A 12-Day Course of Imiquimod 5% for the Treatment of Actinic Keratosis: Effectiveness and Local Reactions. / Tratamiento con imiquimod al 5% durante 12 días para las queratosis actínicas: estudio de la eficacia y la reacción local.

INTRODUCTION AND OBJECTIVES: Imiquimod is an excellent option for patients with actinic keratosis, although its use may be limited by the long course of treatment required (4 weeks) and the likelihood of local skin reactions. The objectives of the present study were to demonstrate the effectiveness of a 12-day course of imiquimod 5% for the treatment of actinic keratosis and to examine the association between treatment effectiveness and severity of local reactions. PATIENTS AND METHODS: We included patients with at least 8 actinic keratoses treated with imiquimod 5% cream for 12 consecutive days. Local reactions were classified as mild, moderate, or severe. The statistical analysis of the association between local reactions and clinical response was based on the Pearson χ2 test and the Spearman rank correlation test. RESULTS: Sixty-five patients completed the study. Complete response was recorded in 52.3% and partial response in 75.4%. We found a statistically significant association between severity of the local reaction and response to treatment in both the Pearson χ2 test and the Spearman rank correlation test. CONCLUSIONS: A 12-day course of imiquimod 5% proved effective for the treatment of actinic keratosis. Severity of local reactions during treatment was correlated with clinical response.

Immune responses and outcome after vaccination with glioma-associated antigen peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade gliomas.

BACKGROUND: Low-grade gliomas (LGGs) are the most common brain tumors of childhood. Although surgical resection is curative for well-circumscribed superficial lesions, tumors that are infiltrative or arise from deep structures are therapeutically challenging, and new treatment approaches are needed. Having identified a panel of glioma-associated antigens (GAAs) overexpressed in these tumors, we initiated a pilot trial of vaccinations with peptides for GAA epitopes in human leukocyte antigen-A2+ children with recurrent LGG that had progressed after at least 2 prior regimens. METHODS: Peptide epitopes for 3 GAAs (EphA2, IL-13Rα2, and survivin) were emulsified in Montanide-ISA-51 and administered subcutaneously adjacent to intramuscular injections of polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose every 3 weeks for 8 courses, followed by booster vaccines every 6 weeks. Primary endpoints were safety and T-lymphocyte responses against GAA epitopes. Treatment response was evaluated clinically and by MRI. RESULTS: Fourteen children were enrolled. Other than grade 3 urticaria in one child, no regimen-limiting toxicity was encountered. Vaccination induced immunoreactivity to at least one vaccine-targeted GAA in all 12 evaluable patients: to IL-13Rα2 in 3, EphA2 in 11, and survivin in 3. One child with a metastatic LGG had asymptomatic pseudoprogression noted 6 weeks after starting vaccination, followed by dramatic disease regression with >75% shrinkage of primary tumor and regression of metastatic disease, persisting >57 months. Three other children had sustained partial responses, lasting >10, >31, and >45 months, and one had a transient response. CONCLUSIONS: GAA peptide vaccination in children with recurrent LGGs is generally well tolerated, with preliminary evidence of immunological and clinical activity.

Efficacy of combination therapy of oral zinc sulfate with imiquimod, podophyllin or cryotherapy in the treatment of vulvar warts.

AIM: Zinc sulfate is beneficial in the treatment of epithelial warts. We conducted this study to compare the efficacy of combination therapy of oral zinc sulfate with conventional treatments in the treatment of vulvar warts. MATERIAL AND METHODS: This study was a randomized controlled trial. The sample size was 42 in each group. Women aged 20-50 years were placed by the block randomized method into six groups: the podophyllin-, imiquimod- and cryotherapy-treated groups, and another three groups receiving 8-week combination therapy of 400 mg oral zinc sulfate with one of the above-mentioned treatments. Data were analyzed using anova and Fischer's exact test with spss16. RESULTS: A total of 228 patients were recruited and completed the study in six treatment groups. No significant difference was observed in the response to treatment among these groups. Relapse after 6 months was significantly higher in the podophyllin-, imiquimod- and cryotherapy-treated patients compared to patients receiving these treatments in combination with oral zinc sulfate (P<0.05). CONCLUSIONS: Combined therapy of oral zinc sulfate with conventional treatments of vulvar warts appears to reduce the relapse rate.

Prevention of airway allograft tolerance by polyinosinic:polycytidylic acid requires type I interferon responsiveness for mouse airway obliteration.

BACKGROUND: Respiratory RNA viruses are associated with bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTRS); however, the immune mechanisms that regulate airway obliteration remain incompletely understood. METHODS: Using the mouse heterotopic tracheal transplant model of obliterative airway disease (OAD), we studied the role of double-stranded (ds)RNA using polyinosinic:polycytidylic acid (poly[I:C]), a synthetic analog of viral dsRNA, in abrogating airway allograft tolerance established with donor-specific transfusion (DST) and anti-CD154 monoclonal antibody therapy. RESULTS: Wild-type (WT) B6 recipients of accepted BALB/c airway grafts demonstrated significantly reduced intragraft CD8+ T cells, with markedly impaired allospecific interferon (INF)-γ and tumor necrosis factor-α secretion, uncoupled from an activated phenotype, and evidence of proliferation. Administration of poly(I:C) to DST/anti-CD154-treated recipients restored OAD pathology and CD8+ alloeffector responses to levels observed in untreated mice. However, B6 type I IFN receptor-deficient (IFN-αßR(-/-)) recipients were resistant to the abrogation of tolerance mediated by poly(I:C) and did not develop CD8+ alloeffector responses or OAD. Further, adoptive transfers of WT CD8+ T cells or CD11c+ dendritic cells alone into B6 IFNαßR(-/-) recipients treated with poly(I:C) and DST/anti-CD154 were incapable of abrogating airway graft tolerance. CONCLUSIONS: Together, these data indicate abrogation of DST/anti-CD154-induced airway allograft tolerance via dsRNA requires type-I IFN responsiveness for mouse airway obliteration.

Local and systemic adverse effects of imiquimod therapy for external anogenital warts in men: report of three cases.

Imiquimod is a topical immune response modifier used to treat anogenital warts. Although considered a safe drug, mild to moderate local and systemic side-effects may occasionally occur. We report three cases of local and systemic adverse effects related to imiquimod, including one case that mimicked meningitis, which promptly resolved with drug cessation.

Sequential use of photodynamic therapy and imiquimod 5% cream for the treatment of actinic cheilitis: a 12-month follow-up study.

BACKGROUND: Actinic cheilitis (AC) may progress into fully developed squamous cell carcinoma with a relatively high risk of metastasizing and therefore requires early identification and treatment. OBJECTIVES: To assess the clinical and histological long-term outcome as well as the safety and tolerability of sequential use of photodynamic therapy (PDT) and imiquimod in AC. METHODS: Patients with histologically confirmed grade 1 and 2 AC received two methyl aminolaevulinate-PDT sessions 2weeks apart. After a 2-week rest period the patients started applying imiquimod 5% cream 3days per week for 4weeks. At the first follow-up visits at 3 and 6months, noncomplete clinical responders were biopsied and excluded from the study if histological alterations were indicative for AC. At the last 12-month follow-up all remaining patients were biopsied. Adverse events were noted at weeks 2, 4, 6 and 8 of the treatment phase and at every visit of the follow-up period. RESULTS: Of the 34 enrolled patients, 30 completed the study. Complete clinical response was achieved by 27 patients in 3months. At 6months, clinical and histological recurrence occurred in two patients, while at 12months the complete clinical cure rate obtained was 80% and the histological complete cure rate was 73%. Treatment was well tolerated and adverse events were as expected and transient. CONCLUSION: Sequential use of PDT and imiquimod cream is of significant benefit for the treatment of AC. Further studies are needed in order to confirm the improved outcome using the combination treatment, to clarify the involved mechanisms and to optimize the therapeutic protocol.

Acute renal failure caused by imiquimod 5% cream in a renal transplant patient: review of the literature on side effects of imiquimod.

Imiquimod is an immunomodulator of the imidazoquinoline group which possesses antiviral and antitumour activities. Although its mechanism of action has not been entirely elucidated yet, imiquimod 5% cream has been shown to be an efficient, long-lasting and safe therapy for multiple actinic keratoses in non-immunosuppressed patients and in transplant recipients. We report the case of a 44-year-old patient with a third renal transplant who developed an acute tubular necrosis confirmed by renal biopsy after the use of imiquimod 5% cream. The result of a literature search revealed a wide variety of side effects attributable to the use of imiquimod.

The beta2 integrin CD11b attenuates polyinosinic:polycytidylic acid-induced hepatitis by negatively regulating natural killer cell functions.

UNLABELLED: The beta2 integrins play a key role in inflammation and immune responses. The beta2 integrin CD11b has been shown recently to be important in the maintenance of tolerance; however, the underlying mechanisms remain to be fully understood. Natural killer (NK) cells are an important effector of innate immunity but are also a regulator of adaptive immune response. How the activating and inhibitory signals are balanced to determine NK cell function needs to be further identified. CD11b expression was dramatically up-regulated on NK cells once they matured and became activated; therefore, we investigated the role of inducible CD11b in the regulation of NK cells. Neutralizing anti-CD11b antibody enhanced cytotoxicity, interferon-gamma (IFN-gamma) and granzyme B production of Toll-like receptor 3 (TLR3)-triggered NK cells. CD11b-deficient NK cells stimulated with or without the TLR3 ligand polyinosinic:polycytidylic acid [poly(I:C)] exhibited more potent cytotoxicity, and higher production of IFN-gamma and granzyme B. Through in vivo depletion of NK cells and adoptive transfer of CD11b-deficient NK cells, we demonstrated that CD11b-mediated suppression of NK cell function was responsible for attenuation of poly(I:C)-induced acute hepatitis by CD11b. CONCLUSION: Our findings demonstrate that CD11b negatively regulates NK cell activation and thus attenuates poly(I:C)-induced acute hepatitis. Our study provides a new mechanistic explanation for maintenance of tolerance and control of inflammation by CD11b.

Safety, efficacy & recurrence rates of imiquimod cream 5% for treatment of anogenital warts.

Imiquimod 5% cream (Aldara, Graceway Pharmaceuticals) is an immune response modifier used for the topical treatment of anogenital warts in non-HIV-infected patients. Several randomized controlled trials have demonstrated that imiquimod 5% cream is a safe and efficacious treatment. Current data regarding efficacy shows that complete clearance of warts occurred in up to 50% of patients treated with imiquimod 5% cream applied once-daily, 3 times per week for up to 16 weeks. Recurrence rates ranged from up to 19% at 3 months to 23% at 6 months. Imiquimod 5% cream showed an acceptable safety profile; local inflammatory reactions were the most frequent adverse effects, with local erythema being the most common.

Off-label indications for imiquimod.

Due to the ability of imiquimod (Aldara, 3M Pharmaceuticals) to rapidly and potently stimulate both innate and adaptive arms of the immune system, imiquimod has rapidly been recognized as a potential candidate for off-label use in over 60 conditions as presented in numerous case reports, letters, and small trials. It is our goal to examine and consolidate this impressive body of literature in order to provide the practicing dermatologist with a quick reference of the conditions that have been successfully treated with imiquimod, the dosages used, and the success rates of treatments.

Intraindividual, right-left comparison of topical 5-aminolevulinic acid photodynamic therapy vs. 5% imiquimod cream for actinic keratoses on the upper extremities.

BACKGROUND: Actinic keratoses (AKs) are considered as in situ squamous cell carcinoma. Early and effective treatment is important. Objective To compare the efficacy, cosmetic outcome and patient preference of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) with that of 5% imiquimod (IMIQ) cream in patients with AKs on the dorsa of hands and forearms. METHODS: Subjects received two ALA-PDT treatment sessions and one or two courses of imiquimod (three times per week for 4 weeks each). Treatments were randomly allocated to alternate upper extremities. Assessments included lesion response one and six months after treatment, cosmetic outcome evaluated by the investigators and patients' preference 6 months after treatment. Efficacy end point included the individual AK lesion clearance rate. RESULTS: Thirty patients with 256 lesions were included in the study. At the first follow-up, treatment with ALA-PDT resulted in significantly larger rate of cured lesions relative to 5% IMIQ cream (70.16% vs. 18.26%). At the second follow-up both treatments showed a high rate of cured lesions (65.32% for PDT vs. 55.65% for IMIQ cream). Response rates obtained in grade I lesions were higher for both treatments (71.64% for PDT vs. 72.13% for IMIQ), while treatment with PDT resulted in a significant larger rate of cured grade II lesions (57.89% for PDT vs. 37.03 for IMIQ). Difference in cosmetic outcome was not statistically significant. Results for subject preference favoured ALA-PDT. CONCLUSIONS: Our study shows that ALA-PDT and 5% IMIQ cream are both attractive treatment options for upper extremities AKs with comparable efficacy and cosmetic outcomes.

Optimal frequency of imiquimod (aldara) 5% cream for the treatment of external genital warts in immunocompetent adults: a meta-analysis.

BACKGROUND: Postmarketing research has explored the optimal application schedule of imiquimod 5% cream for treatment of external anogenital warts. OBJECTIVES: We systemically reviewed the published literature on the efficacy and safety of the medication when applied either by a three times per week or once-daily regimen for 16 weeks. METHODS: MEDLINE (1966 to Feb 10, 2007), Scopus (1996 to Feb 10, 2007), and Cochrane Library (Issue 1, 2007) databases were searched for randomized trials on the medication. Primary efficacy outcome was the proportion of patients completely cleared of warts by end of treatment. Two primary safety outcomes were as follows: (a) proportion of patients who withdrew and (b) proportion of patients who required at least one rest period from treatment because of drug-related adverse events. RESULTS: Six studies were selected for subgroup analysis of circumcised men, uncircumcised men, and women. The once-daily compared to three times per week regimen did not improve treatment efficacy in any of the 3 subgroups (P <0.05), but resulted in greater incidence and severity of local skin reactions. There was no difference in medication-related withdrawals between the 2 regimens, although significantly more women and uncircumcised men required at least one rest period with the once-daily than the three times per week treatment schedule (P <0.05). CONCLUSIONS: The optimal application schedule of imiquimod 5% cream for external anogenital warts is three times per week.

Effect of imiquimod in anogenital warts from HIV-positive men.

BACKGROUND: HIV-positive patients have unpredictable local immune responses even with severe systemic immunosuppression and data reported to date is insufficient to predict the effect of imiquimod in HIV-positive patients. OBJECTIVE: To evaluate the efficacy of 5% topical imiquimod in HIV-positive male patients with anogenital warts (AGW) and to elucidate its effect on recurrence. STUDY DESIGN: Open-label clinical trial. RESULTS: Of the 43 patients enrolled, 86% completed treatment. Patients' mean age was 34 years (range: 19-50). Thirty-one patients were receiving highly active antiretroviral therapy (HAART) therapy. At week 16, 10 patients completely cleared lesions and 21 patients had a wart size reduction > or =50%. At 20 weeks of therapy, 17 patients achieved total clearance whereas 14 patients had a >50% wart reduction. Clearance was not influenced by CD4-counts, HIV-viral load, previous therapy, or wart localization. Of the patients who experienced a complete clearance, five (29%) had a recurrence. Mean time of recurrence was 14.4 weeks. Erythema, pruritus, and burning sensation were the most frequent local skin reactions. CONCLUSIONS: Topical 5% imiquimod is safe and may benefit HIV-positive patients with anogenital warts particularly when it is used for up to 20 weeks. It is also useful to decrease wart recurrence.

Vehicle-controlled, randomized, double-blind study to assess safety and efficacy of imiquimod 5% cream applied once daily 3 days per week in one or two courses of treatment of actinic keratoses on the head.

BACKGROUND: Imiquimod has been investigated as a safe and effective therapeutic option for the treatment of actinic keratosis (AK). OBJECTIVES: To evaluate imiquimod vs. vehicle applied three times a week for 4 weeks in one or two courses of treatment for AK on the face or balding scalp. PATIENTS AND METHODS: Patients diagnosed with AK were enrolled in this multicentre, vehicle-controlled, double-blind study conducted in Europe. Twenty study centres enrolled a total of 259 patients in this study. Patients applied the study drug for 4 weeks, entered a 4-week rest period and if they did not have complete clearance, they then entered a second course of treatment. RESULTS: Patients in the imiquimod group had an overall complete clearance rate of 55.0% (71/129) vs. a rate of 2.3% (3/130) for the vehicle group. There was a high rate of agreement between the clinical assessment and histological findings with respect to AK lesion clearance. At both 8-week post-treatment visits, the negative predictive value of the investigator assessment was 92.2% for clinical assessments vs. histological results. CONCLUSIONS: A 4-week course of treatment with three times weekly dosing of imiquimod 5% cream, with a repeated course of treatment for those patients who fail to clear after the first course of treatment, is a safe and effective treatment for AK. The overall complete clearance rate (complete clearance after either course 1 or course 2) is comparable to the 16-week treatment regimen, while decreasing drug exposure to the patient and decreasing the overall treatment time.

Ligands to nucleic acid-specific toll-like receptors and the onset of lupus nephritis.

Lupus nephritis develops from a combination of genetic and environmental factors such as microbial infection. A role for microbial nucleic acids (e.g., via nucleic acid-specific Toll-like receptors [TLR]) was hypothesized, in this context, because microbial nucleic acids can trigger multiple aspects of autoimmunity in vitro and in vivo. Eight-week-old MRL(lpr/lpr) and MRL wild-type mice received an injection of pI:C RNA (ligand to TLR-3), imiquimod (ligand to TLR-7), or CpG-DNA (ligand to TLR-9) on alternate days for 2 wk. Only CpG-DNA triggered the onset of lupus nephritis in MRL(lpr/lpr) mice, as defined by diffuse proliferative glomerulonephritis associated with glomerular IgG and complement C3 deposition, proteinuria, and glomerular macrophage infiltrates. None of the compounds caused DNA autoantibody production or glomerulonephritis in MRL wild-type mice. The role of CpG-DNA to trigger lupus nephritis in MRL(lpr/lpr) mice was found to relate to its potent immunostimulatory effects at multiple levels: B cell IL12p40 production, B cell proliferation, double-stranded DNA autoantibody secretion, and dendritic cell IFN-alpha production. The induction of lupus nephritis by CpG-DNA is motif specific and could be prevented by co-injection of inhibitory DNA. In summary, among the ligands tested, CpG-DNA triggers lupus nephritis in genetically predisposed hosts. These data support the concept that systemic lupus erythematosus is triggered by pathogens that release CG-rich DNA.

An open-label phase II pilot study investigating the optimal duration of imiquimod 5% cream for the treatment of external genital warts in women.

Our objective was to determine the optimal duration of treatment with imiquimod for external genital warts over 4, 8, 12 or 16 weeks. A total of 120 women with a history of genital warts for a median of 3-6 months and prior alternative treatments in 73% were evaluated for total clearance rates. There was no statistically significant difference in complete clearance rates after 16-week follow-up across treatment groups: four weeks (40.0%), eight weeks (48.4%), 12 weeks (39.3%) and 16 weeks (51.6%). Imiquimod was well tolerated, and in those treated for four weeks there was a lower incidence of local skin reactions such as erythema and erosion, and no incidences of pain. These preliminary results suggest that a four-week treatment course of imiquimod applied thrice weekly for women with external genital warts may provide a reasonable approach with comparable efficacy and compliance, and minimal adverse events, drug costs and clinic visits.

Imiquimod-induced regression of actinic keratosis is associated with infiltration by T lymphocytes and dendritic cells: a randomized controlled trial.

BACKGROUND: Imiquimod 5% cream is a topically applied immune response modifier that has been shown to give effective treatment of actinic keratosis (AK). The therapeutic effects of imiquimod are likely to involve the provocation of a cutaneous immune response against abnormal cells, an assumption based on a strong correlation between complete clearance rates and the severity of the local skin reactions (erythema, oedema, erosion/ulceration, weeping/exudation and scabbing/crusting); however, no clinical studies have conclusively proved this mechanism. OBJECTIVES: To determine the nature of cellular infiltrates induced by the application of imiquimod to AK lesions and to study cells involved in the cutaneous immune response. METHODS: Eighteen patients participated in this phase I, randomized, double-blind, parallel group, vehicle-controlled study. Enrolled patients were randomized in a 2 : 1 ratio to receive imiquimod cream or vehicle cream and applied study cream to five lesions on the scalp, forearm or upper trunk once daily, three days per week for up to 16 weeks. Each patient had punch biopsies of two distinct AK lesions: a lesion was biopsied before treatment to obtain baseline biomarker levels, and a different lesion was biopsied after 2 weeks of treatment. Biopsy specimens were examined using routine and immunohistochemical staining. RESULTS: The imiquimod group showed statistically significant increases from baseline to week 2 in tissue biomarker levels for CD3, CD4, CD8, CD11c, CD86/CD11c, CD68, HLA-DR and TUNEL. No significant differences were seen for the vehicle group. Complete clearance of all treated AK lesions was achieved in five of 11 (45%) imiquimod patients and in none of six vehicle patients. CONCLUSIONS: Imiquimod stimulates a cutaneous immune response characterized by increases in activated dendritic cells and CD4+ and CD8+ T cells.