Ligelizumab for Chronic Spontaneous Urticaria Maurer, Marcus; Giménez-Arnau, Ana M; Sussman, Gordon ...
The New England journal of medicine,
10/2019, Volume:
381, Issue:
14
Journal Article
Peer reviewed
Open access
In the majority of patients with chronic spontaneous urticaria, most currently available therapies do not result in complete symptom control. Ligelizumab is a next-generation high-affinity humanized ...monoclonal anti-IgE antibody. Data are limited regarding the dose-response relationship of ligelizumab and the efficacy and safety of ligelizumab as compared with omalizumab and placebo in patients who have moderate-to-severe chronic spontaneous urticaria that is inadequately controlled with H
-antihistamines at approved or increased doses, alone or in combination with H
-antihistamines or leukotriene-receptor antagonists.
In a phase 2b dose-finding trial, we randomly assigned patients to receive ligelizumab at a dose of 24 mg, 72 mg, or 240 mg, omalizumab at a dose of 300 mg, or placebo, administered subcutaneously every 4 weeks for a period of 20 weeks, or a single 120-mg dose of ligelizumab. Disease symptoms of hives, itch, and angioedema were monitored by means of weekly activity scores. The main objective was to determine a dose-response relationship for the complete control of hives (indicated by a weekly hives-severity score of 0, on a scale from 0 to 21, with higher scores indicating greater severity); the primary end point of this response was assessed at week 12. Complete symptom control was indicated by a weekly urticaria activity score of 0 (on a scale from 0 to 42, with higher scores indicating greater severity). Safety was analyzed throughout the trial.
A total of 382 patients underwent randomization. At week 12, a total of 30%, 51%, and 42% of the patients treated with 24 mg, 72 mg, and 240 mg, respectively, of ligelizumab had complete control of hives, as compared with 26% of the patients in the omalizumab group and no patients in the placebo group. A dose-response relationship was established. At week 12, a total of 30%, 44%, and 40% of the patients treated with 24 mg, 72 mg, and 240 mg, respectively, of ligelizumab had complete control of symptoms, as compared with 26% of the patients in the omalizumab group and no patients in the placebo group. In this small and short trial, no safety concerns regarding ligelizumab or omalizumab emerged.
A higher percentage of patients had complete control of symptoms of chronic spontaneous urticaria with ligelizumab therapy of 72 mg or 240 mg than with omalizumab or placebo. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT02477332.).
Background
Angioedema is a common presentation in the emergency department (ED). Airway angioedema can be fatal; therefore, prompt diagnosis and correct treatment are vital.
Objective of the review
...Based on the findings of two expert panels attended by international experts in angioedema and emergency medicine, this review aims to provide practical guidance on the diagnosis, differentiation, and management of histamine- and bradykinin-mediated angioedema in the ED.
Review
The most common pathophysiology underlying angioedema is mediated by histamine; however, ED staff must be alert for the less common bradykinin-mediated forms of angioedema. Crucially, bradykinin-mediated angioedema does not respond to the same treatment as histamine-mediated angioedema. Bradykinin-mediated angioedema can result from many causes, including hereditary defects in C1 esterase inhibitor (C1-INH), side effects of angiotensin-converting enzyme inhibitors (ACEis), or acquired deficiency in C1-INH. The increased use of ACEis in recent decades has resulted in more frequent encounters with ACEi-induced angioedema in the ED; however, surveys have shown that many ED staff may not know how to recognize or manage bradykinin-mediated angioedema, and hospitals may not have specific medications or protocols in place.
Conclusion
ED physicians must be aware of the different pathophysiologic pathways that lead to angioedema in order to efficiently and effectively manage these potentially fatal conditions.
Chronic rhinosinusitis (CRS) affects up to 12% of the general population and is traditionally divided into two main phenotypic subsets, based on the presence of nasal polyps (CRSwNP) or their ...absence. It is well-established that many patients with CRSwNP report poor quality of life (QoL), which is further compromised by comorbidities (eg, asthma, bronchiectasis, aspirin-exacerbated respiratory disease). Chronic rhinosinusitis CRS with nasal polyps is managed with a combination of medical therapy and surgical interventions, and biologics are emerging as a promising new treatment option for patients with inadequate response to the standard of care. A range of patient-reported outcome measures have been used to assess QoL for patients with CRSwNP in clinical trials, including disease-specific questionnaires (eg, Sino-Nasal Outcome Test-22) and generic ones (eg, Short Form-36). Significantly impaired QoL has been identified as a criterion for the indication to use biologics in patients with CRSwNP. This review summarizes clinical evidence (2010-2021) on QoL outcomes with currently available treatments for CRSwNP and assesses the improvement in QoL after biologic treatments, especially for patients with comorbidities reported in interventional studies (randomized controlled trials and real-world experience).
Atopic dermatitis (AD) is an inflammatory skin disease caused by allergen exposures and estimated to affect ∼20% of children. Children in urban areas have a higher prevalence of AD compared with ...those living outside of urban areas. AD is believed to lead to asthma development as part of the "atopic march."
Our objective was to determine the sequential and chronological relationships between AD and asthma for children in an under-resourced community.
The progression from AD to asthma in the under-resourced, urban community of Sun Valley, Colorado, was examined by assessing Medicaid data for the years 2016 to 2019 for a diagnosis of AD or asthma in children 6 and 7 years old.
Pearson correlations between AD and asthma diagnoses were significant only with respect to AD at age 6 years compared with asthma 1 year later, at age 7 years.
By studying a susceptible community with a consistent but mixed genetic background, we found sequential and chronological links between AD and asthma.
Atopic dermatitis (AD), food allergy, allergic rhinitis, and asthma are common atopic disorders of complex etiology. The frequently observed atopic march from early AD to asthma, allergic rhinitis, ...or both later in life and the extensive comorbidity of atopic disorders suggest common causal mechanisms in addition to distinct ones. Indeed, both disease-specific and shared genomic regions exist for atopic disorders. Their prevalence also varies among races; for example, AD and asthma have a higher prevalence in African Americans when compared with European Americans. Whether this disparity stems from true genetic or race-specific environmental risk factors or both is unknown. Thus far, the majority of the genetic studies on atopic diseases have used populations of European ancestry, limiting their generalizability. Large-cohort initiatives and new analytic methods, such as admixture mapping, are currently being used to address this knowledge gap. Here we discuss the unique and shared genetic risk factors for atopic disorders in the context of ancestry variations and the promise of high-throughput “-omics”–based systems biology approach in providing greater insight to deconstruct their genetic and nongenetic etiologies. Future research will also focus on deep phenotyping and genotyping of diverse racial ancestry, gene-environment, and gene-gene interactions.
Reduced calorie, low fat diet is currently recommended diet for overweight and obese adults. Prior data suggest that low carbohydrate diets may also be a viable option for those who are overweight ...and obese.
Compare the effects of low carbohydrate versus low fats diet on weight and atherosclerotic cardiovascular disease risk in overweight and obese patients.
Systematic literature review via PubMed (1966-2014).
Randomized controlled trials with ≥8 weeks follow up, comparing low carbohydrate (≤120gm carbohydrates/day) and low fat diet (≤30% energy from fat/day).
Data were extracted and prepared for analysis using double data entry. Prior to identification of candidate publications, the outcomes of change in weight and metabolic factors were selected as defined by Cochrane Collaboration. Assessment of the effects of diets on predicted risk of atherosclerotic cardiovascular disease risk was added during the data collection phase.
1797 patients were included from 17 trials with <1 year follow up in 12. Compared with low fat diet, low carbohydrate was associated with significantly greater reduction in weight (Δ = -2.0 kg, 95% CI: -3.1, -0.9) and significantly lower predicted risk of atherosclerotic cardiovascular disease events (p<0.03). Frequentist and Bayesian results were concordant. The probability of greater weight loss associated with low carbohydrate was >99% while the reduction in predicted risk favoring low carbohydrate was >98%.
Lack of patient-level data and heterogeneity in dropout rates and outcomes reported.
This trial-level meta-analysis of randomized controlled trials comparing LoCHO diets with LoFAT diets in strictly adherent populations demonstrates that each diet was associated with significant weight loss and reduction in predicted risk of ASCVD events. However, LoCHO diet was associated with modest but significantly greater improvements in weight loss and predicted ASCVD risk in studies from 8 weeks to 24 months in duration. These results suggest that future evaluations of dietary guidelines should consider low carbohydrate diets as effective and safe intervention for weight management in the overweight and obese, although long-term effects require further investigation.
Angioedema is a sudden, transient swelling of well-demarcated areas of the dermis, subcutaneous tissue, mucosa, and submucosal tissues that can occur with or without urticaria. Up to 25% of people in ...the US will experience an episode of urticaria or angioedema during their lifetime, and many will present to the emergency department with an acute attack. Most cases of angioedema are attributable to the vasoactive mediators histamine and bradykinin. Histamine-mediated (allergic) angioedema occurs through a type I hypersensitivity reaction, whereas bradykinin-mediated (non-allergic) angioedema is iatrogenic or hereditary in origin.
Although their clinical presentations bear similarities, the treatment algorithm for histamine-mediated angioedema differs significantly from that for bradykinin-mediated angioedema. Corticosteroids, and epinephrine are effective in the management of histamine-mediated angioedema but are ineffective in the management of bradykinin-mediated angioedema. Recent advancements in the understanding of angioedema have yielded pharmacologic treatment options for hereditary angioedema, a rare hereditary form of bradykinin-mediated angioedema. These novel therapies include a kallikrein inhibitor (ecallantide) and a bradykinin β2 receptor antagonist (icatibant). The physician’s ability to distinguish between these types of angioedema is critical in optimizing outcomes in the acute care setting with appropriate treatment. This article reviews the pathophysiologic mechanisms, clinical presentations, and diagnostic laboratory evaluation of angioedema, along with acute management strategies for attacks.
Atopic dermatitis (AD) is a complex multifactorial inflammatory skin disease that affects ~280 million people worldwide. About 85% of AD cases begin in childhood, a significant portion of which can ...persist into adulthood. Moreover, a typical progression of children with AD to food allergy, asthma or allergic rhinitis has been reported ("allergic march" or "atopic march"). AD comprises highly heterogeneous sub-phenotypes/endotypes resulting from complex interplay between intrinsic and extrinsic factors, such as environmental stimuli, and genetic factors regulating cutaneous functions (impaired barrier function, epidermal lipid, and protease abnormalities), immune functions and the microbiome. Though the roles of high-throughput "omics" integrations in defining endotypes are recognized, current analyses are primarily based on individual omics data and using binary clinical outcomes. Although individual omics analysis, such as genome-wide association studies (GWAS), can effectively map variants correlated with AD, the majority of the heritability and the functional relevance of discovered variants are not explained or known by the identified variants. The limited success of singular approaches underscores the need for holistic and integrated approaches to investigate complex phenotypes using trans-omics data integration strategies. Integrating omics layers (e.g., genome, epigenome, transcriptome, proteome, metabolome, lipidome, exposome, microbiome), which often have complementary and synergistic effects, might provide the opportunity to capture the flow of information underlying AD disease manifestation. Overlapping genes/candidates derived from multiple omics types include
, and
in AD pathogenesis. Overlapping pathways include macrophage, endothelial cell and fibroblast activation pathways, in addition to well-known Th1/Th2 and NFkB activation pathways. Interestingly, there was more multi-omics overlap at the pathway level than gene level. Further analysis of multi-omics overlap at the tissue level showed that among 30 tissue types from the GTEx database, skin and esophagus were significantly enriched, indicating the biological interconnection between AD and food allergy. The present work explores multi-omics integration and provides new biological insights to better define the biological basis of AD etiology and confirm previously reported AD genes/pathways. In this context, we also discuss opportunities and challenges introduced by "big omics data" and their integration.
Urticaria and Angioedema Across the Ages Saini, Sarbjit; Shams, Marissa; Bernstein, Jonathan A ...
The journal of allergy and clinical immunology in practice (Cambridge, MA),
06/2020, Volume:
8, Issue:
6
Journal Article
Peer reviewed
Chronic urticaria (CU) and angioedema can occur at any age. Although most CU with or without angioedema occurs in adults, it can also present in children or the elderly and can complicate pregnancy ...and breast-feeding. The presentations of CU and angioedema are different in children, middle-aged adults, and older patients as are the differential diagnoses. Therefore, the management of CU and angioedema in these different age groups and special populations needs to take into account the age-specific features of urticaria and angioedema. Here, we describe the evaluation, diagnosis, and treatment of CU and angioedema in children, middle-aged adults, and older patients. This review focuses on CU with or without angioedema and does not discuss acute urticaria or bradykinin-mediated angioedema.
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