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
Angioedema is defined as localized and self‐limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive ...mediator(s). When angioedema recurs without significant wheals, the patient should be diagnosed to have angioedema as a distinct disease. In the absence of accepted classification, different types of angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying angioedema. Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of angioedema.
Hereditary angioedema with C1 inhibitor deficiency is characterized by recurrent, unpredictable swelling episodes caused by uncontrolled plasma kallikrein generation and excessive bradykinin release ...resulting from cleavage of high-molecular-weight kininogen. Lanadelumab (DX-2930) is a new kallikrein inhibitor with the potential for prophylactic treatment of hereditary angioedema with C1 inhibitor deficiency.
We conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients with hereditary angioedema with C1 inhibitor deficiency were randomly assigned in a 2:1 ratio to receive either lanadelumab (24 patients) or placebo (13 patients), in two administrations 14 days apart. Patients assigned to lanadelumab were enrolled in sequential dose groups: total dose of 30 mg (4 patients), 100 mg (4 patients), 300 mg (5 patients), or 400 mg (11 patients). The pharmacodynamic profile of lanadelumab was assessed by measurement of plasma levels of cleaved high-molecular-weight kininogen, and efficacy was assessed by the rate of attacks of angioedema during a prespecified period (day 8 to day 50) in the 300-mg and 400-mg groups as compared with the placebo group.
No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group.
In this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; ClinicalTrials.gov number, NCT02093923 .).
The inflammatory hypothesis of schizophrenia (SZ) posits that inflammatory processes and neural-immune interactions are involved in its pathogenesis, and may underpin some of its neurobiological ...correlates. SZ is the psychiatric disorder causing the most severe burden of illness, not just owing to its psychiatric impairment, but also owing to its significant medical comorbidity. C-reactive protein (CRP) is a commonly used biomarker of systemic inflammation worldwide. There are some conflicting results regarding the behaviour of CRP in SZ. The aims of this study were to verify whether peripheral CRP levels are indeed increased in SZ, whether different classes of antipsychotics divergently modulate CRP levels and whether its levels are correlated with positive and negative symptomatology. With that in mind, we performed a meta-analysis of all cross-sectional studies of serum and plasma CRP levels in SZ compared to healthy subjects. In addition, we evaluated longitudinal studies on CRP levels before and after antipsychotic use. Our meta-analyses of CRP in SZ included a total of 26 cross-sectional or longitudinal studies comprising 85 000 participants. CRP levels were moderately increased in persons with SZ regardless of the use of antipsychotics and did not change between the first episode of psychosis and with progression of SZ (g=0.66, 95% confidence interval (95% CI) 0.43 to 0.88, P<0.001, 24 between-group comparisons, n=82 962). The extent of the increase in peripheral CRP levels paralleled the increase in severity of positive symptoms, but was unrelated to the severity of negative symptoms. CRP levels were also aligned with an increased body mass index. Conversely, higher age correlated with a smaller difference in CRP levels between persons with SZ and controls. Furthermore, CRP levels did not increase after initiation of antipsychotic medication notwithstanding whether these were typical or atypical antipsychotics (g=0.01, 95% CI -0.20 to 0.22, P=0.803, 8 within-group comparisons, n=713). In summary, our study provides further evidence of the inflammatory hypothesis of SZ. Whether there is a causal relationship between higher CRP levels and the development of SZ and aggravation of psychotic symptoms, or whether they are solely a marker of systemic low-grade inflammation in SZ, remains to be clarified.
Rhinitis is an umbrella term that encompasses many different subtypes, several of which still elude complete characterization. The concept of phenotyping, being the definition of disease subtypes on ...the basis of clinical presentation, has been well established in the last decade. Classification of rhinitis entities on the basis of phenotypes has facilitated their characterization and has helped practicing clinicians to efficiently approach rhinitis patients. Recently, the concept of endotypes, that is, the definition of disease subtypes on the basis of underlying pathophysiology, has emerged. Phenotypes/endotypes are dynamic, overlapping, and may evolve into one another, thus rendering clear‐cut definitions difficult. Nevertheless, a phenotype‐/endotype‐based classification approach could lead toward the application of stratified and personalized medicine in the rhinitis field. In this PRACTALL document, rhinitis phenotypes and endotypes are described, and rhinitis diagnosis and management approaches focusing on those phenotypes/endotypes are presented and discussed. We emphasize the concept of control‐based management, which transcends all rhinitis subtypes.
Major scholars in the field, on the basis of a 3-day consensus, created an in-depth review of current knowledge on the role of diet in cardiovascular disease (CVD), the changing global food system ...and global dietary patterns, and potential policy solutions. Evidence from different countries and age/race/ethnicity/socioeconomic groups suggesting the health effects studies of foods, macronutrients, and dietary patterns on CVD appear to be far more consistent though regional knowledge gaps is highlighted. Large gaps in knowledge about the association of macronutrients to CVD in low- and middle-income countries particularly linked with dietary patterns are reviewed. Our understanding of foods and macronutrients in relationship to CVD is broadly clear; however, major gaps exist both in dietary pattern research and ways to change diets and food systems. On the basis of the current evidence, the traditional Mediterranean-type diet, including plant foods and emphasis on plant protein sources provides a well-tested healthy dietary pattern to reduce CVD.
We measure the weak lensing masses and galaxy distributions of four massive galaxy clusters observed during the Science Verification phase of the Dark Energy Survey (DES). This pathfinder study is ...meant to (1) validate the Dark Energy Camera (DECam) imager for the task of measuring weak lensing shapes, and (2) utilize DECam's large field of view to map out the clusters and their environments over 90 arcmin. We conduct a series of rigorous tests on astrometry, photometry, image quality, point spread function (PSF) modelling, and shear measurement accuracy to single out flaws in the data and also to identify the optimal data processing steps and parameters. We find Science Verification data from DECam to be suitable for the lensing analysis described in this paper. The PSF is generally well behaved, but the modelling is rendered difficult by a flux-dependent PSF width and ellipticity. We employ photometric redshifts to distinguish between foreground and background galaxies, and a red-sequence cluster finder to provide cluster richness estimates and cluster–galaxy distributions. By fitting Navarro–Frenk–White profiles to the clusters in this study, we determine weak lensing masses that are in agreement with previous work. For Abell 3261, we provide the first estimates of redshift, weak lensing mass, and richness. In addition, the cluster–galaxy distributions indicate the presence of filamentary structures attached to 1E 0657−56 and RXC J2248.7−4431, stretching out as far as 1°(approximately 20 Mpc), showcasing the potential of DECam and DES for detailed studies of degree-scale features on the sky.
We report results of a search for light (≲10 GeV) particle dark matter with the XENON10 detector. The event trigger was sensitive to a single electron, with the analysis threshold of 5 electrons ...corresponding to 1.4 keV nuclear recoil energy. Considering spin-independent dark matter-nucleon scattering, we exclude cross sections σ(n)>7×10(-42) cm(2), for a dark matter particle mass m(χ)=7 GeV. We find that our data strongly constrain recent elastic dark matter interpretations of excess low-energy events observed by CoGeNT and CRESST-II, as well as the DAMA annual modulation signal.
Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective ...bradykinin B2 receptor antagonist.
In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms.
A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported.
In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)
Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most ...challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added.
We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care.
A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes.
The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).
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