Pharmacological Research, Vol . 26, Supplement 2, 1992
Angelo Agostoni and Marco Cicardi, Clinica Medica III, Istituto di Medicina Interna, University di Milano Hereditary angioedema (HAE) is a disease due to mutations within ClINH gene, transmitted as an autosomal dominant trait, leading to plasma deficiency in C1-INH (antigen and/or function) that allows autoactivation of the first component of complement (Cl) with consumption of its substrates C4 and C2 . Probably because of uncontrolled activation of the contact system (physiologically regulated by C1-INH), kinin-like mediator/s are episodically released resulting in edema of the subcutaneous or submucosal tissues (1) . Therapy with androgen derivatives (by increasing C1-INH synthesis) prevents patients from swelling (2) and administration of C1-INH plasma concentrate can revert attacks (3) . An acquired form of Cl-INH deficiency (Acquired angioedema AAE) has been also described where this protein is more rapidly catabolized by an autoantibody (4-5) or by an associated disease . Clinical characteristics are analogous to HAE, but effectiveness of treatment is impaired by the rate of C 1-INH consumption . Subcutaneous and abdominal attacks of HAE and AAE are harmless for the patients' life and therefore do not usually represent a critical therapeutic problem . However abdominal attacks can be particularly severe and difficult to differentiate from a surgical emergency. In these cases analgesic and antispastic drugs are little effective and Cl-INH concentrate is the only useful therapy . Such a treatment is otherwise mandatory in the lifethreatening event of HAE : the edema of the larynx . It usually occurs rarely compared to cutaneous and abdominal symptoms, but most of the patients will experience at least one episode in their lifetime . We are now following 220 patients with HAE . A total of 83 infusions of Cl-INH concentrate have been performed at our Clinic . Different CI-INH preparations are approved in European countries . Our experience is mainly based on the C1-INH concentrate from Immuno (Vienna, Austria), the one approved in Italy . However we also infused, for experimental purpose, the preparations from The Netherlands Red Cross and from Behring (Marburg, Germany) and did not find relevant differences among these three preparations . Treatment of attacks with C1-INH concentrate in HAE patients Site of edema Cutaneous Abdominal Laryngeal
Units of CI-INH
500 1,000 1,000/1,500
Ineffective 60/120 min 30/60 min
© 1992 The Italian Pharmacological Society
Pharmacological Research, Vol . 26, Supplement 2, 1992
Administration of 1,000/1,500 units of the preparation from Immuno (one unit correspond to the amount of Cl-INH contained in 1 ml of normal human plasma) has always been effective in laryngeal and abdominal attacks . The infusion of 1,000 U of concentrate rises functional C1-INH plasma levels from 10 to 50 % of the normal mean that decreases back to pretreatment levels during the following 48 hours . C4 levels increase after 12/24 hours, as a consequence of the normalization of C 1 activation, and are still elevated 48 hours later . No acute adverse reactions were ever registered . The main problem with this emoderivative arose in 1983/84 when, probably due to a contaminated batch, we registered 13 cases of acute nAnB hepatitis . However no antibodies to the AIDS virus were ever detected, to our knowledge, as a result of treatment with C 1-INH concentrate . Starting from 1986 the preparation is steam treated and since that time no infection problems were registered out of 56 infusions . Our series of angioedema patients now includes 9 subjects with acquired CI-INH deficiency. Only one has a true lymphoprolypherative disorder, the others have either unusual associated diseases or no disease at all . All these patients, but the one with chronic lymphocytic leukemia (CLL) have autoantibodies to Cl-INH (autoimmune AAE) . Two of the patients with autoimmune AAE had repeated laryngeal edema treated with C1-INH concentrate . In both these patients we noted that subsequent episodes required progressively higher doses (up to 4,000 U .) of concentrate to revert the symptoms . As a counterpart of the reduced clinical effectiveness C1-INH and C4 had only minimal increase or no increase at all . Similar experience has been reported by other authors and it probably depends on the rapid C 1-INH catabolism that is characteristic of patients with AAE . In conclusions it appears, from our experience that C1-INH concentrate is an effective and safe treatment for lifethreatening laryngeal edema and for abdominal attacks in patients with HAE . In AAE such an effectiveness is reduced and doses need to be increased three/four times . REFERENCES 1 . Davis AE III . C 1 inhibitor and hereditary angioneurotic edema . Ann Rev Immunol . 1988, 6: 595-62 . 2 . Cicardi M, Brgamaschini L, Cugno M, Hack E, Agostoni G, Agostoni A. Long-term treatment of hereditary angioedema with attenuated androgens : A survey of a 13 years experience . J Allergy Clin Immunol . 1991, 87 : 768-773 . 3 . Bergamaschini L, Agostoni A, Cicardi M . C 1 inhibitor concentrate in the therapy of hereditary angioedema . Allergy . 1983, 38 : 81-84 . 4 . Jackson J, Sim RB, Whelan A, Feighery C . An IgG autoantibody which inactivates C 1 inhibitor. Nature . 1986 323: 722-724. 5 . Alsenz J, Lambris JD, Bork K and Loos M . Acquired C 1 inhibitor (C 1 INH) deficiency type II . J . Clin . Invest . 1989 . 83 : 1794-1799 .