Experimental proof of symptom reduction in cold urticaria patients by increasing the dose of desloratadine

Hintergrund und Zielsetzung Nicht-sedierende Antihistaminika (nsAH) stellen die Therapie der ersten Wahl bei der Behandlung der Kälteurtikaria (KU) und anderer Urtikariaerkrankungen dar. Die aktuellen EAACI/GA2LEN/EDF/WAO- Leitlinien empfehlen eine bis zu vierfache Steigerung der Standarddosis von nsAH bei Patienten, die auf eine solche Therapie nicht zufriedenstellend ansprechen. Bisher gibt es jedoch nur wenig Belege für diese Empfehlung, da kontrollierte Studien fehlen. In der vorliegenden Arbeit werden durch objektive bildgebende Methoden die Wirkungen von 5 mg und 20 mg Desloratadin (DL) sowie Placebo auf kälteinduzierte urtikarielle Hautveränderungen dargelegt. Material und Methoden Es wurde eine prospektive, randomisierte, doppelblinde, Cross-Over-Studie mit 30 KU-patienten durchgeführt. Die Patienten erhielten täglich Placebo, 5 mg oder 20 mg DL für jeweils 7 Tage. Zwischen den Therapien erfolgte eine 14-tägige Auswaschphase. Am Ende jeder Behandlung wurden die Patienten einer standardisierten Kälteprovokation mit TempTest® 2.0 und 2.1 unterzogen. Entwicklung und Ausmaß der provozierten urtikariaspezischen Hautreaktion wurde mittels Volumetrie und Thermographie gemessen. Schwellentemperaturen und Schwellenzeiten (CTT, CSTT) wurden bestimmt. Ebenso wurden Kälteurtikaria-spezifische Symptome und unerwünschte Ereignisse (AE) erfasst. Ergebnisse Die Gabe von 5 mg und 20 mg DL über 7 Tage resultierte bei den KU-Patienten in einer signifikanten Reduktion des Volumens der kälteinduzierten Quaddeln sowie des hyperthermen Hautareals und verbesserte die Werte der CTT und CSTT im Vergleich zu Placebo. Die Behandlung mit 20 mg DL pro Tag lieferte eine noch größere Reduzierung des Volumens der kälteinduzierten Quaddeln als auch der Werte für CTT und CSTT verglichen zu 5 mg DL täglich. Pruritus und Beschwerdefreiheit wurden unter der hohen Dosis DL im Gegensatz zu Placebo und zur Standardtherapie ebenfalls signifikant verbessert. Beide Dosierungen wurden gut vertragen. Es kam zu keinem Anstieg von Somnolenz oder anderen AE unter 20 mg DL. Schlussfolgerung Diese Studie zeigt, dass die Standarddosis von DL die Symptome der KU nach standardisierter Kälteprovokation mittels TempTest® signifikant verbessert. Die Steigerung auf das vierfache der Standarddosis ermöglicht eine weitere Verbesserung der Symptome über die Ergebnisse mit 5 mg DL und Placebo hinaus, ohne einen Anstieg von AE nach sich zu ziehen. Somit unterstützt diese Arbeit die aktuellen Empfehlungen der Leitlinie, dass eine Dosissteigerung der nsAH von Vorteil für Patienten ist, die nicht zufriedenstellend auf die Standarddosis ansprechen.Background and Rationale Non-sedating antihistamines (nsAH) are the recommended first line treatment for patients with acquired cold urticaria (ACU) and other Urticaria forms. The current EAACI/GA2LEN/EDF/WAO guidelines call for updosing of nsAH up to four times of the standard dose in urticaria patients who do not respond satisfactorily to that dose. As of now, however, there is little evidence to support this recommendation due to a lack of controlled studies. This Study assesses the effects of 5 mg and 20 mg of desloratadine (DL) and placebo on cold-induced urticarial lesions by using objective methods of imaging. Material and Methods A prospective, randomized, double-blind, three-way crossover trial involving 30 ACU patients was performed. Eligible patients received placebo, DL 5 mg and DL 20 mg once a day each for 7 days, separated by 14 day washout periods. At the end of each treatment phase, patients were subjected to cold provocation testing with the TempTest® 2.0 und 2.1 system. The development and extent of the provoked urticarial skin reaction was assessed using volumetric and thermographic imaging. Critical temperature and stimulation time thresholds (CTT, CSTT) were measured. ACU symptoms and adverse events (AE) were assessed. Results In ACU patients, DL administration for 7 days at both the 5 mg and 20 mg dose resulted in significant reductions in the volume of cold-induced wheals, areas of hyperthermic skin and improved CTT and CSTT results, as compared with placebo. Treatment with DL 20 mg/day provided a significantly greater reduction in cold-induced weal volume and CTT and CSTT values as compared to DL 5 mg/day. Pruritus and the total symptom control were significantly improved under high dose therapy compared to placebo and DL at standard dose. It was well tolerated at both doses and there was no increased rate of somnolence or other AE under 20 mg DL. Conclusion This study shows that DL at standard and high doses significantly improved objective signs of ACU provoked by standardized cold exposure using the TempTest® system. Increasing the dose of DL to four times the standard dose offered significant improvements over those provided by DL 5mg and placebo without an increase in AE. This study supports the suggestion of the current guideline that increased doses of nsAH may be of benefit in ACU patients who do not respond satisfactorily to standard doses

RIKADA Study Reveals Risk Factors in Pediatric Primary Cardiomyopathy

Background: Cardiomyopathies are heterogeneous diseases with clinical presentations varying from asymptomatic to life-threatening events, including severe heart failure and sudden cardiac death. The role of underlying genetic and disease-modulating factors in children and adolescents is relatively unknown. In this prospective study, in-depth phenotypic and genetic characterization of pediatric patients with primary cardiomyopathy and their first-degree family members (FMs) was performed. Outcome was assessed to identify clinical risk factors. Methods and Results: Sixty index patients with primary cardiomyopathy (median age: 7.8 years) and 124 FMs were enrolled in the RIKADA (Risk Stratification in Children and Adolescents with Primary Cardiomyopathy) study. Family screening included cardiac workup and genetic testing. Using cardiologic screening, we identified 17 FMs with cardiomyopathies and 30 FMs with suspected cardiomyopathies. Adverse events appeared in 32% of index patients and were more common in those with lower body surface area (P=0.019), increased NT-proBNP (N-terminal pro-brain natriuretic peptide; P<0.001), and left ventricular dysfunction (P<0.001) and dilatation (P=0.005). The worst prognosis was observed in dilated and restrictive cardiomyopathies. Genetic variants of interest were detected in patients (79%) and FMs (67%). In all 15 families with at least 1 FM with cardiomyopathy, we found a variant of interest in the index patient. Increased number of variants of interest per patient was associated with adverse events (P=0.021). Late gadolinium enhancement was related to positive genotypes in patients (P=0.041). Conclusions: Lower body surface area, increased NT-proBNP, left ventricular dysfunction or dilatation, late gadolinium enhancement, and increased number of variants of interest were associated with adverse outcome and should be considered for risk assessment in pediatric primary cardiomyopathies. Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT03572569

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel‐based next‐generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP

Familial Recurrent Myocarditis Triggered by Exercise in Patients With a Truncating Variant of the Desmoplakin Gene

BACKGROUND: Variants of the desmosomal protein desmoplakin are associated with arrhythmogenic cardiomyopathy, an important cause of ventricular arrhythmias in children and young adults. Disease penetrance of desmoplakin variants is incomplete and variant carriers may display noncardiac, dermatologic phenotypes. We describe a novel cardiac phenotype associated with a truncating desmoplakin variant, likely causing mechanical instability of myocardial desmosomes. METHODS AND RESULTS: In 2 young brothers with recurrent myocarditis triggered by physical exercise, screening of 218 cardiomyopathy-related genes identified the heterozygous truncating variant p.Arg1458Ter in desmoplakin. Screening for infections yielded no evidence of viral or nonviral infections. Myosin and troponin I autoantibodies were detected at high titers. Immunohistology failed to detect any residual DSP protein in endomyocardial biopsies, and none of the histologic criteria of arrhythmogenic cardiomyopathy were fulfilled. Cardiac magnetic resonance imaging revealed no features associated with right ventricular arrhythmogenic cardiomyopathy, but multifocal subepicardial late gadolinium enhancement was present in the left ventricles of both brothers. Screening of adult cardiomyopathy cohorts for truncating variants identified the rare genetic variants p.Gln307Ter, p.Tyr1391Ter, and p.Tyr1512Ter, suggesting that over subsequent decades critical genetic/exogenous modifiers drive pathogenesis from desmoplakin truncations toward different end points. CONCLUSIONS: The described novel phenotype of familial recurrent myocarditis associated with a desmoplakin truncation in adolescents likely represents a serendipitously revealed subtype of arrhythmogenic cardiomyopathy. It may be caused by a distinctive adverse effect of the variant desmoplakin upon the mechanical stability of myocardial desmosomes. Variant screening is advisable to allow early detection of patients with similar phenotypes

Toward evidence-based diagnosis of myocarditis in children and adolescents: Rationale, design, and first baseline data of MYKKE, a multicenter registry and study platform

Aims The aim of this registry is to provide data on age-related clinical features of suspected myocarditis and to create a study platform allowing for deriving diagnostic criteria and, at a later stage, testing therapeutic interventions in patients with myocarditis. Study design and results After an initial 6-month pilot phase, MYKKE was opened in June 2014 as a prospective multicenter registry for patients from pediatric heart centers, university hospitals, and community hospitals with pediatric cardiology wards in Germany. Inclusion criteria consisted of age 12 years), show higher proportions of males, and document a high prevalence of severe disease courses in pediatric patients with suspected myocarditis. Severe clinical courses and early adverse events were more prevalent in younger patients and were related to severely impaired leftventricular ejection fraction at initial presentation. Summary MYKKE represents a multicenter registry and research platform for children and adolescents with suspected myocarditis that achieve steady recruitment and generate a wide range of real-world data on clinical course, diagnostic workup, and treatment of this group of patients. The baseline data reveal the presence of 2 age peaks and provide important insights into the severity of disease in children with suspected myocarditis. In the future, MYKKE might facilitate interventional substudies by providing an established collaborating network using common diagnostic approaches