Alain Dupuy

Background: Merkel Cell Carcinoma (MCC) is a rare, aggressive neuroendocrine and epithelial skin cancer. Somatostatin analogues, such as lanreotide, have shown efficacy in managing other neuroendocrine tumors. Retrospective studies suggest that lanreotide may induce partial response or disease stabilization in patients with advanced MCC. To test this hypothesis, we conducted a Phase II, non‐randomized, open trial investigating lanreotide in MCC patients with advanced disease ( ClinicalTrials.gov identifier: NCT02351128). Methods: Patients with Stage IIIB‐IV MCC received lanreotide monotherapy (120 mg every 28 days) at any line of systemic therapy, until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR) (defined as the proportion of patients with complete response, partial response, and stable disease) at 3 months. Secondary endpoints included progression‐free survival (PFS), overall survival (OS), somatostatin receptor (SSTR) tumor expression, and treatment safety. Results: Between April, 2015, and November, 2016, 35 patients received lanreotide, with 12 evaluable at 3 months. The DCR at 3 months was 33.3% (4) among evaluable patients (all with stable disease) and 11.4% for the full cohort. Statistical analyses showed no significant difference from the expected 20% response rate ( p = 0.205 for intention‐to‐treat; p = 0.939 for per‐protocol). Kaplan–Meier analysis revealed median OS and PFS of 3.1 months (95% CI, 2–5.5) and 3.5 months (95% CI, 2.3–5.5), respectively. SSTR tumor expression did not correlate with treatment response. Conclusion: Although limited by its implementation before the era of immunotherapy, this non‐randomized study shows the limited effectiveness of lanreotide as monotherapy in treating patients with advanced MCC. Trial Registration: Identifier: NCT02351128

Background: Dupilumab is reimbursed in France for adult patients with moderate‐to‐severe atopic dermatitis ( AD ), in cases of failure, intolerance or contraindication to cyclosporin A (CsA). The French National Authority for Health requested collection of data on dupilumab‐treated patients' characteristics and prior systemic treatments to examine conformity with the reimbursement scope. Objectives: This study aimed to describe characteristics of adult patients initiating dupilumab for AD and their prior lines of systemic treatments with a focus on CsA. Methods: Our dual approach combined information from two databases: the SNDS database allowing access to nationwide prescriptions for dupilumab (DUPIXAM study) and data collected by a sponsor‐initiated multicentre, cross‐sectional, observational study on patients initiating dupilumab for AD (MOVE study). Results: From December 2019 to May 2021, 594 eligible patients were included in the MOVE study. In parallel, from March 2019 to December 2020, 3216 adult patients with presumed indications of moderate‐to‐severe AD were extracted from SNDS. Patients' characteristics were quite similar: median age was > 34 years old and they were gender balanced. More than 69% of MOVE patients had severe AD and 82.8% had at least one atopic comorbidities. Previous systemic treatments were used by over 62.8% of patients, of whom over 75.0% had received CsA. Among the 25.0% without previous CsA, the indirect combinatory approach made it possible to estimate an unbiased proportion of CsA contraindications in 71.0% of patients. Conclusion: This joint analysis provided a detailed view of real‐world conditions of dupilumab use in France through the completeness of data, and constitutes a proof of concept that could be extended to address other health‐related questions.

Background: There are limited data on the impact of the route of administration of methotrexate (MTX) on drug survival in psoriasis. Objective: To evaluate the impact of the initial route of administration of MTX (monotherapy) on drug survival in patients with moderate to severe skin psoriasis. Materials and Methods: A prospective cohort study based on the Psobioteq registry, included from July 2012 to January 2023, patients with plaque, erythrodermic or guttate psoriasis, naive to MTX, biologics and apremilast, who initiated MTX monotherapy. Factors associated with drug survival were identified using Kaplan–Meier curves and Cox regression analyses. Results: In total, 406 patients were included, 58.1% received MTX per os (MTX‐PO) and 41.9% subcutaneously (MTX‐SC). At MTX initiation, the median PASI score was 11, and 67.3% had DLQI ≥6. Adjusted drug survival did not statistically differ according to the route of administration ( p = 0.15). Limitations: Limited number of patients leading to a potential lack of power. Residual confounding cannot be waived due to the observational nature of the data. Conclusions: Overall MTX survival did not significantly differ according to the route of administration. However, with MTX‐SC, the hazard of discontinuation for ineffectiveness was lower and of discontinuation for intolerance was higher than with MTX‐PO.

Background: Tanning addiction is a behavioral addiction characterized by an irrepressible desire for sun or ultraviolet light exposure. It is thought to affect 10% to 25% of the population.Objectives: This study aimed to estimate the prevalence of this behavior in patients with moderate‐to‐severe psoriasis and identify associated factors.Methods: A cross‐sectional study of baseline data from patients included in the PsoBioTeq cohort between 2012 and 2022. Tanning addiction was approximated by patient‐reported excessive sun exposure (ESE), defined by the response “I try to expose myself to the sun as often as possible” to a registry question on current behavior. Factors associated with ESE including clinical characteristics, psoriasis and medical history, and previous treatments were also analyzed.Results: Among 3705 patients included in the analysis, 636 (17.2%) reported ESE. In multivariate analysis, being younger (OR 0.97, 95% CI [0.96; 0.97]) and female (OR 1.52, 95% CI [1.20; 1.93]), and having a normal weight (OR 0.57, 95% CI [0.42; 0.77]), intermediate skin phenotype (OR 1.80, 95% CI [1.36; 2.38]), and history of phototherapy (OR 1.53, 95% CI [1.19; 1.96]) were associated with a higher ESE risk, whereas previous ustekinumab treatment (OR 0.40, 95% CI [0.19; 0.84]) was associated with a lower ESE risk.Conclusions: The prevalence of ESE in patients with psoriasis was 17% and revealed demographic factors that may help to identify the patient population most risk of ESE behavior. Education about photoprotection and optimal rapid control of psoriasis may be particularly important for this population.

“Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic” (VEXAS) syndrome is caused by acquired somatic mutations in the ubiquitin-activating enzyme 1 (UBA1) gene. Sweet-syndrome-like skin disorders (and especially histiocytoid Sweet syndrome (HSS)) may be associated with VEXAS syndrome. To characterize the clinical and histopathological features of HSS in patients with VEXAS syndrome. The skin biopsies with a histological diagnosis of HSS had been collected at Rennes University Medical Center (Rennes, France) between October 2011 and January 2022. Sanger sequencing and digital PCR were used to screen skin, blood, and bone marrow samples for UBA1 variants, and thus classify patients as having VEXAS syndrome or not. We evaluated the clinical, histological, and molecular (UBA1) characteristics of patients with or without VEXAS syndrome. We compared 15 skin biopsies from seven patients found to have VEXAS syndrome and 19 skin biopsies from 15 patients without VEXAS syndrome. Persistent inflammatory syndrome, macrocytosis, anemia, and hematological malignancies were more prevalent in patients with VEXAS syndrome (86%, 86%, 100%, and 86%, respectively) than in patients without (36%, 40%, 53%, and 53%, respectively). These features sometimes appeared after the first skin manifestations, and a UBA1 mutation was found in the skin of five patients with VEXAS syndrome. Dermal infiltration by myeloperoxidase-positive, CD163-positive, reniform histiocytoid cells and a periadnexal distribution were more frequently observed in VEXAS syndrome biopsies (100% and 20% respectively, vs. 58% and 0% in non-VEXAS syndrome biopsies, respectively). Our findings might help the pathologist to consider a diagnosis of VEXAS syndrome and to initiate early genetic testing.

On the basis of safety data on patients with inflammatory rheumatism or inflammatory bowel disease, treatment with Janus kinase (JAK) inhibitors has been linked to the occurrence of major adverse cardiovascular events (MACEs). However, these inflammatory diseases are pro-atherogenic; in contrast, patients with atopic dermatitis (AD) do not usually have a high cardiovascular (CV) comorbidity burden. We systematically searched the PubMed, Embase, Cochrane Library and Google Scholar databases from their inception to September 2^nd, 2022. Cohort studies, randomized controlled trials and pooled safety analyses providing CV safety data on patients taking JAK inhibitors for AD were selected. We included patients aged 12 and over. We built a “controlled-period” cohort (9,309 patients: 6,000 exposed to JAK inhibitors and 3,309 exposed to comparators) and an “all JAK inhibitors” cohort (9,118 patients exposed to a JAK inhibitor in any of the included studies). The primary outcome was a composite of acute coronary syndrome (ACS), ischemic stroke, and CV death. The broader secondary MACE outcome encompassed ACS, stroke (whether ischemic or hemorrhagic), transient ischemic attack, and CV death. The frequency of primary and secondary MACEs was assessed in both cohorts. A fixed-effects meta-analysis using Peto’s method was used to calculate the odds ratio (OR) [95% confidence interval (CI)] for MACEs in the “controlled-period” cohort. Risk of bias evaluation was made using the Cochrane Risk of bias tool version 2. Certainty of evidence used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eight percent of the initially identified records met the selection criteria, corresponding to 23 records included in the “all JAK inhibitors” cohort”. The patients had been exposed to baricitinib, upadacitinib, abrocitinib, ivarmacitinib, placebo or dupilumab. Four primary events (3 with JAK inhibitors and 1 with placebo) and 5 secondary events (4 with JAK inhibitors and 1 with placebo) occurred among 9,309 patients in the “controlled-period” cohort (MACE frequency = 0.04 % and 0.05%, respectively). Eight primary events and 13 secondary events occurred among 9,118 patients in the “all JAK inhibitors” cohort (MACE frequency = 0.08 and 0.14 %, respectively). Odds ratio for primary MACEs in patients with AD treated with JAK inhibitors compared to placebo or dupilumab was 1.35 (95% CI 0.15-12.21; I², 12%, very low certainty of evidence). Our review highlighted rare cases of MACE among JAK inhibitors users for AD. Janus kinase inhibitors may have little to no effect on the occurrence of MACEs in patients with AD compared to comparators but the evidence is very uncertain. Real-life, long-term, population-level safety studies are needed.

Background: Little is known about phototype and the response to systemic treatment in psoriasis. Objectives: To assess the characteristics of psoriasis, the therapeutic choice and its efficacy according to phototype. Methods: We included patients from the PsoBioTeq cohort initiating a first biologic. Patients were classified according to their phototype. The evaluation included disease characteristics, choice of the initial biologic and therapeutic response at 12 months based on 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) and Dermatology Life Quality Index (DLQI) 0/1. Results: Of the 1400 patients included, 423 (30.2%), 904 (64.6%) and 73 (5.2%) were in the phototype I–II, III–IV and V–VI groups, respectively. The V–VI group had a higher initial DLQI, and more frequently initiated ustekinumab. Patients in the V–VI group maintained the initial biologic prescribed as did the other phototype groups, even though the proportion of patients reaching PASI 90 and DLQI 0/1 at 12 months was lower in this group than the other groups. Conclusions: Patient phototype seems associated with quality of life and choice of the initial biologic in psoriasis. The phototype V–VI group less frequently switched treatments than did the other groups when the response was not efficient.

Background: Proton-pump inhibitors (PPIs) are commonly used by patients with cancer, although they could reduce the absorption of oral anticancer targeted therapies. The US Food and Drug Administration states that the effect of PPIs on the efficacy of dabrafenib use by patients with metastatic melanoma is unknown. As a precautionary measure, the European Society for Medical Oncology recommends avoiding PPIs for patients receiving dabrafenib. Objectives: To determine the effect of the concomitant use of PPIs and BRAF/MEK inhibitors in patients with metastatic melanoma. Methods: Patients with advanced melanoma receiving BRAF/MEK inhibitors as first-line treatments between 2015 and 2017 in France were selected using the French National Health Insurance database. We compared time-to-treatment discontinuation (TTD) and overall survival (OS) according to concomitant PPI exposure. We balanced the baseline characteristics of patients exposed and nonexposed to PPIs using an overlap weighting method based on a propensity score. Results: The metastatic melanoma cohort comprised 1028 patients receiving BRAF/MEK inhibitors, including 361 (35.1%) patients using PPIs. PPI users had more comorbidities and a more severe metastatic disease. After having equally distributed metastatic sites and comorbidities across patients exposed and nonexposed to PPIs, concomitant PPI use was not associated with shorter TTD [weighted hazard ratio (wHR) 1.03, 95% confidence interval (CI) 0.86–1.24] or OS (wHR 1.11, 95% CI 0.88–1.39). Consistent results were observed when restricting the population to patients receiving dabrafenib, or when narrowing exposure to PPIs with stronger inhibition of cytochromes. Conclusions: In a population-based cohort of patients with advanced melanoma, the concomitant use of PPIs and BRAF/MEK inhibitors was not associated with worse outcome.