Imiquimod Cream Research Articles

CB2R Deficiency Exacerbates Imiquimod-Induced Psoriasiform Dermatitis and Itch Through the Neuro-Immune Pathway.

Background: Cannabinoid receptor 2 (CB2R) is a potential target for anti-inflammatory and pain therapeutics given its significant immunomodulatory and analgesic effects. However, the role of CB2R in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) and itch is poorly understood. Objective: To investigate the function and mechanism of CB2R in PsD and itch in mice. Methods: Following daily treatment with topical IMQ cream for 5-7 consecutive days in C56BL/6 wild-type (WT) and CB2R gene knockout (KO) mice, we assessed the Psoriasis Area and Severity Index (PASI) scores and the scratch bouts every day, and hematoxylin and eosin (H&E) staining, toluidine blue staining were used to observe the histological changes. mRNA levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Protein levels were detected by western blotting (WB), immunohistochemistry (IHC), immunofluorescence (IF) and cytometric bead array (CBA). Flow cytometry (FCM) was used to examine the proportion of Th17/Treg cells. Results: We found that CB2R expression levels were increased in mice with psoriasis. Compared with WT mice, CB2R deficiency exacerbated IMQ-induced PsD and scratching bouts and upregulated the expression of proinflammatory cytokines by increasing the infiltration of CD4+ T cells and the Th17/Treg ratio. Obvious proliferation and prolongation of nerve fibers and high expression of nerve growth factor (NGF) were observed in PsD and CB2R KO mice. Pretreatment with the CB2R agonist, JWH-133 significantly reversed inflammation and scratching bouts. CB2R didn't participate in the induction of itch in psoriasis by regulating the expression of IL-31, thymic stromal lymphopoietin (TSLP) and mast cells in mouse skins. Conclusion: Our results demonstrate that CB2R plays a pivotal role in the pathophysiology of psoriasis, providing a new potential target for anti-inflammatory and antipruritic drugs.

Effect of moxibustion on skin lesions and immune inflammatory response in psoriasis mice

To observe the effect of moxibustion on skin lesions and immune inflammatory response in psoriasis mice, and to explore the possible mechanism of moxibustion for psoriasis. A total of 32 male BALB/c mice were randomly divided into a normal group, a model group, a moxibustion group and a medication group, 8 mice in each group. Psoriasis model was induced by applying 5% imiquimod cream on the back for 7 days in the model group, the moxibustion group and the medication group. At the same time of model establishment, the moxibustion group was treated with suspension moxibustion on skin lesions on the back, 20 min each time, once a day; the medication group was treated with 1 mg/kg methotrexate tablet solution by gavage, once a day. Both groups were intervened for 7 days. The daily changes of skin lesions were observed, and the psoriasis area and severity index (PASI) score was evaluated; the histopathological changes of skin lesions were observed by HE staining; the positive expression of proliferating cell nuclear antigen (PCNA) and T lymphocyte surface marker CD3 were detected by immunohistochemistry; the expression level of serum interleukin (IL) -17A was detected by ELISA, and the relative expressions of tumor necrosis factor-α (TNF-α), IL-1β and IL-6 mRNA in skin lesions were detected by real-time PCR. The increased and hypertrophy scale, dry skin, red and swollen epidermis and obvious infiltration were observed in the model group, and each score and total score of PASI were higher than those in the normal group (P<0.01). The scale score, infiltration score, and total score of PASI in the moxibustion group were lower than those in the model group (P<0.01); the infiltration score and total score of PASI in the medication group were lower than those in the model group (P<0.01, P<0.05). The inflammatory cell infiltration in the model group was obvious, and the thickness of epidermal layer was increased compared with that in the normal group (P<0.01); the inflammatory cell infiltration and Munro micro abscess were decreased in the moxibustion group and the medication group, and the thickness of epidermal layer was decreased compared with that in the model group (P<0.01). Compared with the normal group, the positive cell number of PCNA and T was increased (P<0.01), and the body mass was decreased, and the spleen index was increased (P<0.01), and the expression of serum IL-17A and the relative expression of TNF-α, IL-1β and IL-6 mRNA in the skin lesions was increased in the model group (P<0.01). Compared with the model group, the positive cell number of PCNA and T was reduced (P<0.01), and the spleen index and the relative expression of TNF-α, IL-1β and IL-6 mRNA were reduced (P<0.01) in the moxibustion group and the medication group; the body mass of mice in the moxibustion group was higher than that in the model group (P<0.01); the content of serum IL-17A in the medication group was lower than that in the model group (P<0.01); the relative expression of TNF-α, IL-1β mRNA in the moxibustion group was higher than that in the medication group (P<0.01). Moxibustion could effectively improve the scale and infiltration of skin lesions in psoriasis mice. Its mechanism may be related to inhibiting inflammatory response and regulating immunity.

Forsythoside A Alleviates Imiquimod-Induced Psoriasis-like Dermatitis in Mice by Regulating Th17 Cells and IL-17A Expression.

Psoriasis is a recurrent inflammatory skin disease characterized by redness and scaly skin lesions with itchy or painful sensations. Forsythoside A, one of the main active compounds isolated from the fruit of Forsythia suspensa, has been widely applied to treat inflammatory diseases in the clinical use of traditional oriental medicine. However, the effect of forsythoside A on psoriasis remains unclear. This study aimed to explore the therapeutic effects and immune regulation of forsythoside A on psoriasis. C57BL/6 mice were divided into six groups and treated with imiquimod cream on their shaved back skin to induce psoriasis-like dermatitis. Different doses of forsythoside A (5 mg/kg, 10 mg/kg, or 20 mg/kg) were administered to the respective treatment groups. Skin redness, scaling, and ear thickness were measured; keratinocyte proliferation and inflammatory cytokine expression were detected by hematoxylin–eosin and immunohistochemical staining. Th17 cells in the inguinal lymph nodes were detected by flow cytometric analysis. IL-17A levels were measured using ELISA. The results showed that forsythoside A relieved psoriatic skin symptoms such as skin redness, thickness, scaling, and reduced epidermal thickening. The expression of IL-6, IL-17, and Ki-67 was downregulated in the forsythoside-A-treated groups. Th17 cell expression in inguinal lymph nodes and IL-17A secretion was suppressed by forsythoside A. In conclusion, forsythoside A was found to alleviate imiquimod-induced psoriasis-like dermatitis in mice by suppressing Th17 development and IL-17A secretion. These findings demonstrate the feasibility of forsythoside A in treating human psoriasis.

Penile porokeratosis mimicking annular lichen planus

Sir, Porokeratosis is a group of cutaneous diseases presented by epidermal keratinization [1]. Herein, we report the case of a patient with porokeratosis who responded well to carbon dioxide (CO2) laser therapy. A 22-year-old Vietnamese male visited our department with an asymptomatic plaque on the penis present for three months. He denied a family history of similar lesions. A cutaneous examination of the penis revealed an annular, well-circumscribed plaque with slightly raised borders with scales (Fig. 1a). Other mucocutaneous lesions were absent. Fungal microscopy, a rapid plasma reagin (RPR) test, and a Treponema pallidum hemagglutination (TPHA) test were negative. Histological findings revealed a hyperkeratotic lesion with a discrete parakeratotic column. There was the presence of a cornoid lamella, which was a parakeratotic column overlying a small vertical zone of dyskeratotic and vacuolated cells within the epidermis (Fig. 2a). There was also a focal loss of the granular layer. A mild lymphocytic infiltrate could be seen around an increased number of capillaries in the underlying dermis (Fig. 2b). CO2 laser removal was performed. There was no recurrence after a twelve-month follow-up (Fig. 1b). However, a hypopigmented scar was seen. Porokeratosis is an uncommon disorder of keratinization with clinical variants, such as classical porokeratosis of Mibelli, disseminated superficial actinic porokeratosis, linear porokeratosis, and porokeratosis palmaris et plantaris disseminata [2]. Porokeratosis involving the genital areas and other adjacent sites is rare [2]. Genital porokeratosis was first described by Helfman in 1985 [3]. More than 69 cases have been reported in the literature [1]. The pathophysiology of genital porokeratosis remains unknown. It has been supposed that porokeratosis is linked to repeated minor frictional trauma. A benign lesion may transform into squamous cell carcinoma or basal cell carcinoma [4]. However, no malignant transformation of genital porokeratosis has been noted in the literature. Genital porokeratosis manifests itself clinically as classic or plaque-type porokeratosis of Mibelli [2]. Histological findings revealed a cornoid lamella with the absence of a granular layer and dyskeratotic cells in the upper spinous zone [2]. Our case may mimic some annular lesions, such as secondary syphilis, fungal infection, and annular lichen planus. Because a fungal examination and syphilis serology were negative, we could exclude fungal infection and annular secondary syphilis. The distinctive histology of porokeratosis such as a cornoid lamella with a decreased granular layer may help to differentiate between porokeratosis and annular lichen planus [4]. Numerous therapeutic methods of treatment exist, including surgical excision, CO2 laser, cryotherapy, topical retinoids, 5% 5-fluorouracil, vitamin D3 analogs, imiquimod cream, and 3% diclofenac gel [2,5].

Use of Topical Calcipotriol Plus 5-Fluorouracil in the Treatment of Actinic Keratosis: A Systematic Review.

Actinic Keratosis (AK) is a premalignant lesion that can progress to cutaneous squamous cell carcinoma (cSCC). Topical 5-Fluorouracil (5-FU) and imiquimod have been used for field-directed therapy for AK; however, their use is limited by intolerable skin reactions and long treatment durations. To assess current data on the efficacy, tolerability, and long-term effectiveness of topical calcipotriol plus 5-FU combination for the field-directed therapy of AK. The systematic review will include a critical evaluation of the available evidence. A systematic review of the literature was performed in August 2021 using the EMBASE and MEDLINE databases. Studies that assess the use of calcipotriol and 5-FU to treat actinic keratosis (AK) and cSCC prevention were included. In total, four studies met the inclusion criteria. Our final analysis included three articles. One clinical trial evaluated the efficacy of calcipotriol plus 5-FU in treating AK. Another clinical trial evaluated the long-term effect of calcipotriol plus 5-FU in prevention of cSCC. A retrospective study evaluated the use of calcipotriol plus 5-FU with cryotherapy. A limitation of this systematic review is the limited number of clinical trials that examine the combination of 5-FU plus calcipotriol in treating AK. The active control arm (Petroleum jelly plus 5-FU combination) is not equivalent to topical 5-FU monotherapy; hence, no superiority claim can be made vs topical 5-FU in terms of efficacy. Calcipotriol plus 5-FU reduced greater number of AKs in the treated area (25 cm2) when compared to 5-FU plus petroleum jelly, but only 27% of participants had complete clearance on the face at week-8. Calcipotriol plus 5-FU lowered the risk of cSCC on the face and scalp area over a 3-year period. Adequate and well-controlled studies are needed to compare the efficacy of calcipotriol plus 5-FU to 5-FU monotherapy, and other FDA-approved topical drugs such as imiquimod cream and tirbanibulin ointment. J Drugs Dermatol. 2022;21(1):60-65. doi:10.36849/JDD.6632.

Prenatal infection predisposes offspring to enhanced susceptibility to imiquimod-mediated psoriasiform dermatitis in mice

Background: Infection can upregulate T helper 17 (Th17) signaling and exacerbate psoriasis. Literature has indicated that prenatal infection induces embryonic development toward Th17 signaling and is a risk factor for developing certain Th17-skewing disorders such as autism in offspring. However, it remains unclear if a prenatal infection is a risk factor for developing psoriasis in offspring. Objectives: We investigated if a prenatal infection predisposes mice offspring to enhanced susceptibility to psoriatic inflammation. Methods: Pregnant C57BL/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid poly I:C to simulate prenatal bacterial and viral infection, respectively. Phosphate-buffered saline (PBS) injection was used as the control. When mice offspring were at the age of 9–10 weeks, imiquimod (IMQ) cream or control vehicle was applied topically on ears for 5 consecutive days to induce psoriasiform dermatitis. The extent of epidermal hyperplasia and the number of Munro microabscesses were examined by histologic analysis. Protein expressions of neutrophil marker Ly6 g and Th17-associated cytokines were measured by western blotting. Results: Prenatal infection with LPS or poly I:C induced a greater extent of epidermal hyperplasia and more Munro microabscesses after IMQ application as compared with prenatal PBS injection. Mice offspring with prenatal infection also had higher protein expressions of Ly6 g, IL-17a, and interleukin-23 after IMQ stimulation compared with their PBS controls. Conclusion: Prenatal infection predisposes mice offspring to enhanced susceptibility to IMQ-mediated psoriasiform dermatitis. The data obtained from the present animal study suggest that prenatal infection might be a risk factor for developing psoriasis in offspring.

Resistant Plane Warts Treated by 40% Salicylic Acid and 16% Lactic Acid Combination on the Face

Human papillomaviruses (HPV) cause warts, which are the benign epithelial proliferation of the mucous membrane and skin. HPV-3 and HPV-10 commonly cause plane warts. Multiple treatment options must be used as no specific treatment option is available. We have a lot of limitations for the face as treatment can cause permanent scarring on the face. We report a case of 41 years immunocompetent male presenting with many plane warts on the face who was successfully treated with topical application of 40% Salicylic acid cream and 16% lactic acid cream made up of 44% of bees wax on lesions after a failure of many other treatment options, a) Topical zinc oxide twice per day for 3 months, b) Topical 5% salicylic acid dispensing cream made in 95% bees wax, c) Topical 5% fluorouracil cream, d) Topical imiquimod cream, e) Topical retinoids cream only at night for one month, f) Oral Isotretinoin 20mg twice per day for 2 months, and 3 sessions of cryotherapy. The patient's last treatment was oral isotretinoin 20 mg twice per day for the last 2 months. In general, doctors avoid using more than 5% salicylic acid, but after a detailed discussion with the patient, we decided to try this combination and succeeded.

Effect of Total Glucosides of Paeony on Imiquimod-Induced Psoriatic Skin Lesions by Regulating VEGF.

PurposeThe purpose of this study was to use a murine model of psoriasis to examine the effect of total glycosides of paeony (TGP) on psoriatic skin lesions and on the expression of vascular endothelial growth factor (VEGF) in skin lesions and blood.MethodsA murine model of psoriasis was produced by shaving the backs of the mice and applying 5% imiquimod cream, 50 mg, to the backs of the mice once a day. Mice were killed on day 8, and skin and blood samples were obtained for histopathological examination and analysis of VEGF mRNA expression.ResultsBy day 8 of the application of imiquimod cream, skin lesions characteristic of psoriasis were evident, and histopathological examination of skin sections showed changes consistent with psoriasis (corneum thickening and parakeratosis, attenuation of the stratum granulosum, thickening of the stratum spinosum, and lengthening of the epidermal ridge). In the treatment group, 7 days of treatment with TGP resulted in resolution of the skin lesions, and histopathological examination showed the epidermis and dermis are approximately normal, without corneum thickening, hyperkeratosis, and parakeratosis. On day 7 of treatment, skin expression of VEGF mRNA was significantly lower in the treatment group than in the group that did not receive treatment (p < 0.05). Blood VEGF mRNA expression was not different between the groups.ConclusionTGP is effective for the treatment of psoriasis and may act by decreasing lesion VEGF mRNA expression.

Use of Topical Calcipotriol Plus 5-Fluorouracil in the Treatment of Actinic Keratosis: A Systematic Review

Background: Actinic Keratosis (AK) is a premalignant lesion that can progress to cutaneous squamous cell carcinoma (cSCC). Topical 5-Fluorouracil (5-FU) and imiquimod have been used for field-directed therapy for AK; however, their use is limited by intolerable skin reactions and long treatment durations. Objective: To assess current data on the efficacy, tolerability, and long-term effectiveness of topical calcipotriol plus 5-FU combination for the field-directed therapy of AK. The systematic review will include a critical evaluation of the available evidence. Methods: A systematic review of the literature was performed in August 2021 using the EMBASE and MEDLINE databases. Studies that assess the use of calcipotriol and 5-FU to treat actinic keratosis (AK) and cSCC prevention were included. Results: In total, four studies met the inclusion criteria. Our final analysis included three articles. One clinical trial evaluated the efficacy of calcipotriol plus 5-FU in treating AK. Another clinical trial evaluated the long-term effect of calcipotriol plus 5-FU in prevention of cSCC. A retrospective study evaluated the use of calcipotriol plus 5-FU with cryotherapy. Limitations: A limitation of this systematic review is the limited number of clinical trials that examine the combination of 5-FU plus calcipotriol in treating AK. The active control arm (Petroleum jelly plus 5-FU combination) is not equivalent to topical 5-FU monotherapy; hence, no superiority claim can be made vs topical 5-FU in terms of efficacy. Conclusion: Calcipotriol plus 5-FU reduced greater number of AKs in the treated area (25 cm2) when compared to 5-FU plus petroleum jelly, but only 27% of participants had complete clearance on the face at week-8. Calcipotriol plus 5-FU lowered the risk of cSCC on the face and scalp area over a 3-year period. Adequate and well-controlled studies are needed to compare the efficacy of calcipotriol plus 5-FU to 5-FU monotherapy, and other FDA-approved topical drugs such as imiquimod cream and tirbanibulin ointment. J Drugs Dermatol. 2022;21(1):60-65. doi:10.36849/JDD.6632Topical Calcipotriol Plus 5-Fluorouracil

Terrestrosin D ameliorates skin lesions in an imiquimod-induced psoriasis-like murine model by inhibiting the interaction between Substance P and Dendritic cells

BackgroundPsoriasis is a psychosomatic immune skin disease with psychological factors contributing to the disease. Substance P (SP) is highly expressed in the psoriatic lesions of patients and is involved in pathological disease progression. Tribulus terrestris L. has been used as a Chinese herbal medicine for disease prevention for thousands of years. Terrestrosin D (TED) has been identified as the effective monomeric component of Tribulus terrestris L.. PurposeWe investigated whether TED could reverse imiquimod-induced psoriatic lesions, and then, investigated its potential mechanism of action both in vivo and in vitro. Methods5% imiquimod cream was applied onto the backs of mice for 6 days to induce psoriasis-like skin lesions. The psoriatic area and severity index (PASI) was then used for scoring disease severity. Pathological changes and Ki-67 expression levels in skin lesions were measured using hematoxylin and eosin (H&E) and immunofluorescence staining after TED administration. The in vivo and in vitro expression levels of inflammatory cytokines, the ratio of DCs, and SP were measured using ProcartaPlex Mouse Cytokine panels, flow cytometry, and western blotting. Behavioral assessments were determined using the open field and elevated plus-maze (EPM) test. ResultsTED decreased PASI scores, epidermal thickness, Ki-67 expression levels, the ratio of DCs in the spleen, and secretion of IL-12p70, IL-18, and TNF-α in imiquimod-induced psoriasis-like murine models. Furthermore, TED increased IL-10 secretion levels, improved behavior, and down-regulated the expression levels of SP. Additionally, TED inhibited the in vitro maturation and activation of SP-induced CD11c+ DCs and the release of IL-12p70 and IL-23. ConclusionTED reduced DCs maturation, down-regulated the expression levels of inflammatory factors, and improved skin lesions and behavior of psoriasis-like murine models by inhibiting the interaction between Substance P and Dendritic cells.

Successful treatment of a keratoacanthoma in a young patient with the application of topical 5% imiquimod cream.

Keratoacanthomas (KA) are epithelial tumors that present as rapidly evolving nodules with a central hyperkeratotic plug and occasionally show signs of spontaneous regression. A 21‐year‐old patient strongly refused the diagnostic biopsy and insisted on a nonsurgical treatment. He was successfully treated with imiquimod 5% cream.

Complications and dosing frequency of 5% imiquimod for genital warts in a young man

A clinical decision report using: Fife KH, Ferenczy A, Douglas JM Jr, et al. Treatment of external genital warts in men using 5% imiquimod cream applied three times a week, once daily, twice daily, or three times a day. Sex Transm Dis. 2001;28(4):226-231. https://doi.org/10.1097/00007435-200104000-00007 for a patient with genital warts and an unstable social support network.

Acute induction of psoriasis-like skin inflammation disturbes vascular tone and provokes a rapid blood pressure response in mice

Abstract Background Psoriasis is the most common chronic skin disease worldwide. Furthermore, it is an independent cardiovascular risk factor. Several genetic and inducible murine models reproduce specific aspects of the human disease. In mice genetically overexpressing IL-17A in keratinocytes or dendritic cells, we coulod show both aspects of the disease: cutaneous hallmarks and the vascular phenotype. The most popular inducible model consists of topical application of Imiquimod (IMQ), a Toll-like receptor 7/8 agonist. In this model, cardiovascular aspects have not been studied yet. Therefore, we examined vascular and hemodynamic effects in this most popular murine psoriasis model. Methods C57BL/6J mice were treated with 5% IMQ or sham cream. During treatment, we measured bodyweight, skin thickness and skin water loss. After 10 days, aortic relaxation studies were performed. For assessment of vascular inflammation, inflammatory cell infiltration into the aortic tissue was investigated by flow cytometric analysis. To record physical activity, blood pressure and heart rate, carotid catheters were implanted two weeks before treatment with IMQ. Blood pressure and heart rate were continuously recorded by receiver platforms. Results IMQ treatment resulted in severe skin inflammation and induced a skin barrier defect resulting in a 7-fold increase of transcutaneous water loss (from 11±6 ml/m2h to 77±30 ml/m2h). Physical activity decreased more than 50% after d1 of treatment and normalized at d7. Telemetric recording revealed a reflex tachycardia at 1d of IMQ-application (from 492±21 bpm to 524±20 bpm) followed by a significant reduction of heart rate for the next two days (456±18bpm). Systolic blood pressure showed a similar trend: after a fast increase (from 120±13 mmHg to 127±18 mmHg), blood pressure dropped below baseline at d2/3 with a subsequent recovery. We could display a highly significant positive correlation between blood pressure and heart rate during the treatment (R=0.6; p≤0.0001). Aortas from animals after 10d of IMQ-treatment showed an increased infiltration of CD45+ and CD11b+ inflammatory cells but no change of responsiveness to endothelium dependent and independent vasodilators in organ chamber studies. Conclusion Skin treatment with IMQ had severe implications on the hemodynamic system: After an initial peak of heart rate and blood pressure, mice showed significantly lower values for two days with a subsequent full recovery. Moreover, bodyweight and physical activity were significantly altered during treatment. Our data indicate that skin inflammation and inflammatory skin barrier disruption by IMQ forces a compensatory whole-body response. 10 days of IMQ-treatment resulted in vascular inflammation without mediating vascular dysfunction. In summary, we could reveal that IMQ-induced psoriasis, as the most popular murine psoriasis model worldwide, has extensive effects on the cardiovascular system. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Boehringer Ingelheim Foundation “Novel and neglected cardiovascular risk factors: molecular mechanisms and therapeutic implications”German Federal Ministry for Education and Research (BMBF EDU-V24)

Intra-Anal Imiquimod Cream against Human Papillomavirus Infection in Men Who Have Sex with Men Living with HIV: A Single-Arm, Open-Label Pilot Study.

Men who have sex with men (MSM) living with HIV have a high prevalence and incidence of anal high-risk human papillomavirus (hrHPV) and anal cancer. We conducted an open-label, single-arm pilot study to examine the tolerability of imiquimod cream among MSM aged ≥18 years, living with HIV, who tested positive for anal hrHPV at Melbourne Sexual Health Centre between April 2018 and June 2020. We instructed men to apply 6.25 mg imiquimod intra-anally and peri-anally 3 doses per week for 16 weeks (period 1) and then one dose per week for a further 48 weeks (period 2). Twenty-seven MSM enrolled in period 1 and 24 (86%) applied at least 50% of doses. All men reported adverse events (AEs), including 39.5% grade 1, 39.5% grade 2, and 21% grade 3 AEs on at least one occasion. Eighteen MSM (67%) temporarily stopped using imiquimod during period 1, most commonly due to local AEs (n = 11) such as irritation and itching. Eighteen MSM continued in period 2 and all applied at least 50% of doses with no treatment-limiting AEs reported. Imiquimod 3 doses per week caused local AEs in most men and was not well tolerated. In contrast, once-a-week application was well tolerated over 48-weeks with no treatment-limiting AEs.

A practical guide on the use of imiquimod cream to treat lentigo maligna.

Lentigo maligna (LM) is a common insitu melanoma subtype arising on chronically sun-damaged skin and mostly affects the head and neck region. Localisation in cosmetically sensitive areas, difficulty to obtain wide resection margins and advanced patient age/comorbidities have encouraged investigation of less invasive therapeutic strategies than surgery in managing complex cases of LM. Radiotherapy and imiquimod have emerged as alternative treatment options in this context. The treatment of LM with imiquimod cream can be challenging due to the nature of the disease including its often large size, variegated appearance, involvement of adnexal structures, poorly defined peripheral edge and frequent localisation close to sensitive structures such as the eyes and lips, and elderly patients with multiple comorbidities. Prolonged and unpredictable inflammatory reaction and side effects and compliance with a patient-delivered therapy can also be challenging. In the literature to date, studies evaluating the use of imiquimod to treat LM have utilised varying methodologies and provided short follow-up and these limitations have impaired the development of clear guidelines for dosage and management of side effects. Based on our multidisciplinary experience and review of the literature, we propose practical clinical strategies for the use of imiquimod for treating LM, detailing optimal administration procedures in various clinical scenarios and long-term management, with the aim of facilitating optimal patient outcomes.

TNFα siRNA delivery by nanoparticles and photochemical internalization for psoriasis topical therapy

Psoriasis is a chronic inflammatory skin disease that presents increased expression of tumor necrosis factor α (TNFα), a proinflammatory cytokine. The discovery of RNA interference (RNAi), mediated by short interfering RNA (siRNA), made it possible for the expression of some genes to be eliminated. However, for its application, it is necessary to use carriers that can protect siRNA and release it in the target cells. Herein, we developed a delivery system for siRNA based on hybrid polymer-lipid nanoparticles (PLNs) and combined this system with photochemical internalization (PCI), photoactivating the photosensitizer TPPS2a, to optimize the endosomal escape of TNFα siRNA in the cytoplasm, aiming to use the system as a topical formulation to treat psoriasis. The PLNs composed of 2.0% of Compritol® 888 ATO (lipid), 1.5% of poloxamer 188 and 0.1% of the cationic polymer poly(allylamine hydrochloride) showed an average nanoparticle size of 142 nm, a zeta potential of +25 mV, and the ability to efficiently coencapsulate TPPS2a and complexed siRNA. In addition, these materials did not present cellular toxicity and showed high cellular uptake. In vitro delivery studies using porcine skin model revealed that the PLNs delivered siRNA and TPPS2a into the skin. The efficacy was verified using an in vivo psoriasis animal (hairless mouse) model induced by imiquimod (IMQ) cream. The results revealed that PLN-TPPS2a-TNFα siRNA combined with PCI resulted in a decrease in the levels of TNFα, showing the efficiency of the treatment to silence this cytokine in psoriatic lesions, which was accompanied by a reduction in the redness and scaling of the mouse skin. The results showed the potential of the developed PLNs in combined silencing gene therapy and PCI for topical treatment of psoriasis.

Anoctamin1 Induces Hyperproliferation of HaCaT Keratinocytes and Triggers Imiquimod-Induced Psoriasis-Like Skin Injury in Mice.

Psoriasis, a long-lasting and multifactorial skin disease, is related to comorbidities such as metabolic disease, depression, and psoriatic arthritis. Psoriasis occurs due to a variety of factors including keratinocyte hyperproliferation, inflammation, and abnormal differentiation. Proinflammatory cytokines upregulated by increased activation of keratinocytes and immune cells in the skin trigger progression of psoriasis. This study aimed to investigate the effects of anoctamin1 (ANO1) on psoriasis development in vitro and in vivo. We analyzed the proliferation of HaCaT keratinocytes and ANO1-related ERK and AKT signaling pathways after ANO1 inhibitor (T16Ainh-A01 and Ani9) treatment and knock-down of ANO1. Furthermore, after applying imiquimod (IMQ) cream or coapplying IMQ cream and T16Ainh-A01 on mouse ears, we not only observed psoriatic symptoms, including ear thickening, but also quantified the effects of treatment on ERK and AKT signaling-involved proteins and proinflammatory cytokines. Inhibition of ANO1 attenuated the proliferation of HaCaT cells and induced reduction of pERK1/2. Coapplication of IMQ and T16Ainh-A01 on ears of mice reduced not only symptoms of IMQ-induced psoriasis such as thickening and erythema, but also expression of ANO1 and pERK1/2 compared to that of application of IMQ alone. In addition, the expression levels of IL-17A, IL-17F, IL-22, IL-23, IL-6, IL-1β, and TNF-α increased after applying IMQ and were significantly reduced by coapplying IMQ and T16Ainh-A01. These results aid in understanding the underlying mechanisms of ANO1 in epidermal layer keratinocyte hyperproliferation and suggest the potential of ANO1 as a target to treat psoriasis.

Giant Condyloma Acuminata (Buschke-Lowenstein Tumor): Review of an Unusual Disease and Difficult to Manage.

Giant condyloma acuminatum (GCA) or Buschke-Loewenstein tumor is a rare disease, with an estimated prevalence of 0.1%. It was initially described in 1896 by Buschke and later in 1925 by Buschke and Loewenstein. Classic condyloma acuminata (CCA) and squamous cell carcinoma (SCC) were initially described as different entities. These three entities are currently considered to correspond to the same spectrum of different but not exclusive malignant transformations, associated with multiple risk factors such infection by human papilloma virus (HPV), immunodeficiencies, poor hygiene, multiple sexual partners, and chronic genital infections. HPV subtypes 6 and 11 are associated with 90% of GCA. It presents as a cauliflower-like tumor in the genital region with bad odor, bleeding, and local infection, differential diagnosis with multiple conditions should be considered, and sexually transmitted diseases should always be investigated. GCA has a higher rate of malignant transformation than CCA and tends to infiltrate adjacent soft tissues. The therapeutic approach is controversial but is considered that the resection with free edges is the gold standard and can be combined with adjuncts. The recurrence rate is high. Overall mortality is 21% and is associated with morbidity caused by recurrences. Imiquimod cream 5% has recently shown good results as monotherapy and in combination with ablative and surgical treatments. The quality of life is diminished in patients with this condition. In this review, we address the different aspects of this rare entity including the therapeutic approach.

Impact of barrier tissue inflammation and physical activity on joint homeostasis in mice.

To investigate whether physical activity interferes with joint homeostasis in the presence of distant inflammation originating at barrier tissues such as skin or gut. Eight-week-old male C57/Bl6 mice were treated with imiquimod cream on a shaved area of the back skin or with dextran sodium sulphate dissolved in the drinking water to induce psoriasis-like skin or inflammatory bowel disease-like gut inflammation. Afterwards, one group of mice was subjected to a 4-week forced running routine (n = 10 per group). Severity of cutaneous or intestinal inflammation was assessed clinically, by histology and by quantitative PCR. Knees and paws were analysed by micro-CT, histology, immunohistochemistry, second-harmonic generation microscopy and quantitative PCR. Local induction of inflammation triggered a systemic response with splenomegaly, loss of bone mass and bone marrow changes. Psoriasis- but not inflammatory bowel disease-like inflammation led to synovial lining layer hyperplasia, an increase in infiltrating CD45+ synovial cells, and suppressed entheseal extracellular matrix gene expression levels. Mechanical loading decreased the amount of F4/80+ synovial macrophages in untreated mice only and led to morphological alterations in the collagen fibres of the enthesis. Systemic inflammation and mechanical loading act independently of each other. The former, originating from distant sites, can trigger mild synovial inflammation in mice, a propensity that may also impact the development of arthritis in patients; the latter has no impact on the severity of systemic inflammation, but independently affects joint homeostasis.

Ionic Liquid-Enabled Topical Delivery of Immunomodulators.

Skin is one of the most immunologically active organs of the body due to the presence of diverse immune cells and its active involvement in the innate and adaptive immunity. Because of its unique location and immunological role, skin offers an excellent site for the introduction of immunomodulators to synergize with the active immune microenviroment for the desired outcome. However, delivery of immunomodulators to the skin remains a significant challenge due to the skin's barrier properties. Here, we report an ionic liquid (IL)-based strategy to formulate and deliver immunomodulators to the skin. Using imiquimod (IMQ) and triamcinolone acetonide (TCA) as the respective model immunoactive and immunosuppressive drugs, we demonstrated that ILs significantly enhanced the solubility of immunomodulators. In addition, ILs enabled the formulation of the immunomodulators into stable, topically applicable forms. Our ex vivo skin penetration studies revealed that the IL formulations outperformed respective commercial topical comparators and delivered significantly more immunomodulators to deep skin layers. The lead IMQ formulation exhibited >10-fold better efficacy in delivering IMQ to the deep skin layers as compared to the commercial 5% IMQ cream. Lead TCA formulations achieved a dose level in deep skin layers that is comparable to that by clinically used intralesional injections. Our data collectively suggest that the IL-based strategy can be a simple and effective platform for delivery of immunomodulators to the skin.