Laboratory Approaches for Assessing Contact System Activation

Christiansen, Sandra C.; Zuraw, Bruce L.

doi:10.1016/j.iac.2017.04.008

Cited by 9 publications

(5 citation statements)

References 70 publications

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“…Recently, plasma enzymatic cascade systems, endothelium-derived factors, and inflammatory mediators have been extensively studied with regards to the mechanistic contributions to the pathology of HAE. Some have important implications for the discovery of biomarkers that could be used in the diagnosis and monitoring [13][14][15][16][17]. However, only a few laboratory tests (antigenic and functional C1-INH, complement C4) with established threshold values are currently used in clinical practice for diagnosis and decision-making [14] ( Table 1).…”

Section: Biochemical Biomarkersmentioning

confidence: 99%

Biomarkers in Hereditary Angioedema

Porębski

Kwitniewski

Reshef

2021

Clinic Rev Allerg Immunol

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A biomarker is a defined characteristic measured as an indicator of normal, biologic, pathogenic processes, or biological responses to an exposure or intervention. Diagnostic biomarkers are used to detect a disease or a subtype of a disease; monitoring biomarkers are measured serially to assess a medical condition; response biomarkers are used to check biologic response following a medical intervention; predictive biomarkers are used to identify patients who are more likely to respond to a medical intervention; and prognostic biomarkers are used to assess the future likelihood of a clinical event. Although biomarkers have been extensively investigated and validated in many diseases and pathologies, very few are currently useful for the diagnosis, evaluation of disease activity, and treatment of hereditary angioedema (HAE). Pathophysiologic pathways involved in HAE reveal a plethora of molecules from the complement, coagulation, and fibrinolysis systems or from the vascular endothelium, which may serve as biomarkers. The most promising candidates, together with their laboratory readout systems, should be evaluated with regard to their analytical and clinical validity and utility. To be highly specific, such biomarkers should be linked to the pathomechanisms of HAE, particularly the bradykinin-generating cascade. Additionally, major advances in high-throughput omics-based technologies may facilitate the discovery of new candidate biomarkers in the future. This review will cover the existing as well as future potential biomarkers that will support the diagnosis, monitor disease activity, and can be used to assess the efficacy of new avenues of therapy of HAE and other forms of angioedema.

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Section: Biochemical Biomarkersmentioning

confidence: 99%

Biomarkers in Hereditary Angioedema

Porębski

Kwitniewski

Reshef

2021

Clinic Rev Allerg Immunol

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“…Hereditary angioedema (HAE) due to C1INH deficiency (HAE‐C1INH) and acquired C1INH deficiency are the best characterized forms of bradykinin‐mediated angioedema . A novel form of HAE with normal C1INH (HAE‐nl‐C1INH) was initially described in 2000 .…”

Section: Introductionmentioning

confidence: 99%

“…Hereditary angioedema (HAE) due to C1INH deficiency (HAE-C1INH) and acquired C1INH deficiency are the best characterized forms of bradykinin-mediated angioedema. [3][4][5][6] A novel form of HAE with normal C1INH (HAE-nl-C1INH) was initially described in 2000. 7,8 Subsequently, a minority of HAE-nl-C1INH patients were found to have mutations in F12 (the gene encoding FXII; HAE-FXII) that segregated with disease activity.…”

mentioning

confidence: 99%

Threshold‐stimulated kallikrein activity distinguishes bradykinin‐ from histamine‐mediated angioedema

Lara-Marquez

Christiansen

Riedl

et al. 2018

Clin Experimental Allergy

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“…functional levels of C1-INH, the primary inhibitor of the contact system proteases plasma kallikrein and activated coagulation factor XII, result in dysregulation of the contact system with excess generation of bradykinin, the primary mediator of swelling in HAE-C1-INH. 3,4 HAE-C1-INH is a rare disorder characterized by recurrent episodes of subcutaneous or mucosal angioedema. 1 HAE attacks typically first occur during childhood and recur with variable severity and frequency throughout life.…”

mentioning

confidence: 99%

Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial

Zuraw

Lumry

Johnston

et al. 2021

Journal of Allergy and Clinical Immunology

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Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. Objective: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial). Methods: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. Results: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n 5 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P 5 .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred. Conclusion: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day. (J Allergy Clin Immunol 2020;nnn:nnn-nnn.)

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Laboratory Approaches for Assessing Contact System Activation

Cited by 9 publications

References 70 publications

Biomarkers in Hereditary Angioedema

Biomarkers in Hereditary Angioedema

Threshold‐stimulated kallikrein activity distinguishes bradykinin‐ from histamine‐mediated angioedema

Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial

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