Resiquimod for Actinic Keratosis: Is This a new Treatment Option?

R. Rajaratnam


The British Journal of Dermatology. 2019;180(2):254-255. 

This issue of the BJD highlights a novel therapy for treating actinic keratosis.[1] Resiquimod, like imiquimod, belongs to the class of imidazoquinolines, small organic molecules with potent antiviral and anticancer activity. Resiquimod is a Toll-like receptor (TLR)-7 and TLR-8 agonist that activates myeloid and plasmacytoid dendritic cells.[2] In addition, resiquimod may promote cytokine release such as interleukin-6, tumour necrosis factor-α and interferon-γ more effectively than imiquimod.[3] Resiquimod is emerging as a new topical pharmacotherapy for skin cancer.

In a small trial of early-stage cutaneous T-cell lymphoma a third of patients had clearance of all treated lesions.[2] Resiquimod has also shown efficacy in treating actinic keratosis in a phase II study with high complete clearance rates.[3] In that trial, doses of resiquimod gel up to 0·1% were used but were associated with high rates of adverse events and discontinuation.[3] In this issue of BJD, Stockfleth et al. randomized patients with actinic keratosis to different regimens of topical resiquimod to identify an optimal concentration and dosing schedule.[1] In three placebo-controlled arms, patients were randomized to 0·03% resiquimod gel three times a week for 4 weeks, seven times within 2 weeks or five times in 1 week followed by a treatment-free interval and one repetition of the cycle (i.e. total of 24, 14 and 10 gel applications). In two additional arms, patients applied either 0·01% or 0·03% resiquimod three times a week up to a biological end point of skin erosion for a maximum duration of 8 weeks. Overall, resiquimod 0·03% gel was more effective than 0·01% gel in terms of clearance rates clinically and histologically.

Complete clinical clearance in all the resiquimod-treated arms was more significant than placebo varying from 56% to 74%. Partial clinical clearance (disappearance of >75% of actinic keratosis lesions) was also significantly higher in the resiquimod arms varying from 75% to 87%. However, histologically, in arms 2 and 3 where the total number of gel applications was less (i.e. 14 and 10, respectively), there was no significant difference from placebo. Although the authors conclude clearance rates were comparable in the first three arms, and a clinical response was reached with fewer gel applications, the lack of significant difference to placebo in histological clearance needs attention.

In the fifth arm of this trial, patients were allowed to stop resiquimod 0·03% when they reached their own biological end point of erosion. The mean number of gel applications was 22·2. In this arm, the highest rates of clinical and histological clearance were seen. This individualized method of dosing may allow for a more tailored approach, improving adherence and maintaining efficacy.

Overall, the most common adverse drug reactions were erythema and scabbing. This correlates with clinical experience of treating patients with immune-response modifiers whereby inflammation and irritation precede response. Tolerability of local skin reactions remains an inherent issue with all topical pharmacotherapy for actinic keratosis and resiquimod appears to be no different.[4]

Although resiquimod shows potential efficacy in treating actinic keratosis, data on sustained lesion clearance is needed. Additionally, in this trial, a contiguous area of 25 cm2 on the scalp, forehead and face was treated. Future trials treating a larger area or a different body part are therefore needed.

In a Cochrane review of field treatments for actinic keratosis, 5-fluorouracil, 5% imiquimod, 3% diclofenac and ingenol mebutate showed similar efficacies.[5] Direct comparisons between resiquimod with one of these standard treatments and stratification of response on variants, for example thicker or keratotic lesions, would allow treating physicians to make an informed decision and close the gap in understanding which formulations are more suitable for a particular patient.[6] Nonetheless, topical pharmacotherapies continue to play an important role. They provide a noninvasive alternative in elderly patients or those wanting to avoid cosmetically disfiguring scars and more importantly treat both visible and subclinical disease, which may prevent further lesions.[6] New molecules such as resiquimod may potentially add to the armamentarium of treatments as we seek the ideal balance between simple regimens, good efficacy and minimal side-effects.