Cosmetic injectables in skin of color: A review of uses, safety, and effectiveness of neuromodulators and dermal fillers

Skin of color (SOC) individuals represent a growing market for cosmetic injectables and can have different aesthetic goals and responses to treatment.

variations in facial morphology, which exists across various races and ethnicities is key to successful aesthetic enhancements.
In the face of divergent structural, cultural and aesthetic considerations in SOC, this article provides an overview of the available literature on the applications as well as the safety and efficacy of neuromodulators and soft tissue augmentation in SOC with an emphasis on Asian populations, for which there is the greatest amount of data.There remains a paucity of data for non-Asian SOC populations and this limited data will also be reviewed.

| ME THODS
A literature search of the PubMed/MEDLINE database was conducted spanning dates August 1960 to December 2020.Keywords included "botulinum toxin," "dermal filler," "Asian," "skin of color," "people of color," "ethnic skin," "race," "Black," "African American," "Caucasian," "White," "Hispanic," "Latino," "Fitzpatrick," and variations of these terms.Criteria for inclusion included a focus on SOC (>20% SOC study participants or dedicated article content commenting on the safety and/or efficacy of injectables in SOC participants), being written in the English language, and institutional access.Priority was given to randomized controlled trials and other included study types were meta-analyses, reviews, prospective and retrospective studies, case series, case reports, and expert consensus guidelines.Articles were excluded if they did not include human subjects, participant racial and/or ethnic demographics (if not published internationally), use of injectables for non-facial cosmetic purposes, or if injectables were used in combination with other therapies (laser, grafting).

| RE SULTS
Of the 503 publications identified through the search strategy, a total of 88 articles were selected for this review.Of these 88 articles, 50 had level I and II evidence and were assessed to investigate the uses, safety, and effectiveness of injectable neuromodulators and dermal fillers in SOC individuals.A flow chart for the selection of articles is shown in Figure 1.Articles were categorized according to participant race/ethnicity demographics, this included Asian, Black/Latinx, and combined SOC patient groups.The total number of analyzed patients in this review was 9 940.Details regarding the type of study, number of patients, race/Fitzpatrick phototype, treated areas, dose, treatment period, outcome measure/scoring method, and adverse event information for each of these studies are summarized in Tables 1-3.
Differences in aging and cultural factors can influence aesthetic goals amongst SOC populations.Available data suggests that BTX and dermal fillers are safe and effective in SOC populations, with the largest amount of data available for Asian populations.There remains a paucity of research on Black and Latinx populations.

| Asians
The Asian population is heterogenous and encompasses those with countries of origin in the Asian continent.Regions include East Asia (e.g., China, Korea, Japan, Taiwan), Southeast Asia (e.g., Thailand, Singapore, Indonesia, Philippines), and South Asia (e.g., India, Bangladesh, Sri Lanka). 34,35The majority of the studies in this F I G U R E 1 Flow diagram for review of injectable studies on skin of color (SOC).Flow diagram depicting review process and the inclusion and exclusion process of studies identified on PubMed/Medline databases.
review originated from Korea, Japan, and China.7][38] In Asians, pigmentary changes including solar lentigines, pigmented seborrheic keratoses, hypochromia, and mottled hyperpigmentation are seen in the early stages of aging with deep, coarse rhytides typically developing by the 5th decade of life. 39,40It has been suggested that Asians have a more malleable skeletal framework, resulting in gravitational soft tissue descent and ptosis of the midface and malar fat pad, along with tear trough formation. 41udies have found preferential differences amongst East Asian population, such as Japanese women tend to prefer thinner lips while Korean women tend to prefer thicker lips. 36In addition, Koreans generally elect to highlight their palpebral creases and soften their mandibular angles to eliminate any "square jaw" appearance. 36ongst Chinese patients, some favor larger earlobes, a symbol of "richness" in traditional Chinese culture. 42ltiple high quality studies have assessed the safety and effectiveness of botulinum toxin (BTX) in the treatment of glabellar lines in Asian populations (Table 1).Two double-blind, randomized, placebo controlled studies demonstrated that BTX A was effective in treating glabellar lines in both Chinese and Japanese subjects. 8,11e response rate at maximum contraction at Day 30 was 94.1% in Chinese subjects, 11 which was similar to the 88.6% response rate in Japanese subjects. 8In another study of glabellar line treatment in Japanese subjects, 20 U doses of BTX A provided longer duration, greater subject satisfaction, and greater subject-rated improvement compared to 10 U doses, while both doses provided long term safety and efficacy. 9Comparing Asians to non-Asians in a pooled analysis of four phase II/phase III trials, 20 U incobotulinumtoxin A provided a slightly higher response rate in the improvement of glabellar lines and lower rate of adverse events. 15ere have been several consensus guidelines on use of BTX in Asians. 43,44In 2016, the Pan-Asian Aesthetics Toxin Consensus Group described three Asian facial morphotypes (northern, intermediate, and southern) and recommended specific strategies for each including using bony and muscular landmarks rather than soft tissues for injections and injecting 0.5 U into the frontalis on each side to prevent the arched "Samurai eyebrow". 43Although specific to Koreans, consensus guidelines from 2013 address BTX treatment of glabellar lines, crow's feet, infraorbital wrinkles, nasal flare, depressed nasal tip, and benign masseter hypertrophy. 44garding adverse effects, a meta-analysis of six double-blinded, randomized, placebo-controlled and three open-label studies (n = 1678) with an aggregate cohort that was 52% Asian and 43% White, Asian patients trended towards a higher likelihood of eyelid sensory disorders and eyelid edema but a lower likelihood of eyelid ptosis as adverse events. 10This was attributed to awareness of the differences in Asian and White eyelid anatomy, including aponeurotic insertion locations and the fact that Asian levator muscles do not penetrate the orbicularis muscle and orbital septum. 10A more recent literature review suggested a 1.4% incidence of BTX induced eyelid edema, with an elevated risk amongst Asians. 45The rate of these adverse events can be lowered by using doses less than 20 U, which was found to be effective for treating all glabellar line patterns in a randomized pilot study of 465 Chinese volunteers. 46Though lower doses of BTX may help reduce the rate of adverse events, as discussed by Kawashima et al., a shorter duration of response after treatment may be observed with the use of 10 U doses as compared to 20 U doses. 9 A common off-label use of BTX in Asians is for masseter muscle hypertrophy to reduce the width of the lower face, converting a square face to a more oval shape. 35This minimally invasive strategy has largely replaced surgical resection of the masseter.rimabotulinum toxin B, onabotulinum toxin A, and incobotulinum toxin A have been studied for this indication.Rimabotulinum toxin B has similar efficacy to onabotulinum toxin A, but may have a shorter duration of action 13 and incobotulinumtoxin A has been established as non-inferior to onabotulinum toxin A. 12 In Indians of Asian descent, BTX A injections every 12 weeks were effective at maintaining significantly reduced masseter volume through a 4-year follow-up period. 19Other studies have found this application of BTX to be generally both safe and effective, 6,7,16,19,47,48,49 however, high quality randomized controlled trials evaluating the safety and efficacy of this treatment are lacking. 50garding safety, the incidence of complications included temporary mastication force decrease (30%), bruising (2.5%), headaches (0.58%), smile limitation (0.15%), paradoxical bulging (0.49%), sub zygomatic volume loss (0.44%), and sagging (0.4%) in a recent study. 50jecting within the "safe zone," described as 3-4 different locations at least 1 cm from any border was recommended to prevent complications. 51Many of these complications are transient. 51,52rmal fillers have been studied extensively in Asian populations (Table 1).There were several studies evaluating the safety and effectiveness of hyaluronic acid (HA) fillers for the treatment of nasolabial folds (NLFs) in the Asian population. 20,27,31,32,33,53,54Generally, HA fillers were effective for the treatment of NLFs in Asian patients with significant improvement in the appearance of moderate to severe NLFs. 27,31,32,33,53,54Adverse effects included injection site swelling and pain, but the majority were mild to moderate and transient. 20,27,31,32,33,53,54Other studies are highlighted in Table 2.
4][65][66][67] Vascular compromise can result in visual impairment. 68Large volume HA fillers may also cause bone resorption in the mentum in Asians, which doesn't impact the aesthetic result, but should be disclosed to patients in informed consent. 69Of note, this has not been studied in other racial/ethnic groups.
Consensus guidelines for use of fillers capture the specific aesthetic goals of Asians. 35,70,71When injecting the midface, volume should be placed in the medial half to correct structural deficits of the medial maxilla with projection and to restore volume in older patients. 35Caution should be exercised when volumizing the lateral TA B L E 1 Studies on injectables in Asian patients (levels I-II evidence).

| Black
The safety and efficacy of injectables have also been studied in Black and Latinx populations to a lesser extent (Table 2).There are three publications describing the safety and efficacy of the neuromodulator, BTX A, specifically in the Black population. 55,56,72Overall, treatment with BTX A was well tolerated in Black populations.In one study, there were no significant differences in terms of clinical response and response duration between subjects injected at the glabellar lines with 30 U of BTX A compared to those injected with 20 U BTX A. 55 These results are supported by a more recent study showing similar effectiveness and tolerability of BTX A in Black patients compared to Whites. 72Interestingly, another study demonstrated a significantly greater response rate as assessed 30 days after treatment in SOC patients included in the study. 56Adverse effects were generally mild and transient. 55,56,72ree studies evaluated the safety and efficacy of injectable fillers in the Black populations.8][59] Most changes in pigmentation started within a few days of the procedure and most resolved within 12 weeks. 57,58 a randomized split faced trial evaluating the safety dermal fillers for NLF treatment in 150 patients with SOC, only three patients developed post-inflammatory hyperpigmentation, characterized by hyperpigmentation that did not resolve by 12 weeks. 57In an openlabel, multicenter trial evaluating the safety and effectiveness of dermal fillers for NLF treatment in 93 patients with Fitzpatrick skin types IV, V, and VI, hyperpigmentation was reported in one patient at Week 12 and in one patient at Week 24. 59Overall, the rates of PIH were low. 57,59In patients with SOC, pigmentary changes at treated sites have been observed with fast injection rates and with multiple puncture techniques. 57To minimize the risk of PIH in patients with SOC, it is recommended to inject sub-dermally, use slower injection rates, and utilize injection techniques that minimize the number of punctures, such as linear threading. 57,73,74 regard to scarring, no keloid scars were observed. 57,59One patient developed a mild hypertrophic scar, which was resolved by the subsequent visit. 57Hypertrophic scars are not included in the keloid classification, as these two types of scars differ in etiology and natural course. 57Further, the acute tolerability and adverse event profile seen in patients with SOC were similar to those reported in a trial involving predominantly White patients. 57Moreover, the incidence of systemic adverse events reported was low and ranged from 7.3% to 11.8%. 57,59These systemic adverse events were considered to be unrelated to treatment and were described as conditions seen in healthy adults such as influenza and gingival abscess. 59Furthermore, HA fillers were effective in the treatment of facial rhytids and NLF, reducing rhytids by at least one Wrinkle Severity Rating Scale (WSRS) grade in >90% of patients at 6 and 12 weeks in one of the studies. 58 another study, the Wrinkle Severity Scale ratings in patients with Fitzpatrick skin types IV-VI combined demonstrated improvement at all-time points over the 24-week study period. 59

| Latinx
In the Latinx population, there are no robust prospective studies evaluating the safety and efficacy of cosmetic BTX.In a small descriptive study of mostly Latinx patients, BTX was the most popular cosmetic option. 75There are three studies that focus on the safety and efficacy of injectable fillers in Latinx populations.These studies evaluated HA filler 62,76 and Poly-L-Lactic acid filler. 62Treatment

TA B L E 3 (Continued)
with dermal filler in the Latinx population was well tolerated as there were no serious treatment related adverse events in any of the studies. 61,62,76It was also effective as measured by at least a 1-grade improvement on a 4 point volume loss scale (VLS) 62 and improvements lasted long term in studies with greater than 1 year follow-up periods. 61,76ere are few studies broadly evaluating the safety and efficacy of BTX in multiple SOC populations (Table 3).Proper injection techniques may reduce the risk of adverse events associated with treating patients of color.Specific minimal injection techniques, including linear threading, have been noted to reduce bruising in patients of color. 77A prospective, blinded, randomized, controlled trial of 283 diverse patients investigated injection techniques and their correlation to adverse events and concluded that injection volume and correction time affected the rate of post-inflammatory events. 78e study also noted that more adverse events occurred with fanlike injections (54%) compared to linear threading and multiple puncture injection techniques combined (20%).

ACK N OWLED G M ENTS
There are no additional acknowledgements.

FU N D I N G I N FO R M ATI O N
No funding was received for this work.

CO N FLI C T O F I NTE R E S T S TATE M E NT
Poly-L-lactic acid NLFs Talarico et al., 2015 62 Prospective cohort (II) 60 Brazillian/I-V HA filler At least two of the following: chin, temporal areas, jawline, cheeks, cheekbones, and NLFs Note: Summary of level I-II studies on botulinum toxin and filler in Black and Latinx individuals.TA B L E 2 (Continued) TA B L E 3 Studies on injectables in combined skin of color (SOC) patient groups (level I-II evidence).

5 |
CON CLUS IONNeuromodulators and dermal fillers are useful and safe as cosmetic and anti-aging treatments in SOC populations, with the greatest amount of data supporting its use in Asian populations.These injectable agents offer patients effective treatments with minimal downtime and complications.During cosmetic consultations, physicians should consider the impact of different cultural beauty norms on the aesthetic goals of diverse patient populations.In this review, most of the recent data and formal consensus guidelines on injectables originated in Asian countries with a relative paucity of research on Black and Latinx populations.Therefore, more studies with Black and Latinx populations are warranted to fully understand and strengthen recommendations regarding the efficacy and appropriate use of cosmetic injectables in all skin types.Additionally, as new injectables, both fillers and neuromodulators are created, these also should be evaluated across diverse patient populations to determine best uses, safety, and efficacy.With a knowledge of anatomical differences amongst diverse populations, an understanding of cultural cosmetic norms combined with a background in treatment methods and techniques, physicians can provide patients of all backgrounds with the highest levels of patient satisfaction while minimizing adverse outcomes.AUTH O R CO NTR I B UTI O N S S.M., J.W., P.U.Methodology, investigation, writing-original draft, review and editing, visualization; A.C.M.H. Writing-review and editing; S.C.T. Writing-review and editing, supervision; N.E.Conceptualization, methodology, investigation, writing-original draft, review and editing, supervision, project administration.

Dose Treatment period Outcome measures/scoring method Adverse events Legend
NR = not reported 5-10 U in each muscle One to four treatment sessions Duration of effective response, patient satisfaction Altered facial appearance, mild local swelling, injection site ecchymosis NLFs = Nasolabial folds Variable Up to three sessions Lower face width, patient satisfaction Transient buccal weakness, transient masseter fatigue after vigorous chewing BTX A= botulinum toxin A 120 U per masseter One treatment session Masseter volume measured by CT scan, subjectrated discomfort via 5-point VAS, subject-rated facial change by 11-point VAS Fatigue with chewing, bite weakness with certain foods, injection site discomfort, soreness, ecchymosis, and swelling OBTX A = onabotulinum toxin A 10 U, 20 U or placebo Authors,

year Type of study (level of evidence) n (number of patients) Race/Fitzpatrick phototype Product Treated area
NLFsTA B L E 1 (Continued)Authors,

year Type of study (level of evidence) n (number of patients) Race/Fitzpatrick phototype Product Treated area
Note: Summary of levels I-II studies on botulinum toxin and filler in Asian individuals.TA B L E 1 (Continued)TA B L E 2 Studies on injectables in Black and Latinx patients (levels I-II evidence).

Authors, year Type of study (level of evidence) n (number of patients) Race/Fitzpatrick phototype Product Treated area
Summary of level I-II studies on botulinum toxin and filler in combined SOC populations.
. Elbuluk is the director of the Skin of Color and Pigmentary Disorders Program as well as the Diversity and Inclusion program at the University of Southern California.She serves as a consultant for Avita, Scientis, Incyte, VisualDx, La Roche Posay, Beiersdorf, Unilever.She has served on advisory boards for Allergan, Eli Lilly, Galderma, Incyte, Pfizer, Janssen, La Roche Posay, L'Oreal, McGraw Hill, Dior.She has been a speaker for Estee Lauder, La Roche Posay, Scientis, Medscape, Beiersdorf, Dior.She has received royalties from Investigator assessed NLF Severity Scale, ease of injection, product moldability, subject rated pain, and subject assessed FACE-Q and satisfaction scales Most common AEs included firmness, swelling, tenderness to touch, and lumps/bumps, redness, pain, bruising, itching, discoloration McGraw-Hill book royalties.She has served as an investigator for Avita.Dr. Taylor has been a speaker for Beiersdorf, LivDerm, L'Oreal USA, MedScape, and MJH LifeSciences.She is on the advisory board for Abbvie, Arcutis, Avita Medical, Beiersdorf, Biorez, Bristol Myers Squibb, Cara Therapeutics, Dior, Eli Lilly, EPI Health, Evolus, Galderma, Hugel, J&J, L'Oreal USA, MedScape, Pfizer, Regeneron/