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ABSTRACT: Icatibant, a bradykinin B2 receptor antagonist, is an established treatment for acute attacks of hereditary angioedema (HAE) with C1-inhibitor (C1-INH) deficiency. We describe our experience with icatibant in eight patients with angioedema because of acquired C1-INH deficiency (AAE). Forty-eight moderate-to-severe attacks were treated with subcutaneous icatibant 30 mg; two moderate attacks resolved without treatment. The median (range) duration of treated attacks (onset to complete resolution) was 9.33 (1.67-39.00) h; durations of the untreated attacks were 72 and 96 h. Symptom improvement following icatibant treatment occurred in 0.5 (0.25-2.10) h and complete resolution in 6.75 (0.50-30.75) h. A single icatibant injection achieved complete symptom resolution in 47 attacks; one facial attack required a second injection. One peripheral attack responded less quickly than other treated attacks. Five patients reported transient injection site reactions. Icatibant appeared to provide effective symptom relief and was generally well tolerated.
Allergy 06/2012; 67(8):1074-7. · 6.27 Impact Factor
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D Moldovan,
A Reshef,
J Fabiani,
S Kivity,
E Toubi,
M Shlesinger,
M Triggiani,
V Montinaro,
E Cillari,
G Realdi,
M Cancian,
S Visscher,
A Zanichelli,
A Relan, M Cicardi
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ABSTRACT: Background Hereditary angioedema (HAE) owing to C1 inhibitor deficiency is an autoso-mal dominant disorder, characterized by recurrent, potentially life-threatening, localized attacks of tissue swelling. Current treatment involves the infusion of C1 inhibitor protein (C1-INH) isolated from human plasma. Objectives This open-label extension to a European, Israeli and Argentinean randomized study (NCT00262301) aimed to investigate the efficacy and safety of recombinant human C1 inhibitor (rhC1-INH) as a first-line treatment following an HAE attack, together with its effect on subsequent attacks. Methods An HAE-specific visual analogue scale (VAS) 0–100 mm was used by patients to assess the severity of attack at four anatomical locations. Patients were treated with one, single-vial, fixed-dose of rhC1-INH (2100 U), followed by up to two further vials at the investigators discretion. The primary end-point was the time from first rhC1-INH injection to first onset of relief of symptoms (20 mm decrease on VAS). Response to treatment was defined as the onset of relief within 4 h. Results A total of 57 patients were treated for 194 HAE attacks. Overall, sustained relief of symptoms was achieved in 87% of rhC1-INH-treated patients within 4 h of treatment, with 57% of attacks requiring only one vial of rhC1-INH. When categorized by successive attacks experienced by individual patients, the response rate to rhC1-INH treatment was 96%, 83%, 87%, 80% and 80% for attacks 1–5 respectively. Treatment with rhC1-INH was well tolerated, with no discontinuations owing to treatment-emergent adverse events and no adverse events relating to immunogenicity. Conclusions and Clinical Relevance Treatment with rhC1-INH provides fast-onset relief for an HAE attack, with a high rate of therapeutic response maintained throughout subsequent attacks.
Clinical and Exprimental Allergy. 06/2012; 42:2012--929.
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D Moldovan,
A Reshef,
J Fabiani,
S Kivity,
E Toubi,
M Shlesinger,
M Triggiani,
V Montinaro,
E Cillari,
G Realdi,
M Cancian,
S Visscher,
A Zanichelli,
A Relan, M Cicardi
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ABSTRACT: Hereditary angioedema (HAE) owing to C1 inhibitor deficiency is an autosomal dominant disorder, characterized by recurrent, potentially life-threatening, localized attacks of tissue swelling. Current treatment involves the infusion of C1 inhibitor protein (C1-INH) isolated from human plasma.
This open-label extension to a European, Israeli and Argentinean randomized study (NCT00262301) aimed to investigate the efficacy and safety of recombinant human C1 inhibitor (rhC1-INH) as a first-line treatment following an HAE attack, together with its effect on subsequent attacks.
An HAE-specific visual analogue scale (VAS) 0-100 mm was used by patients to assess the severity of attack at four anatomical locations. Patients were treated with one, single-vial, fixed-dose of rhC1-INH (2100 U), followed by up to two further vials at the investigators discretion. The primary end-point was the time from first rhC1-INH injection to first onset of relief of symptoms (≥ 20 mm decrease on VAS). Response to treatment was defined as the onset of relief within 4 h.
A total of 57 patients were treated for 194 HAE attacks. Overall, sustained relief of symptoms was achieved in 87% of rhC1-INH-treated patients within 4 h of treatment, with 57% of attacks requiring only one vial of rhC1-INH. When categorized by successive attacks experienced by individual patients, the response rate to rhC1-INH treatment was 96%, 83%, 87%, 80% and 80% for attacks 1-5 respectively. Treatment with rhC1-INH was well tolerated, with no discontinuations owing to treatment-emergent adverse events and no adverse events relating to immunogenicity.
Treatment with rhC1-INH provides fast-onset relief for an HAE attack, with a high rate of therapeutic response maintained throughout subsequent attacks.
Clinical & Experimental Allergy 06/2012; 42(6):929-35. · 5.03 Impact Factor
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ABSTRACT: on behalf of HAWK (Hereditary Angioedema International Working Group). Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy 2012; 67: 147–157. Hereditary angioedema with C1 inhibitor (C1-INH) defi-ciency (HAE) is a rare disease with an estimated frequency of 1 : 50 000 in the general population without major racial or gender differences (1). HAE is clinically manifested by recurrent episodes of localized subcutaneous or submucosal edema lasting for 2–5 days. The most commonly involved organs include the skin, upper respiratory tract, oropharynx, and gastrointestinal tract. The disease is disabling and can be lethal (2, 3). Effective management of HAE is targeted to either preventing or treating attacks. Drugs for both approaches have been available since the late 1970s, but not uniformly registered. Owing to the paucity of controlled studies, treatment modalities had been mostly empiric, and consensus guidelines were primarily based on limited case series, observational studies, and expert opinions, until now (4–6). Treatment for HAE has been revolutionized in the last 10 years by three new drugs developed for the treatment for acute attacks. To obtain marketing authorization, the three new drugs and two plasma-derived C1-INHs (pdC1-INH) already available in some countries underwent controlled trials (7–12). Recent publication of these trials prompted a re-evaluation of existing guidelines to move from expert opin-ions to evidence-based recommendation. With this in mind, a conference was held in Gargnano del Garda, Italy, from September 26 to 29, 2010. The meeting
Allergy 01/2012; · 6.27 Impact Factor
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ABSTRACT: Angioedema owing to hereditary deficiency of C1 inhibitor (HAE) is a rare, life-threatening, disabling disease. In the last 2 years, the results of well-designed and controlled trials with existing and new therapies for this condition have been published, and new treatments reached the market. Current guidelines for the treatment for HAE were released before the new trials and before the new treatments became available and were essentially based on observational studies and expert opinion. To provide evidence-based HAE treatment guidelines supported by the new studies, a conference was held in Gargnano del Garda, Italy, from September 26 to 29, 2010. The meeting hosted 58 experienced HAE expert physicians, representatives of pharmaceutical companies and representatives of HAE patients' associations. Here, we report the topics discussed during the meeting and evidence-based consensus about management approaches for HAE in adult/adolescent patients.
Allergy 11/2011; 67(2):147-57. · 6.27 Impact Factor
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ABSTRACT: Hereditary angioedema (HAE) is a heterozygous deficiency of first component of complement-inhibitor (C1INH). Insufficient C1INH activity leads to uncontrolled activation of plasma cascade systems, which results in acute angioedema attacks in patients with HAE. Plasma-derived or recombinant C1INH products are approved for the treatment of such angioedema attacks. The target level of C1INH activity needed to achieve optimal efficacy, however, remains unknown. We determined the plasma level of C1INH associated with optimal clinical efficacy in the treatment of angioedema attacks.
Efficacy and pharmacokinetic data were reviewed from recently published placebo-controlled randomized trials in the treatment of HAE with either plasma-derived or recombinant C1INH products, tested at various doses.
A dose-dependent effect was observed on time to the beginning of relief of symptoms, on time to resolution of symptoms, and on the response rate within 4 h. Optimal efficacy of C1INH therapy is achieved at doses ≥50 U/kg. This dose increases plasma C1INH activity in almost all patients to values ≥0.7 U/ml (70% of normal), the lower limit of the normal range. The differences in half-lives of the various C1INH products do not have an obvious effect on clinical efficacy.
A review of the efficacy and pharmacokinetic data from recently published controlled studies in the treatment of HAE attacks suggests that efficacy of C1INH therapy is optimal when C1INH activity levels are restored to the normal range.
Allergy 09/2011; 67(1):123-30. · 6.27 Impact Factor
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M Maurer,
M Bader,
M Bas,
F Bossi, M Cicardi,
M Cugno,
P Howarth,
A Kaplan,
G Kojda,
F Leeb-Lundberg,
J Lötvall,
M Magerl
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ABSTRACT: Bradykinin has been implicated to contribute to allergic inflammation and the pathogenesis of allergic conditions. It binds to endothelial B(1) and B(2) receptors and exerts potent pharmacological and physiological effects, notably, decreased blood pressure, increased vascular permeability and the promotion of classical symptoms of inflammation such as vasodilation, hyperthermia, oedema and pain. Towards potential clinical benefit, bradykinin has also been shown to exert potent antithrombogenic, antiproliferative and antifibrogenic effects. The development of pharmacologically active substances, such as bradykinin receptor blockers, opens up new therapeutic options that require further research into bradykinin. This review presents current understanding surrounding the role of bradykinin in nonallergic angioedema and other conditions seen by allergists and emergency physicians, and its potential role as a therapeutic target.
Allergy 08/2011; 66(11):1397-406. · 6.27 Impact Factor
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ABSTRACT: Angioedema due to hereditary C1 inhibitor deficiency (HAE) is a highly disabling and potentially lethal disease with an estimated prevalence of 1:50,000 in the general population worldwide. Treatment of this condition by replacing the deficient protein started shortly after discovery of the underlying genetic defect. Along with other therapeutic approaches developed over the years, C1 inhibitor replacement therapy maintains a central role for the treatment of angioedema attacks in patients with HAE. Two plasma-derived C1 inhibitors and a recombinant form, produced in transgenic rabbits, have successfully completed controlled trials that reinforced the evidence of the safety and efficacy of this treatment.
Drugs of today (Barcelona, Spain: 1998) 11/2010; 46(11):867-74. · 1.28 Impact Factor
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ABSTRACT: Hereditary angioedema (HAE) due to the deficiency of C1 inhibitor (C1-INH) causes chronically recurrent cutaneous, abdominal and laryngeal angioedema that are disabling and potentially life-threatening.
We designed a prospective study to quantify the residual disease in patients with HAE treated according to the existing consensus documents.
Data were collected from diaries recording occurrence, duration, location and treatment of acute angioedema attacks. A total of 386 semesters properly completed were analyzed. Forty-seven of 103 patients were on prophylactic treatment, 41 with attenuated androgens and six with tranexamic acid. A total of 1532 angioedema attacks (one every 45.3 days) were registered.
Peripheral attacks were the most frequent (698), followed by abdominal (503) and combined locations (232), laryngeal edema was less common (99). Patients on prophylaxis with attenuated androgens had 7.7 attacks/year lasting 1.47 days, those on tranexamic acid had 8.1 attacks/year lasting 1.59 days, and those without prophylaxis had 8.9 attacks/year lasting 1.68. Plasma-derived C1-INH was used by 44 patients to treat a total of 376 acute attacks that resolved faster (1.1 day) than those not treated (1.85 day) or treated with tranexamic acid (1.79 day). No adverse events related to C1-INH infusion were reported.
Our data demonstrate that tranexamic acid is not effective in the treatment of acute attacks and indicate that under the current therapeutic approach, the HAE related disability is effectively but partially reduced. Incomplete success does not appear to depend on limited efficacy of the drugs but on their limited use that can be overcome by implementing specific treatment strategies.
Allergy 10/2010; 66(2):192-6. · 6.27 Impact Factor
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ABSTRACT: Acquired deficiency of C1 inhibitor (C1-INH) with angioedema symptoms (acquired angioedema, AAE) is characterized by local increase in vascular permeability (angioedema) of the skin and the gastrointestinal and oro-pharyngo-laryngeal mucosa. The mediator of symptoms is bradykinin, a potent vasoactive peptide, released from high molecular weight kininogen when it is cleaved by plasma kallikrein a serine protease controlled by C1-INH. Autoantibodies inactivating C1-INH are detected in the majority of patients and account for the deficiency. Irrespectively to the presence of anti-C1-INH autoantibodies lymphoproliferative diseases, ranging from benign monoclonal gammopathies to malignant lymphoma, are frequently associated with AAE. Demonstration that monoclonal components correspond to anti-C1-INH autoantibodies and correlation between course of lymphoma and course of AAE provide strong support to consider the two diseases expression of the same pathologic process.
Current Molecular Medicine 06/2010; 10(4):354-60. · 5.10 Impact Factor
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ABSTRACT: Cl-inhibitor (C1-INH) deficiency leads to recurrent attacks of mucocutaneous edema and may be inherited (hereditary angioedema [HAE]) or acquired (acquired angioedema [AAE]), which have the same clinical picture characterized by angioedema involving the skin, gastrointestinal tract, and larynx. Although cutaneous swelling is evident, abdominal angioedema is still a diagnostic challenge and attacks can mimic surgical emergencies. There is currently no laboratory marker for identifying angioedema attacks.
As coagulation and fibrinolysis are activated during angioedema attacks, we assessed if plasma measurements of prothrombin fragment F1 + 2 (marker of thrombin generation) and D-dimer (marker of fibrin degradation) can be useful for the diagnosis of angioedema because of C1-INH deficiency, especially in case of hidden locations as abdominal attacks. Methods: In addition to complement, we measured plasma levels of F1 + 2 and D-dimer in 28 patients with C1-INH deficiency during acute attacks and remission, 35 patients without C1-INH deficiency during abdominal colics, and 20 healthy subjects.
Plasma F1 + 2 levels were higher in patients with C1-INH deficiency during remission than in healthy controls (P = 0.001), and further increased during cutaneous and abdominal attacks (P = 0.0001); patients without C1-INH deficiency had normal F1 + 2 levels during abdominal colics. Plasma D-dimer levels were higher in patients with C1-INH deficiency during remission than in controls (P = 0.012) and increased during angioedema attacks, reaching higher levels than in patients without C1-INH deficiency during colics (P = 0.002).
During acute angioedema attacks, patients with C1-INH deficiency have high prothrombin fragment F1 + 2 and D-dimer levels, the measurement of which may have an important diagnostic value.
Allergy 01/2009; 64(2):254-7. · 6.27 Impact Factor
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High Blood Pressure & Cardiovascular Prevention 09/2007; 14(3):145.
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ABSTRACT: C1-inhibitor deficiency can be inherited or acquired; both conditions lead to recurrent angioedema that can be life threatening when the larynx is involved (hereditary angioedema, HAE; acquired angioedema, AAE). The genetic defect is due to the heterozygous deficiency of C1-Inh that is transmitted as an autosomal dominant trait. Mutations causing HAE have been found distributed over all exons and splice sites of C1-Inh structural gene: only a few of them have been found more than once. Depending on DNA defect, C1-Inh is not transcribed, or not translated or not secreted. Finally, in 15% of HAE patients, an antigenically normal, but non-functional C1-Inh is present in serum (HAE type II). C1-Inh deficiency can be acquired, due to an accelerated consumption. Such an accelerated consumption can depend on circulating autoantibodies that bind C1-Inh causing its inactivation and catabolism; or to associated diseases, usually lymphoproliferative diseases, that consume C1-Inh with different mechanisms. Effective therapies can prevent or revert angioedema symptoms in C1-Inh deficiency, the main problem of this condition remaining misdiagnosis. The common knowledge that angioedema is an allergic symptom frequently prevents a correct diagnostic approach: C1-Inh deficiency goes unrecognized and the disease can still be lethal. Correct prophylactic treatment is based on attenuated androgens in HAE and on antifibrinolytic agents in AAE. Life threatening laryngeal attacks and severe abdominal attacks are effectively reverted, in both conditions, with C1-Inh plasma concentrate. A special remark to this treatment should be made for autoantibody-mediated AAE where very high doses can be needed depending on the rate of C1-Inh consumption.
Molecular Immunology 09/2001; 38(2-3):161-73. · 2.90 Impact Factor
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ABSTRACT: The purpose of this study was to investigate the self-perceived dental care needs and dental experiences of patients with angioedema. At the 1998 annual meeting of the Voluntary Association for the Fight, Study and Treatment of Hereditary Angioedema ("Associazione volontaria per la lotta, lo studio e la terapia dell'angioedema ereditario"), a self-administered questionnaire was distributed to participants affected by hereditary or acquired angioedema. Fifty-seven persons completed the questionnaire (37 females, 20 males; mean age, 39 +/- 17 yrs; range, 5-76). The vast majority (91%) had the hereditary form of the disease. One-third of the respondents had some problems in obtaining oral treatment, with one person having been refused care. About half of the group had experienced an acute attack following dental treatment. Preventive measures needed improvement in about two-thirds of respondents. More than half (58%) of the group perceived a need for dental care. We conclude that persons with angioedema may experience difficulty in obtaining dental treatment, a common cause of acute attacks.
Special Care in Dentistry 02/2001; 21(1):27-31.
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ABSTRACT: Angioedema without urticaria is a clinical syndrome characterised by self-limiting local swellings involving the deeper cutaneous and mucosa tissue layers. Most occurrences of angioedema respond to treatment with a histamine H1 receptor blocker (antihistamine) because they are an allergic or parallergic reaction. A small number of cases do not respond to antihistamine treatment. Such cases tend to occur in patients with deficiency or dysfunction of the inhibitor of the first component of the complement (C1-INH), but more rarely can occur in patients with other conditions and as an adverse drug reaction. Angioedema is well documented in patients taking ACE inhibitors. Considering that 35 to 40 million patients are treated worldwide with ACE inhibitors, this drug class could account for several hundred deaths per year from laryngeal oedema. ACE inhibitors certainly do not mediate angioedema through an allergic or idiosyncratic reaction. For this reason the relationship with this drug is often missed and consequently quite underestimated. Rare instances of angioedema have also been reported with angiotensin II receptor antagonists. This adverse effect seems to occur less frequently with angiotensin II receptor antagonists than with ACE inhibitors. However, we do not know whether this adverse effect has the same mechanism with the 2 classes of medications. Some cases of severe angioedema have been recently reported after treatment with fibrinolytic agents. Scattered reports suggest the possibility of angioedema associated with the use of estrogens, antihypertensive drugs other than ACE inhibitors, and psychotropic drugs. Angioedema can also occur with nonsteroidal anti-inflammatory drugs. Prevention of angioedema relies first on the patient history. Estrogen and ACE inhibitors should be avoided in a patient with congenital or acquired C1-INH deficiency. In the case of ACE inhibitors, the appearance of angioedema following long term treatment does not lessen the probability that such an agent could be the cause. The most important action to take in a patient with suspected drug-induced angioedema is to discontinue the pharmacological agent. Epinephrine (adrenaline), diphenydramine and intravenous methylprednisolone have been proposed for the medical management of airway obstruction, but so far no controlled studies have demonstrated their efficacy. If the acute airway obstruction leads to life-threatening respiratory compromise an emergency cricothyroidotomy must be performed.
Drug Safety 02/2001; 24(8):599-606. · 3.63 Impact Factor
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ABSTRACT: Cases of angioedema with no family history but with functionally low levels of C1 inhibitor and recurrent attacks are often observed. Clinical and biochemical data do not distinguish these cases from proven inherited forms of hereditary angioedema.
We sought to test the hypothesis of de novo mutations in patients affected by angioedema without a family history of the disease.
Among 137 independent kindreds followed for hereditary angioedema, 45 (32.8%) patients with early onset of the disease were registered as sporadic cases. Nineteen patients with unaffected parents were screened for point mutations and microdeletions-insertions by using fluorescence-assisted mismatch analysis. The biologic paternity of these patients was verified by determining their alleles at 4 microsatellite loci. Gross deletions were detected with Southern blot analysis.
C1 inhibitor plasma levels measured in both parents of 24 sporadic patients were normal in all but 3 patients. Among the 19 patients studied at the DNA level, 9 de novo single nucleotide substitutions and 6 de novo microdeletions were found. De novo exon deletions were detected in 3 additional patients with Southern blot analysis.
De novo C1inhibitor mutations and exon deletions account for at least 25% of all unrelated cases of angioedema. This finding has implications relevant to the genetic epidemiology and genetic counseling of this disease. The observation that 5 of the 9 de novo point mutations reproduce previously reported changes underlines the presence of multiple hot spots, two of which contain a CpG dinucleotide.
Journal of Allergy and Clinical Immunology 01/2001; 106(6):1147-54. · 11.00 Impact Factor
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Annals of internal medicine 12/2000; 133(10):837-8; author reply 839. · 16.73 Impact Factor
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Journal of Thoracic and Cardiovascular Surgery 10/2000; 120(3):609-10. · 3.41 Impact Factor
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ABSTRACT: To assess the prevalence and risk factors for cryoglobulinaemia associated with hepatitis C virus (HCV) infection, we studied 360 consecutive patients with chronic hepatitis C (191 men, median age 57 years; 86 [24%] with cirrhosis). One-hundred and sixty-eight (47%) had circulating cryoglobulins (mean levels 208 +/- 256 mg l-1), predominantly of type III (80%; and 20% type II). Cryoglobulins were more common in women than in men (56% vs 39%, P=0.001) and in patients with cirrhosis than in those with chronic hepatitis (57% vs 43%, P=0.024). Cryoglobulinaemic patients more frequently had high levels of serum immunoglobulin M (IgM) (57% vs 30%, P=0.001), immunoglobulin G (IgG) (84% vs 70%, P=0.002) and rheumatoid factor (45% vs 16%, P=0.001); low levels of serum C3 (15% vs 4%, P=0.001) and C4 (51% vs 26%, P=0.001); and low numbers of platelets (21% vs 12%, P=0.018), than patients without cryoglobulins. The presence of cryoglobulins was not correlated with hepatitis duration (cryopositives, 12 +/- 7 years; cryonegatives, 11 +/- 8 years) or HCV genotype (HCV 1b, 48% vs 53%; HCV 2a, 35% vs 29%, cryopositive vs cryonegative patients respectively). By multivariate analysis, female gender (odds ratio [OR] 1.675; confidence interval [CI] 1. 055-2.661), elevated serum IgM (OR 2.296; CI 1.438-3.665), IgG (OR 1. 952; CI 1.114-3.422), rheumatoid factor (OR 3.213; CI 1.889-5.465) and low C4 (OR 1.859; CI 1.138-3.038) could reliably predict the presence of cryoglobulins. When the pathogenic variables IgG, rheumatoid factor and C4 were excluded from analyses, only levels of serum cholinesterase activity < 4500 U independently predicted (OR 3. 663, CI 1.258-10.184) the presence of cryoglobulins. Fifty per cent of the patients with chronic hepatitis C circulated cryoglobulins, with preference for those with a greater impairment of liver function, as revealed by serum cholinesterase activity.
Journal of Viral Hepatitis 03/2000; 7(2):138-43. · 4.09 Impact Factor
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Journal of Allergy and Clinical Immunology 01/2000; 104(6):1321-2. · 11.00 Impact Factor
