Medical Literature - 2003

Bouillet L, Ponard D, Drouet C, Jullien D, Massot C /2003 Dermatology

BACKGROUND: Oral contraceptives can precipitate attacks of hereditary angioedema (ANE) or induce acquired forms.

OBJECTIVE: We studied 5 patients who had an ANE which had begun under oral contraception and disappeared after stopping the pill.

METHODS: We explored the clinical and biological characteristics of these patients.

RESULTS: The symptoms developed during the first year or later after starting contraception; the patients reported relapsing swelling of the lips, hands, larynx and abdomen. All women had normal serum C4 and C1 inhibitor (C1Inh) antigen levels, but a lowered C1Inh activity, with a marked protein cleavage on the immunoblot. The suppression of the pill was associated with the regression of the edema and normalization of C1Inh function.

CONCLUSION: The mechanism of these ANE is unknown. The could be due to a modulation of C1Inh expression upon androgens or an imbalance between coagulation proteins favoring C1Inh cleavage by its target proteases.Copyright 2003 S. Karger AG, Basel.

206(2):106-109

Available online at: karger.com/Article/Abstract/68456 (small fee)

Zuraw BL 12/2003 Immunology & Allergy Clinics of North America

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of angioedema, and caused by a deficiency of the plasma protein C1 inhibitor. HAE attacks carry a substantial risk of morbidity or even mortality, making it imperative that the correct diagnosis be established and an appropriate management plan be in place. This report reviews the current diagnostic and therapeutic approaches available in the United States. Areas in which the diagnostic or therapeutic tools are deficient are discussed, and the prospects for improved therapeutic modalities highlighted.

Dec;29(3):239-245

Available online at: trasci.com/article/S1473-0502%2803%2900174-5/fulltext (small fee)

Williams A, Baird LG 12/2003 Transfusion & Apheresis Science

An example of an approach to the developmental philosophy of novel recombinant products is explored by using the exemplar of Hereditary Angioedema (HAE). Plasma kallikrein is believed to be an important mediator of angioedema in patients with genetic deficiency of C1 esterase inhibitor (HAE patients). DX-88, a novel Kunitz domain produced by phage display (a powerful method of generating novel binders to potentially therapeutic targets), is a potent and selective inhibitor of plasma kallikrein which in early clinical studies demonstrates a useful efficacy/safety ratio in the treatment of acute attacks of HAE.

Dec;29(3):255-258

Available online at: sciencedirect.com/science/article/pii/S1473050203001708 (small fee)

Molinari F, Meskanaite V, Munnich A, Sonderegger P, Colleaux L 10/2003 Hum.Mol.Genet.

Cumulative evidence has shown that a delicate balance between serine proteases and their inhibitors is crucial for normal functioning of several biological pathways. The importance of proteases and their inhibitors is well documented in several human diseases. Among them, the best documented are hemophilia B, a genetic deficiency of the serine protease coagulation factor IX and serpinophathies. Alpha-1-antitrypsin deficiency (MIM 107400), is associated with early-onset emphysema and liver disease, while hereditary angioedema (HANE; MIM 106100) is caused by mutations in the C1 inhibitor, a serpin involved in the regulation of the complement cascade. Recently, two human genetic diseases of the central nervous system have been related to mutations in components of extracellular proteolytic systems. Here, we review the recent advances in this field. [References: 38].

Oct 15;12(Spec 2):R195-200

Available online at: hmg.oxfordjournals.org/content/12/suppl_2/R195.long

Cicardi M, Zingale L 12/2003 Transfusion & Apheresis Science

Hereditary angioedema (HAE) is due to the inherited deficiency of C1-Inhibitor (C1-Inh). When specific treatment was not available, the mortality rate for this disease was as high as 50% and the disability up to 100-150 days per year (Agostoni and Cicardi, Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients). Such a worrying scenario dramatically improves upon appropriate treatment. Nevertheless, the disease still frequently goes undiagnosed or misdiagnosed as an allergic condition. Both circumstances prevent patients from receiving drugs that could save and/or improve the quality of their life. The interest of our group for patients with HAE goes back to the early seventies. Since that time, 441 such patients have been examined and treated at our department; 403 are still actively followed. Here we present our experience on the treatment of HAE.

Dec;29(3):221-227

Available online at: trasci.com/article/S1473-0502%2803%2900164-2/fulltext (small fee)

Pappalardo E, Zingale LC, Cicardi M 5/2003 Immunol.Lett.

The attenuated androgen Danazol can partially reverse the biochemical defect and prevent angioedema in patients with inherited C1-inhibitor (C1-INH) deficiency (hereditary angioedema, HAE). Though its clinical effectiveness is independent from significant increase of C1-INH plasma levels, its mechanism of action remains unknown. Since angioedema is a local phenomenon, it could be controlled by restoring tissue levels of C1-INH. We measured the expression of C1-INH mRNA in peripheral blood mononuclear cells (PBMCs) of 13 patients with HAE type 1 (seven untreated and asymptomatic, and six on Danazol at the minimal effective dose) and of eight normal controls. mRNA levels were quantitated by computerized optical densitometry of reverse transcriptase-PCR products, normalized for the amount of glyceraldehyde-3-phosphate-dehydrogenase and expressed as percent of normal pooled RNAs. Each determination represented the mean of three separate experiments. Measurement of C1-INH mRNA in two patients before and after 1 month of Danazol 400 mg per day demonstrated a post-treatment increase of 15 and 21%, respectively. When HAE patients and controls were analyzed as groups, C1-INH mRNA levels of patients untreated and asymptomatic (median 73%, range 65-78) were significantly lower (P=0.001) compared to controls (median 101%, range 87-121) and to patients on Danazol (median 91%, range 82-96); the difference among the last two groups was not statistically significant. Our data demonstrate that minimal effective doses of Danazol increase the expression of C1-INH mRNA in PBMC of HAE patients even in the absence of a significant increase of C1-INH plasma levels.

May 1;86(3):271-276

Available online at: sciencedirect.com/science/article/pii/S0165247803000294 (small fee)

Bowen T, Hebert J, Ritchie B, Burnham J, MacSween M, Warrington R, Yang W, Issekutz A, Karitsiotis N, McCombie N, Giulivi T. 12/2003 Transfusion and Apheresis Science

C1 esterase inhibitor (C1-INH) deficiency is a rare disorder that lacks consensus for diagnosis therapy and management. Recognizing that Canada is behind the European approach to this disorder, we have formed the Canadian Hereditary Angioedema Society (CHAES)/Société d’angioédème héréditaire du Canada (SAHC) to foster knowledge of this disorder in Canada and to advance care of patients with this disorder in Canada. We here present a review of treatment of this disorder in Canada including prevention of angioedema events and use of replacement therapy and present an algorithm for diagnosis therapy and management of C1-INH deficiency in Canada for discussion at our International Conference on Hereditary Angioedema to be held in Toronto, Canada, October 24th to 26th, 2003.

Available online at: ncbi.nlm.nih.gov/pubmed/14572811?dopt=Abstract

Ritchie BC 12/2003 Transfusion & Apheresis Science

Deficiency of C1 Inhibitor leads to unopposed activation of complement, with localized, unpredictable, and sometimes life-threatening attacks of angioedema. Treatment with plasma-derived C1 Inhibitor rapidly aborts attacks, and may be lifesaving, but is expensive, requires use of a pooled blood product, may need to be repeated and may not be effective in autoantibody mediated angioedema. The antifibrinolytic agents aprotinin, tranexamic acid, and epsilon-aminocaproic acid are useful for prophylaxis and treatment of angioedema, likely by inhibiting plasmin. Specific drugs to replace the deficient C1 Inh have not been reported. The kallikrein inhibitor DX-88 (Dyax) has received orphan drug status in Europe and is undergoing clinical trial in Europe and the USA. [References: 98].

Dec;29(3):259-267

Available online at: trasci.com/article/S1473-0502%2803%2900169-1/fulltext (small fee)

Bork K, Fischer B, Dewald G 3/2003 The American Journal of Medicine (Am.J.Med.)

PURPOSE: Recurrent angioedema, characterized by skin swelling, colicky attacks of abdominal pain, and life-threatening laryngeal edema, can be either hereditary or acquired. According to anecdotal reports, it may be associated with use of oral contraceptives and hormone replacement therapy. We investigated potential interactions between these medications and various types of recurrent angioedema in a large cohort of women.

METHODS: Women with recurrent angioedema (n = 516) underwent a thorough medical evaluation. They were then classified by type of angioedema, using standard criteria.

RESULTS: Of the 516 women, 228 (44%) had used oral contraceptives or hormone replacement therapy, including 103 (45%) with urticaria-related angioedema, 50 (22%) with idiopathic angioedema, 39 (17%) with hereditary angioedema type III, 32 (14%) with hereditary angioedema type I, and 4 (2%) with angioedema induced by angiotensin-converting enzyme inhibitors. Oral contraceptives or hormone replacement therapy led to angioedema attacks in 46 women (20%), including 20 (63%) of the women with hereditary angioedema type I, 24 (62%) of those with hereditary angioedema type III, and 2 (4%) of those with idiopathic angioedema. These 46 women included 26 in whom symptoms occurred for the first time after use of these medications and 20 in whom pre-existing recurrent angioedema worsened considerably.

CONCLUSION: Oral contraceptives or hormone replacement therapy can either induce or exacerbate symptoms of hereditary angioedema type I or type III, or idiopathic angioedema. However, many women with these diseases tolerate these medications without having any effects on their angioedema.

Mar;114(4):294-298

Available online at: amjmed.com/article/S0002-9343%2802%2901526-7/pdf (small fee)

De Serres J, Groner A, Lindner J /2003 Transfusion & Apheresis Science

Available online at: sciencedirect.com/science/article/pii/S147305020300171X (full text)