Treatment of moderate-to-severe psoriasis in adults: An expert consensus statement using a Delphi method to produce a decision-making algorithm.

BACKGROUND: New highly effective drugs for moderate-to-severe cutaneous psoriasis are regularly marketed, and the hierarchy of treatments thus requires frequent review. OBJECTIVES: A Delphi method was used to enable a structured expert consensus on the use of systemic treatments and phototherapy among adults with moderate-to-severe psoriasis. METHODS: The Delphi method consists in achieving a convergence of opinions among a panel of experts using several rounds of questionnaires with controlled feedback between rounds. A two-part Delphi questionnaire was administered online to French psoriasis experts. In the first part, 180 items related to the prescription of systemic treatments and phototherapy for adult patients with moderate-to-severe psoriasis were grouped into 21 sections covering different lines of treatment and different forms of cutaneous psoriasis. The experts voted on each proposal using an ordinal 7-point Likert scale. The second part comprised 11 open-ended questions about special indications for each therapeutic class. These were converted into 101 questions for subsequent rounds. Consensus was deemed to have been reached if more than 80% of the experts agreed with a given proposal. RESULTS: Three rounds of questionnaires were sequentially sent to 35 participants between November 2021 and March 2022. Thirty-three (94%) completed all three rounds. For plaque psoriasis, only methotrexate was recommended by the experts as first-line systemic treatment (89% of votes). Cyclosporin was advocated in pustular and erythrodermic psoriasis, and acitretin was suggested for hyperkeratotic and palmoplantar psoriasis. In the event of failure of or intolerance to non-biological systemic treatments, guselkumab, risankizumab, ixekizumab or secukinumab were recommended by more than 80% of the experts. Tumor Necrosis Factor (TNF) inhibitors remain useful for patients with cardiovascular risk factors. Special indications were provided for each therapeutic class (methotrexate/narrowband ultraviolet B phototherapy, psoralen/ultraviolet A phototherapy, cyclosporin, acitretin, apremilast, TNF inhibitors, interleukin (IL)-12/23 inhibitors, IL-17(R)A inhibitors, and IL-23 inhibitors). CONCLUSIONS: This expert consensus statement indicate that newly available IL-17 and IL-23 inhibitors may be favored over TNF and IL-12/23 inhibitors as first-line biologics. The Centre of Evidence of the French Society of Dermatology has drawn up a decision-making algorithm to guide clinicians in the therapeutic management of moderate-to-severe psoriasis.

Relevance of body mass index as a predictor of systemic therapy outcomes in metastatic melanoma: analysis of the MelBase French cohort data☆.

BACKGROUND: The 'obesity paradox' suggests that higher body mass index (BMI) is associated with better survival values in metastatic melanoma patients, especially those receiving targeted and immune checkpoint inhibitor therapy. Higher BMI is also associated with higher incidences of treatment-related adverse events (TRAEs). This study assesses whether BMI is associated with survival outcomes and adverse events in metastatic melanoma patients with systemic therapy. PATIENTS AND METHODS: This multicentric retrospective study, conducted from 1 March 2013 to 29 April 2019, enrolled adults with unresectable stage III or IV melanoma from the French multicentric prospective cohort-MelBase (NCT02828202). Patients with first-line chemotherapy and targeted and immune therapy were included. Underweight people and those with metastatic mucosal or ocular melanoma were excluded. BMI was categorized using the World Health Organization criteria. Co-primary outcomes included the association between BMI and progression-free survival and overall survival, stratified by treatment type, sex, and age. Secondary endpoints were the association of BMI with overall response and TRAEs. Multivariate analyses were carried out. RESULTS: A total of 1214 patients were analyzed. Their median age was 66.0 years (range, 53-75). Male predominance was observed [n = 738 (61%)]. Most patients received immune checkpoint inhibitor therapy (63%), followed by targeted therapy (32%), and had stage M1c disease (60.5%). Obese patients represented 22% of the cohort. The median follow-up duration was 13.5 months (range, 6.0-27.5). In the pooled analysis, no positive or negative association between BMI and progression-free survival (P = 0.88)/overall survival (P = 0.25) was observed, regardless of treatment type, sex, and age. These results were nonsignificant in the univariate and multivariate analyses. The objective response rate, according to BMI category, did not differ significantly regardless of age. TRAEs were not associated with BMI. CONCLUSION: The observed lack of an association between BMI and survival demonstrates that BMI is not a valuable marker of systemic treatment-related outcomes in metastatic melanoma. Future approaches might focus on the whole-body distribution.

Psoriatic epidermis is associated with upregulation of CDK2 and inhibition of CDK4 activity.

BACKGROUND: The cyclin-dependent kinases (CDKs) CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. CDK inhibitory proteins (CKIs) such as p16INK 4A (p16) bind CDK4/6 kinases and prevent their interaction with D-type cyclins. CKIs such as p21Cip1 (p21) and p27Kip1 (p27) associate with CDK-cyclin complexes and prevent their activation. OBJECTIVES: To gain insight into the molecular implication of CDK2 and CDK4 kinases in psoriasis, we sought to characterize expression of these kinases and associated cyclins, as well as of CKIs, and addressed the status of CDK2 and CDK4 activity in human psoriatic epidermis. METHODS: A cohort of 24 patients with psoriasis participated in the study. Biopsies were removed from a chronic plaque and from nonlesional skin. CDK2, CDK4, cyclin D1, cyclin E and CKI protein expression was assessed by immunoblotting, immunohistochemistry and immunofluorescence. CDK4 and CDK2 mRNA expression was determined by real-time polymerase chain reaction. Specific kinase activities of CDK2 and CDK4 were evaluated using fluorescent peptide biosensors. RESULTS: CDK2-cyclin E expression and activity were significantly increased in psoriatic epidermis compared with uninvolved adjacent skin. In contrast, CDK4-cyclin D1 activity was inhibited, although its expression was increased in psoriatic epidermis and its transcription slightly inhibited. p27 expression was reduced, while p16 and p21 expression was induced in psoriatic epidermis. CONCLUSIONS: Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. What's already known about this topic? Cyclin-dependent kinases (CDKs) are involved in cell-cycle progression. The levels of cyclin partners and CDK inhibitors regulate their activity. Psoriasis is a chronic T-cell-driven inflammatory skin disease characterized by hyperproliferation of basal epidermal cells. What does this study add? Thanks to fluorescent peptide biosensors, this study demonstrates that epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations involve post-translational control mediated by decreased expression of p27, and p16 overexpression, respectively. What is the translational message? CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. Pharmacological modulation of CDK2 and CDK4 may constitute a promising therapeutic strategy.

Update of survival and cost of metastatic melanoma with new drugs: Estimations from the MelBase cohort.

PURPOSE: Since 2011, significant progress was observed in metastatic melanoma (MM), with the commercialisation of seven immunotherapies or targeted therapies, which showed significant improvement in survival. In France, in 2004, the cost of MM was estimated at €1634 per patient; this cost has not been re-estimated since. This study provided an update on survival and cost in real-life clinical practice. METHODS: Clinical and economic data (treatments, hospitalisations, radiotherapy sessions, visits, imaging and biological exams) were extracted from the prospective MelBase cohort, collecting individual data in 955 patients in 26 hospitals, from diagnosis of metastatic disease until death. Survival was estimated by the Kaplan-Meier method. Costs were calculated from the health insurance perspective using French tariffs. For live patients, survival and costs were extrapolated using a multistate model, describing the 5-year course of the disease according to patient prognostic factors and number of treatment lines. RESULTS: Since the availability of new drugs, the mean survival time of MM patients has increased to 23.6 months (95%confidence interval [CI] :21.2;26.6), with 58% of patients receiving a second line of treatment. Mean management costs increased to €269,682 (95%CI:244,196;304,916) per patient. Drugs accounted for 80% of the total cost. CONCLUSION: This study is the first that evaluated the impact of immunotherapies and targeted therapies both on survival and cost in real-life conditions. Alongside the introduction of breakthrough therapies in the first and subsequent lines, MM has been associated with a significant increase in survival but also in costs, raising the question of financial sustainability.

[What's new in dermatological research?] / Quoi de neuf en recherche dermatologique ?

This manuscript provides a selection of dermatological research manuscripts published from September 2016 to August 2017. It is not an exhaustive review but rather a selection of manuscripts susceptible to modify the dermatological practice or affording new pathophysiologic mechanisms and new therapeutic approaches. The following areas of interest are concerned: recognition of dermatological images by artificial intelligence, new concepts in atopic dermatitis, wound repair and hair growth cycle. New data concerning melanomagenesis, epidermolysis bullosa simplex and drug eruption are also highlighted.

Clinical and immunological features and outcome of anti-p200 pemphigoid.

BACKGROUND: Anti-p200 pemphigoid is a rare autoimmune blistering disease (AIBD) of the dermoepidermal junction, characterized by autoantibodies to laminin γ1. The clinical course of anti-p200 pemphigoid in patients remains poorly investigated. OBJECTIVES: We aimed to describe the clinical and immunological features and the course of a series of patients with anti-p200 pemphigoid. METHODS: We conducted a retrospective study by immunoblotting detection of sera on 200-kDa dermal protein extracts from the register of the French reference centre for AIBD. We recorded the clinical and immunological features and the course of patients. RESULTS: A total of 14 patients with a mean age 81·6 ± 6·5 years were included. Only one patient had an associated neurological condition and one had psoriasis. Twelve patients had atypical clinical presentation, including eczematous, urticarial, prurigo-like, dyshydrosis-like and rosette-like skin lesions. Eight patients (57%) had mucosal involvement. Immunoblot analysis of sera on dermal and epidermal extracts showed a 200-kDa band in 14 and 10 cases, respectively. All eight of the sera tested by enzyme-linked immunosorbent assay detected recombinant human laminin γ1. Disease control was obtained in six of nine patients treated with topical corticosteroids, and four of five patients who received systemic treatment. Seven patients relapsed (50%) and five patients (36%) died during the median follow-up time of 12·6 months. At the end of the study, only one of the nine living patients was in complete remission off therapy. CONCLUSIONS: Many patients with anti-p200 pemphigoid had heterogeneous clinical presentation and a more severe prognosis than previously suspected.

[Massive localized lymphedema]. / Lymphœdèmes massifs localisés.

BACKGROUND: Massive localized lymphedema (MLL) is a benign soft-tissue lesion that usually presents as a large and isolated mass in morbidly obese adults. PATIENTS AND METHODS: We report the case of a 39-year-old woman presenting obesity and multiple MLL. There was a large tumor in the left groin and two smaller lesions on the backs of the thighs. DISCUSSION: MLL is a benign tumor that must be removed wherever possible because such tumors may degenerate into angiosarcomas in 13% of cases. MLL is probably secondary to a prolonged obstruction of lymphatic vessels due to marked excess of adipose tissue.

[Metastatic cervical fasciitis revealing invasive lobular breast carcinoma]. / Fasciite cervicale métastatique révélant un carcinome lobulaire infiltrant du sein.

BACKGROUND: We describe the case of a 71-year-old woman presenting cervical metastatic fasciitis with invasive lobular carcinoma (ILC) of the breast. PATIENTS AND METHODS: The patient consulted for a deep and painless skin infiltration of the neck associated with dysphagia and restricted cervical mobility. Skin and muscle biopsies were normal. Muscle fascia biopsy showed a linear infiltration of metastatic cells in "single file", revealing ILC of the right breast. DISCUSSION: ILCs have a particular metastatic pattern. They can permeate through tissue planes, infiltrate solid organs and spread on serous membranes in an insidious fashion. CONCLUSION: Our case shows that ILC can metastasise into muscular fascia, causing "fasciitis-like" symptoms. Dermatologists should be aware of this particular pattern of dissemination.

[Multiple primary cutaneous plasmacytoma]. / Plasmocytomes cutanés primitifs multiples.

BACKGROUND: Primary cutaneous plasmacytoma is a rare form of cutaneous B-cell lymphoma. PATIENTS AND METHODS: A 51 year-old male with an unremarkable history gradually presented erythematous papulonodular lesions that had appeared gradually over the whole body throughout a two-year period and showing histologic and immunohistochemical features of cutaneous plasmacytoma. Staging investigations confirmed the primary character of the disease, and because of this and the absence of functional impairment, we opted for therapeutic abstention. No progression was noted after 4 years of regular monitoring. DISCUSSION: Primary cutaneous plasmacytoma (PCP) is characterized by clonal proliferation of plasma cells in skin. Multiple PCPs are extremely rare and to date have been treated in most cases by chemotherapy, either with or without radiotherapy. The prognosis is poor, with 2-year survival of only 25%. The present case is original, being the only one to our knowledge in which therapeutic abstention was followed by a lack of progression after 4 years of regular follow-up. Consequently, certain indolent forms of PCP do not warrant automatic institution of chemotherapy.

[Spontaneous remission of congenital leukemia cutis]. / Lésions cutanées à type de leucémie congénitale "aleucémique" de rémission spontanée.

BACKGROUND: Aleukaemic leukaemia--without blasts in the blood or the bone marrow--with isolated cutaneous manifestations has been very rarely reported since only seven patients have been described to date. The prognosis is variable, and the indications for an aggressive treatment such as polychemotherapy are currently unclear. We report a case of spontaneously remitting aleukaemic leukaemia in a newborn child and compare it with other cases in the literature. CASE REPORT: A male newborn presented diffuse, violaceous skin nodules reminiscent of the so-called "blueberry muffin syndrome" present since birth. Blood and marrow examinations did not show any blasts and karyotype was normal. Biopsy of a nodule established the diagnosis of acute myeloid leukaemia type 5. The course was spontaneously favourable despite the absence of specific therapy and the boy was asymptomatic after one year of follow-up. DISCUSSION: Of the eight reported infants (including ours), three died, including two through acute transformation of the leukaemia. The prognosis seems to be highly dependent on cytogenetic features with the 11q23 rearrangement being at higher risk of acute transformation, prompting recourse to aggressive chemotherapy. Our case further illustrates the favourable prognostic value of a normal karyotype, a situation in which therapeutic abstention seems possible, and is even recommended.

Proteolytic activity and expression of the 20S proteasome are increased in psoriasis lesional skin.

BACKGROUND: Deregulation of the proteasome pathway has been shown to be involved in the pathogenesis of several inflammatory disorders. To date limited information exists on proteasome and immunoproteasome expression and activity in psoriasis skin. OBJECTIVES: To investigate the potential role of proteasomes in the pathogenesis of psoriasis. METHODS: Thirty-six patients with psoriasis and 40 healthy subjects were included. The protein and mRNA expression levels and proteolytic activity of proteasome and immunoproteasome subunits were determined using immunohistochemistry, quantitative polymerase chain reaction and fluorogenic peptide substrate in lesional and nonlesional psoriasis skin. We additionally measured the plasmatic proteasome (p-proteasome) levels using enzyme-linked immunosorbent assay. RESULTS: We reveal an increased expression of proteasome and immunoproteasome subunits but stable mRNA levels in lesional psoriasis skin as compared with nonlesional psoriasis skin (n = 19), suggesting that proteasome and immunoproteasome expression is regulated post-transcriptionally. This proteasome overexpression was associated with a significant increase of the proteasomal chymotrypsin-like activity that was threefold higher in lesional skin than in nonlesional skin (n = 3). p-Proteasome levels were enhanced in patients with psoriasis (mean ± SEM 3960 ± 299 ng mL(-1) , range 1484-8987) when compared with controls (2535±187 ng mL(-1) , range 654-6446, P<0·001) and were significantly higher in psoriatic arthritis (4937±572 ng mL(-1) , range 2600-8987). In addition, they were correlated to the body surface area involved and appeared thus as a new biomarker of psoriasis severity. CONCLUSIONS: Altogether these results strongly suggest the involvement of the proteasome system in the pathogenesis of psoriasis and support the relevance of proteasome inhibitors in local or systemic treatment of psoriasis.

[Necrotic arachnidism in the south of France: two clinical cases of loxoscelism]. / Envenimation nécrotique dans le Sud de la France : deux observations de loxoscélisme cutané

BACKGROUND: loxosceles spiders are found throughout the world and are responsible for numerous cases of envenomation in America and Southern Europe. We describe, to our knowledge for the first time in France, two clinical cases of cutaneous loxoscelism. CASE REPORT: two cases of skin necrosis arising after supposed spider bites were grouped together because of their similar clinical presentation: an initial painless bite and rapid development of an inflammatory and painful cutaneous lesion with a central hemorrhagic bulla surrounded by a perimeter of blanched skin (the "red, white, and blue" sign). The outcome in both cases was deep skin necrosis and chronic ulceration requiring surgical treatment. DISCUSSION: loxoscelism can result in dermonecrosis. Although our cases were not documented by capture of the spider, the diagnosis of cutaneous loxoscelism was supported by the characteristic appearance of the lesion, a typical clinical course, elimination of differential diagnoses, and the confirmed presence of Loxosceles rufescens in the region. CONCLUSION: loxoscelism can occur in the south of France and although rare, must be considered in this region as a possible cause of skin necrosis.

[Cutaneous metastasis revealing epithelioid angiosarcoma of the abdominal aorta]. / Métastases cutanées révélatrices d'un angiosarcome épithélioïde de l'aorte abdominale.

BACKGROUND: Epithelioid angiosarcomas (EAS) of the aorta are a rare form of tumour usually diagnosed by histopathological analysis of the aorta. We report a case revealed by skin metastasis. CASE REPORT: An 85-year-old man presented skin tumours associated with deterioration of his general condition and intense pain of the right lower limb. Physical examination showed three nodules of the lumbar area associated with an ipsilateral livedo extending to the right lower limb. The course of the disease involved distal ischaemia. Arterial ultrasound, aortography and CAT showed ectasia of the abdominal aorta with thrombosis and right subpopliteal occlusion. Histological examination of a nodule showed proliferation of malignant cells with expression of vimentin, CD 31, cytokeratins AE1/AE3 and cytokeratin 7. Stain for CD34 was negative. Histological investigation of the livedo showed a vascular embolus with epithelial-type cells positive for cytokeratin 7 and CD 31. The PET scan showed intense F-FDG uptake of the aorta extended to the iliac artery. Moreover, skin and osseous F-FDG uptake was seen. These findings suggested a diagnosis of EAS of the aorta with skin and osseous metastasis and vascular emboli. DISCUSSION: Only 27 previous case reports of EAS based on appropriate immunohistochemical analysis have been published in the literature. These tumours typically arise in the abdominal aorta in association with metastasis in more than 80% of cases. Skin metastasis causes papular eruption, nodules and peripheral vascular disease. Embolic vascular occlusion results in ischaemia and in rare cases vasculitis. Our case report emphasizes four key points: the diagnostic value of an association of localized malignant skin tumours, extensive livedo, ipsilateral distal ischaemia, deterioration of the general condition and intense pain; the diagnostic value of endothelial markers, especially CD31, and potentially misleading co-expression of cytokeratin markers; in selected cases, additional imaging, such as PET scans, performed in our case for the first time prior to surgery of the aorta, may be helpful for the diagnosis of such neoplastic lesions of the aortic wall.

Management and outcome of metastatic melanoma during pregnancy.

BACKGROUND: Although metastatic melanoma occurrence during pregnancy challenges the physician in several ways, only a few studies have been published. OBJECTIVES: Our aim was to investigate therapeutic management together with maternal and fetal outcomes in pregnant women with advanced melanoma. METHODS: A French national retrospective study was conducted in 34 departments of Dermatology or Oncology. All patients with American Joint Committee on Cancer (AJCC) stage III/IV melanoma diagnosed during pregnancy were included. Data regarding melanoma history, pregnancy, treatment, delivery, maternal and infant outcomes were collected. RESULTS: Twenty-two women were included: 10 AJCC stage III and 12 stage IV. Abortion was performed in three patients. Therapeutic abstention during pregnancy was observed in three cases, 14 patients underwent surgery, four patients received chemotherapy and one patient was treated with brain radiotherapy alone. The median gestational age was 36 weeks amenorrhoea. Neither neonatal metastases nor deformities were observed. Placenta metastases were found in one case. Among 18 newborns, 17 are currently alive (median follow up, 17 months); one died of sudden infant death. The 2-year maternal survival rates were 56% (stage III) and 17% (stage IV). CONCLUSIONS: Faced with metastatic melanoma, a majority of women chose to continue with pregnancy, giving birth, based on our samples, to healthy, frequently premature infants. Except during the first trimester of pregnancy, conventional melanoma treatment was applied. No serious side effect was reported, except one case of miscarriage after surgery. Mortality rates do not suggest a worsened prognosis due to pregnancy but larger prospective controlled studies are necessary to assess this specific point.

[Neonatal Volkmann's syndrome]. / Syndrome de Volkmann néonatal.

BACKGROUND: Acute limb compartment syndrome or Volkmann's ischaemic contracture is an acquired ischaemia of nerve and muscle causes by raised pressure within a closed fascial space. Congenital Volkmann's ischaemic contracture (CVIC) is a rare entity. PATIENTS AND METHODS: A 2-day-old girl was referred with a problem of the left forearm and arm, which exhibited cold oedema with decreased mobility. Lesions were present at birth and were rapidly complicated by skin necrosis. The mother was taking olazanpine, prazepam and valpromide throughout the entire pregnancy. Delivery was complicated by shoulder dystocia requiring obstetric procedures such as suprapubic pressure, Couder's maneuver and episiotomy. On physical examination her left hemi-thorax, left arm, forearm and hand exhibited marked oedema. A large and well-demarcated bullous, fibrous and ulcerated area of skin necrosis was observed on the elbow fold and on the inner anterior part of the arm. Digital flexion with cyanosis was present. MR angiography revealed extensive oedema of the soft tissue and muscle with fascial effusion, associated with compression of the arm arteries and reduced blood flow in the forearm. A fasciotomy was performed at Day 3 of life. The postsurgical arterial MRI was normal. At Day 10 of life, the patient developed opisthotonos involving spasms and tremors associated with numerous intercritical abnormalities evoking benzodiazepine weaning syndrome. The child's neurological status was stabilized by treatment with phenobarbital and clonazepam. She was subsequently lost to follow-up. DISCUSSION: CVIC has been ascribed to multiples causes. Mechanical compression is the main recognized factor: amniotic band constriction, umbilical cord loops, compression in utero by a deceased co-twin, malposition of the hand, arm or forearm, local or general factors that can add to extraction problems: brachypelvic disproportion, extraction with forceps, oligo/polyhydramnios, pre-term delivery, pre-eclampsia, caesarean section, premature labour, excessive maternal weight gain or diabetes. Our case emphasized three main points. First, the diagnostic value of early MR angiography in the event of associated extensive tissue oedema, multiple arterial compression and decreased vascular perfusion. Second, the role of shoulder dystocia in triggering the traumatic factor reported for the first time. Third, the role of neuroleptic and anxiolytic treatments taken by the mother during pregnancy. Prazepam is a long-acting benzodiazepine that can cause impregnation and withdraw syndromes in neonates. Impregnation "floppy infant syndrome" is an early event characterized by hypotonia, hypoventilation and lethargy. Hypotonia and decreased foetal movements may favour prolonged pressures and malposition with secondary crush injury during delivery. Maternal medication has not been cited hitherto as an aetiological factor in neonatal compartment syndrome.