glabellar and forehead dynamic lines in routine circumstances. Pragmatic double-blinded, randomized controlled trials are warranted on long-term outcomes for the comparison of techniques and brands of botulinum toxin A for the treatment of dynamic wrinkles of the upper face.

Conclusion

In this real-life series, as much as 70% of the patients sustained a reduction of contraction scores after 120 days of the treatment with INCO for dynamic glabellar and forehead lines. Half of the patients evidenced prolonged benefit at 180 days. The patients with more severe dynamic lines have a greater long-term benefit.

Acknowledgments

The patients in this study who given written informed consent to publication of their case details and images. The authors thank Prof. Hélio Miot for protocol development support, ethics approval, editorial and writing assistance.

Ethics Statement

The study was approved by the Research Ethics Committee of the Faculdade de Medicina de Botucatu, UNESP (Botucatu, São Paulo, Brazil) – approval no. 4.767.103.

Informed Consent Statement

Written informed consent was obtained from patients to publish their data in this paper.

Disclosure

Ana da Cunha is an employed of Merz. Rossana de Vasconcelos, David di Sessa, Gabriel Sampaio, Pitila Ramalhoto, Bruno Zampieri, Bárbara Deus, Suyan Vasconcellos, Talitha Bellote, Juliano de Carvalho, Giseli Petrone, Gustavo Moreira Vinícius Figueredo are medical speakers of Merz Aesthetic. The authors report no other conflicts of interest in this work.

References

1. Zargaran D, Zoller F, Zargaran A, Weyrich T, Mosahebi A. Facial skin ageing: key concepts and overview of processes. Int J Cosmet Sci. 2022;44:414–420. doi:10.1111/ics.12779

2. Griffiths TW. Facial ageing: how do we measure up? Br J Dermatol. 2015;172:1182. doi:10.1111/bjd.13785

3. Rexbye H, Petersen I, Johansens M, Klitkou L, Jeune B, Christensen K. Influence of environmental factors on facial ageing. Age Ageing. 2006;35:110–115. doi:10.1093/ageing/afj031

4. Prager W, Nogueira Teixeira D, Leventhal PS. IncobotulinumtoxinA for aesthetic indications: a systematic review of prospective comparative trials. Dermatol Surg. 2017;43:959–966. doi:10.1097/DSS.0000000000001076

5. Camargo CP, Xia J, Costa CS, et al. Botulinum toxin type A for facial wrinkles. Cochrane Database Syst Rev. 2021;7:CD011301. doi:10.1002/14651858.CD011301.pub2

6. Ianhez M, Peres G, Miot HA. Neutralizing antibodies to botulinum toxin type a are rare following aesthetic indications. Aesthet Surg J. 2021;41:NP1800–NP1801. doi:10.1093/asj/sjab289

7. de Sanctis Pecora C, Ventura Ferreira K, Amante Miot H. ONE21 technique for an individualized assessment and treatment of upper face wrinkles in five pairs of identical twins with IncobotulinumtoxinA. J Cosmet Dermatol. 2022;21:1940–1947. doi:10.1111/jocd.14879

8. Raveendran SS, Anthony DJ. Classification and morphological variation of the frontalis muscle and implications on the clinical practice. Aesthetic Plast Surg. 2021;45:164–170. doi:10.1007/s00266-020-01937-2

9. de Sanctis Pecora C. One21: a novel, customizable injection protocol for treatment of the forehead with IncobotulinumtoxinA. Clin Cosmet Investig Dermatol. 2020;13:127–136. doi:10.2147/CCID.S237519

10. Pavicic T, Prager W, Kloppel M, Ravichandran S, Galatoire O. IncobotulinumtoxinA use in aesthetic indications in daily practice: a European multicenter, noninterventional, retrospective study. Clin Cosmet Investig Dermatol. 2015;8:135–142. doi:10.2147/CCID.S74519

11. Yutskovskaya Y, Gubanova E, Khrustaleva I, et al. IncobotulinumtoxinA in aesthetics: Russian multidisciplinary expert consensus recommendations. Clin Cosmet Investig Dermatol. 2015;8:297–306. doi:10.2147/CCID.S72301

12. Sundaram H, Huang PH, Hsu NJ, et al. Aesthetic applications of botulinum toxin a in asians: an international, multidisciplinary, pan-asian consensus. Plast Reconstr Surg Glob Open. 2016;4:e872. doi:10.1097/GOX.0000000000000507

13. Barnish MS, Turner S. The value of pragmatic and observational studies in health care and public health. Pragmat Obs Res. 2017;8:49–55. doi:10.2147/POR.S137701

14. Stella E, Di Petrillo A. Standard evaluation of the patient: the Merz scale. In: Injections in Aesthetic Medicine. Springer; 2014:33–50.

15. Bland JM, Altman DG. Statistics notes: bootstrap resampling methods. BMJ. 2015;350:h2622. doi:10.1136/bmj.h2622

16. Hu M, Lachin JM. Application of robust estimating equations to the analysis of quantitative longitudinal data. Stat Med. 2001;20:3411–3428. doi:10.1002/sim.962

17. Miot HA. Analysis of ordinal data in clinical and experimental studies. J Vasc Bras. 2020;19:e20200185. doi:10.1590/1677-5449.200185

18. Miot HA. Correlation analysis in clinical and experimental studies. J Vasc Bras. 2018;17:275–279. doi:10.1590/1677-5449.174118

19. Katz MH. Multivariable Analysis: A Practical Guide for Clinicians and Public Health Researchers. Cambridge university press; 2011.

20. Parpia S, Morris TP, Phillips MR, et al. Sensitivity analysis in clinical trials: three criteria for a valid sensitivity analysis. Eye. 2022;36(11):2073–2074. doi:10.1038/s41433-022-02108-0

21. Miola AC, Miot HA. P-value and effect-size in clinical and experimental studies. J Vasc Bras. 2021;20:e20210038. doi:10.1590/1677-5449.210038

22. Miot HA. Sample size in clinical and experimental studies. J Vasc Bras. 2011;10:275–278. doi:10.1590/S1677-54492011000400001

23. de Sanctis Pecora C, Pinheiro MVB, Ventura Ferreira K, Jacobino de Barros Nunes G, Miot HA. The one21 technique: an individualized treatment for glabellar lines based on clinical and anatomical landmarks. Clin Cosmet Investig Dermatol. 2021;14:97–105. doi:10.2147/CCID.S281901

24. Jia Z, Lu H, Yang X, et al. Adverse events of botulinum toxin type a in facial rejuvenation: a systematic review and meta-analysis. Aesthetic Plast Surg. 2016;40:769–777. doi:10.1007/s00266-016-0682-1

25. Hexsel D, Cartier H, Heden P, et al. Efficacy, safety, and subject satisfaction after abobotulinumtoxina treatment of upper facial lines. Dermatol Surg. 2018;44:1555–1564. doi:10.1097/DSS.0000000000001679

26. Ferreira LM, Talarico Filho S, Costa RO, et al. Efficacy and tolerability of a new botulinum toxin type A for cosmetic treatment of dynamic facial wrinkles: a prospective, Phase III, multicenter study. Surg Cosm Dermatol. 2009;1:58–63.

27. Monheit GD, Baumann L, Maas C, Rand R, Down R. Efficacy, safety, and subject satisfaction after abobotulinumtoxina treatment for moderate to severe glabellar lines. Dermatol Surg. 2020;46:61–69. doi:10.1097/DSS.0000000000002013

28. Glogau R, Kane M, Beddingfield F, et al. OnabotulinumtoxinA: a meta-analysis of duration of effect in the treatment of glabellar lines. Dermatol Surg. 2012;38:1794–1803. doi:10.1111/j.1524-4725.2012.02582.x

29. Carruthers JA, Lowe NJ, Menter MA, et al. A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol. 2002;46:840–849. doi:10.1067/mjd.2002.121356

30. de Sanctis Pecora C, Bussamara Pinheiro MV, Figueiredo V, Guerra R. Aesthetic ONE21 technique for injecting incobotulinumtoxina into the forehead: initial experience with 86 patients. J Drugs Dermatol. 2021;20:31–37. doi:10.36849/JDD.5617

31. Alexander C, Elliott C, Valentine J, et al. Muscle volume alterations after first botulinum neurotoxin A treatment in children with cerebral palsy: a 6-month prospective cohort study. Dev Med Child Neurol. 2018;60:1165–1171. doi:10.1111/dmcn.13988

32. Boswell RG, Sun W, Suzuki S, Kober H. Training in cognitive strategies reduces eating and improves food choice. Proc Natl Acad Sci U S A. 2018;115:E11238–E11247. doi:10.1073/pnas.1717092115

33. Slimani M, Bragazzi NL, Tod D, et al. Do cognitive training strategies improve motor and positive psychological skills development in soccer players? Insights from a systematic review. J Sports Sci. 2016;34:2338–2349. doi:10.1080/02640414.2016.1254809

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