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Novel Dermatologic Uses of the Immune Response Modifier Imiquimod 5% Cream

B. Berman, MD, PhD, V.N. Poochareon, BS, A.M. Villa, MD
Department of Dermatology and Cutaneous Surgery,
University of Miami School of Medicine, Miami, FL

ABSTRACT

Imiquimod is the first of a new class of drugs to emerge in the treatment of various dermatologic disorders. As an immune response modifier, it has been shown to have potent antiviral and antitumor properties through the stimulation of innate and cell mediated immune pathways. It is currently approved for the treatment of external genital and perianal warts, but has also been found to be an effective treatment for a host of other virus-associated dermatologic lesions, including common and flat warts, molluscum contagiosum and herpes simplex 2. Oncological lesions showing improvement with the use of imiquimod include basal cell carcinoma, actinic keratosis, squamous cell carcinoma in situ, malignant melanoma, cutaneous T-cell lymphoma, and cutaneous extramammary Paget’s disease. Recent case studies have also found this product to be effective for treating keloids, infantile hemangioma, porokeratosis of Mibelli, leishmaniasis, and tattoo removal. This extensive array of disorders treated successfully with imiquimod warrants further study of this novel and valuable drug.

Key Words: imiquimod, immune response modifier

As an immune response modifier, imiquimod 5% cream (Aldara™, 3M) indirectly acts to enhance the body’s natural ability to heal through the induction of innate and cell mediated pathways. Stimulation of these immune pathways leads to the synthesis and release of cytokines, most often interferon-α, tumor necrosis factor-α, interferon-γ and interleukin-12. Activity of natural killer cells, macrophages, B lymphocytes, and Langerhans cells is also enhanced significantly.1 At present, imiquimod is approved as a topical, patient-applied treatment option for external genital and perianal warts produced by human papillomavirus (HPV).2 The efficacy of treatment with imiquimod has been shown to effectively clear external genital warts from 50% up to 75.5%, with the higher numbers present in uncircumcised males, as well as in female patients.3,4 Owing to its broad immunologic properties, imiquimod has also been documented as a safe and effective treatment for several other skin conditions. In 2001, Sauder categorized a range of conditions that was reported to have been successfully treated with imiquimod into virus-associated conditions, oncological conditions, and other conditions.5 Since then, the array of skin conditions successfully treated with imiquimod has expanded.

Virus-associated conditions

Human papillomavirus (HPV)

The antiviral activity of imiquimod has been useful for clearing genital warts produced by HPV, but indirectly. It is not specifically targeted against the HPV types (HPV 6 and 11) that result in genital warts. Therefore, patients with nongenital warts caused by other subtypes of HPV are felt to be prime candidates for treatment, and several case reports illustrate imiquimod’s efficacy in these patients. Fifty patients with common warts were treated with imiquimod once daily for 5 consecutive days over a span of 12 weeks; 30% showed complete clearance and 26% showed a reduction in wart size greater than 50%.6 Muzio, et al, reported 10 cases of recurrent common warts, with 8/10 patients showing total remission after application of imiquimod under occlusion once daily for 4 weeks, with no recurrences reported at 3-month follow-up.7 In a case report, imiquimod applied nightly 3 times/week demonstrated its potential use in recalcitrant facial flat warts, with complete clearing after 3 weeks of therapy.8 Successful treatment of HIV-positive patients with common warts was reported with the length of treatment ranging from 4-12 weeks.6,9 Other successful cases of treating warts in immunosuppressed patients were reported using a combination of imiquimod with CO2 laser therapy and occlusive treatment.10 In addition to HPV-induced common warts, Stockfleth, et al, reported a case of HPV DNA-positive generalized stucco keratosis, successfully treated with imiquimod, 3 times/week for 5 weeks.11

Molluscum contagiosum virus (MCV)

Imiquimod has been shown to be effective in other non- HPV associated virally-induced conditions as well. Molluscum contagiosum (MC), caused by a large doublestranded DNA virus of the Poxviridae family, has been successfully treated with imiquimod in both children and adults. Barba, et al, treated the MC lesions of 13 children with imiquimod in an open-label safety study for 4 weeks, with full resolution of baseline target lesions in 12/13 children and no evidence of systemic toxicity. The one patient who did not complete the study experienced severe erythema, local superficial forehead erosion, and hypopigmentation that slowly resolved.12 Liota, et al, also included children in their patient population, as the molluscum contagiosum virus (MCV) is most commonly seen in young children, sexually active adults, and in some immunosuppressed patient populations. In a 16-week trial using imiquimod 3 times/week, 14/19 immunocompetent adults, 4/4 HIV-positive adults, and 6/13 children had resolution of their MC lesions, with more local inflammatory and pruritic reactions occurring among the children. In areas expected to have greater penetration of a topical agent (e.g., the axillae) clearing was more consistently observed.13 An open-label study also examined imiquimod’s effect on patients with common warts or MC, and showed total clearance of MC lesions in 8/15 (53%) patients or a >50% reduction in molluscum size in 4/15 (27%) patients. The mean duration of treatment was 9.8 months (range 2-24), and there were no differences found with regard to gender or HIV status.6 As MCV does not develop latency, but evades the immune system in other ways, the clearance of MC lesions tends to reflect longterm cure.13 Several case studies have also illustrated the efficacy of imiquimod for treating MC lesions of immunocompromised populations. Buckley, et al, described the case of an HIV-1 positive woman with extensive disfiguring MC lesions who had failed cryotherapy, 0.5% podofilox, and 0.5% tretinoin.14 Brown, et al, described a similar case of MC, which had also failed conventional therapies with cryotherapy and trichloroacetic acid crystalline solution.15 In both cases, topical imiquimod resulted in full clearance of the treated lesions with no systemic adverse effects, but stable postinflammatory hyperpigmentation developed.

Herpes simplex virus 2 (HSV-2)

Topical imiquimod offers an alternative for treating herpes simplex virus (HSV) infections, particularly in the setting of emerging resistance. A 34-year old HIV-positive man who developed a HSV-2 infection of the penis resistant to acyclovir, valacyclovir hydrochloride, and famiciclovir was successfully treated with imiquimod applied 3 times/week for 1 week, with no recurrences after 1-month of follow-up. This report may support the use of topical imiquimod as an effective treatment for HSV infections, particularly in the setting of acyclovir resistance or unresponsiveness.16

Oncological and oncologically related conditions

Basal cell carcinoma (BCC)

A series of clinical trials and case reports document the effectiveness of imiquimod for treating superficial or nodular basal cell carcinomas (BCCs) on low-risk sites.17-22 Efficacy seems to be dose-related. For superficial basal cell carcinoma, cure rates vary from 69.7% up to 100%.19,20 Nodular BCC cure rates are just below 80%, and do not reach the level of complete clearance expected of a first line monotherapy.22-24 Currently, there is no consensus as to the most effective treatment regimen using imiquimod, and complete response has been reported in as little as 6 weeks up to 18 weeks.20, 26 Optimal dosing to minimize cutaneous side-effects and maximize efficacy has not been determined; studies suggest that treatment should be dosed 3-5 times/week. Rest periods have also been recommended.20 Complete (100%) compliance with dosing did not appear necessary to achieve a complete efficacy response.20 Though statistically significant correlation has been established between the most intense erosion reaction assessed by the investigator and a complete response, twice daily application was reported to produce unacceptable skin reactions. Daily application seems the most suitable for use in clinical practice on the basis of efficacy, tolerability, potential cost of treatment, and likelihood of compliance for a lengthy period of treatment.20, 24 The cosmetic outcome has been excellent.20, 22 Special cases of BCCs treated with imiquimod include a large (5x6 cm) superficial BCC,25 a patient with Basal Cell Nevus Syndrome and multiple BCCs,26, 27 and a report of two siblings with xeroderma pigmentosum, in whom topical imiquimod reduced the rate of new tumor formation, permitting dermatologists to “keep up” with the surgical treatment of new lesions.28 Further clinical trials are required to confirm efficacy in larger BCCs and BCCs with aggressive growth patterns.

Actinic keratosis (AK)

Imiquimod was documented in a few studies as a useful treatment option for AK. A double-blind pilot study29 examined 41 AK patients applying imiquimod or a vehicle cream in different dosing groups to three target AKs for up to 16 weeks, with clinical resolution of all target lesions. In another randomized, double-blind study,30 36 patients with AK lesions applied imiquimod or a vehicle cream 3 times/week for 12 weeks or until resolution, which occurred in >80% of patients. Six case reports of men with AK were described, where imiquimod was applied 3 times/week for 6-8 weeks. In the event of a local skin reaction, treatment was modified to 2 times/week. All of the AK lesions successfully cleared and there were no reports of recurrence (ranging from 2-12 months post-treatment).31 In a small trial involving 22 patients, their AKs were treated with imiquimod initially at 3 times/week for 8 weeks or until there was total clearance of the lesions. 32 By the end of the study, a significant reduction in the average number of lesions per patient was observed. Salache, et al, used imiquimod to treat 25 AK patients in specific dosing cycles, alternating treatment weeks with weeks of rest and continuing such treatment until complete clearance was achieved.33 This study, along with others requiring rest periods for local adverse reactions, underscores the need to determine appropriate dosing regimens for patients with AK and other cutaneous lesions.

Squamous cell carcinoma in situ (Bowen’s disease)

Treatment modalities for squamous cell carcinoma in situ (Bowen’s disease) often have significant risk of scarring, deformity, and poor cosmetic appearance. Surgery on common areas for Bowen’s disease (lower limbs, head, neck) may be anatomically difficult. With this in mind, Mackenzie-Wood, et al, treated 16 patients in a phase II, open-label study, where imiquimod was applied to biopsyproven plaques of Bowen’s disease once daily for 16 weeks. Six-week post-treatment biopsies revealed no residual tumor in 14/15 patients (the 16th patient was unavailable for biopsy), although 6 patients found it necessary to stop treatment early due to intense local skin reactions during the study.34 Several case reports have illustrated the efficacy of imiquimod in treating Bowen’s disease of the penis.35, 36 A 65-year old circumcised male applied imiquimod nightly until intense local erythema and erosions developed. A rest period was given before treatment was resumed. Follow-up at 18-months post-treatment revealed no residual or recurring tumor and no evidence of scarring, deformity, or loss of function.36 Imiquimod has also been shown to be effective in combination with 5% flurouracil (5-FU) therapy in immunosuppressed populations. A recent case study reported an HIV-positive male with perianal Bowen’s disease treated with 5-FU and imiquimod in the same time frame. By 16 weeks, clinical and symptomatic improvement occurred without persisting or recurring lesions.37 Smith, et al, also presented five cases of renal transplant patients treated with imiquimod and 5-FU for Bowen’s disease in multiple areas following their transplants. Topical application of both imiquimod and 5-FU was instigated 3 times/week until complete resolution of the lesions was achieved in all of the patients, with no residual lesion at 3-15 month post-treatment follow-up visits.38

Bowenoid papulosis

Bowenoid papulosis is histologically seen as a carcinoma in situ, despite the benign course of the condition. In 2001, a case report described the effect of imiquimod applied on alternating days for 10 days, or until the skin became visibly irritated and a new dosing schedule was assigned (application once daily for another 10 days, washed off after 2 hours). Complete clinical resolution was noted within 8 weeks and histology revealed no persisting or recurring disease. The patient remained clinically clear after more than 18 months off treatment.39

Vulvar intraepithelial neoplasia (VIN)

A large percentage of vulvar intraepithelial neoplasias (VIN3) have been shown to harbor human papillomavirus (HPV). Imiquimod, an effective treatment for external and perianal genital warts caused by HPV, is thought to be a potentially beneficial treatment for patients with VIN3 of viral (HPV) etiology. A prospective study of 15 patients with high-grade VIN3 examined the effects of imiquimod, self-applied 3 times/week to vulvar lesions for 16 weeks. Only 13/15 patients were able to complete the study, and of those, only 4 showed visible clinical improvement in the state of their condition. The rest of the patients did not improve using imiquimod, although local side-effects such as soreness and burning limited the frequency of cream application, and therefore may have contributed to the patients’ lack of improvement.40 Four cases of imiquimodtreated VIN3 were also reported, with a regimen of selfapplied imiquimod to vulvar lesions 3 times/week until all lesions cleared, for up to 16 weeks. Three of the patients had recurrence of their lesions, with one of the recurrences occurring (and treated with further imiquimod use) during the trial. Other recurrences developed 1 year posttreatment, inside and outside the original field of treatment. These patients were only instructed to use imiquimod during the time of the study, and it is postulated that extended treatment and long-term follow-up may prevent future recurrences.41

Melanoma

Imiquimod has also been useful for treating melanoma. In a case report, a patient reluctant to have a large lentigo maligna of the scalp excised underwent a complete clinical and histological cure after application of imiquimod for 7 months to an initial test area inside the lesion, then to the entire lesion. No clinical recurrence was reported at 9-month follow-up. The recommended treatment for lentigo maligna is conventional surgery, using a 5-10mm margin. Imiquimod may be a novel treatment option worthy of consideration for carefully selected patients in whom more traditional therapy is not considered feasible.42 Likewise, a 50-year-old female suffering from disseminated cutaneous metastatic melanoma lesions was treated with imiquimod 3 times/day with continuance of dacarbazine. Lesions were too initially widespread to be treated with excision or radiotherapy, and failed to improve after a cycle of dacarbazine alone. After 12 weeks of treatment with imiquimod, metastases were no longer detected.43

Cutaneous T-cell lymphoma (CTCL)

A case of cutaneous T-cell lymphoma (CTCL) recently reported complete clearance of clinical and subclinical disease after 4 months of therapy with imiquimod. There was no recurrence at the treatment site at 10-month followup. The authors have initiated a double blind, placebocontrolled trial to better evaluate the efficacy of imiquimod in the treatment of CTCL.44

Cutaneous extramammary Paget’s disease (EMPD)

Extramammary Paget’s disease is an infrequent epidermal malignancy, occurring most commonly in the anogenital and vulvar regions. Berman, et al, treated a case of cutaneous scrotal EMPD with once-daily, self-applied imiquimod over a period of 6 weeks. Though local erythema developed in the treatment area, no systemic symptoms were noted and clinical resolution occurred by week-4 of treatment, with no remaining pathology at 6-month followup. 45 Two other cases of perineal and genital EMPD have also been recently reported, with clinical cure occurring after applying imiquimod on alternating days of the week for 7.5 to 12 weeks. Although it was concluded that this treatment modality was a much less invasive therapeutic option, both cases were associated with systemic symptoms that included flu-like symptoms (malaise, fatigue, lowgrade fever), as well as nausea and vomiting.46

Actinic cheilitis

A retrospective review of 15 patients receiving topical imiquimod as a single agent 3 times/week for the treatment of actinic cheilitis was recently published. Clearance of the treated area was reported in six patients after 4 weeks of treatment, and in the remaining nine patients after week 6. Since it is possible for this condition to progress to invasive squamous cell carcinoma, it is mentioned in this category of oncologically-related conditions.47

Other conditions

Keloids

Berman and Kaufman recently examined the effects of postoperative, topical application of imiquimod to 13 keloids excised from 12 patients. It was applied nightly for 8 weeks, with no recurrence of keloidal growth among the 11 keloids (10 patients completed the study) evaluated at 24 weeks, a rate that was lower than previously reported recurrence rates. The two remaining patients, though lost to follow-up, had completed the 8-week treatment phase and had no keloid recurrence at the time they left the study. Mild local reactions occurred, but were resolved with temporary discontinuation, and no systemic effects were noted.48

Infantile hemangioma

Imiquimod, used to treat two cases of infantile hemangioma of postnatal onset showed complete resolution of these scalp lesions in the proliferative state within 3-5 months. Though the development of erythema and crusting necessitated resting periods, both cases showed virtually complete clinical regression without scarring and neurologic abnormalities. The authors have launched a larger clinical study with pathologic correlation and a mechanism-oriented investigation.49

Porokeratosis of Mibelli

Agarwal and Berth-Jones recently reported a patient with a clinical and histological diagnosis of porokeratosis of Mibelli, successfully treated with imiquimod once-daily for 5 days/week. The initial 3-month treatment showed no response. Subsequently, the same dosage and frequency of imiquimod was used, but under occlusion with an adhesive polythene dressing (Tegaderm®, 3M). The lesion cleared after 5 weeks of treatment, without recurrence at 1-year follow-up. The authors suggested that in the case of porokeratosis of Mibelli, imiquimod application may need to be followed by occlusion due to its inability to penetrate the lesion sufficiently. Although it is possible that occlusion alone would have proven to be therapeutic, the authors believe it is unlikely.50

Leishmaniasis

An open-label, prospective study of combined meglumine antimonate plus imiquimod therapy was conducted in 12 patients with cutaneous leishmaniasis who had previously not responded to a complete course of meglumine antimonate monotherapy. All of the patients responded well to this combination therapy, and 90% were cured at the 6- month follow-up period. Although imiquimod as a solo agent has previously failed to be effective in the treatment of cutaneous leishmaniasis, this study shows that there may be a synergistic effect between imiquimod and meglumine antimonate responsible for the cure of these cases of cutaneous leishmaniasis.51

Tattoo removal

Imiquimod was used for experimental nonsurgical tattoo removal in a guinea pig model using topical imiquimod. Application began 6 hours after tattooing, and treatments were applied every 6 hours for up to 7 days, with no visible tattoo showing at day 28. This is consistent with greatly diminished or no dye evident on histopathology, but is associated with fibrosis and the loss of dermal appendages. This study addressed the treatment of acute-phase tattoos. The authors suggested that early clinical intervention with imiquimod may eventually play a role in the nonsurgical management of tattoo allergy, especially if laser therapy is not an option.52

Conclusion

Imiquimod 5% cream is currently approved for use in genital and perianal warts. However, it may also be an effective treatment for a variety of other entities. As a topical agent, application of imiquimod is convenient because it is patient-applied and reduces the necessity for surgical excision. It is important to note that recent literature regarding imiquimod’s newer uses consists mostly of case studies. Additional assessment in controlled studies is warranted for each of these conditions. Such studies should take place over longer periods of time, during and after the treatment phase and attention should be paid to the dosing frequency. Furthermore, because imiquimod induces production of interferons, and enhances Th1 cell-mediated immune responses, it can be potentially useful in the treatment of conditions that respond to interferon therapy, such as Kaposi’s sarcoma and chronic granulomatous disease.53 Other potential uses may stem from imiquimod’s ability to also inhibit Th2 responses, and therefore may be useful in treating such entities as atopic dermatitis.5

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In this issue:

  1. Novel Dermatologic Uses of the Immune Response Modifier Imiquimod 5% Cream
  2. Fat Rebalancing: The New “Facelift”
  3. Update on Drugs and Drug News - November 2002