A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality-of-life (ISIS721744-CS2, NCT04030598). We report the 2-year interim analysis of the phase 2 open-label extension (OLE) study (ISIS 721744-CS3, NCT04307381). METHODS: In the OLE, the on-treatment study period consisted of fixed (weeks 1-13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17-105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments. RESULTS: Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02-0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94-3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0-1.7; 95% CI, -0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen. CONCLUSION: The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.

Development and validation of a US quality of life instrument for hereditary angioedema due to C1 inhibitor deficiency.

BACKGROUND: Hereditary angioedema (HAE) attacks are unpredictable, cause a substantial and enduring burden of illness, and are potentially fatal. Because of issues unique to the US health care system, there is a need for a US-validated, HAE-specific quality of life (QoL) instrument. OBJECTIVE: To develop and validate a US HAE-specific QoL instrument according to US Food and Drug Administration guidelines and established methodologies. METHODS: We generated 41 QoL-related items likely relevant to US patients with HAE due to C1 inhibitor (C1INH) deficiency (HAE-C1INH) and performed a 10-patient pilot study to refine the question wording. A total of 415 US patients with HAE-C1INH completed the initial 41-item instrument online, thereby providing data for item reduction, factor analysis, and the assessment of validity and reliability. We used a multiple linear regression to identify the drivers of the total and domain scores. Convergent validity analysis was used to assess the extent to which the HAE-C1INH QoL instrument (HAE-C1INH-QoL) is theoretically related to the angioedema-QoL instrument (AE-QoL). RESULTS: Item reduction and factor analysis yielded a final instrument of 31 items across 5 domains, and the assessment analysis showed that the HAE-C1INH-QoL is valid and reliable. Attack frequency and severity were statistically significant factors that influenced the total and domain scores. Correlation analysis of the 2 instruments indicated that 8 items of the HAE-C1INH-QoL were not included or well-described in the AE-QoL. CONCLUSION: The HAE-C1INH-QoL is the first HAE-specific QoL tool validated in the United States. When compared with the AE-QoL, the items in our instrument are more relevant to US patients with HAE.

Lower serum 15-HETE level predicts nasal ILC2 accumulation during COX-1 inhibition in AERD.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D2, and low levels of prostaglandin E2. Further, 15-hydroxyeicosatetraenoic acid (15-HETE) levels may have predictive value in therapeutic outcomes of aspirin desensitization. Accumulation of nasal group 2 innate lymphoid cells (ILC2s) has been demonstrated during COX-1 inhibition in AERD, although the relationships between tissue ILC2 accumulation, reaction symptom severity, and novel lipid biomarkers are unknown. OBJECTIVE: We sought to determine whether novel lipid mediators are predictive of nasal ILC2 accumulation and symptom scores during COX-1 inhibitor challenge in patients with AERD. METHODS: Blood and nasal scraping samples from patients with AERD were collected at baseline and COX-1 inhibitor reaction and then processed for flow cytometry for nasal ILC2s and serum for lipidomic analysis. RESULTS: Eight patients with AERD who were undergoing aspirin desensitization were recruited. Of the 161 eicosanoids tested, 42 serum mediators were detected. Baseline levels of 15-HETE were negatively correlated with the change in numbers of airway ILC2s (r = -0.6667; P = .0428). Docosahexaenoic acid epoxygenase metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) was positively correlated with both changes in airway ILC2s (r = 0.7143; P = .0305) and clinical symptom scores (r = 0.5000; P = .0081). CONCLUSION: Low levels of baseline 15-HETE predicted a greater accumulation of airway ILC2s in patients with AERD who were receiving COX-1 inhibition. Further, increases in the cytochrome P pathway metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) were associated with increased symptoms and nasal ILC2 accumulation. Future studies to assess how these mediators might control ILC2s may improve the understanding of AERD pathogenesis.

The US Hereditary Angioedema Association Scientific Registry: hereditary angioedema demographics, disease severity, and comorbidities.

BACKGROUND: Hereditary angioedema (HAE) and idiopathic nonhistaminergic angioedema (INHA) are ultra-rare diseases whose natural histories and comorbidities are incompletely understood. OBJECTIVE: To develop a national patient-centric registry to address these deficiencies in our knowledge and improve our ability to assess the real-world impact of therapeutic interventions. METHODS: Data from members of the US HAE Association were collected into an online registry between 2009 and April 7, 2021. Cohorts were categorized by reported physician diagnosis. Patient reported data were collected using a series of questionnaires. Demographic, natural history, and family history outcomes of the HAE due to C1 inhibitor deficiency (HAE-C1INH) participants were compared with those of the combined HAE with normal C1 inhibitor (HAE-nl-C1INH) plus INHA group. The prevalence of comorbid conditions in the HAE-C1INH group was compared with the general US population. RESULTS: A total of 485 HAE-C1INH, 26 HAE-nl-C1INH, and 70 INHA participants were included in the analysis. Delay to diagnosis was shorter in HAE-C1INH (5 vs 11 years), but both had decreasing delays over time. Differences in attack frequency and location were found between the groups. Morbidity surrogates including emergency department visits, hospitalizations, unnecessary abdominal surgeries, and intubations were strikingly high as was mortality with 36.9% of HAE-C1INH and 15.4% of HAE-nl-C1INH participants reporting family members who died from a HAE attack. Females with HAE-C1INH had a significant increase in the prevalence of depression, sleep disorders, kidney disease, anemia, and hepatitis. Cardiovascular comorbidities were significantly reduced in the HAE-C1INH group. CONCLUSION: The US HAEA Scientific Registry provides a mechanism to enhance our knowledge of HAE and INHA.

Hereditary Angioedema: Impact of COVID-19 pandemic stress upon disease related morbidity and well-being.

Background: Individuals with hereditary angioedema (HAE) experience stress-related sequelae, including enhanced disease morbidity and reduced quality of life. The pervasive societal strain that surround the coronavirus disease 2019 (COVID-19) pandemic may theoretically pose a disproportionate risk for patients with HAE. Objective: To dissect the interrelationship(s) among the COVID-19 pandemic, stress, and HAE disease-related morbidity and overall well-being. Methods: Subjects with HAE (either due to C1-inhibitor deficiency or with normal C1 inhibitor) as well as non-HAE household members (normal controls) completed online questionnaires that covered the impact of the COVID-19 pandemic on attack frequency, observed effectiveness of HAE medications, stress, and perceived quality of life and/or well-being. The subjects scored each of the questions to reflect their current status as well as their status before being aware of the pandemic. Results: Disease morbidity and psychologic stress outcomes were significantly worse in patients with HAE during the pandemic compared with before they were aware of the pandemic. A COVID-19 infection further increased attack frequency. Control subjects also experienced deterioration of well-being and optimism. A comorbid diagnosis of anxiety, depression, or posttraumatic stress disorder (PTSD) was generally associated with worse outcomes. Women consistently showed greater decrements in wellness during the pandemic compared with men. Women also reported higher levels of comorbid anxiety, depression, or PTSD than men and experienced a higher rate of job loss during the pandemic. Conclusion: The results implicated a deleterious impact of stress in the aftermath of COVID-19 awareness on HAE morbidity. The female subjects were universally more severely affected then were the male subjects. Overall well-being and/or quality of life, and optimism for the future deteriorated after awareness of the COVID-19 pandemic for the subjects with HAE and non-HAE household controls.

Therapeutic monoclonal antibodies with a focus on hereditary angioedema.

Monoclonal antibodies (mAbs) have been shown to be effective and generally safe across a continually expanding list of therapeutic areas. We describe the advantages and limitations of mAbs as a therapeutic option compared with small molecules. Specifically, we discuss a novel mAb in the treatment of hereditary angioedema (HAE), a rare and potentially life-threatening condition characterized by recurrent unpredictable swelling attacks. HAE is mediated by dysregulation of plasma kallikrein activity leading to overproduction of bradykinin. Current prophylactic treatment for HAE includes androgens or replacement of the endogenous plasma kallikrein inhibitor, C1 inhibitor. However, there remains an unmet need for an effective, less burdensome treatment option. Lanadelumab is a fully human mAb targeting plasma kallikrein. Results from clinical trials, including a pivotal Phase 3 study and its ensuing open-label extension study, demonstrated that lanadelumab is associated with few treatment-related adverse events and reduced the rate of HAE attacks. This novel treatment option has the potential to significantly improve the lives of patients with HAE.

Intranasal ketorolac, diagnosis, and desensitization for aspirin-exacerbated respiratory disease.

BACKGROUND: Intranasal ketorolac has been proposed as a diagnostic test for aspirin-exacerbated respiratory disease (AERD) and a faster, safer, and reliable addition to facilitating aspirin (ASA) desensitization. OBJECTIVE: We conducted the first prospective study to dissect the impact of intranasal ketorolac incorporation during ASA desensitization vs standard oral protocols in concert with evaluating its diagnostic use for AERD. METHODS: Patients with AERD were enrolled in a prospective open-label observational study between November 2006 and August 2013. Participants selected either one of the following desensitization protocols: intranasal ketorolac 1 day before oral ASA (group 1, combined) or ketorolac challenge with greater than 2 weeks elapsing until oral ASA (group 2, washout). All patients were on a leukotriene-modifying drug (montelukast) for at least 1 week before the challenge. RESULTS: A total of 20 patients were enrolled: 13 in group 1 and 7 in group 2. No significant differences were seen for baseline symptom scores or forced expiratory volume in 1 second. Group 1 exhibited significant increases for the threshold dose of ASA (P = .009), the likelihood of having silent ASA desensitization (P = .01), and decreased reaction severity to oral ASA (P = .04). There were no significant differences in reaction forced expiratory volume in 1 second, the incidence of extrapulmonary symptoms, limited nasoocular reactions, rescue treatment requirements, or time to symptom resolution. There was 100% concordance between reactions to intranasal ketorolac and oral ASA for group 2, supporting its use as a diagnostic test for AERD. CONCLUSION: Intranasal ketorolac is a useful diagnostic test and adjunct within the combined ketorolac/ASA protocol to achieve effective, efficient, and perhaps safer desensitization to ASA for patients with AERD.

COVID-19 and hereditary angioedema: Incidence, outcomes, and mechanistic implications.

Background: Patients with hereditary angioedema (HAE) have been postulated to be at increased risk for coronavirus disease 2019 (COVID-19) infection due to inherent dysregulation of the plasma kallikrein-kinin system. Only limited data have been available to explore this hypothesis. Objective: To assess the interrelationship(s) between COVID-19 and HAE. Methods: Self-reported COVID-19 infection, complications, morbidity, and mortality were surveyed by using an online questionnaire. The participants included subjects with HAE with C1 inhibitor (C1INH) deficiency (HAE-C1INH) and subjects with HAE with normal C1-inhibitor (HAE-nl-C1INH), and household controls (normal controls). The impact of HAE medications was examined. Results: A total of 1162 participants who completed the survey were analyzed, including: 695 subjects with HAE-C1INH, 175 subjects with HAE-nl-C1INH, and 292 normal controls. The incidence of reported COVID-19 was not significantly different between the normal controls (9%) and the subjects with HAE-C1INH (11%) but was greater in the subjects with HAE-nl-C1INH (19%; p = 0.006). Obesity was positively correlated with COVID-19 across the overall population (p = 0.012), with a similar but nonsignificant trend in the subjects with HAE-C1INH. Comorbid autoimmune disease was a risk factor for COVID-19 in the subjects with HAE-C1INH (p = 0.047). COVID-19 severity and complications were similar in all the groups. Reported COVID-19 was reduced in the subjects with HAE-C1INH who received prophylactic subcutaneous C1INH (5.6%; p = 0.0371) or on-demand icatibant (7.8%; p = 0.0016). The subjects with HAE-C1INH and not on any HAE medications had an increased risk of COVID-19 compared with the normal controls (24.5%; p = 0.006). Conclusion: The subjects with HAE-C1INH who were not taking HAE medications had a significantly higher rate of reported COVID-19 infection. Subcutaneous C1INH and icatibant use were associated with a significantly reduced rate of reported COVID-19. The results implicated potential roles for the complement cascade and tissue kallikrein-kinin pathways in the pathogenesis of COVID-19 in patients with HAE-C1INH.

Assessing the cost and quality-of-life impact of on-demand-only medications for adults with hereditary angioedema.

Background: Novel subcutaneous (SC) prophylactic therapies are transforming the treatment landscape of hereditary angioedema (HAE). Although questions are being raised about their cost, little attention has been paid to the cost and quality of life (QoL) impact of using on-demand-only medications. Objective: We assessed the overall economic burden of on-demand-only treatment for HAE and compared patient QoL with patients who received novel SC prophylactic therapies. Methods: US Hereditary Angioedema Association members were invited to complete an anonymous online survey to profile attack frequency, treatment use, and the presence of comorbidities as well as economic and socioeconomic variables. We modeled on-demand treatment costs by using net pricing of medications in 2018, indirect patient and caregiver costs, and attack-related direct billed costs for emergency department admissions, physician office visits, and/or hospitalizations. QoL was assessed by using the Angioedema Quality of Life questionnaire. Results: A total of 1225 patients (31.4%) responded. Of these, 737 adults with HAE (type I or II) met the inclusion criteria and completed the survey. Per patient/year direct costs associated with modeled on-demand-only treatment totaled $363,795, with additional indirect socioeconomic costs of $52,576 per patient/year. The greatest improvement in QoL was seen in patients who used novel SC prophylactic therapies, with a 59.5% (p < 0.01) improvement in median impairment scores versus on-demand-only treatment. In addition, patients who used novel SC prophylactic therapies reported a 77% reduction in the number of attacks each year when compared with those who used on-demand-only treatment. Conclusion: Our real-world patient data showed the cost and QoL burden of HAE treatment with on-demand-only therapy. Use of novel SC prophylaxis can lead to sizeable reductions in attack frequency and statistically significant and clinically relevant improvements in QoL. These data could be useful to clinicians and patients as they consider therapy options for patients with HAE.

Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).

Hereditary angioedema: On-demand treatment of angioedema attacks.

The availability of effective acute treatment for angioedema has been fundamental in reducing the burden of illness for patients with hereditary angioedema (HAE). In building on the foundation of scientific advances that elucidate the pathomechanism(s) of attacks related to vascular permeability, novel targeted on-demand treatments have been developed and approved. These therapies have provided the means to arrest episodes of swelling, which, in the past, had the potential to inexorably lead to morbidity, and even mortality, for patients with HAE. Access to these medications, along with an emphasis on early administration and guidance that all attacks are candidates for treatment, has shifted the management paradigm for HAE. Although unmet needs remain, these acute therapies, coupled with advances in prophylactic treatment, have furthered the goal for all patients with HAE to live a normal life.

What is in your pantry? Entomologic anaphylaxis.

Background: The booklouse, Liposcelis bostrychophila, is a potent environmental allergen clinically associated with rhinoconjunctivitis and asthma. Despite its known infestation of grain products, anaphylaxis from ingestion of this organism has, to our knowledge, not been previously reported. We present the case of a 44-year-old woman who developed anaphylaxis to ingested oats and rice shown to be contaminated with L. bostrychophila. Objective: The objective was to isolate a distinct antigen from L. bostrychophila implicated in a case of unexplained anaphylaxis. Methods: In vitro studies were obtained for relevant ingested materials and aeroallergens. Skin-prick testing (SPT) was performed with standard extracts, contaminated oats, fresh oats, and crushed L. bostrychophila. Western blots were conducted using subject and control serum to detect specific immunoglobulin E (IgE) against the grains and L. bostrychophila extract. Competitive inhibition immunoblotting was used to assess specificity of IgE binding. Results: In vitro studies and SPT were notable for positive responses to dust mite and flour contaminated by L. bostrychophila, along with contaminated oats. Testing results for fresh oat and rice were negative. Immunoblots that used the subject's serum revealed a strongly positive band in the contaminated oat and rice extracts at 24 kD, whereas dust-mite extract yielded a single 14-kD band. Isolated L. bostrychophila extract also yielded a 24-kD band. Competitive inhibition experiments demonstrated that the 24-kD band in the contaminated oat extract was immunologically distinct from the 14-kD dust-mite band. Conclusion: Our case highlights the importance of considering L. bostrychophila as a potential culprit for unexplained anaphylaxis due to ingested grain products. Given the ubiquitous presence of this insect, we suspect that this may be a more common problem than previously recognized.

Threshold-stimulated kallikrein activity distinguishes bradykinin- from histamine-mediated angioedema.

BACKGROUND: The lack of specific biomarkers makes the diagnosis of hereditary angioedema (HAE) with normal levels of C1-inhibitor (C1INH) protein (HAE-nl-C1INH) and idiopathic non-histaminergic angioedema (INHA) difficult. Confirming or excluding these diagnoses is a significant challenge for clinicians evaluating patients with angioedema. OBJECTIVE: To develop a reliable biomarker that would aid the diagnosis of HAE-nl-C1INH and INHA. METHODS: A total of 154 consecutive patients referred for angioedema at a single centre were enrolled and evaluated. Subjects were clinically phenotyped based on clinical history and response to treatment by clinicians blinded to laboratory assay results. Plasma kallikrein activity was measured by the cleavage of the fluorometric substrate Z-Phe-Arg-AMC-HCL in plasma samples stimulated ex vivo with submaximal doses of dextran sulphate. RESULTS: Stimulated plasma kallikrein activity (mean relative fluorescence units/min ± SD) was significantly increased in both HAE-nl-C1INH (1804 ± 600) and INHA (1579 ± 371) subjects compared to non-swelling controls (171 ± 46) and histaminergic angioedema (133 ± 30) subjects. Using a threshold cut-off based on the normal controls, HAE-nl-C1INH and INHA subjects could be differentiated from histaminergic angioedema subjects with high sensitivity (negative predictive value 86%-89%) and specificity (positive predictive value 80%-100%). CONCLUSION AND CLINICAL RELEVANCE: The stimulated kallikrein activity assay allows differentiation of bradykinin- from histamine-mediated angioedema. The assay could feasibly be considered as a potential clinical tool for the diagnosis of bradykinin-mediated angioedema.

Group 2 innate lymphoid cells are recruited to the nasal mucosa in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by tissue eosinophilia and mast cell activation, including abundant production of prostaglandin D2 (PGD2). Group 2 innate lymphoid cells (ILC2s), which promote tissue eosinophilia and mast cell responses, undergo chemotaxis and cytokine production in response to PGD2, but it is unknown whether ILC2s are active in patients with AERD. OBJECTIVE: We sought to determine whether ILC2 numbers change in peripheral blood and the nasal mucosa during COX-1 inhibitor-induced reactions in patients with AERD. METHODS: Blood and nasal scrapings were collected at baseline, during reactions, and after completion of ketorolac/aspirin challenge/desensitization in 12 patients with AERD. ILC2s and eosinophils were quantitated by means of flow cytometry. Urine was also collected, and quantification of PGD2 metabolite and leukotriene E4 levels was done by using ELISA. Baseline and nonsteroidal anti-inflammatory drug reaction clinical data were correlated with cell changes. RESULTS: ILC2 numbers significantly increased in nasal mucosal samples and decreased in blood at the time of COX-1 inhibitor reactions in 12 patients with AERD. These changes were not observed in 2 patients without AERD. Furthermore, eosinophil numbers decreased in blood concurrently with significant increases in urinary PGD2 metabolite and leukotriene E4 levels. The magnitude of increases in nasal mucosal ILC2 numbers positively correlated with maximum symptom scores during challenges. Furthermore, blood ILC2 numbers during the reaction correlated with time for the reaction to resolve, possibly reflecting reaction severity. CONCLUSIONS: ILC2s are recruited to the nasal mucosa during COX-1 inhibitor-induced reactions in patients with AERD, correlating with enhanced production of prostaglandins and leukotrienes.

Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial.

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.

Anabolic androgen use in the management of hereditary angioedema: Not so cheap after all.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE) is a rare, life-threatening disease that imposes a significant burden on affected patients. 17α-alkylated androgens (anabolic androgens) decrease attack frequency and severity but carry the risk of potentially serious dose-related adverse effects. Despite the emergence of targeted therapies for HAE, continued anabolic androgen use has been driven in part by their low cost. OBJECTIVE: To examine the hidden cost of anabolic androgen use related to the risk of developing non-HAE comorbidities. METHODS: Patients with HAE were identified in the Southern California Kaiser Permanente database using clinical and laboratory findings compatible with HAE. These patients were stratified into anabolic androgen exposed and nonexposed groups. Matched controls were selected from the Kaiser database who did not have HAE or anabolic androgen exposure. Using multivariate analysis, we determined the number of non-HAE comorbidities linked to anabolic androgen use. We next determined the association between dosing and increasing exposure to anabolic androgens and the likelihood of having various comorbidities. RESULTS: Patients with HAE exposed to anabolic androgens had a 28% increase (P = .04) in non-HAE comorbidities when compared with their matched (nonexposed) controls. With each gram per month increase in exposure, a 12% increase in non-HAE comorbidities is observed (P < .01). The most commonly occurring non-HAE comorbidities were psychiatric, muscle cramps, obesity, and hyperlipidemia. CONCLUSION: Our data suggest that long-term anabolic androgen use enhances the risk of developing comorbid health conditions, thus amplifying the cost of care. Our report provides additional support for the preferred use of newer, targeted therapies for the management of HAE.

Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33.

BACKGROUND: Rhinovirus infection at an early age has been associated with development of asthma, but how rhinovirus influences the immune response is not clear. OBJECTIVE: Tolerance to inhaled antigen is mediated through induction of regulatory T (Treg) cells, and we examined whether rhinovirus infection of the respiratory tract can block airway tolerance by modulating Treg cells. METHODS: The immune response to intranasal ovalbumin in mice was assessed with concomitant infection with RV1B, and the factors induced in vivo were compared with those made by human lung epithelial cells infected in vitro with RV16. RESULTS: RV1B infection of mice abrogated tolerance induced by inhalation of soluble ovalbumin, suppressing the normal generation of forkhead box protein 3-positive Treg cells while promoting TH2 cells. Furthermore, RV1B infection led to susceptibility to asthmatic lung disease when mice subsequently re-encountered aeroantigen. RV1B promoted early in vivo expression of the TNF family protein OX40 ligand on lung dendritic cells that was dependent on the innate cytokine thymic stromal lymphopoietin (TSLP) and also induced another innate cytokine, IL-33. Inhibiting each of these pathways allowed the natural development of Treg cells while minimizing TH2 differentiation and restored tolerance in the face of RV1B infection. In accordance, RV16 infection of human lung epithelial cells upregulated TSLP and IL-33 expression. CONCLUSIONS: These results suggest that infection of the respiratory epithelium with rhinovirus can antagonize tolerance to inhaled antigen through combined induction of TSLP, IL-33, and OX40 ligand and that this can lead to susceptibility to asthmatic lung inflammation.

How we manage persons with hereditary angioedema.

Hereditary angioedema (HAE) is a rare autosomal dominant genetic disorder clinically characterized by recurrent attacks of subcutaneous and mucosal swelling that can result in significant morbidity and even mortality. Several novel therapies introduced since 2008 have dramatically transformed the approach to management. In this review we will discuss the current understanding of the pathophysiology of HAE, diagnostic evaluation of recurrent angioedema without urticaria, and the therapeutic approach to HAE. We advocate taking an integrative approach to care in order to normalize the lives of affected patients.