Current and potential uses of imiquimod.

Abstract: Imiquimod, an imidazoquinoline amine, is an immune response modifier first FDA-approved for the treatment of external genital and perianal warts in 1997. Since its appearance on the market, its antiviral and antitumor properties have been used in the treatment of a variety of dermatologic conditions. In this review article, the basic mechanism of action of imiquimod, current FDA-approved and non-FDA-approved uses of imiquimod, and key points of medication application frequency, possible adverse effects, and use in combination therapy are discussed. Common skin conditions that may be eradicated with imiquimod are emphasized.

Key Words: imiquimod, immune response modifier, antiviral, antitumor

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Skin conditions, ranging from malignant-appearing moles to benign warts, are reasons that patients frequently seek the advice of a physician. More skin cancers occur in the United States annually than all other cancers combined. All physicians, whether general practitioners or subspecialists, should be aware of common skin manifestations and potential medications available on the market for treatment. A topical medication that is currently widely used by dermatologists for a number of cutaneous conditions is imiquimod. Imiquimod is an immune response modifier approved by the FDA for treatment of external genital warts, actinic keratosis (face and scalp), and superficial basal cell carcinomas. It exhibits a unique mechanism of action with antiviral and antitumor properties. A growing body of evidence exists for potential uses of imiquimod in many dermatologic conditions (Table 1).

Imiquimod [1-(2-methylpropyl)-1H-imidazo[4,5-c] quinolin-4-amine] is part of the imidazoquinoline family. Each gram of the 5% cream contains 50 mg of imiquimod in an off-white vanishing cream. (1) Imiquimod is packaged in single-use packets, with 12 packets per box. Patients should apply a thin layer of medication to the affected area for 6 to 10 hours, then wash off the treated area with mild soap and water. Application frequency varies with the treatment indication. Although imiquimod is FDA-approved for people 12 years old and up, in clinical practice, it is often used safely and effectively in the pediatric population younger than 12 years.

Local site reactions such as erythema and irritation are common and should not be mistaken as adverse effects. Symptoms such as itching, burning, pain, tenderness, bleeding, and infection may occur. In cases of severe reaction, the patient should immediately discontinue use of the medication, wash off the treated area, and contact his or her physician. The systemic absorption of imiquimod is slight and associated more with the surface area of application than the amount applied. (1) Systemic symptoms are rare but may include fatigue, fever, myalgia, central and peripheral nervous system disorder, and influenza-like or gastrointestinal symptoms.

Imiquimod is considered a class B medication in pregnant women. No adequate, well-controlled studies of its use during pregnancy have been conducted. However, in animal models, no mutagenic potential or impairment of fertility was identified, and no embryofetal developmental abnormalities were appreciated in the absence of maternal toxic levels of imiquimod. A risk-to-benefit analysis should be done before initiation of therapy in pregnant women.

Mechanism of action

Imiquimod enhances the activity of both the innate and acquired arms of the immune system through stimulation of toll-like receptors (TLRs) on antigen-presenting cells. TLRs are cell-surface receptors that signal the activation of macrophages in response to microbial products. Imiquimod is a TLR-7 agonist, which, in a rapid cascade, can induce the synthesis and production of Th1 cytokines (interferon [IFN]-, tumor necrosis factor-, interleukin [IL]-12, IL-6) that further perpetuate the immune reaction and generate a targeted adaptive immune response. (2) Imiquimod activates antigen-presenting cells and enhances antigen presentation and maturation of Langerhans cells. A cell-mediated, type 1 immunity response predominates, and immunologic memory is produced. Activated cytotoxic T cells kill virus-infected host cells and tumor cells. In animal models, imiquimod aids the innate arm of the immune system by stimulating natural killer cell activity and the proliferation and differentiation of B-lymphocytes as well. (3) In addition, use of the medication stimulates the production of chemokines and upregulates endothelial cell adhesion molecules, attracting other immune cells to the targeted area of activity. Tumors treated with imiquimod exhibit decreased cell proliferation and increased expression of TIMP-1 (inhibitor of angiogenesis and cell motility) and display increased susceptibility to proapoptotic signals. (4)

FDA-approved uses

External genital and perianal warts

Anogenital warts are the most common sexually transmitted viral disease in the United States.

Imiquimod cream is FDA-approved for the treatment of external genital and perianal warts/condyloma acuminata in those 12 years of age and up. The recommended treatment regimen consists of 3 applications per week for up to 16 weeks. With compliant therapy, approximately 56% of all patients with genital warts will clear in 8 to 12 weeks. (5) At the minimum, patients who do not obtain complete clearance will have a reduction in wart size and number. Adequate penetration of thick, hyperkeratotic nongenital warts can be a limiting factor. Increasing the frequency of imiquimod application and combination therapy with salicylic acid, topical retinoids, treatment under occlusion, and paring of thicker lesions before medication application are helpful adjuncts. Sexual contact during imiquimod therapy necessitates extra precautions. (6) Imiquimod cream can weaken latex contraceptives and reduce barrier function.

Actinic keratoses

Actinic keratoses (AKs) are common premalignant lesions that develop on sun-damaged skin.

Imiquimod cream is FDA-approved for the treatment of nonhyperkeratotic, nonhypertrophic actinic keratoses of the face and scalp in immunocompetent individuals. In a multicentered, double-blinded, vehicle-controlled study of 436 patients, topical imiquimod applied twice per week for 16 weeks resulted in 45.1% complete clearance of AK versus 3.2% in the control group, with an overall median percent reduction of 83.3%. (7)

In a similar study, AKs treated with imiquimod cream 3 times per week for 12 weeks were clinically cleared in 21 (84%) of 25 patients and partially cleared (50-75% reduction in AK lesion size) in 2 (8%). Histologic clearance was confirmed in all clinically cleared cases.

Treated patients (n = 25) where observed for up to 2 years. Of these, four patients (16%) developed new AKs or were lost to follow-up at 18 months and 5 patients (20%) developed new AKs or were lost to follow-up at 24 months. After 24 months, no patients developed squamous cell carcinoma in the treated areas. (9)

The standard regimen of imiquimod for AK is typically once-per-day application for 2 days of the week, 3 to 4 days apart, for 16 weeks. If a rest period is necessary, secondary to the intensity of the reaction, imiquimod may be resumed once symptoms subside. Even with rest periods, the treatment period should not be extended past the specified duration of treatment. Visible as well as subclinical lesions may become perceptible during treatment. For patients unable to tolerate imiquimod-induced irritation, a cycled approach of 4 weeks of active treatment followed by a rest period of 4 weeks (maximum of 3 cycles) may prove efficacious with a lower incidence of adverse effects. (10) Interestingly, it was noted that during these resting intervals. AKs continued to clear while the inflammation subsided.

Superficial basal cell carcinomas

More than 1 million cases of nonmelanoma skin cancers occurred in 2004, of which the majority was basal cell carcinomas (BCC). (11) BCCs are the most common type of skin cancers in human beings. Four distinct types of BCC are recognized: nodular, pigmented, scarring, and superficial basal cell carcinomas (sBCC). Imiquimod cream is FDA-approved for the treatment of biopsy-proven sBCC of a maximum diameter of 2.0 cm located on the neck, trunk, or extremities. Geisse et al (12) conducted two separate randomized, vehicle-controlled studies evaluating the treatment of sBCC with topical imiquimod 5 times per week or 7 times per week, histologically proven clearances ranged from 79% to 82%. The difference in clearance rates between the two groups was not statistically significant. Hence, for sBCC, imiquimod cream should be applied 5 times per week for 6 weeks. The targeted treatment area should include 1 cm of peripheral skin surrounding the tumor.

Off-labeled uses of imiquimod

Actinic cheilitis

Actinic cheilitis is a premalignant change on the surface epithelium of the lips caused by excessive sun exposure. In a review of 15 patients with biopsy-proven actinic cheilitis treated with imiquimod 3 times per week for 4 to 6 weeks, all patients showed clinical clearing 4 weeks after discontinuation of therapy. (13) Notably, the majority of patients had moderate to marked inflammatory symptoms.

Bowen disease (Squamous Cell Carcinoma in situ)

Several case reports have documented the clearance of Bowen disease (BD) in situ with the use of imiquimod. The frequency and duration of applications varies from daily use, twice-per-day cycled therapy, to several weeks of continuous therapy. An open-label study of 16 patients with BD showed that daily application of imiquimod for 16 weeks can achieve clinical and histologic clearances in 93% of patients. (14) Smith et al (15) reported a case series of renal transplant patients with BD who were successfully treated with a combination of imiquimod and 5% 5-fluorouracil. Further studies establishing guidelines and evaluating treatment efficacy need to be conducted.

Nodular basal cell carcinomas

Although imiquimod is approved for the treatment of sBCC, the treatment of nodular basal cell carcinomas (nBCC) is still undergoing investigational studies. Nodular BCCs are more difficult to eradicate with topical therapy, relative to sBCC, due to deeper dermal extension of malignant cells. Shumack et al (16) studied different treatment durations for nBCC in phase 2 study trials. They concluded that topical imiquimod cream is effective in treating nBCC when applied daily for either 6 or 12 weeks, with no significant differences in clearance rates between the two groups. The 6-week treatment period was better tolerated and fewer adverse side effects were seen. In a recent open-label study, Huber et al (17) treated 15 nBCC with imiquimod 3 times per week for 12 weeks. Mohs surgery resection confirmed complete clearance of all patients, with no recurrence at the 18-month follow up.

Lentigo maligna

The incidence of cutaneous melanoma continues to rise every year. Lentigo maligna (LM) is a preinvasive lesion that occurs most commonly on the sun-exposed areas of the head and neck of elderly individuals. If left unchecked. LM can acquire the capacity to invade and progress to lentigo maligna melanoma. Although the standard treatment of LM is surgical therapy, various treatment modalities exist if surgery is not a feasible option. In a study of 30 patients with LM, patients applied imiquimod daily for 3 months. Of the 28 patients who completed the treatment, 26 (93%) patients were complete responders, of whom greater than 80% of this group had no recurrence at the 1-year follow up. (19) In 2004, Powell et al (20) also treated 12 patients with LM with imiquimod with a starting application frequency of 3 times per week for 6 weeks. If no inflammation occurred, the application frequency was then increased to daily use. At the end of the treatment phase, 10 (83%) patients had complete clearance, with no recurrence at the 6-month follow up. With further studies, imiquimod may be added to the collection of nonsurgical therapeutic options for LM.

Metastatic melanoma

Melanoma is the sixth most common cancer in the United States, with incidence rates rapidly rising.

Few case reports have documented the treatment of cutaneous malignant melanoma metastases with the use of imiquimod. Ugurel et al (21) described a case of an 81-year-old male with multiple satellite metastases around the site of a previous melanoma excision. Imiquimod was applied daily to targeted areas under occlusion for 12 weeks. Although biopsy of the areas showed no viable tumor cells after the treatment phase, surgical dissection of an enlarging lymph node in the area of drainage showed nodal melanoma metastasis. Wolf et al (22) reported the complete clinical and histopathological clearance of cutaneous melanoma in 2 patients, an 86-year-old female and a 49-year-old male, with application of imiquimod 3 times per week for 4 and 8 months, respectively. Imiquimod appears to have a marked effect on cutaneous metastatic melanoma. However, its role relative to melanoma size, depth, and other patient variables needs further study and clarification.

Cutaneous T-cell lymphoma 

Cutaneous T-cell lymphoma (CTCL) results in skin lesions arising from the proliferation of malignant T-cells in the dermis that migrate into the epidermis. Suchin et al (23) described a patient with stage IA CTCL who was treated successfully with application of imiquimod nightly for 4 months, with no relapse at the 10-month follow-up visit. A pilot study evaluating the treatment of imiquimod for CTCL is currently underway. Imiquimod may be a future addition in the armamentarium for CTCL therapy.

Vulvar intraepithelial neoplasia 

Vulvar intraepithelial neoplasia (VIN) is a precancerous cutaneous lesion of the vulva that if left untreated, can progress to form invasive vulvar cancer. Over the past decade, there has been a striking increase in the incidence of VIN and invasive vulvar SCC in young women. (24) Risk factors for development of VIN are similar to those for vulvar cancer and include HPV, cigarette smoking, and immunosuppression. Definitive therapeutic options include surgery or laser ablation, which can lead to scarring and physical and psychological morbidities. In a prospective pilot study, imiquimod was used 1 to 3 times per week for up to 34 weeks in the treatment of VIN-2 to 3- in 15 women. (25) Of the 13 patients who completed the study, 4 patients achieved complete remission in 6, 7, 11, or 30 weeks and 9 patients had partial remission. Although imiquimod shows activity against high-grade intraepithelial neoplasia of the genital tract, its exact role in VIN therapy needs further investigation.

Extramammary Paget disease

Extramammary Paget disease (EMPD) is a clinical entity that refers to the formation of erythematous patches and plaques on areas of the body that contain apocrine glands, such as the genital and perianal skin. It is a diagnosis often associated with primary malignancy. Zampogna et al (26) documented clinical or histological cleareance in two patients with scrotal, inguinal, and perineal limited cutaneous EMPD with imiquimod. The medication was applied from 4 times per week to nightly for 7.5 to 12 weeks. Nausea and vomiting occurred in one patient, who improved with a decrease in application frequency and meclizine use. Another case study documented the eradication of recurrent EMPD of the penis in a 68-year-old male with nightly application of imiquimod for 6 weeks with no signs of recurrence 6 months after discontinuation of therapy. Although the patient had moderate erythema, he was able to complete the course of therapy. (27)

Herpes simplex virus 2

Herpes simplex virus 2 (HSV-2) is a sexually transmitted disease that often appears as grouped vesicles on an erythematous base. Seroepidemiology surveys suggest that more than 45 million individuals currently have genital HSV. (28) A few case reports of successful imiquimod treatment of HSV-2 appear in the literature. Gilbert et al (29) described a 34-year-old male with HIV and a 5-month history of HSV-2 infection refractory to acyclovir, valacyclovir, or famciclovir that was eradicated with a 1-week course of topical imiquimod. Schaker et al (30) conducted a randomized, double-blinded, placebo-controlled trial in which patients with recurrent herpes genitalis applied imiquimod or placebo 1 to 3 times per week for 3 weeks. Of the 93 patients who completed the treatment and observation period, the median time to first genital herpes recurrence was 53 days for those who received placebo and 54, 60, and 64 days for those who received imiquimod 1, 2, or 3 times per week, respectively. No significant statistical differences existed in the recurrence time or in the annualized recurrence rate between the imiquimod and placebo groups. Although imiquimod shows promise in the clearance of refractory HSV-2, its effect on the prevention of HSV-2 recurrence appears limited.

Molluscum contagiosum

Molluscum contagiosum (MC) is caused by a DNA virus of the Poxviridae family. Clinically, umbilicated, domeshaped papules manifest on the skin. The condition is transmitted through direct skin contact or indirect contact with contaminated objects and appears more common in children and those who are immunocompromised. In an open-label pilot study. Bayer et al (31) applied imiquimod 3 times per week for 16 weeks in 13 children with MC. Two patients had complete clearance of lesions, and seven had partial remission. Another study in pediatric patients showed that combination therapy with cantharidin and nightly application of imiquimod for 5 weeks resulted in greater than 90% clearing in 12 of 16 (75%) patients. (32) Several case reports have also documented the efficacy of treating molluscum contagiosum with imiquimod in immunocompromised patients. Buckley et al (33) reported a case of a 32-year-old female with HIV and a 3-year history of recalcitrant molluscum contagiosum that was treated with imiquimod 3 times per week for 3 months, with resolution of all lesions and no signs of recurrence 5 months after discontinuation of therapy. Imiquimod enhances the body's immunologic and inflammatory response and is a potential agent in the treatment of MC virus in children and adults. Treatment should begin with a 3-times-per-week regimen and then adjusted to achieve an inflammatory response. Notably, combination therapy with cantharidin achieves a higher percentage of clearance. A longer duration of therapy in immunocompromised patients may be necessary for optimum results.

Bowenoid papulosis

Bowenoid papulosis (BP) refers to epidermal hyperplasia and dysplasia of the anogenital region secondary to HPV-16, 18, 31, or 33 infection. Clinically, they appear as solitary or multiple wart-like papules and occur more often in the immunocompromised. Whereas in general, BP is a benign condition, it is often regarded as a form of squamous cell carcinoma in situ. Richter et al (34) reported the case of a 34-year-old female with BP of the vulva that was successfully treated with imiquimod cream 3 times per week for 14 weeks. Although the patient had a partial ulceration and a bacterial superinfection 8 weeks into therapy, she received topical antibiotics and was able to continue on with treatment. Other case reports in the literature also identify imiquimod as a potential agent of therapy for BP. Treatment frequency ranges from 3 times per week to daily application. Imiquimod may be effective as either a primary or adjuvant therapeutic alternative for those with limited disease or those refractory to conventional measures.

Stucco keratosis

Stucco keratoses are small, wart-like, keratotic papules of unknown cause typically found on the lower extremities of elderly persons. Stockfleth et al (35) reported a case of a 75-year-old male with recurring, generalized stucco keratoses that were treated with imiquimod 3 times per week for 5 weeks, with resolution of all lesions. The investigators performed polymerase chain reaction on four biopsies and were able to identify several HPV types, suggesting the possibility of a viral pathology.

Porokeratosis of Mibelli

Porokeratosis is a disorder of abnormal proliferation of keratinocytes that manifests as small atrophic patches surrounded by a ridge-like border or the cornoid lamellae. A small percentage of these keratin proliferations can undergo malignant degeneration. Porokeratosis of Mibelli is one subset form of porokeratosis. In 2002, Agarwal et al (36) first reported the case of a 55-year-old male with a biopsy-proven porokeratosis of Mibelli that was initially treated with imiquimod 5 days per week for 3 months, without improvement. The patient then applied imiquimod 5 days per week under occlusion with an adhesive polythene dressing, and within 5 weeks the lesion had resolved with no evidence of recurrence at the 1-year visit. Imiquimod may prove useful in the treatment of porokeratosis, especially in areas where excision may be difficult or cosmetically unacceptable.

Granuloma annulare

Granuloma annulare presents with violaceous dermal papules arranged in an annular configuration. Although its natural course is one of spontaneous resolution, regression may take several years, and recurrences are common. One case report exists in the literature concerning the treatment of a 12-year-old female with multiple annular plaques consistent with granuloma annulare. The patient applied imiquimod nightly to one large plaque, and, progressively over 6 weeks, the lesion resolved, although plaques that were not treated remained present. (37)

Keloids 

Keloids are benign dermal tumors of collagen that represent an overactive wound-healing response. Those of African-American, Hispanic, or Asian heritage are often more prone to keloid formations. Although a variety of methods exist for keloid treatment, no therapeutic regimen is without a substantial chance of recurrence, the pain of repeated injections, or the inconvenience of multiple follow-up visits. Berman et al (38) investigated the use of postexcision imiquimod in 12 patients with earlobe keloids. After the removal of the keloids, patients applied imiquimod nightly, beginning the night of surgery for 8 weeks. Of the 10 patients who completed the study, no keloid recurrences were observed at the 6-month visit. Imiquimod induces synthesis of cytokines (IFN-[alpha] and IFN-that help decrease collagen production. In addition, imiquimod alters apoptotic gene expression, another mechanism by which it may exert its effects.

Leishmaniasis 

Leishmaniasis is a protozoan infection transmitted by the bite of the sandfly. Each year, approximately 12 million people worldwide are affected by the disease. Depending on the species-specific virulence of the Leishmania protozoan and host susceptibility, a clinical spectrum of manifestations can occur, of which the cutaneous form is the most common. Papules, nodules, and ulcers occur along a sporotrichoid distribution and can progress to widespread cutaneous involvement. The standard treatment for leishmaniasis is pentavalent antimony, an expensive medication with multiple adverse effects and variable treatment success made even more difficult with the emergence of drug-resistant parasites. Arevalo et al (39) conducted an open-label, prospective trial in which 12 patients with meglumine antimonite-resistant cutaneous leishmaniasis were treated with a combination regimen of meglumine antimonite and topical imiquimod applied every other day for 20 days. At the end of the treatment period, 50% of patients had achieved clinical cure, whereas the other 50% of patients had substantial improvement of their lesions. Imiquimod in combination with meglumine antimonite is a potential therapy option for those with leishmaniasis refractory to standard therapy.

Tattoo removal

Conventional methods of tattoo removal are often painful, with possible adverse effects such as infection, scarring, and dyspigmentation. In a guinea pig animal model, the application of imiquimod to areas of tattoo for 7 days, beginning 6 hours after tattooing, resulted in clinical tattoo removal and no visible or greatly reduced pigment on histopathology. (40) Side effects included fibrosis and loss of dermal appendages. Although further studies must be conducted, imiquimod may prove useful as a nonsurgical method for tattoo removal if initiated within a few hours of the tattooing. Combination treatment with lasers followed by topical imiquimod for remaining pigment is a potential treatment modality worthy of investigation.

Morphea

Morphea presents as localized induration of the skin as the result of dermal and subcutaneous fibrosis. Imiquimod, an inducet of Th1 cytokines, may help downregulate fibrotic cytokines that induce fibroblast proliferation and deposition of extracellular matrix. Man et al (41) reported a case of a 28-year-old female with areas of erythematous, ill-defined plaques consistent with morphea that was treated with imiquimod 3 times per week for 8 months, with resolution of induration and decreased erythema and skin atrophy. Investigations on the treatment of morphea with imiquimod and analysis of the relevant cytokines are currently underway.

Infantile hemangioma 

Infantile hemangiomas are benign vascular tumors that occur in approximately 5 to 10% of infants. The natural progression of hemangiomas involves first a proliferative phase, followed by an involutionary phase. Regression of hemangiomas occurs to variable degrees and can leave behind scars and more serious defects such as amblyopia or anatomic deformities. Two infants with typical infantile frontal scalp hemangiomas were successfully treated with imiquimod within 3 to 5 months of therapy. (42) During the treatment period, erythema and crusting occurred, necessitating frequent rest periods. Virtually complete clinical regression was achieved with no recurrence at the 4-month follow-up visit. Imiquimod induced IFN-[alpha], IL-12, and TIMP-1 (antiangiogenic cytokine), which may play active roles in the response of hemangiomas to imiquimod.

Keratoacanthoma

Keratoacanthomas are epidermal tumors of ambiguous malignant potential. Although the majority of these lesions regress spontaneously, a small percentage develops into invasive SCCs. Anecdotal reports of successful treatment of keratoacanthomas with daily application of imiquimod have recently been reported in the literature. (43)

Conclusion

Imiquimod is an immune response modifier that is a potential therapy for cutaneous diseases commonly encountered by many physicians. Although it is only FDA approved for the treatment of anogenital warts, actinic keratoses, and superficial basal cell carcinomas, its antitumor and antiviral properties have been used in the successful treatment of a wide variety of dermatological conditions. However, for these novel uses, much of the data are anecdotal case reports without sufficient investigational experience. Large clinical trials with long-term evaluation and appropriate follow-up visits will be necessary to further define guidelines for effective therapy.

Topical immunotherapy with imiquimod is a patient-friendly, well-tolerated therapy that can achieve cosmetically pleasing treatment outcomes. The era of topical immunomodulators in the treatment of dermatologic disease has just begun. It would be of benefit for the general practitioner to be aware of the current and potential uses of imiquimod.

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40. Solis RR, Diven DG, Colome-Grimmer MI, et al. Experimental nonsurgical tattoo removal in a guinea pig model with topical imiquimod and tretinoin. Dermatol Surg 2002;28:83-86.

41. Man J, Dytoc MT. Use of imiquimod 5% cream in the treatment of localized morphea. J Cutan Med Surg 2004;8:166-169.

42. Martinez MI, Sanchez-Carpintero I, North PE, et al. Infantile hemangioma: clinical resolution with 5% imiquimod cream. Arch Dermatol 2002;138:881-884.

43. Dendorfer M, Oppel T, Wollenberg A, et al. Topical treatment with imiquimod may induce regression of facial keratoacanthoma Eur J Dermatol 2003;13:80-82.

Yuchi C. Chang, MD, Vandana Madkan, MD, Robert Cook-Norris, BS, Karan Sra, MD, and Stephen Tyring, MD, PHD, MBA 

From the Department of Internal Medicine and the Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX; the Center for Clinical Studies, Houston, TX; Texas Tech University School of Medicine, Lubock, TX; and the Department of Dermatology, University of Texas Medical Branch, Galveston, TX.

Reprint requests to Dr. Stephen Tyring, Department of Dermatology, University of Texas Health Science Center at Houston, 6655 Travis, Suite 820, Houston, TX 77030. Email: [e-mail]

Accepted April 18, 2005.

Dr. Tyring is a consultant and speaker for 3M Company.

RELATED ARTICLE: Key Points

* Imiquimod is a topical medication prescribed frequently for a number of viral and neoplastic cutaneous conditions. It induces the synthesis of multiple cytokines and creates a Th1-dominant, cell-mediated immune milieu with antiproliferative and antiviral characteristics.

* Although it is FDA-approved for external and perianal warts, superficial basal cell carcinomas, and actinic keratoses of the face and scalp, it has also been used in the treatment of a wide range of skin diseases.

* Application frequencies vary, based on the condition under treatment. Treatment under occlusion or simultaneously with a retinoid product may improve penetration.

RELATED ARTICLE: General tips in imiquimod treatment:

1.) Start application frequencies at 3 times per week and titrate up as needed to establish and maintain a mild inflammatory response;

2.) Discuss with patients the difference between site reactions and adverse reactions;

3.) In general, a regimen with more frequent applications correlates with a shorter overall duration of therapy;

4.) On thin or well-vascularized surfaces such as lips and hemangiomas, inflammation, ulceration, and superinfections are more likely to occur;

5.) In cases of severe reactions, a rest period may be necessary. Therapy can be restarted with less frequent application once symptoms improve;

6.) For thicker lesions or patients who do not respond to therapy, consider treatment under occlusion or combination treatment with a retinoid product to improve penetration; and

7.) Immunocompromised patients may require a longer period of therapy than their immunocompetent counterparts.

Table. Current FDA approved and potential uses of imiquimod (a)

                               Application      Treatment
Condition                      Frequency        Duration (b)

FDA-approved uses
  External genital/perianal    3 X a week       16 weeks
  warts
  Actinic keratosis            2-3 X a week     16 weeks
  Superficial BCCs             5 X a week        6 weeks
Off-Label uses
  Actinic cheilitis            3 X a week       weeks
  Bowen disease                3-7 X a week     weeks
  Nodular BCCs                 3-7 X a week     weeks
  Lentigo maligna              3-7 X a week     months
  Metastatic melanoma          3-7 X a week     weeks-months
  Cutaneous T-cell               nightly        months
  lymphoma
  Vulvar intraepithelial       3 X a week       weeks
  neoplasia
  Extramammary Paget           4-7 X a week,    weeks
  disease                        nightly
  Herpes simplex virus 2       1-3 X a week     weeks-months
  Molluscum contagiosum        3-7 X a week     weeks
  Bowenoid papulosis           3-7 X a week,    weeks
                                 nightly
  Stucco keratosis             3 X a week       weeks
  Porokeratosis of Mibelli     3 X a week       weeks
  Granuloma annulare           nightly          weeks
  Keloids                      nightly          weeks
  Leishmaniasis                3-4 X a week     weeks
  Tattoo removal (c)           nightly          weeks
  Morphea                      3 X a week       months
  Infantile hemangioma         3-4 X a week     weeks-months
  Keratoacanthoma              nightly          months

(a) FDA, Federal Drug Administration; BCCs, basal cell carcinomas.
(b) Treatment duration for off-label uses of imiquimod are not listed
more specifically as data is often based on few case reports without
substantial clinical studies to justify wide use guidelines.
(c) Animal study only.