Resiquimod: a new topical immune-response modifier for the treatment of actinic keratosis

KEYWORDS:

• Resiquimod
• actinic keratosis
• squamous cell carcinoma
• toll-like receptor
• immune response

We read with great interest the review article by Cramer and Stockfleth, which highlights novel therapies for actinic keratosis (AK) [1]. In particular, the authors note imiquimod to be of therapeutic value in AK. Resiquimod is an emerging therapy that too should be considered part of the therapeutic armamentarium against AK. Like imiquimod, resiquimod 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. In addition, resiquimod may promote the release of cytokines – interleukin-6, tumor necrosis factor-α, and interferon-α – more effectively than imiquimod. Therefore, resiquimod may achieve greater efficacy than imiquimod based on its pharmacodynamic profile and thus is emerging as a new topical pharmacotherapy for AK [2].

The clinical efficacy of resiquimod in treating AK is well documented. Resiquimod is available at concentrations of 0.01, 0.03, 0.06, or 0.1%, with the greatest efficacy observed with application three times weekly for four weeks. One report revealed that resiquimod 1% applied twice daily for 90 days resulted in complete regression of AKs in 48% of cases [3]. Other studies, though, have reported high rates of adverse events associated with resiquimod 0.1%, resulting in discontinuation [4]. Because of the safety profile of resiquimod, a large study of 217 patients with AK investigated the optimal dose with respect to efficacy, safety, and tolerability. Patients were randomized to daily resiquimod 0.01% or 0.03% cream in five different treatment schedules until skin erosion or eight weeks of treatment. Complete clinical clearance was obtained in 56% to 85% of patients, with maximal efficacy among individuals receiving the 0.03% formulation [5].

A trial by Stockfleth et al. randomized patients with AK to different regimens of topical resiquimod, with the goal of identifying an optimal concentration and dosing schedule. Regardless of regimen, complete clinical clearance in all resiquimod-treated arms was more significant than placebo, ranging from 56% to 74%. Partial clinical clearance, defined as disappearance of >75% of AKs, was also significantly higher in the resiquimod arms, ranging from 75% to 87%. Although clinical clearance of AK with the use of resiquimod provides promising data, the same study by Stockfleth et. al revealed that in regimens with fewer gel applications, there was no significant histological difference from placebo [5]. While a clinical response was reached with fewer gel applications, the lack of significant difference in histological clearance compared with placebo warrants further study.

Tolerability of local skin reactions remains an issue with all topical pharmacotherapy for AK, including resiquimod. In the aforementioned study by Stockfleth et. al, 59% of patients reported adverse reactions to resiquimod. Overall, the most common adverse events were erythema and scabbing. This finding correlates with clinical experience of treating patients with immune-response modifiers whereby inflammation and irritation precede response [5]. In another study by Szeimes et. al, non-application site adverse events included influenza-like symptoms such as arthralgias, myalgias, headache, lethargy, fatigue, and rigors. In this trial, influenza-like symptoms were reported by 0%, 3%, 13% and 12% of patients, respectively, for resiquimod 0.01%, 0.03%, 0.06% and 0.1% groups. During the trial, 0%, 13%, 31% and 38% of patients discontinued treatment for adverse events or local skin reactions, for resiquimod 0.01%, 0.03%, 0.06%, and 0.1% groups, respectively [6]. With higher concentrations correlating with higher rates of adverse events and discontinuation, it is crucial to consider the use of resiquimod against AK at lower concentrations. In one arm of the trial by Stockfleth et. al, patients were allowed to discontinue resiquimod 0.03% when they reached their own biological endpoint of erosion. In this arm, the highest rates of clinical and histological clearance were seen, suggesting that an individualized method of dosing may maximize adherence and efficacy wit h resiquimod [5].

Overall, resiquimod appears to be a promising therapy for AK, although current evidence is limited. The study by Stockfelth et al. only investigated the application of resiquimod on a 25 cm² contiguous area of the balding scalp, forehead, or face [5]; thus, the efficacy of resiquimod in clearing lesions on larger areas and other body parts remains to be established. Moreover, data on sustained lesion clearance are needed, as the phase II study by Szeimies et al. evaluated patients only at eight weeks of follow-up [6]. Resiquimod remains a promising therapy for AK, although additional studies are needed to further evaluate its efficacy.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Funding

This paper was not funded.