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Scientific reviews
C1-inhibitor Deficiencies (Hereditary Angioedema): Where Are We with Therapies?
Lock RJ, Gompels MM.
Curr Allergy Asthma Rep.2007 Jul;7(4):264-9.
Abstract
Hereditary angioedema, an autosomal dominant disorder, presents clinically as recurrent episodes of swelling. It results from either deficient production or function of C1 inhibitor. Acquired angioedema is associated with lymphoproliferative or autoimmune disease. Conventionally attenuated androgens and antifibrinolytics have been used for prophylaxis, both for the long term and presurgically. Fresh frozen plasma and plasma-derived C1 inhibitor concentrate have been used primarily for treatment of acute attacks. All have drawbacks in side effects or potential for infection transmission. New treatments (recombinant C1 inhibitor, icatibant, DX-88, and for acquired angioedema, rituximab) so far show good safety profiles. Early data suggest these may be effective treatment alternatives. The efficacy of current treatment and the potential held by newer agents that target specific elements in complement or kinin pathways are examined. Some agents are likely to have a wider role in treatment of other, more common, forms of angioedema.Full paper via SpringerLink (subscribers only)
Hereditary Angioedema: The Clinical Syndrome and its Management in the United States.
Frank MM
Immunol Allergy Clin N Am (2006) Nov;26(4):653-668
Abstract
Hereditary angioedema (HAE) is an episodic swelling disease with autosomal Mendelian dominant inheritance. One of the oldest descriptions of the disease is from the 1840s by Graves, who clearly described patients with episodic angioedema. In 1882, Quincke described a constellation of angioedema symptoms including peripheral swelling and self-limited attacks of abdominal pain; the disease is known in Europe as Quincke’s disease. His original description includes concern about compromise of the airway. Because the attacks he described usually lasted a matter of hours rather than days, the length of time we commonly associate with HAE today, we cannot be completely certain that the attacks described 124 years ago were hereditary angioedema.Full paper via theclinics (subscribers only)
Permeability-increasing activity in hereditary angioneurotic edema plasma. II. Mechanism of formation and partial characterization.
Donaldson VH, Ratnoff OD, Dias da Silva W, Rosen FS.
J Clin Invest. 1969 Apr;48(4):642-53
Abstract
Plasma from persons with hereditary angioneurotic edema readily developed the capacity to increase vascular permeability and to induce the isolated rat uterus to contract. Both activities resided in a small, heat-stable molecule that was apparently a polypeptide. Crude preparations of the polypeptide were inactivated during incubation with trypsin. They also failed to produce pain and erythema, but caused markedly increased vascular permeability in human skin. These characteristics differ from those of bradykinin, from which crude preparations of the polypeptide could also be distinguished by electrophoretic mobility and paper chromatographic behavior. Proof that the polypeptide is truly different from bradykinin must await its further purification. Histamine played no role in the activities observed.
Although the enzymes functioning to release the permeability factor and kinin activities in hereditary angioneurotic edema plasma were not clearly defined, one or more plasma enzymes other than C′1 esterase presumably participated either in conjunction with C′1 esterase or in pari passu events to release the polypeptide mediating these activities.
A biochemical abnormality in herediatry angioneurotic edema: Absence of serum inhibitor of C' 1-esterase.
Donaldson VH, Evans, RR.
Am J Med. 1963 Jul;35:37-44
Abstract
not availableFull paper via theclinics (subscribers only)
The pathogenesis of hereditary angioedema.
Davis AE 3rd.
Transfusion and Apheresis Science 29 (2003) 195–203
Abstract
Hereditary angioedema (HAE), which is characterized by episodic localized angioedema of the skin or mucosa, results from heterozygous deficiency of the plasma protease inhibitor, C1 inhibitor (C1INH). The most obvious biologic role of C1INH, therefore, is prevention of excessive vascular permeability. A variety of data indicate that this role is primarily a product of regulation of the contact system proteases, factor XIIa and plasma kallikrein. The C1INH deficient mouse, although it does not have episodes of cutaneous angioedema, does have increased vascular permeability which is reversed by treatment with C1INH, with the plasma kallikrein inhibitor, DX88, and with the bradykinin 2 receptor (Bk2R) antagonist, Hoe140. In addition, mice deficient in both C1INH and the Bk2R do not have increased vascular permeability. These analyses strengthen the argument that angioedema is mediated by bradykinin. This mouse also provides a system to test new potential therapeutic approaches. In addition to its role in the regulation of vascular permeability, C1INH also is an important modulator of inflammatory responses via regulation of activation of both the contact and the complement systems, and very likely via activities unrelated to protease inhibition.Full paper via ScienceDirect
Mechanism of angioedema in first complement component inhibitor deficiency.
Davis AE 3rd.
Immunol & Alle Clin N Am (2006) Nov;26(4):633-51
Abstract
Since shortly after the discovery that hereditary angioedema resulted from deficiency of first complement component (C1) inhibitor, the characterization of the mediator of angioedema has been a major goal. However, because C1 inhibitor regulates activation of both the contract and complement systems, identification of the mediator was not immediately accomplished. For a number of years, some studies appeared to indicate involvement of one system, whereas other studies suggested involvement of the other. However, the vast majority of the evidence accumulated over the past years indicates quite clearly that the major mediator is bradykinin. Therefore, unregulated contact system activation is the defect that leads directly to the development of angioedema.Full paper via theclinics (subscribers only)
The pathophysiology of hereditary angioedema.
Davis AE 3rd.
Clin Immunol. 2005 Jan;114(1):3-9
Abstract
Hereditary angioedema (HAE), characterized by recurrent episodes of angioedema involving the skin, or the mucosa of the upper respiratory or the gastrointestinal tracts, results from heterozygosity for deficiency of the serine proteinase inhibitor (serpin), C1 inhibitor (C1INH). The primary biological role of C1INH is to regulate activation of the complement system, the contact system, and the intrinsic coagulation system. During attacks of angioedema, together with decreasing levels of C1INH, the complement and contact systems are activated: C2 and C4 levels fall and high molecular weight kininogen is cleaved. Although previous data suggested that symptoms in HAE might be mediated via complement system activation, a combination of recent clinical data, in vitro studies, and analysis of C1INH-deficient mice all indicate that the major mediator of angioedema is bradykinin: (1) a vascular permeability enhancing factor can be generated in vitro in C1INH-depleted, C2-deficient plasma, but not from C1INH-depleted, contact system-deficient plasma; this factor was identified by sequence analysis as bradykinin; (2) bradykinin can be detected in the plasma of HAE patients during attacks of angioedema; (3) in several members of one family, expression of a C1INH variant that inhibits contact system proteases but has defective inhibition of C1r and C1s does not result in HAE; (4) C1INH-deficient (C1INH-/-) mice have a defect in vascular permeability that is suppressed by treatment with specific plasma kallikrein inhibitors and by bradykinin type 2 receptor (Bk2R) antagonists, and is eliminated in C1INH-/-, Bk2R-/- double-deficient mice.Full paper via Science direct
Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies
Bernstein JA,
Ann Allergy Asthma Immunol. 2008; 100 (suppl2): S41-S46
Abstract
OBJECTIVE: To provide an overview on the current status of emerging therapies for hereditary angioedema (HAE) in the United States. DATA SOURCES: Summary statements were obtained from each pharmaceutical company regarding their agent. STUDY SELECTION: Each agent is undergoing or has completed phase 3, double-blind, placebo-controlled trials. RESULTS: Berinert P, a purified, virus-inactivated, human plasma-derived C1 inhibitor (C1-INH) concentrate, is being investigated in 2 international, multicenter, prospective trials. Experience with this agent in Europe and Canada indicates it is effective and safe. Cinryze is a nanofiltered C1-INH replacement therapy demonstrated to be effective and safe in acute and prophylactic arms of a phase 3, double-blind, placebo-controlled study. Rhucin, a recombinant human C1-INH replacement therapy from transgenic rabbits, has been shown to be effective and safe in phase 2 and phase 2/3 studies, with an additional phase 3 study ongoing. DX-88 or ecallantide, a potent and specific inhibitor of plasma kallikrein, achieved all primary and secondary efficacy end points in a placebo-controlled, double-blind, phase 3 study, with a second phase 3 study ongoing. Icatibant, a potent and specific peptidomimetic bradykinin 2 receptor antagonist, was studied in 2 phase 3 trials: FAST 1 (For Angioedema Subcutaneous Treatment) did not achieve statistical significance for the primary end point but did so for secondary end points, whereas FAST 2 achieved statistical significance for primary and secondary end points. CONCLUSIONS: The future treatment of HAE in the United States appears promising based on progress being made in drug development for this orphan disease.Only abstract available (Full paper to subscribers only)
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