Treatment of extramammary Paget's disease with imiquimod in a real-life setting: a multicenter retrospective analysis in Spain.

BACKGROUND: Topical imiquimod has shown to be an effective treatment for EMPD, although available evidence supporting its use is based on case reports and small series of patients. OBJECTIVES: To investigate the therapeutic outcomes and analyze potential clinico-pathological factors associated with imiquimod response in a large cohort of EMPD patients. METHODS: Retrospective chart review of 125 EMPD patients treated with imiquimod at 20 Spanish tertiary-care hospitals. RESULTS: During the study period, patients received 134 treatment regimens with imiquimod, with 70 (52.2%) cases achieving complete response (CR), 41 (30.6%) partial response and 23 (17.2%) no response. The cumulative CR rates at 24 and 48 weeks of treatment were 46.3% and 71.8%, respectively, without significant differences between first-time and previously treated EMPD. Larger lesions (≥6 cm; p = 0.038) and EMPD affecting >1 anatomical site (p = 0.002) were significantly associated with a worse treatment response. However, the CR rate did not differ significantly by the number of treatment applications (≤4 vs. > 4 times/week; p = 0.112). Among patients who achieved CR, 30 (42.9%) developed local recurrences during a mean follow-up period of 36 months, with an estimated 3 and 5-year recurrence free-survival of 55.7% and 36.4%, respectively. CONCLUSIONS: Imiquimod appears as an effective therapeutic alternative for both first-line and previously treated EMPD lesions. However, a less favorable therapeutic response could be expected in larger lesions and those affecting >1 anatomical site. Based on our results, a 3-4 times weekly regimen of imiquimod with a treatment duration of at least 6 months could be considered an appropriate therapeutic strategy for EMPD patients.

Therapeutic outcomes and survival analysis of Extramammary Paget's disease: A multicentre retrospective study of 249 patients.

BACKGROUND: Evidence regarding long-term therapeutic outcomes and disease-specific survival (DSS) in Extramammary Paget's disease (EMPD) is limited. OBJECTIVES: To assess the DSS and outcomes of surgical and nonsurgical therapeutic modalities in a large cohort of EMPD patients. METHODS: Retrospective chart review of EMPD patients from 20 Spanish tertiary care hospitals. RESULTS: Data on 249 patients with a median follow-up of 60 months were analyzed. The estimated 5-, 10-, and 15-year DSS was 95.9%, 92.9%, and 88.5%, respectively. A significantly lower DSS was observed in patients showing deep dermal invasion (≥1 mm) or metastatic disease (P < .05). A ≥50% reduction in EMPD lesion size was achieved in 100% and 75.3% of patients treated with surgery and topical therapies, respectively. Tumor-free resection margins were obtained in 42.4% of the patients after wide local excision (WLE). The 5-year recurrence-free survival after Mohs micrographic surgery (MMS), WLE with tumor-free margins, WLE with positive margins, radiotherapy, and topical treatments was 63.0%, 51.4%, 20.4%, 30.1%, and 20.8%, respectively. LIMITATIONS: Retrospective design. CONCLUSIONS: EMPD is usually a chronic condition with favorable prognosis. MMS represents the therapeutic alternative with the greatest efficacy for the disease. Recurrence rates in patients with positive margins after WLE are similar to the ones observed in patients treated with topical agents.

Real-World Experience with Vismodegib on Advanced and Multiple BCCs: Data from the RELIVIS Study.

BACKGROUND: Vismodegib is approved for advanced cases of basal cell carcinomas not amenable to surgery or radiotherapy. Large studies on the use of vismodegib in clinical practice are scarce. OBJECTIVES: The main objective of the study was to analyse the evolution and therapeutic management of relapses and lack of response in patients who had received vismodegib for locally advanced and/or multiple basal cell carcinomas in a real-life multicentre setting. METHODS: This nationwide retrospective study collected data on patients treated with vismodegib in 15 specialized centres. We included patients who first received vismodegib until intolerable toxicity, maximum response, or progressive disease. Exploratory research variables referred to patient and tumour characteristics, vismodegib effectiveness and safety, relapse rate and management, and mortality. A multivariable logistic regression model was used to identify predictors of complete clinical response. RESULTS: 133 patients with advanced BCC were included in the registry. The objective response rate (ORR) was 77.5% and nearly half of the patients (45.9%) achieved complete remission. Long-term information and detailed information of subsequent treatments after a regime of vismodegib was available for 115 patients. Only 34% of the patients in this group were subsequently treated with other therapies or vismodegib rechallenge. Sixty-nine percent of the patients who had shown a complete remission with vismodegib remained free of recurrence while 30.7% relapsed. Almost half of the patients who received additional therapies after the first course of vismodegib achieved complete tumour remission. Three and 2 out of 9 patients who were rechallenged with vismodegib achieved complete and partial responses, respectively, with an ORR of 55.5%. CONCLUSION: Our study confirms efficacy of vismodegib in routine clinical practice. The risk of recurrence after achieving complete response with vismodegib was lower than previous reports. Rechallenge with vismodegib is feasible and most patients responded to re-treatment.

Prognostic factors for satellitosis or in-transit metastasis in cutaneous squamous cell carcinoma: A multicentric cohort study.

BACKGROUND: Satellitosis or in-transit metastasis (S-ITM) has clinical outcomes comparable to node-positivity in cutaneous squamous cell carcinoma (cSCC). There is a need to stratify the risk groups. OBJECTIVE: To determine which prognostic factors of S-ITM confer an increased risk of relapse and cSCC-specific-death. METHODS: A retrospective, multicenter cohort study. Patients with cSCC developing S-ITM were included. Multivariate competing risk analysis evaluated which factors were associated with relapse and specific death. RESULTS: Of a total of 111 patients with cSCC and S-ITM, 86 patients were included for analysis. An S-ITM size of ≥20 mm, >5 S-ITM lesions, and a primary tumor deep invasion was associated with an increased cumulative incidence of relapse (subhazard ratio [SHR]: 2.89 [95% CI, 1.44-5.83; P = .003], 2.32 [95% CI, 1.13-4.77; P = .021], and 2.863 [95% CI, 1.25-6.55; P = .013]), respectively. Several >5 S-ITM lesions were also associated with an increased probability of specific death (SHR: 3.48 [95% CI, 1.18-10.2; P = .023]). LIMITATIONS: Retrospective study and heterogeneity of treatments. CONCLUSION: The size and the number of S-ITM lesions confer an increased risk of relapse and the number of S-ITM an increased risk of specific-death in patients with cSCC presenting with S-ITM. These results provide new prognostic information and can be considered in the staging guidelines.

Loss of dyskerin facilitates the acquisition of metastatic traits by altering the mevalonate pathway.

The initial dissemination of cancer cells from many primary tumors implies intravasation to lymphatic nodes or blood vessels. To investigate the mechanisms involved, we analyzed the expression of small non-coding RNAs in cutaneous squamous cell carcinoma (cSCC), a prevalent tumor that mainly spreads to lymph nodes. We report the reduced expression of small nucleolar RNAs in primary cSCCs that metastasized when compared to non-metastasizing cSCCs, and the progressive loss of DKC1 (dyskerin, which stabilizes the small nucleolar RNAs) along the metastasis. DKC1 depletion in cSCC cells triggered lipid metabolism by altering the mevalonate pathway and the acquisition of metastatic traits. Treatment of DKC1-depleted cells with simvastatin, an inhibitor of the mevalonate pathway, blocked the expression of proteins involved in the epithelial-to-mesenchymal transition. Consistently, the expression of the enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 1 was associated with pathological features of high metastatic risk in cSCC patients. Our data underpin the relevance of the mevalonate metabolism in metastatic dissemination and pave the possible incorporation of therapeutic approaches among the antineoplastic drugs used in routine patient care.

Unilateral ulcerations on the forehead and scalp.

We describe a patient with unilateral ulcerations on the forehead and scalp, occurring 3 months after herpes zoster infection. Further investigations were unremarkable. Histology showed epidermal and upper dermal ulceration associated with a mild nonspecific dermal inflammatory infiltrate composed of lymphoid cells and histiocytes.

IgE and high-affinity IgE receptor in chronic inducible urticaria, pathogenic, and management relevance.

BACKGROUND: IgE and high-affinity IgE receptor (FcεRI) expression on basophils have been scarcely explored in patients with chronic inducible urticaria (CIndU). OBJECTIVES: To investigate baseline serum IgE and FcεRI expression on blood basophils in a large cohort of CIndU patients and its relationship to treatment response. METHODS: Baseline total serum IgE and basophil FcεRI expression measured by flow cytometry in 165 patients with CIndU was studied. The relationship of both parameters with the response to antihistamine and anti-IgE (omalizumab) treatment was considered in a subsample of CIndU patients. FcεRI expression in basophils was assessed by mean fluorescence intensity (MFI) and basophil FcεRI standardized density (receptors/cell). RESULTS: The median FcεRI expression standardized per density in blood basophils was found significantly higher in patients with CIndU compared to HCs. A positive correlation was found between IgE serum levels and basophil FcεRI expression. Basal FcεRI expression was not related to antihistamine treatment response. However, it was related to omalizumab, and patients responding to omalizumab showed higher basal basophil expression of FcεRI levels. Non-responders to the antihistamine showed significantly higher IgE serum levels. CONCLUSIONS: FcεRI receptor overexpression in patients with CIndU shows almost the same pattern than chronic spontaneous urticaria. It seems to be independent of CIndU subtypes. Although additional studies would be welcome, our work highlights the relevance of FcεRI receptor regulation in CIndU supporting autoimmune basophil and mast cell activation and may be a biomarker for response to anti-IgE therapy.

Generalized Necrobiotic Palisading Granulomatous Follicular Eruption: A Peculiar Pustular Variant of Perforating Granuloma Annulare or an Individualized Disease?

Herein, we report a case of an adult male patient with a chronic and recurrent papulopustular eruption mainly involving the trunk and lower extremities. A dense superficial perifollicular inflammatory infiltrate with palisading necrobiotic granuloma formation and infundibular perforation was observed at the histological examination, with no granulomatous inflammatory infiltrates in deeper areas. The possibility that this peculiar clinicopathological presentation constitutes a case of generalized perforating granuloma annulare (PGA) or an individualized skin condition is discussed. The observation of a pustular follicular generalized PGA represents an exceedingly rare phenomenon and constitutes an infrequent subtype of PGA that can mimic pustular eruptions secondary to many different etiologies. The clinicopathological features of this rare variant may represent a diagnostic challenge, often requiring multiple biopsies to establish a definite diagnosis.

Acquired Cold Urticaria vs. Autoinflammatory Diseases, Genetic and Clinical Profile and Differential Diagnosis: Study of a Cohort of Patients in a Tertiary Reference Centre.

Acquired cold urticaria (ACU) is characterized by the development of itchy wheals after cold exposure. Generalized urticarial skin rashes triggered by cold exposure characterize certain monogenic autoinflammatory diseases (AIDs). The objective of this study is to investigate the presence of variants in genes causing AIDs that present with cold-induced urticarial skin rashes in patients clinically diagnosed with ACU, in order to look for susceptibility factors for the disease. Fifty patients with primary ACU were studied. Germline and post-zygotic variants on the NLRP3, NLRP12, NLRC4 and PLCG2 genes were investigated using next-generation sequencing technology. Seven patients (14%) carried 8 heterozygous germline variants in the following genes: NLRP3 (n = 1), NLRP12 (n = 3), NLRC4 (n = 1), PLCG2 (n = 3). No pathogenic or likely pathogenic variants were detected, and deep analyses of the sequences obtained did not identify any post-zygotic variant. In conclusion, ACU is not related to post-zygotic or germline pathogenic variants in the NLRP3, NLRP12, NLRC4 and PLCG2 genes.

Relevance of the Basophil High-Affinity IgE Receptor in Chronic Urticaria: Clinical Experience from a Tertiary Care Institution.

BACKGROUND: The high-affinity IgE receptor (FcεRI) expression on effector cells has been poorly characterized in patients with chronic urticaria (CU) to date. OBJECTIVES: To investigate the FcεRI expression on blood basophils in a large cohort of patients with CU and its potential relationship with relevant features of the disease. METHODS: Basophil FcεRI expression was measured by flow cytometry in 287 patients with CU (192 with chronic spontaneous urticaria and 95 with chronic inducible urticaria) at their initial evaluation in our department. A control group of healthy nonatopic individuals was included to provide reference data, and the effect of antihistamine and anti-IgE therapy on the basophil FcεRI expression was also evaluated in a cohort of patients with CU. RESULTS: The median FcεRI expression was found significantly higher in patients with CU compared with healthy controls (P < .0001). A positive correlation was found between serum IgE levels and basophil FcεRI expression (R = 0.422; P < .001). Significantly higher FcεRI levels on basophils were detected in patients with CU who presented with concomitant atopic features (P = .003), negative autologous serum skin test (P = .002), negative autologous plasma skin test (P = .009), or undetected levels of antithyroid antibodies (P = 0.01). Baseline FcεRI expression was not related to the activity and duration of the disease, and was not significantly modified during antihistamine therapy; however, it correlated with the clinical response to omalizumab (P = .003). CONCLUSIONS: Although further multicenter studies are needed to corroborate these findings, the assessment of basophil FcεRI levels might be relevant in daily clinical practice supporting an autoimmune pathogenesis and predicting response to anti-IgE treatment.

Self-healing Cutaneous Mucinosis in Adulthood: The Adult Counterpart of the Juvenile Variant of the Disease?

Self-healing cutaneous mucinosis (SHCM) is an idiopathic localized cutaneous mucinosis mainly described in children and characterized clinically by an acute onset of papules and nodules that exhibit a spontaneous resolution in a period ranging from weeks to few months. Histologically, a diffuse mucin deposition in the dermis and/or hypodermis associated with a proliferation of spindle-shaped cells and some large epithelioid gangliocyte-like mononuclear cells is usually observed. An uncommon adult variant of SHCM has also been reported; however, the clinicopathological features described in these patients are extremely heterogeneous and differ significantly from the juvenile variant of the disease, often showing exclusively dermal involvement. We report a case of a 37-year-old female patient with multiple asymptomatic nodules located on the legs and arms that resolved spontaneously in a period of 2 years, showing the typical subcutaneous features of the juvenile variant of SHCM at the histological examination (ie, mucinous areas associated with dense bands of fibrosis containing arborizing thin-walled vessels, spindle-shaped fibroblasts, and some gangliocyte-like cells). To the best of our knowledge, this is the first report of SHCM showing the classic pattern of deep-seated subcutaneous involvement of the disease in an adult patient. We also review the cases of adult-onset SHCM reported in the literature.

Treatment of patients with plaque psoriasis with secukinumab in a real-life setting: a 52-week, multicenter, retrospective study in Spain.

Background: The efficacy and safety of secukinumab in patients with plaque psoriasis (PsO) have been demonstrated in randomized clinical trials (RCTs). However, data regarding its efficacy and safety in real-life settings are scarce. Objectives: To evaluate the efficacy and safety of secukinumab in clinical practice in patients with PsO attending 10 dermatology centers in Spain. Methods: Data from 136 patients consecutively treated with secukinumab for at least 52 weeks were collected in a retrospective observational study. Results: After 52 weeks of treatment, 69% and 46% of patients achieved a PASI-75, PASI-90, respectively. PASI-score ≤5 was achieved in 83% of patients, PASI-score ≤3 in 73% and PASI-score ≤1 in 47%. Response rates were found significantly lower in patients with obesity and non-naïve to biologics (p < .05). The most common adverse event (AE) was candidiasis (5/136). Thirty-six patients (26.5%) discontinued treatment by week 52 due to lack or loss of response (n = 29), AEs (n = 2) or other causes (n = 5). Conclusion: These findings complement the efficacy and safety profiles of secukinumab in PsO outlined in RCTs. The effectiveness in clinical practice may be lower in patients with a BMI ≥30 and those previously treated with other biologic agents.

Ultrasound Assessment of Psoriatic Onychopathy: A Cross-sectional Study Comparing Psoriatic Onychopathy with Onychomycosis.

This cross-sectional study evaluated the usefulness of an ultrasound technique in assessment of nail changes in 35 patients with psoriatic onychopathy and 25 with nail dystrophy secondary to onychomycosis. All patients underwent 3 examinations: a complete clinical assessment; a nail ultrasound study; and fungal culture. Nails of patients with psoriatic onychopathy presented a thinner nail plate and nail bed, measured by ultrasound, than did those with onychomycosis. The percentage of patients with a power Doppler signal ?2 at nail bed was significantly higher in psoriatic onychopathy than in onychomycosis, and structural bone lesions were more frequent in psoriatic onychopathy than in onychomycosis. These results suggest that the presence of structural damage and high-power Doppler signal are the main ultrasound findings supporting a diagnosis of psoriatic onychopathy.

Long-term etanercept survival in patients with psoriatic arthritis: a multicenter retrospective analysis in daily clinical practice in Spain.

Although several randomized clinical trials and observational studies have evaluated the effectiveness, safety and drug survival of etanercept (ETN) in the treatment of psoriatic arthritis (PsA), long-term data regarding these aspects are currently scarce. For this reason, we sought to investigate the long-term survival and safety of ETN in PsA patients in 4 tertiary care Spanish hospitals over a 13-year observation period (from 2004 to 2017). The records of 85 PsA patients were reviewed. ETN showed an excellent survival profile, with rates of treatment discontinuation at 1, 3, 5 and 10 years of 15, 37, 46 and 59%, respectively. In our cohort, a trend toward longer drug survival in patients with shorter disease duration and those who were treated with ETN as their first biologic agent was observed. On the other hand, combination therapy with conventional disease-modifying antirheumatic drugs did not provide greater improvement on the long-term drug survival. Only 12% of the patients reported adverse events (AEs) during therapy, being most of them of mild to moderate intensity, and in only 7% AEs led to drug discontinuation. To the best of our knowledge, the present study shows the largest follow-up period of ETN-treated population analyzed in a real-life setting, and these results demonstrate the positive safety profile and long-term effectiveness of this biologic agent in the management of PsA patients.

Omalizumab Updosing for Better Disease Control in Chronic Spontaneous Urticaria Patients.

The recommended dose of omalizumab for the treatment of chronic spontaneous urticaria (CSU) is 300 mg every 4 weeks, but there is no recommendation for patients who do not benefit from this dose. Our aim is to present the experiences on the use of doses of omalizumab higher than those recommended for CSU patients and to propose a protocol for updosing. This was a retrospective analysis of patients treated with omalizumab for CSU from 2 urticaria centers in Istanbul and Barcelona. The weekly urticaria activity score and/or the Urticaria Control Test (UCT) were used to monitor response. In Barcelona, a stepwise updosing regimen was preferred (450 mg first, then increasing to 600 mg), while in Istanbul, direct updosing to 600 mg was chosen. In Istanbul, 81 (88%) patients were treated with 300 mg, while 11 (12%) received 600 mg of omalizumab. In Barcelona, 7 (8.8%), 45 (56.3%), 17 (21.3%), and 11 (13.8%) patients received 150, 300, 450, and 600 mg of omalizumab, respectively. Urticaria control was achieved in 82.6% of the patients with 300 mg and in 8.7% of the patients with 600 mg in Istanbul, while it was achieved with 150 mg in 10%, with 300 mg in 48.8%, with 450 mg in 16.3%, and with 600 mg in 6.3% of the patients in Barcelona. In total, 123 (71.5%) patients responded to 150-300 mg and 26 (15.1%) to 450-600 mg. When responders to 150-300 mg (n = 123) were compared with responders to 450-600 mg (n = 26), BMI was found to be higher, and pre-omalizumab UCT was found to be lower in patients receiving updosed omalizumab (p = 0.029). Baseline data of the patients, especially BMI and pre-oma UCT, might be useful to determine if the patient will require higher doses of omalizumab. We recommend a stepwise approach starting from 450 mg and then updosing to 600 mg in CSU patients who do not respond or partially respond to 300 mg of omalizumab after 3-6 months of treatment.

CLA+ T Cell Response to Microbes in Psoriasis.

Streptococcus pyogenes throat infection is a clinically relevant trigger of both guttate and chronic plaque psoriasis, and it provides an ideal context in which to study the pathogenesis of these diseases using an antigen-dependent approach. Circulating cutaneous lymphocyte-associated antigen (CLA) positive (+) memory T cells are a subset of peripheral lymphocytes whose phenotype and function are related to immunological mechanisms in the skin. These cells are considered peripheral biomarkers of T-cell-mediated skin diseases. The coculture of autologous epidermal cells with CLA+ T cells from psoriasis patients activated by S. pyogenes allows the reproduction of the ex vivo initial molecular events that occur during psoriatic lesion formation. With cooperation of autologous epidermal cells, S. pyogenes selectively activates CLA+ T cells both in guttate and plaque psoriasis, inducing key mediators, including an IL-17 response. Here, we explore potential new mechanisms of psoriasis development including the influence of HLA-Cw6 on S. pyogenes CLA+ T cell activation in guttate psoriasis, the relevance of IL-9 on microbe induced IL-17 response in guttate and plaque psoriasis, and novel effector functions of Candida albicans. This review will summarize recent knowledge of psoriatic mechanisms elicited by microbes that have been studied through an innovative translational perspective based on CLA+ T cell-mediated cutaneous immune response.