Treatment of non-genital warts with topical imiquimod 5% cream

ARTICLE

The treatment of common warts (verrucae vulgaris) tends to be unsatisfactory for both the dermatologist and the patient. Current therapies are either ablative, such as cryotherapy, laser therapy, electrodessiccation and salicylic acid, or interrupt cell division such as podophyllotoxin and 5-fluorouracil. There is no single treatment that is 100% effective [1] and all of these therapies are associated with tissue destruction and discomfort [2]. Recurrence is also likely as these therapies eradicate the lesion but do not eliminate the underlying viral infection. Common warts located on periungueal folds can be particularly difficult to treat as the proximity of the nail matrix and the superficial nerves have to be taken into consideration [2].

Common warts are HPV-related lesions, and are associated particularly with HPV types 1, 2, 4, and 57 [2]. The topical immune response modifier, imiquimod 5% cream, is an effective patient-applied treatment for external genital warts, the clinical manifestation of HPV types 6 and 11 [3]. As the antiviral activity of imiquimod stems from enhancement of innate and cell-mediated immunity [4], it is probable that imiquimod will be an effective treatment for other cutaneous HPV-associated conditions. We therefore investigated the effectiveness of imiquimod treatment on common warts, determining the effect of occlusion, which enhances drug penetration through the skin, on the clinical response to imiquimod.

Materials and methods

We report 10 cases of patients with recalcitrant common warts. The mean age of the 4 male patients and 6 female patients was 32.5 years and 36.6 years, respectively. Warts persisted for a period between 3 months and 2 years. Patients were referred to our centre because all previously received treatment for their warts, including salicylic acid, electrodessiccation or cryotherapy had failed, and lesions recurred. The medical history was negative for relevant medical problems, atopic constitution and allergies to medication. Patients had not had any other treatment for warts within 4 weeks before enrolment. Prior to therapy, all patients underwent a serological screening including HBV, HCV and HIV tests and a lymphocyte count. All of the patients were immunocompetent.

In 7 patients warts were located in the periungueal region, 2 patients had plantar warts and in one case a single wart was located on the Achille's heel (Table I). All lesions had a minimum diameter of 3 mm. The warts were clinically diagnosed, with a biopsy sample obtained from one patient.

Imiquimod 5% cream was self-administered under occlusion once daily for 4 weeks. Occlusion was performed using a Tegaderm^® foil. The medication was applied at night prior to sleep and removed after 8 ± 2 hours.

Results

At the end of the 4-week treatment period, complete remission, i.e. anatomical and functional recovering of the treated area was observed in 8 of the 10 patients. A reduction in wart size was observed for patient 9 and complete remission occurred after a further 4-week treatment period. One patient (patient 10) was not responsive to the imiquimod treatment. No wart recurrences were observed during 3 months of follow up after treatment. A typical response to imiquimod treatment is shown in Figures 1 and 2. No local or systemic side effects were observed.

Discussion

Several treatment modalities of warts are currently utilized, but all are based on destruction of infected keratinocytes and are often painful. Moreover, as these therapies are not addressed to the specific pathogenetic mechanism of warts, recurrences are frequent. The immune system has been proposed to be a factor in the spontaneous regression of this condition due to the high prevalence of common warts in immunosuppressed patients [5, 6].

Imiquimod 5% cream is an immune response modifier, which exhibits antiviral activity that stems from the stimulation of innate and cell-mediated immunity [4]. Genital warts clearance by imiquimod is associated with enhanced levels of specific cytokines including interferon-alpha, inteferon-gamma and tumour necrosis factor-alpha and a decrease in the levels of HPV DNA [7]. Stimulation of the immune response by imiquimod could therefore be an effective strategy for the treatment of other HPV-associated conditions such as common warts.

Treatment of common warts with imiquimod has also been shown to be effective in both immunocompetent and immunocompromised patients [8, 9]. In one open-label study, complete clearance of warts, or a greater than 50% reduction in wart size was observed in 28 of the 50 (56%) patients treated with imiquimod 5% cream once daily for 5 days per week [8]. In that study, patients were treated until warts cleared or for up to 16 weeks.

The degree of keratinisation of the epidermis may influence the absorption of imiquimod: in the treatment of genital warts, an increased efficacy was reported in uncircumcised men with foreskin warts, where the drug was applied on an anatomically semiocclusive site [10]. Conversively, imiquimod efficacy without occlusion is lower in plantar warts, where keratinization is more evident [8]: efficacy is higher when imiquimod is applied under occlusion or after treatments that weaken the stratum corneum and facilitate its penetration [11].

In our study, patients applied the cream under occlusive dressing once daily for a period of 4 weeks. A total of 80% of patients experienced total remission of their warts within the 4-week treatment period. It might be expected that occlusion determines a higher frequency of inflammatory reactions at the application site: however, in our study the drug was well tolerated and no relevant local or systemic side effects were recorded. Thus, occlusion appears to be an effective method to increase efficacy and decrease the duration of treatment.

Treatment of common warts with current therapies is frequently unsuccessful, particularly if they are located in difficult-to-treat areas such as the periungueal region. In these cases, conventional therapies like salicylic acid, cryotherapy or electrodesiccation can produce irreversible damage to the ungueal matrix. Imiquimod 5% cream is a non-invasive topical treatment that effectively clears recurrent common warts, including those located in difficult-to-treat areas.

A limiting factor of the treatment with imiquimod is related to its high cost. However, the economic impact of a therapy should be evaluated in comparison to the additional benefits for patients, in terms of clearance rate and prevention of recurrences. In the treatment of external genital warts, it was reported that where imiquimod was used as first-line therapy, its clinical efficacy was such that it provided the most cost-effective approach in comparison to existing therapies [12], with a positive patient's acceptance of this therapeutic option [13]. In our patients, the high cost of therapy was balanced by the clinical results as well as by the possibility of self - application at home. Moreover, the excellent cosmetic outcome compared to painful and potentially scarring alternative therapies represents a further advantage.

CONCLUSION

In conclusion, even if larger and controlled trials are need-ed to verify its efficacy, imiquimod has the potential to become a routinely used therapy for common warts in the future.

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