Successful use of lanadelumab in a patient with hereditary angioedema with normal C1 inhibitor and negative genetic testing

We report an approximately 80% reduction in angioedema attacks with lanadelumab, a mAb targeting plasma kallikrein, case of hereditary normal C1 inhibitor levels. This finding supports central pathophysiologic role for kallikrein levels and the need prospective studies lanadelumab use this condition. Hereditary (HAE) is rare genetic condition characterized by recurrent cutaneous submucosal swelling affecting oropharynx, face, extremities, genitals, abdomen.1Busse P.J. Christiansen S.C. angioedema.N Engl J Med. 2020; 382: 1136-1148Crossref PubMed Scopus (155) Google Scholar Most cases HAE are due to monoallelic mutations SERPING1 that result (HAE-C1-INH) deficiency. In HAE-C1-INH deficiency, deficiency causes excessive activation contact pathway, leading increased generation bradykinin, bradykinin 2 receptor, subsequent fluid extravasation.1Busse Patients frequent symptoms have conventionally been treated plasma-derived long-term prophylaxis. 2018, fully humanized IgG1κ (the activated form prekallikrein), was also approved prophylaxis deficiency.2Maurer M. Magerl Betschel S. Aberer W. Ansotegui I.J. Aygoren-Pursun E. et al.The international WAO/EAACI guideline management angioedema-the 2021 revision update.Allergy. 2022; 77: 1961-1990Crossref (54) Some patients function (HAE-nC1). The pathophysiology HAE-nC1 poorly understood, but aberrant pathway implicated.3Magerl Germenis A.E. Maas C. Maurer inhibitor: update on evaluation treatment.Immunol Allergy Clin North Am. 2017; 37: 571-584Abstract Full Text PDF (35) Mutations genes cause phenotype (eg, factor XII,4Bork K. Wulff Meinke P. Wagner N. Hardt J. Witzke G. A novel mutation coagulation 12 gene subjects C1-inhibitor.Clin Immunol. 2011; 141: 31-35Crossref (106) plasminogen,5Bork Steinmuller-Magin L. Braenne I. Staubach-Renz al.Hereditary plasminogen gene.Allergy. 2018; 73: 442-450Crossref (187) angiopoietin-16Baffert F. Le T. Thurston McDonald D.M. Angiopoietin-1 decreases leakage reducing number size endothelial gaps venules.Am Physiol Heart Circ Physiol. 2006; 290: H107-H118Crossref (124) Scholar) recently reported. These findings greatly enhanced our understanding facilitated sequencing diagnosis some patients. However, many remain without diagnosis, disease mechanisms these unclear. 62-year-old female her tongue, larynx, abdomen since she adolescent. Her episodes develop over several hours resolve 3 days. She has no history urticaria, therapies histaminergic process, including high-dose antihistamines (40 mg cetirizine per day weeks) oral glucocorticosteroids (60 orally administered prednisone daily 24 weeks), not effective. Omalizumab never trialed patient. medical notable Behçet diagnosed when 47 years old presented posterior uveitis ulcers genital mucosa. colchicine hydroxychloroquine. serum C4 concentration were multiple occasions, during episodes. Gene FXII, PLG, ANGPT1, did identify any pathogenic variants; results HS3ST6, KNG1, MYOF, each which described only 1 proband HAE-nC1,2 available. patient daughters, whom complement study respond weeks or dose 40 weeks. daughter thus based expert consensus criteria.7Zuraw B.L. Bork Binkley K.E. Banerji A. Castaldo function: panel.Allergy Asthma Proc. 2012; 33: S145-S156Crossref (146) For highly symptomatic, week. used icatibant, 30 subcutaneously, acute treatment most episodes, led noticeable symptom relief minutes prevented emergency department care, still had frequency unpredictability continued significantly impair quality life caused reduce occupational social activities. offered intravenous prophylaxis, able obtain access own because vision impairment from at time. began taking 300 subcutaneously every weeks, attempt burden. months, average attack reduced month, became sufficiently mild require icatibant cases. continues take ongoing benefit, last visit control test score 14 (of possible 16 points, scores >10 indicating well-controlled disease).8Weller Donoso Staubach Martinez-Saguer al.Validation Angioedema Control Test (AECT)-a patient-reported outcome instrument assessing control.J Immunol Pract. 8 (e4): 2050-2057Abstract (31) Here, we high burden who responded antikallikrein biologic severity. There randomized controlled trials HAE-nC1; hence, there condition.3Magerl Typically, similarly those reports observational studies; believe it reasonable trial symptomatic HAE-nC1. Jones al reported 10 lanadelumab.9Jones D.H. Bansal Bernstein J.A. Fatteh Harper Hsu F.I. al.Clinical profile outcomes esterase inhibitor.World Organ 15100621Abstract (3) Of patients, stopped therapy account lack efficacy, 7 frequency, required weekly dosing criteria detailed, whether genotyped unclear.9Jones Future evaluating efficacy needed. successful suggests plays least subset HAE-nC1, likely genetically physiologically heterogenous further investigation search additional monogenic phenotype. do may conversely involve pathway. other targeted therapeutics therefore help subgroups alternate should be investigated.