A study identified novel noninvasive biomarkers that discriminated between the effects of topical corticosteroids and non-steroidal anti-inflammatory treatments on the skin. The research found that betamethasone valerate 0.1% cream induced 2.3 times more epidermal thinning than crisaborole 2% ointment after 4 weeks of twice-daily application in patients with atopic dermatitis.

In a randomized, observer-blind, within-subject controlled trial, published in JEADV Clinical Practice, researchers examined 37 participants aged 18 to 65 years with atopic dermatitis. Over 4 weeks, each participant applied crisaborole to one forearm and betamethasone to the other. The primary outcome of the trial was the difference in epidermal thickness from baseline to day 29, assessed by optical coherence tomography (OCT). The participants received detailed product application training, and compliance was monitored closely through daily logs.

The mean age of the patients was 23 years (range 18 to 60), with 65% female and 35% male participants. Ethnicity distribution was 70% White-UK, 8% other White background, and 22% from other backgrounds. Fitzpatrick skin types ranged from type 1 (14%) to type 5 (5%).

• Current severity (ISGA): 19% clear, 51% almost clear, 22% mild, 8% moderate.
• Median EASI score: 0.6 (range 0 to 9.9).
• Median time since last flare: 1 month (range 0 to 10 months).
• 57% had > 3 flares in the past 12 months.
• FLG genotyping: 24% of participants had at least one known FLG variant allele.

Among the key findings were:

• Epidermal thinning: betamethasone induced significantly greater epidermal thinning (–31.66 μm, 95% confidence interval [CI] = –35.31 to –28.01) compared with crisaborole (–13.76 μm, 95% CI = –17.42 to –10.10) after 4 weeks (P < .0001).
• Superficial plexus depth: decreased more with betamethasone (–20.34 μm) compared with crisaborole (–9.51 μm) (P = .0067).
• Collagen matrix index: increased significantly with betamethasone (100.02 AU) compared with crisaborole (–3.99 AU) (P < .0001).
• Transepidermal water loss (TEWL): increased with crisaborole (2.06 g/m²/h) but decreased with betamethasone (–0.52 g/m²/h) (P < .0001).
• Skin barrier integrity (TEWL20): Significantly better with crisaborole (TEWL20 34.13 g/m²/h) than betamethasone (45.44 g/m²/h) (P = .0006).

The study utilized several advanced imaging and spectroscopic techniques to assess skin properties. OCT provided high-resolution cross-sectional skin images, allowing measurement of epidermal thickness and superficial plexus depth. Polarization-sensitive OCT (PS-OCT) was used to evaluate collagen density and arrangement through the collagen matrix index. Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy assessed the stratum corneum’s molecular structure. Compliance monitoring showed consistent product usage with mean daily application amounts of 2.13 ± 0.158 g for crisaborole and 2.12 ± 0.204 g for betamethasone.

Detailed epidermal thickness changes:

• Day 15: crisaborole –14.41 μm vs betamethasone –28.65 μm (P < .0001).
• Day 29 to 57 recovery: crisaborole +11.63 μm vs betamethasone + 24.94 μm (P < .0001). Betamethasone-treated sites showed a faster but incomplete recovery compared to crisaborole-treated sites.

NMF levels and lipid order:

• Total NMF: crisaborole 1.331 nmol/μg protein vs betamethasone 1.299 nmol/μg protein (P = .7395).
• Pyrrolidone carboxylic acid: crisaborole 0.157 vs betamethasone 0.156 nmol/μg protein (P = .9228).
• Urocanic acid: crisaborole 0.039 vs betamethasone 0.032 nmol/μg protein (P = .0215).

Lipid chain conformational order: measured by the symmetric stretching of CH2 band center of gravity, was 2849.68 cm-1 for crisaborole vs 2849.74 cm-1 for betamethasone (P = .2219), indicating no statistically significant differences in lipid structure.

Objective skin redness:

• Baseline to day 29: crisaborole –1.16 AU vs betamethasone –27.61 AU (P = .0005).
• Baseline to day 15: crisaborole –23.61 AU vs betamethasone –45.04 AU (P = .0006).
• Day 29 to 57 recovery: crisaborole +2.84 AU vs betamethasone +37.66 AU (P < .0001).

Safety data showed that 81% of participants experienced at least one treatment-emergent adverse event. One serious adverse event occurred, which was unrelated to treatment. The researchers emphasized that while adverse events were expected, proper monitoring and compliance were crucial for minimizing risks.

The study also conducted exploratory analyses on OCT and ATR-FTIR images, revealing significant biomarkers like superficial plexus depth and collagen matrix index as potential indicators of local adverse effects. These findings suggested that betamethasone’s impact on skin structure is detectable early, supporting the need for tailored application strategies to minimize long-term risks.

The researchers concluded that the extent of skin changes may vary with age, anatomical site, ethnicity, and level of subclinical inflammation. Future studies should explore the effects of lower potency corticosteroids and reduced application frequencies to further optimize treatment.

Conflict of interest disclosures can be found in the study.