Increased number of mast cells in the dermis in actinic keratosis lesions effectively treated with imiquimod

Actinic keratosis (AK) is a cutaneous cancer in situ which develops as a result of excessive exposure to ultraviolet (UV). Toll‐like receptor (TLR)7 agonist imiquimod is a topical immune response modifier and is effective for the treatment of non‐melanoma skin cancers. Recently, the diagnostic role of the dermatoscope has been reported in the course of treatment of AK. In addition, mast cells are now considered to contribute to both the innate and adaptive immune systems in topical imiquimod therapy. We assessed the effect of imiquimod treatment by dermatoscopic and immunohistochemical findings in 14 patients with a total of 21 AK lesions. With the dermatoscope, though the mean erythema score was not significantly different between the cured lesions and the unresponsive lesions, the erythema/red pseudo‐network (“strawberry”) pattern was decreased significantly in the cured lesions. By immunohistochemistry, the number of Ki‐67‐positive proliferative cells in the epidermis was decreased and that of CD117‐positive mast cells in the dermis was increased in the responding lesions. To the best of our knowledge, this is the first study demonstrating that the number of mast cells in the dermis was increased in AK lesions effectively treated with imiquimod. Our present result suggests that mast cells may contribute an antitumor effect in human skin treated with topical imiquimod.     

Actinic keratosis and field cancerization

While actinic keratoses (AKs) have been considered precancerous until recently for being able to turn into squamous cell carcinomas (SCCs), it is now agreed that it would be more appropriate to call them cancerous. Although not all AKs turn into SCC and some of them may even have a spontaneous regression, there is an obvious association between SCC and AK. Approximately 90% of SCs have been reported to develop from AKs and AKs are the preinvasive form of SCCs. The presence of two or more AKs on a photodamaged skin is an indicator of field cancerization and represents an increased risk of invasive SCC. All lesions should be treated since it cannot be foreseen which of the lesions will regress and which will progress to SCC. AK can be a single lesion or it can involve multiple lesions in a field of cancerization; thus, AK treatment is grouped under two headings: (1) Lesion-specific treatment; and (2) Field-targeted treatment. Lesion-specific treatments are practicable in patients with a small number of clinically visible and isolated lesions. These treatments including cryotherapy, surgical excision, shave excision, curettage and laser are based on physical destruction of the visible lesions. Field-targeted treatments are effective in the treatment of visible lesions, subclinical lesions and keratinocyte changes in the areas surrounding the visible lesions. Field targeted treatment options are topical imiquimod cream, 5% 5-fluorouracil cream, ingenol mebutate, diclofenac gel, resimiquimod and photodynamic therapy.     

Association between the clinical and histopathological classifications of actinic keratosis and the efficacy of topical imiquimod treatment

We investigated the association between the clinical and histopathological classifications of actinic keratosis (AK) and the efficacy of topical imiquimod treatment. Forty patients (55 lesions) with AK were treated with topical 5% imiquimod and the efficacy of imiquimod for AK was evaluated based on the clinical/histopathological changes. The complete remission (CR) rates in patients with the different clinical classifications of AK were 85.4% (erythematous type) and 46.2% (hyperkeratotic type). The CR rates in the different histopathological classifications of AK were 80% (hypertrophic type), 81.8% (atrophic type) and 42.9% (bowenoid type). The results revealed that determining the clinical and histopathological type of AK was important for selecting a therapeutic method. The topical imiquimod treatment could be expected to be more effective for AK clinically classified as the erythematous type, or histopathologically classified as the atrophic or hypertrophic type. However, it would be expected to be less effective for the treatment of AK clinically classified as the hyperkeratotic type or histopathologically classified as the bowenoid type. Our observations suggest that we can predict the efficacy of topical imiquimod therapy in AK by determining its clinical and histopathological type.     

New and emerging topical approaches for actinic keratoses

Actinic keratoses (AKs) are intraepidermal foci of malignancy and represent the earliest clinical stage in the continuum of squamous cell carcinoma (SCC). A variety of topical, physical, and surgical modalities are available for treatment. Until recently, topical 5-fluorouracil was the only topical agent approved by the US Food and Drug Administration (FDA) for the treatment of AK. Topical diclofenac 3% gel, an inhibitor of arachidonic acid, is the second topical approved for the treatment of AK. Although not currently approved in the United States, multiple studies have substantiated the efficacy of topical imiquimod for AKs. This article reviews the efficacy and safety of topical diclofenac and topical imiquimod for the treatment of AKs.     

Clinical effect of imiquimod 5% cream in the treatment of actinic keratosis

BACKGROUND: Actinic keratosis (AK) is the earliest clinical manifestation of squamous cell carcinoma. Metastatic SCC causes the majority of the 1300 to 2300 deaths attributed to nonmelanoma skin cancer in the United States each year. Recent studies have shown that intralesional administration of interferon can be used successfully in the treatment of AK. OBJECTIVE: Imiquimod is an immune response modifier, currently approved for the treatment of genital warts. The topically applied immune response modifier acts by up-regulating interferon and other cytokines involved in the cell-mediated immune response at the site of application. The aim of this was to determine the efficacy and safety of imiquimod 5% cream for the treatment of AK. METHODS: Twenty-two patients with AK lesions were treated with imiquimod 5% cream, initially at 3 times per week for 8 weeks, or until total clearance of lesions. Patients applied imiquimod to lesions on one side of the body and vehicle cream to the other side. A total of 17 patients who completed treatment were evaluated for number of lesions and adverse reactions before treatment and at weeks 2, 4, 6, and 8 after initiation of treatment. AK lesions were also assessed 4 and 8 weeks after treatment. RESULTS: A significant reduction in the average number of lesions per patient was observed for patients treated with imiquimod. The most frequent reactions to treatment were erythema, itching, and scabbing; however, all adverse events were mild to moderate. CONCLUSION: Imiquimod 5% cream may be a promising treatment for AK.     

Imiquimod in dermatology: an overview

Imiquimod is an immune response modifier commercially available as a 3.75 and 5% cream. Topical imiquimod stimulates the innate and adaptive immune responses and induces cytokine production. This allows its use for the treatment of a wide variety of benign and malignant skin conditions due to its potential antiviral, antitumor, and immunoregulatory effects. Currently, topical imiquimod is US Food and Drug Administration (FDA)‐approved for the treatment of anogenital warts, actinic keratosis, and superficial basal cell carcinomas. However, it has also shown a beneficial effect in the treatment of many other skin disorders. In this review, we describe existing evidence on the mechanism of action of topical imiquimod, its FDA‐approved indications, off‐label uses, and side effects.     

Successful treatment of multiple actinic keratoses in organ transplant patients with topical 5% imiquimod: a report of six cases

BACKGROUND: Nonmelanoma skin cancer represents a significant cause of morbidity in organ transplant recipients (OTRs). Cutaneous malignancies, mainly invasive squamous cell carcinoma and its precursor actinic keratosis (AK), appear approximately 5-10 years after organ transplantation. Impaired wound healing and high recurrence rates in immunocompromised patients treated with destructive therapies such as cryosurgery or topical 5-fluorouracil represent frequently known complications. OBJECTIVES: To evaluate the safety and efficacy of imiqimod 5% in the treatment of AKs in OTRs. METHODS: Six OTRs (two kidney, two heart, one lung and one liver) with extensive AKs were treated with imiquimod 5% cream two to three times weekly in an open-label uncontrolled, nonrandomized pilot study. RESULTS: In five of six patients treated with imiquimod 5% cream all AK lesions were cleared after 12-16 weeks. One patient showed partial response. Local adverse events at the site of application included erythema, oedema and mild erosion. No wound infection or scarring was observed in any of these patients. All graft-related laboratory parameters were stable during and after treatment. Immunosuppressive therapy remained unchanged throughout the treatment. CONCLUSIONS: These results suggest that imiquimod 5% cream may be useful for the local treatment of precancerous AK lesions in OTRs.     

A randomized,double-blind,vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses

BACKGROUND: Actinic keratoses (AKs) are precancerous epidermal lesions found most frequently on areas of the skin exposed to the sun. Several case studies published recently have indicated that 5% imiquimod cream, currently licensed for the treatment of genital warts, may be an effective treatment for AK. OBJECTIVE: To assess the efficacy and safety of imiquimod for the treatment of AK. DESIGN: Patients in this randomized, double-blind, vehicle-controlled study applied 5% imiquimod cream or vehicle to AK lesions 3 times per week for a maximum of 12 weeks or until lesions had resolved. In the event of an adverse reaction, application of imiquimod was reduced to 1 or 2 times per week. Rest periods were also allowed if necessary. SETTING: A specialized outpatient dermatology clinic within a state-funded hospital in Germany. PATIENTS: The study population was aged 45 to 85 years. Of 52 patients screened, 36 men and women with AK confirmed by histological diagnosis were enrolled. Patients were excluded from the study if they did not have a histological diagnosis for AK, if they were older than 85 years, or if they did not comply with the protocol. All patients had responded to a notice asking for volunteers. MAIN OUTCOME MEASURES: The number and appearance of lesions were evaluated before, during, and after treatment. All adverse effects were recorded. RESULTS: Lesions treated with 5% imiquimod cream were clinically cleared in 21 (84%) of 25 patients and partially cleared in 2 (8%). Clearance was histologically confirmed 2 weeks after the last application of imiquimod in all patients clinically diagnosed as lesion free. Only 10% of patients treated with imiquimod were clinically diagnosed with recurrence 1 year after treatment. No reduction in the size or number of AK lesions was observed in vehicle-treated patients. Adverse effects reported by patients treated with imiquimod included erythema, edema, induration, vesicles, erosion, ulceration, excoriation, and scabbing. However, imiquimod was well tolerated since all patients completed the 12-week treatment. Only a few, mild adverse reactions to the vehicle cream were reported. CONCLUSION: Application of 5% imiquimod cream for 12 weeks is an effective and well-tolerated treatment for AK.     

Open-label study to assess the safety and efficacy of imiquimod 5% cream applied once daily three times per week in cycles for treatment of actinic keratoses on the head

BACKGROUND: Local skin reactions are common during imiquimod treatment of actinic keratosis (AK). Cyclical application of imiquimod may improve tolerability while maintaining efficacy. OBJECTIVE: To assess the tolerability of imiquimod and clearance rate of AK lesions after imiquimod application. METHODS: Imiquimod 5% cream was administered three times per week for 4 weeks followed by 4 weeks of rest (cycle 1) to AK lesions on the head. If AK lesions remained visible at the end of cycle 1, a second treatment cycle was instituted. RESULTS: Fifty percent (30 of 60) of patients experienced complete clearance of AK lesions, and 75% (30 of 40) of patients experienced partial clearance of AK lesions after imiquimod treatment at the end of cycle 2. Moreover, 77% of patients who achieved complete clearance had no visible AK lesions 12 weeks post-treatment. Imiquimod was well tolerated. CONCLUSION: Imiquimod cycle therapy may be a safe and effective treatment option for AK lesions.     

Successful treatment of actinic keratosis with imiquimod cream 5%: a report of six cases

BACKGROUND: Actinic keratoses (AK) are premalignant lesions, which are routinely treated by destructive procedures such as cryotherapy, electrodessication or topical 5-fluorouracil. OBJECTIVES: The aim of this study is to report six cases of AK treated with a potential new topical therapy, imiquimod. METHODS: Subjects included in this study had suffered with recurrent AK for between 5 and 16 years. All six men were treated with imiquimod 5% cream three times a week for 6-8 weeks. In the event of a local skin reaction treatment was modified to two times per week. RESULTS: All the AK lesions were successfully cleared after treatment with imiquimod cream 5% for 6-8 weeks. Histologically, no apparent signs of persisting AK could be detected, and no recurrences were reported during follow up. CONCLUSIONS: This study suggests that imiquimod may be useful as a new therapy for the treatment of actinic keratoses.     

Evidence for field cancerisation treatment of actinic keratoses with topical diclofenac in hyaluronic acid

Actinic keratosis (AK) is a common skin disease seen in daily practice. It is associated with a risk of progression to invasive squamous cell carcinoma and can be regarded as a marker of increased risk for nonmelanoma skin cancer. The use of a field-directed treatment approach reflects the need to initiate early treatment over an affected area to prevent tumour development and local recurrence. Candidate field-directed treatments require a mechanism of action compatible with an effect on field cancerisation, immediate and long-term efficacy against visible lesions and efficacy against subclinical AK. Applicability to large treatment areas, tolerability compatible with long-term use, utility in organ transplant patients and, ideally, evidence of extended long-term activity may also be desirable. We review the evidence of a role for topical diclofenac sodium 3% administered in a 2.5% hyaluronic acid gel (diclofenac/HA) as field-directed treatment. Diclofenac/HA directly targets AK pathophysiology through multiple mechanisms, including induction of apoptosis, inhibition of angiogenesis and reduced inflammation. Clearance of visible field cancerisation is safely and rapidly achieved with a 90-day treatment course in patients with affected areas of up to 50 cm² and is associated with a ≥75% reduction in target lesion number score in 85% and 91% of patients, respectively, at 30 days and 1 year post-treatment. Following treatment of AK in high-risk transplant patients, 45% remained free of lesions in the treatment area at 2 years post-treatment. We conclude that diclofenac/HA fulfils most criteria necessary to be considered an appropriate candidate for a field-directed treatment in AK.     

Earliest stage treatment of actinic keratosis with imiquimod 3.75% cream: Two case reports—Perspective for non melanoma skin cancer prevention

Imiquimod 3.75% cream is licensed for the treatment of actinic keratosis (AK). Two case reports on the treatment of facial UV‐exposed skin shall open the discussion if subclinical AKs can be detected by the use of imiquimod cream in UV‐exposed areas even if no lesions can be found clinically. A 87‐year old female showing small scaly AK lesions on her right cheek was treated with imiquimod 3.75% cream. A 59‐year old female without obvious clinical signs of UV‐damage on the face experimentally applied imiquimod 3.75% cream twice daily on the entire face for 2 weeks. In the 87‐year old, inflammatory reaction developed from day 3 onward and showed field cancerization, the lesions healed without scarring. In the 59‐year old at the end of the treatment phase, distinct signs of inflammation appeared, then taking 2 weeks for healing without sequalae. These results open the discussion if the use of imiquimod 3.75% cream could be recommended preventively in UV‐exposed skin areas to obviate a later development of AKs/squamous cell carcinoma/nonmelanoma skin cancer.     

Current and novel treatment options for actinic keratosis

Actinic keratosis (AK), located on sun-exposed areas of the skin, is an increasing global health burden. Multiple ablative and topical treatment options are available to manage this disease; however, topical treatment options are receiving significant interest because AK is commonly associated with areas of substantial photodamage, and destructive modalities cannot effectively treat subclinical AK. Several topical therapies, including 0.5% and other 5-fluorouracil concentrations, photodynamic therapy, 3% diclofenac sodium gel, and imiquimod 5% cream, are indicated in the treatment of AK. This article will review key data on the efficacy and safety of several topical therapies in the treatment and management of AK. The review includes discussions of imiquimod 5% cream, approved in 2004 in the treatment of AK of the face or scalp. Whether administered as monotherapy or adjunctive therapy, topical therapies provide the opportunity to effectively manage AK and will likely emerge as an important tool for healthcare providers.     

Current and Novel Treatment Options for Actinic Keratosis

Actinic keratosis (AK), located on sun-exposed areas of the skin, is an increasing global health burden. Multiple ablative and topical treatment options are available to manage this disease; however, topical treatment options are receiving significant interest because AK is commonly associated with areas of substantial photodamage, and destructive modalities cannot effectively treat subclinical AK. Several topical therapies, including 0.5% and other 5-fluorouracil concentrations, photodynamic therapy, 3% diclofenac sodium gel, and imiquimod 5% cream, are indicated in the treatment of AK. This article will review key data on the efficacy and safety of several topical therapies in the treatment and management of AK. The review includes discussions of imiquimod 5% cream, approved in 2004 in the treatment of AK of the face or scalp. Whether administered as monotherapy or adjunctive therapy, topical therapies provide the opportunity to effectively manage AK and will likely emerge as an important tool for healthcare providers.     

Current and Novel Treatment Options for Actinic Keratosis

Actinic keratosis (AK), located on sun-exposed areas of the skin, is an increasing global health burden. Multiple ablative and topical treatment options are available to manage this disease; however, topical treatment options are receiving significant interest because AK is commonly associated with areas of substantial photodamage, and destructive modalities cannot effectively treat subclinical AK. Several topical therapies, including 0.5% and other 5-fluorouracil concentrations, photodynamic therapy, 3% diclofenac sodium gel, and imiquimod 5% cream, are indicated in the treatment of AK. This article will review key data on the efficacy and safety of several topical therapies in the treatment and management of AK. The review includes discussions of imiquimod 5% cream, approved in 2004 in the treatment of AK of the face or scalp. Whether administered as monotherapy or adjunctive therapy, topical therapies provide the opportunity to effectively manage AK and will likely emerge as an important tool for healthcare providers.

     

Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials

OBJECTIVE: To evaluate the efficacy and safety of 5% imiquimod cream compared with vehicle in the treatment of actinic keratosis (AK). DESIGN: Two phase 3 randomized, double-blind, parallel-group, vehicle-controlled studies. SETTING: Twenty-six ambulatory care offices, including dermatologists in private practice or research centers. PATIENTS: Four hundred ninety-two patients, 18 years and older, with 4 to 8 AK lesions in a 25-cm(2) treatment area on the face or the balding scalp were randomized; an additional 162 patients underwent screening but were ineligible. INTERVENTIONS: Patients applied 5% imiquimod (Aldara) or vehicle cream to the treatment area once daily, 3 times per week, for 16 weeks, followed by an 8-week posttreatment period. MAIN OUTCOME MEASUREMENTS: Complete clearance rate (proportion of patients at the 8-week posttreatment visit with no clinically visible AK lesions in the treatment area), partial clearance rate (proportion of patients at the 8-week posttreatment visit with a >/=75% reduction in the number of baseline AK lesions in the treatment area), and frequency and severity of adverse events and local skin reactions were measured. RESULTS: Complete and partial clearance rates for imiquimod-treated patients (48.3% and 64.0%, respectively) were clinically and statistically significantly higher than for vehicle-treated patients (7.2% and 13.6%, respectively). The median percentage reduction of baseline lesions was 86.6% for the imiquimod-treated group and 14.3% for the vehicle-treated group. CONCLUSION: The 5% imiquimod cream dosed 3 times weekly for 16 weeks is safe and effective for the treatment of AK.     

Comparison of topical 3% diclofenac sodium gel and 5% imiquimod cream for the treatment of actinic keratoses

Background. There is a wide spectrum of treatments available for actinic keratosis (AK). Topical diclofenac sodium and imiquimod are two topical treatments, which are noninvasive, easily applied, well‐tolerated and effective. Aim. To compare the effects of topical 3% diclofenac sodium plus hyaluranon (DFS) gel, 5% imiquimod (IMQ) cream, and base cream (BC) in patients with AK. Methods. In total, 61 patients, diagnosed clinically and histopathologically as having AK, were randomized into three treatment groups to receive topical treatment with either DFS (twice daily for 12 weeks), IMQ (twice per week for 16 weeks) or BC (twice daily for 12 weeks). Patients were evaluated clinically at 0, 4, 8, 12, 16, 20 and 24 weeks. Treatment efficacy was assessed by Total Thickness Score (TTS) and Patient Global Improvement Index (PGII). Results. Complete clearance rates for DFS, IMQ and BC at the end of the treatment and at the end of the total follow‐up period were 19.1%, 20% and 0%, and 14.3%, 45% and 0%, respectively. Although the average TTS value of the DFS group at week 24 was significantly higher than that of the IMQ group, the PGII values were not significantly different. Conclusions. Although DFS and IMQ each had considerable efficacy in the treatment of AK, the efficacy of DFS seemed to decrease after cessation of treatment.     

Patient preferences for topical treatment of actinic keratoses: a discrete-choice experiment

Actinic keratoses are rough patches of skin caused by years of sun damage. There is a small risk that AK patches could progress into a form of skin cancer called cutaneous Squamous Cell Carcinoma (cSCC). Treatment of AK might therefore provide an effective strategy for cSCC prevention, although this theory has not been rigorously tested. Also, the patient perspective on potential benefits of AK treatment in terms of skin cancer reduction has received little attention to date. Treatments for AK include freezing with liquid nitrogen (cryotherapy), surgical removal, topical treatments such as creams or gels (5-fluorouracil, imiquimod, ingenol mebutate gel, diclofenac and retinoic acid), photodynamic (light) therapy, or laser treatment. The aims of this study were (i) to investigate patient preferences for topical treatments for AK using a discrete-choice experiment (DCE); (ii) to evaluate patient willingness to trade between clinical benefit (i.e. how well it works) and medical burden (e.g. inconvenience and unwanted side effects). 109 patients were presented with a series of choices between two hypothetical topical treatments for AK, and a ‘no treatment’ opt-out option in each choice set. Different attributes of the hypothetical treatments related to the burden of medication, (intensity and length of treatment, severity of local skin reaction, and occurrence of flu-like side effects) and the efficacy of treatment (improvement in skin appearance and reduction in skin cancer risk). The analysis of the data is complex, but showed that most patients would be prepared to accept a lower reduction in skin cancer risk (e.g. a 50% reduction in the risk of skin cancer as opposed to a 60% reduction in the risk) and reduced efficacy of treatment (e.g. 50% clearance of AK lesions as opposed to 100% clearance) in order to reduce the length and intensity of the regimen, and side effects including skin inflammation and pain. This highlights the importance for doctors of taking individual patient preferences into account, to improve their views of their AK treatment and the likelihood that they will stick with their treatment.     

Microarray analysis of aberrant gene expression in actinic keratosis: effect of the Toll-like receptor-7 agonist imiquimod

BACKGROUND: The molecular events leading to actinic keratosis (AK) are not well understood. OBJECTIVE: To identify and compare gene expression changes in AK lesions and in sun-exposed nonlesional skin and to determine the effect of imiquimod 5% cream on these changes. METHOD: A double-blind, vehicle-controlled, randomized study was conducted to evaluate the molecular changes in AK treated with imiquimod. Seventeen male subjects with >/= 5 AK lesions on the scalp applied vehicle or imiquimod three times a week for 4 weeks. Gene expression analysis using Affymetrix oligonucleotide arrays was performed on shave biopsies of lesions taken before and after treatment. Confocal microscopy was performed on the study area as an adjunctive diagnostic procedure. RESULTS: We identified gene expression changes which occur in sun-exposed, nonlesional skin as well as in AK lesions. These changes include, but are not limited to, the overexpression of oncogenic and proliferative genes and diminished expression of tumour suppressor genes. The gene expression changes observed in AK lesions and in sun-exposed, nonlesional skin were consistent with the confocal microscopy observations, which showed abnormalities in the sun-exposed, nonlesional skin, similar in nature but less pronounced than abnormalities seen in AK. Imiquimod partially or totally reversed the aberrant expression of some of the genes observed in AK, consistent with clearing of lesions and normalization of confocal cellular images. CONCLUSIONS: The data show that profound gene expression changes occur in sun-exposed, nonlesional skin which progress further in AK lesions. The data also suggest that imiquimod may play a role in normalizing gene expression and cellular morphology in sun-damaged skin.     

Use of topical immunomodulators in organ transplant recipients

Solid organ transplant recipients are a growing population at increased risk for the development of cutaneous premalignant and malignant lesions, resulting in significant morbidity and mortality. Topical immunomodulators, in particular imiquimod, have shown efficacy in the management of multiple malignant, precancerous, and viral conditions. The ability to locally induce an immune response, presumably against tumor and viral antigens, and induce apoptosis makes topical immunomodulators a promising therapeutic option in organ transplant recipients. Although limited, data have begun to accumulate on the use of imiquimod in transplant patients for the management of superficial, nodular, and infiltrative basal cell carcinomas; in situ and invasive squamous cell carcinomas; condyloma acuminata; and common warts. As more experience is gathered, the role of imiquimod and other topical immunomodulators in the care of OTRs will be clarified. The authors reviewed the existing data on the use of topical imiquimod in OTRs with mention of its presumed mechanisms of action and other immunomodulators with potential efficacy against cancerous and precancerous lesions.