The present study evaluated the efficacy and tolerability of oral retinol, administered alone or in combination with a topical medical photoprotection, in patients with mild-to-moderate AK. Within this selected population, AKASI scores decreased over time in the active treatment groups, with a more rapid and pronounced effect observed in the combination group (“In&Out” strategy). In contrast, no significant changes were observed in the control group receiving standard photoprotection alone. The magnitude and temporal pattern of AKASI reduction differed between the two active treatment arms. While oral retinol alone was associated with a gradual improvement that became significant at later timepoints, the combination with medical photoprotection resulted in an earlier and more sustained clinical response.

This finding is compatible with a potential complementary effect between systemic modulation of keratinocyte differentiation and local photoprotective or anti-inflammatory mechanisms. However, because the study did not include a medical photoprotection-only arm, the present data cannot determine whether the greater reduction observed in the combination group was driven by oral retinol, regular application of the dispensed SPF50+ product, piroxicam, or their combined use.

These results are consistent with previous evidence supporting a preventive role of oral retinol in UV-induced skin carcinogenesis. In a large randomized controlled trial, oral retinol supplementation significantly reduced the incidence of squamous cell carcinoma in moderate-risk individuals, while no effect was observed on basal cell carcinoma [7]. Additional studies have demonstrated dose-dependent biological activity of oral retinol on sun-damaged skin, including reduction of actinic damage at the cellular level and modulation of retinoid receptor expression [8]. Taken together, these data provide a strong biological and clinical rationale for the use of oral retinol as a field-directed strategy in patients with AK.

The findings of the LC-OCT substudy further support this interpretation. The significant reduction in epidermal and stratum corneum thickness observed in the combination group suggests a measurable impact on structural features of actinic damage. Although improvements in keratinocyte atypia did not reach statistical significance, the observed trend toward lower atypia grades is consistent with a potential normalization of epidermal architecture. Given the limited sample size, these results should be considered exploratory but provide preliminary mechanistic insight into the effects of treatment.

An additional clinically relevant aspect concerns treatment adherence, although this was not formally assessed in the present study. Topical therapies, including photoprotective agents, are highly dependent on patient compliance, which may be suboptimal in older populations. Factors such as difficulty in consistent application, sensory characteristics of topical products, comorbidities, and reduced perception of disease severity may contribute to poor adherence. Moreover, seasonal variations may further influence treatment behavior, with reduced use of topical photoprotection during periods of lower perceived sun exposure. In this context, the oral component of an “In&Out” strategy may have practical relevance as part of a multimodal approach in clinical settings where adherence to topical regimens is suboptimal. Future studies should include predefined adherence measures to determine whether this strategy offers any real-world adherence advantage over topical regimens alone.

The clinical tolerability profile was favorable over 6 months, with no treatment-related adverse events formally recorded in the CRFs. These findings are consistent with previous evidence supporting the acceptable tolerability of moderate-dose oral retinol supplementation. In particular, Alberts et al. evaluated oral vitamin A at doses ranging from 25,000 to 75,000 IU/day for 12 months in 129 subjects with severe sun-damaged skin and found no significant increase in clinical or laboratory toxicities compared with placebo, even at higher dose levels. The study also reported no clear dose–response relationship for adverse events, supporting the short- to medium-term safety of oral retinol supplementation in this setting [8]. Nevertheless, potential long-term safety concerns associated with chronic retinoid exposure, including metabolic alterations and possible effects on lipid profile and bone metabolism, should still be considered in clinical practice, particularly in older patients and during prolonged treatment courses. Therefore, prolonged oral retinol supplementation in patients who are older or polymedicated should be considered cautiously and ideally accompanied by appropriate clinical and laboratory monitoring in future studies and in clinical practice.

Some limitations should be acknowledged. The open-label design may have introduced performance and assessment bias, particularly for investigator-rated outcomes. However, to increase the internal validity of our results, we adopted the assessor-blinded approach for the evaluation of the clinical endpoints. The absence of a control group for certain secondary endpoints limits the interpretability of comparative analyses.

In addition, the study did not include a treatment arm receiving medical photoprotection alone. Consequently, the study cannot isolate the independent contribution of the topical medical device, the sunscreen component, piroxicam, or oral retinol within the combined strategy. Nevertheless, previous clinical data have suggested that piroxicam may have activity in AK, including a preliminary open-label study of piroxicam 1% gel showing regression of a proportion of treated lesions [17], and several studies have reported clinical improvement with formulations combining piroxicam 0.8% and SPF50+ photoprotection [9,10,11,12,13]. In addition, the clinical use and labelling of topical non-steroidal anti-inflammatory drugs for AK emphasize strict avoidance of ultraviolet exposure during treatment, supporting the broader rationale for combining anti-inflammatory topical strategies with photoprotection. Therefore, the present study was primarily designed to evaluate the clinical outcomes associated with adding oral retinol to a combined “In&Out” strategy, rather than to deconstruct the independent efficacy of each topical component. Finally, adherence to photoprotection and oral supplementation was not formally measured, which further limits the interpretation of between-group differences and should be addressed in future trials.

Furthermore, participants had mild-to-moderate AK, a limited number of clinically evident lesions, relatively low baseline AKASI scores, and no previous history of skin cancer. As a result, the findings may not be directly generalizable to patients with high-risk clinical settings. The relatively small sample size, short follow-up, and the exploratory nature of the LC-OCT substudy (that restrict the generalizability of mechanistic findings) are other limitations. Despite these limitations, the consistency of clinical improvement, the supportive mechanistic signals, and the favorable safety profile collectively suggest that oral retinol supplementation, particularly when combined with medical photoprotection, may represent a rational and clinically relevant strategy in the management of AK. Further randomized controlled trials with larger sample sizes and longer follow-up are warranted to confirm these findings and to better define the role of systemic retinoid-based approaches in the prevention and treatment of actinic damage.