Efficacy and safety of apremilast in pediatric patients with moderate-to-severe plaque psoriasis: 16-week results from SPROUT, a randomized controlled trial.

BACKGROUND: Approved systemic treatment options are limited for pediatric patients with moderate to severe plaque psoriasis. OBJECTIVE: To assess the efficacy and safety of apremilast over 16 weeks in pediatric patients with plaque psoriasis. METHODS: SPROUT (NCT03701763) was a phase 3, multicenter, randomized, double-blind, placebo-controlled study of apremilast in patients aged 6-17 years with moderate-to-severe psoriasis (Psoriasis Area and Severity Index [PASI] ≥12, body surface area ≥10%, static Physician Global Assessment [sPGA] ≥3) inadequately controlled by/inappropriate for topical therapy. Patients were stratified by age group and randomized (2:1) to apremilast (20 or 30 mg BID based on weight) or placebo for 16 weeks, followed by apremilast extension to 52 weeks. RESULTS: Of 245 patients randomized (apremilast: 163; placebo: 82), 221 (90%) completed the double-blind phase (apremilast: 149; placebo: 72). Significantly more patients achieved sPGA response and ≥75% reduction in PASI with apremilast than placebo, regardless of baseline age, weight, or disease severity. No new safety signals were observed. LIMITATIONS: Sample size of subgroup analyses. CONCLUSIONS: Improvements in global disease activity and skin involvement were significantly greater in pediatric patients treated with apremilast versus placebo. Adverse events were consistent with the known apremilast safety profile.

(New) antenatal ultrasound signs of fetal junctional epidermolysis bullosa: A case report and systematic review of literature.

Epidermolysis bullosa is a rare hereditary autosomal disease that is included in the heterogeneous group of genodermatosis. It is characterized by skin and mucous membranes fragility and denudation, and it can be associated with pyloric atresia. Prognosis is often poor, and death can occur in neonatal period due to severe sepsis. We present a case of fetal junctional epidermolysis bullosa in a consanguineous couple, highly suggested by previous obstetric history and several antenatal ultrasound signs, such as polyhydramnios, gastric enlargment, the "snowflake sign", abnormal external ears, signs of skin desquamation, lower limbs anomalies and chorioamniotic membrane separation. We describe a marked perioral hipoecogenicity as a novel sign of skin-mucous denudation, which could be helpful for future diagnosis. A review of literature, focused specifically on the antenatal sonography role, is also reported. Prenatal ultrasound-based diagnosis of epidermolysis bullosa is difficult, especially in apparently low risk contexts, but may be possible.

Bloodstream Infection in Children With Epidermolysis Bullosa.

BACKGROUND: Epidermolysis bullosa (EB) is frequently complicated by skin infection, which can lead to bacteremia. However, bloodstream infections (BSI) in patients with EB have not been well described. METHODS: Retrospective study of BSI in children 0-18 years with EB from a national reference unit in Spain, in 2015-2020. RESULTS: Among 126 children with EB, we identified 37 BSI episodes in 15 patients (14 recessive dystrophic EB, 1 junctional EB). The most frequent microorganisms were Pseudomonas aeruginosa (n = 12) and Staphylococcus aureus (n = 11). Five P. aeruginosa isolates were ceftazidime-resistant (42%), 4 of which were also resistant to meropenem and quinolones (33%). As for S. aureus , 4 (36%) were methicillin-resistant and 3 (27%) clindamycin-resistant. In 25 (68%) BSI episodes skin cultures had been performed in the previous 2 months. The most frequent isolates were also P. aeruginosa (n = 15) and S. aureus (n = 11). In 13 cases (52%), smear and blood cultures grew the same microorganism, with the same antimicrobial resistance pattern in 9 isolates. Twelve patients (10%) died during follow-up (9 RDEB and 3 JEB). BSI was the cause of death in 1 case. In patients with severe RDEB, a history of BSI was associated with higher mortality (OR 6.1, 95% CI: 1.33-27.83, P = 0.0197). CONCLUSIONS: BSI is an important cause of morbidity in children with severe forms of EB. The most frequent microorganisms are P. aeruginosa and S. aureus , with high rates of antimicrobial resistance. Skin cultures can help guide treatment decisions in patients with EB and sepsis.

Comorbidity identification and referral in atopic dermatitis: a consensus document.

BACKGROUND: Atopic dermatitis (AD) is associated with different comorbidities. OBJECTIVE: To develop evidence-based and practical recommendations for comorbidity detection in patients with AD in daily practice. METHODS: We employed a modified RAND/UCLA methodology, including a systematic literature review (SLR). A group of six experts on AD was established. We conducted a comprehensive search strategy on Medline, Embase, and Cochrane Library up to June 2020. The selection criteria included studies with AD patients with any comorbidity reporting data on comorbidity prevalence, burden, and management. The included studies quality was assessed. The SLR results were discussed in a nominal group meeting, and several recommendations were generated. The recommendation agreement grade was tested on additional experts through a Delphi process. RESULTS: The recommendations cover the following issues: (1) Which comorbidities should be investigated at the first and subsequent visits; (2) how and when should comorbidities be investigated (screening); (3) how should patients with specific comorbidities be referred to confirm their diagnosis and initiate management; (4) specific recommendations to ensure an integral care approach for AD patients with any comorbidity. CONCLUSIONS: These recommendations seek to guide dermatologists, patients, and other stakeholders in regard to early comorbidity identification and AD patient referral to improve decision-making.

Evaluation of Systemic Gentamicin as Translational Readthrough Therapy for a Patient With Epidermolysis Bullosa Simplex With Muscular Dystrophy Owing to PLEC1 Pathogenic Nonsense Variants.

IMPORTANCE: Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) is an autosomal recessive disorder caused by pathogenic variants in PLEC1, which encodes plectin. It is characterized by mild mucocutaneous fragility and blistering and muscle weakness. Translational readthrough-inducing drugs, such as repurposed aminoglycoside antibiotics, may represent a valuable therapeutic alternative for untreatable rare diseases caused by nonsense variants. OBJECTIVE: To evaluate whether systemic gentamicin, at a dose of 7.5 mg/kg/d for 14 consecutive days, is clinically beneficial in a patient with EBS-MD. DESIGN, SETTING, AND PARTICIPANTS: A single patient in Madrid, Spain, received 2 treatment courses with gentamicin on July 2019 and February 2020 with a follow-up period of 120 and 150 days, respectively. RESULTS: In this case report of a woman in her 30s with EBS-MD, before gentamicin treatment, the patient had mucocutaneous involvement, skeletal and respiratory muscle weakness, and myalgia that negatively affected her quality of life. Outcomes were evaluated with extensive laboratory tests and clinical scales. No nephrotoxic or ototoxic effects were detected after intravenous gentamicin administration. Gentamicin treatment was followed by plectin expression in the skin for at least 5 months. Although minimal changes were noted in skeletal muscle function (as measured by the Hammersmith functional motor scale and its expanded version: 6/40 to 7/40 and from 10/66 to 11/66, respectively) and respiratory musculature (maximal inspiratory and expiratory pressures D0 vs D16, MIP: 2.86 vs 3.63 KPa and MEP: 2.93 vs 4.63 KPa), myalgia disappeared (VAS dropped from 6 to 0), and quality of life improved (EuroQoL-5D-3L pain and anxiety dropped from 2 to 1). CONCLUSIONS AND RELEVANCE: The findings of this single case report suggest that gentamicin treatment may help suppress PLEC1 premature termination codons and induce plectin expression in EBS-MD primary keratinocytes and skin. Our study suggests that gentamicin may play an important role in treating EBS-MD owing to nonsense variants.

Patient Journey in Atopic Dermatitis: The Real-World Scenario.

INTRODUCTION: The diagnosis and management of atopic dermatitis (AD) is extensively addressed in detailed clinical guidelines. However, the high heterogeneity regarding presentation and progression and the increasingly broad therapeutic landscape suggest a complex real-world scenario, leading to multiple trajectories of AD patients. METHODS: Using a Delphi methodology for assessing the degree of consensus, we explored the views of a panel of dermatologists regarding the patients' trajectory through the diagnosis (block 1), treatment (block 2), and long-term management (block 3) of AD. Based on a systematic search of the literature, a scientific committee prepared a questionnaire of relevant items that were rated on a 10-point scale (from "totally agree" to "totally disagree") by a panel of dermatologists attending patients with AD in the hospital setting. Consensus was established based on predefined rules. RESULTS: The final questionnaire included 58 items and was answered by 17 dermatologists. Overall, consensus was reached on 22 items (37.9%), each of which was a consensus for agreement. The consensus rates in blocks 1, 2, and 3 were 22.7%, 19.0%, and 86%, respectively. CONCLUSIONS: Our analysis revealed a remarkable lack of consensus on various aspects of the routine diagnosis and treatment of AD. These findings suggest the presence of unmet needs or limited implementation of guidelines for the management of AD and encourage further research to explore the causes of this low consensus on the management of AD in the real-world setting.

Quality of life in patients with breakthrough cancer pain in radiation oncology departments in Spain: the CAVIDIOR study.

Aim: The CAVIDIOR study evaluated quality of life (QoL) in patients with breakthrough cancer pain receiving palliative radiation therapy in radiation oncology departments (RODs) in Spain. Patients & methods: Prospective observational study at 11 Spanish RODs (July 2016-November 2017). QoL was assessed using Short Form Health Survey 12. Secondary end points were sleep quality, caregiver burden and patient/perception of improvement. Results: QoL improved according to the Short Form Health Survey 12 mental component. Sleep quality and caregivers' burden improved significantly. Conclusion: Breakthrough cancer pain is highly prevalent and can be substantially reduced with appropriate diagnosis and management in RODs. Along with the QoL questionnaire, sleep quality and caregiver burden provide a more comprehensive assessment of overall health status in patients receiving radiation therapy in RODs. Clinical trial registration: NCT02836379 (ClinicalTrials.gov).

Beneficial Effect of Systemic Allogeneic Adipose Derived Mesenchymal Cells on the Clinical, Inflammatory and Immunologic Status of a Patient With Recessive Dystrophic Epidermolysis Bullosa: A Case Report.

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable inherited mucocutaneous fragility disorder characterized by recurrent blisters, erosions, and wounds. Continuous blistering triggers overlapping cycles of never-ending healing and scarring commonly evolving to chronic systemic inflammation and fibrosis. The systemic treatment with allogeneic mesenchymal cells (MSC) from bone marrow has previously shown benefits in RDEB. MSC from adipose tissue (ADMSC) are easier to isolate. This is the first report on the use of systemic allogeneic ADMSC, correlating the clinical, inflammatory, and immunologic outcomes in RDEB indicating long-lasting benefits. We present the case of an RDEB patient harboring heterozygous biallelic COL7A1 gene mutations and with a diminished expression of C7. The patient presented with long-lasting refractory and painful oral ulcers distressing her quality of life. Histamine receptor antagonists, opioid analgesics, proton-pump inhibitors, and low-dose tricyclic antidepressants barely improved gastric symptoms, pain, and pruritus. Concomitantly, allogeneic ADMSC were provided as three separate intravenous injections of 106 cells/kg every 21 days. ADMSC treatment was well-tolerated. Improvements in wound healing, itch, pain and quality of life were observed, maximally at 6-9 months post-treatment, with the relief of symptoms still noticeable for up to 2 years. Remarkably, significant modifications in PBL participating in both the innate and adaptive responses, alongside regulation of levels of profibrotic factors, MCP-1/CCL2 and TGF-ß, correlated with the health improvement. This treatment might represent an alternative for non-responding patients to conventional management. It seems critical to elucidate the paracrine modulation of the immune system by MSC for their rational use in regenerative/immunoregulatory therapies.

Evidence of ongoing complement activation on adipose tissue from an 11-year-old girl with Barraquer-Simons syndrome.

Barraquer-Simons syndrome (BSS), a form of acquired partial lipodystrophy, is a rare condition characterized by gradual loss of adipose tissue from the upper body, keeping intact the white adipose tissue of the lower extremities. The etiology of BSS is not well understood, and clinical follow-up studies have not been assessed in these patients. Moreover, no histological studies have been conducted during the active phase of the disease, and complement system activation products have not been sought in the affected areas. The objective of this work was to analyze the clinical, immunological and histological events in an 11-year-old girl with BSS over a 5-year follow-up period. Clinical data were collected during six regular visits for a time period of 5 years. The circulating levels of C3, C3adesArg (a product released upon C3 activation), C4 and immunoglobulins (Ig) were quantified in serum while fat tissue from lipoatrophic areas was examined by immunohistochemical and immunofluorescence approaches. In her regular visits, no clinical or laboratory abnormalities had been observed in the patient, except for the progression of lipoatrophy linked to the C3 hypocomplementemia and the occurrence of C3 nephritic factor. Adipose tissue from the patient showed atrophied and dead adipocytes, an abnormal production of extracellular matrix, and a remarkable accumulation of infiltrating CD68 macrophages and adipocyte precursors (marked by c-Kit positiveness). Simultaneous detection of IgG, C3, C5a and C5b-9 proved the ongoing complement activity and complement-directed injury within the adipose tissue. Our results showed the first evidence that the complement system hyperactivation occurs within the adipose tissue and is linked with fat loss in patients with BSS.

A six-attribute classification of genetic mosaicism.

Mosaicism denotes an individual who has at least two populations of cells with distinct genotypes that are derived from a single fertilized egg. Genetic variation among the cell lines can involve whole chromosomes, structural or copy-number variants, small or single-nucleotide variants, or epigenetic variants. The mutational events that underlie mosaic variants occur during mitotic cell divisions after fertilization and zygote formation. The initiating mutational event can occur in any types of cell at any time in development, leading to enormous variation in the distribution and phenotypic effect of mosaicism. A number of classification proposals have been put forward to classify genetic mosaicism into categories based on the location, pattern, and mechanisms of the disease. We here propose a new classification of genetic mosaicism that considers the affected tissue, the pattern and distribution of the mosaicism, the pathogenicity of the variant, the direction of the change (benign to pathogenic vs. pathogenic to benign), and the postzygotic mutational mechanism. The accurate and comprehensive categorization and subtyping of mosaicisms is important and has potential clinical utility to define the natural history of these disorders, tailor follow-up frequency and interventions, estimate recurrence risks, and guide therapeutic decisions.

Keratosis pilaris-like eruption secondary to nilotinib in a child.

Nilotinib is a new multitargeted tyrosine kinase inhibitor, which is used to treat chronic myelogenous leukemia when intolerance or recurrence to imatinib occurs. We report the case of a 14-year-old patient being treated with nilotinib who developed a keratosis pilaris-like eruption. This cutaneous adverse effect is a rare but increasingly reported side effect of this therapy.

Pharmacokinetics and safety of apremilast in pediatric patients with moderate to severe plaque psoriasis: Results from a phase 2 open-label study.

BACKGROUND: No oral systemic treatments are approved for pediatric patients with psoriasis. OBJECTIVE: To evaluate the pharmacokinetics and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in pediatric patients with psoriasis. METHODS: This phase 2, multicenter, open-label study enrolled pediatric patients with moderate to severe plaque psoriasis. Patients received apremilast twice daily without titration for 2 weeks (group 1 [age, 12-17 years; weight, ≥35 kg]: apremilast 20 or 30 mg; group 2 [age, 6-11 years; weight, ≥15 kg]: apremilast 20 mg), followed by a 48-week extension. Primary endpoints were pharmacokinetics and safety. Other endpoints were taste/acceptability and change from baseline in score on the Psoriasis Area and Severity Index. RESULTS: A total of 42 enrolled patients (21 adolescents [age, 12-17 years] and 21 children [age, 6-11 years]) received apremilast. Pharmacokinetics modeling and noncompartmental analyses showed that weight-based dosing with apremilast 20 mg twice daily in children or apremilast 20 or 30 mg twice daily in adolescents provides exposure (area under the concentration-time curve from time 0 to 12 hours after the dose) that is comparable to that achieved with apremilast 30 mg twice daily in adults. The safety profile was generally similar to that in adults. Most study participants liked the taste of the tablet. Improvements from baseline in mean Psoriasis Area and Severity Index score were 68% for adolescents (overall) and 79% for children. LIMITATIONS: No children weighing less than 20 kg were enrolled. CONCLUSIONS: This first-time-in-children phase 2 study supports weight-based apremilast dosing for future phase 3 studies of pediatric plaque psoriasis.

New Cosmetic Formulation for the Treatment of Mild to Moderate Infantile Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic cutaneous inflammatory disorder, characterized by skin barrier disruption. Dermacare is a new cosmetic formulation, which enhances moisturization, reinforces and repairs the skin barrier, and prevents cutaneous microbiota imbalance. To demonstrate its safety and efficacy, a prospective, open-label, and multicenter study was carried out on patients diagnosed with mild to moderate AD. Transepidermal water loss (TEWL), clinical severity, Desquamation Index, Patient/Investigator Global Assessments, quality of life index, and tolerance were assessed. Adverse events were recorded. Daily application of the new treatment was well tolerated, and adverse events were absent. After 14 days, TEWL showed a 36.7% significant decrease (p = 0.035). At the end of the 28-day treatment, the Desquamation Index showed a reduction in 70% of patients; Eczema Area and Severity Index were reduced by 70.4% (p = 0.002); and skin irritation showed a significant reduction (p = 0.024). Likewise, Patient and Investigator Global Assessments reported a significant improvement in conditions and an overall global worsening when patients restarted their normal treatment. Parent's Index of Quality of Life Index significantly increased by 36.4% (p < 0.05) with Dermacare. In conclusion, a regular use of this new formulation can reduce the risk of relapse and extend the steroid-free treatment periods.

Mutations in PERP Cause Dominant and Recessive Keratoderma.

Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds. Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers. Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress. Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins. These discoveries highlight the essential role of PERP in human desmosomes and epidermal homeostasis and further expand the heterogeneous spectrum of inherited keratinization disorders.

Congenital tufted angioma: A multicenter retrospective study of 30 cases.

BACKGROUND: Recent reports indicate that tufted angioma is a rare vascular neoplasm that manifests more frequently at birth than previously thought. Few studies specifically address congenital presentation. OBJECTIVES: We analyzed the clinicopathological characteristics, clinical course, and treatment of congenital tufted angioma (cTA) and evaluated variables that were indicative of problematic lesions. METHODS: We performed an observational retrospective study of 30 patients with cTA in 9 Spanish hospitals over a 14-year period. Histopathology and immunohistochemistry studies were performed. RESULTS: Congenital tufted angioma mainly affected the limbs (56.67%), followed by the face and/or neck (23.33%). Almost three-quarters of facial cTA were located over the mandibular area. Immunohistochemically, proliferating cells expressed markers of endothelial cells, with some clusters of cells, especially at the periphery of the aggregates, showing positivity for podoplanin. As no associated complications were observed in 66.67% of cases, no treatment was started. LIMITATIONS: Data were collected retrospectively. CONCLUSIONS: Our findings emphasize the clinical features and course of cTA. The possibility of cTA should be considered when a poorly defined congenital infiltrative vascular tumor with(out) overlying hirsutism appears over the mandibular area. Location on the face and/or neck requires a more comprehensive workup, since potentially severe complications often appear early.

Ulcerated congenital plexiform fibrohistiocytic tumor: Case report and literature review.

A newborn boy presented with a progressively infiltrating and painful congenital ulcerated plaque on the back of his left foot. A partial excision was performed and histopathologic examination confirmed a diagnosis of a plexiform fibrohistiocytic tumor. This rare tumor usually appears in children and adolescents, with congenital presentations even more uncommon. This case details the exceptional presentation of a congenital ulcerated plexiform fibrohistiocytic tumor with a review of the current literature.

Identical COL71A1 heterozygous mutations resulting in different dystrophic epidermolysis bullosa phenotypes.

Dystrophic epidermolysis bullosa is a rare blistering condition caused by mutations in the COL7A1 gene. Different clinical variants have been described, with dominant and recessive inheritance, but no consistent findings have been elucidated to establish a genotype-phenotype correlation. We present three unrelated patients with two identical pathogenic compound heterozygous mutations in the COL7A1 gene that developed different clinical forms of dystrophic epidermolysis bullosa-epidermolysis bullosa pruriginosa and mild recessive non-Hallopeau-Siemens-raising the possibility of other genetic or environmental modifying factors responsible for the phenotype of the disease.

Fever and Multiple Eschars After an African Safari: Report of Three Cases.

African tick-bite fever (ATBF), a tickborne disease endemic in rural areas of sub-Saharan Africa and the West Indies caused by Rickettsia africae, has been recognized as an emerging health problem in recent years. ATBF has been reported as the second most commonly documented etiology of fever, after malaria, in travelers who return ill from sub-Saharan Africa. Most cases reported in the literature occurred in middle-aged adults, so the incidence of ATBF in children is unclear. We report a cluster of three cases of ATBF that occurred in children ages 7 to 16 years after returning from a game-hunting safari in South Africa.