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As with adults, paediatric patients may benefit from a number of advanced targeted therapies for inflammatory skin disease. This brief report aims to be an accessible reference tool with respect to regulatory approval and reimbursement of these treatments within Australia.
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Fármacos Dermatológicos , Humanos , Austrália , Criança , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Ustekinumab/uso terapêutico , Ustekinumab/administração & dosagem , Dermatopatias/tratamento farmacológicoRESUMO
BACKGROUND: Itch is common and distressing in epidermolysis bullosa (EB) but has not previously been studied in depth in different recessive dystrophic EB (RDEB) subtypes. OBJECTIVES: As part of a prospective register study of the natural history of RDEB we explored features of itch, medications used, and correlation with disease severity and quality of life. METHODS: Fifty individuals with RDEB aged 8 years and above completed the Leuven Itch Scale (LIS) (total 243 reviews over a 7-year period). Data included itch frequency, severity, duration, distress, circumstances, consequences, itch surface area and medications for itch. The iscorEB disease severity score and the validated EB quality of life tool, QOLEB, were compared to LIS domains and analysed by RDEB subtype. RESULTS: Itch was frequent, present in the preceding month in 93% of reviews. Itch severity and distress were significantly greater in severe (RDEB-S) and pruriginosa (RDEB-Pru) subtypes compared to intermediate RDEB (RDEB-I). Itch medications were reported in just over half of reviews including emollients, topical corticosteroids and antihistamines; the proportion of participants not using medication despite frequent pruritus suggests limited efficacy. In inversa RDEB (RDEB-Inv) and RDEB-I, LIS domains correlated with iscorEB and QOLEB. In contrast to previous studies, correlations were lacking in RDEB-S suggesting that global disease burden relatively reduces the contribution of itch. CONCLUSIONS: This comprehensive study of RDEB-associated itch highlights differences between RDEB subtypes, suggests an unmet need for effective treatments and could serve as control data for future clinical trials incorporating itch as an endpoint.
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Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Humanos , Epidermólise Bolhosa Distrófica/complicações , Qualidade de Vida , Epidermólise Bolhosa/complicações , Prurido , Estudos ProspectivosRESUMO
Alterations in the microbiome correlate with improved metabolism in patients following bariatric surgery. While fecal microbiota transplantation (FMT) from obese patients into germ-free (GF) mice has suggested a significant role of the gut microbiome in metabolic improvements following bariatric surgery, causality remains to be confirmed. Here, we perform paired FMT from the same obese patients (BMI > 40; four patients), pre- and 1 or 6 months post-Roux-en-Y gastric bypass (RYGB) surgery, into Western diet-fed GF mice. Mice colonized by FMT from patients' post-surgery stool exhibit significant changes in microbiota composition and metabolomic profiles and, most importantly, improved insulin sensitivity compared with pre-RYGB FMT mice. Mechanistically, mice harboring the post-RYGB microbiome show increased brown fat mass and activity and exhibit increased energy expenditure. Moreover, improvements in immune homeostasis within the white adipose tissue are also observed. Altogether, these findings point to a direct role for the gut microbiome in mediating improved metabolic health post-RYGB surgery.
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Cirurgia Bariátrica , Microbioma Gastrointestinal , Resistência à Insulina , Camundongos , Animais , Tecido Adiposo Marrom , Obesidade/cirurgia , Metabolismo EnergéticoRESUMO
The breakdown of the intestinal mucosal barrier is thought to underlie the progression to Crohn disease (CD), whereby numerous risk factors contribute. For example, a genetic polymorphism of the autophagy gene ATG16L1, associated with an increased risk of developing CD, contributes to the perturbation of the intestinal epithelium. We examined the role of Atg16l1 in protecting the murine small intestinal epithelium from T-cell-mediated damage using the anti-CD3 model of enteropathy. Our work showed that mice specifically deleted for Atg16l1 in intestinal epithelial cells (IECs) (Atg16l1ΔIEC) had exacerbated intestinal damage, characterized by crypt epithelial cell death, heightened inflammation, and decreased survival. Moreover, Atg16l1 deficiency delayed the recovery of the intestinal epithelium, and Atg16l1-deficient IECs were impaired in their proliferative response. Pathology was largely driven by interferon (IFN)-γ signaling in Atg16l1ΔIEC mice. Mechanistically, although survival was rescued by blocking tumor necrosis factor or IFN-γ independently, only anti-IFN-γ treatment abrogated IEC death in Atg16l1ΔIEC mice, thereby decoupling IEC death and survival. In summary, our findings suggest differential roles for IFN-γ and tumor necrosis factor in acute enteropathy and IEC death in the context of autophagy deficiency and suggest that IFN-γ-targeted therapy may be appropriate for patients with CD with variants in ATG16L1.
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Proteínas Relacionadas à Autofagia , Doença de Crohn , Mucosa Intestinal , Animais , Camundongos , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Morte Celular/genética , Doença de Crohn/genética , Doença de Crohn/patologia , Interferon gama/metabolismo , Interferon gama/farmacologia , Enteropatias/metabolismo , Enteropatias/patologia , Mucosa Intestinal/metabolismo , Intestinos/metabolismo , Intestinos/patologia , Fator de Necrose Tumoral alfaRESUMO
Invariant Natural Killer T (iNKT) cells are unconventional T cells that respond to glycolipid antigens found in microbes in a CD1d-dependent manner. iNKT cells exert innate-like functions and produce copious amounts of cytokines, chemokines and cytotoxic molecules within only minutes of activation. As such, iNKT cells can fuel or dampen inflammation in a context-dependent manner. In addition, iNKT cells provide potent immunity against bacteria, viruses, parasites and fungi. Although microbiota-iNKT cell interactions are not well-characterized, mounting evidence suggests that microbiota colonization early in life impacts iNKT cell homeostasis and functions in disease. In this study, we showed that CD1d-/- and Vα14 Tg mice, which lack and have increased numbers of iNKT cells, respectively, had no significant alterations in gut microbiota composition compared to their littermate controls. Furthermore, specific iNKT cell activation by glycolipid antigens only resulted in a transient and minimal shift in microbiota composition when compared to the natural drift found in our colony. Our findings demonstrate that iNKT cells have little to no influence in regulating commensal bacteria at steady state.Abbreviations: iNKT: invariant Natural Killer T cell; αGC: α-galactosylceramide.
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Microbioma Gastrointestinal , Microbiota , Células T Matadoras Naturais , Animais , Citocinas , Glicolipídeos , CamundongosRESUMO
Segmental infantile hemangiomas affecting the upper body are associated with PHACE(S) (Posterior fossa anomalies, Hemangioma, Arterial anomalies, Cardiac anomalies, Eye anomalies, and Sternal defects) syndrome, whereas segmental infantile hemangiomas affecting the lower body are the cutaneous hallmark of LUMBAR (Lower body hemangioma and other skin defects, Urogenital anomalies and Ulceration, Myelopathy, Bony deformities, Anorectal malformations and Arterial anomalies, and Renal anomalies) syndrome. We present two individuals with concurrent features of both PHACE and LUMBAR syndromes demonstrating an overlap phenotype. The overlapping features seen in our patients suggest that these syndromes occur on the same phenotypic spectrum and derive from a common embryonic pathophysiology.
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Anormalidades Múltiplas , Coartação Aórtica , Anormalidades do Olho , Hemangioma , Síndromes Neurocutâneas , Anormalidades Múltiplas/diagnóstico , Anormalidades do Olho/diagnóstico , Hemangioma/diagnóstico , Humanos , Síndromes Neurocutâneas/diagnóstico , SíndromeRESUMO
BACKGROUND: There is limited evidence on the best available treatment options for capillary malformations (CMs), mainly due to the absence of uniform outcome measures in trials on therapies. A core outcome set (COS) enables standard reporting of trial outcomes, which facilitates comparison of treatment results. OBJECTIVES: To develop a core outcome domain set (CDS), as part of a core outcome set (COS), for clinical research on CMs. METHODS: Sixty-seven potentially relevant outcome subdomains were recognized based on the literature, focus group sessions, and input from the COSCAM working group. These outcome subdomains were presented in an online Delphi study to CM experts (medical specialists and authors of relevant literature) and (parents of) patients with CM (international patient associations). During three e-Delphi study rounds, the participants repeatedly scored the importance of these outcome subdomains on a seven-point Likert scale. Participants could also propose other relevant outcome subdomains. Consensus was defined as ≥ 80% agreement as to the importance of an outcome subdomain among both stakeholder groups. The CDS was finalized during an online consensus meeting. RESULTS: In total 269 participants from 45 countries participated in the first e-Delphi study round. Of these, 106 were CM experts from 32 countries, made up predominantly of dermatologists (59%) and plastic surgeons (18%). Moreover, 163 (parents of) patients with CM from 28 countries participated, of whom 58% had Sturge-Weber syndrome. During the two subsequent e-Delphi study rounds, 189 and 148 participants participated, respectively. After the entire consensus process, consensus was reached on 11 outcome subdomains: colour/redness, thickness, noticeability, distortion of anatomical structures, glaucoma, overall health-related quality of life, emotional functioning, social functioning, tolerability of intervention, patient satisfaction with treatment results, and recurrence. CONCLUSIONS: We recommend the CDS to be used as a minimum reporting standard in all future trials of CM therapy. Our next step will be to select suitable outcome measurement instruments to score the core outcome subdomains. What is already known about this topic? Besides physical and functional sequelae, capillary malformations (CMs) often cause emotional and social burden. The lack of uniform outcome measures obstructs proper evaluation and comparison of treatment strategies. As a result, there is limited evidence on the best available treatment options. The development of a core outcome set (COS) may improve standardized reporting of trial outcomes. What does this study add? A core outcome domain set (CDS), as part of a COS, was developed for clinical research on CMs. International consensus was reached on the recommended core outcome subdomains to be measured in CM trials: colour/redness, thickness, noticeability, distortion of anatomical structures, glaucoma, overall health-related quality of life, emotional functioning, social functioning, tolerability of intervention, patient satisfaction with treatment results, and recurrence. This CDS enables the next step in the development of a COS, namely to reach consensus on the core outcome measurement instruments to score the core outcome subdomains. What are the clinical implications of this work? The obtained CDS will facilitate standardized reporting of treatment outcomes, thereby enabling proper comparison of treatment results. This comparison is likely to provide more reliable information for patients about the best available treatment options.
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Glaucoma , Qualidade de Vida , Humanos , Consenso , Técnica Delphi , Avaliação de Resultados em Cuidados de Saúde , Projetos de Pesquisa , Resultado do Tratamento , Ensaios Clínicos como AssuntoRESUMO
An infant girl developed a hemangioma affecting her left iris concurrently with diffuse cutaneous infantile hemangiomas from day 2 of life. Intraocular hemangiomas are rarely reported and are usually associated with neonatal hemangiomatosis, the presence of which indicates a high risk for visceral lesions. This striking case highlights the unusual clinical presentation of iris hemangioma and demonstrates the importance of conducting visceral screening when faced with these lesions. Oral propranolol was commenced and resulted in rapid improvement of all lesions without complication.
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Hemangioma Capilar , Hemangioma , Neoplasias Cutâneas , Feminino , Hemangioma/diagnóstico , Hemangioma/tratamento farmacológico , Hemangioma Capilar/diagnóstico , Hemangioma Capilar/tratamento farmacológico , Humanos , Recém-Nascido , Iris , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
BACKGROUND: The success of clinical trials in Epidermolysis Bullosa (EB) is dependent upon the availability of a valid and reliable scoring tool that can accurately assess and monitor disease severity. The Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) and Instrument for Scoring Clinical Outcomes of Research for Epidermolysis Bullosa (iscorEB) were independently developed and validated against the Birmingham Epidermolysis Bullosa Severity Score but have never been directly compared. OBJECTIVE: To compare the reliability, convergent validity, and discriminant validity of the EBDASI and iscorEB scoring tools. METHODS: An observational cohort study was conducted in 15 patients with EB. Each patient was evaluated using the EBDASI and iscorEB-clinician scoring tools by 6 dermatologists with expertise in EB. Quality of life was assessed using the iscorEB-patient and Quality of Life in EB measures. RESULTS: The intraclass correlation coefficients for interrater reliability were 0.942 for the EBDASI and 0.852 for the iscorEB-clinician. The intraclass correlation coefficients for intrarater reliability was 0.99 for both scores. The two tools demonstrated strong convergent validity with each other. CONCLUSION: Both scoring tools demonstrate excellent reliability. The EBDASI appears to better discriminate between EB types and disease severities.
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Epidermolysis bullosa (EB), notably severe recessive dystrophic EB (RDEB-S), is associated with increased risk of aggressive mucocutaneous squamous cell carcinomas, the major cause of mortality in early adulthood. This observational, retrospective case review describes a series of EB patients with cutaneous squamous cell carcinomas over a 28-year period. Forty-four EB patients with squamous cell carcinomas were identified with a total of 221 primary tumours. They comprised: 31 (70%) with RDEB-S, 4 (9%) with other RDEB subtypes, 5 (11.4%) with dominant dystrophic EB, 3 (6.8%) with intermediate junctional EB and 1 (2.3%) with Kindler EB. Squamous cell carcinomas occurred earlier in RDEB-S (median age 29.5 years; age range 13-52 years) than other groups collectively (median age 47.1 years; age range 30-89 years) and most had multiple tumours (mean 5.8; range 1-44). Squamous cell carcinoma-associated mortality was high in RDEB-S (64.5%), with median survival after first squamous cell carcinoma of 2.4 years (range 0.5-12.6 years), significantly lower than previous reports, highlighting the need for early surveillance and better treatments.
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Carcinoma de Células Escamosas , Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Neoplasias Cutâneas , Adolescente , Adulto , Carcinoma de Células Escamosas/terapia , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/diagnóstico , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
IMPORTANCE: Spitz nevi are benign melanocytic neoplasms that classically present in childhood. Isolated Spitz nevi have been associated with oncogenic gene fusions in approximately 50% of cases. The rare agminated variant of Spitz nevi, thought to arise from cutaneous genetic mosaicism, is characterized by development of clusters of multiple lesions in a segmental distribution, which can complicate surgical removal. Somatic single-nucleotide variants in the HRAS oncogene have been described in agminated Spitz nevi, most of which were associated with an underlying nevus spilus. The use of targeted medical therapy for agminated Spitz nevi is not well understood. OBSERVATIONS: A girl aged 30 months presented with facial agminated Spitz nevi that recurred rapidly and extensively after surgery. Owing to the morbidity of further surgery, referral was made to a molecular tumor board. The patient's archival nevus tissue was submitted for extended immunohistochemical analysis and genetic sequencing. Strong ROS1 protein expression was identified by immunohistochemistry. Consistent with this, analysis of whole-genome sequencing data revealed GOPC-ROS1 fusions. These results indicated likely benefit from the oral tyrosine kinase inhibitor crizotinib, which was administered at a dosage of 280 mg/m2 twice daily. An excellent response was observed in all lesions within 5 weeks, with complete flattening after 20 weeks. CONCLUSIONS AND RELEVANCE: Given the response following crizotinib treatment observed in this case, the kinase fusion was believed to be functionally consequential in the patient's agminated Spitz nevi and likely the driver mutational event for growth of her nevi. The repurposing of crizotinib for GOPC-ROS1 Spitz nevi defines a new treatment option for these lesions, particularly in cases for which surgery is relatively contraindicated.
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Crizotinibe , Nevo de Células Epitelioides e Fusiformes , Neoplasias Cutâneas , Proteínas Adaptadoras de Transdução de Sinal , Pré-Escolar , Crizotinibe/uso terapêutico , Feminino , Proteínas da Matriz do Complexo de Golgi , Humanos , Recidiva Local de Neoplasia , Nevo de Células Epitelioides e Fusiformes/diagnóstico , Nevo de Células Epitelioides e Fusiformes/tratamento farmacológico , Nevo de Células Epitelioides e Fusiformes/genética , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genéticaRESUMO
Heterozygous missense mutations in the human COL7A1 gene - coding for collagen VII - lead to the rare, dominantly inherited skin disorder dominant dystrophic epidermolysis bullosa (DDEB), which is characterised by skin fragility, blistering, scarring and nail dystrophy. To better understand the pathophysiology of DDEB and develop more effective treatments, suitable mouse models for DDEB are required but to date none have existed. We identified the two most common COL7A1 mutations in DDEB patients (p.G2034R and p.G2043R) and used CRISPR-Cas9 to introduce the corresponding mutations into mouse Col7a1 (p.G2028R and p.G2037R). Dominant inheritance of either of these two alleles results in a phenotype that closely resembles that seen in DDEB patients. Specifically, mice carrying these alleles show recurrent blistering that is first observed transiently around the mouth and paws in the early neonatal period and then again around the digits from 5-10â weeks of age. Histologically, the mice show micro-blistering and reduced collagen VII immunostaining. Biochemically, collagen VII from these mice displays reduced thermal stability, which we also observed to be the case for DDEB patients carrying the analogous mutations. Unlike previous rodent models of epidermolysis bullosa, which frequently show early lethality and severe disease, these mouse models, which to our knowledge are the first for DDEB, show no reduction in growth and survival, and - together with a relatively mild phenotype - represent a practically and ethically tractable tool for better understanding and treating epidermolysis bullosa. This article has an associated First Person interview with the first author of the paper.
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Epidermólise Bolhosa Distrófica/genética , Mutação Puntual , Animais , Sistemas CRISPR-Cas , Colágeno Tipo VII/genética , Modelos Animais de Doenças , Humanos , CamundongosAssuntos
Betacoronavirus/imunologia , Consenso , Infecções por Coronavirus/prevenção & controle , Epidermólise Bolhosa/terapia , Pandemias/prevenção & controle , Equipe de Assistência ao Paciente/normas , Pneumonia Viral/prevenção & controle , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/transmissão , Epidermólise Bolhosa/imunologia , Humanos , Comunicação Interdisciplinar , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/transmissão , Guias de Prática Clínica como Assunto , SARS-CoV-2RESUMO
Breast cancer is the most common cancer in women worldwide. Most current guidelines recommend using multigene profiling assays to aid the decision on the addition of chemotherapy to adjuvant hormone therapy for women who present with early-stage, hormone receptor-positive, HER2-negative disease. One of these assays is the Oncotype DX, which predicts the disease recurrence risk and adjuvant chemotherapy benefits. Given its high cost, there is an economic incentive to evaluate its surrogates, such as the Magee equations. We assessed health system costs associated with the use of the Magee scores. A probabilistic decision tree was used to calculate the difference in mean health system costs based on data obtained from a randomized trial and the published literature. Costs were calculated from a perspective of Canada's publicly funded health care system. A series of sensitivity analysis was conducted to assess the robustness of the study findings. The Magee equations were associated with a total cost savings of C$100 per patient (95% CI, -C$3068 to C$5022) compared with standard of care. The difference in costs was highly sensitive to the extent that the Magee scores could reduce the frequency of adjuvant chemotherapy and Oncotype DX requests.
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Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Custos e Análise de Custo , Testes Diagnósticos de Rotina , Feminino , Humanos , RiscoRESUMO
Prostaglandin E2 receptor EP1 (PGE2/EP1) promotes diabetic renal injury, and EP1 receptor deletion improves hyperfiltration, albuminuria, and fibrosis. The role of EP1 receptors in hypertensive kidney disease (HKD) remains controversial. We examined the contribution of EP1 receptors to HKD. EP1 null (EP1-/-) mice were bred with hypertensive TTRhRen mice (Htn) to evaluate kidney function and injury at 24 weeks. EP1 deletion had no effect on elevation of systolic blood pressure in Htn mice (HtnEP1-/-) but resulted in pronounced albuminuria and reduced FITC-inulin clearance, compared with Htn or wild-type (WT) mice. Ultrastructural injury to podocytes and glomerular endothelium was prominent in HtnEP1-/- mice; including widened subendothelial space, subendothelial lucent zones and focal lifting of endothelium from basement membrane, with focal subendothelial cell debris. Cortex COX2 mRNA was increased by EP1 deletion. Glomerular EP3 mRNA was reduced by EP1 deletion, and EP4 by Htn and EP1 deletion. In WT mice, PGE2 increased chloride reabsorption via EP1 in isolated perfused thick ascending limb (TAL), but PGE2 or EP1 deletion did not affect vasopressin-mediated chloride reabsorption. In WT and Htn mouse inner medullary collecting duct (IMCD), PGE2 inhibited vasopressin-water transport, but not in EP1-/- or HtnEP1-/- mice. Overall, EP1 mediated TAL and IMCD transport in response to PGE2 is unaltered in Htn, and EP1 is protective in HKD.