Assessing changes in facial skin quality using noninvasive in vivo clinical skin imaging techniques after use of a topical retinoid product in subjects with moderate‐to‐severe photodamage

Abstract

Background

Studies utilizing reflectance confocal microscopy (RCM) and dynamic optical coherence tomography (D‐OCT) to assess cosmetic skin changes are limited.

Methods

A 12‐week, open‐label study was conducted using RCM and D‐OCT to evaluate the effects of a topical cosmetic retinol (RET05) on subjects with facial photodamage. Study endpoints included investigator grading, standardized (VISIA‐CR) and 3D photography (Antera 3D), independent RCM (VivaScope1500) and D‐OCT (VivoSight) image analysis, validated FACE‐Q scales, and subject questionnaires.

Results

Twenty‐three subjects, 45‐ to 68‐year old, with Fitzpatrick skin types II–IV completed the study. After 12 weeks of repeated application, RET05 demonstrated significant corresponding cosmetic improvements for overall photodamage, skin tone unevenness, tactile roughness, fine lines/wrinkles (forehead, periocular, and perioral), and coarse lines/wrinkles (forehead, periocular, and cheeks), and Allergan Skin Roughness Scale. FACE‐Q assessments also demonstrated significant improvements from baseline at week 12. RCM analysis showed decreases in all epidermis, less compact stratum corneum (SC), more non‐compact SC, decreases in coarse/huddled dermal fibers, and increases in fibrillar dermal fibers, as compared to baseline. D‐OCT analysis showed significant decreases in epidermal thickness (ET), reduction of moderate/many collagen fragments and collagen bundles, and significant increases in the stroma attenuation coefficient and collagen density. Moreover, the dermal–epidermal junction was more pronounced, and vascular abundance at 300 and 500 μm depth increased. Independent evaluation of RCM and D‐OCT images showed similar decreases in ET and improvements in dermal fibers.

Conclusion

This study was the first to utilize RCM and D‐OCT to evaluate the cosmetic effects of a topical retinoid and further substantiate improvements in skin quality.

1. INTRODUCTION

One of the most apparent signs of aging includes the appearance of facial lines and wrinkles. Topical retinoids have been shown to improve the visible signs of aging, including the appearance of lines and wrinkles, uneven skin tone, and skin roughness. ¹ , ² , ³

A topical cosmetic retinol RET05 was previously shown to have comparable cosmetic improvements to Tretinoin 0.05% in overall photodamage, fine lines/wrinkles, coarse lines/wrinkles, skin tone brightness, mottled pigmentation, and tactile roughness. ¹ Kong et al. have also compared retinol with retinoic acid, and both products have shown an increase in epidermal thickening and clinically significant reductions in facial wrinkles after 12 weeks of topical use. ² Duell et al. showed that retinol can produce similar histological results to retinoic acid, such as epidermal thickening and keratinocyte proliferation, with an improved irritancy profile. ⁴ Similarly, in a study conducted by Kang et al., retinol showed comparable increases in epidermal thickening with lower erythema compared to retinoic acid. ⁵ Retinol can also stimulate collagen synthesis in photodamaged skin. ⁶ Although many studies highlight the improvements that retinoids have on visible signs of aging, there is limited research looking at the cosmetic changes utilizing noninvasive in vivo skin imaging instrumentation after the application of retinoids. ¹ , ² , ³

Reflectance confocal microscopy (RCM) and dynamic optical coherence tomography (D‐OCT) are powerful techniques for the noninvasive evaluation of skin structure and morphology. Although historically used for dermatological skin cancers, these instruments have great utility for cosmetic research, such as monitoring skin changes after treatment with a topical product. D‐OCT has been used to characterize photoaged skin by evaluating differences in epidermal thickness (ET) and attenuation coefficient. ⁷ RCM has also been used to characterize photoaged skin by keratinocyte irregularity, loss of fibrillar collagen and subsequent increase in huddled and curled collagen fibers, epidermal atrophy, and increased and unevenly distributed pigmented keratinocytes. ⁸ Vasquez‐Pinto et al. have investigated and quantified surface roughness and wrinkles depth changes after using a topical antiaging cosmetic product. ⁹ Campione et al. investigated the effects of using a topical product containing 0.02% retinoic acid and 4% glycolic acid for 1 month using RCM and found improvements in the honeycomb keratinocyte pattern and reduction in mottled pigmentation. ⁹ , ¹⁰ However, few studies have examined the cosmetic effects of retinol on facial photodamage using either RCM and D‐OCT, and none using both technologies in a single study.

The aim of the following clinical study was to utilize RCM and D‐OCT to explore the cosmetic changes in the skin after treatment with RET05. Additional standardized digital photography, clinical efficacy assessments, and the validated FACE‐Q questionnaires were performed in parallel to allow objective comparison between the physical changes to the skin and clinical outcomes.

2. METHODS

2.1. Subjects

Twenty‐nine subjects were enrolled in this open‐label single‐center study. Informed consent was obtained for all subjects before performing any study procedure. Three volunteers withdrew consent prior to the study, and one volunteer was lost to follow‐up. Two volunteers discontinued the study due to mild skin‐related adverse events.

Eligible participants were males and females aged 40‐ to 70‐year old with Fitzpatrick skin types I–IV that presented moderate‐to‐severe overall photodamage, assessed as a score of 5–9 on the following scale: 0 = none, 1–3 = mild, 4–6 = moderate, and 7–9 = severe. All subjects were in good general health. Main exclusion criteria included those who could not avoid sun exposure or were nursing, pregnant, or planning to become pregnant.

Subjects were asked to avoid direct and excessive sun exposure and tanning beds for the duration of the study.

The study was conducted at the Skincare Clinical Research and Innovation Center in Irvine, California from September 2017 to April 2018.

2.2. Treatment protocol

2.2.1. Study products

The test product was a topical cosmetic retinol (RET05) containing 0.5% retinol in a cream base. Basic skincare products, including a facial cleanser, moisturizing lotion, and sunscreen, were used for the duration of the study.

2.2.2. Product application

After enrollment and 2 weeks prior to the baseline visit, subjects had a wash‐out period in which a basic skincare regimen (facial cleanser, moisturizing lotion, and sunscreen SPF35) was used. At the baseline visit, subjects were provided with RET05 and basic skincare products. In the morning, subjects were instructed to use their basic skincare regimen only. In the evening, subjects were instructed to apply a nickel‐sized amount of RET05 after cleansing the face, every other evening in the first week of use and to increase frequency to every evening as tolerated. The moisturizing lotion was applied after RET05.

2.2.3. Clinical grading of efficacy parameters

Clinical grading of efficacy parameters were conducted at baseline and weeks 4, 8, and 12.

Subjects were clinically graded for the following parameters on each the left and right side of the face using the modified Griffiths’ 10‐point scale ¹¹ according to the following numerical definitions:

• Overall photodamage (0 = none, 1–3 = mild, 4–6 = moderate, 7–9 = severe).

• Skin tone unevenness (0 = none, 1–3 = mild, 4–6 = moderate, 7–9 = severe).

• Tactile roughness (0 = none, 1–3 = mild, 4–6 = moderate, 7–9 = severe).

• Fine lines/wrinkles (forehead, periocular, cheeks, perioral—individually assessed) (0 = none, 1–3 = mild, 4–6 = moderate, 7–9 = severe).

• Coarse lines/wrinkles (forehead, periocular, cheeks, perioral—individually assessed) (0 = none, 1–3 = mild, 4–6 = moderate, 7–9 = severe).

Subjects were clinically graded using the following validated scales:

• Allergan Skin Roughness Scale (0 = none, 1 = minimal, 2 = moderate, 3 = severe, 4 = extreme).

• Allergan fine lines scale (0 = none, 1 = minimal, 2 = moderate, 3 = severe, 4 = diffuse).

2.2.4. Investigator's global improvement assessment

Investigator's global improvement assessment was conducted at weeks 4, 8, and 12 for overall photodamage, fine lines/wrinkles of forehead, periocular, cheeks, perioral areas (individually assessed), coarse lines/wrinkles of forehead, periocular, cheeks, perioral areas (individually assessed), and tactile roughness for the face of each subject using the following scale:

• 0 = no change or worsening.

• 1 = mild improvement (∼25% overall improvement).

• 2 = moderate improvement (∼50% overall improvement).

• 3 = marked improvement (∼75% overall improvement).

• 4 = complete clearing (∼95%+ overall improvement).

2.2.5. Tolerability evaluations

Tolerability assessments were conducted at baseline and weeks 4, 8, and 12.

• Erythema and dryness/scaling were clinically assessed by the investigator/sub‐investigator on a 0–3 scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe.

• Burning/stinging and itching were assessed by the subject on a 0–3 scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe.

2.2.6. Imaging procedures

Prior to imaging, subjects were instructed to remove any makeup, including foundation makeup, lipstick/gloss, and eye shadow. Study staff ensured that jewelry was removed from ears/neck and hair was pushed back away from the face, ensuring that no stray hairs were in the facial area. Subjects were instructed to adopt neutral facial expressions and neutral angles (e.g., avoiding hypo‐ or hyperextension of the neck).

• Full face digital images were taken of each subject (left, right, and center views) using the VISIA‐CR Blue 4.3 Camera Imaging System (Canfield Imaging Systems, Fairfield, NJ, USA).

• Triplicate 3D images using the Antera 3D System (Miravex) were taken of a target location on the subjects’ face.

• Images of a designated region of interest (ROI) taken with the VivoSight D‐OCT system (Michelson Diagnostics, UK) (system setting: 6 mm at 500 frames).

• Images of a designated ROI were taken with the VivaScope 1500 RCM system (Caliber Imaging and Diagnostics, NJ, USA) (five stacks up to 150 μm of the center, top, bottom, left, and right of ROI; three 4 mm × 4 mm blocks of the epidermis, dermal–epidermal junction (DEJ), and dermis of ROI).

2.2.7. VivoSight D‐OCT image acquisition and evaluation

D‐OCT images were acquired and analyzed as previously described. ¹² Briefly, D‐OCT images were taken of an investigator‐selected area on the subjects’ face, which was kept consistent for all follow‐up visits. Images were captured with a 6 mm × 6 mm area of 500 frames by a trained operator. For the D‐OCT analysis, the original image scans (500 frames) were reduced to a smaller number of frames while maintaining the resolution of each individual frame to process with analysis software. One in every four frames was utilized for analysis. The images were analyzed by an independent expert physician. The parameters evaluated were as follows:

• ET

  • ○Mean of three measurements taken at three different areas as determined by the evaluator. Pre‐evaluation is conducted to exclude areas with artifacts or anomalies.

• Contoured DEJ (present or absent)

• Collagen fibers (normal or in bundles)

• ROI density and attenuation coefficient

  • ○A standardized box for the ROI is positioned in the center of the scan immediately below the epidermis (ensuring that hair follicles and artifacts are excluded from the ROI).

• Integrity of collagen—4‐point descriptive and visual scale ¹³

  • ○0 = not fragmented
  • ○1 = few fragmented collagen fibers
  • ○2 = moderate fragmented collagen fibers
  • ○3 = many fragmented collagen fibers

• Score of vessels (at 300 and 500 μm)—4‐point descriptive and visual scale ¹³

  • ○0 = vascular network fragmented/not perceivable
  • ○1 = thin vascular network
  • ○2 = evident vascular network
  • ○3 = prominent/thick vascular network

• Vascularity quantification using ImageJ with thresholds at 300 and 500 μm depth.

2.2.8. VivaScope 1500 RCM image acquisition and evaluation

The VivaCam image was captured of the target location and the orientation was documented. Three VivaBlock images (4 mm × 4 mm) of the epidermis, DEJ, and the dermis and five 150 μm VivaStacks were taken at 1.5 μm steps starting right above the level of the stratum corneum (SC).

RCM analysis was done by an independent expert physician. The parameters evaluated were as follows:

• SC thickness.

• ET.

• Compactness of SC (compact or uncompact).

• Keratinocyte contour (normal or blurred).

• Pigmented keratinocytes at the DEJ (4 mm × 4 mm VivaBlock—16 frame semi‐quantification).

• Inflammatory cells in the dermis.

• Dilated vessels.

• Collagen bundles (fibrillar, coarse, or huddled) (4 mm × 4 mm VivaBlock images divided in quarters).

2.2.9. Antera 3D image acquisition and evaluation

Triplicate images were taken of a 5 cm × 5 cm area on the face determined by the investigator. The images were analyzed utilizing the Antera 3D software with Spot‐On technology that automatically registers the follow‐up images with their respective baseline for the following parameters:

• Color (L*, a*, b*, ΔE).

• Texture (R _a, R _q).

• Pores—small filter (volume, index, count, density).

• Wrinkles—2‐mm filter (overall size, depth, width, max depth).

• Melanin (level and hyperconcentration).

• Redness (level and hyperconcentration).

2.2.10. Spectrophotometer measurements

Triplicate spectrophotometer measurements were taken. One target hyperpigmented lesion was selected on the face and measured by the spectrophotometer CM‐700d/600d. Measurements at subsequent visits were taken from the exact target lesion locations as at the baseline visit within each subject.

One target “normal” measurement was also taken from an unaffected skin area on the face representing normal skin. The values from the target hyperpigmented lesions will be compared to the normal lesion value.

2.2.11. FACE‐Q‐validated scales

Subjects completed the following validated subject skin and age self‐assessments and quality of life questionnaires:

• Satisfaction with skin (baseline and weeks 4, 8, and 12).

• Aging appearance appraisal (baseline and week 12).

• Age appraisal—visual analog scale (VAS) (baseline and week 12).

• Lines—overall (baseline and week 12).

• Social confidence (baseline and week 12).

• Psychological well‐being (baseline and week 12).

2.2.12. Subject self‐assessment questionnaire

Subjects completed a sponsor‐provided self‐assessment questionnaire regarding their experience and overall satisfaction with the test product (RET05) at weeks 4, 8, and 12.

3. RESULTS

3.1. Final study population

Twenty‐three volunteers completed the 12‐week study.

3.2. Investigator grading efficacy parameters

There were early significant improvements at week 4 compared to baseline in the appearance of fine lines/wrinkles (forehead) (p = 0.0461; Wilcoxon signed rank test) and of coarse lines/wrinkles (cheeks) (p = 0.0005; Wilcoxon signed rank test). Significant improvements at week 8 compared to baseline was observed for overall photodamage, skin tone unevenness, tactile roughness, fine lines/wrinkles (forehead, periocular, perioral), coarse lines/wrinkles (periocular and cheeks), and Allergan Skin Roughness Scales (all p ≤ 0.0474; Wilcoxon signed rank test). All significant efficacy parameters at week 8 continued to show significant long‐term improvements at week 12 compared to baseline (p ≤ 0.03; Wilcoxon signed rank test). Additionally, for coarse lines/wrinkles, insignificant efficacy was observed at week 8, but significant improvements were noted at week 12 relative to the baseline measure (p = 0.0347, Wilcoxon signed rank test).

3.3. Investigator's global improvement assessment

The investigator's global improvement assessment of overall photodamage showed a high response rate, defined as at least 1‐point improvement (>85%) at weeks 4, 8, and 12. For tactile roughness, there was a response rate, defined as the proportion of subjects with at least 1‐point improvement in the tactile roughness assessment, for more than 50% of subjects at week 4 and continued increase in response rate at weeks 8 and 12 (61% and 70%, respectively). For coarse lines/wrinkles, there was a response rate of over 60% of subjects at week 12 for forehead, periocular, cheeks, and perioral areas (61%, 91%, 70%, and 61%, respectively). For fine lines/wrinkles, there was a response rate for a high percentage of subjects (>85%) at week 12 for forehead, periocular, cheeks, and perioral areas (87%, 87%, 96%, and 91%, respectively). For the coarse lines/wrinkles and fine lines/wrinkles, a response was defined as a 1‐point decrease in the scale assessment.

3.4. Tolerability evaluations

No significant increases in the investigator assessed tolerability (erythema and dryness/scaling), and no changes in subject‐assessed tolerability (burning/stinging and itching) were observed throughout the study.

3.5. VISIA‐CR and Antera 3D measurements

Standard digital photography using the VISIA‐CR Camera System showed clinical improvements in color, texture, appearance of lines/wrinkles, and skin tone unevenness (Figure 1A).

FIGURE 1.

VISIA‐CR and Antera 3D imaging: (A) VISIA‐CR images (Standard lighting 2) of a 67‐year‐old female showing improvements in the appearance of wrinkles, skin texture, and skin tone unevenness at weeks 4 and 12 compared to baseline. (B) Antera 3D images using the color and wrinkles (small filter) of a 67‐year‐old female at baseline and week 12 showing improvements in width, length, and depth of lines and improvements in skin tone and texture after use with RET05

Results of the Antera 3D analysis using the internal software showed significant improvements in the following parameters:

• Skin texture—Decrease in R _a and R _q values at weeks 4, 8, and 12 compared to baseline (p ≤ 0.004; Student's paired t‐test) (Figure 1B).

• Wrinkles (2‐mm filter)—Decrease in overall size, depth, width, and maximum depth at weeks 4, 8, and 12 compared to baseline (p ≤ 0.0004; Student's paired t‐test) (Figure 1B).

• Pores—Decrease in volume, index, count, and density at weeks 4, 8, and 12 compared to baseline (p < 0.02; Student's paired t‐test).

• Melanin—Decrease in the average level of melanin, affected area, and hyperconcentration at weeks 4, 8, and 12 compared to baseline (p < 0.02; Student's paired t‐test).

Results of the redness parameter showed a nonsignificant increase in redness at week 4, and a significant increase at week 8. At week 12, the redness decreased close to the baseline level.

3.6. Spectrophotometer measurements

Results of the spectrophotometer analysis did not show statistically significant changes in the L* value at weeks 4, 8, or 12 compared with baseline.

3.7. Validated FACE‐Q scales

All FACE‐Q scales transformed scores (satisfaction with skin, aging appearance appraisal, lines—Overall, social confidence, and psychological well‐being) showed statistically significant improvements at week 12 compared with baseline (All p ≤ 0.0015; paired t‐test) (Figure 2A). The FACE‐Q satisfaction with skin scale transformed score showed that subjects were significantly more satisfied with the appearance of their skin at weeks 4, 8, and 12 compared to baseline (p < 0.0001; paired t‐test). From baseline, subjects were significantly more satisfied with the appearance of their skin, the appearance of their lines, and how their skin looked compared to their age at week 12 (p ≤ 0.0015; paired t‐test). In addition, subjects showed significant improvements by the end of the study from baseline in the quality‐of‐life scales (social confidence and psychological well‐being) when considering the appearance of their skin (p ≤ 0.0004; paired t‐test). The mean results of the age appraisal VAS showed that subjects felt that they looked approximately 5‐year younger at week 12 compared to baseline (Figure 2B).

FIGURE 2.

Subject assessment by FACE‐Q scales: (A) significant improvements in transformed mean scores for all FACE‐Q validated scales at 12 weeks versus baseline (*all p ≤ 0.0015; paired t‐test). (B) A 5‐year reduction in appearance of mean self‐assessed age by the subjects after 12 weeks of RET05

3.8. Subject self‐assessment questionnaire

High overall subject satisfaction where over 90% of subjects rated their satisfaction with RET05 as excellent or good at week 12 compared to baseline.

3.9. D‐OCT analysis

3.9.1. Epidermal thickness

There were significant decreases in ET at week 8 (p = 0.032; Student's paired t‐test) and week 12 (p < 0.0001; Student's paired t‐test) compared to baseline (Figure 3).

FIGURE 3.

Dynamic optical coherence tomography (D‐OCT) images showing improvements of a 66‐year‐old female in integrity of collagen (less fragmented), collagen bundles (normal), improved texture, and decrease in epidermal thickness after 12 weeks of RET05 use

3.9.2. DEJ contour presence or absence

There were an increased number of subjects where the DEJ contour was detectable at week 12 (95.7%) compared to baseline (78.3%).

3.9.3. Collagen fibers

There was a significant decrease in collagen fibers that were in bundles (non‐homogenous) and a significant increase in normal (homogenous) collagen fibers at week 12 as compared to baseline (p < 0.0001; McNemar's test). In addition, there was a significant decrease in the number of subjects with many and moderately fragmented collagen fibers and a significant increase in the number of subjects with normal and few fragmented collagen fibers (p < 0.0001; McNemar's test) (Figure 3).

3.9.4. Attenuation coefficient and collagen density

There was a significant increase in attenuation coefficient at week 12 compared to baseline (p < 0.001; Student's paired t‐test) and a significant increase in collagen density at weeks 4, 8, and 12 compared to baseline (p < 0.03; Student's paired t‐test).

3.9.5. Score of vessels and threshold with ImageJ

There were significant increases in vascularization at 300 μm at weeks 4 and 12 (p < 0.02; McNemar's test) and at 500 μm at weeks 4, 8, and 12 (p ≤ 0.003; McNemar's test) compared to baseline. There were significant increases in the number of vessels at weeks 4 and 12 compared to baseline at the 300 and 500 μm depth (p < 0.025; Student's paired t‐test).

3.10. RCM analysis

3.10.1. Epidermal thickness

There was a significant decrease in SC thickness at weeks 4, 8, and 12 compared to baseline (all p < 0.02; Student's paired t‐test) and a 5.3% overall decrease in the whole epidermis thickness (including SC) at week 12 compared to baseline. The change was primarily due to the significant reduction in SC thickness as there was a nonsignificant increase in sub‐corneal epidermal layer thickness (epidermis without SC) by 5.5%.

3.10.2. Stratum corneum compactness

There was a significant increase in the number of subjects who had uncompact SC at weeks 4, 8, and 12 compared to baseline, where uncompact corneum was observed (all p ≤ 0.0339; McNemar's test).

3.10.3. Pigmented keratinocytes at the DEJ

There was a nonsignificant 7% decrease in the presence of pigmented keratinocytes at the DEJ at week 12 compared to baseline.

3.10.4. Dermal fibers (fibrillar, coarse, and huddled)

There was a significant increase in the presence of fibrillar collagen in the dermis at weeks 8 and 12 compared to baseline (all p ≤ 0.0469; Wilcoxon signed rank test) (Figure 4). There was an inverse effect observed with huddled collagen fibers in the dermis. There was a significant decrease in the presence of huddled collagen at week 12 compared to baseline (all p = 0.0313; Wilcoxon signed rank test). There was an overall 18% nonsignificant decrease in subject's with coarse collagen fibers at week 12 compared to baseline (p = 0.3169; Wilcoxon signed rank test).

FIGURE 4.

Reflectance confocal microscopy (RCM) imaging of improvement in dermal fibers. Images show a decrease in coarse dermal fibers and increase in fibrillar dermal fibers of a 46‐year‐old female after 8 weeks of RET05 use

3.10.5. Keratinocyte contour

For subjects with normal contour at baseline, the proportion of subjects with blurred contour at weeks 8 and 12 are significantly lower than 50% (p ≤ 0.0164; independent test of proportions).

3.10.6. Inflammatory cells and dilated vessels

For subjects with no epidermal inflammatory cells at week 4, the proportion of subjects with epidermal inflammatory cells at baseline is significantly lower than 50% (p < 0.0001; independent test of proportions). Meanwhile, there was a nonsignificant change in the number of subjects with epidermal inflammatory cells to noninflammatory cells at week 8 (p = 0.0588; McNemar's test) and week 12 (p = 0.1797; McNemar's test) compared to baseline.

There was a nonsignificant change in subjects with dermal inflammatory cells at week 4 compared to baseline (p = 0.5637; McNemar's test) but a significant increase in the number of subjects who had dermal noninflammatory cells at baseline to dermal inflammatory cells at weeks 8 and 12 (both p = 0.0339; McNemar's test).

For subjects with no dilated vessels at baseline, the proportion of subjects with dilated vessels at weeks 4 and 8 are significantly lower than 50% (p ≤ 0.0004; independent test of proportions). Meanwhile, there is no significant difference in the proportion of subjects with dilated vessels and non‐dilated vessels at week 12 for those subjects who have no dilated vessels at baseline (p = 0.2752; independent test of proportions).

4. DISCUSSION

In this comprehensive study, clinical assessments, validated questionnaires, and instrumentation, including noninvasive in vivo skin imaging technology, standard photography, and 3D photography, were used to investigate the effects of a topical retinol product. D‐OCT and RCM are noninvasive skin imaging techniques that allow real‐time imaging of the structural changes in the skin. RCM allows a top‐down view of the skin with a high resolution of 0.5–1 μm, similar to conventional histopathology but has a limited depth of penetration of 0.2 mm. D‐OCT provides a lower, yet‐acceptable resolution of 4–10 μm but has a greater penetration depth of up to 2 mm. ⁸ , ¹⁴ There have been no published studies comparing both skin imaging technologies, RCM and D‐OCT, in a single study to evaluate the cosmetic effects of retinol for moderate‐to‐severe facial photodamage.

Topical tretinoin creams are considered the gold‐standard treatment for photoaging. ¹⁵ Topical retinoids have been commonly used to address cosmetic skin concerns such as rough skin texture, wrinkles, and discoloration associated with aging and photodamage for decades. ¹⁶ Griffiths et al. first showed the potential of utilizing low‐strength retinoids by showing significant improvements in all histological and clinical photoaging parameters in both 0.1% and 0.025% tretinoin compared to vehicle but no significant differences between concentrations; however, the adverse event incidences were significantly greater with the higher 0.1% strength compared to 0.025%. ¹⁷ Babcock et al. compared three strengths of topical tretinoin‐based products (0.1%, 0.05%, and 0.025%) with three topical retinol‐based products (1%, 0.5%, and 0.25%), and comparable cosmetic improvements were observed in subjects with moderate‐to‐severe facial photodamage. ¹ In the present study with RET05, the patient‐reported outcomes using the FACE‐Q‐validated questionnaires demonstrated the clinical significance to the patient with regard to satisfaction with skin, the appearance of lines, appearance of skin compared to age. In addition, quality‐of‐life assessments for social confidence and psychological well‐being associated with facial skin appearance showed significant improvements at the end of the 12‐week study. There was high overall subject satisfaction with RET05 where over 90% of the subjects rated their experience as excellent or good.

Independent evaluation of RCM and D‐OCT data provided additional support to the clinical improvements and patient‐reported outcomes. Although epidermal thickening was observed after the use of tretinoin and retinol in other studies, ² , ¹⁶ in the present study both RCM and D‐OCT showed significant reductions in ET, likely due to the exfoliating effects of RET05. However, if the SC was excluded, there was an increase in ET at week 12. Thus, the apparent overall reduction in epidermal thickness resulted from the significant decrease in SC thickness.

One of the major applications of D‐OCT in dermatology is the ability to visualize dermal collagen and the ability to detect the formation of new collagen fibers. ¹⁴ Collagen is the primary scattering media in the skin, so the attenuation coefficient is very similar to the scattering coefficient of the skin. ⁷ Wu et al. found that the attenuation coefficient in the dermis decreased with UV‐irradiation due to collagen destruction. ⁷ In the present study using RET05, both RCM and D‐OCT analyses showed significant improvements in collagen quality with the decrease of coarse and huddled fibers upon RCM, and bundled and fragmented collagen fibers upon D‐OCT, with the appearance of fibrillar collagen at RCM and corresponding homogeneous, well compacted stroma upon D‐OCT, similar to the collagen aspect observed in youth. ⁸ , ¹⁸ With the improvement of the quality of collagen fibers, there was also a significant increase in attenuation coefficient and collagen density that indicate more compact and organized collagen. D‐OCT analysis showed a lack of visualization of the DEJ contour at baseline, which is characteristic of photodamaged skin. ¹⁴ After 12 weeks of RET05 treatment, there was a significant increase in DEJ visualization compared to baseline. This effect may be due to the combined effect on epidermis that was better resolved due to SC thinning, and stroma, which became more compact and brighter, increasing the contrast and differences in reflectivity index between the keratinocytes and collagen fibers. In short, these effects measured by RCM and D‐OCT are consistent with the clinical photoaging improvements observed in all efficacy parameters (except perioral coarse lines/wrinkles).

The “retinoid reaction,” common retinoid‐related side effects due to the free carboxylic acid in the polar end of the retinoid, includes erythema, irritation, burning, and skin peeling. ¹⁶ RCM results showed a significant increase in the number of subjects with uncompact SC, dermal inflammatory cells, and dilated blood vessels at week 12 compared to baseline. Similarly, D‐OCT results showed significant increases in the appearance of vessels at 300 and 500 μm, by both subjective image grading and objective threshold analysis. These observations are consistent with the expected effects of retinoids as an irritant and skin exfoliator. The increase erythema is also an expected clinical effect of retinoid use that was observed both in RCM and D‐OCT. Kligman et al. showed new dermal collagen formation and angiogenesis in the papillary dermis in histological examination after use of 0.05% tretinoin. ¹⁹ In the Kligman et al. study, subjects treated with tretinoin had a “rosy glow” that was not observed in the control group. ¹⁶ , ¹⁹ Fluhr et al. showed that there is less transepidermal water loss, erythema, and scaling with a retinol compared to tretinoin. ¹⁸ In this study, investigator tolerability assessments showed no significant increases in redness and dryness, and subject tolerability assessments showed no changes in burning/stinging and itching after RET05 treatment, confirming a well‐tolerated product. ¹⁸

The accompanying Antera 3D imaging provided additional support to the clinical improvements observed. The analysis showed significant reduction in the overall size, depth, width, and maximum depth of wrinkles. Furthermore, the images showed smoother skin texture, reduction in volume, count, and density of pores, and decreases in melanin levels, affected area, and hyperconcentration. Analysis of redness showed an increase in redness at weeks 4 and 8 followed by a decrease to baseline at week 12, which was overall consistent with the investigator evaluation and the RCM and D‐OCT imaging.

In summary, this study exemplified the cosmetic application of in vivo skin imaging technology in moderate‐to‐severe photodamage and shows their utility to objectively assess improvements in the skin. In addition to the structural improvements observed with skin imaging, these changes were confirmed by the clinical improvements assessed through investigator grading, standard digital photography, 3D photography, and patient‐reported outcomes.

CONFLICT OF INTEREST

This study was sponsored by Allergan plc, Dublin, Ireland (now AbbVie Inc., North Chicago, IL, USA). Neither honoraria nor payments were made for authorship. Financial arrangements of the authors with companies whose products may be related to the present report are listed, as declared by the authors. Lisa T. Goberdhan, Elizabeth T. Makino, Katie Schneider, and Rahul C. Mehta are employees of AbbVie Inc. and may hold AbbVie stock. Giovanni Pellacani, MD, and Marco Ardigo, MD, PhD, have received consulting fees from Allergan Aesthetics, an AbbVie Company.

Goberdhan LT, Pellacani G, Ardigo M, Schneider K, Makino ET, Mehta RC. Assessing changes in facial skin quality using noninvasive in vivo clinical skin imaging techniques after use of a topical retinoid product in subjects with moderate‐to‐severe photodamage. Skin Res Technol. 2022;28:604–613. 10.1111/srt.13172

DATA AVAILABILITY STATEMENT

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial‐level data (analysis data sets), as well as other information (e.g., protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. This clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research and will be provided following the review and approval of a research proposal and statistical analysis plan (SAP) and execution of a data sharing agreement (DSA). Data requests can be submitted at any time, and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our‐science/clinical‐trials/clinical‐trials‐data‐and‐information‐sharing/data‐and‐information‐sharing‐with‐qualified‐researchers.html