Unveiling the value of C-reactive protein as a severity biomarker and the IL4/IL13 pathway as a therapeutic target in recessive dystrophic epidermolysis bullosa: A multiparametric cross-sectional study.

Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience numerous complications, which are exacerbated by inflammatory dysregulation and infection. Understanding the immunological mechanisms is crucial for selecting medications that balance inflammation control and immunocompetence. In this cross-sectional study, aiming to identify potential immunotherapeutic targets and inflammatory biomarkers, we delved into the interrelationship between clinical severity and systemic inflammatory parameters in a representative RDEB cohort. Encompassing 84 patients aged 1-67 and spanning all three Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) severity categories, we analysed the interrelationship of infection history, standard inflammatory markers, systemic cytokines and Ig levels to elucidate their roles in RDEB pathophysiology. Our findings identify C-reactive protein as an excellent biomarker for disease severity in RDEB. A type 2 inflammatory profile prevails among moderate and severe RDEB patients, correlating with dysregulated circulating IgA and IgG. These results underscore the IL4/IL13 pathways as potential evidence-based therapeutic targets. Moreover, the complete inflammatory scenario aligns with Staphylococcus aureus virulence mechanisms. Concurrently, abnormalities in IgG, IgE and IgM levels suggest an immunodeficiency state in a substantial number of the cohort's patients. Our results provide new insights into the interplay of infection and immunological factors in the pathogenesis of RDEB.

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.

A new topical biotechnological phytocomplex for truncal mild-moderate acne restores skin microbiota balance.

BACKGROUND: The disruption of the microbial community or dysbiosis alters the functional composition, metabolic activity, and local distribution of the microbiota leading the development of acne. The aim of this study is to evaluate the effect of a lotion containing a biotechnological phytocomplex, niacinamide, and succinic acid in the bacterial diversity of subjects with truncal mild-moderate acne and its clinical benefits due to microbiota changes. MATERIALS AND METHODS: Open, clinical study in 43 subjects with truncal mild-moderate acne treated with a lotion for 8 weeks. Bacterial diversity was analyzed by 16S rRNA gene sequencing of skin samples. Clinical effects were evaluated through IGA acne severity scale, biometric measurements, and safety. RESULTS: After 56 days of product's use, an increase in richness alpha diversity was found (p = 0.005), with a decrease in Cutibacterium acnes relative abundance (66.43% vs. 58.11%, p = 0.009). The clinical results showed a decrease in IGA score (27.59% decrease; p = 0.001), the inflammatory lesions (52.12% decrease, p = 0.006) and erythema (18.33% decrease, p = 0.007), and desquamation index (63.83% decrease, p = 0.02). The responder analysis of the IGA score showed that 60.47% of patients improved by at least one point at day 56. The product was well tolerated along the study. CONCLUSION: The use of the lotion on acneic skin was effective on rebalancing the microbiota, inhibiting biofilm formation and other virulence factors, reducing erythema and desquamation, and improving acne's severity.

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).

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.

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.

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.

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.

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.

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.

Identification of two rare and novel large deletions in ITGB4 gene causing epidermolysis bullosa with pyloric atresia.

Epidermolysis bullosa with pyloric atresia (EB-PA) is a rare autosomal recessive hereditary disease with a variable prognosis from lethal to very mild. EB-PA is classified into Simplex form (EBS-PA: OMIM #612138) and Junctional form (JEB-PA: OMIM #226730), and it is caused by mutations in ITGA6, ITGB4 and PLEC genes. We report the analysis of six patients with EB-PA, including two dizygotic twins. Skin immunofluorescence epitope mapping was performed followed by PCR and direct sequencing of the ITGB4 gene. Two of the patients presented with non-lethal EB-PA associated with missense ITGB4 gene mutations. For the other four, early postnatal demise was associated with complete lack of ß4 integrin due to a variety of ITGB4 novel mutations (2 large deletions, 1 splice-site mutation and 3 missense mutations). One of the deletions spanned 278 bp, being one of the largest reported to date for this gene. Remarkably, we also found for the first time a founder effect for one novel mutation in the ITGB4 gene. We have identified 6 novel mutations in the ITGB4 gene to be added to the mutation database. Our results reveal genotype-phenotype correlations that contribute to the molecular understanding of this heterogeneous disease, a pivotal issue for prognosis and for the development of novel evidence-based therapeutic options for EB management.

Notalgia Paresthetica and Multiple Endocrine Neoplasia Syndrome 2A: A Case Report.

Notalgia paresthetica is characterized by a hyperpigmented macular pruritic skin lesion most commonly localized unilaterally in the middle and upper back region. This condition has been reported in association with multiple endocrine neoplasia syndrome type 2A (MEN 2A) in several families; it rarely affects children and it may serve as an early marker of MEN 2A. We report a 9-year-old girl diagnosed with MEN 2A and notalgia paresthetica.

Adherence to drug treatments and adjuvant barrier repair therapies are key factors for clinical improvement in mild to moderate acne: the ACTUO observational prospective multicenter cohort trial in 643 patients.

BACKGROUND: In acne, several studies report a poor adherence to treatments. We evaluate, in a real-life setting conditions, the impact of compliance to physician's instructions, recommendations and adherence to the treatments on clinical outcome in patients with mild to moderate acne in an observational, non-interventional prospective study carried out in 72 Dermatologic Services in Spain (ACTUO Trial). METHODS: Six-hundred-forty-three subjects were enrolled and 566 patients (88 %) completed the 3 study visits. Study aimed to evaluate the impact of adherence (assessed with ECOB scale) on clinical outcome, as well as how the use of specific adjuvant treatments (facial cleansing, emollient, moisturizing and lenitive specific topical products) influences treatment's adherence and acne severity (0-5 points score). Recommendation of specific adjuvant skin barrier repair products was made in 85.2 %. RESULTS: Overall, clinical improvement was observed throughout follow-up visits with an increased proportion of patients who reported reductions of ≥50 % on the total number of lesions (2 months: 25.2 %; 3 months: 57.6 %) and reductions of severity scores (2.5, 2.0 and 1.3 at 1, 2 and 3 months after treatment, respectively). Adherence to treatment was associated with a significant reduction on severity grading, a lower number of lesions and a higher proportion of patients with ≥50 % improvement. CONCLUSIONS: Good adherence to medication plus adherence to adjuvants was significantly associated with a higher clinical improvement unlike those that despite adherence with medication had a low adherence to adjuvants. A good adherence to adjuvant treatment was associated with improved adherence and better treatment outcomes in mild to moderate acne patients. (ISRCTN Registry: ISRCTN14257026).

New clinical approach in facial mild-moderate acne: Re-stabilization of skin microbiota balance with a topical biotechnological phytocomplex.

OBJECTIVES: Dysbiosis of the skin microbiota has been identified as a key factor in the development of acne. This study was aimed to evaluate the effect of a facial cream gel containing a biotechnological phytocomplex, niacinamide and succinic acid on the bacterial diversity of subjects with mild-moderate acne and its clinical benefits due to microbiota changes. METHODS: Open-label, clinical study in 44 subjects with mild-moderate acne treated with a facial cream gel for 8 weeks. Bacterial diversity was analyzed by 16S rRNA gene sequencing of skin samples. Clinical effects were evaluated using the IGA acne severity scale, biometric measurements, and safety. RESULTS: After 56 days of product's use, an increase in alpha and beta diversity was found (p < 0.01), with a decrease in the relative abundance of C. acnes (48.99% vs. 38.83%, p < 0.001). Regarding clinical results, a decrease in acne severity on the IGA scale (27.33%, p < 0.001), number of non-inflammatory and inflammatory lesions (respectively: 31.12%, p = 0.05; 47.27%, p < 0.001), amount of sebum (89.00%, p < 0.01) and erythema (15.35%, p < 0.01), was found. [Correction added on 19 September 2024, after first online publication: In the preceding sentence, "42.27%" has been changed to "47.27%" in this version.] Responder analysis of the IGA score showed that 61.36% of patients improved by at least one point at day 56. The product was well tolerated throughout the study. CONCLUSIONS: The use of the facial cream gel on skin was effective in rebalancing the microbiota, inhibiting biofilm formation and other virulence factors, reducing the number of mild-moderate acne lesions and sebum secretion, and consequently improving acne's severity.

Postvaccination bullous pemphigoid in infancy: report of three new cases and literature review.

Bullous pemphigoid (BP) is an acquired autoimmune blistering disorder of unknown etiology uncommon in childhood. Unlike adult BP, infantile BP shows acral distribution and resolves rapidly with systemic steroids. We report three infants with infantile BP presenting shortly after vaccination for diphtheria, pertussis, tetanus, poliomyelitis, hepatitis B, Haemophilus influenzae B, and meningococcus C. Our cases further reinforce the causal association between childhood BP and vaccination.

(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.

Prevalence of autosomal recessive congenital ichthyosis: a population-based study using the capture-recapture method in Spain.

BACKGROUND: Previous reports on the prevalence of autosomal recessive congenital ichthyosis (ARCI) were based on single source data, such as lists of members in a patient association. These sources are likely to be incomplete. OBJECTIVES: We sought to describe the prevalence of ARCI. METHODS: We obtained data from 3 incomplete sources (dermatology departments, a genetic testing laboratory, and the Spanish ichthyosis association) and combined them using the capture-recapture method. RESULTS: We identified 144 living patients with ARCI. Of these, 62.5% had classic lamellar ichthyosis and 30.6% had congenital ichthyosiform erythroderma. The age distribution included fewer elderly patients than expected. The prevalence of ARCI in patients younger than 10 years, the best estimate as less subject to bias, was 16.2 cases per million inhabitants (95% confidence interval 13.3-23.0). According to the capture-recapture model, 71% of the patients were not being followed up in reference units, 92% did not have a genetic diagnosis, and 78% were not members of the ichthyosis association. LIMITATIONS: The prevalence of ARCI in Spain and findings related to the Spanish health care system might not be generalizable to other countries. CONCLUSIONS: The prevalence of ARCI is higher than previously reported. Many patients are not being followed up in reference units, do not have a genetic diagnosis, and are not members of a patient association, indicating room for improvement in their care. Data suggesting a reduced number of older patients might imply a shorter life expectancy and this requires further study.