Possible mechanisms in the induction of vitiligo-like hypopigmentation by topical imiquimod

The pathogenesis of vitiligo was examined for clues to the pigmentary changes that may occur after treatment with topical imiquimod. The literature varies on the pigmentary changes induced by topical use of imiquimod. The US Food and Drugs Administration lists 68 reports of pigmentary changes out of a total of 1257 reports related to imiquimod lodged from 1997 to 2003. Some studies describe vitiligo-like hypopigmentation associated with imiquimod treatment of genital warts (as with the patient described in this report), molluscum contagiosum, basal cell carcinoma, extramammary Paget's disease and murine melanoma. Other studies report hyperpigmentation associated with imiquimod. The possible mechanisms of hypopigmentation associated with imiquimod treatment are discussed, including antibodies found in sera of patients with vitiligo to nonpigment cell antigens, cytoplasmic pigment cell antigens and pigment cell-surface antigens; stimulation by imiquimod of both the innate immune response and cell-mediated adaptive immunity; and increased sensitivity of melanocytes to oxidative stress. The vitiligo-like hypopigmentation following topical imiquimod treatment is in line with the mode of action of this drug.     

Pityriasis rubra pilaris exacerbation with topical use of imiquimod

The role of immune response modifiers is increasing in the treatment of dermatologic diseases. Imiquimod, a toll-like receptor agonist, results in up-regulation of proinflammatory cytokines for improved immune surveillance. Although topical use is generally well-tolerated, imiquimod can potentially result in systemic effects and exacerbate generalized inflammatory papulosquamous diseases of the skin. We report the case of a 67-year-old man who was treated with imiquimod for actinic keratosis and developed fever and a progressive erythematous papulosquamous eruption that was histologically consistent with pityriasis rubra pilaris.     

Imiquimod in mycosis fungoides

Imiquimod is a topically active imidazoquinoline immunomodulator agent. It works as an indirect antiviral and antitumoral and stimulates the production of INF-alpha and various other cytokines. We assayed topical imiquimod in treating early stages of mycosis fungoides. We applied imiquimod 5% cream in four patients with multi-treatment resistant plaques of MF (stages IA and IIB). We applied it on one patient in association with systemic INFalpha-2a. We observed a complete clinical clearance of the lesions in all four patients. In three cases we achieved a complete histopathological clearance and in one case a partial histopathological clearance. The patient treated with imiquimod and systemic INFalpha-2a showed the most spectacular improvement with a rapid total response. We ascribe this improvement to a synergic effect of imiquimod and systemic INFalpha-2a treatment. Before the introduction of imiquimod, this patient had been treated for 2 years with systemic INFalpha-2a alone, without any evidence of clinical response. Imiquimod could be an effective therapy for early-stage disease of CTCL, used alone or in combination with systemic immunomodulatory therapy.     

Rapid improvement of human orf (ecthyma contagiosum) with topical imiquimod cream: report of four complicated cases

Orf is a zoonosis caused by an epitheliotropic DNA parapox virus. Human orf is a generally benign, self-limiting condition that usually regresses in 6-8 weeks without specific treatment. However, it may be accompanied by local symptoms including pain, pruritus, lymphangitis and axillary adenitis, or less frequently by systemic symptoms such as fever or malaise. Furthermore, it may be complicated by erythema multiforme, Stevens-Johnson syndrome, erysipelas, generalized mucocutaneous eruption, toxic erythema, eyelid oedema and giant, persistent or recurrent lesions in immunocompromised patients. Imiquimod, a potent topical immune response modifier, enhances both the innate and acquired immunity by stimulation of immune system cells resulting in local antiviral, antitumour and immunoregulatory activity. We present, for the first time, four complicated cases of orf successfully treated by topical imiquimod resulting in rapid regression of both orf and associated lesions. Two of the cases were complicated with erythema multiforme, one with recurrent eyelid oedema, and another had giant orf associated with axillary lymphadenitis. We suggest that topical imiquimod may be an effective and safe therapy for complicated orf cases.     

Immunomodulation by imiquimod in patients with high-risk primary melanoma

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80-100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A(*)0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted.     

Solitary plaque mycosis fungoides on the penis responding to topical imiquimod therapy

Mycosis fungoides (MF) presenting in the genitalia is rare. We report a case of long-standing penile MF in a young man. Commonly used treatments for limited plaque MF include topical corticosteroids and ultraviolet light therapy. There are a few anecdotal reports on the use of topical imiquimod in MF. Our patient responded well and remained in complete remission after treatment with topical imiquimod.     

Extramammary Paget's disease treated with topical imiquimod 5% cream

Extramammary Paget's disease (EMPD) is a rare cutaneous, intraepithelial adenocarcinoma usually found in the apocrine gland bearing areas. It is traditionally treated with surgery but has a high rate of recurrence. Of late, topical imiquimod 5% cream has come into use as another treatment option. We present two cases of EMPD in Asian skin treated successfully with topical imiquimod 5% cream.     

Pyogenic granuloma in children: treatment with topical imiquimod

We report the successful treatment of five children with facial pyogenic granuloma using topical imiquimod 5% cream. In all cases, resolution of the lesions was achieved within 2-4 weeks. Local erythema and scaling, consistent with a typical imiquimod response, was the most commonly observed side effect. No systemic complications were observed in any of the patients. There has been no recurrence of any of the lesions to date. Small mildly erythematous or hypopigmented macules remain at this stage of follow up.     

Characterization of the cellular infiltrate during successful topical treatment of lentigo maligna with imiquimod

Lentigo maligna (LM) is an in situ melanoma which usually occurs in sun-damaged skin on the head and neck of elderly patients. Depending on the anatomical site and its size treatment of LM can be problematic and usually includes surgical excision or radiotherapy. Recent reports indicate that topical imiquimod may be an effective treatment. However, no data on the underlying immune response in the skin during treatment of LM with topical imiquimod are available so far. We report a 62-year-old caucasian woman with a histologically verified LM which was successfully treated with topical imiquimod 5% cream. Skin biopsy specimens were obtained before, during (at week 10) and 4 weeks after cessation of topical treatment with imiquimod 5% cream. Histological and immunohistochemical examination was performed in order to detect residual atypical melanocytes and to characterize the inflammatory infiltrate. A complete clinical and histological clearance of the skin lesion was achieved, with no recurrence up to 9 months after the end of treatment. During topical application of imiquimod 5% cream a depletion of epidermal and dermal CD1a+ dendritic cells was observed. The inflammatory infiltrate consisted of CD68+ macrophages and mainly of CD3+ T cells with a slight predominance of CD8+ T cells. An enhanced expression of granzyme B and TIA-1 was also noted particularly in the epidermis and near the dermoepidermal junction. In conclusion, our data indicate that imiquimod 5% cream induces a cytotoxic T-cell-mediated immune response in situ which may account for the complete destruction of the malignant melanocytes in LM. Further clinical trials and longer follow-up periods on the use of imiquimod for LM are warranted.     

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.     

Extramammary Paget's disease resistant to surgery and imiquimod monotherapy but responsive to imiquimod combination topical chemotherapy with 5-fluorouracil and retinoic acid: a case report

Extramammary Paget's disease (EMPD) is an uncommon skin neoplasm that usually affects the elderly population and occurs in the genital, anorectal, or axillary areas. The recommended treatment of EMPD involves surgical excision, including Mohs micrographic surgery; however, surgery is associated with a high rate of recurrence. There have been reports of successful treatment of recurrence with monochemotherapy involving topical imiquimod 5% cream. We report a case of EMPD recurrence after surgery that was resistant to imiquimod monotherapy but that completely resolved after imiquimod was combined with topical 5-fluorouracil (5-FU) and retinoic acid. To our knowledge, this is the first reported case of imiquimod combination therapy with 5-FU and retinoic acid for the treatment of recurrent EMPD.     

The use of topical imiquimod for the treatment of actinic keratosis: a status report

Topical imiquimod 5% cream is approved for the treatment of actinic keratosis (AK), superficial basal cell carcinoma, and external genital warts. The drug's mechanism of action is via stimulation of innate and acquired immune responses, which ultimately leads to inflammatory cell infiltration within the field of drug application followed by apoptosis of diseased tissue. This article reviews available data on the use of topical imiquimod for AK. Topical imiquimod is an effective and safe treatment option for AK that produces complete eradication or marked reduction in the number of lesions in most patients. Subclinical lesions also emerge during treatment of the affected skin region ("field treatment"). In addition, there is evidence that topical imiquimod at least partially reverses some of the cellular, molecular, and genetic photocarcinogenic changes that develop in skin damaged by UV light. Recent evidence suggests that many patients who effectively are cleared of AK lesions after topical imiquimod use remain free of lesions for several months to 2 years or develop a minimal number of new AK lesions.     

Topical imiquimod treatment of aciclovir-resistant herpes simplex disease: case series and literature review

Infection with herpes simplex virus (HSV) is extremely common worldwide. In immunocompromised patients anogenital HSV disease may have atypical features and may be very severe. Treatment of aciclovir-resistant anogenital HSV disease is challenging, as resistance to alternative treatments may occur, and effective treatment generally involves intravenous therapy with relatively toxic agents such as foscarnet. This case report presents three immunocompromised patients with presumed aciclovir-resistant anogenital HSV disease who were successfully treated with topical imiquimod. Imiquimod promotes local immune activation, which results in resolution of viral lesions such as anogenital warts and HSV disease. It is convenient to use and avoids the necessity for intravenous treatment with substantial systemic toxicity. In addition, as the mode of action of imiquimod is related to immune stimulation rather than direct antiviral activity, it may be used repeatedly without resistance developing.     

Imiquimod induces apoptosis of human melanocytes

Development of vitiligo-like hypopigmentary lesions associated with topical imiquimod has been reported. We hypothesized that mode of action of imiquimod in melanocytes may include triggering of apoptosis resulted in loss of cells, which may be a possible mechanism of imiquimod-induced hypopigmentary lesions. Therefore, we investigated whether imiquimod induces apoptosis of human melanocytes and also whether it modulates expression of apoptosis-related molecules in human melanocytes. Imiquimod treatment induced apoptosis of melanocytes, which was observed by TUNEL assay and Hoechst 33258 staining. Imiquimod-induced apoptosis was further shown by measuring mitochondrial membrane potential in melanocytes. The apoptotic activity of imiquimod was associated with caspase-3, Bcl-2 and mitogen-activated protein kinase expression in melanocytes. These results indicated that imiquimod induces apoptosis of melanocytes. These findings may provide a clue to understand pathogenesis of imiquimod-induced vitiligo-like hypopigmentary lesions.     

Topical treatment with imiquimod may induce regression of facial keratoacanthoma

Keratoacanthoma (KA) is a rapidly growing tumour histologically resembling squamous cell carcinoma. Although it may regress spontaneously, KA is routinely treated by excision or radiation therapy. Here we report on the successful therapeutic use of imiquimod for the treatment of KA. Four patients with a one to six week history of facial KA were treated with imiquimod cream 5 % every second day for four to 12 weeks. In each patient, KA fully regressed under topical treatment with imiquimod. In three of the patients, KA had disappeared within four to six weeks. In two patients, disappearance was confirmed histologically. No recurrence occurred during a four- to six-month follow-up-period. Our observations indicate that topical immunostimulation with imiquimod may induce or promote immune defence mechanisms leading to KA regression. Imiquimod might therefore prove to be an effective non-invasive treatment modality for KA that warrants more extensive evaluation by clinical studies.     

Topical imiquimod treatment prevents UV-light induced loss of contact hypersensitivity and immune tolerance

Imiquimod (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine) is a TLR7 agonist that induces cytokine production in TLR7 bearing antigen-presenting cells (APCs), including IL-12, a cytokine that has been demonstrated to be a critical effector molecule for contact hypersensitivity (CHS). To test our hypothesis that topical applications of imiquimod may protect the skin immune system against the deleterious effects of UV light exposures, we treated animals with this agent, or its vehicle or nothing before UV exposures. Although topical imiquimod exposures before UV light did not prevent the depletion of epidermal Langerhans cells, it did prevent the loss of CHS. IL-12 was important in the protective role of imiquimod in preventing UV-induced loss of CHS, as systemic treatment of mice with an anti-IL-12 p70 monoclonal antibody blocked the protective effects of imiquimod. Additionally, only imiquimod-treated mice were resistant to hapten-specific tolerance induction after UV irradiation at the site of the initial sensitization with the hapten 2,4 dinitro-1-fluorobenzene. To model for the effects of TLR7 activation on the UV effect on antigen-APCs, XS52 cell line was used to study this interaction in an in vitro model system. This cell line expressed mRNA for TLR7, downregulated IkappaB, phosphorylated c-Jun N-terminal kinase, and secreted cytokines after exposure to imiquimod or lipopolysaccharide. Activation of the TLR7 signaling pathway on XS52 before UV-light exposures enhanced IL-12p70 secretion by this cell line. Similarly, activation of TLR7 on XS52 before UV-light exposure also prevented the UV-induced loss of IFN-gamma triggering in T cells during an allogeneic mixed lymphocyte reaction. Imiquimod-treated, UV-irradiated XS52 triggered a more vigorous IFN-gamma production than did either imiquimod-treated XS52 or UV-irradiated XS52, again suggesting a synergy between the two treatments. Lastly, enriched lymph node CD11c+ APCs from mice treated with UV irradiation, imiquimod alone or the combination of UV irradiation and imiquimod indicated the same in vivo synergy between imiquimod irradiation and UV irradiation in enhancing IL-12p70 production. These data suggest that topical imiquimod applications may play a role in preventing UV-induced impairment of the skin immune system, which is thought to be one of the critical events that allow the development of UV-induced skin cancers.     

Focal epithelial hyperplasia by human papillomavirus (HPV)‐32 misdiagnosed as HPV‐16 and treated with combination of retinoids,imiquimod and quadrivalent HPV vaccine

Focal epithelial hyperplasia (FEH) or Heck's disease is a rare, benign and asymptomatic mucosal proliferation associated with human papillomavirus (HPV) infection, mainly with genotypes 13 and 32. We report a florid case of FEH in an 11‐year‐old Haitian girl with systemic lupus erythematosus receiving immunosuppressive therapy. Cryotherapy was previously performed on numerous occasions with no results. We decided to prescribe a non‐invasive and more comfortable treatment. A combination of topical retinoid and imiquimod cream was well tolerated and led to an important improvement. The evidence of infection by HPV‐16 detected by polymerase chain reaction (PCR) technique, prompted us to prescribe the quadrivalent HPV vaccine (types 6, 11,16 and 18). Subsequent PCR sequencing with generic primers GP5–GP6 and further BLAST comparative analysis confirmed that genomic viral sequence in our case truly corresponded with HPV‐32. This molecular misdiagnosis can be explained by the similarity between genomic sequences of both HPV‐16 and ‐32 genotypes. At the 1‐year follow up, we observed total clinical improvement and no recurrences of the disease. Complete healing in this case may correspond to a potential action of topical retinoid, imiquimod and the cross‐protection mechanism of the quadrivalent HPV vaccine.     

A case of epidermodysplasia verruciformis associated with squamous cell carcinoma and Bowen's disease: a therapeutic challenge

Epidermodysplasia verruciformis (EV) is a very rare and chronic disease characterized by a susceptibility to cutaneous infections by a group of phylogenetically related human papillomavirus (HPV) types. We present here a 52-year-old man previously diagnosed and treated as squamous cell carcinoma but also found to have epidermodysplasia verruciformis lesions in association with Bowen's disease. The patient was effectively treated with a combination of interferon therapy (6 million units, twice a week) and topical imiquimod for Bowen's disease (five times a week). We conclude that topical imiquimod is very effective in the treatment of Bowen's disease and may be combined with systemic interferon therapy in rare cases with multiple vivid presentations of HPV infections.     

Complete remission of recalcitrant genital warts with a combination approach of surgical debulking and oral isotretinoin in a patient with systemic lupus erythematosus

Genital warts in immunocompromised patients can be extensive and recalcitrant to treatment. We report a case of recalcitrant genital warts in a female patient with systemic lupus erythematosus (SLE), who achieved complete remission with a combination approach of surgical debulking and oral isotretinoin at an initial dose of 20 mg/day with a gradual taper of dose over 8 months. She had previously been treated with a combination of topical imiquimod cream and regular fortnightly liquid nitrogen. Although there was partial response, there was no complete clearance. Her condition worsened after topical imiquimod cream was stopped because of her pregnancy. She underwent a combination approach of surgical debulking and oral isotretinoin after her delivery and achieved full clearance for more than 2 years duration. Oral isotretinoin, especially in the treatment of recalcitrant genital warts, is a valuable and feasible option when other more conventional treatment methods have failed or are not possible. It can be used alone or in combination with other local or physical treatment methods.     

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.