Background
Hereditary angioedema (HAE) with normal C1‐INH (HAEnCI) may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE‐FXII) or functional mutations in other genes that ...are still unknown. We sought to identify and characterize a hitherto unknown type of HAE with normal C1‐INH and without mutation in the F12 gene.
Methods
The study comprised analysis of whole‐exome sequencing, Sanger sequencing, and clinical data of patients.
Results
We detected a mutation in the plasminogen (PLG) gene in patients with HAEnCI. The mutation c.9886A>G was located in exon 9 leading to the missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of the PLG protein. The mutation was identified by next‐generation sequencing in 14 patients with HAEnCI belonging to 4 of 7 families. Family studies revealed that this type of HAE was transmitted as an autosomal dominant trait. The PLG gene mutation was present in all studied symptomatic patients and was also found in 9 of 38 index patients from 38 further families with HAEnCI. Most patients had swelling of face/lips (78.3%) and tongue (78.3%). A total of 331 of all 3.795 tongue swellings (8.7%) were associated with dyspnea, voice changes, and imminent asphyxiation. Two women died by asphyxiation due to a tongue swelling.
Conclusions
Hereditary angioedema with a mutation in the PLG gene is a novel type of HAE. It is associated with a high risk of tongue swellings.
This evidence‐ and consensus‐based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working ...group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU‐founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell‐driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence‐based diagnostic and therapeutic approaches for the different subtypes of urticaria.
A parametric study on the long-term deformations of monopile foundations for offshore wind turbines is presented. The finite element calculations of a monopile in fine sand were performed with a ...high-cycle accumulation (HCA) model. The results are analyzed with respect to the horizontal displacements, the tilting of the pile head, settlement of the ground surface and effective stress changes in the surrounding soil. The dimensions of the pile (diameter, length of embedding, wall thickness), the initial density of the sand and the cyclic loading (average value, amplitude, lever arm) have been varied. The influence of the drainage conditions (either fully drained or partially drained) is also discussed. The validity of Miner’s rule is checked for both types of drainage conditions. Furthermore, the effect of changes of the direction of the cycles and of a multidimensional cyclic loading is addressed. The interesting phenomenon of a “self-healing”, i.e. a re-erection of the deformed monopile after a storm event, is demonstrated based on simulations with small cycles following a large preloading. Simulations with homogeneous and stochastically fluctuating fields of void ratio are compared.
Summary
Chronic urticaria (CU) affects about 1% of the world population of all ages, mostly young and middle‐aged women. It usually lasts for several years (> 1 year in 25–75% of patients) and often ...takes > 1 year before effective management is implemented. It presents as chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU) or both in the same person. More than 25% of cases are resistant to H1‐antihistamines, even at higher doses, and third‐ and fourth‐line therapies (omalizumab and ciclosporin) control the disease only in two‐thirds of H1‐antihistamine‐resistant patients. Here we review the impact of CU on different aspects of patients’ quality of life and the burden of this chronic disease for the patient and society. CU may have a strong impact on health‐related quality of life (HRQoL), particularly when CSU is associated with angio‐oedema and/or CIndU (Dermatology Life Quality Index > 10 in 30% of patients). Comorbidities, such as anxiety and depression, which are present in more than 30% of patients with CSU, compound HRQoL impairment. Severe pruritus and the unpredictable occurrence of weals and angio‐oedema are responsible for sleep disorders; sexual dysfunction; limitations on daily life, work and sports activities; interfering with life within the family and in society; and patients’ performance at school and work (6% absenteeism and 25% presenteeism). Apart from treatment costs, with annual values between 900 and 2400 purchasing power parity dollars (PPP$) in Europe and the USA, CU is associated with a high consumption of medical resources and other indirect costs, which may reach a total annual cost of PPP$ 15 550.
Plain language summary available online
In this work, 1 g model tests on vibratory pile driving in saturated sand are simulated, using different coupled element formulations in conjunction with a hypoplastic constitutive model. Owing to ...the high frequency of the vibrator in the model tests, the influence of the relative acceleration between the solid and water phases cannot be neglected a priori. The frequently applied u-p formulation assumes the relative acceleration to be zero; hence, two additional element formulations (the u-U and u-p-U approaches) are applied. A general investigation regarding the relative acceleration is first conducted using a semi-analytical approach, based on which the impact of the relative acceleration can be expressed by the wave frequency and hydraulic conductivity alone. Further, a threshold level of applicability of the u-p formulation is established. A comparison of the different element formulations used in the simulation of the vibratory driving model tests reveals that the relative acceleration has little impact, and the frequency threshold level obtained by the analytical solution holds. The simulations exhibit strong accordance with the experimental data in terms of pile penetration and pore pressure development. Different numerical aspects of the element formulations are discussed, including problems regarding volumetric locking and conditioning of the stiffness matrices.
Background
Chronic spontaneous urticaria (CSU) severely impacts quality of life (QoL), especially in patients with wheals and angioedema. Omalizumab is approved as add‐on therapy for CSU patients; ...however, its effect on patients who are double‐positive for wheals and angioedema has not been systematically studied.
Objective
The primary objective was to evaluate the efficacy of omalizumab vs placebo at week 28 using the Chronic Urticaria Quality of Life (CU‐Q2oL) questionnaire. Number of angioedema‐burdened days, time interval between successive angioedema episodes, disease activity, angioedema‐specific and overall QoL impairment were secondary objectives.
Methods
X‐ACT was a phase III, randomized, double‐blind study conducted in 24 centres (Germany), which selectively included CSU patients with angioedema and wheals. Patients were randomized (1 : 1) to omalizumab 300 mg or placebo (every 4 weeks up to week 24) (ClinicalTrials.gov number: NCT01723072).
Results
Of the 91 patients randomized to omalizumab (n = 44) or placebo (n = 47) at baseline, 68 completed the 28‐week treatment phase (omalizumab, 35; placebo, 33). Omalizumab was superior to placebo in improving CU‐Q2oL scores at week 28 (P < 0.001). There was a threefold improvement in angioedema‐burdened days/week with omalizumab (0.3) vs placebo (1.1). The median time to first recurrence of angioedema was 57–63 days with omalizumab and <5 days with placebo. Omalizumab significantly improved angioedema‐specific QoL (P < 0.001). The adverse events reported are in line with the established safety profile of omalizumab.
Conclusion
Omalizumab was an effective treatment option for patients with moderate‐to‐severe CSU symptoms and angioedema unresponsive to high doses of antihistamine treatment.
Background
The Angioedema Quality of Life Questionnaire (AE‐QoL) has recently been developed and validated as the first specific patient‐reported outcome tool to assess quality of life (QoL) ...impairment in recurrent angioedema patients. As of yet, its sensitivity to change and minimal clinically important difference (MCID) have not been established.
Methods
Recurrent angioedema patients with chronic spontaneous urticaria or hereditary angioedema were repeatedly asked to complete the AE‐QoL along with the SF‐12 and other anchors for QoL impairment and disease activity during routine care visits. The sensitivity to change of AE‐QoL was determined by correlating changes in its scores over time with changes in the applied anchors. In addition, the MCID was determined using anchor‐based and distributional criterion‐based approaches.
Results
Two hundred and seventy‐eight patients contributed data sets for analysis. Baseline AE‐QoL values were found to correlate well with SF‐12 results as well as all other applied anchors for angioedema‐related QoL impairment and disease activity. In addition, AE‐QoL score changes over time correlated significantly with changes in the above anchors, thus demonstrating its sensitivity to change. The MCID of the AE‐QoL total score was found to be six points.
Conclusion
The AE‐QoL is a valuable tool to assess changes of QoL impairment in recurrent angioedema patients over time, including changes due to treatment.
Background
Recurrent angioedema (RecA) is a frequent clinical problem characterized by suddenly occurring cutaneous and/or mucosal swellings. Depending on their location, RecA may be painful, ...hindering, disfiguring, or even life‐threatening. The assessment of disease activity in affected patients is important to guide treatment decisions. Currently, however, there is no standardized and validated outcome measure available to do so.
Objective
To develop and validate the first specific patient‐reported outcome instrument to assess disease activity in RecA patients, the Angioedema Activity Score (AAS).
Methods
After a set of potential AAS items was developed, item evaluation and reduction were performed by means of impact analysis, factor analysis, regression analysis, and by checking for face validity. In addition, the items of the final AAS questionnaire were tested for their validity and reliability during a 12‐week validation study.
Results
In total, data from 110 and 80 RecA patients were used during the AAS item evaluation and validation phase, respectively. The resulting AAS consisted of five items and was found to have a one‐dimensional structure and excellent internal consistency. It correlated well with other measures of disease activity and quality‐of‐life impairment, thus demonstrating its convergent validity. In addition, the known‐groups validity and test–retest reliability of the AAS were found to be good.
Conclusions
The AAS is the first validated and reliable tool to determine disease activity in RecA patients, and it may serve as a valuable instrument in future clinical studies and routine patient care.
Background
Recurrent angioedema is a frequent clinical problem characterized by unpredictably and rapidly occurring cutaneous and mucosal swellings. These swellings may be painful and/or disfiguring. ...Upper airway involvement can also lead to dyspnea and suffocation. Although the disease burden is high, there is currently no specific instrument to measure health‐related quality of life (QoL) impairment.
Objective
To develop and validate the first symptom‐specific tool to assess QoL impairment in recurrent angioedema patients, adhering to established methodological recommendations.
Methods
During the development phase, 29 questions (items) were generated. Subsequently, item reduction was performed by means of impact analysis and factor analysis as well as by checking for content and face validity. As a result, 17 items were selected and included in the final instrument, the Angioedema QoL Questionnaire (AE‐QoL). AE‐QoL was then tested for its validity, reliability, and influence factors.
Results
One hundred and ten angioedema patients took part in the validation of AE‐QoL. AE‐QoL was found to have a four‐dimensional structure as well as a valid total score. All of its four domains (functioning, fatigue/mood, fears/shame, food) showed good levels of internal consistency with Cronbach's alpha > 0.8. Test–retesting revealed a good reliability of the instruments total score and domain scores. Gender as well as the patients' self‐rated disease activity was found to be predictors of the AE‐QoL total score.
Conclusions
Angioedema Quality of Life Questionnaire is the first angioedema‐specific QoL questionnaire. It is a short, valid and reliable instrument that may serve as a valuable tool in future clinical studies and in routine patient care.
Background
Dry skin is a frequent and multifaceted condition which can be associated with skin irritation, itch, patient discomfort and manifest skin disease. In spite of being frequent, little is ...known about the epidemiology of dry skin in the population.
Objective
To determine the prevalence of dry skin in the German adult population.
Methods
Data of 48 630 employed persons were assessed on a cross‐sectional level in whole‐body examinations by experienced dermatologists during company‐based skin screenings conducted in 343 German companies. Next to the current dermatologic findings, age, gender, allergies, atopic diseases and the skin type were assessed.
Results
In total, n = 14 300 persons (29.4%) were rated as having xerotic skin. Older age but not gender was associated with xerosis. In the regression analyses controlling for age and gender, dry skin was a significant predictor for: axillary dermatitis (OR: 4.51; CI 2.70–7.54), atopic eczema (OR: 3.99; CI 3.42–4.65), exsiccation eczema (OR: 2.96; CI 2.40–3.65), psoriasis (OR: 1.57; CI 1.38–1.78), plantar warts (OR: 1.42; CI 1.26–1.60), seborrhoeic dermatitis (OR: 1.28; CI 1.16–1.42) and atopic disposition (OR: 1.17; CI 1.12–1.22).
Conclusion
Dry skin is a frequent condition in the adult general population and needs special attention. Known risk factors may facilitate identifying patients at risk for deterioration.
Linked article: This is a commentary on M.‐Q. Man et al., pp. 15–16 in this issue. To view this article visit
https://doi.org/10.1111/jdv.15374.
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