C1 Inhibitor Replacement Research Articles

The utility of shared decision making in the management of hereditary angioedema.

Background: Hereditary angioedema (HAE) is a complex disorder with a wide array of treatment options. Shared decision-making (SDM) should be used to ensure that patients are choosing their best treatment option. The goal was to develop and psychometrically test a brief instrument for assessing the patient's perspective of the SDM process during his or her clinical encounters with an HAE specialist/allergist. Method: We hypothesized that SDM could be used effectively to help patients in their choice of therapy for HAE. Ten HAE treating physicians from the United States with a total of 50 patients with HAE used SDM to help patients choose the best prophylactic therapies (oral kallikrein inhibitor, androgens, subcutaneous C1 inhibitor replacement therapy, intravenous C1 inhibitor replacement therapy, monoclonal antibody kallikrein inhibitor) for their HAE and then completed surveys to analyze the effectiveness of the implementation of SDM as a quality indicator in health services assessment. Results: The congruence of answers between the physicians and the patients was then analyzed; 90% of the patient-physician pairs agreed that the advantages and disadvantages of the treatment options were precisely explained; 92% of the patient-physician pairs agreed that the physician helped them understand all the information and that the physician asked them which treatment option they preferred; 88% of the pairs agreed that the different treatment options were thoroughly weighed and 92% of the pairs felt that they selected a treatment option together. Conclusion: In summary, SDM is being implemented by treating physicians to determine the best management options for their patients with HAE.

A Review of Randomized Controlled Trials of Hereditary Angioedema Long-Term Prophylaxis with C1 Inhibitor Replacement Therapy: Alleviation of Disease Symptoms Is Achievable.

Through its fluctuating disease activity and unpredictable attacks, hereditary angioedema (HAE) imposes a substantial patient burden. To minimize HAE burden and improve quality of life, treatment should involve individualized management strategies that address on-demand therapy and short-term/long-term prophylaxis. Goals of long-term prophylaxis include reducing the number, severity, and burden of HAE attacks. The best characterized forms of HAE arise from deficiency or dysfunction of C1-inhibitor (C1-INH; types I/II), and C1-INH replacement therapy is a first-line intervention for on-demand (acute) treatment of HAE attacks, short-term prophylaxis before high-risk procedures, and long-term prophylaxis. Randomized, double-blind, placebo-controlled crossover trials have shown dose-dependent efficacy with plasma-derived C1-INH (pdC1-INH) 40-60 IU/kg subcutaneously, pdC1-INH 1000 U intravenously, and recombinant human C1-INH (rhC1-INH) 50 IU/kg (maximum 4200 IU) intravenously, all administered twice weekly, as long-term prophylaxis in patients with a history of 2 to ≥4 attacks/month. Overall, up to 83% (pdC1-INH 60 IU/kg) of patients experienced an HAE attack reduction threshold of ≥70%, and up to 58% (pdC1-INH 60 IU/kg) achieved an attack reduction threshold of ≥90%. Lower-dose intravenous pdC1-INH therapy (1000 U) was seemingly less effective, with 45% of 22 patients experiencing an HAE attack reduction threshold of ≥70%, and up to 23% achieving an attack reduction threshold of ≥90%. Higher-dose intravenous rhC1-INH 50 IU/kg (maximum, 4200 IU) twice weekly was of intermediate benefit. Despite a baseline mean attack frequency of 17.9 (during the 3 months prior to study treatment) and a mean attack frequency during a 4-week placebo period of 7.2, 52% of 23 patients experienced ≥70% reduction in attack frequency and 26% of 23 patients experienced ≥90% reduction in attack frequency. The increasing patient percentages treated with C1-INH replacement therapy as long-term prophylaxis meeting these high thresholds reinforces hopes and expectations that "attack freedom" is achievable, including for those with moderate or severe disease.

Hereditary angioedema is associated with an increased risk of venous thromboembolism

Hereditary angioedema is associated with an increased risk of venous thromboembolism

Prophylactic therapy with subcutaneous C1-inhibitor is associated with sustained symptom control in patients with hereditary angioedema.

Background: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is a rare genetic disorder characterized by disabling episodes of edema that commonly affect the skin as well as the gastrointestinal tract and upper airway. Prophylactic therapy can decrease the severity and number of attacks. Long-term symptom control and rescue medication use were evaluated in patients with HAE who received subcutaneous (SC) C1-INH enrolled in an open-label extension (OLE) of the phase III COMPACT (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy) trial, including a subgroup analysis of patients treated for ≥12 months. Methods: The OLE study evaluated patients ≥ 6 years old who had had four or more attacks over 2 consecutive months before enrollment. Patients naive for C1-INH (SC) and patients in the COMPACT rollover trial were included. The patients were randomized to receive C1-INH (SC) 40 or 60 IU/kg twice weekly for 52 weeks. U.S. patients were eligible to continue for up to 140 weeks. Results: A total of 63 patients were randomized to the U.S. Food and Drug Administration approved dose of 60 IU/kg; 24 subjects were treated for at least 12 months. For the 63 subjects, the median (range) attacks per month were 0.09 (0.0-4.0) and per year were 1.0 (0.0-48.0). Two-thirds of the patients used rescue medication fewer than once per year. For the 24 patients with ≥ 12 months of exposure, the median (range) attacks per month and per year were 0.017 (0.000-2.4) and 0.199 (0.000-28.94), respectively. Of these patients, 12 (50%) were attack free throughout the duration of the study, and 3 (12.5%) had fewer than one attack per year. Conclusion: Prophylaxis with C1-INH (SC) provided sustained reductions in attack frequency and decreased rescue medication use, with a substantial proportion of patients being attack free.

Recognition and Management of Hereditary Angioedema: Best Practices for Dermatologists.

ObjectiveThe goal of this article is to discuss the importance of differentiating hereditary angioedema (HAE) from other types of angioedema, describe advances in HAE management, especially long-term prophylaxis (LTP), and offer practical recommendations for dermatologists.CommentaryWhile HAE is rare, dermatologists are likely to encounter patients with this condition at some point over the course of their clinical practice due to the fact that HAE episodes typically involve subcutaneous swelling and sometimes erythema marginatum. HAE is characterized by recurrent episodes of painful and/or disabling bradykinin-mediated angioedema. Unfortunately, HAE is commonly mistaken for other conditions such as allergic and other mast cell-mediated angioedema, but has very different treatment requirements. Delayed diagnosis of HAE can result in years of avoidable debilitating symptoms, inappropriate treatment, potentially unnecessary invasive intervention, and reduced quality of life, and can be life threatening. Thus, timely identification of HAE is essential to ensure appropriate clinical management. Patients with HAE have either deficiency or dysfunction of the C1 inhibitor (C1INH) protein that inhibits proteases in the contact, complement, and fibrinolytic systems. Pathway-specific HAE treatments include C1INH replacement, kallikrein inhibitors, and bradykinin receptor antagonists. Treatment options for managing acute attacks include C1INH replacement (plasma-derived or recombinant formulations), icatibant (kallikrein inhibitor), and ecallantide (bradykinin B2 receptor antagonist). In the past 5 years, several new options for LTP have been approved, including a subcutaneous plasma-derived C1INH formulation and two kallikrein inhibitors (lanadelumab; berotralstat). Optimal management of HAE entails the creation of a comprehensive management plan that addresses both acute and long-term patient needs and includes input from an HAE expert and the patient/caregivers.

Letting the patients speak: an in-depth, qualitative research-based investigation of factors relevant to health-related quality of life in real-world patients with hereditary angioedema using subcutaneous C1 inhibitor replacement therapy

BackgroundWhile many studies of effective hereditary angioedema (HAE) therapy have demonstrated improved health-related quality of life (HRQoL) using validated instruments, specific reasons behind the improved scores have never been investigated using qualitative methods. A non-interventional, qualitative research study was designed to investigate the reasons for improvements in HRQoL while using effective prophylaxis, in this case subcutaneous C1INH (C1INH[SC]) replacement therapy.MethodsAdult patients with HAE-C1INH type 1 or 2 who had been using C1INH(SC) for ≥ 3 consecutive months were recruited through four HAE specialty practices in the US to participate in a 60-min phone interview performed by a trained qualitative research specialist (ICON plc) using a semi-structured interview guide with open-ended questions developed with the Angioedema Quality of Life (AE-QoL) items in mind. Interview transcripts were analyzed using thematic analysis methods to identify concepts (specific symptoms/impacts) and themes (higher-level categories grouping related concepts). A cross-mapping exercise was performed between interview-identified concepts and items included in the AE-QoL.ResultsFourteen patients were interviewed and included in the analysis (age range, 28–82 years [mean 47.5 years]; 64% female; 93% white). In 10 interviews, patients mentioned having no or nearly no HAE attacks, no longer feeling limited by HAE, less HAE-related anxiety/worry and depression, an improved ability to travel, fewer emergency room/hospital visits, and ease of administration of C1INH(SC), including not requiring assistance from others. Other commonly expressed concepts included: increased feelings of confidence, independence, optimism, and normalcy; less absence from work/school; better productivity; improved sleep and energy; healthier family relationships; and improved cognition. While all AE-QoL items emerged from patient interviews, a number of identified concepts were not addressed by the AE-QoL, including sensitivity to various potential attack-triggers (e.g., stress/anxiety, sports), attack frequency, not having to cancel social plans, improvements in ability to perform day-to-day tasks, and a lower burden from medical visits.ConclusionsFrom these interviews, a large number of common themes and concepts emerged: a greater sense of freedom and normalcy, increased productivity, and improved interpersonal relationships while using convenient and effective prophylaxis. These findings provide insights into real-world experiences and the many facets of HRQoL that are important to patients with HAE-C1INH.

Managing Chronic Urticaria and Recurrent Angioedema Differently with Advancing Age

Angioedema and urticaria affect people of all ages. Accurate diagnosis and optimum management is essential for healthy aging. Older people continue to experience mast cell-mediated urticaria and angioedema, with a higher prevalence of autoimmune and a lower prevalence of autoallergic disease. Bradykinin-mediated angioedemas are more common in the elderly because of their association with angiotensin-converting enzyme inhibitor (ACEI) treatment. Acquired C1-inhibitor deficiency, another bradykinin-mediated angioedema, occurs predominantly in older people, whereas hereditary angioedema due to C1-inhibitor deficiency continues to cause symptoms, even in old age. Drug-induced angioedemas disproportionately affect older people, the most frequent users of ACEIs, aspirin, and nonsteroidal anti-inflammatory drugs. Accurate diagnosis and targeted treatment prevent unnecessary morbidity and mortality. Second-generation antihistamines with omalizumab if required are effective and well tolerated in older people with mast cell-mediated urticaria. For bradykinin-mediated angioedemas, these drugs are ineffective. C1-inhibitor replacement or blockade of kallikrein or the bradykinin B2 receptor of the contact pathway is required to treat hereditary angioedema and may be considered in other bradykinin-mediated angioedemas, if supportive treatment is insufficient. For aspirin-related angioedema and urticaria, alternative medications or, exceptionally, desensitization may be required.

Long-term health-related quality of life in patients treated with subcutaneous C1-inhibitor replacement therapy for the prevention of hereditary angioedema attacks: findings from the COMPACT open-label extension study

BackgroundLong-term prophylaxis with subcutaneous C1-inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) in patients with hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE) was evaluated in an open-label extension follow-up study to the international, double-blind, placebo-controlled COMPACT study. The current analysis evaluated patient-reported health-related quality of life (HRQoL) data from 126 patients in the open-label extension study randomized to treatment with C1-INH(SC) 40 IU/kg (n = 63) or 60 IU/kg (n = 63) twice weekly for 52 weeks. HRQoL was evaluated at the beginning of the open-label study and at various time points using the European Quality of Life-5 Dimensions Questionnaire (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication. The disease-specific Angioedema Quality of Life Questionnaire (AE-QoL) and HAE quality of life questionnaire (HAE-QoL) instruments were administered in a subset of patients. Statistical significance was determined by change-from-baseline 95% confidence intervals (CIs) excluding zero. No adjustment for multiplicity was done.ResultsMean baseline EQ-5D scores (Health State Value, 0.90; Visual Analog Scale, 81.32) were slightly higher (better) than United States population norms (0.825, 80.0, respectively) and mean HADS anxiety (5.48) and depression (2.88) scores were within “normal” range (0–7). Yet, patients using C1-INH(SC) 60 IU/kg demonstrated significant improvement from baseline to end-of-study on the EQ-5D Health State Value (mean change [95% CI], 0.07 [0.01, 0.12] and Visual Analog Scale (7.45 [3.29, 11.62]). In the C1-INH(SC) 60 IU/kg group, there were significant improvements in the HADS anxiety scale (mean change [95% CI], − 1.23 [− 2.08, − 0.38]), HADS depression scale (− 0.95 [− 1.57, − 0.34]), and WPAI-assessed presenteeism (mean change [95% CI], − 23.33% [− 34.86, − 11.81]), work productivity loss (− 26.68% [− 39.92, − 13.44]), and activity impairment (− 16.14% [− 26.36, − 5.91]). Clinically important improvements were achieved in ≥ 25% of patients for all domains except WPAI-assessed absenteeism (which was very low at baseline). Mean AE-QoL total score by visit ranged from 13.39 to 17.89 (scale 0–100; lower scores = less impairment). Mean HAE-QoL global scores at each visit (115.7–122.3) were close to the maximum (best) possible score of 135.ConclusionsLong-term C1-INH(SC) replacement therapy in patients with C1-INH-HAE leads to significant and sustained improvements in multiple measures of HRQoL.Trial registration A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema, NCT02316353. Registered December 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02316353.

Advances in Hereditary Angioedema: The Prevention of Angioedema Attacks With Subcutaneous C1-Inhibitor Replacement Therapy.

Hereditary angioedema (HAE) is a debilitating condition caused by a functional C1-inhibitor (C1-INH) deficiency and characterized clinically by episodes of subcutaneous or submucosal swelling. C1-INH replacement is highly effective for preventing HAE attacks and can improve health-related quality of life. Once available only for intravenous use, C1-INH is now available as a subcutaneous formulation for self-administration, shown to provide sustained plasma levels of C1-INH and reducing the monthly median HAE attack rate by 95% versus placebo in the phase 3 COMPACT study. Subcutaneously administered C1-INH satisfies multiple unmet needs in the management of patients with HAE.

Manufacturing of plasma-derived C1-inhibitor concentrate for treatment of patients with hereditary angioedema.

Background: Replacement therapy with plasma-derived C1-inhibitor (C1-INH) has been used for decades to treat patients with hereditary angioedema (HAE) with C1-INH deficiency. Objective: This article reviewed the rationale for using C1-INH replacement therapy in patients with HAE and the process of manufacturing plasma-derived C1-INH. Methods: The manufacture of C1-INH is an involved and carefully monitored process that includes screening and selection of prospective donors, the collection of source plasma, and purification with dedicated pathogen reduction steps. Donor eligibility is determined by restrictive criteria established and monitored by regulatory agencies as well as voluntary standards implemented by plasma collection centers that exceed government regulations. Individual and pooled donations are tested for transfusion-transmissible infections, including hepatitis B virus, hepatitis C virus, human immunodeficiency virus, parvovirus B19, and hepatitis A virus, by using enzyme-linked immunosorbent assays or nucleic acid amplification technologies. Frozen plasma that is cleared for manufacturing undergoes controlled thawing and centrifugation, and the resulting supernatant (i.e., cryoprecipitate-depleted plasma) is used to manufacture several plasma-derived therapies, including C1-INH. In addition to chromatography steps, the manufacturing process consists of dedicated and effective pathogen reduction steps, including pasteurization, hydrophobic interaction chromatography or polyethylene glycol precipitation, and virus filtration. Manufacturers continuously monitor the safety profile of C1-INH products by robust pharmacovigilance processes that enable systematic collection and evaluation of all suspected adverse drug reaction reports as well as evaluation of safety information from all other sources. Results and Conclusion: These procedures used in donor screening, donation and manufacturing pool testing, manufacturing, and pharmacovigilance ensure that plasma-derived C1-INH products have the safety, quality, identity, potency, and purity that is necessary to provide the intended therapeutic effect.

C1 Inhibitor Activity and Angioedema Attacks in Patients with Hereditary Angioedema

Hereditary angioedema (HAE) is caused by deficiency or dysfunction in the C1 inhibitor (C1-INH) protein. C1-INH replacement therapy is used to treat patients with HAE to restore the missing or dysfunctional protein. Invitro studies showed that C1-INH inhibits prekallikrein activation and bradykinin formation in a dose-dependent manner when added to the plasma of patients with HAE. HAE is highly variable in clinical presentation, and early studies suggested that there was not a clear relationship between functional C1-INH levels and disease activity. Later, a threshold of approximately 40% functional C1-INH was identified, above which patients' risk of an attack was diminished. Long-term prophylaxis with plasma-derived C1-INH effectively reduces attack frequency and severity. Pharmacokinetic modeling shows that functional C1-INH levels are associated with the relative risk of having an attack. Subcutaneous administration of C1-INH results in consistently high levels of functional C1-INH activity, whereas intravenous administration results in periods of low trough functional C1-INH activity before the next scheduled dose, increasing the risk of an angioedema attack. These studies suggest that measurement of functional C1-INH activity may be useful as a biomarker of the risk of an attack in patients with HAE who are receiving long-term prophylaxis with plasma-derived C1-INH.

Hereditary angioedema C1-inhibitor replacement therapy and coexisting autoimmune disorders: findings from a claims database

Background: Autoimmune diseases are a leading cause of morbidity and mortality in the US (estimated prevalence: 4.5%) and often associated with dysregulation of the complement system (innate and adaptive immune response). The classic complement pathway is regulated by the C1-inhibitor (C1-INH), which binds to C1 to prevent its activation. Hereditary angioedema with C1-INH deficiency (C1-INH-HAE) may be linked to increased autoimmunity due to secondary deficiency of C1r, C1s, and other components. Aims: It was hypothesized that increased regulation of the complement system via C1-INH replacement therapy may reduce autoimmunity in patients with C1-INH-HAE. The coexisting autoimmune disease claims frequency was compared between C1-INH-HAE patients treated with plasma-derived (pd) C1-INH vs “other (non-C1-INH)” treatments. Methods: C1-INH-HAE patients were identified in the IMS Health PharMetrics Plus claims database between January 2012 and December 2015 by International Classification of Diseases 9/10 diagnosis code, and classified based on the use of pdC1-INH or “other (non-C1-INH)” treatments for HAE. Index date was the first claim for HAE treatment. For patients using pdC1-INH, the first fill was the index date, even if other HAE medications were used previously. Frequency of visit claims for autoimmune conditions was identified by diagnostic codes (primary or secondary). Mean visits per patient per year by treatment group, gender, and age (<50 vs ≥50 years) were summarized for autoimmune conditions. Results: Of 589 patients with HAE identified (69% female, 38% aged ≥50 years), 276 (729 patient-years) received pdC1-INH and 313 (860 patient-years) received “other (non-C1-INH)” treatments. In this cohort, 12.9% of patients had ≥1 visit associated with a coexisting autoimmune disorder – the most common were lupus, alopecia, rheumatoid arthritis, sicca (Sjogren) syndrome, and connective tissue disorders. The mean (95% CI) number of visits for autoimmune diagnoses per patient per year was numerically lower for patients treated with pdC1-INH compared to those receiving “other (non-C1-INH)” treatments (1.37 [0.56–2.19] vs 2.28 [0.83–3.73]). Conclusions: Based on these findings, it is concluded that treatment of C1-INH-HAE with pdC1-INH may have a positive impact on coexisting autoimmune conditions by normalizing complement. Further research is needed on this important issue. There may be implications for healthcare resource utilization among patients with HAE and coexisting autoimmune disorders.

Contradictory to its effects on thrombin, C1-inhibitor reduces plasmin generation in the presence of thrombomodulin.

C1-inhibitor (C1INH) was shown to enhance thrombin generation (TG) in the presence of thrombomodulin (TM) by reducing production of activated protein C. Because C1INH is known to inhibit fibrinolytic system proteases, the objective of this study was to evaluate the effect of moderate (3IU/ml) and high (16IU/ml) C1INH concentrations on TG and plasmin generation (PG) in the presence of TM. These concentrations were evaluated based on expected maximum plasma levels following C1INH replacement therapy and recently suggested supraphysiologic dosing. TG and PG were investigated in platelet poor plasmas obtained from 21 healthy donors. An assay designed to monitor the continuous generation of the 7-amino-4-methylcoumarin fluorescence from substrates specific to thrombin or plasmin was used to evaluate the impact of C1INH activity. To characterize the C1INH effects on TG and PG, the thrombin and plasmin concentration peaks and production rates were calculated. TM addition to donor plasma shifted the concentration dependence of C1INH on TG parameters from reduction to enhancement. Conversely, PG parameters were significantly reduced by 16IU/ml in both the presence and absence of TM. Moderate C1INH concentration (3IU/ml) reduced TG and PG in the absence of TM but did not significantly affect these parameters in the presence of TM. Finally, 3IU/ml of C1INH reduced PG more so than TG in the absence of TM. The presented results suggest a mechanism by which C1INH could potentiate thrombosis by inhibition of fibrinolysis.

Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks

For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with thevast majority of patients becoming free from debilitating disease symptoms.

Exploring the Quality of Life Benefits of Subcutaneous C1-Inhibitor (C1-INH) Replacement Therapy Using Qualitative Research Methods

Exploring the Quality of Life Benefits of Subcutaneous C1-Inhibitor (C1-INH) Replacement Therapy Using Qualitative Research Methods

Long-term Health-related Quality of Life in Patients Treated With Subcutaneous C1-Inhibitor Replacement Therapy for the Prevention of Hereditary Angioedema Attacks

Long-term Health-related Quality of Life in Patients Treated With Subcutaneous C1-Inhibitor Replacement Therapy for the Prevention of Hereditary Angioedema Attacks

SUBCUTANEOUS C1-INHIBITOR FOR LONG-TERM PROPHYLAXIS IN HEREDITARY ANGIOEDEMA WITH NORMAL C1 INHIBITOR

Introduction Hereditary angioedema (HAE) is a rare disorder characterized by episodes of swelling without urticaria. HAE presents with decreased C1 inhibitor (C1INH) antigen (type I) or function (type II), or with normal C1INH (HAE-nC1INH). Case Description A 25-year-old female presented with intermittent airway, abdominal and extremity angioedema without hives every 2-4 weeks for 3 years, often coinciding with ovulation or menstruation. She had up to 24 emergency room (ER) visits and 5 hospitalizations annually, historically requiring intubation, abdominal laparoscopy and appendectomy. Pathology revealed normal appendix. C4, ANA, tryptase, C1INH antigen level, C1INH function, C1q and Factor XII gene testing were normal. Angioedema was unresponsive to high-dose antihistamines, systemic corticosteroids, and omalizumab. She was diagnosed with suspected HAE-nC1INH. Progesterone contraceptives and fresh frozen plasma were ineffective. On-demand ecallantide or icatibant reduced episode duration but she continued with frequent symptoms. Prophylactic tranexamic acid and subsequently IV C1INH 1000 units every 3-4 days resulted in modest preventative effects but she had ER visits, hospitalizations and decreased quality of life due to angioedema. In September 2017, she transitioned to prophylactic subcutaneous C1INH replacement 60 IU/kg twice weekly and has since experienced only 3 ER visits with rapid recovery, no hospitalizations, international travel and permanent employment. Discussion Plasma-derived human C1-INH has been reported as a successful acute treatment in HAE-nC1INH. A lower threshold for contact system activation might explain the benefit of higher C1INH levels in some HAE-nC1INH patients. Our report demonstrates that SQ C1INH may be effective for long-term prophylaxis in a subset of HAE-nC1INH.

Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks: An Open-Label Extension Study of the COMPACT Trial

Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks: An Open-Label Extension Study of the COMPACT Trial

Hereditary angioedema: Clinical presentation and socioeconomic cost of 200 French patients

Treatment options of patients with hereditary angioedema (HAE) are large and are codified in recent guidelines.1 Use of health care system may be high. Two studies suggest that HAE may lead to substantial costs and burden, associated with attack severity.2,3 Lumry et al4 reported reasonably high health-related quality-of-life (HRQOL) scores for patients included in the Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor (C1-INH) Replacement Therapy trial.

Health-Related Quality of Life with Subcutaneous C1-Inhibitor for Prevention of Attacks of Hereditary Angioedema

Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) impairs health-related quality of life (HRQoL). The objective of this study was to assess HRQoL outcomes in patients self-administering subcutaneous C1-INH (C1-INH[SC]; HAEGARDA) for routine prevention of HAE attacks. Post hoc analysis of data from the placebo-controlled, crossover phase III COMPACT study (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy). Ninety patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH(SC) 40 or 60 IU/kg twice weekly for 16 weeks, preceded or followed by 16 weeks of twice weekly placebo injections. All HAE attacks were treated with open-label on-demand treatment as necessary. HRQoL assessments at week 14 (last visit) included the European Quality of Life-5 Dimensions Questionnaire (EQ-5D-3L), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication (TSQM). Compared with placebo (on-demand treatment alone), treatment with twice weekly C1-INH(SC) (both doses combined) was associated with better EQ-5D visual analog scale general health, less HADS anxiety, less WPAI presenteeism, work productivity loss, and activity impairment, and greater TSQM effectiveness and overall treatment satisfaction. More patients self-reported a "good/excellent" response during routine prevention with C1-INH(SC) compared with on-demand only (placebo prophylaxis) management. For each HRQoL measure, a greater proportion of patients had a clinically meaningful improvement during C1-INH(SC) treatment compared with placebo. In patients with frequent HAE attacks, a treatment strategy of routine prevention with self-administered twice weekly C1-INH(SC) had a greater impact on improving multiple HAE-related HRQoL impairments, most notably anxiety and work productivity, compared with on-demand treatment alone (placebo prophylaxis).