Hereditary angioedema with normal C1 inhibitor (HAE-nl-C1INH) was initially described almost a quarter century ago. Considerable progress toward unraveling the mysteries of this complex disease has been made during the intervening years. The ability to diagnose, classify, and treat HAE-nl-C1INH, however, continues to present daunting clinical challenges. In this article we have attempted to summarize current areas of scientific consensus and provide some insights to assist physicians caring for affected individuals. Coherently describing the field of HAE-nl-C1INH in many ways embodies a precarious balance between assertions anchored by data versus conjecture. In this Rostrum we have tried to encapsulate the numerous scientific developments over the past 25 years into a proposed classification schema intended to facilitate decisions when evaluating patients with recurrent angioedema. Founded on an accurate diagnosis in conjunction with an appreciation of the underlying pathomechanism, targeted patient treatment strategies can be appropriately designed. It is hoped that this approach will lay the groundwork for future advances in our understanding of HAE-nl-C1INH while bringing patients ever closer to the goal of leading a normal life.

Background: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. Objective: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). Methods: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). Results: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. Conclusion: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.

IntroductionTezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP). In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced blood eosinophil counts and fractional exhaled nitric oxide levels from week 2 and serum total immunoglobulin E (IgE) levels from week 12 compared with placebo in patients with severe, uncontrolled asthma. Given the gradual reductions in IgE levels observed with tezepelumab, this post hoc analysis assessed the timing of exacerbations with tezepelumab in patients with and without confirmed symptomatic perennial allergy to dust mite or animal allergens.MethodsNAVIGATOR was a multicenter, randomized, double-blind, placebo-controlled study. Patients (12–80 years old) were randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. The cumulative number of exacerbations was assessed over 52 weeks in patients grouped by confirmed symptomatic perennial allergy status. Symptomatic perennial allergy status was defined as investigator-reported history of allergy to dust mite or animal allergens and a positive fluorescence enzyme immunoassay test result for serum-specific IgE to the corresponding allergen at baseline.ResultsIn patients with (n = 318) and without (n = 741) confirmed symptomatic perennial allergy, tezepelumab reduced the cumulative number of exacerbations compared with placebo over 52 weeks. Reductions with tezepelumab compared with placebo were observed early in patients with and without confirmed symptomatic perennial allergy (Figure).ConclusionIn patients with severe, uncontrolled asthma, tezepelumab treatment resulted in early and sustained reductions in the cumulative number of exacerbations compared with placebo, irrespective of confirmed symptomatic perennial allergy status.

IntroductionSecond-generation H1-antihistamines are first-line treatment for chronic spontaneous urticaria (CSU), up-dosed to 4 times the standard dose if needed. The objective of this analysis was to assess control and antihistamine treatment patterns including switching and up-dosing as reported by patients and physicians.MethodsUrticaria Voices was a multinational, cross-sectional, online survey study with adult CSU patients and specialists managing CSU. Patients completed a survey comprising socio-demographics, Urticaria Control Test (UCT) and treatments received. Physicians' survey assessed treatment and disease management. Data by responder type were analyzed descriptively.ResultsOverall, 582 CSU patients (62% women; mean[SD] age, 42.2[11.9] years) and 862 physicians participated in the study. Of the patients currently on H1-antihistamines (79%; n=460), 84% were inadequately controlled (UCT<12). Since the initiation of their first prescribed treatment for CSU (mean[SD], 6.3[8.2] years), 80% of patients reported H1-antihistamine-switching and 62% reported up-dosing (average, 2.3 and 2.9 times, respectively). Up-dosing provided no/partial relief in 75% of patients, who also experienced drowsiness (46%) or additional side effects (11%). Physicians' second line of treatment comprised of quadrupling H1-antihistamine dose (32%), double-dosing (21%), switching to omalizumab (11%), and to another second-generation H1-antihistamine (10%). Similar patterns were reported across countries (Table). Physicians reported switching patients on average of 4 different second-generation antihistamines before prescribing biologics.ConclusionA high proportion of CSU patients remain inadequately controlled despite updosing/switching of antihistamines. Accordingly, updosing/switching of antihistamines may delay timely escalation to effective treatments in these patients. This study highlights the need for new treatment options that offer rapid and sustained relief for CSU patients.

Atopic dermatitis (AD) is a chronic, relapsing–remitting illness. In moderate-to-severe instances, recommendations urge patient-centered systemic therapy. Existing standards lack long-term treatment success requirements. A treat-to-target methodology was proposed for systemic therapy patients that requires global improvements to prompt decisions about treatment. We conducted an observational study between May 2021 and June 2022 in three Ecuadorian patients with severe AD who were treated with dupilumab to assess the clinical evolution and behavior of the subdomains evaluated by clinimetric tools. Patients A and C satisfied disease-domain response criteria to dupilumab at 12 and 24 weeks, but B did not complete the algorithm objectives. Nonetheless, patient A improved AD severity, itching, bleeding, desquamation, sleep, daily activities, mood, emotions, sexual troubles, clothing, and sports subdomains. Patient B experienced reduced symptomatology, AD aggravation, daily activities impact, and work/study impairment. Patient C improved from severe to mild desquamation, itching, exudate, lichenification, and rough/dry skin. Sleep, shame, and study subdomains improved the most. We provide a new operational construct for analyzing current patient-reported outcome measures (PROMs) and clinician-reported outcome measures (CROMs) based on subdomains to widen our understanding of the state of disease activity and make clinical decisions when the treat-to-target strategy is not attained.

Introduction We designed this study to gain a more holistic understanding of clinical and quality-of-life (QOL) impacts of subcutaneous C1INH (C1INH[SC]) used as long-term prophylaxis (LTP) in patients with hereditary angioedema (HAE), as well as on-demand medication use patterns. Methods A hybrid design combining semi-structured, qualitative interviews was used in parallel with a retrospective medical records review. Participants (n=16) were adults (≥18 years) with type I/II HAE using C1INH(SC) as LTP for ≥1 year. Interviews were thematically analyzed using qualitative methods to identify baseline symptoms, treatment impacts and changes. Medical records were reviewed for 12 months prior and after starting C1INH(SC) LTP for data relating to HAE attacks, attack treatment, and patient impact. Results Fifteen of 16 patients experienced a reduction in attack frequency from baseline (12 months on-demand only prior to C1-INH(SC) start) to post-treatment with C1-INH(SC) at 12 months. Two-thirds of patients who responded noted a reduction in attack severity (8/12). Of 12 patients who reported rescue medication use, 7 (58%) used it for every attack pre-C1INH(SC) and 6 (50%) for every attack while on C1INH(SC). One of 12 patients (8.3%) never used rescue medication while on C1INH(SC). Improvements in QOL included emotional/mental health (n=7), social life/relationships (n=5), and daily activities (n=5). Conclusions The preliminary results of this hybrid chart review/qualitative research study indicate that implementation of C1INH(SC) as LTP resulted in a decrease in HAE attacks and use of rescue medication, as well as enhanced patient confidence/QOL. Full results of this retrospective study will be presented at ACAAI 2022.

Introduction Hereditary angioedema (HAE) subtypes I/II are defined by abnormal plasma levels/activity of C1 esterase inhibitor (C1-INH). Diagnosis and management of the ultra-rare subtype with normal C1-INH (NC1-INH) is challenging without routine diagnostic assessments1 and phase 3 trial data. This study describes diagnostic pathways used in real-world lanadelumab-treated patients with NC1-INH-HAE. Methods Four expert HAE clinicians were interviewed about NC1-INH-HAE diagnosis in their clinical practice, 3 then completed a case report form using data from patient records. Patients eligible for retrospective chart review had physician-diagnosed NC1-IHN-HAE, initiated lanadelumab treatment (index date) with prior medical and treatment history available and ≥ 1 follow-up assessment. Results Physician-experts discussed 6 diagnostic criteria, 4 were endorsed by all (Table). Charts from 24 patients (3 US centers) were reviewed: mean (SD) age at index 44.0 (18.0) years, 92% female, median (range) 5.0 (0-40.3) years between symptom onset and NC1-INH-HAE diagnosis. Top 3 previous misdiagnoses: ‘other GI disorder' (71%), ‘irritable bowel syndrome' (67%), and ‘anaphylaxis' (54%). Of 4 criteria endorsed by all experts at interview, 3 were well-represented in patient charts (100-92%), except family history (25%). Expert endorsement was lower for criteria 3 (50%) and 6 (75%) found in 8% and 100% of patient charts, respectively. For patients on prophylaxis prior to index date, monthly attack rates were 5.60 at baseline (n=10) and 2.41 7-12 months after lanadelumab treatment (n=7). Conclusion Real-world NC1-INH-HAE diagnosis aligned with US guidelines on diagnostic criteria, except genetic testing and family history. Broader study of diagnostic guideline implementation in clinical practice is warranted.

Introduction In the HELP Open-Label Extension Study (OLE; NCT02741596), lanadelumab reduced attack rates by 87.4% versus baseline in patients ≥12 years old with hereditary angioedema type 1/2. Efficacy and safety of lanadelumab among patients <18 years old were analyzed. Methods HELP OLE enrolled "rollovers" (previously completed the HELP study [NCT02586805]) and "nonrollovers" (newly enrolled). Rollovers received a single dose of 300mg lanadelumab, followed by 300mg every 2 weeks (Q2W) for ≤33 months after their first attack. Nonrollovers received 300mg Q2W. Attack rates were summarized using descriptive statistics. Health-related quality of life (HRQoL) was assessed using validated instruments including the Angioedema Quality of Life Questionnaire (AE-QoL). Results 21 adolescent patients were enrolled (8 rollovers, 13 nonrollovers). 20(95.2%) completed ≥30 months' on-study. A prior history of laryngeal attacks was reported in 8(38.1%) patients. Overall, mean(SD) attack rates were reduced from 1.58(1.02) attacks/month at baseline to 0.11(0.20) during treatment (94.7% reduction). 8(38.1%) patients were attack-free during treatment. On average, 99.1% of days were attack-free (mean 27.7 days/month) during treatment. Patients reported an AE-QoL mean(SD) total score of 27.5(17.5) at baseline versus 7.5(13.2) at end-of-study, indicating achievement of clinically meaningful improvement. 12(57.1%) patients reported 251 related treatment-emergent adverse events (TEAEs); the majority pertained to the injection site, including 11(52.4%) patients who reported 227 events of injection site pain which were all mild or moderate in severity. There were no discontinuations due to TEAEs and no related serious AEs. Conclusion Lanadelumab demonstrated efficacy in preventing attacks in adolescent patients, and improved HRQoL. Most related TEAEs were injection site reactions.

L’angio-œdème héréditaire (AOH) est habituellement pris en charge avec des traitements prophylactiques injectables qui peuvent parfois être lourds pour les adolescents. Le bérotralstat est une option de traitement prophylactique administré par voie orale une fois par jour, qui permet de réduire significativement le taux des crises d’AOH par rapport au placebo. Nous présentons ici les résultats d’efficacité et de tolérance du bérotralstat chez les patients adolescents atteints d’AOH qui ont été recrutés dans l’étude APeX-S, toujours en cours (NCT03472040). Les patients ont reçu, en ouvert, soit une dose de bérotralstat de 150 mg, soit de 110 mg. La tolérance et l’efficacité à long terme ont été évaluées. La satisfaction des patients à l’égard du traitement a été évaluée à l’aide du Treatment Satisfaction Questionnaire for Medication (TSQM ; scores de 0 à 100) ; des scores plus élevés indiquent une plus grande satisfaction. Vingt-deux patients adolescents (âgés de 12 à 17 ans) atteints d’AOH ont été recrutés et 12 patients ont complété 6 mois de traitement par bérotralstat 150 mg. Le taux moyen des crises (± SD) au premier mois était de 0,5 (± 1,4) crises par mois et s’est maintenu à ce niveau au cours des 5 mois suivants (taux moyen des crises à 6 mois : 0,6 [± 1,16] crises par mois). Des résultats similaires ont été observés avec les taux médians des crises. Le taux médian était de 0 crise par mois au cours des 6 mois de traitement. L’utilisation moyenne de médicaments à la demande était de 0,2 (± 0,39) doses par mois au premier mois et s’est maintenu à ce niveau au cours des 6 premiers mois de traitement (au 6e mois : 0,3 [± 0,89] doses par mois) pour ces patients. Des améliorations ont été observées dans tous les domaines du TSQM. De l’inclusion jusqu’au 6e mois (M6), des améliorations ont été observées en matière de commodité (score total 82 à M6), d’efficacité (score total 87 à M6), de satisfaction globale (score total 86 à M6) et d’effets secondaires (score total 100 à M6). Les effets indésirables les plus courants étaient la diarrhée, les maux de tête, la grippe, la sinusite, l’inconfort abdominal, la rhinopharyngite, un malaise vagual, l’infection des voies urinaires et les vomissements. Les patients adolescents traités par bérotralstat oral 150 mg ont maintenu de faibles taux des crises dans l’étude APeX-S. En outre, les patients ont signalé une amélioration de la satisfaction, faisant du bérotralstat une option de traitement prophylactique précieuse et potentiellement moins contraignante pour les patients adolescents.

Anti-IgE therapy is recommended for patients with uncontrolled chronic spontaneous urticaria (CSU) despite treatment with H1-antihistamines. Here, we analyze the effect of ligelizumab, a next-generation anti-IgE antibody, in CSU patients who were treated with locally approved or escalated doses of H1-antihistamines.

Assessing the holistic effect of a treatment in patients with chronic spontaneous urticaria (CSU) requires evaluating different patient reported outcomes (PROs). In this post-hoc analysis, we evaluated complete response in patients with CSU using a composite score of various PROs.

Chronic cough (CC) is not well-understood outside of cough clinics. This analysis aimed to describe variations in patient reported triggers of CC.