Real-world effectiveness of anti-interleukin-23 antibodies in chronic plaque-type psoriasis of patients from the Austrian Psoriasis Registry (PsoRA).

With the introduction of the latest class of biologic drugs targeting interleukin (IL)-23p19, three new, highly effective drugs can be used for the treatment of chronic plaque psoriasis. However, poorer skin improvement as well as higher rates of serious adverse events have been reported for patients under real-world conditions (outside clinical trials). This accounts especially for patients who have already been treated with biologic drugs. We therefore aimed to determine effectiveness and safety of IL-23p19 inhibitors in real-world patients by analysing data from the Psoriasis Registry Austria (PsoRA) in this observational, retrospective, multicentre cohort study. Data for 197 patients (52.3% biologic-non-naïve), who were treated with anti-IL-23p19 antibodies (127 guselkumab, 55 risankizumab and 15 tildrakizumab) for at least 3 months, were eligible for analysis. In general, biologic-non-naïve patients displayed a less favourable response to anti-IL-23 treatment as compared to biologic-naïve patients. However, after correction for previous biologic exposure, few differences in PASI improvement were detected among biologic-naïve and -non-naïve patients treated with different IL-23p19 inhibitors. This indicates that treatment effectiveness is not related to the class of the previously administered therapy in biologic-non-naïve patients. Therefore, IL-23p19 inhibitors represent a promising treatment alternative for patients who have not responded to previous biologics. However, as with other biologic agents (including IL-17 inhibitors), we did not observe an entirely satisfactory treatment response (i.e. PASI < 3 and/or PASI 75) to anti-IL-23 treatment in one out of four to five patients. Adverse events (mainly non-severe infections) were observed in 23 (11.7%) patients with no major differences regarding the administered IL-23 inhibitor or previous biologic exposure.

Biologic drug survival rates in the era of anti-interleukin-17 antibodies: a time-period-adjusted registry analysis.

BACKGROUND: Drug survival rates reflect efficacy and safety and may be influenced by the availability of alternative treatment options. Little is known about time-dependent drug survival in psoriasis and the effect of increasing numbers of biologic treatment options. OBJECTIVES: To determine whether drug survival is influenced by the availability of treatment options and by factors such as gender, psoriatic arthritis or previous biologic treatment. METHODS: This observational, retrospective, multicentre cohort study analysed data from patients registered in the Austrian Psoriasis Registry (PsoRA) who were treated with biologics between 1 January 2015 and 30 November 2019. RESULTS: A total of 1572 patients who received 1848 treatment cycles were included in this analysis. The highest long-term Psoriasis Area and Severity Index improvement was observed after treatment with ixekizumab, followed by ustekinumab and secukinumab, adalimumab and etanercept. Overall, ustekinumab surpassed all other biologics in drug survival up to 48 months. However, when adjusted for biologic naïvety, its superiority vanished and drug survival rates were similar for ixekizumab (91·6%), secukinumab (90·2%) and ustekinumab (92·8%), all of them superior to adalimumab (76·5%) and etanercept (71·9%) at 12 months and beyond. Besides biologic non-naïvety (2·10, P < 0·001), the introduction of a new drug such as secukinumab or ixekizumab (relative hazard ratio 1·6, P = 0·001) and female gender (1·50, P = 0·019) increased the risk of treatment discontinuation overall, whereas psoriatic arthritis did not (1·12, P = 0·21). CONCLUSIONS: The time-dependent availability of drugs should be considered when analysing and comparing drug survival. Previous biologic exposure significantly influences drug survival. Women are more likely to stop treatment.

A simple and versatile phase detector for heterodyne interferometers.

The measurement of the relative phase of two sinusoidal electrical signals is a frequently encountered task in heterodyne interferometry, but also occurs in many other applications. Especially in interferometry, multi-radian detectors are often required, which track the temporal evolution of the phase difference and are able to register phase changes that exceed 2π. While a large variety of solutions to this problem is already known, we present an alternative approach, which pre-processes the signals with simple analog circuitry and digitizes two resulting voltages with an analog-to-digital converter (ADC), whose sampling frequency can be far below the frequency of the sinusoidal signals. Phase reconstruction is finally carried out by software. The main advantage of this approach is its simplicity, using only few low-cost hardware components and a standard 2-channel ADC with low performance requirements. We present an application on the two-color interferometer of the ASDEX Upgrade tokamak, where the relative phase of 40 MHz sinusoids is measured.

Symptomatic dermographism: an inadequately described disease.

BACKGROUND: Symptomatic dermographism is the most common form of physical urticaria with a prevalence of 2-5%. However, its clinical picture has rarely been described. OBJECTIVE: To understand more of patients' views about the practical aspects of their condition, its cause and impact on quality of life. METHODS: Ninety-one of 150 patients with symptomatic dermographism from our specialist urticaria clinic completed a 38-question questionnaire sent them by mail. RESULTS: The mean duration of disease was 6» years. In most patients, the condition was continuous, but ~25% had prolonged symptom-free phases. Severity was evaluated as moderate in 45%, severe in 33% and very severe in 6% of respondents. Other responses included: symptoms worse in the evening in 81%; quality of life significantly impaired in 44%; normal life not possible 7%; stress induces acute episodes 44%; other urticarial forms coexist 21%; allergy coexist 48%. A family history was reported in 14%. Almost all patients were taking H1 -anti-histamines, 49% getting marked improvement and 23% becoming symptoms free. LIMITATIONS: It is a survey only of patient opinions. CONCLUSIONS: This questionnaire survey confirmed that symptomatic dermographism is a debilitating condition with profound effects on quality of life but its underlying cause and disease mechanisms remain obscure.

Fringe jump analysis and implementation of polarimetry on the ASDEX Upgrade DCN interferometer.

The ASDEX Upgrade tokamak is equipped with a 5-channel DCN interferometer with a probing wavelength of 195 µm. Up to now, phase measurement and density calculation have been accomplished by hard-wired phase counting electronics. Meanwhile, a fast digitizer has been installed which acquires the raw signals. That way, the various causes of counting errors by integer multiples of 2π, so-called fringe jumps, can be analyzed, and phase reconstruction schemes based on digital signal processing can be developed. In addition, a prototype polarimeter setup has been installed on one channel and allows for measurement of the Faraday rotation experienced by the probing beam.

Calcitonin gene-related peptide and vascular endothelial growth factor are expressed in lesional but not uninvolved skin in chronic spontaneous urticaria.

BACKGROUND: The mechanisms for producing weals in chronic spontaneous (idiopathic) urticaria (CSU) are incompletely understood. Leucocyte infiltration with vascular leakage and expression of the potent vasoactive agents' calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) are features of late-phase allergic skin reactions, previously proposed as a model of CSU. OBJECTIVE: To measure CGRP and VEGF expression in lesional and non-lesional skin from CSU patients and to compare results with a control group. METHODS: Eight paired biopsies (one from 4-8 h spontaneous weals and one from uninvolved skin) were taken from eight patients with CSU and nine control subjects and studied by immunohistochemistry and confocal microscopy. RESULTS: Lesional skin in CSU contained significantly more CGRP+ and VEGF+ cells than non-lesional skin. No significant differences were observed in CGRP and VEGF expression between non-lesional skin and controls. In lesional skin, VEGF and CGRP co-localised to UEA-1+ blood vessels. CGRP was also expressed by neutrophils and eosinophils and to a lesser extent by CD90(+) fibroblasts, mast cells, CD3(+) and CD68(+) cells. CGRP and VEGF expression was not related to the duration of disease. CONCLUSION AND CLINICAL RELEVANCE: Increased expression of CGRP and VEGF in lesional, but not uninvolved, skin indicates that these potent vasoactive agents may play a role in wealing and tissue oedema in CSU so representing novel targets in therapy.

Elevations in vascular markers and eosinophils in chronic spontaneous urticarial weals with low-level persistence in uninvolved skin.

BACKGROUND: In chronic spontaneous urticaria (CSU) mast cell activation together with inflammatory changes in the skin are well documented and may play an important role in mechanisms of tissue oedema. OBJECTIVES: To confirm and extend these observations by measuring microvascular markers, leucocytes and mast cell numbers in lesional and uninvolved skin and to compare findings with a control group. METHODS: Paired biopsies (one from 4-8-h spontaneous weals and one from uninvolved skin) were taken from eight patients with CSU and nine control subjects and studied using immunohistochemistry and confocal microscopy using the lectin Ulex europaeus agglutinin 1 (UEA-1). RESULTS: Lesional skin in CSU contained significantly more CD31+ endothelial cells; CD31+ blood vessels, neutrophils, eosinophils, basophils and macrophages; and CD3+ T cells than nonlesional skin. Increased vascularity was confirmed by confocal imaging using the lectin UEA-1. Uninvolved skin from CSU contained significantly more CD31+ endothelial cells, CD31+ blood vessels and eosinophils compared with the control subjects. There was a threefold increase in mast cell numbers when CSU was compared with controls but no difference was observed between lesional and uninvolved skin. CONCLUSIONS: Increased vascular markers together with eosinophil and neutrophil infiltration are features of lesional skin in CSU and might contribute to tissue oedema. Eosinophils and microvascular changes persist in uninvolved skin, which, together with increased mast cells, suggests that nonlesional skin is primed for further wealing.

Spectrally resolved motional Stark effect measurements on ASDEX Upgrade.

A spectrally resolved Motional Stark Effect (MSE) diagnostic has been installed at ASDEX Upgrade. The MSE data have been fitted by a forward model providing access to information about the magnetic field in the plasma interior [R. Reimer, A. Dinklage, J. Geiger et al., Contrib. Plasma Phys. 50, 731-735 (2010)]. The forward model for the beam emission spectra comprises also the fast ion Dα signal [W. W. Heidbrink and G. J. Sadler, Nucl. Fusion 34, 535-615 (1994)] and the smearing on the CCD-chip. The calculated magnetic field data as well as the revealed (dia)magnetic effects are consistent with the results from equilibrium reconstruction solver. Measurements of the direction of the magnetic field are affected by unknown and varying polarization effects in the observation.

A novel, simple, validated and reproducible instrument for assessing provocation threshold levels in patients with symptomatic dermographism.

BACKGROUND: Symptomatic dermographism is a common urticarial condition. There is a need for an objective method to determine the provocation threshold for patients, in order to facilitate individualized diagnosis and treatment. AIM: To compare the dermal responses evoked by a new type of dermographometer (FricTest) with those evoked by a spring-loaded dermographometer (the Dermographic tester). METHODS: Dermal provocation was performed in 30 patients with symptomatic dermographism and 30 healthy controls. The FricTest consists of six tips of varying length, which are stroked over the skin, while the Dermographic tester has a single tip. The widths and volumes of the resulting weals were measured. RESULTS: Both instruments were similar in their ability to produce dermal responses. The weal widths of 1 and 3 mm induced by the FricTest were used as the provocation thresholds to distinguish between patients and controls, and to indicate the different levels of severity within the patient group. CONCLUSIONS: The FricTest was easy to use and produced an objective response. This simple and inexpensive instrument could be used to individualize diagnosis and treatment of patients with symptomatic dermographism, allowing for better personalized management.

First observation of edge localized modes mitigation with resonant and nonresonant magnetic perturbations in ASDEX Upgrade.

First experiments with nonaxisymmetric magnetic perturbations, toroidal mode number n=2, produced by newly installed in-vessel saddle coils in the ASDEX Upgrade tokamak show significant reduction of plasma energy loss and peak divertor power load associated with type-I edge localized modes (ELMs) in high-confinement mode plasmas. ELM mitigation is observed above an edge density threshold and is obtained both with magnetic perturbations that are resonant and not resonant with the edge safety factor profile. Compared with unperturbed type-I ELMy reference plasmas, plasmas with mitigated ELMs show similar confinement, similar plasma density, and lower tungsten impurity concentration.

Adaptation and initial results of the Polish version of the GA(2)LEN chronic urticaria quality of life questionnaire (CU-Q(2)oL).

BACKGROUND: Strong negative influence upon the quality of life in chronic urticaria is well proved. Before the GA(2)LEN Chronic Urticaria Quality of Life Questionnaire (CU-Q(2)oL) was introduced, the quality of life in chronic urticaria had been measured with general or dermatology specific questionnaires. CU-Q(2)oL was initially developed in Italy and consisted of 23 items divided into 6 quality of life dimensions. OBJECTIVE: The aim of our study was to adapt the Polish version of CU-Q(2)oL and to provide initial results from the Polish sample. METHODS: To prepare the Polish version forward and back translation was prepared. After cognitive debriefing, we collected a group of 126 chronic urticaria patients who completed Polish CU-Q(2)oL, Dermatology Life Quality Index (DLQI) and Skindex-29 questionnaire. Disease severity was assessed with Urticaria Activity Score (UAS). We performed the factorial analysis to identify CU-Q(2)oL subscales in our study, internal consistency and convergent validity assessment as well as factors driving the results. Moreover, we analysed tool's reproducibility and responsiveness. RESULTS: The factor analysis resulted in six subscales of Polish CU-Q(2)oL version with satisfying face validity: Itching, Swelling/Mental status, Functioning, Sleep, Eating/Limits, Embarrassment. All subscales presented recommended internal consistency and convergent validity. Disease severity was the only factor predicting results of all the subscales. Polish CU-Q(2)oL version was reproducible and sensitive to change. We noticed the highest quality of life impairment in Itching and Embarrassment subscales whereas Eating/Limits was the least affected. CONCLUSIONS: Our study supports reliability, responsiveness and validity of the Polish version of CU-Q(2)oL - easy in use, non time-consuming instrument to be used in research, clinical management and treatment outcome assessment and is one more step to confirm quality of life impairment in chronic urticaria.

Design of a digital multiradian phase detector and its application in fusion plasma interferometry.

We discuss the circuit design of a digital multiradian phase detector that measures the phase difference between two 10 kHz square wave TTL signals and provides the result as a binary number. The phase resolution of the circuit is 1/64 period and its dynamic range is 256 periods. This circuit has been developed for fusion plasma interferometry with submillimeter waves on the ASDEX Upgrade tokamak. The results from interferometric density measurement are discussed and compared to those obtained with the previously used phase detectors, especially with respect to the occurrence of phase jumps. It is illustrated that the new phase measurement provides a powerful tool for automatic real-time validation of the measured density, which is important for feedback algorithms that are sensitive to spurious density signals.

Results and relevance of critical temperature threshold testing in patients with acquired cold urticaria.

Background Acquired cold urticaria (ACU) is a physical urticaria characterized by local skin reactions after cold exposure. Objective markers of disease severity and activity would be helpful. Unfortunately, such markers are not yet available, even though stimulation time and temperature thresholds are promising candidates. Objectives We assessed and correlated critical temperature thresholds (CTTs) with disease severity and activity in patients with ACU. Methods CTTs were determined in 45 patients with ACU by TempTest-based cold contact stimulation tests (Emo Systems GmbH, Berlin, Germany), and ACU severity and activity were assessed using Likert scales. Results Patients with ACU exhibited mean +/- SEM CTTs of 17 +/- 6 degrees C (range 4-27 degrees C). These thresholds and their changes correlated with the severity (r = 0.53, P < 0.05) and activity of disease (r = 0.64, P < 0.05), respectively. Conclusions These findings indicate that temperature threshold measurements may be used for assessing disease severity and activity as well as the efficacy of therapeutic measures including novel treatment approaches for cold urticaria.

The definition and diagnostic testing of physical and cholinergic urticarias--EAACI/GA2LEN/EDF/UNEV consensus panel recommendations.

The recommendations for the definition and diagnosis presented in this position paper are the result of a panel consensus meeting held in December 2008 in Berlin. This consensus meeting was a joint initiative of EAACI (European Academy of Allergology and Clinical Immunology) Dermatology Section, the EU-funded network of excellence, GA(2)LEN (Global Allergy and Asthma European Network), the EDF (European Dermatology Forum) and UNEV (urticaria network e.V.). The aim of these recommendations is to improve the diagnosis and management of patients with physical urticaria or cholinergic urticaria and to promote research and a better understanding of these diseases. Our recommendations used the paper produced by a 1996 expert meeting (1) and they acknowledge the latest changes in our understanding of physical urticarias and cholinergic urticaria as well as the recent development of novel diagnostic tools. In addition, this consensus paper highlights areas of need for further research.

The German version of the Chronic Urticaria Quality-of-Life Questionnaire: factor analysis, validation, and initial clinical findings.

BACKGROUND: Chronic urticaria (CU) is a common skin disorder that causes a substantial burden on patients' quality-of-life (QoL). The aim of this work was to generate and validate a German version of the Chronic Urticaria Quality of Life Questionnaire (CU-Q(2)oL) and to provide reference assessments of QoL. METHODS: The Italian CU-Q(2)oL was translated into German and administered to 157 CU patients. They also completed two well-established general dermatology QoL questionnaires, the Dermatology Life Quality Index (DLQI) and Skindex-29. Factor analysis was used to identify scales of the German CU-Q(2)oL. Correlation to the DLQI and Skindex-29 was used for validation. Multiple linear regression was used to determine which patient characteristics were associated with which dimensions of QoL. RESULTS: The factor analysis identified six scales of the German CU-Q(2)oL: functioning, sleep, itching/embarrassment, mental status, swelling/eating, and limits looks, which accounted for 70% of the data variance. Five of these six scales showed good internal consistency, and another five demonstrated convergent validity. On a percentile scale, they had these median CU-Q(2)oL scores: 29 functioning, 44 sleep, 50 itching/embarrassment, 50 mental status, 31 swelling/eating, 31 limits looks. Disease severity significantly predicted scores on all scales. Age predicted functioning, sleep, itching/embarrassment, and swelling/eating. Sex predicted itching/embarrassment and limits looks. CONCLUSION: This study yielded a robust validation of the German version of the CU-Q(2)oL. It confirmed previous studies that CU has a clinically meaningful burden on QoL, especially for sleep and mental health, and that women are more severely affected by pruritus. The German CU-Q(2)oL should be widely adopted in clinical research on the treatment of CU.

Beyond flat weals: validation of a three-dimensional imaging technology that will improve skin allergy research.

Skin-prick tests (SPTs) are a standard way to test for sensitizations to allergens, but to date, techniques that allow for high-quality measurements of the resulting weals for research purposes are lacking. In this study, we assessed a new three-dimensional (3D) imaging technology for its accuracy and consistency. We found that this new technology showed very little intraoperator and interoperator variation for repeated measurements of a model of known area by each of two operators. We also found that repeated measurements of the same object over 4 months showed virtually no variation. Finally, 3D imaging was superior to traditional ruler measurements for assessing SPT reactions to histamine and allergen. For high-quality measurements of SPT reactions, 3D imaging is accurate, consistent and reliable.

How to assess disease activity in patients with chronic urticaria?

BACKGROUND: The current EAACI/GA(2)LEN/EDF guidelines recommend assessing disease activity in chronic urticaria (CU) by using an established and well-defined symptom score, i.e. the urticaria activity score (UAS), which combines daily wheal numbers and pruritus intensity. However, this UAS has never been formally tested for its suitability in assessing CU activity. AIM: To determine the UAS correlation with quality of life (QoL) in CU patients and to compare the UAS to other symptom scores. METHODS: Chronic urticaria symptoms (wheals, erythema, angioedema, pruritus) were assessed on seven consecutive days in 111 CU patients for their numbers, duration, size, and/or intensity. Quality of life was assessed by using the Dermatology Life Quality Index. Both, urticaria activity and QoL were determined before and after a 3-week period, in which the patients followed a pseudoallergen-low diet. RESULTS: Urticaria activity score values correlated positively, albeit weakly, with QoL impairment in CU patients (r(2) = 0.31, P < 0.05). Also, changes in QoL following a pseudoallergen-low diet were reflected by the changes observed in the UAS (r(2) = 0.30, P < 0.05). No significant differences were found comparing the QoL correlation of the UAS and other symptom scores combining up to four CU symptom qualities. Quality of life correlation with UAS values increased with the number of days the UAS was assessed and plateaued starting from the fourth consecutive day. CONCLUSIONS: Our findings back the current guideline recommendations to use the UAS for monitoring disease activity in CU patients. Urticaria activity score mean values of at least four consecutive days should be used.

Acquired cold urticaria: clinical picture and update on diagnosis and treatment.

Acquired cold urticaria (ACU) is a frequent subtype of physical urticaria that is caused by the release of proinflammatory mast cell mediators after cold exposure. Although the underlying causes of ACU still remain to be clarified in detail, a wide range of diseases has been reported to be associated with ACU. This review gives an overview of the clinical picture, the differential diagnoses, diagnostic tests and the aetiology of ACU, and summarizes current and novel therapeutic options based on the current literature.