This update to the 2019 Canadian Hereditary Angioedema (HAE) Guideline broadens its focus to include the management of patients with HAE worldwide, building on its established international framework. It has been developed through a collaboration of Canadian and international HAE experts and patient groups, coordinated by the Canadian Hereditary Angioedema Network. The objective is to provide evidence-based recommendations, using the Grading of Recommendations Assessment, Development and Evaluation system, for the management of patients with HAE. These include recommendations for the treatment of attacks, short-term prophylaxis, and long-term prophylaxis, as well as recommendations for self-administration, individualized therapy, health-related quality of life, and comprehensive care. New to the 2024 edition are specific recommendations for the treatment of angioedema attacks in individuals with HAE who are breastfeeding/lactating, as well as a dedicated section on shared decision-making. HAE results in spontaneous and often unpredictable attacks of painful swelling, typically affecting the extremities, bowel mucosa, genitals, face, and upper airway. These attacks are associated with significant functional impairment, reduced health-related quality of life, and in the case of laryngeal attacks, a high risk of mortality. Managing HAE is complex, and patient care in Canada, similar to many other countries, remains inconsistent and suboptimal. Care delivery lags behind nations that have implemented more structured management models for HAE, and offer broader access to a wider range of approved therapies. This guideline is intended to be used to optimize HAE management, highlight the importance of individualized care, and provide guidance to healthcare providers, policymakers, patients, and advocates. Primary target users include healthcare providers who are managing patients with HAE, as well as emergency and intensive care physicians, primary care physicians, gastroenterologists, dentists, otolaryngologists, pediatricians, hematologists, dermatologists, and gynecologists who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.

Background:Limited data are available on the clinical profile and disease burden of hereditary angioedema (HAE) in Canadians.Objective:This study aimed to assess HAE disease characteristics and the burden of disease in Canadians with HAE types I, II, and normal levels of C1 inhibitor (nC1-INH).Materials and Methods:A 46-item patient survey evaluating clinical characteristics and burden of disease was developed and disseminated by the HAE patient organization Angio-oédeme héréditaire du Québec in Quebec, Canada, from May 2019 to February 2020. The survey received Research Review Board ethics approval.Results:In the 35 respondents, HAE type I was the most common (46%), followed by nC1-INH (43%). Female participants were significantly younger at first symptom presentation than males (p=0.04). Prior to diagnosis, 69% of participants underwent unnecessary treatments and procedures, with a 10-year delay between first symptoms and diagnosis. Before starting the current treatment, 42% of participants experienced weekly HAE attacks. Most participants identified experiencing attacks in the abdomen (89%), followed by the larynx (66%), feet (66%), hands (63%), and face (63%). Most attacks were severe or moderate, yet almost half of patients waited >1 hr before getting medical attention at their last emergency department (ED) visit. HAE was associated with decreased health-related quality of life, leading to significant functional impairment in personal and professional life. As compared to HAE type I/II, patients with HAE nC1-INH were treated more often with tranexamic acid for long-term prophylaxis, and their condition was less controlled, resulting in more attacks and ED visits.Conclusion:HAE manifests in this patient population as frequent moderate-to-severe attacks and a high disease burden; the HAE subtype may differentially affect care requirements. There is an urgent need for increased awareness and education on HAE among treating physicians.

Niniejsza aktualizacja i rewizja międzynarodowych wytycznych dotyczących pokrzywki została opracowana zgodnie z metodami zalecanymi przez Cochrane i grupę roboczą Grading of Recommendations Assessment, Development and Evaluation (GRADE). Jest to wspólna inicjatywa Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), Global Allergy and Asthma European Network (GA2LEN) i jej Urticaria and Angioedema Centers of Reference and Excellence (UCAREs i ACAREs), European Dermatology Forum (EDF; EuroGuiDerm) oraz Asia Pacific Association of Allergy, Asthma and Clinical Immunology z udziałem 64 delegatów z 50 towarzystw krajowych i międzynarodowych z 31 krajów. Konferencja uzgodnieniowa odbyła się 3 grudnia 2020 r. Niniejsze wytyczne zostały uznane i zaakceptowane przez European Union of Medical Specialist s (UEMS). Pokrzywka jest częstą chorobą, w której pośredniczą komórki tuczne, objawiającą się bąblami, obrzękiem naczynioruchowym lub obydwoma tymi objawami. Częstość występowania ostrej pokrzywki w ciągu życia wynosi około 20%. Przewlekła pokrzywka spontaniczna lub indukowalna powoduje niesprawność, pogarsza jakość życia oraz wpływa na aktywność w pracy i w szkole. Ta zaktualizowana wersja międzynarodowych wytycznych dotyczących pokrzywki obejmuje definicję i klasyfikację pokrzywki oraz przedstawia opracowane przez ekspertów i oparte na dowodach metody diagnostyki i leczenia w przypadku różnych podtypów pokrzywki.

BACKGROUND:CRUSE® is an app that allows patients with chronic spontaneous urticaria (CSU) to monitor their daily disease activity through the use of visual analogue scales (VASs). We aimed to determine the concurrent validity, reliability, responsiveness and minimal important difference (MID) of CRUSE® VASs. METHODS:We evaluated the properties of three daily VASs: VAS for how much patients were affected by their CSU ('VAS urticaria'), VAS for the impact of urticaria on work/school productivity ('VAS productivity') and the VAS of EQ-5D. Concurrent validity was assessed by measuring the association between each VAS and the Urticaria Activity Score (UAS). Intra-rater reliability was determined based on the data of users providing multiple daily questionnaires within the same day. Test-retest reliability and responsiveness (ability to change), respectively, were tested in clinically stable and clinically unstable users. MIDs were determined using distribution-based methods. RESULTS:We included 5938 patients (67,380 days). Concurrent validity was high, with VAS urticaria being more strongly associated with the UAS score than the remaining VASs. Intra-rater reliability was also high, with intraclass correlation coefficients (ICC) being above 0.950 for all VASs. Moderate-high test-retest reliability and responsiveness were observed, with reliability ICC being highest for VAS EQ-5D and responsiveness being highest for VAS urticaria. The MID for VAS urticaria was 17 (out of 100) units, compared to 15 units for VAS productivity and 11 units for VAS EQ-5D. CONCLUSION:Daily VASs for CSU available in the CRUSE® app display high concurrent validity and intra-rater reliability and moderate-high test-retest reliability and responsiveness.

BackgroundHereditary angioedema (HAE) is a rare autosomal dominant disease; the most well understood forms concern the haplodeficiency of C1 esterase inhibitor (C1INH) and a gain of function mutation of factor XII (FXII). The acute forms of these conditions are mediated by an excessive bradykinin (BK) formation by plasma kallikrein.MethodsA validated LC-MS/MS platform of picomolar sensitivity developed for the analysis of eleven bradykinin-related peptides was applied to the plasma of HAE-C1INH and HAE-FXII sampled during remission.ResultsIn HAE-C1INH plasma, the concentrations of the relatively stable BK1−5 fragment (mean ± S.E.M.: 12.0 ± 4.2 pmol/L), of BK2−9 (0.7 ± 0.2 pmol/L) and of the sums of BK and its tested fragments (18.0 ± 6.4 pmol/L) are significantly greater than those recorded in the plasma of healthy volunteers (1.9 ± 0.6, 0.03 ± 0.03 and 4.3 ± 0.8 pmol/L, respectively), consistent with the previous evidence of permanent plasma kallikrein activity in this disease. Kinin levels in the plasma of HAE-FXII patients did not differ from controls, suggesting that triggering factors for contact system activation are not active during remission.ConclusionBK1−5, BK2−9 and the sum of BK and its fragments determined by the sensitive LC-MS/MS technique are proposed as potential biomarkers of HAE-C1INH in remission while this was not applicable to HAE-FXII patients.

Background Acute airway angioedema commonly occurs through two distinct mechanisms: histamine- and bradykinin-dependent. Although they respond to distinct treatments, these two potentially life-threatening states present similarly. Poor recognition of the bradykinin-dependent pathway leads to treatment errors in the emergency department (ED), despite the availability of multiple pharmacologic options for hereditary angioedema (HAE) and other forms of bradykinin-induced angioedema. Here, we consider the pathophysiology and clinical features of bradykinin-induced angioedema, and we present a systematic literature review exploring the effectiveness of the available therapies for managing such cases. Methods PubMed searches using ‘emergency’, ‘bradykinin’ and various therapeutic product names identified studies reporting the efficacy of treatments for bradykinin-induced angioedema in the ED setting. In all, 22 studies met prespecified criteria and are analysed here. Findings Whereas histamine-induced angioedema has a faster onset and often presents with urticaria, bradykinin-induced angioedema is slower in onset, with greater incidence of abdominal symptoms. Acute airway angioedema in the ED should initially be treated with anaphylactic protocols, focusing on airway management and treatment with epinephrine, antihistamine and systemic steroids. Bradykinin-induced angioedema should be considered if this standard treatment is not effective, despite proper dosing and regard of beta-adrenergic blockade. Therapeutics currently approved for HAE appear as promising options for this and other forms of bradykinin-induced angioedema encountered in the ED. Conclusion Diagnostic algorithms of bradykinin-induced angioedema should be followed in the ED, with early use of approved therapies to improve patient outcomes.

This update and revision of the international guideline for urticaria was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA²LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), the European Dermatology Forum (EDF; EuroGuiDerm), and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology with the participation of 64 delegates of 50 national and international societies and from 31 countries. The consensus conference was held on 3 December 2020. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease that presents with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous or inducible urticaria is disabling, impairs quality of life, and affects performance at work and school. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

We report here the results of a phase 3 study to assess the efficacy, safety, and tolerability of GC5107, a new 10% liquid intravenous immunoglobulin (IVIG) in preventing serious bacterial infections in patients with primary immunodeficiency (ClinicalTrials.gov: NCT02783482). Over a 12-month study period, 49 patients aged 3 to 70 years with a confirmed diagnosis of primary immunodeficiency received GC5107 at doses ranging from 319 to 881 mg/kg body weight every 21 or 28 days, according to their previous IVIG maintenance therapy. A total of 667 infusions of GC5107 were administered comprising a total of 45.86 patient-years of treatment. A single acute serious bacterial infection occurred during the study, resulting in an incidence of 0.02 events per patient-year (upper 99% one-sided confidence interval limit: 0.21), meeting the prespecified primary efficacy endpoint. The mean incidence of infections other than acute serious bacterial infections was 2.9 infections per patient-year. Efficacy was also demonstrated by the low mean annualized rate of hospitalizations due to infection (0.1 day) and the mean annualized duration of hospitalizations (0.1 day). The mean rate of intravenous and oral antibiotic use was 0.1 day and 13.2 days, respectively. There was a mean of 7.1 days of missed work, school, or daycare days. The proportion of infusions with temporally associated adverse events (TAAEs) occurring during or within 72 hours after GC5107 infusion was 0.24 (upper 95% one-sided confidence interval limit: 0.31), meeting the pre-specified primary safety endpoint. Overall, 149 of 667 infusions (22%) were associated with TAAEs. The most common TAAE was headache, reported by 49% of patients. More than 98% (731/743) of all adverse events that occurred throughout the 12-month study period were mild or moderate. More than 98% of infusions were completed without discontinuation, interruption or rate reduction. There were no treatment-emergent serious adverse events related to GC5107 or study discontinuations due to an adverse event. Overall, pharmacokinetic parameters for GC5107 were within the range of those reported in studies of other marketed IVIG products. Results of the present study demonstrate that GC5107 is an effective, safe and well-tolerated treatment for patients with primary immunodeficiency.

Bradykinin (BK)-mediated angioedema (AE) states are rare acquired or hereditary conditions involving localized edema of the subcutaneous and submucosal tissues. Citrated plasma from healthy volunteers or patients with hereditary angioedema (HAE) with normal level of C1-inhibitor (C1-INH) was used to investigate pathways of BK formation and breakdown relevant to AE physiopathology. The half-life of BK (100 nM) added to normal plasma was 34 s, a value that was increased ~12-fold when the angiotensin converting enzyme (ACE) inhibitor enalaprilat (130 nM) was added (enzyme immunoassay measurements). The BK half-life was similarly increased ~5-fold following 2 daily oral doses of enalapril maleate in healthy volunteers, finding of possible relevance for the most common form of drug-associated AE. We also addressed the kinetics of immunoreactive BK (iBK) formation and decline, spontaneous or under three standardized stimuli: tissue kallikrein (KLK-1), the particulate material Kontact-APTT™ and tissue plasminogen activator (tPA). Relative to controls, iBK production was rapid (10-20 min) and very intense in response to tPA in plasma of female heterozygotes for variants in gene F12 coding for factor XII (FXII) (p.Thr328Lys, 9 patients; p.Thr328Arg, one). An increased response to Kontact-APTT™ and an early tPA-induced cleavage of anomalous FXII (immunoblots) were also observed. Biotechnological inhibitors showed that the early response to tPA was dependent on plasmin, FXIIa and plasma kallikrein. Results from post-menopausal and pre-menopausal women with HAE-FXII were indistinguishable. The iBK production profiles in seven patients with the plasminogen p.Lys330Glu variant (HAE-PLG) did not significantly differ from those of controls, except for an unexpected, rapid and lanadelumab-resistant potentiation of KLK-1 effect. This enzyme did not cleave plasminogen or factor XII, suggesting a possible idiosyncratic interaction of the plasminogen pathogenic variant with KLK-1 activity. KLK-1 abounds in salivary glands and human saliva, hypothetically correlating with the clinical presentation of HAE-PLG that includes the swelling of the tongue, lips and contiguous throat tissues. Samples from HAE patients with normal C1-INH levels and F12 gene did not produce excessive iBK in response to stimuli. The ex vivo approach provides physiopathological insight into AE states and supports the heterogeneous physiopathology of HAE with normal C1-INH.

Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical application of a BK receptor ligand, the B2 receptor antagonist icatibant, is the treatment of the rare hereditary angioedema (HAE) caused by the deficiency of C1-esterase inhibitor (C1-INH). Less common forms of HAE (genetic variants of factor XII, plasminogen, kininogen) are presumably mediated by increased BK formation. Acquired forms of BK-mediated angioedema, such as that associated with angiotensin-I converting enzyme (ACE) inhibition, are also known. Antibody-based analytical techniques are briefly reviewed, and support that kinins are extremely short-lived, prominently cleared by ACE. Despite evidence of continuous activation of the kallikrein–kinin system in HAE, patients are not symptomatic most of the time and their blood or plasma obtained during remission does not generate excessive immunoreactive BK (iBK), suggesting effective homeostatic mechanisms. HAE-C1-INH and HAE-FXII plasmas are both hyperresponsive to fibrinolysis activation. On another hand, we suggested a role for the alternate tissue kallikrein–kinin system in patients with a plasminogen mutation. The role of the BK B1 receptor is still uncertain in angioedema states. iBK profiles under in vitro stimulation provide fresh insight into the physiopathology of angioedema.

BACKGROUND: Omalizumab shows greater clinical benefit with 300 mg dose than with the 150 mg dose. OBJECTIVE: To determine outcomes postwithdrawal, relapse, and re-treatment in omalizumab responders, and from stepping up to 300 mg after insufficient symptom control with 150 mg. METHODS: This was a prospective, randomized (3:4), open-label, noncomparator study (clinicaltrials.gov: NCT02161562). A total of 314 adult patients with chronic spontaneous urticaria and symptomatic on H-1-antihistamines were enrolled between August 1, 2014, and November 6, 2015. Patients received 150 mg/300 mg omalizumab, every 4 weeks for 24 weeks. Omalizumab 150 mg dose could be stepped up to 300 mg between week 8 and week 24, if the 7-day sum of the daily Urticaria Activity Score (UAS7) was more than 6. If patients relapsed after treatment withdrawal at week 24, they could be re-treated with the same dose on which omalizumab was started. Patients on 300 mg could extend treatment by 12 weeks if they did not achieve symptom control on 300 mg in the initial dosing phase. The primary end point was the proportion of well-controlled patients who relapsed postwithdrawal, and achieved symptom control at the end of re-treatment. Symptom control was assessed using UAS7 (UAS7 <= 6 = well controlled). RESULTS: Overall, 115 of 314 patients had adequate symptom control at week 24 (end of the initial dosing period) and 56 were re-treated after relapse postwithdrawal; 87.8% (95% CI, 78.6%-96.9%) regained symptomatic control (UAS7 <= 6). Most (141 of 178) patients initially treated with 150 mg required step-up to 300 mg, which resulted in a 9.5-point (95% CI, 7.6-11.3) improvement in UAS7 over the mean change observed initially on 150 mg. CONCLUSIONS: Step-up to 300 mg helps a greater proportion of patients achieve symptom control, and re-treatment with omalizumab is as effective as initial therapy. (C) 2020 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Zuberbier T, Aberer W, Asero R, et al. Wytyczne EAACI/GA2LEN/EDF/WAO dotyczące definicji, klasyfikacji, diagnostyki i leczenia pokrzywki. Alergologia Polska - Polish Journal of Allergology. 2020;7(1):1-28. doi:10.5114/pja.2020.93827. APA Zuberbier, T., Aberer, W., Asero, R., Latiff, A. H., Baker, D., & Ballmer-Weber, B. et al. (2020). Wytyczne EAACI/GA2LEN/EDF/WAO dotyczące definicji, klasyfikacji, diagnostyki i leczenia pokrzywki. Alergologia Polska - Polish Journal of Allergology, 7(1), 1-28. https://doi.org/10.5114/pja.2020.93827 Chicago Zuberbier, T., W. Aberer, R. Asero, A. H Latiff, D. Baker, B. Ballmer-Weber, and J. A Bernstein et al. 2020. "Wytyczne EAACI/GA2LEN/EDF/WAO dotyczące definicji, klasyfikacji, diagnostyki i leczenia pokrzywki". Alergologia Polska - Polish Journal of Allergology 7 (1): 1-28. doi:10.5114/pja.2020.93827. Harvard Zuberbier, T., Aberer, W., Asero, R., Latiff, A., Baker, D., Ballmer-Weber, B., Bernstein, J., Bindslev-Jensen, C., Brzoza, Z., Bedrikow, R., Canonica, G., Church, M., Craig, T., Danilycheva, I., Dressler, C., Ensina, L., Giménez-Arnau, A., Godse, K., Gonçalo, M., Grattan, C., Hebert, J., Hide, M., Kaplan, A., Kapp, A., Katelaris, C., Kocatürk, E., Kulthanan, K., Larenas-Linnemann, D., Leslie, T., Magerl, M., Mathelier-Fusade, P., Meshkova, R., Metz, M., Nast, A., Nettis, E., Oude-Elberink, H., Rosumeck, S., Saini, S., Sánchez-Borges, M., Schmid-Grendelmeier, P., Staubach, P., Sussman, G., Toubi, E., Vena, G., Vestergaard, C., Wedi, B., Werner, R., Zhao, Z., and Maurer, M. (2020). Wytyczne EAACI/GA2LEN/EDF/WAO dotyczące definicji, klasyfikacji, diagnostyki i leczenia pokrzywki. Alergologia Polska - Polish Journal of Allergology, 7(1), pp.1-28. https://doi.org/10.5114/pja.2020.93827 MLA Zuberbier, T. et al. "Wytyczne EAACI/GA2LEN/EDF/WAO dotyczące definicji, klasyfikacji, diagnostyki i leczenia pokrzywki." Alergologia Polska - Polish Journal of Allergology, vol. 7, no. 1, 2020, pp. 1-28. doi:10.5114/pja.2020.93827. Vancouver Zuberbier T, Aberer W, Asero R, Latiff A, Baker D, Ballmer-Weber B et al. Wytyczne EAACI/GA2LEN/EDF/WAO dotyczące definicji, klasyfikacji, diagnostyki i leczenia pokrzywki. Alergologia Polska - Polish Journal of Allergology. 2020;7(1):1-28. doi:10.5114/pja.2020.93827.

Introduction: Allergic conditions frequently require treatment with antihistamines. First-generation antihistamines can potentially interfere with restful sleep, cause “morning after” effects, impair learning and memory, and reduce work efficiency. Second-generation antihistamines, such as bilastine, have been demonstrated to decrease allergy symptoms effectively without causing night-time sleep disturbances and related adverse events. Method: A real-world case project was developed to help optimize patient care by recognizing the role bilastine can play for allergic conditions where antihistamine treatment is needed. The presented real-world patient cases conducted by the panel members are supported with evidence from the literature, where available. Any discussion concerning off-label use should be considered an expert opinion only. Results: The real-world cases presented here used bilastine in conditions such as perennial and seasonal allergic rhinitis, chronic urticaria, as well as urticarial vasculitis and pruritus associated with inflammatory skin conditions. The treated patients were between 9 and 76-years old providing information on a full spectrum of patients that require treatment with antihistamines. Conclusions: The presented real-world cases using the second-generation antihistamine, bilastine, demonstrated favorable outcomes for the treated patients. While effectively relieving symptoms, the antihistamine was reported to be safe and well-tolerated. J Drugs Dermatol. 2020;19(2)145-154. doi:10.36849/JDD.2020.4835

Hereditary angioedema (HAE) results from a deficiency of C1 esterase inhibitor, allowing for excessive conversion of prekallikrein (PK) into plasma kallikrein. Lanadelumab specifically inhibits plasma kallikrein, and prevented HAE attacks in the HELP Study (NCT02586805). Plasma kallikrein contributes to the aPTT coagulation test; therefore, a prolonged aPTT is an expected effect of lanadelumab. No effect on prothrombin time (PT) is expected. We evaluated the effects of lanadelumab on coagulation parameters in HAE patients. Patients ≥12 years old with type I/II HAE and ≥1 attack during a 4-week run-in received subcutaneous lanadelumab 150mg q4wks, 300mg q4wks, 300mg q2wks, or placebo over 26 weeks. Coagulation testing was performed at screening and throughout the study using standard laboratory tests. Lanadelumab reduced plasma kallikrein activity (indicated by cleaved high molecular weight kininogen; cHK) by mean±SD 31.9%±37.6–48.2%±19.3 from baseline to Day 182. At baseline, mean±SD (range) aPTT was 28.21±3.013s (22.2-34.1), 28.46±4.066s (19.6-37.2), and 28.61±5.465s (20.0-42.3) in the lanadelumab 150mgq4wks, 300mgq4wks, 300mgq2wks groups vs 28.38±3.835s (24.3-40.5) for placebo. At Day 182, mean±SD (range) aPTT was 30.60±3.013s (25.5-35.3), 34.06±4.979s (27.0-46.8), and 35.26±4.764s (26.9±44.3) with increasing lanadelumab doses vs 27.15±2.857s (21.4-33.9) with placebo. These data show the prolongation in aPTT assay with lanadelumab as expected. PT was not altered. These data indicate that lanadelumab prolonged aPTT in treated groups, but not outside the normal range and with no association with abnormal bleeding events. Based on these data, lanadelumab inhibition of plasma kallikrein activity is sufficient for effective HAE prophylaxis without alteration of hemostasis or thrombosis in vivo.

We recently investigated the pathways of immunoreactive bradykinin (iBK) formation in fresh blood of normal volunteers and of patients with hereditary angioedema due to C1-esterase inhibitor deficiency (HAE-1/-2). Herein, we adapted the techniques to small volumes (200 μl) of previously frozen citrated plasma and further analyzed the mechanisms of iBK formation with additional biotechnological inhibitors. Measurable iBK formation was observed under stimulation with tissue kallikrein (KLK-1, 10 nM), the particulate material Kontact-APTT (concentration reduced to 2% v/v) or recombinant tissue plasminogen activator (tPA, 169 nM), with little background in unstimulated plasma incubated for up to 2 h. Plasma samples from HAE-1/-2 patients responded earlier to tPA than those from controls, as previously reported with whole blood. Lanadelumab inhibited iBK formation induced by Kontact-APTT and tPA. A highly specific plasmin inhibitor, DX-1000, abolished tPA-induced iBK formation in plasma but had no effect against Kontact-APTT, confirming the role of fibrinolysis in tPA-induced kinin formation. The anti-lanadelumab neutralizing antibody M293-D02 reversed the inhibitory effects of lanadelumab. Frozen plasma is a suitable material for measuring iBK formation kinetics, with possible applications such as investigating the effect of rare disease states on the kallikrein–kinin system and monitoring the effect of HAE prophylactic treatments.

BACKGROUND:For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). OBJECTIVE:To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). METHODS:Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). RESULTS:A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. CONCLUSIONS:In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms.

Importance:There are currently no approved treatments for peanut allergy. Objective:To assess the efficacy and adverse events of epicutaneous immunotherapy with a peanut patch among peanut-allergic children. Design, Setting, and Participants:Phase 3, randomized, double-blind, placebo-controlled trial conducted at 31 sites in 5 countries between January 8, 2016, and August 18, 2017. Participants included peanut-allergic children (aged 4-11 years [n = 356] without a history of a severe anaphylactic reaction) developing objective symptoms during a double-blind, placebo-controlled food challenge at an eliciting dose of 300 mg or less of peanut protein. Interventions:Daily treatment with peanut patch containing either 250 μg of peanut protein (n = 238) or placebo (n = 118) for 12 months. Main Outcomes and Measures:The primary outcome was the percentage difference in responders between the peanut patch and placebo patch based on eliciting dose (highest dose at which objective signs/symptoms of an immediate hypersensitivity reaction developed) determined by food challenges at baseline and month 12. Participants with baseline eliciting dose of 10 mg or less were responders if the posttreatment eliciting dose was 300 mg or more; participants with baseline eliciting dose greater than 10 to 300 mg were responders if the posttreatment eliciting dose was 1000 mg or more. A threshold of 15% or more on the lower bound of a 95% CI around responder rate difference was prespecified to determine a positive trial result. Adverse event evaluation included collection of treatment-emergent adverse events (TEAEs). Results:Among 356 participants randomized (median age, 7 years; 61.2% male), 89.9% completed the trial; the mean treatment adherence was 98.5%. The responder rate was 35.3% with peanut-patch treatment vs 13.6% with placebo (difference, 21.7% [95% CI, 12.4%-29.8%; P < .001]). The prespecified lower bound of the CI threshold was not met. TEAEs, primarily patch application site reactions, occurred in 95.4% and 89% of active and placebo groups, respectively. The all-causes rate of discontinuation was 10.5% in the peanut-patch group vs 9.3% in the placebo group. Conclusions and Relevance:Among peanut-allergic children aged 4 to 11 years, the percentage difference in responders at 12 months with the 250-μg peanut-patch therapy vs placebo was 21.7% and was statistically significant, but did not meet the prespecified lower bound of the confidence interval criterion for a positive trial result. The clinical relevance of not meeting this lower bound of the confidence interval with respect to the treatment of peanut-allergic children with epicutaneous immunotherapy remains to be determined. Trial Registration:ClinicalTrials.gov Identifier: NCT02636699.