A core outcome set for efficacy of acute treatment of hereditary angioedema.

BACKGROUND: Clinical trials investigating drugs for acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a Core Outcome Set comprising key outcomes that should ideally be utilized in all clinical efficacy trials involving acute treatment of hereditary angioedema attacks. METHODS: A Delphi consensus study was conducted involving all relevant parties: hereditary angioedema patients, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS: Fifty-eight worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of ≥90% was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSION: This international study obtained a high level of consensus on a core outcome set for acute treatment of hereditary angioedema attacks consisting of five key outcomes.

Prevalence and Patient Characteristics of Ectodermal Dysplasias in Denmark.

Importance: Ectodermal dysplasias constitute a group of rare genetic disorders of the skin and skin appendages with hypodontia, hypotrichosis, and hypohidrosis as cardinal features. There is a lack of population-based research into the epidemiology of ectodermal dysplasias. Objective: To establish a validated population-based cohort of patients with ectodermal dysplasia in Denmark and to assess the disease prevalence and patient characteristics. Design, Setting, and Participants: This nationwide cohort study used individual-level registry data recorded across the Danish universal health care system to identify patients with ectodermal dysplasias from January 1, 1995, to August 25, 2021. A 3-level search of the Danish National Patient Registry and the Danish National Child Odontology Registry was conducted to identify patients with diagnosis codes indicative of ectodermal dysplasias; patients registered in the Danish RAREDIS Database, the Danish Database of Genodermatoses, and local databases were also added. The search results underwent diagnosis validation and review of clinical data using medical records. Of 844 patient records suggestive of ectodermal dysplasias, 791 patients (93.7%) had medical records available for review. Positive predictive values of the diagnosis coding were computed, birth prevalence was estimated, and patient characteristics were identified. Data analysis was performed from May 4 to December 22, 2023. Results: The identified and validated study cohort included 396 patients (median [IQR] age at diagnosis, 13 [4-30] years, 246 females [62.1%]), of whom 319 had confirmed ectodermal dysplasias and 77 were likely cases. The combined positive predictive value (PPV) for ectodermal dysplasia-specific diagnosis codes was 67.0% (95% CI, 62.7%-71.0%). From 1995 to 2011, the estimated minimum birth prevalence per 100 000 live births was 14.5 (95% CI, 12.2-16.7) for all ectodermal dysplasias and 2.8 (95% CI, 1.8-3.8) for X-linked hypohidrotic ectodermal dysplasias. A molecular genetic diagnosis was available for 241 patients (61%), including EDA (n = 100), IKBKG (n = 55), WNT10A (n = 21), TRPS1 (n = 18), EDAR (n = 10), P63 (n = 9), GJB6 (n = 9), PORCN (n = 7), and other rare genetic variants. Conclusions and Relevance: The findings of this nationwide cohort study indicate that the prevalence of ectodermal dysplasias was lower than previously reported. Furthermore, PPVs of the search algorithms emphasized the importance of diagnosis validation. The establishment of a large nationwide cohort of patients with ectodermal dysplasias, including detailed clinical and molecular data, is a unique resource for future research in ectodermal dysplasias.

The Depressiveness, Quality of Life and NEO-FFI Scale in Patients with Selected Genodermatoses.

Background: Dermatological conditions extend beyond physical symptoms, profoundly impacting the psychological well-being of patients. This study explores the intricate relationship between depressive symptoms, quality of life (QoL), and personality traits in individuals diagnosed with specific genodermatoses. Methods: The study cohort comprised 30 patients with genodermatoses treated at the dermatology clinic, and a healthy control group. Standardized survey questionnaires: The Dermatology Life Quality Index (DLQI), Beck's Depression Inventory (BDI), and NEO Five-Factor Inventory (NEO-FFI) were employed for assessments. Results: The findings indicate a significantly elevated risk of severely or very severely reduced QoL in the study group compared to matched controls (OR = 22.2, 95% CI: 2.7-184.8). Specifically, individuals with ichthyosis exhibited a staggering 131-fold higher risk of diminished QoL compared to the control group. Furthermore, the prevalence of depression was higher in the study group than in the control group (36.7% vs. 10%; p = 0.0086). A detailed analysis revealed that patients with low or average agreeableness exhibited a notably higher incidence of depression compared to those with high agreeableness (100% or 75% vs. 28.6%; p = 0.0400). Similarly, individuals with high levels of neuroticism had a significantly higher incidence of depression compared to those with average or low levels of neuroticism (rates: 66.7% vs. 9.1% or 0%, respectively; p = 0.0067). Conclusions: The study underscores a substantial correlation between genodermatoses and the mental health of affected individuals, underscoring the imperative consideration of psychological factors in the management of hereditary skin disorders. Our study's primary limitation is the small sample size, stemming from difficulties in recruiting participants due to the rare nature of the studied conditions.

Screening of dermatology drugs for aberrant use-patterns: An application of epidemiologic estimates and measures of inequality in drug use.

AIMS: Dermatology treatments require adherence for safe and effective use. Real-world healthcare databases can reveal drug utilization patterns and uncover inappropriate or unexpected use. This study aimed to analyse dermatology drug utilization patterns using epidemiological and inequality measures, leveraging Danish nationwide registries. It also assessed the feasibility of this method for detecting aberrant drug use. METHODS: We formed a 2019 cohort of all patients treated for skin conditions through Danish healthcare registries. We calculated prevalence, incidence rates and treatment duration for dermatological drugs. Inequality in drug utilization was assessed using Lorenz curves, Gini coefficients and other measures. RESULTS: The study encompassed 1 021 255 patients using 94 dermatology drugs. Most usage aligned with 'expected clinical use', but we detected inequality, with some drugs having high Gini coefficients and disproportionate consumption by the top percentile of users. Notable findings included potential inappropriate antibiotic use, excessive topical corticosteroid use and unexpected drug use duration. CONCLUSIONS: In Denmark, dermatology drugs are used primarily as anticipated, with minimal unexpected patterns. Specific follow-up is required to draw conclusions about inappropriate use. This approach demonstrates broad applicability for screening aberrant drug utilization.

Identification of a founder variant AAGAB c.370C>T, p.Arg124Ter in patients with punctate palmoplantar keratoderma in Southern Denmark.

Palmoplantar keratoderma (PPK) is a heterogeneous group of rare skin diseases characterized by hyperkeratosis on the palms or soles. The subtype isolated punctate PPK is caused by heterozygous variants in AAGAB. We investigated if the variant AAGAB c.370C>T, p.Arg124Ter in patients with punctate PPK in the Region of Southern Denmark represented a founder variant and estimated the age to the most recent common ancestor. We performed haplotype analysis on samples from 20 patients diagnosed with punctate PPK and the AAGAB c.370C>T, p.Arg124Ter variant. Using the Gamma Method, we calculated the years to the most recent common ancestor. We also explored the presence of the variant in other populations through literature and databases (HGMD, ClinVar, and gnomAD). Our analysis revealed a shared haplotype of 3.0 Mb, suggesting shared ancestry. The ancestral haplogroup was estimated to an age of 12.1 generations (CI: 4.9-20.3) equivalent to approximately 339 years (CI: 137-568). This study confirms that the frequently observed variant AAGAB c.370C>T, p.Arg124Ter in punctate PPK among patients in the Region of Southern Denmark is caused by a founder variant. We recommend testing for the variant as initial screening in our region and potentially for all Danish patients presenting with punctate PPK.

Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Application of the waiting time distribution in a nationwide screening of real-world dermatology drug utilization for aberrant use patterns.

BACKGROUND: Inappropriate use of medicines may have critical consequences from individual, public health, and economic perspectives. Discovering wrongful medicine use may require intentional surveillance or screening. OBJECTIVES: The objectives of this study were to: (i) apply and evaluate the waiting time distribution (WTD) method as a screening tool for identifying aberrant drug use and (ii) evaluate the nationwide use of Dermatology drugs in Denmark for signals of aberrant drug use. METHOD: Dermatology drug use data from the Danish nationwide healthcare registries from 2018 to 2020 were used to produce WTDs that were analyzed for drug use patterns. The method provides estimates of the prevalence and incidence and enables estimation of mean treatment duration, drug relapse, and unexpected drug prescribing. RESULTS: The study included 2 027 889 individual drug users and analyzed 6 141 449 prescriptions. The analysis included approximately 100 dermatology drugs and drug categories and produced 56 WTD drug curves. The WTD patterns and epidemiological estimates confirmed that most drugs are used as intended and revealed few unexpected patterns for further investigation. Three unexpected findings were identified concerning (i) short-term use that would entail suboptimal clinical efficiency for minoxidil, (ii) sub-optimal use of topical tacrolimus, and (iii) potential undesirable increase in short-course doxycycline treatments. CONCLUSION: In Denmark, dermatology drugs are predominantly used as expected, with few unexpected use patterns identified. Targeted specific follow-up on the identified signals is necessary for conclusions about inappropriate use. The findings suggest that the WTD method is applicable for screening for aberrant drug use.

Christmas article: Case of uncombable hair syndrome discovered after publication of article in Ugeskrift for Læger.

Uncombable hair syndrome is a rare hair shaft anomaly presenting in childhood with blond, frizzy, and unruly hair. This case report presents a 9-year-old boy with remarkable hair where the mother, after reading a medical paper on hair shaft anomalies, suspected uncombable hair syndrome. She reached out to the author group, and the employment of molecular genetics later confirmed the diagnosis of uncombable hair syndrome. This case report serves as an example of how digital access enables the attention of patients and relatives to be directed towards rare conditions.

Majocchi's Granuloma - The Great Mimicker: A Case Report.

Fungal infections can be challenging to diagnose, but doctors of every specialty may encounter this issue. They can be mistaken for other common dermatoses such as eczema or psoriasis and inadvertently be treated with topical corticosteroids or calcineurin inhibitors. This may lead to tinea incognita, a term used to describe a fungal infection with an altered clinical appearance, which may confuse the clinician even further. This case report presents a 54-year-old previously healthy man with a 4-month history of a painful and pruritic rash in the genitoinguinal region. The patient's general practitioner had unsuccessfully attempted to treat the rash with topical terbinafine, econazole-triamcinolone, and betamethasone-fusidic acid, in addition to peroral dicloxacillin capsules. On examination, there were multiple red-bluish nodules and pustules coalescing into infiltrating erythematous plaques on both thighs and in the pubic region. Fungal cultures were negative, but the clinical features together with the history of prolonged use of combined topical steroids and antifungals raised suspicion of a deep fungal infection. Histopathological skin examination revealed deep suppurative and granulomatous folliculitis with ruptured hair follicles which was consistent with a diagnosis of Majocchi's granuloma. Treatment with itraconazole capsules was initiated, and after a 16-week course of systemic antifungal therapy, the rash resolved. In conclusion, our case report presents a case of Majocchi's granuloma, which is a great mimicker, especially for non-dermatologists. It is therefore important that the diagnosis is considered as a differential diagnosis, even though a patient has previously been treated with a topical antifungal.

Identification of a Novel PLCD1 Variant in a Danish Family with Hereditary Leukonychia.

A 1-year-old girl presented with porcelain white fingernails, accidentally discovered when she was referred for an infantile hemangioma consultation. The family reported that the nails had been milky white since birth and her father had similar white finger and toenails. The father remembered that additional family members on his side of the family presented with white nails; however, he could not provide exact information about the number of other relatives affected by this nail abnormality. The girl and her father were the only available family members with white nails presented for this study (Figure 1). The girl presented with leukonychia totalis on all fingernails only, while the father had this abnormality on all finger and toenails (Figure 2). We were not aware of any association with other diseases or features in this family, except hemangioma in the girl. (SKINmed. 2023;21:44-46).

Keratosis pilaris. / Keratosis pilaris.

Keratosis pilaris, or 'plucked chicken skin', is a very common condition. It is caused by keratin accumulation in the hair follicles. Although mild cases of the condition can be considered to be a normal variant, it can lead to multiple appointments with general practitioners and dermatologists. In rare cases, keratosis pilaris can form part of specific syndromes or be associated with other diseases. The aim of this article is to give an overview of the different variants of keratosis pilaris and discuss the pathogenesis and treatment options.