One-Year Data on the Longevity and Safety of Hyaluronic Acid Filler for Static Horizontal Neck Rhytids

Abstract

BACKGROUND

The long-term efficacy and safety of hyaluronic acid fillers injected into the neck have yet to be analyzed in a prospective trial in the United States.

OBJECTIVE

Analyze the long-term efficacy and safety of a hyaluronic acid filler for static horizontal neck rhytids.

MATERIALS AND METHODS

Twenty-six subjects were enrolled in the study. Six subjects were randomized to receive saline and 20 subjects were randomized to receive HA_RR. All subjects were randomized to use a cannula on 1 side and needle on the other with optional retreatment on day 30 and optional crossover treatment with different assignment on day 60. The subjects were graded using the Transverse Neck Line Scale, Canfield photography, and the Global Aesthetic Improvement Scale on day 360.

RESULTS

A significant improvement from baseline on day 360 was achieved on the Transverse Neck Line Scale according to the blind evaluator, subjects, and investigator without any delayed-onset or prolonged side effects. There was no significant difference in the average improvement from the short-term analysis on day 60 to the long-term analysis on day 360.

CONCLUSION

HA_RR achieved significant long-term improvement in static horizontal neck rhytids without any long-term side effects.

Transverse or horizontal neck lines are commonly called necklace lines or more recently “tech neck” (constant bending of the neck to look at cell phones and tablets is believed to be contributing to these lines). Just as lines on the face are treated with hyaluronic acid (HA) filler, these neck lines are also increasingly being treated the same way off-label. Although there are other treatment options for the neck, HA filler remains the obvious choice for horizontal neck lines given the limited downtime, minimal side effects, ease of treatment, cost, and efficacy. Most other treatments require multiple sessions for modest improvements^1–4 or are too dangerous to perform on the neck, such as deep ablative full-field laser resurfacing.^5,6

Although HA for neck lines has gained popularity, the long-term safety and efficacy of HA fillers have only been studied extensively on certain areas on the face; long-term data regarding neck treatments is lacking. Most publications on HA in the neck are retrospective reviews or case reports,^1,7–9 with few prospective studies lasting only 1 to 3 months (Table 1).^10–13 Although there is a 5-point validated scale to assess transverse neck lines (TNLS) in clinical trials,¹⁴ only 2 publications have used this scale for a prospective study, and both used a 1-month endpoint without any long-term data.^10,11

TABLE 1.

Neck Hyaluronic Acid Literature Review

Study Type	Location	Efficacy Time Point	No.	Technique	HA Filler Type	1st Author, Journal, Year
Case reports	United States	5 and 12 wk	2	22 G and 27 G C	VYC-15L and CPM-HA	Minokadeh, Derm Surg, 2018
Prospective	Korea	2 mo	12	Pneumatic jet	“Heavy HA”	Han, Derm Surg, 2011
Retrospective	Taiwan	36 wk	26	30 G N and 25 G C	CPM-HA and Xylocaine	Tseng, PRS, 2019
Retrospective	Korea	2 mo	14	31 G N	Many HA types	Lee, JCD, 2017
Prospective	China	3 mo	8	4 mm 30 G N	NCHA w/carnosine	Wang, Aesth Plas Surg, 2021
Prospective	Italy	1 mo	42	32 G N	VYC-12	Renga, Derm Surg, 2022
RPC	United States	1 mo	26	27 G C or 32 G N	HARR	Siperstein, Derm Surg, 2022
Prospective	United States	360 d	24	27 G C and 32 G N	HARR	Current paper

RPC, randomized placebo controlled; G, gauge; C, cannula; N, needle; NCHA, noncrosslinked hyaluronic acid.

The data from the current studies show short-term improvement with minimal transient side effects; however, the question of long-term efficacy and delayed onset side effects remains unanswered. Given the high degree of neck mobility, there is concern regarding the long-term efficacy with HA treatment in this area, despite newer longer-lasting HA options now available in the United States. In addition, many are concerned about delayed onset swelling, nodules, or bluish discoloration given the thin skin, minimal fatty layer, and the need to place the filler in the dermis for optimal results.¹⁰ Therefore, an extension to a previously published trial¹⁰ was performed, because the results from a long-term prospective clinical trial are vital for clinician knowledge.

Materials and Methods

A single-center study with an extension to provide a 1-year endpoint was performed at a private practice in Boynton Beach, FL. The study was conducted in accordance with the ethical guidelines and principles of the 1975 Declaration of Helsinki and good clinical practice. The protocol received Investigational Device Exemption approval on June 5th, 2020, from the FDA, and was approved on August 10th, 2020, by Sterling IRB.

Patient Selection

Subjects 22 years of age and older with neck lines ranging from 1 to 3 on the Transverse Neck Line Scale (TNLS)¹⁴ in good general health were eligible to enroll. Exclusion criteria included the following: allergy to HA or lidocaine, neuromodulators in the neck in the previous 6 months, HA filler in the neck in the previous 2 years, history of surgery or nonhyaluronic acid fillers in the neck, pregnancy or nursing, oral or topical retinoid use on the neck in the previous 6 months, and the need to use anticoagulants, chemotherapy, immunosuppressive agents, immunomodulatory agents, diuretics, antihistamines, or anti-inflammatory 2 weeks before or during planned treatments.

Study Design

Twenty-six subjects (52 neck halves) were assigned using random sorting with a computer-generated sequence to receive Restylane Refyne (HA_RR, Galderma S.A., Lausanne, Switzerland) (n = 20) or saline (n = 6) with a cannula on 1 side and a needle on the other.

Subjects received up to 1 cc on each side of the neck with an optional additional treatment with the same group assignment on day 30 if deemed appropriate by the primary investigator. On day 60, subjects were allowed to crossover receiving a cannula treatment on the needle side and vice versa if the subject or investigator rated the 2 sides unequally. In addition, the control subjects were allowed to have 1 treatment with up to 2 cc of HA_RR on each side with a cannula, needle, or both as determined by the primary investigator on day 60. Subjects were graded by a live blind evaluator, Canfield standardized photos were taken, and questionnaires were obtained from patients. Subjects were blind until day 60 and the evaluator remained blind throughout the study.

Treatment

A single dermatologist (Dr. Siperstein) performed the injections. The treatment area included any horizontal rhytids in the anterior neck region. A 32-Gauge 4-mm needle with approximately 0.002 cc aliquots (measured by averaging the total volume injected divided by the number of injections for each subject) or a 27-Gauge cannula with approximately 0.05 cc aliquots were used to inject according to the grouping. Manual molding with a cotton tip applicator was performed after the injections. The total amount of filler used was based on the number, width, and depth of the rhytids according to the primary investigator.

Study Endpoints

The primary endpoint of the long-term extension study was the mean change from baseline to day 360 on the TNLS according to a live blind evaluator. The primary endpoint was scored in 24 of the 26 subjects with 2 subjects lost to follow-up. Secondary endpoints included the Global Aesthetic Improvement Scale (GAIS), side effects, the mean difference between the TNLS score from day 60 to day 360, and TNLS score when viewing standardized Canfield Vectra photos.

Safety Assessments

At all visits, the blind evaluator and investigator assessed the subject for any side effects and subjects were asked about side effects in questionnaires.

Statistical Analysis

When analyzing the mean change on the TNLS (continuous variables) from day 0 to day 360 or day 60 to day 360, a dependent Student t test with a one-tailed hypothesis was used to verify HA_RR's efficacy. Descriptive summaries of categorical outcomes include the types of side effects and skin type and sex of the subjects, whereas descriptive summaries of continuous measures include the subject's age, and baseline scores on TNLS, which are reported with the number of subjects (n), mean, median, minimum, and maximum.

Results

Demographics

All subjects' ages ranged from 35 to 75 (mean 53.46, median 54). There were 2 men and 24 women with Fitzpatrick Skin Types 1 to 6 (at least 2 subjects with each skin type). The mean baseline score of all subjects on the TNLS was 2.7 (range 1–3, median 3) for both sides of the neck.

Product Amount

The average volume of HA_RR used in treatment groups 1 and 2 (N = 20) on day 0 was 0.43 cc (range: 0.05–1.00 cc) on each side. The average volume injected on day 30 was 0.27 cc (range: 0.05–0.95 cc) on each side. When combining day 0 and day 30 treatments for those in groups 1 and 2, subjects used an average of 1.4 cc total of HA_RR for both sides of the neck over the 2 treatments. Subjects in groups 3 and 4 (saline control) were eligible to receive up to 2 cc of Restylane Refyne on each side of their neck with any method on day 60 as a crossover treatment. The average volume injected at that time for these groups was 0.995 cc in total for both sides.

Long-Term Efficacy Primary Endpoint

The mean reduction in the TNLS from day 0 to day 360, in those receiving 2 treatments, 1 month apart (n = 18), with an optional third crossover treatment if they were uneven (12/18), as rated by a blind evaluator viewing live patients, was −1.84 ([t(36) = −14.201, p < .00001]). Similarly, the subject (−1.64) and investigator (−1.75) scores showed the same significant findings, as shown in Figure 1.

Figure 1.

TNLS scores.

Secondary Endpoints

When comparing the day 60 scores to the day 360 scores, there was no significant difference or loss in improvement according to the blind evaluator, subject, and investigator. The maintenance of reduction on the TNLS from day 60 to day 360 can also be observed in the Canfield standardized photographs. When the blind evaluator rated photos, there was a slightly smaller but still highly significant decrease in score (−1.1) from day 0 to day 360, t(36) = −10.712, p < .00001] with no significant decrease in effect from day 60 to day 360 in most patients as can be shown in Figures 2–4 below, with the minority of patients having minimal regression, Figures 5–7. On day 360, 100% of subjects receiving 2 active treatments reported an improvement (1–3 on GAIS) in their neck lines (18/18). In addition, 67% (12/18) reported the lines as much or very much improved on day 360 (2–3 on GAIS), which is a similar percentage (67% vs 68%) to those reporting much or very much improved (2–3 on GAIS) on day 60.

Figure 2.

Representative outcome no. 1 day 0.

Figure 4.

Representative outcome no. 1 day 360.

Figure 5.

Representative outcome no. 2 day 0.

Figure 7.

Representative outcome no. 2 day 360.

Figure 3.

Representative outcome no. 1 day 60.

Figure 6.

Representative outcome no. 2 day 60.

Safety

All side effects (erythema, bruising, lumps, pain, swelling, and itching) resolved within 30 days of treatment. There were no long-lasting side effects or delayed-onset side effects such as granuloma, nodules, hyperpigmentation (Figures 8, 9), or bluish discoloration reported by the subjects, blind evaluator, or investigator. There were no related AEs to the study product or injection procedure. There were no serious AEs and no action needed to be taken by the PI.

Figure 8.

Darker Fitzpatrick skin type, baseline day 0.

Figure 9.

No hyperpigmentation, day 360.

Discussion

Although there are many cosmetic procedures that can be performed on the neck, most are not effective specifically for transverse neck lines. The literature on HA alone for the neck is limited and summarized in Table 1. Although most agree HA is ideal for filling lines, there is concern for superficial HA in the neck because of the thin skin and limited fat layer, causing increased risks of long-term contour irregularities, delayed-onset nodules, and a bluish discoloration often called the “Tyndall Effect.” The first author has used HA fillers for many years to treat this condition with long-term patient satisfaction and obtained an Investigational Device Exemption from the FDA to perform the first prospective long-term trial in the United States.

There are MRI studies showing the presence of filler for many years after injection^15,16 and surgeons have also noted this same phenomenon,¹⁷ lending to the plausibility of improvement from HA filler to persist beyond its on-label indication. However, this longevity has been noted to differ based on the area.¹⁶ In addition, in the author's opinion, filler on MRI or found in tissue during surgery does not always correlate with remaining clinical improvement, because the muscle movement that caused the line in the first place can also cause the filler to be pushed away, creating a recurrence of the line despite the persistence of the HA filler in the surrounding area. Therefore, it was hypothesized that because of the frequent movements in the neck, the longevity for transverse neck lines would be less than that of the face. Surprisingly, that was not the case and believed to be a combination of the technique and rheology of the filler used in this trial.

HA_RR is known for its flexibility, which is beneficial in dynamic areas to allow it to appear more natural and maintain its shape during movement contributing to its longevity in mobile areas. Comparisons of the flexibility of HA gel products can be performed using the amplitude sweep method, in which the yield point (endpoint where the deformation of material is large enough that it can no longer return to its original shape) is called xStrain.¹⁸ Higher xStrain values indicate more flexibility. When comparing most of the available HA products in the United States, HA_RR has the highest xStrain¹⁹ and is therefore described as the most stretchable, or flexible and may be 1 of the reasons for the longevity of this filler in the neck, which is one of the most dynamic areas. Another term often used in rheological literature is gel cohesion, which is described as the capacity to remain intact without disassociating. In a study analyzing over 18 HA fillers, HA_RR was one of the most cohesive products, also likely contributing to its longevity.²⁰

In the first 30 days of this trial, there were some contour irregularities that were effectively treated with massage and resolved; however, there were no reports of long-term or delayed-onset swelling, nodules, granulomas, contour irregularities, or bluish color during the 360-day trial. The lack of long-term side effects is also likely because of the injection technique with small aliquots of a filler with the proper rheology (HA_RR is a soft HA gel with small particles and low G′).²¹ Although this clinical study showed no long-lasting side effects, this may not have been the case if a filler with different rheological properties and different injection techniques were used.

As a reminder, the author recommends visualization of the cannula in the proper plane above the platysma by lifting it and seeing the outline before injection and the utilization of a 4-mm needle, which prevents being able to reach any important structures even if directing it vertically into the skin as opposed to parallel as observed in Figure 10. In fact, the copacked needle is capable of injecting filler into the carotid artery, which could have devastating consequences and is why the knowledge of anatomy in this area is vital to safe outcomes. Thankfully, all significant arteries and veins (internal jugular vein and carotid artery) and the critical organs of the neck (thyroid, larynx, and parathyroid) are located underneath the platysma and the superficial fatty layer of the neck is free of neurovascular structures, so the risk for adverse events is reduced compared with other areas of the head and neck as long as the anatomy is properly understood (Figure 11).

Figure 10.

Ultrasound imaging with depth of carotid artery.

Figure 11.

Cadaver dissection showing platysma protecting vital organs courtesy of Dr. Cotofana.

Despite the neck area being difficult to treat, with the correct product, technique, and knowledge of anatomy, patients are likely to have high satisfaction rates as observed in our trial. Because many injectors may not be able or willing to inject aliquots of 0.002 cc, another option would be to dilute the filler before injection, however then additional treatments are likely needed.

The most surprising finding is that in some cases, the outcome was rated better on day 360 compared with day 60. A few possible reasons for this outcome include (1) better integration of the HA filler over time; (2) collagen production from injection with a needle into the rhytid over 100 times in most subjects; and (3) lifting untanned skin from a depression to allow it to tan similarly to surrounding skin in the following months creating an illusion of improved lines as seen in Figures 12–14.

Figure 12.

Baseline, day 0.

Figure 14.

Continual improvement, day 360.

Figure 13.

Day 60.

A limitation of this analysis was the small sample size, and a larger study will still be necessary to assess the findings in a larger population. In addition, now that the results have been shown to last 1 year, an even longer prospective trial is necessary to determine the exact longevity of this treatment.

Although the trial only lasted 1 year, many of the patients continued to return to the practice since then for other treatments at which time their photos were taken and enabled the first author to perform a more recent longer-term retrospective study. In that review, 4 patients had been seen for facial treatments 2 years since the start of the trial, none had further neck treatments, and all consented to use of their photos. The longest post-treatment photos found during the retrospective review was 2 years and 3 months after the last treatment as shown in Figures 15–17 with significant remaining improvement. Blind evaluators were able to choose the after photo in all 4 subjects, and although this review of 4 patients is small, it shows the potential for this treatment to last many years.

Figure 15.

Baseline, day 0.

Figure 17.

Improvement remains after more than 2 years.

Figure 16.

Day 360.

Conclusion

The neck has many vital structures and lots of movement; however, this area can be safely injected with HA_RR above the platysma, with patient and injector satisfaction lasting at least 1 year, making it a long-lasting treatment.