Actinic keratoses (AKs) are a common skin neoplasm that develop from excessive exposure to UV radiation (UVR). AKs belong to a wider type of skin cancers called Non-Melanoma Skin Cancer (NMSC), that affects about 60% of the population aged over 40 and frequently exposed to sun radiation.

Risk factors for AKs include fair skin (Fitzpatrick skin phototypes I-II), sun exposure due to latitude (in fact, people who live closer to the tropics are at higher risk), gender, immunosuppression and simultaneous HPV infection of parts of the skin.

There are two kinds of treatment for AKs: treatments aimed at resolving single lesions (targeted therapies) and field cancerization treatments (field-directed treatment). A cancerization field is an area affected by actinic damage and containing at least three AKs in 25 cm². The choice of treatment must take into account not only the number and distribution of lesions, but also the patient’s ability to comply with the therapy and the presence of diffuse actinic damage.

For the field cancerization treatment, we can rely on topical therapies with anti inflammatory agents with antitumour properties, with immunomodulators(e.g. Imiquimod), with antineoplastic or photodynamic therapy, effective through the sunlight activation of the photoactive agent (ALA or MET-ALA) or via LED light sources for ample areas. The range of treatments available for single lesions is also wide: cryosurgery with liquid nitrogen, diathermy, CO2 and/or Erbium 2930 laser therapy and conventional photodynamic therapy (cPDT), use of topical antiblastic drugs or surgery. Each therapy has specific activity and safety profiles, with potential side effects like whitish atrophic scars, erythematous areas, surgical scars and global texture alterations.²

The clinician can select a personalised plan from a complex, varied range of treatments that relies on the use of several therapeutic devices in the same patient to optimise their effectiveness and reduce their side effects. At the same time, identifying effective strategies to prevent the onset of actinic keratoses seems now essential.

To reach this objective it has now been amply demonstrated that the use of wide spectrum sunscreen (SPF>50) helps reduce cumulative UVR-related skin damage, by reducing the onset of new lesions in patients already affected by AK and slowing down their development in patients presenting with actinic damage only.³ UVR is in fact the main culprit for the onset of skin cancer, as it causes direct and indirect damage to the cell DNA. The most common damage caused to DNA by UVR is cyclobutane pyrimidine dimers (CPDs), considered the fingerprint of sun damage on skin cells.⁴

Sunscreen formulas contain several ingredients able to block, absorb or deflect UV radiation.⁵ In addition, other molecules with systemic and/or topical use are frequently used today to increase the effectiveness of photoprotection. Among them, one of the most studied is Nicotinamide (NAM) or niacinamide, a water-soluble vitamin B3 derivative, found in many foods. NAM is essential for cellular energy homeostasis and affects many metabolic processes. It has many positive effects on the skin, including reducing itchiness, boosting moisture, relieving inflammation (enhancing the skin barrier function) and lightening pigmentation.⁶ Additionally, NAM has been shown to reduce skin immunosuppression (in murine models both topically and systemically and in humans with doses of 500-1,500 mg/daily or with the application of a 5% NAM topical treatment)⁷ and cancerogenesis linked to UVR exposure both in murine and in human models. ^{8,9,10,11,12,13} showing excellent effectiveness also in patients whose immune system has been weakened by previous organ transplant.¹⁴ Specifically, in a phase 2 study, 1% nicotinamide topical treatment helped reduce to 3 months the onset of AK in more than 21% of the patients treated vs. 10% of the patients who had received the placebo. A very significant result, as UVR exposure causes cancerogenesis and photoageing with a series of mechanisms that range from the substitution of the DNA pirimidin bases to oxidative damage, from the activation of inflammatory processes to the suppression of cancer immunity up to the creation of energy crises that do not allow the cells to overcome the damage caused to their DNA. NAM is thus essential in reducing or stopping UVR-related damages. Many works have also explored the effective dose of NAM to be administered at different ages to obtain the best photoprotective effect. The effectiveness of vitamin. B3 in photoprotection is also demonstrated by the onset of pellagra (a disease caused by a lack of vitamin B3) characterised by high skin photosensitivity, as well as a variety of symptoms. Additionally, compared with vitamin B3, NAM has a better safety profile, with few side effects.

For the above properties, NAM seems to represent a very useful and promising drug in the prevention and treatment of AKs. Besides offering obvious advantages when combined with sunscreen in reducing acute actinic damage, NAM could act as an active treatment by reducing the cumulative actinic damage, but, most importantly, a role in association with existing treatments for actinic keratoses could be envisioned. In fact, its use could be of key importance in reducing relative immunosuppression induced by photodynamic therapy,¹⁵ thereby reducing the potential failures of this therapy and enhancing its global performance. NAM could also be helpful in modulating inflammatory phenomena linked to the use of topical agents (Imiquimod, 5-fluorouracil) or destructive devices (laser), while improving hydration and restoring the treated tissue to a healthy state. The possibility of a synergic effect of PDT and NAM is increasingly finding consensus to the point that a recent study suggested NAM as a second-line therapy in patients with post-PDT cancerization field and the chronic use of sunscreen.¹⁶

In conclusion, as AKs should be considered today a very common social health problem, the use of sunscreen and nicotinamide could be suggested as minimum devices useful in the prevention of this disorder and for its long-term treatment. New studies on large patient cohorts will eventually confirm the effectiveness of this therapeutic-preventive approach.

This article has been written by Dr. Auriemma