Longitudinal Study of Different Progression Patterns in High-Risk Cutaneous Squamous Cell Carcinoma. / Estudio longitudinal de los diferentes patrones de progresión en el carcinoma cutáneo de células escamosas de alto riesgo.

BACKGROUND AND OBJECTIVE: Cutaneous squamous cell carcinoma (cSCC) is the second leading cause of skin cancer mortality in Europe. Few studies have analyzed the different pathways of this tumor progression in its natural history. The main objective of this study was to analyze the different metastatic and progression pathways and their temporal occurrence in the evolution of cSCC. MATERIAL AND METHOD: We conducted a multicenter, retrospective, and observational study of consecutive high-risk sSCCs included in the SQUAMATA project. RESULTS: A total of 222 out of the 1346 patients included relapsed. The most frequent route of progression was the lymphatic one (62.6%). A total of 20.2% of the cases with lymphatic progression developed distant metastases. Only 1 case (3.1%) of distant metastasis followed local recurrence without previous lymphatic metastasis. The median time to disease-related mortality was longer in patients who developed systemic metastases than in those who died of locoregional progression. CONCLUSIONS: The mortality of patients with cSCC is mostly due to the regional progression of their lymphatic metastases. The appearance of distant metastases is practically always (96.9%) associated with previous lymphatic metastatic progression. Therefore, in the future, new studies will be needed to assess the regional management of cSCC in both surgical and adjuvant therapies.

Clinicopathological definition, management and prognostic value of mogamulizumab-associated rash and other cutaneous events: A systematic review.

Mogamulizumab is a first-in-class IgG1k monoclonal antibody that selectively targets the chemokine receptor type 4. The drug has received Food and Drug administration authorisation for mycosis fungoides and Sézary syndrome following failure of at least one previous course of systemic therapy and now is available in Europe. One of the most common treatment-related side effects observed has been the mogamulizumab-associated rash (MAR), which affects up to a quarter of patients and is the most frequent adverse event leading to drug discontinuation. The aim of this study is to perform a systematic review of the literature on patients diagnosed with MAR and other mogamulizumab-related cutaneous events to describe the clinical and histological characteristics, the management in clinical practice and to assess whether these events have prognostic implications. In total, 2073 records were initially identified through a literature search, 843 of which were duplicates. After screening for eligibility and inclusion criteria, 49 articles reporting mogamulizumab-associated cutaneous events were included. Totally, 1516 patients were retrieved, with a slight male prevalence as for the available data (639 males and 570 females, i.e. 52.9% vs. 47.1%). Regarding the reported clinicopathological findings of the cutaneous reactions, the five most common patterns were spongiotic/psoriasiform dermatitis (22%), eruptions characterized by the presence of papules and/or plaques (16.1%), cutaneous granulomatosis (11.4%), morbilliform or erythrodermic dermatitis (9.4%) and photodermatitis (7.1%). Our results highlight how the majority of the reported cutaneous adverse events on mogamulizumab are of mild-to-moderate entity and generally manageable in clinical practice, though prompt recognition is essential and case-by-case assessment should be recommended. Future research will need to focus on the MAR prognostic implications and to identify genomic and molecular markers for a more rapid and accurate diagnosis.

Drug survival, effectiveness and safety of ixekizumab for moderate-to-severe psoriasis up to 5 years.

INTRODUCTION: Ixekizumab proved to be effective and safe for psoriasis treatment in several randomized clinical trials and real-life studies. Nevertheless, long-term real-world experiences are still lacking, with little data up to 4 years of treatment. OBJECTIVES: To analyse survival, effectiveness and safety of ixekizumab in a real-life cohort of patients affected by moderate-to-severe psoriasis or psoriatic arthritis up to 260 weeks (5 years). METHODS: We included all patients treated with ixekizumab from December 2017 to March 2021. Drug survival (DS) was analysed in patients at risk for up to 5 years. Cox analysis was adopted to evaluate possible predictive factors of discontinuation. Psoriasis Area Severity Index (meanPASI and PASI100, 90, and ≤3) was used as outcomes of effectiveness on observed patients at 16, 52, 104, 156, 208 and 260 weeks. Logistic regression was performed to identify possible predictive factors of response. RESULTS: DS was 65.5% at 260 weeks, with being a super-responder patient (achievement of PASI100 at 16 weeks and maintained at 28 weeks) correlated with less risk of discontinuation. PASI100, 90 and ≤3 was achieved by 54.1%, 60.5% and 73% of observed patients, respectively, at 16 weeks, and by 59.1%, 81.8% and 95.5%, respectively, at 260 weeks. High mean BMI was the only factor strongly associated with less achievement of the outcomes at the earlier time points: PASI100 at 16 weeks (OR 0.93, CI 0.87-0.98, p = 0.014) and at 104 weeks (OR 0.91, CI 0.84-0.98, p = 0.019), PASI90 achievement at 16 weeks (OR 0.94, CI 0.88-0.99, p = 0.028) and 104 weeks (OR 0.91, CI 0.83-0.99, p = 0.027), and PASI ≤3 (OR 0.86, CI 0.76-0.97, p = 0.018) at 104 weeks. No severe adverse events were observed. CONCLUSIONS: Ixekizumab showed high effectiveness and safety for up to 5 years, with survival of 2/3 of treated patients. Rapid response to treatment is predictive of long-term response.

Current treatment goals are achieved by the majority of patients with atopic dermatitis treated with tralokinumab: results from a multicentric, multinational, retrospective, cohort study.

BACKGROUND: Tralokinumab is a human monoclonal antibody targeting interleukin-13 that is approved for the treatment of moderate-severe atopic dermatitis. Studies analyzing the efficacy and safety of tralokinumab in a real-world setting are scarce. RESEARCH DESIGN AND METHODS: A European, multicentric, real-world, retrospective cohort study was defined to assess the effectiveness and safeness profile of tralokinumab, investigating the achievement of pre-specified treatment goals; and to detect potential differences in terms of effectiveness and safeness across some selected patient subcohorts. RESULTS: A total of 194 adult patients were included in this study. A significant improvement in physician-assessed disease severity was detected at each follow-up visit as compared with baseline and similar trend was observed for patient-reported outcomes and quality of life. No meaningful difference in effectiveness was found when considering patient age (<65 versus ≥65 years), neither dissecting patient cohort in dupilumab-naive vs dupilumab-treated subjects. Among tralokinumab-treated patients, 88% achieved at least one currently identified real-world therapeutic goal at week 16. CONCLUSIONS: This retrospective multicenter study confirmed the effectiveness and safeness of tralokinumab throughout 32 weeks of observation, showing the achievement of therapeutic goals identified in both trial and real-world settings in a large proportion of tralokinumab-treated patients.

Topical ruxolitinib: A new treatment for vitiligo.

Vitiligo is a chronic autoimmune skin disorder whose diagnosis is often psychologically upsetting. The efficacy of the available therapies, including topical corticosteroids and topical calcineurin inhibitors, has historically been limited and the management of vitiligo is still challenging. As vitiligo is a chronic disease limited to the skin, topical rather than systemic therapies may be preferable (especially among patients with localised lesions) to avoid the long-term side-effects of the latter. A topical formulation of ruxolitinib, a selective JAK1/2 inhibitor, has recently been approved in the United States for the treatment of non-segmental vitiligo in patients aged >12 years based on data from the phase III TRuE-V1 and TRuE-V2 clinical trials. The aim of this review is to describe the current evidence concerning the efficacy and safety of topical ruxolitinib in the treatment of vitiligo, and discuss issues regarding its use in younger children and pregnant or breastfeeding women, as well as the duration and durability of treatment. The promising results obtained so far suggest that 1.5% ruxolitinib cream is an effective means of treating vitiligo.

Efficacy of anti-IL-23 and anti-IL-17 after adalimumab failure in psoriatic patients.

BACKGROUND: Many national guidelines at the European level recommend first-line therapy based on the anti-TNF-alpha adalimumab for treatment of psoriasis and psoriatic arthritis, mainly for economic reasons. Consequently, patients being treated with newer IL-17 and IL-23 inhibitors underwent previous unsuccessful first-line adalimumab-based therapy. OBJECTIVES: Evaluate the efficacy and safety of IL-17 and IL-23 inhibitors after treatment with adalimumab compared to adalimumab-naive psoriatic patients. METHODS: We retrospectively analysed 1053 psoriatic patients treated with anti-IL17 and anti-IL23 agents, which included 68 and 24 adalimumab-experienced and 399 and 260 bio-naive patients. Efficacy was assessed with mean PASI, PASI90, PASI100, and <3. RESULTS: Concerning the achieving of PASI100, PASI90 and PASI < 3 in patients treated with anti-IL17 agents, no significant differences were observed between adalimumab-experienced and bio-naive patients. In patients treated with an anti-IL-23 agent, a faster response was observed in bio-naive patients, with PASI < 3 significantly higher than ADA-experienced patients at 16 weeks (77% vs. 58% p = 0.048). In a sub-analysis that evaluated the performance of anti-IL17 and anti-IL23 agents in adalimumab-experienced patients with a history of secondary failure, no significant differences were found. In multivariate analysis of PASI100, only anti-IL-17 therapy appeared to have a negative impact at 52 weeks (OR: 0.54 p = 0.04) independently of previous treatment. For PASI90, type of treatment and bio-naïve status did not seem to have an impact at any time point. CONCLUSIONS: Anti-IL 23 and anti-IL 17 agents are not significantly different in terms of efficacy in bio-naive patients or as second-line therapy after failure with a biosimilar or originator adalimumab.

Primary cutaneous lymphoma patients seen at a referral dermatological centre in 1 year: A single-centre observational retrospective cohort study of the diagnoses and staging, comorbidities and associated symptoms, treatment performed and clinical course.

IMPORTANCE: Primary cutaneous lymphomas (PCL) are rare diseases, but the indolent course makes their prevalence high. Although there are many treatment options, no hierarchy is recommended. OBJECTIVE: To identify the burden of PCL and describe clinical-pathologic features; associated comorbidities; analyse treatment approaches in real-life and the parameters associated with the achievement of complete response (CR). DESIGN, SETTING AND PARTICIPANTS: In this study, all the PCL patients (384 patients) consecutively seen at the Dermatologic Clinic of the University of Turin from January 1, 2019 to December 31, 2019, with follow-up updated to December 2020, were included. MAIN OUTCOMES AND MEASURES: Subtype of PCL, demographic data, time elapsed between first lesions and diagnosis, associated symptoms, comorbidities, staging at diagnosis, high-grade transformation, blood involvement, stage progression, therapies used and response were assessed. RESULTS: 247 were cutaneous T-cell lymphomas (CTCL, 64.3%), 137 cutaneous B-cell lymphomas (CBCL, 35.7%) and the most frequent subtype was MF (48.4%). 62.3% of CTCL patients showed at least one comorbidity, mainly cardiovascular (28.7%), 20.2% show other not cutaneous neoplasms. The main approaches were skin-directed therapies (topical steroids 65.6%; phototherapy 50.2%). 39.3% patients achieved a CR during the disease course. Pruritus, the presence of comorbidities and high-grade transformation were factors associated with failure to achieve CR, whereas stage IA of MF was associated with greater achievement of CR. CONCLUSIONS AND RELEVANCE: The Th2 cytokine related development of pruritus could justify increased resistance to treatment, while the presence of associated comorbidities could reduce treatment options as well as treatment compliance.

Use of Dupilumab in 543 Adult Patients With Moderate-to-Severe Atopic Dermatitis: A Multicenter, Retrospective Study.

BACKGROUND: Dupilumab has proven to be an effective treatment for patients with moderate-to-severe atopic dermatitis (AD) in clinical trials. However, real-world experience with dupilumab in a broader population is limited. METHODS: The study population comprised adult patients with moderate-to-severe AD, defined as an Eczema Area Severity Index (EASI) score of 24 or higher, treated with dupilumab at 10 Italian teaching hospitals. We analyzed physician-reported outcome measures (EASI), patient-reported outcome measures (pruritus and sleep score, Dermatology Life Quality Index [DLQI]), and serological markers (IgE and eosinophil count) after 16 weeks. RESULTS: We enrolled 543 patients with moderate-to-severe AD. Two patients (0.4%) discontinued treatment. The median (IQR) change from baseline to 16 weeks of treatment in the EASI score was -87.5 (22.0) (P<.001). The EASI-50, EASI-75, and EASI-90 response rates were 98.1%, 81.5%, and 50.8% after 16 weeks. At 16 weeks, 93.0% of the patients had achieved a 4-point or higher improvement in DLQI from baseline. During treatment with dupilumab, 12.2% of the patients developed conjunctivitis, and total IgE decreased significantly (P<.001). Interestingly, in the multivariate logistic regression model, the risk of developing dupilumab-related conjunctivitis was associated with early onset of AD (OR, 2.25; 95%CI, 1.07-4.70; P=.03) and presence of eosinophilia (OR, 1.91; 95%CI, 1.05-3.39; P=.03). CONCLUSION: This is the broadest real-life study in AD patients treated with dupilumab to date. We observed more significant improvements induced by dupilumab in adult patients with moderate-to-severe AD than those reported in clinical trials.

Digital dermoscopy monitoring of melanocytic lesions: Two novel calculators combining static and dynamic features to identify melanoma.

BACKGROUND: Early diagnosis is the most effective intervention to improve the prognosis of cutaneous melanoma. Even though the introduction of dermoscopy has improved the diagnostic accuracy, it can still be difficult to distinguish some melanomas from benign melanocytic lesions. Digital dermoscopy monitoring can identify dynamic changes of melanocytic lesions: To date, some algorithms were proposed, but a universally accepted one is still lacking. OBJECTIVES: To identify independent predictive variables associated with the diagnosis of cutaneous melanoma and develop a multivariable dermoscopic prediction model able to discriminate benign from malignant melanocytic lesions undergoing digital dermoscopy monitoring. METHODS: We collected dermoscopic images of melanocytic lesions excised after dermoscopy monitoring and carried out static and dynamic evaluations of dermoscopic features. We built two multivariable predictive models based on logistic regression and random forest. RESULTS: We evaluated 173 lesions (65 cutaneous melanomas and 108 nevi). Forty-two melanomas were in situ, and the median thickness of invasive melanomas was 0.35 mm. The median follow-up time was 9.8 months for melanomas and 9.1 for nevi. The logistic regression and random forest models performed with AUC values of 0.87 and 0.89, respectively, were substantially higher than those of the static evaluation models (ABCD TDS score, 0.57; 7-point checklist, 0.59). Finally, we built two risk calculators, which translate the proposed models into user-friendly applications, to assist clinicians in the decision-making process. CONCLUSIONS: The present study demonstrates that the integration of dynamic and static evaluations of melanocytic lesions is a safe approach that can significantly boost the diagnostic accuracy for cutaneous melanoma. We propose two diagnostic tools that significantly increase the accuracy in discriminating melanoma from nevi during digital dermoscopy monitoring.