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Background: The long-term effectiveness of immune checkpoint inhibitor (ICI) rechallenge for progressive or recurrent advanced melanoma following previous disease control induced by ICI has not been thoroughly described in the literature. Patients and methods: In this retrospective multicenter national real-life study, we enrolled patients who had been rechallenged with an ICI after achieving disease control with a first course of ICI, which was subsequently interrupted. The primary objective was to evaluate tumor response, while the secondary objectives included assessing the safety profile, identifying factors associated with tumor response, and evaluating survival outcomes. Results: A total of 85 patients from 12 centers were included in the study. These patients had advanced (unresectable stage III or stage IV) melanoma that had been previously treated and controlled with a first course of ICI before undergoing rechallenge with ICI. The rechallenge treatments consisted of pembrolizumab (n = 44, 52%), nivolumab (n = 35, 41%), ipilimumab (n = 2, 2%), or ipilimumab plus nivolumab (n = 4, 5%). The best overall response rate was 54%. The best response was a complete response in 30 patients (35%), a partial response in 16 patients (19%), stable disease in 18 patients (21%) and progressive disease in 21 patients (25%). Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1–2 AEs in 14 patients (16%) and 10 grade 3–4 AEs in nine patients (11%). The median progression-free survival (PFS) was 21 months, and the median overall survival (OS) was not reached at the time of analysis. Patients who received another systemic treatment (chemotherapy, targeted therapy or clinical trial) between the two courses of ICI had a lower response to rechallenge (p = 0.035) and shorter PFS (p = 0.016). Conclusion: Rechallenging advanced melanoma patients with ICI after previous disease control induced by these inhibitors resulted in high response rates (54%) and disease control (75%). Therefore, ICI rechallenge should be considered as a relevant therapeutic option.

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Resume Introduction L’elastolyse du derme papillaire – pseudoxanthome elastique-like (PXE-PDE) est une entite rare, ressemblant cliniquement au pseudoxanthome elastique (PXE). Nous en rapportons un cas typique. Observation Une femme de 77 ans consultait pour une eruption papuleuse acquise qui evoluait depuis environ quatre ans. Son seul antecedent pathologique etait un cancer du sein en remission. L’eruption avait debute sur l’aisselle droite puis s’etait etendue sur l’hemithorax droit puis l’aisselle gauche, ainsi que sur le haut de la nuque et le pli inguinal droit. Il n’y avait pas de signe fonctionnel associe. Les papules etaient non folliculaires, molles, couleur chair, sans anetodermie. L’examen histologique en coloration hematoxyline-eosine et a l’orceine mettait en evidence une elastolyse du derme papillaire et moyen, sans elastorrhexie. Devant cet aspect clinique de PXE mais avec une elastolyse histologique, le diagnostic de PXE-PDE etait pose. Discussion Le PXE-PDE est une maladie rare, acquise, qui affecte exclusivement la femme, habituellement apres 60 ans. Bien que cliniquement proche du PXE, le PXE-PDE s’en differencie par son âge d’apparition tardif, l’absence d’atteinte systemique et son aspect histologique. L’examen dermoscopique peut egalement contribuer au diagnostic differentiel. L’anatomopathologie fait le diagnostic de certitude en montrant des fibres elastiques normales mais rarefiees, voire totalement absentes, dans le derme papillaire et moyen. La physiopathologie reste imprecise ; elle impliquerait le vieillissement cutane, des anomalies de l’elastogenese et l’exposition aux UV. Aucun traitement n’a montre d’efficacite. Conclusion Le PXE-PDE est une pathologie rare, d’aspect anatomoclinique stereotype. La connaissance de cette entite permet d’eviter les explorations complementaires inutiles et de rassurer rapidement le patient.

Summary Introduction Incontinentia pigmenti (IP) is an X-linked genodermatosis caused by mutation of the NEMO/IKBKG gene. While lethal in male foetuses, heterozygous females survive because of X-inactivation mosaicism. Herein we discuss 9 male patients with IP. Materials and methods This is an observational, descriptive, retrospective, multicentre, French study carried out with the help of the SFDP research group. Statistical analysis was performed both on our own patients and on those reported in the literature. Results Nine boys with no family history of IP but with typical neonatal skin reactions were included. Genetic analysis of blood (n = 8) and skin biopsy (n = 3) confirmed the diagnosis of IP by identification of common deletion of the IKBKG/NEMO gene (exons 4 to 10) in the state of somatic mosaic in 6 and 2 cases respectively. Where analysed, the karyotype was normal (n = 6). Over a median follow-up period of 48 months (3 months to 10 years), 3 patients had neurological abnormalities, 2 had severe ophthalmologic abnormalities, and 1 had dental abnormalities. Extensive skin involvement is a systemic risk factor, unlike cutaneous scarring. Conclusion IP in boys is often due to a mosaic mutation that should be sought in blood and skin. Long-term neurological and ophthalmological monitoring is essential, especially in cases of extensive skin involvement.

CD4 T cells play a key role in anticancer immunity. In this study, we investigate the clinical relevance of circulating CD4 T helper type 1 (Th1) response against telomerase (anti-TERT Th1 response) in patients with melanoma. The spontaneous anti-TERT Th1 response was detected in 54.5% (85/156) of patients with melanoma before treatment. The prevalence of this systemic response was inversely related to Breslow thickness >1 mm and American Joint Committee on Cancer stage ≥II (P = 0.001 and 0.032, respectively). In contrast to patients treated with targeted therapies, the anti-TERT Th1 immunity was associated with an objective response after immune checkpoint inhibitors treatment. Hence, 86% (18/21) of responder patients exhibited pre-existing anti-TERT Th1 versus 35% (6/19) in nonresponders (P = 0.001). This response was also associated with increased progression-free survival and overall survival in patients with melanoma treated with immune checkpoint inhibitors (P = 0.0008 and 0.012, respectively). Collectively, the presence of circulating anti-TERT Th1 response is inversely related to melanoma evolution and appears to be a predictive factor of response to immunotherapy. Our results highlight the interest in telomerase-specific CD4 Th1 response as a promising blood-based biomarker of immune checkpoint inhibitors therapy in melanoma.

Angiosarcoma (AS) is a rare aggressive sarcoma with differentiation toward blood or lymphatic endothelium. There are few epidemiological data available on AS. To address this limitation, we investigated the epidemiological and clinical features of angiosarcoma diagnosed in a French administrative area (the Doubs department) from 1979 to 2016. A retrospective cohort study was conducted using the Doubs cancer registry database. A total of 45 patients with invasive AS were diagnosed between 1979 and 2016 in the Doubs department. Among the 45 AS, 51% were either cutaneous AS (27%), including head and neck and extremities, or breast AS (24%) as compared to visceral AS (42%). Eleven patients had metastasis at diagnosis (26%). Age-standardized incidence rate was 0.15 per 100,000 persons-years (95%CI, 0.10–0.20) for the entire study period (1979–2016) and 0.26 (95%CI, 0.15–0.42) for the last decade (2007–2016). Crude survival at 1, 3, 5 years after diagnosis was 44%, 21%, and 12%, respectively. Our population-based study provides updated data on the incidence and overall survival of AS in a French population-based cancer registry.

Dear Editor,Since late December 2019, the outbreak of COVID-2019 caused by the severe acute respiratory syndrome coronavirus 2 in Wuhan has rapidly spread worldwide (1). COVID-19 carries a case-fat...

International audience; Systemic immunosuppressive treatments (IS) are restricted to severe atopic dermatitis (AD) in children. We described the IS use (first and second-line) for children with AD in a French retrospective national cohort, by using two survival analyses 'drug survival' (DS, defined as the duration of treatment) and 'post-drug survival' (PDS, defined as the time between the end of first-line and the beginning of second-line).

Little is known about whether immunosuppressed patients mount the immunological response necessary to ensure tubal occlusion. Theoretical concern for non-occlusion has limited the use of hysteroscopic sterilization in patients on immunosuppressive therapies. The effects of tumor necrosis factor-alpha (TNF-α) blockers and interleukin (IL)-17 inhibitors on contraception and pregnancy for patients with psoriasis are poorly documented. We report a case of pregnancy that ended in miscarriage in a patient treated first with TNF-α and then with IL-17 inhibitors for severe psoriasis after tubal sterilization with micro-inserts. Our observation suggests that the efficacy of tubal sterilization by micro-inserts may be impaired by these two biologics and that the risk of miscarriage may be increased in women with psoriasis treated with secukinumab.

Introduction Le belimumab est indique dans le lupus erythemateux systemique (LES), actif notamment dans ses manifestation cutaneomuqueuses. Le but de cette etude etait d’evaluer l’efficacite du belimumab dans le lupus erythemateux cutane (LEC) refractaire aux therapeutiques conventionnelles. Materiel et methodes Cette etude retrospective realisee entre 2014 et 2018 incluait tous les patients presentant un LEC evolutif, en poussee et resistant aux therapeutiques habituelles, qui ont ete traites par belimumab. L’efficacite de ce traitement etait evaluee cliniquement par les scores RCLASI, CLASI et DLQI apres 6 a 12 mois de traitement. Le suivi global sous belimumab, incluant la tolerance et l’evolution des traitements associes, etait egalement analyse. Resultats Sept patients suivis pour un LEC ont ete inclus. Une amelioration significative des scores d’activite RCLASI et CLASI etait constatee chez 83 % des patients (5/6), avec 1 reponse complete et 4 reponses partielles, sans aggravation des sequelles cutanees. Le score de qualite de vie DLQI etait significativement ameliore chez 80 % des patients (4/5). La corticotherapie orale a pu etre arretee chez tous les patients concernes. La tolerance etait bonne, avec la survenue d’un seul effet indesirable severe (bacteriemie). Discussion Le belimumab (anticorps monoclonal recombinant anti-BAFF (B-cell activating factor)), en bloquant la liaison de la proteine BAFF sur les lymphocytes B, inhibe la differenciation et la survie anormale des lymphocytes B a l’origine de la perte de tolerance du soi dans le LES. L’efficacite du belimumab sur les manifestations cutaneo-muqueuses du LES a ete observee dans une analyse post-hoc des etudes pilotes du medicament et dans plusieurs etude en vie reelle. Le belimumab est ainsi indique en 3e intention dans le traitement des manifestations dermatologiques du LES, apres le methotrexate et le thalidomide (PNDS Lupus systemique, 2017). Chong et al. (2014), ont montre des taux sanguins de BAFF plus eleves chez les patients avec un LEC chronique (LECC) associe a un LES que chez les patients atteints de LECC isole. Neanmoins, cette equipe a egalement montre une augmentation significative des taux d’ARNm de BAFF et de ses recepteurs dans la peau de LECC compare a la peau normale ou psoriasique, sans difference significative en fonction de la presence ou non d’un LES. Wenzel et al. (2018) ont confirme ces travaux, en montrant une augmentation de l’expression de BAFF et de ses recepteurs dans la peau de chaque sous type de LEC compare a la peau normale. Ces resultats suggerent l’interet du belimumab dans l’atteinte cutanee lupique, independamment de la presence d’une atteinte systemique lupique associee. Conclusion Notre travail demontre donc l’interet du belimumab sur l’activite de la maladie, sur la qualite de vie et sur la cortico-dependance dans une cohorte de 7 patients atteints de LEC severe, refractaire aux traitements habituels.

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Introduction Le 11 mars 2020, la Franche-Comte a ete incluse dans les zones a haut risque d’exposition (zone rouge) pour la COVID-19. Les recommandations de la filiere des maladies auto-immunes et auto-inflammatoires rares proposant la poursuite des traitements biologiques ont ete adressees a tous nos patients psoriasiques. Nous avons souhaite evaluer l’impact de l’epidemie de SARS-CoV-2 chez ces patients. Materiel et methodes Tous les patients ont ete contactes par telephone entre le 1er et le 10 juin 2020 et interroges sur leurs symptomes cliniques eventuellement apparus depuis le 11 mars 2020. Resultats Quatre cent quatre-vingt-cinq patients psoriasiques traites par biotherapies ont ete interroges. L’âge moyen des patients etait de 54,5 ans ± 10 et 320 (66 %) etaient de sexe masculin. Parmi ces 485 patients, 219 (45 %) etaient traites par anti-TNF, 118 (24 %) par anti-IL-17 et 148 (31 %) par anti-IL-12/IL-23. Vingt-six patients (5 %) declaraient avoir interrompu le traitement biologique malgre la connaissance des recommandations. En termes de comorbidite, 107 patients (22 %) presentaient une hypertension arterielle traitee, 44 (9 %) etaient traites pour un diabete, 107 (22 %) avaient un IMC > 30 kg/m2 et 138 (28 %) declaraient un tabagisme actif. Des symptomes potentiellement en lien avec la COVID-19 (syndrome pseudo-grippal, toux, anosmie, etc.) etaient rapportes par 30 patients (6 %), et seul un patient declarait un prelevement nasal positif en PCR. Aucune hospitalisation n’etait signalee. Une poussee de psoriasis etait declaree par 15 patients (3 %). Discussion Le 9 juin 2020, la France declarait 154 188 cas de COVID-19, 102 729 patients hospitalises et 29 209 deces. Les taux les plus eleves de deces etaient observes dans le nord est de la France (regions Grand-Est et Franche-Comte) et en Ile-de-France. La Franche-Comte declarait 845 deces lies a la COVID-19 (IR = 2,4 pour 10 000 habitants/mois) versus 0 chez nos patients psoriasiques traites par biotherapies. Malgre le caractere retrospectif de cette etude, nos resultats confirment les observations italiennes en Lombardie, egalement zone d’exposition a haut risque, ne montrant pas de sur-risque d’infection par le SARS-CoV-2 chez les patients psoriasiques sous biotherapies. Il est cependant possible que ces patients bien informes des risques de contamination aient adopte des mesures de confinement et d’hygiene plus strictes que la population generale. Enfin, l’effet protecteur des biotherapies a egalement ete suggere.

Objective.Ischemic digital ulcers (DU) are frequent and severe complications of systemic sclerosis (SSc). The purpose of our study was to assess the effect of DU on hand disability and pain in patients with SSc.Methods.The Evaluation of the Impact of Recurrent Ischemic DU on Hand Disability in Patients with SSc (ECLIPSE) is a prospective, multicenter, noninterventional study with a 2-year followup. Patients with SSc who experienced at least 1 DU in the previous year and received bosentan therapy were included between October 2009 and March 2011. This cohort is described at the time of inclusion.Results.There were 190 patients (132 females) from 53 centers. Mean age ± SD was 43 ± 15 years at SSc diagnosis and 53 ± 15 years at inclusion. In 105 patients (56.2%), DU were the first non-Raynaud symptoms of SSc. The mean time interval between the occurrence of Raynaud phenomenon and the first DU episode was 6.6 ± 9.1 years. The mean numbers of active DU and fingers affected per patient for both hands were 2.3 ± 1.8 and 2.2 ± 1.6, respectively. Presence of active DU at inclusion was significantly associated with pain and impaired hand function: Visual Analog Scale for pain (0 to 10) was 6.2 ± 2.6 versus 2.5 ± 2.4 (p < 0.0001) and Cochin Hand Function Scale for hand disability (0 to 90) was 38 ± 20 versus 25 ± 19 (p < 0.0001), respectively.Conclusion.DU represent a major sign of SSc, often affecting multiple fingers and both hands. They are significantly associated with pain and hand disability.

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.

Summary Backround Propranolol is now widely used to treat severe infantile haemangiomas (IHs). Very few cases of propranolol-resistant IH (PRIH) are mentioned in the literature. Objectives To describe the characteristics of PRIHs. Methods A national, multicentre, retrospective, observational study was conducted from February 2011 to December 2011. All patients with PRIH evaluated by the members of the Groupe de Recherche Clinique en Dermatologie Pediatrique from 1 January 2007 to 1 December 2011 were eligible. Results Among 1130 patients treated with propranolol for infantile haemangioma, 10 (0·9%) had PRIHs. Haemangioma propranolol resistance was observed at all ages during early childhood and at any proliferation stage. Conclusions PRIH is a rare phenomenon that raises questions and merits further investigation.

International audience; The aim of this study was to define the skin patterns at high risk for upper airway infantile haemangioma. A retrospective multicentre French observational study was conducted between January 2006 and January 2015 and all confirmed airway haemangioma were included. Thirty-eight patients with airway haemangioma from 9 centres were included. Thirty-one patients had a cutaneous or mucosal haemangioma: 21 with a location considered at high risk for airway haemangioma (large segmental mandibular haemangioma), 4 with a very mild facial involvement (lower lip or S1 (frontotemporal segment according to Haggstrom and Frieden)) and 6 with either lesions of the neck or body, or association of both. We report here the largest cohort of airway haemangioma. A third of patients do not completely fit with the definition of the high-risk area of airway haemangioma. Segmental lower lip and neck involvement also seem to be very suggestive areas. Clinicians must be able to recognize these areas.

Background Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients. Methods Clinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected. Results Key features consist of: (i) early-onset poikiloderma, hypotrichosis and hypohidrosis; (ii) multiple contractures, in particular triceps surae muscle contractures; (iii) diffuse progressive muscular weakness; (iv) pulmonary fibrosis in adulthood and (v) other features including exocrine pancreatic insufficiency, liver impairment and growth retardation. Muscle magnetic resonance imaging was informative and showed muscle atrophy and fatty infiltration. Histological examination of skeletal muscle revealed extensive fibroadipose tissue infiltration. Microscopy of the skin showed a scleroderma-like aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two recurrent mutations were found respectively in three and four independent families). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain-of-function or dominant-negative mutations resulting in FAM111B enzymatic activity changes. Conclusions HFP with tendon contractures, myopathy and pulmonary fibrosis, is a multisystemic disorder due to autosomal dominant FAM111B mutations. Future functional studies will help in understanding the specific pathological process of this fibrosing disorder.

A 72-year-old diabetic woman was referred with a painful chronic leg ulcer associated with venous and arterial insufficiency. She then developed a polymorphous skin infection due to Pseudomonas aeruginosa, with ecthyma gangrenosum, subcutaneous abscess and panniculitis of the homolateral inferior limb, without general sepsis. Although P. aeruginosa infection may induce polymorphous skin lesions, they are most often observed in immunocompromised patients following septicaemia.

Background: Interstitial lung disease (ILD) is a leading cause of death in systemic sclerosis (SSc). Sensitivities and specificities of the current pulmonary function tests (PFTs) for the detection of ILD in SSc are poor. Objective: To determine whether diffusion capacity of the lungs for carbon monoxide (DLCO) partitioned into membrane conductance for CO (DmCO) and alveolar capillary blood volume (Vcap) could provide more sensitive clues to ILD than current PFTs. Methods: DmCO and Vcap were determined in 35 consecutive SSc patients in whom a cardiac and/or pulmonary vascular abnormality had been rejected according to the recommended screening algorithm. ILD was diagnosed with high-resolution computed tomography. Results: Among 35 patients [6 men; median age (first–third quartile) 61.9 years (49.5–67.7)], 22 had no ILD and 13 did. Total lung capacity (TLC), vital capacity and DLCO [percentage of predicted value (%pred)] were lower in patients with ILD [86 (82–103) vs. 106 (98–112), p = 0.01, 96 (88–112) vs. 114 (104–121), p = 0.04, and 67 (59–81) vs. 80 (71–94), p = 0.02, respectively]. DmCO (%pred) and the ratio of DmCO to Vcap were much lower in patients with ILD [54 (48–72) vs. 83 (66–92), p < 0.001, and 0.22 (0.21–0.27) vs. 0.40 (0.35–0.53), p < 0.0001, respectively]. According to receiver operating characteristic analysis, the DmCO:Vcap ratio displayed higher sensitivity and specificity than TLC, vital capacity and DLCO in identifying ILD in our study group (p < 0.01). Conclusions: These results suggest that the partitioning of DLCO might be of interest for identifying ILD in SSc patients.

Poikiloderma occurs in a number of hereditary syndromes, the best known of which is Rothmund-Thomson syndrome (RTS). Differential diagnoses include Dyskeratosis Congenita (DC) with high genetic heterogeneity and Clericuzio-type Poikiloderma with Neutropenia (CPN) due to mutations in the C16orf57 gene. Mutations in the RECQL4 gene are only observed in two thirds of RTS patients. In this study, 10 patients referred for syndromic poikiloderma and negative for RECQL4 sequencing analysis were investigated for C16orf57 mutations. Two C16orf57 heterozygous nonsense mutations (p.W81X and p.Y89X) were identified in a 5-year-old female child presenting with generalized poikiloderma, dental dysplasia, gingivitis, nail dystrophy, palmoplantar keratoderma and pachyonychia of the great toenails. Previously undetected and silent neutropenia was evidenced after C16orf57 molecular analysis. Neutropenia was absent in the C16orf57-negative patients. This report confirms that neutrophil count should be performed in all patients with poikiloderma to target the C16orf57 gene sequencing analysis, prior to RECQL4 analysis.

Background Since the introduction of sentinel lymph node biopsy (SLNB), its use as a standard of care for patients with clinically node-negative cutaneous melanoma remains controversial. We wished to evaluate our experience of SLNB for melanoma. Methods A single center observational cohort of 203 melanoma patients with a primary cutaneous melanoma (tumour thickness > 1 mm) and without clinical evidence of metastasis was investigated from 2002 to 2009. Head and neck melanoma were excluded. SLN was identified following preoperative lymphoscintigraphy and intraoperative gamma probe interrogation. Results The SLN identification rate was 97%. The SLN was tumor positive in 44 patients (22%). Positive SLN was significantly associated with primary tumor thickness and microscopic ulceration. The median follow-up was 39.5 (5–97) months. Disease progression was significantly more frequent in SLN positive patients (32% vs 13%, p = 0.002). Five-year DFS and OS of the entire cohort were 79.6% and 84.6%, respectively, with a statistical significant difference between SLN positive (58.7% and 69.7%) and SLN negative (85% and 90.3%) patients (p = 0.0006 and p = 0.0096 respectively). Postoperative complications after SLNB were observed in 12% of patients. Conclusion Our data confirm previous studies and support the clinical usefulness of SLNB as a reliable and accurate staging method in patients with cutaneous melanoma. However, the benefit of additional CLND in patients with positive SLN remains to be demonstrated.