The Paget Trial: topical 5% imiquimod cream for noninvasive vulvar Paget disease.

BACKGROUND: Vulvar Paget disease is an extremely rare skin disorder, which is most common in postmenopausal women. Most vulvar Paget disease cases are noninvasive; however, it may be invasive or associated with an underlying vulvar or distant adenocarcinoma. The current treatment of choice for noninvasive vulvar Paget disease is wide local excision, which is challenging because of extensive intraepithelial spread and may cause severe morbidity. Recurrence rates are high, ranging from 15% to 70%, which emphasizes the need for new treatment options. Imiquimod, a topical immune response modifier, has been shown to be effective in a few studies and case reports, and is a promising new treatment modality. OBJECTIVE: To prospectively investigate the efficacy, safety, and effect on quality of life of a standardized treatment schedule with 5% imiquimod cream in patients with noninvasive vulvar Paget disease. STUDY DESIGN: The Paget Trial is a multicenter prospective observational clinical study including 7 tertiary referral hospitals in the Netherlands. A total of 24 patients with noninvasive vulvar Paget disease were treated with topical 5% imiquimod cream 3 times a week for 16 weeks. The primary efficacy outcome was the reduction in lesion size at 12 weeks after the end of treatment. Secondary outcomes were safety, clinical response after 1 year, and quality of life. Safety was assessed by evaluation of adverse events and tolerability of treatment. Quality of life was investigated with 3 questionnaires taken before, during, and after treatment. RESULTS: Data were available for 23 patients, 82.6% of whom responded to therapy. A complete response was reported in 12 patients (52.2%), and 7 patients (30.4%) had a partial response. A histologic complete response was observed in 10 of the 12 patients with a complete response. Patients experienced side effects such as fatigue (66.7%-70.9%) and headaches (16.7%-45.8%), and almost 80% needed painkillers during treatment. Eight patients (34.8%) adjusted the treatment protocol to 2 applications a week, and 3 patients (13.0%) stopped treatment because of side effects after 4 to 11 weeks. Treatment improved quality of life, whereas a slight, temporary negative impact was observed during treatment. Two patients with a complete response developed a recurrence within 1 year after treatment. Follow-up showed 6 patients with a noninvasive recurrence after a median of 31 months (14-46 months) after the end of treatment. CONCLUSION: Topical 5% imiquimod cream can be an effective and safe treatment alternative for noninvasive vulvar Paget disease, particularly when compared with treatment with surgical excision.

Ixekizumab Improved Patient-Reported Genital Psoriasis Symptoms and Impact of Symptoms on Sexual Activity vs Placebo in a Randomized, Double-Blind Study.

INTRODUCTION: Genital psoriasis (GenPs) is common and distressing for patients, but is often not discussed with physicians, and no previous clinical trials have assessed the effects of biologics specifically on GenPs and its associated symptoms. AIM: To report results for novel patient-reported outcomes (PROs) for the assessment of symptoms and the sexual impact of GenPs before and after treatment in the IXORA-Q study. METHODS: IXORA-Q (NCT02718898) was a phase III, randomized, double-blind, placebo-controlled study of ixekizumab (80 mg/2 weeks after 160-mg initial dose) vs placebo for GenPs. Men and women ≥18 years old with moderate-to-severe GenPs and body surface area (BSA) ≥1% were assessed through 12 weeks. MAIN OUTCOME MEASURE: GenPs symptoms were assessed using the 8-item Genital Psoriasis Symptoms Scale (GPSS), Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ), and Genital Psoriasis Sexual Impact Scale (GPSIS) (validation data presented in the supplemental materials), and the Dermatology Life Quality Index (DLQI) item 9. RESULTS: For patients receiving ixekizumab (N = 75) vs placebo (N = 74), statistically significant improvement in GenPs symptoms were seen from week 1 onward (GPSS total and individual items, all P < .005). Sexual activity avoidance owing to GenPs symptoms (GPSIS) decreased significantly with ixekizumab from week 4 onward (all P <.005), whereas impact of sexual activity on GenPs improved significantly with ixekizumab at weeks 2-8 (all P < 0.05). Ixekizumab resulted in significant improvement vs placebo by week 1 onward in limitations on frequency of sexual activity owing to GenPs (GenPs-SFQ item 2). Sexual difficulties caused by skin (DLQI item 9) decreased significantly with ixekizumab from week 2 onward (all P < .001). CLINICAL IMPLICATIONS: Both GenPs symptoms and impact on sexual activity improved rapidly and significantly with ixekizumab vs placebo through 12 weeks in patients with moderate-to-severe GenPs and BSA ≥1%. STRENGTH & LIMITATIONS: To our knowledge, this is the first phase III, randomized, placebo-controlled, double-blinded clinical trial to evaluate the effect of any treatment on the symptoms and sexual impact related to GenPs. The study did not include an active comparator owing to the lack of any well-established treatment for moderate-to-severe GenPs, and the period assessed herein was of relatively short duration. CONCLUSION: These validated PRO measures may aid in future clinical studies of GenPs and in facilitating discussions of GenPs symptoms and their impact between patients and clinicians. Yosipovitch G, Foley P, Ryan C. Ixekizumab improved patient-reported genital psoriasis symptoms and impact of symptoms on sexual activity vs placebo in a randomized, double-blind study. J Sex Med 2018;15:1645-1652.

Prevalence of genital psoriasis in patients with psoriasis.

BACKGROUND: Psoriatic lesions in the genital area (GenPs) can cause considerable physical and emotional distress. To increase physician awareness, we estimated the GenPs prevalence among patients with psoriasis. METHODS: An English language literature search was performed. Articles reporting GenPs prevalence met the search criteria and were included. Because GenPs is rarely reported in demographics of prospective clinical trials, GenPs prevalence and baseline demographics of patients with and without GenPs in two prospective randomized phase 3b trials (NCT02561806 and NCT02634801) involving patients with moderate-to-severe psoriasis are reported. RESULTS: Overall, 600 references were screened. Eighteen articles met the search criteria. Patient populations were highly heterogeneous across articles. Broadly, the presence of GenPs was either physician-reported (physical examinations) or patient-reported (questionnaires). In the literature, GenPs prevalence at the time of reporting ranged from 7% to 42% and the prevalence of GenPs at any time during the course of psoriasis ranged from 33% to 63%. In the two prospective clinical trials, the prevalence of GenPs at the time of enrollment was 35-42%. CONCLUSION: A substantial proportion of patients experience genital lesions at some time during the course of psoriasis. Increased awareness of GenPs prevalence may drive improved assessment and treatment.

Patients' Perspectives on the Impact of Genital Psoriasis: A Qualitative Study.

INTRODUCTION: Plaque psoriasis is a chronic skin disease where genital involvement is relatively common. Yet health care providers do not routinely evaluate psoriasis patients for genital involvement and patients do not readily initiate discussion of it. METHODS: A qualitative study of 20 US patients with dermatologist-confirmed genital psoriasis (GenPs) and self-reported moderate-to-severe GenPs at screening was conducted to identify key GenPs symptoms and their impacts on health-related quality of life (HRQoL). RESULTS: Patients had a mean age of 45 years, 55% were female, and patients had high rates of current/recent moderate-to-severe overall (65%) and genital (70%) psoriasis. Patients reported the following GenPs symptoms: genital itch (100%), discomfort (100%), redness (95%), stinging/burning (95%), pain (85%), and scaling (75%). Genital itching (40%) and stinging/burning (40%) were the most bothersome symptoms. Impacts on sexual health included impaired sexual experience during sexual activity (80%), worsening of symptoms after sexual activity (80%), decreased frequency of sexual activity (80%), avoidance of sexual relationships (75%), and reduced sexual desire (55%). Negative effects on sexual experience encompassed physical effects such as mechanical friction, cracking, and pain as well as psychosocial effects such as embarrassment and feeling stigmatized. Males reported a higher burden of symptoms and sexual impacts. Other HRQoL impacts were on mood/emotion (95%), physical activities (70%), daily activities (60%), and relationships with friends and family (45%). These impacts significantly affected daily activities. Physical activities were affected by symptoms and flares, and increased sweat and friction worsened symptoms. Patients reported daily practices to control outcomes. CONCLUSION: The high level of reported symptoms and sexual and nonsexual impacts reflects the potential burden of moderate-to-severe GenPs. GenPs can impact many facets of HRQoL and providers should evaluate their patients for the presence of genital psoriasis and its impact on their quality of life. FUNDING: Eli Lilly and Company.

The Paget Trial: A Multicenter, Observational Cohort Intervention Study for the Clinical Efficacy, Safety, and Immunological Response of Topical 5% Imiquimod Cream for Vulvar Paget Disease.

BACKGROUND: Vulvar Paget disease is a rare skin disorder, which is most common in postmenopausal Caucasian women. They usually present with an erythematous plaque that may show fine or typical "cake icing" scaling or ulceration that may cause itching, pain, irritation, or a burning sensation. Although most cases are noninvasive, vulvar Paget disease may be invasive or associated with an underlying vulvar or distant adenocarcinoma. The histological evidence of so-called "Paget cells" with abundant pale cytoplasm in the epithelium confirms the diagnosis. The origin of these Paget cells is still unclear. Treatment of choice is wide local excision with negative margins. Obtaining clear surgical margins is challenging and may lead to extensive and mutilating surgery. Even then, recurrence rates are high, ranging from 15% to 70%, which emphasizes the need for new treatment options. A number of case reports, retrospective case series, and one observational study have shown promising results using the topical immune response modifier imiquimod. OBJECTIVE: This study aims to investigate the efficacy, safety, and immunological response in patients with noninvasive vulvar Paget disease using a standardized treatment schedule with 5% imiquimod cream. METHODS: Topical 5% imiquimod cream might be an effective and safe treatment alternative for vulvar Paget disease. The Paget Trial is a multicenter observational cohort study including eight tertiary referral hospitals in the Netherlands. It is ethically approved by the Medical-Ethical Committee of Arnhem-Nijmegen and registered in the Central Committee on Research Involving Human Subjects (CCMO) Register by as NL51648.091.14. Twenty patients with (recurrent) noninvasive vulvar Paget disease will be treated with topical 5% imiquimod cream three times a week for 16 weeks. The primary efficacy outcome is the reduction in lesion size at 12 weeks after end of treatment. Secondary outcomes are safety, immunological response, and quality of life. Safety will be assessed by evaluation of adverse events and tolerability of treatment. To evaluate the immunological response, various immunological markers will be tested on biopsy specimens taken before, during, and after treatment. Quality of life will be assessed with three questionnaires taken before, during, and after treatment. RESULTS: First results are expected in the summer of 2018. TRIAL REGISTRATION: ClinicalTrials.gov NCT02385188; https://clinicaltrials.gov/ct2/show/NCT02385188 (Archived by WebCite at http://www.webcitation.org/6sXygHuhP).

The Static Physician's Global Assessment of Genitalia: A Clinical Outcome Measure for the Severity of Genital Psoriasis.

Introduction: Genital psoriasis is a common but frequently overlooked manifestation of psoriasis with a considerable impact on patients' quality of life. Currently no validated clinical trial outcome measures exist to assess genital psoriasis severity that meet regulatory agency requirements. Methods: This study describes the development of the static Physician's Global Assessment of Genitalia (sPGA-G) scale, a clinical outcome measure for the assessment of genital psoriasis severity that accounts for the erythematous clinical presentation of genital psoriasis. The reliability of the sPGA-G was evaluated using scores collected from clinician assessments of photographs of genital psoriasis cases. Scores were collected from 10 academic and clinical experts in genital psoriasis and 95 clinician assessors who participated in either in-person (n=28) or online (n=67) sPGA-G training modules. Results: The sPGA-G had a high inter-rater reliability (IRR, measured by Kendall's W) for expert raters (W=0.856, P less than 0.0001), in-person assessors (W=0.822, P less than 0.0001), and online assessors (W=0.678, P less than 0.0001). IRR was also high for all clinical assessors combined, (W=0.714, P less than 0.0001). Discussion: This study demonstrates that the sPGA-G is an intuitive and reliable clinical outcome measure that specifically measures the severity of genital psoriasis. J Drugs Dermatol. 2017;16(8):793-799.

Improvement of Gynecological Screening of Female Renal Transplant Recipients by Self-Sampling for Human Papillomavirus Detection.

OBJECTIVES: Female renal transplant recipients (RTRs) have increased risk for developing human papillomavirus (HPV)-related (pre)malignancies of the lower genital tract. Annual cervical screening is advised for RTRs, but the participation rate is low. The aim of this study is to investigate whether HPV self-sampling is suitable for gynecological screening of RTRs to increase participation rate. METHODS: A large cohort of 253 RTRs was investigated for the prevalence of HPV. All participants received a device for a cervicovaginal self-sample. Questionnaires were sent to assess the experience with this device. High-risk (hrHPV) presence was determined with the SPF10-LiPA25 system and GP5+/6+ PCR. HrHPV-positive patients underwent gynecological examination. RESULTS: More than 90% of the patients rated their experience with the self-sample device as good to excellent, and 77% preferred self-sampling over a physician taken sample. Approximately thirty-five of 217 women tested hrHPV positive with SPF10- LiPA25, and 22 tested positive with the GP5+/6+ PCR. Eleven hrHPV-positive patients had clinically relevant gynecological abnormalities, and they all tested positive with GP5+/6+ PCR. CONCLUSIONS: Self-sampling is clinically applicable in a gynecological screening and is preferred by female RTRs. Therefore, self-sampling could be implemented with the aim to increase the participation rate of female RTRs in yearly gynecological screening.

Genital psoriasis awareness program: physical and psychological care for patients with genital psoriasis.

Genital psoriasis is a neglected manifestation of psoriasis, although it affects numerous patients and has major effects on sexual quality of life (SQoL). We aimed to assess the value of specialised care for patients with genital psoriasis. Patients were treated for at least one year at a specialised research outpatient clinic with extensive attention for genital lesions and SQoL. The genital lesions were treated according to a stepwise algorithm. First follow-up was planned after 6 weeks; subsequent follow-up visits were scheduled every 3 months. At every visit, psoriasis severity and SQoL were measured with validated tools. Differences in scores between visits were analysed by a mixed model for repeated measures. Forty-two patients were included (M:F = 25:17). All objective and subjective genital psoriasis severity and QoL parameters improved significantly within the first follow-up period of approximately 6 weeks. In female patients, SQoL also significantly improved. In conclusion, genital psoriasis can relatively easy be treated within limited time exposure, resulting in significant improvement of QoL. Prompt and simple adjustments in the provided care are enough to accomplish this.

Anogenital malignancies in women after renal transplantation over 40 years in a single center.

BACKGROUND: Renal transplant recipients have an increased risk to develop human papillomavirus (HPV)-related anogenital malignancies. A clinical overview of female anogenital posttransplantation malignancies and possible multifocal premalignancies over a period of 40 years renal transplantation is presented. Additionally, the genotype-specific prevalence of HPV in these (pre)malignancies was investigated. METHODS: Data of 1023 women, who underwent a renal transplantation between 1968 and 2008, were collected. Clinical data of all female renal transplant recipients who developed anogenital malignancies were retrospectively analyzed. The histology, cytology, and distribution of genotype-specific HPV infections were analyzed in all primary anogenital tumors and possible (multifocal) premalignancies. RESULTS: Sixteen anogenital malignancies (1.6%) were found: vulva (n=6), cervix (n=5), and anus (n=5). Twelve of 16 patients never had a cervical smear before transplantation. The median interval between transplantation and diagnosis of malignancy was 136 months (range, 16-288 months). High-risk HPV was detected in 91.7% of investigated lesions, HPV subtype 16 predominated (54.5%). Four of seven patients with two distinct anogenital lesions had different HPV types in the lesions. CONCLUSIONS: A high number of anogenital malignancies developed in our cohort, which are nearly all caused by HPV. Multifocal lesions within one patient frequently contained different high-risk HPV genotypes in both lesions. Our results underline the importance of anogenital screening and monitoring before and periodically after renal transplantation to prevent morbidity and mortality from anogenital malignancies.

(Pre)malignancies of the female anogenital tract in renal transplant recipients.

This mini review describes human papillomavirus-related (pre)malignancies of the lower anogenital tract, for which female renal transplant recipients (RTRs) have a markedly increased risk. Until now, the implementation of intensified cervical cancer screening in RTRs is disappointing. We emphasize the need for improvement of cervical screening programs, combined with close inspection of the vulva and perianal area for potential lethal malignancies in RTRs.

Genital psoriasis: A systematic literature review on this hidden skin disease.

It is well known that the genital skin may be affected by psoriasis. However, little is known about the prevalence and clinical appearance of genital psoriasis, and genital skin is often neglected in the treatment of psoriatic patients. We performed an extensive systematic literature search for evidence-based data on genital psoriasis with respect to epidemiology, aetiology, clinical and histopathological presentation, diagnosis and treatment. Three bibliographical databases (PubMed, EMBASE and the Cochrane Library) were used as data sources. Fifty-nine articles on genital psoriasis were included. The results show that psoriasis frequently affects the genital skin, but that evidence-based data with respect to the efficacy and safety of treatments for genital psoriasis are extremely limited. An advised treatment paradigm for genital psoriasis, based on the levels of evidence, is: first-line: (weak) topical corticosteroids; second-line: vitamin D preparations or tar-based treatments.

The effect of vulvar lichen sclerosus on quality of life and sexual functioning.

Lichen sclerosus (LS) is a chronic skin disorder mostly seen on the female anogenital skin. The aim of this study was to evaluate the quality of life (QoL) and sexuality in female patients with LS and to compare their scores with healthy controls. In addition, we wanted to find factors associated with impaired sexual functioning in patients with LS. Members of the Dutch LS foundation and support group were asked to fill in three questionnaires: the Dermatology Quality of Life Index, Female Sexual Function Index (FSFI) and Female Sexual Distress Scale (FSDS). 215 of 368 patients returned their questionnaire (58.4%). Their scores were compared to a control group which consisted of 61 women of similar age (p = 0.472) without a skin disorder. Of all domains of QoL, LS interfered most with sexual functioning. Patients significantly scored lower on all subscales of the FSFI (desire (p = 0.016), arousal (p < 0.001), lubrication (p < 0.001), orgasm (p < 0.001), satisfaction (p < 0.001) and pain (p < 0.001), indicating worse sexual functioning. These problems with sexual functioning brought about significant sexual distress (p < 0.001). Patients who experienced more influence on their QoL had more sexual difficulties, leading to more sexual distress independent of their age.

Skin cancer and (pre)malignancies of the female genital tract in renal transplant recipients.

SUMMARY: Immunosuppressive therapy in renal transplant recipients (RTRs) is associated with an increased risk for the development of (pre)malignancies involving the skin and the female lower genital tract. We assessed whether yearly cervical screening was performed and evaluated the development of skin cancer and gynaecological (pre)malignancies in RTRs. Female RTRs (n = 224), transplanted between 1991 and 1995, were analysed retrospectively. Sociodemographic patient characteristics, frequency and results of cervical smears and prevalence of cutaneous, cervical, vaginal or vulvar (pre)malignancies were investigated and compared with that in the general population. A mean of 0.2 cervical smears per patient per year was found to have been performed in RTRs, which is significantly less than the recommended screening ratio of 1.0 for female RTRs (P < 0.001). The risk for RTRs to develop malignancies of the female lower genital tract was increased: twofold to sixfold for cervical intraepithelial neoplasia, threefold for cervical carcinoma and 50-fold for vulvar carcinoma. Cervical screening is not performed in accordance with the advised yearly intervals, and the risk for RTRs to develop vulvar and cervical (pre)malignancies is increased. More attention should be paid to the vulvar and cervical surveillance of RTRs by both medical specialists and general physicians.