C1 esterase inhibitor (C1-INH) response as a supportive diagnostic criterion for patients with suspected hereditary angioedema with normal C1-INH.

Support for preparation of the manuscript was provided by Pharming Healthcare, Inc (Warren, NJ). Other than the authors, no other sponsor representatives actively contributed to the study design, content, or had a role in the decision to submit, but may have reviewed the manuscript for medical accuracy.

AMS contributed to the conception and design of the study and developed the initial manuscript draft. AMS, HJK, JR, YH, LML, SF, JMK, and DHJ were involved in data acquisition, analysis, and interpretation. All authors critically revised the manuscript and approved the final version for submission.

Data were retrospectively analyzed in an anonymized fashion and all patients provided written informed consent for their data to be included.

Medical records were searched retrospectively, without any time frame limitations, for codes for angioedema or HAE to evaluate the diagnostic process for HAE-nl-C1INH in a clinical practice setting. Favorable response to rhC1-INH (Ruconest® Pharming Healthcare, Inc, Warren, NJ) during an angioedema attack was defined as symptom reduction or resolution within 4 h. Data were retrospectively analyzed in an anonymized fashion, and all patients provided written informed consent for their data to be included.

Thirty-one patients with HAE-nl-C1INH from 6 US centers were identified, with the majority being female (87.1%) and having a mean current age of 46.2 years (range, 16–74 years; Table ). Laboratory testing (not during an angioedema attack) indicated near-normal to normal C1–INH levels/function and C4 levels. All 31 patients had experienced recurrent episodes of angioedema and a documented lack of response to >1 antihistamine (eg, cetirizine 10–20 mg twice daily [BID], famotidine 10–40 mg BID, fexofenadine 180 mg BID, ketotifen 2 mg BID, levocetirizine 5 mg BID, ranitidine 300 mg BID) and mast cell–targeted therapy (eg, montelukast 10 mg once daily, omalizumab 300 mg every 4 weeks, prednisone 40 mg/d for 5 days, zafirlukast 20 mg BID). Genetic testing was reported for 9 patients, with no known pathogenic variants of HAE identified; of note, 1 patient had a plasminogen gene variant of uncertain significance. Diagnosis of HAE-nl-C1INH was confirmed in the 31 patients via a favorable response after intravenous administration of rhC1-INH at the recommended dosage (50 U/kg body weight; maximum dose, 4200 U 10 ) during an angioedema attack ( Fig. ). All patients continued to do well (eg, reduced angioedema attack frequency and/or severity) following subsequent prophylaxis and/or on-demand treatment with HAE-specific medications (data not shown). Only 9 of 30 patients (30.0%) had a documented family history of recurrent angioedema/HAE prior to diagnosis ( Table ). For 3 patients, other family members were diagnosed with HAE-nl-C1INH after the index patient (1 patient: mother, grandmother, 2 maternal great-aunts; 1 patient: sister, aunt, grandmother; 1 patient: suspected in grandfather who had a history of swelling). Table Demographic and baseline characteristics. Table Case Gender Age at diagnosis, y Current age, y Weight, kg Comorbid conditions and surgery of interest Family history of recurrent angioedema prior to diagnosis Laboratory testing Attacks per month prior to HAE treatment C1–INH, mg/dL C1–INH functional concentration, % C4, mg/dL 1 F 61 62 145.1 – No a 42 93 22 4–6 2 F 40 43 79.4 Hypothyroidism Yes (3 sisters; mother) 39 106 38 ≥4 3 F 30 31 124.7 Hashimoto’s disease; unspecified CTD; thyroidectomy No a NA b 83 32 8 4 F 24 32 64.9 Endometriosis No a 24 94 24 3–4 5 F NR 40 87.1 Hysterectomy No WNL c WNL c 30 4–8 6 F 40 45 160.1 Hysterectomy No 38 105 23 ≥4 7 F 26 26 100.2 – Yes (mother, grandmother, aunt) 31 94 29 4–5 8 F 23 24 64.9 – No WNL c WNL c WNL c 4–5 9 F 40 40 109.3 Hysterectomy No 30 >100 34 100 22 1 11 F 44 44 68.0 Hysterectomy No 33 >100 35 4 12 F 45 54 123.4 Hysterectomy No 30 >100 42 2–3 13 F 49 56 126.5 – No 30 >100 26 1 14 M 43 49 99.8 – No 24 100 27 3 15 M 49 53 101.6 Gastritis Yes (brother) 25 89->100 35 4–6 16 F 16 26 74.4 IBS Yes (mother) 36–37 96->100 19–20 <1 17 F 47 59 117.9 RA; hypothyroidism No (deceased father suspected) 32 88 28 1–3 18 F 48 57 73.9 Allergic rhinitis Yes (aunt, great-great grandmother and grandmother, sister, son) 26 92 24 4–5 19 M 10 16 43.9 – No 32 >100 29 109 44 ∼1 21 F 51 53 65.8 – Yes (siblings) 34 >100 29 3 22 M 64 74 103.4 Allergic rhinitis No 28 95 35 1–2 23 F 46 48 88.4 – Yes (uncle) 32 >100 31 ∼3 24 F 59 62 59.0 Allergic rhinitis; celiac disease, possible Hashimoto’s thyroiditis, RA No 32 90 20 1–2 25 F 54 58 71.7 Allergic rhinitis; RA No 24 90 7 1 26 F 60 62 74.8 Sjögren syndrome Yes 39 >100 50 5–10 27 F 30 39 63.5 RA No 34 89 10 1–2 28 F 49 59 81.6 Diverticulitis, hypothyroidism, hysterectomy No 32 110 48 ∼1 29 F 28 33 76.6 – No 30 105 38 ∼1 30 F 58 68 103.4 – No 34 85 40 ∼1 31 F 36 41 85.7 – No 38 121 30 ∼1 Abbreviations: C1–INH = C1 esterase inhibitor; CTD = connective tissue disease; HAE = hereditary angioedema; IBS = irritable bowel syndrome; RA = rheumatoid arthritis; WNL = within normal limits. a Family member(s) diagnosed with HAE-nl-C1INH after the index patient. b Not conducted due to lab error. c Data collected by different health care provider and transferred chart only stated “WNL”. Figure Diagnosis of HAE-nl-C1INH using responsiveness to C1–INH replacement therapy as a supportive criterion. A bbreviations: C1– INH, C1 esterase inhibitor; HAE-nl-C1INH, hereditary angioedema with normal C1 inhibitor level; HCP, health care provider; IV, intravenous; rhC1-INH, recombinant human C1 esterase inhibitor Figure Demographic and baseline characteristics. Abbreviations: C1–INH = C1 esterase inhibitor; CTD = connective tissue disease; HAE = hereditary angioedema; IBS = irritable bowel syndrome; RA = rheumatoid arthritis; WNL = within normal limits. Family member(s) diagnosed with HAE-nl-C1INH after the index patient. Not conducted due to lab error. Data collected by different health care provider and transferred chart only stated “WNL”. Diagnosis of HAE-nl-C1INH using responsiveness to C1–INH replacement therapy as a supportive criterion. A bbreviations: C1– INH, C1 esterase inhibitor; HAE-nl-C1INH, hereditary angioedema with normal C1 inhibitor level; HCP, health care provider; IV, intravenous; rhC1-INH, recombinant human C1 esterase inhibitor

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This case series supported the use of responsiveness of an acute angioedema attack to rhC1-INH as a way to confirm a diagnosis of HAE-nl-C1INH in patients with near-normal to normal C1–INH levels/function and C4 levels and recurrent episodes of angioedema with a documented lack of response to antihistamine and mast cell–targeted therapy. These descriptive data highlight the potential use of C1–INH administration as a diagnostic tool for HAE-nl-C1INH. This is important, given the lack of biomarkers and standardized diagnostic criteria. At the time of diagnosis, 70% of patients lacked a documented family history of HAE, and only 1 patient among those who had undergone genetic testing had an associated variant (of uncertain significance). The percentage of patients without a family history in the current case series is similar to findings from an analysis of US HAE Association Scientific Registry data, in which 72.9% of patients with a health care provider diagnosis of HAE-nl-C1INH lacked a positive family history. 11 Furthermore, a survey of 81 US physicians reported that, despite guideline recommendations for genetic testing for HAE-nl-C1INH–associated mutations, only 43% reported using Factor XII genetic testing and ≤5% reported using other genetic testing to inform the diagnosis. 3 Barriers such as cost, limited accessibility or commercial availability, and lack of awareness may limit the use of genetic testing to aid in the diagnosis of HAE-nl-C1INH. 3 , 8 Notably, 74.1% of the physicians surveyed reported using response to HAE-specific medication (ie, icatibant, ecallantide, lanadelumab-flyo, and/or various C1–INH therapies) to inform the diagnosis of HAE-nl-C1INH. These results suggest that it may be worthwhile to consider whether responsiveness to HAE-specific therapy should play a more prominent role in diagnosis (eg, rather than merely supportive). Data are limited on the potential mechanism(s) by which C1–INH is effective for treating angioedema attacks in patients with HAE-nl-C1INH. Several identified genetic mutations in HAE-nl-C1INH are characterized by reduced control of the fibrinolytic and kallikrein-kinin system, leading to increased bradykinin levels, bradykinin-associated vascular leakage, and angioedema in HAE. 12 , 13 Current HAE-nl-C1INH management strategies, which reduce excessive production of bradykinin, are similar to those for HAE-C1INH, although it is counterintuitive that C1–INH replacement therapy would resolve angioedema attacks in individuals with normal C1INH levels. 6 In addition to controlling dysregulation of the kallikrein-kinin system, C1INH cleavage to an inactive form during an attack has also been considered a reason for the benefit of C1–INH replacement in individuals with HAE-nl-C1INH. 6 Strengths of the study included exclusion of mast cell-mediated angioedema, based on a lack of response to >1 antihistamine and mast cell-targeted therapies, and multicenter participation. Key limitations included its retrospective nature, low number of non-adult cases, the lack of detailed long-term follow-up data, and evaluation using only 1 type of C1INH replacement therapy. In conclusion, a family history of recurrent angioedema may not be apparent in some patients, and reliance on the diagnostic criterion of family history may delay an accurate diagnosis and patient access to effective treatment. This case series affirms responsiveness to C1–INH replacement therapy (eg, rhC1-INH) as a useful supportive diagnostic criterion for HAE-nl-C1INH.

Nothing to disclose.

The authors confirm that this manuscript is original, has not been published before, and is not currently being considered for publication elsewhere.

Hereditary angioedema (HAE) is a rare and potentially life-threatening autosomal dominant disorder that causes unpredictable episodes of angioedema at various anatomic locations (eg, face, extremities, abdomen). 1 , 2 Subtypes include HAE due to deficient C1 esterase inhibitor (C1–INH) levels (HAE-C1INH) or function and HAE with normal C1–INH (HAE-nl-C1INH). 1 Data from the United States suggest an estimated prevalence of HAE-nl-C1INH of 0.37 per 100,000 people. 3 , 4 Prompt and accurate diagnosis of angioedema is essential to facilitate appropriate management. 5 Factors differentiating HAE from mast cell-mediated angioedema include a slower, progressive onset of symptoms and a lack of response to common mast cell-targeted therapies in HAE. 5 The diagnosis of HAE-nl-C1INH can be challenging due to a lack of definitive diagnostic laboratory tests/biomarkers, as well as heterogeneity of symptom presentation and burden. 4 , 6 , 7 , 8 Accordingly, patients with HAE-nl-C1INH can experience substantial diagnostic delays averaging 6–11 years from initial presentation. 3 Given the lack of available, validated biomarkers, diagnostic criteria have been developed for HAE-nl-C1INH based on clinical expert opinion. The criteria include: a history of recurrent angioedema; documented normal to near-normal C1–INH and C4 levels and C1–INH function; and either demonstration of an associated genetic variant or a family history of recurrent angioedema with documented lack of efficacy of high-dose antihistamine therapy in the patient being evaluated. 1 , 6 Rapid and durable response to a bradykinin-targeted medication plus predominant documented angioedema symptoms is considered a supportive diagnostic criterion. During an HAE attack, administration of C1–INH concentrate increases C1–INH plasma levels and helps to regulate the cascade systems involved in bradykinin production. 7 , 9 The aim of this case series was to evaluate the diagnostic process for HAE-nl-C1INH in US clinical practice and demonstrate that responsiveness to C1–INH replacement therapy (ie, recombinant human C1 esterase inhibitor [rhC1-INH]) is an appropriate supportive criterion for HAE-nl-C1INH.

AMS reports serving as a lecturer or advisory board member for AstraZeneca, Boehringer Ingelheim, Pharming Healthcare, Inc, and Takeda Pharmaceutical Company. HJK is a speaker for AstraZeneca plc, BioCryst Pharmaceuticals, Inc., Pharming Group N.V., and Teva Pharmaceuticals Industries Ltd., and has contracted research with ADMA Biologics, Inc., BioCryst Pharmaceuticals, Inc., BioMarin Pharmaceutical, Inc., Kedrion Biopharma, Inc., Novartis AG, Octapharma AG, Regeneron Pharmaceuticals, Inc., Celldex Therapeutics Inc., Allakos Inc., KalVista Pharmaceutical, Inc., AstraZeneca plc, and Takeda Pharmaceutical Co. Ltd. JR reports serving as a speaker/consultant/advisory board member for Amgen, AstraZeneca, BioCryst Pharmaceuticals, CSL Behring, Grifols International S.A., Cycle Pharma, Dermavent Sciences, Pharming Healthcare, Inc, and Takeda Pharmaceutical Co. Ltd. YH, LML, and SF report having nothing to disclose. HM, TC, MP, and RR are employees of Pharming Healthcare, Inc. JMK reports being a speaker for BioCryst Pharmaceuticals, CSL Behring, Pharming Healthcare Inc., and Takeda Pharmaceutical Co. Ltd. DHJ reports being a speaker and/or consultant for AstraZeneca, Pharming Healthcare Inc., Regeneron Pharmaceuticals Inc./Sanofi, and Takeda Pharmaceutical Co. Ltd.

All the data are included in this paper.