Medical Literature - 2011

Chinen J, Shearer WT. 2/2011 Journal of Allergy and Clinical Immunology

Reports in basic and clinical immunology in 2010 reflected the use of state-of-the-art genetic and immunologic tools to characterize the pathogenesis of immunologic diseases and the development of novel therapies directed to these conditions. B-cell biology has been explained in greater detail, significantly with lessons from the genetic defects found in the humoral immunodeficiencies. Therapeutic mAbs are given for an increasing number of indications, such as anti-CD20 antibodies or rituximab, which was initially developed for non-Hodgkin lymphomas and is currently used in diverse autoimmune and inflammatory disorders. The report of an infant with severe combined immunodeficiency (SCID) in Massachusetts detected by means of newborn screening and successfully treated with hematopoietic stem cell transplantation validated recent efforts toward newborn screening for SCID. Improvement of survival outcomes for patients with primary immunodeficiencies treated with hematopoietic stem cell transplantation was demonstrated in a large European cohort, with significant appreciation of the type of donor graft, particularly the use of HLA-matched unrelated donors for patients with non-SCID. Progress in cellular mechanisms of drug hypersensitivity included the characterization of nitroso-modified drug metabolites as potent T-cell activators and the identification of the relocation of plasmacytoid dendritic cells from blood to skin as a potential risk factor for reactivation of viral disease.Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Available from: jacionline.org/article/S0091-6749%2810%2901864-6/fulltext

Csuka D, Kelemen Z, Czaller I, Molnar K, Fust G, Varga L, et al. 3/2011 European Journal of Gastroenterology and Hepatology

OBJECTIVE: Hereditary angioedema due to C1-inhibitor deficiency is a life-threatening condition, which manifests as edematous attacks involving subcutaneous tissues and/or the upper airway/gastrointestinal mucosa. Celiac disease is a gluten-sensitive small intestinal disorder that can lead to severe villous atrophy, malabsorption, and malignancy. Both hereditary angioedema and celiac disease may present with abdominal symptoms. Our aim was to study the occurrence of celiac disease in the hereditary angioedema population, as well as to analyze the clinical course of cases with both diseases.

METHODS: One hundred and twenty-eight patients with hereditary angioedema were screened for celiac disease, using serological methods [antiendomysial antibodies-immunoglobulin A (IgA), antiendomysial antibodies-IgG and tissue transglutaminase-IgA, tissue transglutaminase-IgG]. Clinical data of a child with hereditary angioedema and celiac disease diagnosed earlier were added to the dataset to be analyzed. Thus, the total number of patients was 129, comprising 107 adults and 22 pediatric patients. In patients with celiac disease, molecular genetics analysis (human leukocyte antigen-DQA1, human leukocyte antigen-DQB1) was carried out along with the introduction of a gluten-free diet and regular follow-up.

RESULTS: Four out of the 22 children were diagnosed with celiac disease in our hereditary angioedema population. The prevalence of celiac disease among our pediatric patients with hereditary angioedema (22 children) was higher than in the general population (18.1 vs. 1.2%). Switching from the wheat starch-containing tranexamic acid product to danazol and introducing a gluten-free diet mitigated abdominal symptoms of hereditary angioedema.

CONCLUSION: Similarities between the symptoms of hereditary angioedema and celiac disease may cause difficulties in differential diagnosis, as well as in choosing the appropriate therapy. In our opinion, screening hereditary angioedema patients for celiac disease is warranted if abdominal attacks or neurological symptoms persist despite adequate management. Complement testing is recommended whenever abdominal symptoms persist despite the histological and serological remission of gluten-sensitive enteropathy after the introduction of a gluten-free diet.

Available from: journals.lww.com/eurojgh/pages/articleviewer.aspx?year=2011&issue=03000&article=00007&type=abstract (small fee)

Blankart CR, Stargardt T, Schreyogg J. 1/2011 Pharmacoeconomics

BACKGROUND: Market authorization does not guarantee patient access to any given drug. This is particularly true for costly orphan drugs because access depends primarily on co-payments, reimbursement policies and prices. The objective of this article is to identify differences in the availability of orphan drugs and in patient access to them in 11 pharmaceutical markets: Australia, Canada, England, France, Germany, Hungary, the Netherlands, Poland, Slovakia, Switzerland and the US.

METHODS: Four rare diseases were selected for analysis: pulmonary arterial hypertension (PAH), Fabry disease (FD), hereditary angioedema (HAE) and chronic myeloid leukaemia (CML). Indicators for availability were defined as (i) the indications for which orphan drugs had been authorized in the treatment of these diseases; (ii) the application date; and (iii) the date upon which these drugs received market authorization in each country. Indicators of patient access were defined as (i) the outcomes of technology appraisals; (ii) the extent of coverage provided by healthcare payers; and (iii) the price of the drugs in each country. For PAH we analysed bosentan, iloprost, sildenafil, treprostinil (intravenous and inhaled) as well as sitaxentan and ambrisentan; for FD we analysed agalsidase alfa and agalsidase beta; for HAE we analysed icatibant, ecallantide and two complement C1s inhibitors; for CML we analysed imatinib, dasatinib and nilotinib.

RESULTS: Most drugs included in this study had received market authorization in all countries, but the range of indications for which they had been authorized differed by country. The broadest range of indications was found in Australia, and the largest variations in indications were found for PAH drugs. Authorization process speed (the time between application and market authorization) was fastest in the US, with an average of 362 days, followed by the EU (394 days). The highest prices for the included drugs were found in Germany and the US, and the lowest in Canada, Australia and England. Although the prices of all of the included drugs were high compared with those of most non-orphan drugs, most of the insurance plans in our country sample provided coverage for authorized drugs after a certain threshold.

CONCLUSIONS: Availability of and access to orphan drugs play a key role in determining whether patients will receive adequate and efficient treatment. Although the present study showed some variations between countries in selected indicators of availability and access to orphan drugs, virtually all of the drugs in question were available and accessible in our sample. However, substantial co-payments in the US and Canada represent important barriers to patient access, especially in the case of expensive treatments such as those analysed in this study. Market exclusivity is a strong instrument for fostering orphan drug development and drug availability. However, despite the positive effect of this instrument, the conditions under which market exclusivity is granted should be reconsidered in cases where the costs of developing an orphan drug have already been amortized through the use of the drug’s active ingredient for the treatment of a common indication.

Available from: link.springer.com/article/10.2165%2F11539190-000000000-00000

Craig TJ, Bewtra AK, Bahna SL, Hurewitz D, Schneider LC, Levy RJ, et al. 12/2011 Allergy

BACKGROUND: The placebo-controlled study International Multicentre Prospective Angioedema C1-INH Trial 1 (I.M.P.A.C.T.1) demonstrated that 20 U/kg C1 esterase inhibitor (C1-INH) concentrate (Berinert; CSL Behring, Marburg, Germany) is effective in treating acute abdominal and facial Hereditary Angioedema (HAE) attacks.

METHODS: I.M.P.A.C.T.2 was an open-label extension study of I.M.P.A.C.T.1 to evaluate the safety and efficacy of long-term treatment with 20 U/kg C1-INH for successive HAE attacks at any body location. Efficacy outcomes included patient-reported time to onset of symptom relief (primary) and time to complete resolution of all symptoms (secondary), analysed on a per-patient and per-attack basis. Safety assessments included adverse events, vital signs, viral safety and anti-C1-INH antibodies.

RESULTS: During a median study duration of 24 months, 1085 attacks were treated in 57 patients (10-53 years of age). In the per-patient analysis, the median time to onset of symptom relief was 0.46 h and was similar for all types of attacks (0.39-0.48 h); the median time to complete resolution of symptoms was 15.5 h (shortest for laryngeal attacks: 5.8 h; 12.8-26.6 h for abdominal, peripheral and facial attacks). Demographic factors, type of HAE, intensity of attacks, time to treatment, use of androgens and presence of anti-C1-INH antibodies had no clinically relevant effect on the efficacy outcomes. There were no treatment-related safety concerns. No inhibitory anti-C1-INH antibodies were detected in any patient.

CONCLUSIONS: A single dose of 20 U/kg C1-INH concentrate is safe and provides reliable efficacy in the long-term treatment of successive HAE attacks at any body location.Copyright © 2011 John Wiley & Sons A/S.

Available from: onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2011.02702.x/full

Gompels MM, Lock RJ. 9/2011 Expert Review of Clinical Immunology

Cinryze is a pasteurized, nanofiltered plasma derived concentrate of C1-inhibitor (pdC1-INH) licensed for the prophylactic treatment of hereditary angioedema. In a double-blind placebo-controlled crossover trial to evaluate Cinryze as prophylaxis, the frequency of attacks was halved (6.26 per 12 weeks on Cinryze versus 12.73 per 12 weeks on placebo). Furthermore, attacks were generally milder and of shorter duration. For treatment of acute attacks in patients receiving Cinryze, 1000 units, within 4 h of the start of an attack, the estimated time to the onset of unequivocal relief was reduced to 2 h, compared with more than 4 h in those treated with placebo. Cinryze and other similar products are going to change the future management of hereditary angioedema and have potential in other areas of medicine.

Available from: tandfonline.com/doi/full/10.1586/eci.11.50

Caballero T, Baeza ML, Cabanas R, Campos A, Cimbollek S, Gomez-Traseira C, et al. /2011 Journal of Investigational Allergology and Clinical Immunology

BACKGROUND: There are no Spanish guidelines or consensus statement on bradykinin-induced angioedema.

AIM: To review the pathophysiology, genetics, and clinical symptoms of the different types of bradykinin-induced angioedema and to draft a consensus statement in light of currently available scientific evidence and the experience of experts. This statement will serve as a guideline to health professionals.

METHODS: The consensus was led by the Spanish Study Group on Bradykinin-Induced Angioedema (SGBA), a working group of the Spanish Society of Allergology and Clinical Immunology. A review was conducted of scientific papers on different types of bradykinin-induced angioedema (hereditary and acquired angioedema due to C1 inhibitor deficiency, hereditary angioedema related to estrogens, angioedema induced by angiotensin-converting enzyme inhibitors). Several discussion meetings of the SGBA were held in Madrid to reach the consensus.

RESULTS: The pathophysiology, genetics, and clinical symptoms of the different types of angioedema are reviewed. Diagnostic approaches are discussed and the consensus reached is described.

CONCLUSIONS: A review of bradykinin-induced angioedema and a consensus on diagnosis are presented.

Available from: jiaci.org/issues/vol21issue5/vol21issue05-1.htm

Riedl M, Gower RG, Chrvala CA. 4/2011 Annals of Allergy, Asthma, and Immunology

BACKGROUND: Hereditary angioedema (HAE) is a potentially life-threatening condition that affects approximately 1 in 50,000 persons. There are no known surveys of US physicians’ knowledge and experience regarding the epidemiology, diagnosis, and management of HAE.

OBJECTIVE: This survey of physicians treating patients with HAE assessed physician characteristics, diagnostic and treatment practices, factors that influence physician and patient treatment choices, and physician awareness of new therapies.

METHODS: From October 2009 to February 2010, physicians (N = 172) voluntarily completed an online survey developed by physician-investigators. Data were analyzed with descriptive statistics.

RESULTS: Most physicians (73.8%) managed 5 patients or fewer in diverse practice settings. Laboratory testing was considered most important in establishing a diagnosis. Fresh frozen plasma and C1 esterase inhibitors were the most frequently administered treatments for acute events; nearly 50% of respondents prescribed C1 esterase inhibitor for acute attacks. More than 80% of respondents prescribed androgens for long-term prophylaxis. Approximately half of respondents were aware of, and likely to use, new therapies for HAE. Other than efficacy, adverse effects were the most important factor that influenced physicians’ treatment recommendations, whereas physicians perceived that patients were most influenced by adverse effects and cost.

CONCLUSIONS: Wide variability exists in the treatment of patients with HAE. Many patients experience acute attacks that require emergency care or hospitalization. Androgens and fresh frozen plasma are frequently used despite recent availability of effective condition-specific agents, and many physicians are only somewhat aware of medications newly approved by the US Food and Drug Administration. Because the survey was completed shortly after approval of additional HAE therapies by the US Food and Drug Administration, these data will be useful for tracking changes in HAE treatment over time. Copyright © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Available from: annallergy.org/article/S1081-1206%2810%2901215-9/abstract

Sheffer AL, Campion M, Levy RJ, Li HH, Horn PT, Pullman WE. 7/2011 Journal of Allergy and Clinical Immunology

BACKGROUND: Hereditary angioedema (HAE) is a rare disorder characterized by recurrent angioedema attacks. Ecallantide, a novel plasma kallikrein inhibitor, inhibits production of bradykinin, the key mediator of these angioedema attacks.

OBJECTIVE: We sought to further characterize the safety and efficacy of ecallantide for HAE attacks by performing an integrated analysis of pooled data from 2 phase 3 studies.

METHODS: An integrated analysis was conducted with data from 2 randomized, double-blind, placebo-controlled studies in which patients with HAE (age >10 years) received 30 mg of subcutaneous ecallantide or placebo within 8 hours of onset of a moderate-to-severe attack at any anatomic site. Efficacy was evaluated by using validated patient-reported outcome measures: the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS).

RESULTS: Compared with placebo, ecallantide resulted in significantly greater reduction in MSCS scores from baseline to 4 hours after dosing (ecallantide [mean +/- SD], -0.97 +/- 0.78; placebo, -0.47 +/- 0.71; P < .001) and a significantly greater increase in TOSs at 4 hours (ecallantide, 55.5 +/- 46.5; placebo, 20.0 +/- 58.9; P < .001). Significantly greater symptomatic improvement over placebo occurred through 24 hours after dosing (MSCS score, P = .028; TOS, P = .039). Ecallantide demonstrated efficacy at all attack sites. The incidence of treatment-emergent adverse events was similar between groups.

CONCLUSIONS: This integrated analysis supports and expands on the results of the phase 3 studies. Ecallantide appears to be effective and well tolerated for the treatment of HAE attacks. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Available from: jacionline.org/article/S0091-6749%2811%2900375-7/fulltext

Anon JB. 1/2011 Ear Nose and Throat Journal

Hereditary angioedema (HAE) is a relatively rare genetic disorder that is usually characterized by either low levels of C1 esterase inhibitor (C1-INH) or the presence of dysfunctional C1-INH. It can present with relatively mild and self-limiting symptoms, but it is also potentially fatal; the most common cause of death is asphyxiation secondary to edema of the upper airway. The diagnosis of HAE, especially in the emergency situation, is not straightforward. HAE must be distinguished from several other types of angioedema that require different management approaches. Management approaches include trigger avoidance and pharmacologic therapy; the latter has traditionally involved the administration of attenuated androgens and antifibrinolytics. Recently, a new class of agent-C1-INH-has been introduced in the United States. This article provides an update on the pathophysiology, clinical picture, diagnosis, prophylaxis, and acute treatment of HAE. We must keep HAE in mind as a possible diagnosis whenever we are faced with a case of unexplained angioedema if we are to take advantage of the effective and more specific therapies that are becoming available.

Parish LC. 10/2011 Journal of the American Academy of Dermatology

Hereditary angioedema (HAE) is a relatively rare, but potentially life-threatening genetic disorder characterized by marked, diffuse mucosal edema that, in extreme cases, can affect the airway leading to asphyxiation. The clinical picture is similar to that of other forms of angioedema; therefore, misdiagnosis or delayed diagnosis is common. HAE is caused by a deficiency in, or a dysfunction of, C1 esterase inhibitor, which has a wide variety of physiologic functions, of which regulation of the contact (kallikrein-kinin) system is most relevant to this condition. Effective management of HAE must consider routine/long-term prophylaxis, short-term prophylaxis (in advance of predicted trauma, eg, surgical or dental procedures), and treatment of acute attacks. Historically, treatment options have been limited to controlling symptoms, but progress in understanding the pathophysiology of HAE has facilitated development of treatments, such as C1 inhibitor therapy, or drugs targeted at the bradykinin pathway, which address the underlying pathologic process. Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Available from: jaad.org/article/S0190-9622%2810%2901801-3/abstract

Bork K, Hardt J. 12/2011 International Archives of Allergy and Immunology

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is characterized by recurrent edema attacks in various organs. The objective of the present study was to assess the efficacy and safety of weekly long-term replacement treatment with one or more injections of plasma-derived C1-INH concentrate per week (WLTC) in patients with HAE-C1-INH.

METHODS: Nineteen patients with HAE-C1-INH underwent WLTC for 9 years on average. The benefits and risks were determined based on regular recording by the patients of the severity and number of attacks at the beginning and the end of the study.

RESULTS: All patients reported that all or most of their attacks were much less severe: the percentage of severe attacks was 93.3% without and 3.8% with treatment. In 8 of the 14 patients undergoing WLTC, the monthly number of attacks was lower at the end of the study than before the study, higher in 5 patients, and unchanged in 1 patient. The mean number of attacks per week in 6 patients (1 patient initially received weekly on-demand treatment for 2 years and then shifted to WLTC) with weekly on-demand treatment was 4.3 (SD 1.9) at the beginning and 8.0 (SD 3.1) at the end of the study.

CONCLUSIONS: HAE-C1-INH can be significantly improved by one or more injections of C1-INH concentrate per week. However, patients have to accept a large number of intravenous injections and, in some cases, an increase in disease activity. Copyright © 2010 S. Karger AG, Basel.

Available from: karger.com/Article/Abstract/319213

Christiansen SC, Zuraw BL. 11/2011 American Journal of Rhinology and Allergy

BACKGROUND: Hereditary angioedema (HAE) patients suffering from laryngeal attacks in the United States faced severely limited treatment options until 2008. These potentially life-threatening episodes occur in over one-half of the patients affected by HAE during their lifetimes. Acute therapy had been relegated to supportive care, intubation, and consideration of fresh frozen plasma (FFP)–the latter with the potential for actually accelerating the speed and severity of the swelling.

METHODS: In this article we will review the recently approved and emerging HAE treatments that have evolved from the recognition that bradykinin generation is the fundamental abnormality leading to attacks of angioedema.

RESULTS: Acute therapy for laryngeal attacks will be discussed including purified plasma-derived C1 inhibitor (C1INH), recombinant C1INH, an inhibitor of plasma kallikrein (ecallantide), and a B2 receptor antagonist (icatibant). Prophylactic care has also been transformed from a reliance on attenuated androgens with their attendant side effects to C1INH replacement.

CONCLUSION: The arrival of these novel therapies promises to transform the future management of HAE.

Available from: ingentaconnect.com/content/ocean/ajra/2011/00000025/00000006/art00016

Bernstein JA, Ritchie B, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz DS, et al. 1/2011 Allergy and Asthma Proceedings

Time to onset of symptom relief in hereditary angioedema (HAE) is a common primary end point in clinical studies but it has never been validated by correlation with the course of HAE symptoms. This study was designed as a retrospective validation of the primary end point for a placebo-controlled phase II/III study in patients with HAE. Ninety-eight abdominal attacks were treated with 10 or 20 U/kg of a highly purified C1 esterase inhibitor (C1-INH) concentrate or placebo. The primary end point was the time to onset of symptom relief, as determined by the patients. Patients assessed the intensity of the symptoms of pain, nausea, vomiting, cramps, and diarrhea over time. By Spearman rank correlation, the primary end point was compared with the time to first reduction of (1) any symptom intensity, (2) the sum of symptom intensity scores, and (3) the intensity of the last symptom present at baseline. The C1-INH, 20 U/kg, and placebo groups were compared by one-sided two-sample Wilcoxon tests. The time to first reduction in intensity of the last symptom present at baseline had the highest correlation with the primary end point (r = 0.77). The time to onset of symptom relief and the time to the first reduction in intensity of the last symptom were significantly shorter for the C1-INH, 20 U/kg, group compared with placebo (p = 0.009 and p = 0.0036, respectively). The association with the intensity of single symptoms confirmed that the time to onset of symptom relief is an appropriate end point for assessing the efficacy of C1-INH therapy.

Available from: ingentaconnect.com/content/ocean/aap/2011/00000032/00000001/art00006

Bork K. 11/2011 Expert Review of Clinical Immunology

Hereditary angioedema is a relatively rare genetic disorder affecting between one in 10,000 and one in 50,000 individuals worldwide. The most common clinical symptoms observed are relapsing swelling of the skin and abdominal pain attacks. However, more serious and potentially fatal laryngeal attacks can also occur. Hereditary angioedema is most frequently caused by a deficiency of C1-inhibitor. Replacement therapy with Berinert, an intravenous pasteurized C1-inhibitor concentrate derived from human plasma, is a recommended treatment for rapid resolution of acute attacks of hereditary angioedema due to C1-inhibitor deficiency. Prophylactic therapy with C1-inhibitor is also available. Future advances may improve morbidity and mortality associated with hereditary angioedema.

Available from: tandfonline.com/doi/full/10.1586/eci.11.72

Bouillet L. 5/2011 Expert Review of Clinical Immunology

Hereditary angioedema (HAE) is a rare condition. Its prognosis depends on whether there is laryngeal involvement with a risk of asphyxia, which is present in 25% of such cases. Improved understanding of the pathophysiology of this disease has resulted in the development of targeted therapies including icatibant, which acts as an antagonist at bradykinin B2 receptors. This agent has been shown to be effective in the treatment of attacks of HAE in three Phase III randomized double-blind published studies. Efficacy data have been collected in all types of attack: cutaneous, abdominal and laryngeal. Safety data are also encouraging. Icatibant is administered subcutaneously, with the potential for patients to self-administer. In the future, this therapy may offer increased independence for HAE patients.

Available from: tandfonline.com/doi/full/10.1586/eci.11.16

11/2011 Medical Letter on Drugs and Therapeutics

Available from: secure.medicalletter.org/w1378d

Morrow T. 11/2011 Managed Care

Available from: managedcaremag.com/content/insurers-will-find-icatibant-lifesaving-expensive-treatment

Fitzharris P, Jordan A. /2011 BMJ

Available from: bmj.com/content/343/bmj.d6607

Fust G, Farkas H, Csuka D, Varga L, Bork K. 3/2011 European Journal of Clinical Investigation

BACKGROUND: No systematic study has been published yet on the long-term efficacy of attenuated androgens in hereditary angioedema (HAE). Our aim was to conduct a follow-up study in two (German and Hungarian) cohorts of HAE patients (45 and 39 patients, respectively) undergoing uninterrupted treatment for 6 years with similar (starting dose 128 +/- 78 mg per day and 136 +/- 70 mg per day, respectively) and constant doses of danazol.

DESIGN: The frequencies of subcutaneous, abdominal and laryngeal attacks were recorded each year.

RESULTS: The annual frequency of all the three types of attacks was significantly lower during the first year of danazol treatment, compared to the last year before baseline. During subsequent years in Hungarian patients, the frequency of both subcutaneous and abdominal attacks – but not that of laryngeal attacks – increased significantly. In the case of abdominal attacks, a significant increase in the attack frequency was observed only in female patients. In the German cohort, by contrast, no change in the frequency of either type of attack was found during the 6-year study period.

CONCLUSIONS: The differences observed between these cohorts cannot be related to drug dose, the age or gender distribution of subjects or the age at the onset of symptoms or the length of diagnostic delay in the patients. There were, however, marked differences in the baseline pattern of attacks: significantly – 3 times – more abdominal attacks were recorded in German patients. Further studies are necessary to clarify the mechanism of these findings. Copyright © 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.

Available from: onlinelibrary.wiley.com/doi/10.1111/j.1365-2362.2010.02402.x/full

Majluf-Cruz A, Nieto-Martinez S. 8/2011 International Immunopharmacology

Hereditary angioedema is caused by a C1-inhibitor deficiency. It is a life-threatening disease. Its management includes treating acute attacks, short-term prophylaxis, and long-term prophylaxis. We report our experience with nadroparin for the short-term prophylaxis and treatment of angioedema attacks. We indicated treatment with nadroparin 0.3-0.6 mL SC 20 min after the onset of prodromes, then every 8-12 h for 1 day; short-term prophylaxis with 0.3-0.6 mL 1 h before a triggering event and then every 12-24 h for 1 more day. For children, treatment included 0.3 mL SC 20 min after the onset of prodromes, then every 12-24 h for 1 day; short-term prophylaxis was 0.3 mL 1 h before a triggering event and 1 more dose after 24 h. For the treatment, a complete response was considered when nadroparin totally stopped an acute attack within 2 h after injection. Partial response was considered if after 2 h analgesics and/or other therapy were required. Failure was established if after 4 h no response was obtained and fresh frozen plasma and other in-patient measures were required. For short-term prophylaxis, only complete responses and failures were considered. We included 29 adults and 5 children. Functional C1-inhibitor and C4 levels rose after nadroparin. We recorded 256 treatments (89.8% complete responses, 8.2% partial responses, and 1.9% failures), and 102 short-term prophylactic regimens (90.2% complete responses, and 9.8% failures). We found 38 mild adverse events without severe hemorrhagic episodes. If our results are reproduced subsequently, nadroparin may be an alternative for the treatment and short-term prophylaxis of angioedema attacks. Copyright © 2011 Elsevier B.V. All rights reserved.

Available from: sciencedirect.com/science/article/pii/S1567576911000786 (small fee)

Maurer M, Magerl M. 2/2011 Journal der Deutschen Dermatologischen Gesellschaft

Androgen derivatives are regarded as standard in the long-term prophylaxis of swelling attacks in patients with hereditary angioedema (HAE). Because of their relatively slow onset of action, they are not suitable for acute therapy. Long-term prophylaxis with androgen derivatives must be regarded critically, especially on account of their androgenic and anabolic effects, some of which are severe. The risk of adverse events increases with the daily dose and the duration of treatment. Thus, treatment always calls for close monitoring of patients with regard to potential adverse events. In addition, androgens are subject to numerous contraindications and they show interactions with a large number of other drugs. Off-label use, doping issues, clarification of reimbursement and the need to import the androgen derivatives, which are no longer marketed in Germany, result in additional effort for the treating physician in terms of logistics and time involved. In symptomatic treatment of acute attacks the intravenous substitution of C1-INH and – since 2008 – subcutaneous administration of icatibant are available. The two substances are well tolerated and their effect occurs rapidly and, when the diagnosis has been confirmed, reliably. In the light of these two treatment options for controlling acute attacks, prophylactic treatment of HAE patients with androgen derivatives such as danazol should be reassessed. Patients might benefit from a dose reduction or the withdrawal of androgen prophylaxis and attacks can be controlled with demand-oriented acute treatment using C1-INH or icatibant. Copyright © The Authors * Journal compilation © Blackwell Verlag GmbH, Berlin.

Available from: onlinelibrary.wiley.com/doi/10.1111/j.1610-0387.2010.07546.x/full

Lyseng-Williamson KA. 10/2011 Biodrugs

Intravenous nanofiltered human C1 inhibitor (C1-INH NF) concentrate (Cinryze) is used as a direct replacement of deficient levels of plasma C1 inhibitor in patients with hereditary angioedema (HAE). In the EU, C1-INH NF concentrate 1000U is indicated in the treatment, pre-procedural prevention, and routine prevention of angioedema attacks in adults and adolescents with HAE. Intravenous C1-INH NF concentrate 1000U effectively relieved angioedema attacks in patients with HAE. In a randomized, double-blind trial in pediatric and adult patients, the median time to onset of unequivocal relief from an attack was significantly shorter with C1-INH NF concentrate than with placebo. In an open-label trial, both unequivocal relief and clinical relief were shown in the majority of attacks within 1 and 4 hours of infusion of C1-INH NF concentrate, regardless of the site (i.e. gastrointestinal, cutaneous, laryngeal, or genitourinary) of the defining symptom. When administered prior to a procedure, open-label intravenous C1-INH NF concentrate 1000U reduced the incidence of angioedema attacks during and after a variety of dental, surgical, or interventional diagnostic procedures in pediatric and adult patients with HAE. Routine preventative treatment with intravenous C1-INH NF concentrate 1000U every 3 or 4 days reduced the number of angioedema attacks. In a randomized, double-blind, crossover trial in pediatric and adult patients with HAE, the mean normalized number of attacks per 12-week period was significantly lower during routine prevention with C1-INH NF concentrate than with placebo. Routine prevention with C1-INH NF concentrate reduced the median monthly attack rate from baseline in an open-label trial. Intravenous C1-INH NF concentrate was well tolerated in clinical trials in patients with HAE. No cases of viral transmission were reported.

Available from: link.springer.com/article/10.2165%2F11208390-000000000-00000

Thomas MC, Shah S. 11/2011 American Journal of Health-System Pharmacy

PURPOSE: New treatment options for acute edema attacks caused by hereditary angioedema (HAE) are reviewed.

SUMMARY: HAE is characterized by mutations in the C1 inhibitor gene leading to either a reduced expression of C1 inhibitor in the plasma or expression of a functionally impaired C1 inhibitor. HAE is classified into two major types based on the cause of the C1 inhibitor deficiency. Type I HAE is defined by a reduced expression of C1 inhibitor in the plasma, whereas type II HAE is characterized by the expression of a dysfunctional C1 inhibitor protein. Clinical data were reviewed for C1 inhibitor, ecallantide, and icatibant in the treatment of acute edema attacks caused by HAE. C1 inhibitor leads to a faster onset of edema relief and is effective in decreasing the duration of edema. Dosing strategies include fixed dosing and weight-based dosing. Optimal dosing strategies have not been established, but fixed dosing (500-1000 units) or 20 units/kg has been effective in clinical trials and reports. No comparative trials suggest that one strategy is superior to another; however, the approved labeling for acute treatment is based on weight. Ecallantide is also efficacious for treating acute episodes; however, the available evidence is limited to a single published trial. Icatibant has shown variable effects in two trials with placebo and active controls.

CONCLUSION: In patients with HAE, most edema episodes only involve the skin and gastrointestinal tract, though airway obstruction caused by laryngeal angioedema is the most common cause of death. I.V. C1 inhibitor should be considered first-line treatment for acute edema attacks because of its fast onset of action and effectiveness, though it is not clear whether fixed or weight-based dosing is preferred. Ecallantide can be considered as a second-line treatment option.

Available from: ajhp.org/content/68/22/2129.long?hw-tma-check=true (small fee)

Zuraw BL, Christiansen SC. 11/2011 American Journal of Rhinology and Allergy

BACKGROUND: Laryngeal angioedema may be associated with significant morbidity and even mortality. Because of the potential severity of attacks, both allergists and otolaryngologists must be knowledgeable about the recognition and treatment of laryngeal angioedema. This study describes the clinical characteristics and pathophysiology of bradykinin-mediated angioedema.

METHODS: A literature review was conducted concerning the clinical characteristics and pathophysiology of types I and II hereditary angioedema (HAE), type III HAE, acquired C1 inhibitor (C1INH) deficiency, and angiotensin-converting enzyme (ACE) inhibitor-associated angioedema.

RESULTS: The diagnosis of type I/II HAE is relatively straightforward as long as the clinician maintains a high index of suspicion. Mutations in the SERPING1 gene result in decreased secretion of functional C1INH and episodic activation of plasma kallikrein and Hageman factor (FXII) of the plasma contact system with cleavage of high molecular weight kininogen and generation of bradykinin. In contrast, there are no unequivocal criteria for making a diagnosis of type III HAE, although a minority of these patients may have a mutation in the factor XII gene. Angioedema attacks and mediator of swelling in acquired C1INH deficiency are similar to those in type I or II HAE; however, it occurs on a sporadic basis because of excessive consumption of C1INH in patients who are middle aged or older. ACE inhibitor-associated angioedema should always be considered in any patient taking an ACE inhibitor who experiences angioedema. ACE is a kininase, which when inhibited is thought to result in increased bradykinin levels. Bradykinin acts on vascular endothelial cells to enhance vascular permeability.

CONCLUSION: Laryngeal swelling is not infrequently encountered in bradykinin-mediated angioedema. Novel therapies are becoming available that for the first time provide effective treatment for bradykinin-mediated angioedema. Because the characteristics and treatment of these angioedemas are quite distinct from each other and from histamine-mediated angioedema, it is crucial that the physician be able to recognize and distinguish these swelling disorders.

Available from: ingentaconnect.com/content/ocean/ajra/2011/00000025/00000006/art00015

Duvancic T, Lugovic-Mihic L, Brekalo A, Situm M, Sinkovic A. 12/2011 Acta Clinica Croatica

Angioedema indicates acute subcutaneous edema that characterizes improperly restricted cutaneous or mucous membrane swelling, which can occur only once or be relapsing. Edema usually occurs in the periorbital area, lips, tongue, extremities and intestinal wall. It has turned out that angioedema is usually caused by the use of angiotensin-converting enzyme inhibitors (ACE) or allergies to certain allergens (allergic or IgE-mediated angioedema), followed by C1 inhibitor deficiency (hereditary and acquired angioedema), or the cause is unknown (idiopathic angioedema). It has been shown that patients with angioedema often have urticaria, which is noted in approximately 50% of cases. Usually there is a type I allergic reaction to some food allergens or drugs or insect stings. The most common causes of allergic angioedema are bee and wasp stings, reactions to medications or injections for sensitivity testing, and certain foods (especially eggs, shellfish and nuts). In diagnostic terms, it is important to determine the potential allergen, which is commonly performed with cutaneous tests, such as prick test, etc. The main risk of angioedema is swelling of the tongue, larynx and trachea, which can lead to airway obstruction and death, therefore tracheotomy is indicated in such cases. The initial treatment of patients with most forms of angioedema included administration of antihistamines and glucocorticoids, while epinephrine is given if there is fear from laryngeal edema.

Available from: hrcak.srce.hr/index.php?show=clanak&id_clanak_jezik=125833 (small fee)

Wasserman RL, Levy RJ, Bewtra AK, Hurewitz D, Craig TJ, Kiessling PC, et al. 1/2011 Annals of Allergy, Asthma, and Immunology

BACKGROUND: hereditary angioedema (HAE) is a rare disorder characterized by a quantitative or functional deficiency of C1 esterase inhibitor (C1-INH), resulting in periodic attacks of acute edema at various body locations. The symptoms of these painful attacks can be treated effectively with C1-INH concentrate.

OBJECTIVE: to document the efficacy and safety of a weight-based dose of C1-INH concentrate in the treatment of successive HAE attacks at abdominal and facial locations.

METHODS: acute facial and abdominal attacks were each treated with C1-INH concentrate using a single intravenous dose of 20 U/kg body weight. Efficacy end points included patient-reported time to onset of symptom relief and time to complete resolution of all symptoms. Safety was assessed by monitoring adverse events and assaying for markers of viral infection.

RESULTS: we treated 663 abdominal attacks in 50 patients and 43 facial attacks in 16 patients (a total of 706 attacks in 53 patients). The median time to onset of relief for all attacks was 19.8 minutes, with a median time to complete resolution of 11.0 hours. The median time to onset of relief was 19.8 minutes for abdominal attacks and 28.2 minutes for facial attacks, indicating efficacy for both types of attack. No treatment-related serious adverse events occurred, and C1-INH concentrate was well tolerated. No human immunodeficiency virus, hepatitis virus, or parvovirus B19 infections arose during the study.

CONCLUSION: the C1-INH concentrate dose of 20 U/kg provides rapid, effective, and safe treatment for successive HAE attacks at abdominal and facial locations.

Available from: annallergy.org/article/S1081-1206%2810%2900956-7/abstract

Lumry WR, Li HH, Levy RJ, Potter PC, Farkas H, Moldovan D, et al. 12/2011 Annals of Allergy, Asthma, and Immunology

BACKGROUND: The For Angioedema Subcutaneous Treatment (FAST)-3 study was a phase III, randomized, double-blind, placebo-controlled study of icatibant (bradykinin B(2) receptor antagonist) in subjects with hereditary angioedema (HAE) resulting from C1-INH deficiency or dysfunction (type I/II).

OBJECTIVE: To investigate icatibant efficacy and safety in subjects with acute HAE attacks.

METHODS: Subjects with moderate to very severe cutaneous or abdominal symptoms received icatibant (n = 43) or placebo (n = 45). Five subjects with laryngeal (mild-to-moderate) first attacks received icatibant (n = 3) or placebo (n = 2), and 5 subjects with severe laryngeal first attacks received open-label icatibant.

RESULTS: Cutaneous or abdominal attacks: icatibant significantly reduced median times (vs placebo) to 50% or more reduction in symptom severity (2.0 vs 19.8 hours; P < .001, primary endpoint), onset of primary symptom relief (1.5 vs 18.5 hours; P < .001, key secondary endpoint), or almost complete symptom relief (8.0 vs 36.0 hours; P = .012) and provided a shorter time to initial symptom relief (0.8 vs 3.5 hours; P < .001). For laryngeal attacks, median time to 50% or more reduction in symptom severity was 2.5 hours (icatibant) and 3.2 hours (placebo). No icatibant-treated subject required rescue medication before symptom relief occurred. The incidence of adverse events (AEs) was similar in icatibant- and placebo-treated subjects (41% and 52%, respectively). All icatibant-treated subjects experienced injection site reactions, but none reported clinically relevant changes in safety parameters or serious AEs.

CONCLUSIONS: FAST-3 demonstrated that icatibant was effective and generally well tolerated in subjects with acute HAE attacks.

TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00912093. Copyright © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Available from: annallergy.org/article/S1081-1206%2811%2900658-2/fulltext

Sardana N, Craig TJ. 12/2011 Pediatrics

CONTEXT: Hereditary angioedema (HAE) is a rare autosomal-dominant disease characterized by recurrent self-limiting episodes of skin and mucosal edema. Morbidity and mortality are significant, and new and pending therapies are now available to reduce the risk associated with the disease.

OBJECTIVE: To update the reader on new advances in HAE to improve patient care.

METHODS: We performed a literature search of Ovid, PubMed, and Google to develop this review. Articles that are necessary for the understanding and use of the new therapeutic options for HAE were chosen, and studies of high quality were used to support the use of therapies, and in most cases, results from phase III studies were used.

RESULTS: Until recently, therapy for HAE attacks in the United States consisted of symptom relief with narcotics, hydration, and fresh-frozen plasma, which contains active C1 inhibitor. Therapy to prevent HAE attacks has been confined to androgens and, occasionally, antifibrinolytic agents; however, both drug groups have significant adverse effects. The approval of C1-inhibitor concentrate for prevention and acute therapy has improved efficacy and safety. Ecallantide has also been approved for therapy of attacks, and icatibant is expected to be approved in the next few months for attacks. Recombinant C1 inhibitor is presently in phase III studies and should be available for attacks in the near future.

CONCLUSION: In this article we review the changing therapeutic options available for patients in 2011 and beyond.

Available from: pediatrics.aappublications.org/content/128/6/1173

Banta E, Horn P, Craig TJ. 7/2011 Allergy and Asthma Proceedings

Hereditary Angioedema (HAE) is a rare, debilitating, genetic disorder characterized by acute attacks of edema without urticaria. Ecallantide, a direct plasma kallikrein inhibitor, is approved for treatment of acute HAE attacks. This article addresses the efficacy of ecallantide in the treatment of moderate-to-severe attacks of HAE based on time to treatment. A post hoc integrated analysis of the EDEMA4 and EDEMA3-DB clinical trials was performed based on the time to patient’s treatment, defined as the time from initial recognition of moderate-to-severe symptoms to dosing (cohort, 0-2, >2-4, >4-6, >6-8, and >8 hours). Mean symptom complex severity (MSCS) score and treatment outcome score (TOS) were analyzed. Complete or near-complete resolution of symptoms was assessed at 4 and 24 hours. In this analysis, 70 patients received 30 mg of subcutaneous (s.c.) ecallantide and 73 patients received placebo. Change from baseline in MSCS score and TOS at 4 hours revealed significantly better response to ecallantide versus placebo for patients treated >2-4 (n = 46; p = 0.002; p = 0.003) or >4-6 (n = 47; p = 0.044; p = 0.043) hours after symptom onset. Fewer patients were treated within 2 hours of symptom onset; for these patients (n = 10; p = 0.752; p = 0.422) treatment did not achieve statistical significance. For overall response, complete or near-complete resolution was greatest within the 0- to 2-hour cohort (71.4%). As with other therapies for HAE early ecallantide therapy is optimal. Treatment with ecallantide within 6 hours of symptom onset leads to more rapid and sustained improvement of symptoms.

Available from: ingentaconnect.com/content/ocean/aap/2011/00000032/00000004/art00009

Varga L, Farkas H. 3/2011 Expert Review of Clinical Immunology

Recombinant human C1 esterase inhibitor (rhC1INH) (Ruconest(), Pharming) is a new drug developed for the relief of symptoms occurring in patients with angioedema due to C1-inhibitor deficiency. Pertinent results have already been published elsewhere; this article summarizes the progress made since then. Similar to the purified C1-inhibitor derived from human plasma, the therapeutic efficacy of rhC1INH results from its ability to block the actions of enzymes belonging to the overactivated bradykinin-forming pathway, at multiple locations. During clinical trials into the management of acute edema, a total of 190 subjects received recombinant C1-inhibitor by intravenous infusion on 714 occasions altogether. Dose-ranging efficacy studies established 50 U/kg as the recommended dose, and demonstrated the effectiveness of this agent in all localizations of hereditary angioedema attacks. Studies into the safety of rhC1INH based on 300 administrations to healthy subjects or hereditary angioedema patients followed-up for 90 days have not detected the formation of autoantibodies against rhC1INH or IgE antibodies directed against rabbit proteins, even after repeated administration on multiple occasions. These findings met favorable appraisal by the EMA, which granted European marketing authorization for rhC1INH. Pharming is expected to file a biological licence with the US FDA by the end of 2010 to obtain marketing approval in the USA. The launch of rhC1INH onto the pharmaceutical market may represent an important progress in the management of hereditary angioedema patients.

Available from: tandfonline.com/doi/full/10.1586/eci.11.5

Bork K, Hardt J, Staubach-Renz P, Witzke G. 7/2011 Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology & Endodontology

OBJECTIVE: Tooth extractions may trigger clinical symptoms of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH). The aim of this study was to determine how many tooth extractions were followed by symptoms of HAE-C1-INH in patients with and without preoperative short-term prophylaxis with C1 inhibitor concentrate.

STUDY DESIGN: Tooth extractions and clinical symptoms of HAE-C1-INH were determined from clinical record files of 171 patients with HAE-C1-INH.

RESULTS: Facial swelling or potentially life-threatening laryngeal edema, or both, occurred in 124/577 tooth extractions (21.5%) without prophylaxis. Similar symptoms occurred in a fewer proportion of patients undergoing extractions (16/128; 12.5%) after short-term prophylaxis with C1 inhibitor concentrate. The graded dose-response relationship was significant at P < .05.

CONCLUSIONS: Short-term prophylaxis with C1 inhibitor concentrate significantly reduces the risk of HAE-C1-INH symptoms after tooth extraction. In some patients, however, facial swellings and laryngeal edema symptoms may occur despite prophylaxis.Copyright © 2011 Mosby, Inc. All rights reserved. : Short-term prophylaxis with C1 inhibitor concentrate significantly reduces the risk of HAE-C1-INH symptoms after tooth extraction. In some patients, however, facial swellings and laryngeal edema symptoms may occur despite prophylaxis. Copyright © 2011 Mosby, Inc. All rights reserved.

Available from: oooojournal.net/article/S1079-2104(11)00108-9/fulltext

Zanichelli A, Vacchini R, Badini M, Penna V, Cicardi M. 2/2011 Allergy

BACKGROUND: 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.

OBJECTIVE: We designed a prospective study to quantify the residual disease in patients with HAE treated according to the existing consensus documents.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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. Copyright © 2010 John Wiley & Sons A/S.

Available from: onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2010.02433.x/full

Kesim B, Uyguner ZO, Gelincik A, Mete Gokmen N, Sin AZ, Karakaya G, et al. 11/2011 International Archives of Allergy and Immunology

BACKGROUND: No published data presently exist concerning hereditary angioedema (HAE) in Turkey. The aim of the study was to initiate a preliminary multicentric evaluation about HAE and to determine the genetic properties of Turkish patients.

METHODS: Based on records drawn from four medical centers we identified a total of 70 subjects, belonging to 60 unrelated families, fulfilling clinical and laboratory criteria for diagnosis of HAE with C1 inhibitor deficiency. Ten type I patients, and their first-degree relatives, underwent genetic analysis for HAE.

RESULTS: The majority of patients were female (60%), the mean age was 37.7 +/- 14.1 years. The mean age at the time of first angioedema symptom was 12.5 +/- 9.2 years. Mean time lag between first symptom and diagnosis was 26 +/- 14.4 years. All but 3 subjects had HAE type I. Family history of angioedema was present in 75.7% of the cases. Cutaneous swelling was reported by 87.1% of the patients, facial edema by 65%, abdominal symptoms by 74.3% and approximately one half (55.7%) had experienced one or more laryngeal attack. Genetic analysis of 10 families demonstrated that 5 carried a mutation that had never been previously described.

CONCLUSION: We found that the clinical features of Turkish HAE patients were consistent with previously described patterns of this rare disease. The most noteworthy feature identified in the study was a significantly long duration between the first symptom appearance and final diagnosis. Our detection of different mutations in 10 patients confirms the allelic heterogeneity of the disease. Copyright © 2011 S. Karger AG, Basel.

Available from: karger.com/Article/Abstract/323915

Antoniu SA. 8/2011 Clinical Reviews in Allergy and Immunology

Hereditary angioedema (HAE) is characterized by acute attacks of edema with multiple localizations, the laryngeal angioedema being the most potentially lethal. In HAE, C1-INH impairments cause episodic increase in kallikrein activity leading to attacks of angioedema. Several therapies have recently become available to treat or to prevent HAE attacks, and others are under evaluation for this indication. Plasma-derived C1-INH, bradykinin receptor antagonists (icatibant), kallikrein inhibitors (ecallantide), or recombinant C1-INH is authorized on the market for HAE attack therapy or prophylaxis. Some of these compounds can be used exclusively to treat HAE attacks, whereas others can also be used as prophylactic therapies. Such therapies, although not available worldwide, can improve disease outcome due to their different mechanisms of action.

Available from: scholar.google.ca/scholar?q=Therapeutic+approaches+in+hereditary+angioedema&hl=en&as_sdt=0&as_vis=1&oi=scholart&sa=X&ved=0ahUKEwi6y4O4x_nQAhVB1mMKHa71BQ0QgQMIGjAA

Drake D. 8/2011 Emergency Medicine Journal

A short-cut review was carried out to establish whether icatibant is effective in the treatment of hereditary angioedema. A total of 168 papers were found using the reported search, of which one represented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of this best paper are tabulated. The clinical bottom line is there is promising evidence for the use of the bradykinin receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema.

Available from: emj.bmj.com/content/28/8/720.full (small fee)

Varga L, Fust G, Csuka D, Farkas H. 1/2011 Molecular Immunology

BACKGROUND: Earlier, we found a higher frequency of IgM type C1-inhibitor autoantibodies (C1INH-Abs) in hereditary angioedema (HAE) patients, regardless of previous treatment with C1INH concentrate. The presence of C1INH-Abs correlated with disease severity in patients who have never been treated with C1INH concentrate. We revisited these topics by analyzing a larger patient population with a longer follow-up.

METHODS: We tested IgM type C1INH-Abs (defined as 2 SD higher, than the mean of control, >5.1 AU/ml) in 1127 sera from 130 HAE patients followed up for 8.67 +/- 3.18 years. Most analysis was done in a subset of 75 patients, with a follow-up of 9-11 years.

RESULTS: IgM C1INH-Abs were found in 178 sera from 69/130 patients and in 51/75 patients followed up on the long term. Twenty-three/75 (31%) patients had IgM type antibodies in more than 3 serum samples. Temporal changes in the titers of IgM type C1INH Abs followed different patterns. The occurrence of IgM type Abs clustered in some families; there was a highly significant (p = 0.0084) heterogeneity in the levels of IgM C1-INH Abs among the 10 families with at least 3 members. We did not find any significant difference between the frequency of IgM type anti-C1INH antibodies in patients who have never received (n = 15) and in those ever treated (n = 60) with C1INH concentrate. Similarly, no significant correlation was found between the mean dose (number of ampoules) of C1INH concentrate and the frequencies of the levels of IgM type C1INH-Abs. At variance with previous data, the frequency of C1INH-Abs did not correlate either with annual attack rate or with other indicators of the severe course of the disease. CONCLUSIONS: This study confirmed that the occurrence of IgM type C1INH-Abs in HAE is not related to previous treatment of attacks with C1-inhibitor concentrate. Familial clustering suggests underlying genetic factors presumably unrelated to HAE. Copyright © 2010 Elsevier Ltd. All rights reserved.

Available from: sciencedirect.com/science/article/pii/S0161589010005924 (small fee)

Bernstein JA. 11/2011 Allergy and Asthma Proceedings

Hereditary Angioedema (HAE) is a multisystem, autosomal dominant disease that affects ~1:10,000 to 1:50,000 individuals in the United States. The disease has several clinical characteristics that distinguish it from other forms of angioedema. Recurrent swelling attacks involve the abdomen, face, extremities, genitalia, oropharynx, or larynx without urticaria. The swelling attacks are typically unilateral, nonpitting, nonpruritic, and, although uncomfortable, are often painless. Other forms of isolated angioedema such as acquired angioedema and angiotensin-converting enzyme-induced angioedema have similar characteristics of HAE. Therefore, evaluation of patients with recurrent angioedema should be directed at excluding these different forms of angioedema before a diagnosis of idiopathic angioedema is made. The objective of this article is to provide an overview of the differential diagnosis of angioedema that reflects the angioedema guidelines that are currently in development.

Available from: ingentaconnect.com/content/ocean/aap/2011/00000032/00000006/art00007

Frank MM. 1/2011 Allergy and Asthma Proceedings

The prophylaxis of patients with hereditary angioedema to prevent attacks has gone through major revision as new agents for prophylaxis have come on the market. Earlier treatments, developed empirically, included the fibinolysis inhibitors epsilon aminocaproic acid and tranexamic acid and attenuated androgens such as danazol. With the development of these agents, many patients had relief of severe symptoms, and drugs in these classes have been the only treatments available in America. Their major disadvantage has been their side effects, which range from minor to severe. In Europe various products containing C1 inhibitor, the serum protein deficient in this disease, were prepared from pooled donor plasma. They were reported to be effective in ending attacks and in prophylaxis, but these products in general were not used in prophylaxis, in part because of the short half life of the plasma protein. One such product, C1 esterase inhibitor, has now been shown in a rigorous double-blind study to be effective in prevention of hereditary angioedema attacks and has been approved by the US Federal Drug Administration for prophylaxis of the disease. Its use has been attended by few side-effects, reflecting the fact that it is the purified naturally circulating product.

Available from: ingentaconnect.com/content/ocean/aap/2011/00000032/00000001/art00004