Medical Literature - 2018

Jung JW, Suh DI, Park HJ, Kim S, Kwon HS, Yang MS, Park CS, Kim JH, Kim SH, Lee YW, Hur GY, Ye YM, Kwon YE, Park HK, Kim CW, Koh YI, Park JW, Lee JM, Min KU, Wickner P, Kang HR 3/2018 International Archives of Allergy & Immunology

BACKGROUND: Hereditary angioedema (HAE) is a genetically heterogeneous autosomal dominant disorder characterized by recurrent episodes of nonpruritic, nonpitting edema increasing after puberty. It can be fatal due to laryngeal or gastrointestinal (GI) involvement with varied and changing frequency of mortality according to studies published from the Western countries. Epidemiological and clinical data of HAE in Asian countries are sparse. We sought to examine the clinical characteristics of HAE patients in Korea.

METHODS: Patients diagnosed with HAE at 15 tertiary hospitals across the country until 2016 were retrospectively reviewed.

RESULTS: A total of 65 patients diagnosed with HAE by 2016 were identified. The prevalence of HAE was estimated at 1.3/1,000,000 in Korea. Of the 65 patients, 21 (32.3%) were males. A total of 90.8% patients had type I HAE, while the remaining 9.2% patients had type II HAE. The first symptom developed after 20 years in 73.8% of patients, with a mean age 28.4 +/- 14.1 years. The age at diagnosis was 36.5 +/- 15.8 years, with a mean time delay of 7.8 +/- 10.5 years. While the face (82.3%) and extremities (upper 71.0%, lower 62.9%) were the most frequently involved, the GI tract was affected in 40.5% of Korean HAE patients. Prophylaxis was maintained in 62.5% of patients. There was no reported case of death from HAE so far.

CONCLUSIONS: The clinical manifestation and severity of HAE may vary according to ethnicity. HAE is more infrequent and GI involvement is less likely in Korea compared with Western countries. Copyright © 2018 S. Karger AG, Basel.

Available from: karger.com/Article/Abstract/488350

Banerji A, Riedl MA, Bernstein JA, Cicardi M, Longhurst HJ, Zuraw BL, Busse PJ, Anderson J, Magerl M, Martinez-Saguer I, Davis-Lorton M, Zanichelli A, Li HH, Craig T, Jacobs J, Johnston DT, Shapiro R, Yang WH, Lumry WR, Manning ME, Schwartz LB, Shennak M, Soteres D, Zaragoza-Urdaz RH, Gierer S, Smith AM, Tachdjian R, Wedner HJ, Hebert J, Rehman SM, Staubach P, Schranz J, Baptista J, Nothaft W, Maurer M, HELP Investigators 11/2018 JAMA

IMPORTANCE: Current treatments for long-term prophylaxis in hereditary angioedema have limitations.

OBJECTIVE: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks.

DESIGN, SETTING, AND PARTICIPANTS: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized.

INTERVENTIONS: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments.

MAIN OUTCOME AND MEASURES: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period.

RESULTS: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab).

CONCLUSIONS AND RELEVANCE: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy.

Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

Available from: jamanetwork.com/journals/jama/fullarticle/2716564

Belbezier A, Boccon-Gibod I, Thanh AD, Fain O, Bouillet L, for CREAK 10/2018 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

Available from: annallergy.org/article/S1081-1206(18)30521-0/fulltext

Baker JW, Bernstein JA, Harper JR, Relan A, Riedl MA. 9/2018 Allergy and Asthma Proceedings

BACKGROUND: Hereditary angioedema (HAE) may occur at or spread to multiple anatomic locations during an acute attack. Recombinant human C1 esterase inhibitor (rhC1-INH) is approved for treating acute HAE attacks.

OBJECTIVE: To examine the time to the beginning of symptom relief with rhC1-INH by attack location.

METHODS: Data for patients >=12 years of age with an acute HAE attack who received rhC1-INH 50 IU/kg or placebo were pooled from two double-blind clinical trials with open-label extensions. The time to the beginning of symptom relief was defined as the first time point that the visual analog scale severity score at an attack location decreased by >=20 mm versus baseline, with persistence. Data were reported as median time values (95% confidence interval [CI]).

RESULTS: For abdominal attacks, the median time to the beginning of symptom relief was 60.0 minutes (95% CI, 47.0-62.0 minutes; n = 194 attacks) with rhC1-INH versus 240.0 minutes (95% CI, 45.0-720.0 minutes; n = 15 attacks) with placebo. The median time to the beginning of symptom relief for peripheral attacks was 105.0 minutes (95% CI, 90.0-120.0 minutes; n = 169 attacks) with rhC1-INH versus 303.0 minutes (95% CI, 180.0-720.0 minutes; n = 17 attacks) with placebo. For oro-facial-pharyngeal-laryngeal attacks or urogenital attacks, the median time to the beginning of symptom relief with rhC1-INH was 64.5 minutes (95% CI, 60.0-120.0 minutes; n = 36 attacks) and 119.0 minutes (95% CI, 40.0-270.0 minutes; n = 13 attacks), respectively, versus 306.0 minutes (95% CI, 30.0-495.0 minutes; n = 6 attacks) and 320.0 minutes (n = 1 attack) with placebo.

CONCLUSION: In shortening the median time to the beginning of symptom relief of acute HAE attacks, rhC1-INH 50 IU/kg was efficacious, regardless of attack location.

Available from: ingentaconnect.com/content/ocean/aap/2018/00000039/00000005/art00006%3bjsessionid=52ip9ffuv2glg.x-ic-live-01#

van den Elzen M, Go MFCL, Knulst AC, Blankestijn MA, van Os-Medendorp H, Otten HG 6/2018 Clinical Reviews in Allergy & Immunology

Non-hereditary angioedema (AE) with normal C1 esterase inhibitor (C1INH) can be presumably bradykinin- or mast cell-mediated, or of unknown cause. In this systematic review, we searched PubMed, EMBASE, and Scopus to provide an overview of the efficacy of different treatment options for the abovementioned subtypes of refractory non-hereditary AE with or without wheals and with normal C1INH. After study selection and risk of bias assessment, 61 articles were included for data extraction and analysis. Therapies were described for angiotensin-converting enzyme inhibitor-induced AE (ACEi-AE), for idiopathic AE, and for AE with wheals. Described treatments consisted of ecallantide, icatibant, C1INH, fresh frozen plasma (FFP), tranexamic acid (TA), and omalizumab. Additionally, individual studies for anti-vitamin K, progestin, and methotrexate were found. Safety information was available in 26 articles. Most therapies were used off-label and in few patients. There is a need for additional studies with a high level of evidence. In conclusion, in acute attacks of ACEi-AE and idiopathic AE, treatment with icatibant, C1INH, TA, and FFP often leads to symptom relief within 2 h, with limited side effects. For prophylactic treatment of idiopathic AE and AE with wheals, omalizumab, TA, and C1INH were effective and safe in the majority of patients.

Available from: link.springer.com/article/10.1007%2Fs12016-016-8585-0

Aygoren-Pursun E, Magerl M, Maetzel A, Maurer M. 5/2018 Orphanet Journal of Rare Diseases

BACKGROUND: Bradykinin-mediated angioedema (Bk-AE) can be life-threatening and requires specific targeted therapies. Knowledge of its epidemiology may help optimize its management.

METHODS: We systematically searched the medical literature to identify abstracts of interest indexed between 1948 and March, 2016. We used published national survey data on the proportion of the population treated with angiotensin-converting enzyme inhibitors (ACEI) to derive estimates of the population prevalence of ACEI-AE in the USA, Germany and France. For hereditary angioedema (C1-INH-HAE) and C1-inhibitor related acquired angioedema (C1-INH-AAE), publications had to contain original epidemiologic data collection within a defined geographical area. Hereditary angioedema with normal C1-INH was not included in the analysis due to lack of clearly defined criteria.

RESULTS: We identified 4 relevant publications on the prevalence of ACEI-AE, 6 on the prevalence of C1-INH-HAE, and 1 on the prevalence of C1-INH-AAE. The 1st year cumulative incidence of ACEI-AE was estimated to vary between 0.12 (population-based analyses) and 0.30 (meta-analyses of clinical trials) per 100 patient-years. The population prevalence of ACEI-AE was modeled to vary between 7 and 26 in 100,000. The prevalence of C1-INH-HAE was estimated to vary between 1.1 and 1.6 per 100,000. The prevalence of C1-INH-AAE was estimated to be 0.15 per 100,000 in one epidemiological investigation of AAE in Denmark.

CONCLUSIONS: Epidemiological evidence on Bk-AE is limited to North America and Europe. ACEI-AE is more common than C1-INH-HAE (~ 10:1), which is more common than C1-INH-AAE (~ 10:1). More studies are needed to comprehensively assess the epidemiological burden of Bk-AE.

Available from: ncbi.nlm.nih.gov/pmc/articles/PMC5935942/?report=classic

Jose J, Lehman EB, Craig T 1/2018 Allergy and Asthma Proceedings

BACKGROUND: Ever-expanding armamentarium of treatments for hereditary angioedema (HAE) are associated with various adverse effects, issues with vascular access, or lack of self-administration.

OBJECTIVE: To understand patients’ impressions and confidence in their past and present treatments, and identifying adverse events while also directly asking patients to reveal their hope for the future of HAE management and treatments.

METHODS: After institutional review board approval, all subjects with laboratory-confirmed HAE were mailed a survey that they completed and returned to the researchers, and data were collected and entered into a secure online web application for surveys. Medication confidence data were summarized and expressed as means, medians, standard deviations, and quartiles by using a 5-point Likert scale. Analyses were performed by using statistical software.

RESULTS: Of 150 surveys, 38 (25.3%) were completed. Among 36 subjects, 27 (75.0%) were female subjects, and the mean age was 50.1 years. Cinryze and Berinert (both C1-esterase inhibitors) had the highest median scores (5.0) for patient confidence, followed by ecallantide (4.5), icatibant (4.0), and androgens (2.0). For Cinryze, 64.3% selected it as the most effective and 57.1% tolerated it best. For Berinert, 50% of the subjects found it to be most effective and 59.1% tolerated it best. Some subjects listed androgens as most effective (33.3%) or best tolerated (16.7%), and many reported that this class caused the most adverse effects (44.4%). Among those who answered, 50% preferred a noninvasive method of administration, such as oral (24%), subcutaneous (18%), or not intravenous (8%) routes.

CONCLUSION: Determining patient predilections and the reasoning behind them can be valuable for determining specific therapies to achieve each individual’s personal goals.

Available from: ingentaconnect.com/content/ocean/aap/2018/00000039/00000001/art00011

Blazina S, Debeljak M, Kosnik M, Simcic S, Stopinsek S, Markelj G, Toplak N, Kopac P, Zakotnik B, Pokorn M, Avcin T 3/2018 Frontiers in Immunology

BACKGROUND: Prevalence of complement deficiencies (CDs) is markedly higher in Slovenian primary immunodeficiency (PID) registry in comparison to other national and international PID registries.

OBJECTIVE: The purposes of our study were to confirm CD and define complete and partial CD in registered patients in Slovenia, to evaluate frequency of clinical manifestations, and to assess the risk for characteristic infections separately for subjects with complete and partial CD.

METHODS: CD was confirmed with genetic analyses in patients with C2 deficiency, C8 deficiency, and hereditary angioedema or with repeated functional complement studies and measurement of complement components in other CD. Results of genetic studies (homozygous subjects vs. heterozygous carriers) and complement functional studies were analyzed to define complete (complement below the level of heterozygous carriers) and partial CD (complement above the level of homozygous patients). Presence of characteristic infections was assessed separately for complete and partial CD.

RESULTS: Genetic analyses confirmed markedly higher prevalence of CD in Slovenian PID registry (26% of all PID) than in other national and international PID registries (0.5-6% of all PID). Complement functional studies and complement component concentrations reliably distinguished between homozygous and heterozygous CD carriers. Subjects with partial CD had higher risk for characteristic infections than previously reported.

CONCLUSION: Results of our study imply under-recognition of CD worldwide. Complement functional studies and complement component concentrations reliably predicted risk for characteristic infections in patients with complete or partial CD. Vaccination against encapsulated bacteria should be advocated also for subjects with partial CD and not limited to complete CD.

Available from: ncbi.nlm.nih.gov/pmc/articles/PMC5871747/

Anonymous. 2/2018 The Medical Letter on Drugs and Therapeutics

Available from: secure.medicalletter.org/article-share?a=1541d&p=tml&title=Haegarda%20-%20A%20Subcutaneous%20C1%20Esterase%20Inhibitor%20for%20Prevention%20of%20Hereditary%20Angioedema&cannotaccesstitle=1

Farkas H, Kohalmi KV 6/2018 Expert Review of Clinical Immunology

INTRODUCTION: Hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) is a rare disorder with life-threatening complications if untreated. It begins during childhood, and reduces the patient’s quality of life. Therefore, the availability of an easily administered agent to relieve unpredictable HAE episodes is indispensable for this age group. Areas covered: Randomized, double-blind, placebo-controlled, open-label extensions and prospective observational studies have proven the safety and efficacy of the subcutaneously administered bradykinin B2 receptor antagonist, icatibant, in the acute treatment of HAE episodes in adult C1-INH-HAE patients. Recently, a Phase 3, multicenter, open-label, non-randomized, single-arm study demonstrated the efficacy, safety, and tolerability of icatibant as an acute treatment for pediatric patients aged 2 years to less than 18 years. Expert commentary: The clinical study in pediatric patients showed that icatibant undergoes rapid absorption, reaches a therapeutic level, and promptly relieves the symptoms. It is well tolerated, and the subcutaneous preparation, presented in a pre-filled syringe, ensures ease of use. It can be administered anytime, anywhere, and instantly – even by the patients themselves, or – in the case of children and adolescents – by a caregiver. Icatibant may greatly contribute to the improvement of the quality of life of pediatric patients.

Available from: tandfonline.com/doi/abs/10.1080/1744666X.2018.1476851?journalCode=ierm20

Toubi E, Kivity S, Graif Y, Reshef A, Botha J, Andresen I 4/2018 The Israel Medical Association Journal: IMAJ

BACKGROUND: Management of patients with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is evolving worldwide. Evaluating the Israeli experience may provide valuable insights.

OBJECTIVES: To compare demographics and icatibant treatment patterns and outcomes in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey (IOS) in Israel with those in other countries.

METHODS: The IOS is an ongoing observational study that prospectively monitors real-world icatibant safety/tolerability and treatment outcomes.

RESULTS: By July 2016, 58 patients from Israel and 594 patients from other countries were enrolled. Median age at diagnosis (16.7 vs. 21.3 years, P = 0.036) and median delay between symptom onset and diagnosis (0.8 vs. 6.6 years, P = 0.025) were lower in Israel compared with other countries, respectively. Differences in attack severity were not significant (P = 0.156); however, during follow-up, Israeli patients were less likely to miss > 7 days of work/school due to C1-INH-HAE-related complications (P = 0.007). A trend was also shown in Israel for earlier time to treatment (median 0.5 vs. 1.3 hours, P = 0.076), attack duration was shorter (median 5.0 vs. 9.0 hours, P = 0.026), and patients more often self-administered icatibant (97.2% vs. 87.5%, P = 0.003), respectively. However, Israeli patients were less likely to treat attacks (P = 0.036). Whereas patients in Israel reported exclusive use of danazol for long-term prophylaxis, those in other countries used various agents, including C1-INH.

CONCLUSIONS: Recognition of C1-INH-HAE and timeliness of icatibant treatment appear more favorable, and attack duration shorter, in Israel compared with other countries.

Available from: ima.org.il/MedicineIMAJ/viewarticle.aspx?year=2018&month=04&page=227

Farkas H, Debreczeni ML, Kohalmi KV 1/2018 Expert opinion on investigational drugs

INTRODUCTION: Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is a rare bradykinin-mediated disease characterized by recurrent subcutaneous and/or submucosal angioedematous attacks (HAE attacks), which occur unpredictably. The recurrent HAE attacks do not respond to conventional treatments, and may evolve into a life-threatening condition; therefore, special therapy is required. Areas covered: The agents used so far for the acute management of HAE attacks act by blocking the release of bradykinin, or its binding to its receptor. By contrast, the investigational medicinal products under evaluation in Phase I and II clinical trials are targeted at the prevention of HAE attacks. Chemically, these new drugs are small synthetic molecules, oligonucleotides, or antibodies, which inhibit either kallikrein, or Factor XII. Expert opinion: The key considerations for the development of new medicinal products include more straightforward dosing, self-administration, longer duration of action, and keeping the patient attack-free. This review summarizes the status and the findings of the currently ongoing Phase I and Phase II clinical trials of C1-INH-HAE.

Available from: tandfonline.com/doi/abs/10.1080/13543784.2018.1415325?journalCode=ieid20

Johnson NM, Phillips MA 1/2018 Skin Therapy Letter

Hereditary angioedema is characterized by severe, episodic edema of the subcutaneous and mucosal tissue. The disease carries significant morbidity and mortality due to involvement of the gastrointestinal tract and upper airway. Recent advances in the treatment of hereditary angioedema include new techniques used to isolate and purify human-derived C1 inhibitor, the production of a recombinant form of C1 inhibitor, and the development of drugs that target the kallikrein-kinin pathway. This paper reviews the mechanisms, efficacy, and adverse reactions associated with these medications.

Available from: skintherapyletter.com/angioedema/new-treatments/

Aygoren-Pursun E, Bygum A, Grivcheva-Panovska V, Magerl M, Graff J, Steiner UC, Fain O, Huissoon A, Kinaciyan T, Farkas H, Lleonart R, Longhurst HJ, Rae W, Triggiani M, Aberer W, Cancian M, Zanichelli A, Smith WB, Baeza ML, Du-Thanh A, Gompels M, Gonzalez-Quevedo T, Greve J, Guilarte M, Katelaris C, Dobo S, Cornpropst M, Clemons D, Fang L, Collis P, Sheridan W, Maurer M, Cicardi M. 7/2018 New England Journal of Medicine

BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks.

METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life.

RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups.

CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).

Available from: nejm.org/doi/full/10.1056/NEJMoa1716995

Farkas H 4/2018 Paediatric drugs

Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is a form of bradykinin-mediated angioedema. It is a rare disorder with an onset during childhood in most instances. Therefore, familiarity with the options for the management of pediatric cases is indispensable. The recurrent angioedematous episodes do not respond to conventional treatments and may evolve into a life-threatening condition. In view of the recommendations adopted by international consensus in 2016, patient management and follow-up should be guided by an individualized strategy. During the last decade, various medicinal products with novel modes of action and different posology have been developed for the treatment of C1-INH-HAE. These drugs either inhibit the release of bradykinin (plasma-derived C1-inhibitors, recombinant C1-inhibitors, kallikrein inhibitors) or prevent the released bradykinin from binding to its receptor (bradykinin B₂ receptor antagonists). This review summarizes the properties of the medicinal products currently available for the treatment of C1-INH-HAE, the indications for their use in pediatric patients, and the findings of the clinical trials conducted in this patient population. It is concluded by a brief outline of future therapeutic options.

Available from: link.springer.com/article/10.1007%2Fs40272-017-0273-x

Fineman SM, Khan DA, Dinakar C, Lang DM, Tilles SA 7/2018 Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology

Available from: annallergy.org/article/S1081-1206(18)30374-0/fulltext

Lawlor CM, Ananth A, Barton BM, Flowers TC, McCoul ED 2/2018 Otolaryngology - Head & Neck Surgery

OBJECTIVE: Angioedema is a potentially life-threatening complication of angiotensin-converting enzyme inhibitor (ACEI) use, occurring in up to 0.5% of users. Although the pathophysiology of ACEI-induced angioedema is attributable to elevated serum bradykinin, standard management typically includes corticosteroids and antihistamines. We sought to summarize the evidence supporting pharmacotherapy for ACEI-induced angioedema.

DATA SOURCES: PubMed, MEDLINE, and Embase portals.

METHODS: A systematic literature review was conducted according to the PRISMA guidelines. Databases were queried by 3 independent reviewers for English-language studies published between 1980 and 2017. The initial search screened for all occurrences of “angioedema” and then was further refined to include studies of ACEI-related cases and exclude hereditary angioedema.

RESULTS: Five articles representing 218 cases were identified, including 3 randomized controlled trials and 2 prospective case series with historical controls. One of 2 studies of icatibant (bradykinin B2 receptor antagonist) found more rapid symptom improvement than that with a control group of corticosteroids and antihistamines. Two studies of ecallantide (plasma kallikrein inhibitor) and 1 study of C1 inhibitor replacement found no significant benefit over control. No studies were identified that compared the efficacy of corticosteroids with antihistamines, of one dose with another, of fresh frozen plasma, or of combination therapy.

CONCLUSION: The efficacy of treatment of ACEI-induced angioedema with bradykinin antagonists, kallikrein inhibitor, and C1 inhibitor warrants further study. Although consistent benefit of these medications has not been demonstrated, their use has not caused harm. One study examining off-label use of icatibant has demonstrated efficacy over control. In addition, further study is needed to establish the efficacy and mechanism of action of standard pharmacotherapy such as corticosteroids and antihistamines in treatment of this condition.

Available from: journals.sagepub.com/doi/abs/10.1177/0194599817737974

Zanichelli A, Azin GM, Cristina F, Vacchini R, Caballero T 4/2018 Orphanet Journal of Rare Diseases

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. Self-treatment is recommended, in order to reduce admissions to the Emergency Room and the time between the onset of the attack and the treatment, resulting in a better treatment outcome and an improved quality of life (QoL). The purpose of this study is to assess the safety, tolerability, and effect on QoL of self-administration of pnf C1-INH for IV use (Berinert®).

METHODS: An observational, monocenter, prospective study was designed. Patients referring to a center for angioedema that attended two sessions of self-infusion training course in the period March 2014-July 2015 were enrolled in the study. The primary endpoint was to monitor the safety and feasibility of pnf C1-INH self-infusion. The secondary endpoint was to evaluate the effect of self-infusion on the QoL, by means of the HAE-QoL questionnaire and the need for access to Emergency Room for infusion of Berinert®. Patients’ medical history data were collected upon the first visit and questionnaires were filled after each attack treated with Berinert® (diary and Treatment Satisfaction Questionnaire for Medication) and upon the first visit and the follow-ups (HAE-QoL).

RESULTS: Twenty patients were enrolled (median age = 42, IQR: 39-49; 60% females). Fifteen patients completed the study. A total of 189 attacks were recorded (annual median rate of 4 attacks/patient). Patients waited a median of 2 h (IQR: 1-4) before self-administration, and the resolution of the attack occurred after a median of 6 h (IQR: 4-11). Most attacks were abdominal (39%) and peripheral (22%). 92% of the attacks were treated through self-/caregiver-administration. In most attacks no side effects were reported. The number of attacks with side effects decreased over time, from 37% to 13%. Global satisfaction grew over time during the study period, reaching statistical significance over the first 6 months. The median total HAE-QoL score at baseline was 86 (IQR: 76-103) and improved in a non-significant manner throughout the study period. 8% of the attacks treated with Berinert® required ER admission/healthcare professional help in the study period, compared with 100% in the 3 years before enrollment (p < 0.0001).

CONCLUSIONS: Self-administration of pnf C1-INH is safe, and increases patients’ confidence in the treatment, showing also a trend towards an improvement in QoL. It reduces the need for ER admission/healthcare professionals help for the acute attacks, as well as the related costs.

Li HH, Mycroft S, Christiansen S, Wood DN, Feuersenger H, Pawaskar D, Jacobs I 9/2018 Allergy and Asthma Proceedings

BACKGROUND: The first subcutaneous (SC) C1-esterase inhibitor concentrate (C1-INH) was approved by the U.S. Food and Drug Administration in June 2017 as routine prophylaxis to prevent hereditary angioedema attacks in adolescents and adults at a dose of 60 IU/kg twice weekly based on the phase III Clinical Study for Optimal Management of Preventing Angioedema With Low-volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT) trial.

OBJECTIVE: This article aimed to evaluate the relationship of the C1-INH (SC) dose regimens tested in the COMPACT trial (40 IU/kg and 60 IU/kg twice weekly) and the occurrence of adverse events (AEs).

METHODS: Patients were instructed to record any AEs in their e-diary daily. Safety and tolerability were assessed based on reported AEs, including injection-site reactions (ISRs); unsolicited AEs (AEs other than ISRs); serious AEs; thrombotic, thromboembolic, anaphylactic, hypersensitivity, sepsis, and bacteremia events; inhibitory antibodies to C1-INH; and clinically significant abnormalities in laboratory assessments. Information on ISRs was specifically solicited.

RESULTS: No relationship between the dose of C1-INH (SC) and the incidence of ISRs or unsolicited AEs was observed. The proportion of injections followed by at least one ISR was 12% with C1-INH (SC) 40 IU/kg versus 5% with 60 IU/kg and 6% with placebo. No ISRs were serious or led to treatment discontinuation, and all resolved. There were no anaphylaxis, thromboembolic, sepsis, or bacteremia events reported during treatment with C1-INH (SC). All hypersensitivity AEs were nonserious, and the majority were assessed as being unrelated to treatment. No inhibitory antibodies to C1-INH were observed.

CONCLUSION: C1-INH (SC) is safe and well tolerated with no dose-dependent safety concerns, as demonstrated in the COMPACT trial.Clinical trial NCT01912456, clinicaltrials.gov.

Available from: ingentaconnect.com/content/ocean/aap/2018/00000039/00000005/art00007#

Loules G, Zamanakou M, Parsopoulou F, Vatsiou S, Psarros F, Csuka D, et al. 8/2018 Gene

SERPING1 genotyping of subjects suspicious for hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is important for clinical practice as well as for research reasons. Conventional approaches towards the detection of C1-INH-HAE-associated SERPING1 variants are cumbersome and time-demanding with many pitfalls. To take advantage of the benefits of next-generation sequencing (NGS) technology, we developed and validated a custom NGS platform that, by targeting the entire SERPING1 gene, facilitates genetic testing of C1-INH-HAE patients in clinical practice. In total, 135 different C1-INH-HAE-associated SERPING1 variants, out of the approximately 450 reported, along with 115 negative controls and 95 randomly selected DNA samples from affected family members of C1-INH-HAE index patients, were included in the forward and reverse validation processes of this platform. Our platform’s performance, i.e. analytical sensitivity of 98.96%, a false negative rate of 1.05%, analytical specificity 100%, a false positive rate equal to zero, accuracy of 99.35%, and repeatability of 100% recommends its implementation as a first line approach for the genetic testing of C1-INH-HAE patients or as a confirmatory method. A noteworthy advantage of our platform is the concomitant detection of single nucleotide variants and copy number variations throughout the whole length of the SERPING1 gene, moreover providing information about the size and the localization of the latter. During our study, 15 novel C1-INH-HAE-related SERPING1 variants were detected. Copyright © 2018 Elsevier B.V. All rights reserved.

Available from: sciencedirect.com/science/article/pii/S0378111918305122?via%3Dihub

Karadza-Lapic L, Pikivaca T, Pervan P, Jovic Zlatovic J, Delin S, Prkacin I 5/2018 Acta Medica Academica

OBJECTIVE: Angioedema (AE) is a potentially life-threatening event. We investigated the etiology of AE, with the emphasis on bradykinininduced angioedema treatment in emergency medicine.

METHODS: The retrospective study included 237 patients with AE, who were examined and treated in two hospitals (group A and B) in Croatia from 2009 to 2016. The location and duration of AE, data about chronic diseases and treatment, potential causative agents (food, drugs, insect bites and chemicals), physical examination data and the subsequent treatment were analyzed.

RESULTS: There was no statistical difference regarding age or comorbidities but there was a statistically significant difference in etiology between the groups (Chi-square, P=0.03). Renin-angiotensin-aldosterone system (RAAS) blocker induced AE was the main cause of emergency attendance in group A (37.5%) and among the leading causes in group B (18.8%). Bradykinin-induced AE (hereditary angioedema (HAE) and RAAS-AE) were the leading causes in a total of 75 (31.5%) patients. RAAS-AE was treated with glucocorticoids and antihistamines. HAE attacks in both groups (2/7 patients, 1.5/6%) were treated with specific therapy. Other causes of AE in groups A/B were insect bites (15/23 patients, 13.5/20%), use of antibiotics/analgetics (11/17 patients, 9/15%), gastroesophageal reflux disease (10/11 patients, 8/9%), neoplasms (5/6 patients, 4/5%) and idiopatic (32/31 patients, 26.5/26%). 21% of patients were hospitalized.

CONCLUSION: Bradykinin-mediated AE was the main cause of emergency attendance associated with AE. Advances in the treatment of HAE, with case reports of patients with RAAS-AE treated with C1 esterase inhibitor concentrate or bradykinin receptor antagonist, may prove to be a new, reliable and efficacious therapy option. Copyright © 2018 by Academy of Sciences and Arts of Bosnia and Herzegovina.

Available from: ama.ba/index.php/ama/article/view/325/pdf

Riedl MA, Banerji A, Manning ME, Burrell E, Joshi N, Patel D, Machnig T, Tai MH, Watson DJ 10/2018 Orphanet Journal of Rare Diseases

BACKGROUND: Real-world data on usage and associated outcomes with hereditary angioedema (HAE)-specific medications introduced to the United States (US) market since 2009 are very limited. The purpose of this retrospective study was to evaluate real-world treatment patterns of HAE-specific medications in the US and to assess their impact on healthcare resource utilization (HCRU). This analysis used IMS PharMetrics PlusTM database records (2006-2014) of patients with HAE, >=1 insurance claim for an HAE-specific medication, and continuous insurance enrollment for >=3 months following the first HAE prescription claim.

RESULTS: Of 631 total patients, 434 (68.8%) reported C1-INH(IV) use; 396 (62.8%) reported using ecallantide and/or icatibant. There were 306 episodes of prophylactic use of C1-INH(IV) (defined by continuous refills averaging >=1500 IU/week for >=13 weeks) in 155 patients; use of >=1 on-demand rescue medication was implicated during 53% (163/306) of those episodes. Sixty-eight (20.2%) of 336 C1-INH(IV) users eligible for the HCRU analysis were hospitalized at least once, and 191 (56.8%) visited the emergency department (ED). Eighteen patients (5.4%) had a central venous access device (CVAD); of these, 5 (27.7%) required hospitalization and 14 (77.7%) had an ED visit. The adjusted relative risk of hospitalization and/or ED visits for patients with a CVAD was 2.6 (95% CI: 0.17, 39.23) compared to C1-INH(IV) users without a CVAD.

CONCLUSIONS: Despite widespread availability of modern HAE medications in the US, we identified a subset of patients requiring long-term prophylaxis who continue to be burdened by frequent rescue medication usage and/or complications related to the use of CVADs for intravenous HAE medication.

Available from: ncbi.nlm.nih.gov/pmc/articles/PMC6186115/