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Clinical Journal of the American... Jul 2021Patients with kidney failure report a high symptom burden, which likely increases while on dialysis due to physical and mental stressors and decreases after kidney...
BACKGROUND AND OBJECTIVES
Patients with kidney failure report a high symptom burden, which likely increases while on dialysis due to physical and mental stressors and decreases after kidney transplantation due to restoration of kidney function.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
We leveraged a two-center prospective study of 1298 kidney transplant candidates and 521 recipients (May 2014 to March 2020). Symptom scores (0-100) at evaluation and admission for transplantation were calculated using the Kidney Disease Quality of Life Short-Form Survey, where lower scores represent greater burden, and burden was categorized as very high: 0.0-71.0; high: 71.1-81.0; medium: 81.1-91.0; and low: 91.1-100.0. We estimated adjusted waitlist mortality risk (competing risks regression), change in symptoms between evaluation and transplantation (=190), and post-transplantation symptom score trajectories (mixed effects models).
RESULTS
At evaluation, candidates reported being moderately to extremely bothered by fatigue (32%), xeroderma (27%), muscle soreness (26%), and pruritus (25%); 16% reported high and 21% reported very high symptom burden. Candidates with very high symptom burden were at greater waitlist mortality risk (adjusted subdistribution hazard ratio, 1.67; 95% confidence interval, 1.06 to 2.62). By transplantation, 34% experienced an increased symptom burden, whereas 42% remained unchanged. The estimated overall symptom score was 82.3 points at transplantation and 90.6 points at 3 months (10% improvement); the score increased 2.75 points per month (95% confidence interval, 2.38 to 3.13) from 0 to 3 months, and plateaued (-0.06 points per month; 95% confidence interval, -0.30 to 0.18) from 3 to 12 months post-transplantation. There were early (first 3 months) improvements in nine of 11 symptoms; pruritus (23% improvement) and fatigue (21% improvement) had the greatest improvements.
CONCLUSIONS
Among candidates, very high symptom burden was associated with waitlist mortality, but for those surviving and undergoing kidney transplantation, symptoms improved.
Topics: Adult; Aged; Fatigue; Female; Humans; Ichthyosis; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Myalgia; Postoperative Period; Preoperative Period; Prospective Studies; Pruritus; Quality of Life; Risk Assessment; Symptom Assessment; Waiting Lists
PubMed: 34597266
DOI: 10.2215/CJN.19031220 -
Frontiers in Immunology 2022Netherton syndrome is a rare, life-threatening autosomal recessive genetic disorder with no effective treatment yet. Skin barrier dysfunction caused by gene mutations...
BACKGROUND
Netherton syndrome is a rare, life-threatening autosomal recessive genetic disorder with no effective treatment yet. Skin barrier dysfunction caused by gene mutations is a hallmark of the disease. Antigen penetration through the defective skin and nonspecific inflammation provide a pro-T helper 2 (Th2) immune microenvironment in the disease. Therefore, Th2 cytokines are considered to be candidate therapeutic targets.
OBJECTIVE
To evaluate the clinical responses of patients with Netherton syndrome to dupilumab, an IL-4Rα antagonist, and identify changes in the Th1/2/17 pathway activity, skin barrier defect protein LEKTI expression after treatment.
METHODS
Four children with severe Netherton syndrome (aged 2 y to 4 y and 6 m) who were treated with dupilumab from January to June 2022 were evaluated at baseline, and at 4, 8, 12, 16, and 20 weeks after the start of dupilumab administration. Treatment response was assessed using the Eczema Area and Severity Index (EASI), the Numerical Rating Scale (NRS), the Dermatology Life Quality Index (CDLQI), and the Dermatitis Family Impact-questionnaire (DFI). Blood eosinophil counts, serum IgE levels and inflammatory cytokines were measured. The immunotyping of Th1/2/17 cells was performed by flow cytometry and cytokine expressions in T cell subsets were analyzed by single-cell RNA sequencing. In addition, expression of the LEKTI in skin lesions was evaluated by immunohistochemical analysis.
RESULTS
All four patients experienced clinical improvement, with significantly reduced EASI scores (by 75.0-83.9%) and NRS (by 87.5-90.0%) from baseline to 20 weeks of treatment. Improved quality of life scores were also seen for all patients, as measured by CDLQI and DFI. Serum IgE levels also fell by 75.6-86.9%. The serum Th2 cytokines IL-4, IL-5 and IL-13 were found at low level, with no significant changes during the treatment. However, Th2 cytokines expressed by T cells, especially IL-4, decreased at single-cell level after treatment ( = 0.029). The baseline percentage of Th2 cells (among total CD3CD4 T cells) was significantly higher in patients than that in healthy controls (HC) ( < 0.0001); this percentage fell from 8.25% ± 0.75% to 4.02% ± 0.62% after 20 weeks dupilumab treatment. There was no noticeable change in LEKTI protein expression in skin lesions pre- and post-treatment. Two patients reported mild ocular adverse effects, but there were no severe adverse events.
CONCLUSION
Dupilumab may be an effective and safe treatment option in a subset of pediatric patients with Netherton syndrome, especially in improving itch and the quality of life. These effects were achieved in part by suppression of the Th2-mediated inflammation.
Topics: Humans; Child; Netherton Syndrome; Interleukin-4; Quality of Life; Cytokines; Skin Diseases; Inflammation; Immunoglobulin E
PubMed: 36569942
DOI: 10.3389/fimmu.2022.1054422 -
Indian Journal of Ophthalmology Jul 2022
Topics: Humans; Retina; Sjogren-Larsson Syndrome
PubMed: 35791223
DOI: 10.4103/ijo.IJO_2994_21 -
Pediatrics and Neonatology Nov 2022
Topics: Humans; Infant, Newborn; Ichthyosis, Lamellar
PubMed: 35659753
DOI: 10.1016/j.pedneo.2022.04.006 -
The Journal of Investigative Dermatology Jul 2021The Mendelian disorders of cornification consist of a highly heterogeneous group of diseases, and the majority of nonsyndromic cases belong to the family of autosomal...
The Mendelian disorders of cornification consist of a highly heterogeneous group of diseases, and the majority of nonsyndromic cases belong to the family of autosomal recessive congenital ichthyosis. Mutations in SDR9C7 have been associated with autosomal recessive congenital ichthyosis, and clinical manifestations include mild to moderately dry, scaly skin with or without hyperkeratosis, palmoplantar keratoderma, and erythroderma. SDR9C7, with short-chain dehydrogenase and/or reductase activity, is known as nicotinamide adenine dinucleotide‒ or nicotinamide adenine dinucleotide phosphate‒dependent oxidoreductase and has been shown to be involved in the final step of epidermal lipid barrier formation by covalent binding of acylceramide to the cornified envelope. In this study, we present the clinical and molecular description of 19 patients with autosomal recessive congenital ichthyosis in five consanguineous families with SDR9C7 mutations. We also downregulated the expression of SDR9C7 in keratinocytes using the small interfering RNA technique in three-dimensional organotypic skin constructs. Our results demonstrated morphological and histological abnormalities in these constructs ex vivo, similar to those observed in patients with ichthyosis. Moreover, the results from keratinocyte migration and epidermal dye penetration assays provided evidence for the role of SDR9C7 in the disease pathomechanism. Collectively, our results indicate that SDR9C7 deficiency by itself is sufficient to disrupt epidermal barrier function leading to ichthyotic phenotype.
Topics: Cell Movement; Consanguinity; Epidermis; Female; Gene Knockdown Techniques; HaCaT Cells; Humans; Ichthyosis; Male; Oxidoreductases; Pedigree; Water Loss, Insensible
PubMed: 33422619
DOI: 10.1016/j.jid.2020.11.030 -
Journal of the European Academy of... Jul 2022The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the... (Review)
Review
The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the erythroderma itself and the occasionally severe and life-threatening underlying disease. Early correct recognition of the underlying cause leads to better treatment and prognosis. Currently, neonatal erythroderma is approached on a case-by-case basis. The purpose of this scoping review was to develop a diagnostic approach in neonatal erythroderma. After a systematic literature search in Embase (January 1990 - May 2020, 74 cases of neonatal erythroderma were identified, and 50+ diagnoses could be extracted. Main causes were the ichthyoses (40%) and primary immunodeficiencies (35%). Congenital erythroderma was present in 64% (47/74) of the cases, predominantly with congenital ichthyosis (11/11; 100%), Netherton syndrome (12/14, 86%) and Omenn syndrome (11/23, 48%). Time until diagnosis ranged from 102 days to 116 days for cases of non-congenital erythroderma and congenital erythroderma respectively. Among the 74 identified cases a total of 17 patients (23%) died within a mean of 158 days and were related to Omenn syndrome (35%), graft-versus-host disease (67%) and Netherton syndrome (18%). Disease history and physical examination are summarized in this paper. Age of onset and a collodion membrane can help to narrow the differential diagnoses. Investigations of blood, histology, hair analysis, genetic analysis and clinical imaging are summarized and discussed. A standard blood investigation is proposed, and the need for skin biopsies with lympho-epithelial Kazal-type related Inhibitor staining is highlighted. Overall, this review shows that diagnostic procedures narrow the differential diagnosis in neonatal erythroderma. A 6-step flowchart for the diagnostic approach for neonatal erythroderma during the first month of life is proposed. The approach was made with the support of expert leaders from international multidisciplinary collaborations in the European Reference Network Skin-subthematic group Ichthyosis.
Topics: Dermatitis, Exfoliative; Diagnosis, Differential; Humans; Ichthyosis; Ichthyosis, Lamellar; Infant, Newborn; Netherton Syndrome; Severe Combined Immunodeficiency
PubMed: 35238435
DOI: 10.1111/jdv.18043 -
Expert Review of Proteomics May 2016Lipidomics is the large-scale profiling and characterization of lipid species in a biological system using mass spectrometry. The skin barrier is mainly comprised of... (Review)
Review
INTRODUCTION
Lipidomics is the large-scale profiling and characterization of lipid species in a biological system using mass spectrometry. The skin barrier is mainly comprised of corneocytes and a lipid-enriched extracellular matrix. The major skin lipids are ceramides, cholesterol and free fatty acids (FFA). Lipid compositions are altered in inflammatory skin disorders with disrupted skin barrier such as atopic dermatitis (AD).
AREAS COVERED
Here we discuss some of the recent applications of lipidomics in human skin biology and in inflammatory skin diseases such as AD, psoriasis and Netherton syndrome. We also review applications of lipidomics in human skin equivalent and in pre-clinical animal models of skin diseases to gain insight into the pathogenesis of the skin disease. Expert commentary: Skin lipidomics analysis could be a fast, reliable and noninvasive tool to characterize the skin lipid profile and to monitor the progression of inflammatory skin diseases such as AD.
Topics: Animals; Dermatitis; Disease Progression; Early Diagnosis; Epidermis; Humans; Lipids; Mass Spectrometry; Netherton Syndrome; Psoriasis
PubMed: 27121756
DOI: 10.1080/14789450.2016.1177462 -
Communications Biology Feb 2024Netherton syndrome (NS) is a rare skin disease caused by loss-of-function mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) gene. Disease severity and...
Netherton syndrome (NS) is a rare skin disease caused by loss-of-function mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) gene. Disease severity and the lack of efficacious treatments call for a better understanding of NS mechanisms. Here we describe a novel and viable, Spink5 conditional knock-out (cKO) mouse model, allowing to study NS progression. By combining transcriptomics and proteomics, we determine a disease molecular profile common to mouse models and NS patients. Spink5 cKO mice and NS patients share skin barrier and inflammation signatures defined by up-regulation and increased activity of proteases, IL-17, IL-36, and IL-20 family cytokine signaling. Systemic inflammation in Spink5 cKO mice correlates with disease severity and is associated with thymic atrophy and enlargement of lymph nodes and spleen. This systemic inflammation phenotype is marked by neutrophils and IL-17/IL-22 signaling, does not involve primary T cell immunodeficiency and is independent of bacterial infection. By comparing skin transcriptomes and proteomes, we uncover several putative substrates of tissue kallikrein-related proteases (KLKs), demonstrating that KLKs can proteolytically regulate IL-36 pro-inflammatory cytokines. Our study thus provides a conserved molecular framework for NS and reveals a KLK/IL-36 signaling axis, adding new insights into the disease mechanisms and therapeutic targets.
Topics: Animals; Humans; Mice; Inflammation; Interleukin-17; Mice, Knockout; Netherton Syndrome; Peptide Hydrolases; Serine Peptidase Inhibitor Kazal-Type 5
PubMed: 38316920
DOI: 10.1038/s42003-024-05780-y -
Frontiers in Immunology 2022Comèl-Netherton syndrome (NS) is a rare disease caused by pathogenic variants in the gene, leading to severe skin barrier impairment and proinflammatory upregulation....
BACKGROUND
Comèl-Netherton syndrome (NS) is a rare disease caused by pathogenic variants in the gene, leading to severe skin barrier impairment and proinflammatory upregulation. Given the severity of the disease, treatment of NS is challenging. Current treatment regimens are mainly topical and supportive. Although novel systemic treatment options for NS have been suggested in recent literature, little is known about their outcomes.
OBJECTIVE
to provide an overview of systemic treatment options and their outcomes in adults and children with NS.
METHODS
Embase, MEDLINE, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar were searched up to July 22, 2021. Empirical studies published in English language mentioning systemic treatment in NS were enrolled. Studies that did not define a treatment period or report at least one outcome were excluded. Methodological quality was evaluated by the Joanna Briggs Institute critical appraisal checklist for case reports or case series. Overall quality of evidence of the primary outcome, skin, was assessed by the GRADE approach.
RESULTS
36 case series and case reports were included. The effects of 15 systemic therapies were described in 48 patients, of which 27 were children. Therapies included retinoids, prednisolone, cyclosporine, immunoglobulins, and biologicals. In retinoids both worsening (4/15 cases) and improvement (6/15 cases) of the skin was observed. Use of prednisolone and cyclosporine was only reported in one patient. Immunoglobulins (13/15 cases) and biologicals (18/21 cases) showed improvement of the skin. Certainty of evidence was rated as very low.
CONCLUSION
NS is a rare disease, which is reflected in the scarce literature on systemic treatment outcomes in children and adults with NS. Studies showed large heterogeneity in outcome measures. Adverse events were scarcely reported. Long-term outcomes were reported in a minority of cases. Nonetheless, a general beneficial effect of systemic treatment was found. Immunoglobulins and biologicals showed the most promising results and should be further explored. Future research should focus on determining a core outcome set and measurement instruments for NS to improve quality of research.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=217933, PROSPERO (ID: 217933).
Topics: Adult; Child; Cyclosporine; Humans; Netherton Syndrome; Prednisolone; Rare Diseases; Retinoids
PubMed: 35464459
DOI: 10.3389/fimmu.2022.864449 -
Archives of Dermatological Research Mar 2023Treatment of congenital ichthyoses primarily focuses on reversing skin scaling and is not pathogenesis based. Recent studies showed Th17 immune skewing, as in psoriasis,... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Treatment of congenital ichthyoses primarily focuses on reversing skin scaling and is not pathogenesis based. Recent studies showed Th17 immune skewing, as in psoriasis, across the spectrum of ichthyosis, suggesting that targeting this pathway might broadly reduce disease severity.
OBJECTIVE
To determine whether secukinumab, an IL-17A inhibitor, can improve ichthyosis across several congenital ichthyosis subtypes.
DESIGN
Exploratory 16-week double-blind, randomized, placebo-controlled trial comparing secukinumab 300 mg every 4wks to placebo (1:1 randomization) in adults with the four major congenital ichthyosis subtypes (NCT03041038), followed by a 16-week open-label phase to evaluate response of the placebo-first group and a 20-week extension for safety. Significant differences in secukinumab- vs. placebo-treated subjects at Wk16 in the Ichthyosis Area Severity Index (IASI) score and lack of increased mucocutaneous bacterial and/or fungal infections were the co-primary efficacy and safety endpoints, respectively.
SETTING
Two tertiary referral centers: Northwestern University Feinberg School of Medicine, Chicago, and Mount Sinai Icahn School of Medicine, New York.
PARTICIPANTS
Twenty subjects ≥ 18 yo with genotype-confirmed epidermolytic ichthyosis, Netherton syndrome, lamellar ichthyosis, or congenital ichthyosiform erythroderma with at least moderate erythroderma.
RESULTS
IL-17A inhibition did not significantly reduce severity or increase mucocutaneous infections among the 18 who completed the 16-week double-blind phase. Five patients with 29-50% clinical improvement at Wk32 requested drug continuation. Th17-related biomarkers were not significantly reduced vs. baseline or placebo-treated levels.
LIMITATIONS
Small sample size; heterogeneous ichthyosis subsets.
CONCLUSION
IL-17 inhibition with secukinumab is safe, but not efficacious across the spectrum of adult ichthyoses.
GOV REGISTRATION NUMBER
NCT03041038; first posted on 02/02/2017.
Topics: Adult; Humans; Ichthyosis, Lamellar; Antibodies, Monoclonal; Interleukin-17; Ichthyosis; Psoriasis; Ichthyosiform Erythroderma, Congenital; Severity of Illness Index; Double-Blind Method; Treatment Outcome
PubMed: 35218370
DOI: 10.1007/s00403-022-02325-3