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Recurrent angioedema, in particular bradykinin-mediated types, constitutes a genuine diagnostic and therapeutic challenge. The 2 forms of recurrent angioedema are hereditary angioedema (HAE) and acquired angioedema (AAE). The more common of the two is AAE, which is associated with angiotensin-converting enzyme inhibitors (ACEi). Acquired deficiency of C1-INH is another, albeit rarer cause of AAE (C1-INH-AAE). Various mechanisms in acquired C1-INH deficiency have been described and are linked mainly to underlying diseases, such as lymphoproliferative disorder and autoimmune disease [1]. In certain patients, both mechanisms (eg, increased consumption of C1-INH in the background of lymphoproliferative disease and the presence of anti– C1-INH autoantibodies) simultaneously participate in the pathophysiology of C1-INH-AAE and the development of clinical symptoms [2]. We present the case of a 67-year-old man with an acquired form of angioedema due to C1-INH deficiency characterized by an unusually high titer of specific autoantibodies against C1-INH. The patient was referred to our center with recurrent nonpruritic angioedema of the face, lips, and tongue and submucosal edema in the larynx associated with dyspnea, which required intubation. No family history for recurrent angioedema or allergies was evident. The patient had been treated in the past for arterial hypertension with ACEi (5 mg of ramipril per day). Discrete symptoms of angioedema were present before the treatment with ACEi, which increased the frequency and, slightly, the severity of angioedema. Owing to recurrent angioedema and cough, the ACEi was switched to amlodipine. However, the angioedema persisted, and its intensity and frequency gradually increased even after cessation of ACEi treatment. Angioedema was treated with antihistamines (single and 4-fold increase in dose) and systemic corticosteroids, with no clinical impact. Given that the patient had second-degree atrioventricular blockage and paroxysmal supraventricular tachycardia, he underwent cardiac pacemaker implantation. After this intervention, he experienced his first severe attack of laryngeal angioedema requiring intubation and was referred to our center. The initial laboratory examination revealed a significantly decreased concentration and function of C1-INH and decreased concentration of C4 and C1q complement components. The diagnosis of AAE with C1-INH deficiency was established through 2 separate measurements in 3 months (Table). Hematological examination excluded any hematologic-oncologic diseases. Indirect fluorescence revealed a strong presence of antinuclear antibodies (coarse speckled pattern), and ELISA revealed anti-dsDNA (62 U/mL, normal range <20 U/mL). The patient did not show any signs of clinical rheumatic diseases. An examination for autoantibodies against C1-INH was conducted in the Complement Laboratory at Semmelweis University, Budapest, Hungary. A high anti–C1-INH IgG titer (35 U/mL; normal range, 0-2 U/mL) was detected, and a diagnosis of C1-INH-AAE type 2 was established (Table). Given the patient’s history of venous thrombosis (contraindication for antifibrinolytics), successful prophylaxis was initiated with attenuated androgens (200 mg of danazol once daily). The breakthrough angioedema attacks were treated with recombinant human C1-INH (rhC1-INH). To date, 6 attacks of facial angioedema and 4 attacks of laryngeal angioedema have been treated with 2100 U (body weight 92 kg), resulting in a significant improvement 0.5-2 hours after treatment and complete resolution of angioedema symptoms in 12-24 hours. AAE with C1-INH deficiency shares the same clinical presentation as other types of bradykinin-mediated angioedema, although its etiology is completely different. Moreover, the clinical symptoms of C1-INH-AAE could precede the diagnosis of the underlying disease. While detection of autoantibodies against C1-INH is useful, only a few laboratories can provide this examination, since commercial kits are not available [3].

journal of investigational allergology and clinical immunology

Successful Use of Recombinant Human C1-INH in a Patient with Acquired Angioedema due to C1 Inhibitor Deficiency and an Unusually High Titer of Anti-C1-Inhibitor Autoantibodies