Medical Literature - 2007

Anti-cholesterol antibody levels in hereditary angioedema

Varga L, Biro A, Szeplaki G, Toth L, Horvath A, Fust G, et al 11/2007 Journal of Cellular & Molecular Medicine

Hereditary angioedema (HAE) is a rare disorder caused by the deficiency of the C1-inhibitor gene (C1INH) and characterized by recurrent bouts of angioedema. Autoimmune disorders frequently occur in HAE. Previously we found, that danazol has an adverse effect on serum lipid profile: reduced high-density lipoprotein (HDL) and elevated low-density lipoprotein (LDL) cholesterol levels are associated with long-term prophylactic use, whereas total cholesterol levels are unchanged. Our aim was to study the anti-cholesterol antibody (ACHA) production in HAE patients and compare it with those of healthy blood donors, and to investigate the possible associations between ACHA levels and serum lipid profile alterations caused by danazol. Anti-cholesterol IgG levels were measured by ELISA and their correlation with serum concentrations of total cholesterol, HDL, LDL, triglycerides was determined in HAE patients receiving/not receiving danazol. Serum ACHA levels were significantly higher in HAE patients, compared to healthy blood donors (P<0.0001). Longterm danazol prophylaxis had no effect on serum ACHA levels in HAE patients. However, we found a significant, negative correlation between ACHA levels and serum total cholesterol (r=-0.4033, P=0.0200), LDL (r=-0.4565, P=0.0076) and triglyceride (r=-0.4230, P=0.0121) levels only in danazol-treated patients, but not in HAE patients who did not receive long-term prophylaxis. Patients with HAE have higher baseline ACHA levels compared to healthy subjects, and this might reflect polyclonal B-cell activation. The latter would be a potential explanation for the lack of an increased incidence of infectious diseases in HAE patients, but might lead to increased autoimmunity.


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C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option

Longhurst HJ, Carr S, Khair K 1/2007 Clinical & Experimental Immunology

Economic and political factors have led to the increased use of home therapy programmes for patients who have traditionally been treated in hospital. Many patients with hereditary angioedema (HAE) experience intermittent severe attacks that affect their quality of life and may be life-threatening. These attacks are treated with C1-inhibitor concentrate which, for most patients, is infused at the local hospital. Home therapy programmes for HAE are currently being established. This paper reviews the extent of use of these programmes and summarizes the advantages and potential disadvantages of the concept so far. [References: 56].


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C1-inhibitor deficiencies (hereditary angioedema): where are we with therapies?

Lock RJ, Gompels MM 7/2007 Current Allergy & Asthma Reports

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. [References: 52].


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Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor

Schneider L, Lumry W, Vegh A, Williams AH, Schmalbach T 8/2007 Journal of Allergy & Clinical Immunology

BACKGROUND: Hereditary angioedema (HAE) is a rare, autosomal-dominant disorder caused by C1 inhibitor gene mutation. Patients with HAE experience intermittent attacks of edema affecting the oropharynx, abdomen, gastrointestinal tract, and limbs. C1 inhibitor is the primary endogenous inhibitor of the kallikrein-kinin (contact) cascade. Unregulated kallikrein activation generates bradykinin, the likely mediator of the swelling and pain characterizing HAE attacks. Ecallantide, a novel, recombinant protein, potently inhibits kallikrein. This is the first placebo-controlled assessment in human beings of a therapeutic intervention to improve symptoms of HAE attacks under the hypothesis that the contact cascade is the putative pathway responsible for HAE pathology.

OBJECTIVE: To determine the safety and efficacy of ecallantide in patients with HAE. METHODS: This double-blind, placebo-controlled, ascending-dose study assessed efficacy and tolerability of ecallantide (5, 10, 20, or 40 mg/m(2) intravenously) in individuals experiencing acute HAE attacks (N = 49). Twelve patients were assigned to each dose level: 10 to ecallantide and 2 to placebo, per cohort.

RESULTS: Ecallantide treatment ameliorated the symptoms of HAE attacks: 72.5% (29/40) of patients treated with ecallantide versus 25.0% (2/8) of placebo patients reported significant improvement in symptoms within 4 hours (P = .0169). Ecallantide was well tolerated at all doses.

CONCLUSION: Ecallantide, a potent, specific inhibitor of plasma kallikrein, significantly improved HAE symptoms over placebo. The trial provides strong support for the role of the kallikrein-kinin cascade and its end product, bradykinin, in the pathophysiology of HAE. Further clinical trials are underway.

CLINICAL IMPLICATIONS: Ecallantide is a promising new therapy for HAE attacks.


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Fresh frozen plasma for the treatment of hereditary angioedema

Prematta M, Gibbs JG, Pratt EL, Stoughton TR, Craig TJ 4/2007 Annals of Allergy, Asthma, & Immunology

BACKGROUND: Fresh frozen plasma (FFP) has been used as a treatment option for patients with hereditary angioedema (HAE) because it contains Cl esterase inhibitor, and alternate therapies are not yet available in the United States. However, because FFP also contains other substrates, it has been hypothesized to have the potential to worsen or precipitate an acute attack of HAE.

OBJECTIVE: To research patient records and the medical literature to determine whether FFP can exacerbate symptoms or precipitate an attack of HAE.

METHODS: The following keywords were searched in PubMed and OVID: hereditary angioedema, angioedema and fresh frozen plasma, angioedema and FFP, and hereditary angioneurotic edema. English-language articles were searched from 1966 to the present. Also, after institutional review board approval, the medical records of patients with HAE at our institution who have received FFP since 1990 were reviewed to determine if there was evidence that FFP exacerbated the symptoms of HAE.

RESULTS: The English-language literature review and our patient medical record review failed to identify instances when FFP exacerbated symptoms of HAE or precipitated an attack. Several reports and our experience suggest that FFP is an effective prophylactic agent before surgery and for treatment of acute HAE attacks without evidence of exacerbation or initiation of symptoms.

CONCLUSIONS: FFP seems to be safe and effective in preventing exacerbations of HAE before surgery and for acute exacerbations of HAE without evidence of it initiating an attack or worsening a preexisting attack. [References: 26].


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Helicobacter pylori infection as a triggering factor of attacks in patients with hereditary angioedema

Visy B, Fust G, Bygum A, Bork K, Longhurst H, Bucher C, et al 6/2007 Helicobacter

BACKGROUND: Helicobacter pylori infection is considered among the causative factors of urticaria and angioedema. Having conducted a study on 65 patients, Hungarian authors reported in 2001 that successful eradication of H. pylori is followed by a significant reduction in the number of attacks in patients with hereditary angioedema (HAE). The present study aimed to reinvestigate the relationship between H. pylori infection and the attack rate in the framework of an international collaborative study.

MATERIALS AND METHODS: Within the framework of the PREHAEAT project launched by the European Union, further 152 patients were studied in seven collaborating centers, and participants of the earlier study were followed up in order to detect any relationship between H. pylori infection and the occurrence of attacks in patients suffered from HAE.

RESULTS: The proportion of patients experiencing frequent (> or = 5 per year) abdominal attacks was higher (p = .002) among the H. pylori-infected participants of the international study who underwent eradication as compared to the rest of patients. Successful eradication of H. pylori significantly (p = .0006) reduced the number of attacks in these patients as well. Nine subjects of the previous Hungarian study who underwent eradication therapy for dyspepsia were followed up for an additional 4 years. In these patients, attack frequency remained consistently low.

CONCLUSIONS: As shown by experience from the Hungarian and the international trial, the number of frequent, edematous abdominal attacks may decrease substantially following the eradication of H. pylori from HAE patients infected with this pathogen. Therefore, screening of patients with HAE for H. pylori infection seems warranted. Eradication of H. pylori may lead to a marked reduction in disease severity.


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Funding for Canadian Hereditary Angioedema Network has been generously provided by unrestricted grants from:


CSL Behring


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