Anaphylactic reaction to chamomile tea
Donya Imanirad, M.D., Enrique Fernandez-Caldas, Ph.D., Richard F. Lockey, M.D.
Introduction: The family Asteraceae (Compositae) is one of the largest angiosperm families characterized by their composite flower heads that includes dog fennel and ragweed among many others.
Case: A 56-year-old male with allergic rhinitis and Hymenoptera hypersensitivity drank a cup with two tea bags of chamomile tea (Traditional Medicinals, Sebastopol, CA). Between 5 and 15 minutes of ingestion, he experienced pruritus of his oral pharynx, palms, and torso, and developed urticaria on his thighs. Within 15 additional minutes, he experienced tightness of his “throat” and felt he “could not breathe.” He became hoarse and more short of breath and developed a feeling of impending doom. He self-administered EpiPen, 0.3 mg, (Mylan Company, Canonsburg, PA) into his thigh, which he carries for Hymenoptera hypersensitivity and improved within 5–10 minutes. His problem resolved over the next hour or so. A history reveals that, when he ate meals prepared with sunflower oil, he developed generalized pruritus, and, when a marigold garland was placed around his neck, he developed generalized pruritus and urticaria. Each tea bag contains 1300 mg of chamomile flower and a warning: “Avoid this product if you are allergic to plants in the daisy (Asteraceae or Compositae) family, such as chamomile or echinacea.” Prick puncture tests were 3–4+ positive to short ragweed, spiny pigweed, dog fennel, sheep sorrel, nettle, and English plantain. Lambs quarters was 4+ to an intradermal test. Sunflower, marigold flower, short ragweed, and dog fennel are all in the Compositae family. Chamomile pollen, Matricaria recutita, cross-reacts with the pollen of other members of the Compositae family, including mugwort (Artemisia spp.) and ragweed (Ambrosia spp.). SDS-PAGE gels reveal the presence of several bands in a wide range of molecular weights corresponding to different allergenic proteins.
Conclusion: This subject experienced anaphylaxis from chamomile tea, which contains allergens from the same botanical family to which he has positive skin test results. Subjects allergic to pollen in the Compositae family are susceptible to systemic allergic reactions and anaphylaxis secondary to the ingestion of chamomile tea.
The stubborn rash
Stephanie N. Hudey, M.D., Mark C. Glaum, M.D., Ph.D.
Introduction: Cutaneous T-cell lymphoma presenting as suspected drug rash is described.
Case Description: A 64-year-old male with rheumatoid arthritis presents for evaluation of progressive skin rash. He initially notes diffuse xerosis 3 years prior, is diagnosed with eczema, and started on topical corticosteroids. One year later, rheumatology initiates methotrexate and he develops worsening skin rash. Given their concern for drug rash, methotrexate is stopped, and he is trialed on adalimumab and sulfasalazine in succession, but the rash persists for longer than 1 year. It transiently improves with oral corticosteroid tapers. A skin biopsy specimen, while on adalimumab, reveals superficial and deep perivascular and periadnexal lymphohistiocytic infiltrate with numerous eosinophils. Eight months later, he is evaluated by an allergy specialist. All medications are discontinued 1 month prior. Examination reveals pruritic, indurated plaques with nodularity on the trunk and upper extremities. CBC and CMP are unremarkable, without eosinophilia. Repeated skin biopsy is performed given rash progression. It now reveals atypical lymphoid infiltrate, predominantly T cells with a preponderance of CD4+ variably sized cells. T-cell β/γ gene rearrangement shows a monoclonal population. Oncology performs further evaluation with bone marrow biopsy, PET scan, and lymph node biopsy, and he is diagnosed with stage IIB mycosis fungoides with large cell transformation. He is initiated on INF-α with total skin external beam radiation therapy.
Discussion/Lessons Learned: This case demonstrates the importance of including cutaneous T-cell lymphoma in the differential diagnosis of rashes that may be encountered by allergists in clinical practice. It also stresses the need to reconsider the diagnosis and repeated skin biopsy for rashes that fail to respond to conventional treatment or evolve in appearance.
The other side of the coin: immunodysregulation in primary immunodeficiency. Analysis of the United States Immunodeficiency Network (USIDNET) data base
Maria Chitty Lopez, M.D., Rahul Mhaskar, M.P.H., Ph.D., Hannah Wright, M.S.P.H., Rebecca A. Marsh, M.D., Elizabeth Garabedian, M.D., Ramsay Fuleihan, M.D., Kathleen E. Sullivan, M.D., and Jennifer W. Leiding, M.D.
Rationale: Substantial effort has been devoted to the characterization of infectious susceptibility in patients with primary immunodeficiencies diseases (PIDD). Noninfectious conditions, especially immunodysregulation, autoimmunity, and auto-inflammation, have been increasingly identified as major PIDD features. Our objective is to describe the frequency of immunodysregulatory conditions in a large U.S. PIDD cohort.
Methods: The USIDNET is a national research consortium with 43 contributing academic and private centers. Data from PIDD patients are collected in a registry after obtaining informed consent. Patients were grouped by their diagnosis according to the IUIS 2019 classification. Immunodysregulatory conditions were categorized by affected organ system by investigators. The frequency of immunodysregulatory conditions and organ systems affected were determined within each IUIS category. The association between immunodysregulatory conditions and survival was investigated by using a chi-square or Fisher exact test.
Results: A total of 4182 subjects with a diagnosis of PIDD were identified. The median age of diagnosis and median age of death (N = 259) were 8 and 17 years, respectively. The male-to-female ratio was 1.2:1. Analysis was performed on patients with known survival status (N = 3672). The majority of patients (57.8%) had one or more organ systems affected; 9.4% had three or more affected. Within IUIS categories, the frequency of organ systems affected varied, the most common systems affected across the cohort were respiratory (30.6%), integumentary (19.3%), gastrointestinal (18.4%), immune (13.9%), and hematopoietic (11.5%). The most frequent IUIS categories to have immunodysregulatory conditions associated were diseases of immune dysregulation (76.4%) and defects of the innate immune system (73.0%). Specific immunodysregulatory conditions were more common within certain IUIS categories: hematologic dyscrasias (34.3%) were most common in diseases of immune dysregulation, gastrointestinal conditions occurred most frequently (32.5%) in those within congenital defects of phagocytes, and respiratory conditions (38.1%) were most common in predominantly antibody deficiency. Immunodysregulatory conditions affecting cardiovascular (p = 0.014), endocrine (p = 0.046), gastrointestinal (p < 0.0001), hematopoietic (p < 0.0001), and immune systems (p < 0.0001) were associated with death. Within each organ system affected, specific immunodysregulatory conditions were also associated with worse survival.
Conclusion: More than half of patients within our PIDD cohort had immunodysregulatory conditions associated with their diagnosis. Hematologic, GI, and respiratory conditions had the most negative effect on survival. This large cohort of patients were predominantly contributed by academic centers that may have influenced the observations toward more severe phenotypes. Given the high frequency of immunodysregulatory features, recognition of autoimmunity and auto-inflammatory symptoms should be used to guide surveillance strategies for recognition and diagnosis of PIDD.
Mepolizumab for chronic rhinosinusitis with nasal polyps: comorbid asthma, NSAID exacerbated respiratory disease, eosinophil stratification
Claus Bachert, M.D., Ph.D., Ana R. Sousa, Ph.D., Joseph Han, M.D., Rodney J. Schlosser, M.D., Leigh J. Sowerby, M.D., Claire Hopkins, D.M. (Oxon), Jorge F. Maspero, M.D., Steven G. Smith, Ph.D., Neil Martin, M.D., Oliver Kante, M.Sc., Despina E. Karidi-Andrioti, M.Sc., Bhabita Mayer, M.Sc., Robert H. Chan, Steven W. Yancey, M.Sc., and Adam Chaker, M.D.
Introduction: SYNAPSE, a phase III study, assessed the efficacy and safety of mepolizumab in chronic rhinosinusitis with nasal polyps (CRSwNP). Additional stratification by comorbid asthma, nonsteroidal anti-inflammatory drug exacerbated respiratory disease (N-ERD), and baseline blood eosinophil count (BEC) was required.
Methods: SYNAPSE (NCT03085797), a randomized, double-blind, placebo controlled, multicenter, 52-week study, included patients with recurrent severe bilateral CRSwNP and CRS symptoms. Patients received intranasal corticosteroids and met criteria for revision surgery. The change in total endoscopic NP score and nasal obstruction visual analog scale (VAS) score (co-primary end points) and time-to-first nasal surgery (key secondary end point) were analyzed by comorbid asthma, N-ERD, and (post hoc) baseline BEC.
Results: In patients with/without comorbid asthma, mepolizumab (n = 140/66) versus placebo (n = 149/52) efficacy (adjusted difference in median change from baseline [95% CI]) was similar for endoscopic NP score at week 52 (–1.00 [–1.40 to –0.60]/–0.42 [–0.98 to 0.13]) and nasal obstruction VAS score at weeks 49–52 (–2.88 [–3.97 to –1.79]/–3.12 [–5.23 to –1.02]); patients receiving mepolizumab without comorbid asthma had fewer surgeries than patients with comorbid asthma (hazard ratio [95% CI]: 0.18 [0.05-0.64]) versus 0.61 [0.32-1.15]). For patients with/without comorbid N-ERD, mepolizumab (n = 45/161) versus placebo (n = 63/168) improvements in endoscopic NP score (−0.89 [–1.73 to –0.05]/–0.50 [–0.89 to –0.11]) and reductions in surgery risk (0.32 [0.11-0.89]/0.47 [0.24-0.92]) were similar; improvements with mepolizumab compared with placebo in nasal obstruction VAS score were greater in patients with N-ERD than in patients without N-ERD (–4.43 [–5.82 to –3.03]/−2.42 [–3.67 to –1.18]). Improvements across end points trended higher with BEC ≥150 versus <150 cells/µL.
Conclusion: Mepolizumab was generally efficacious, irrespective of comorbid asthma or N-ERD; patients without comorbid asthma had fewer surgeries, patients with N-ERD had greater improvements in obstruction VAS score. Mepolizumab efficacy increased with higher BEC. Results suggest mepolizumab is efficacious for treating CRSwNP, particularly in patients with BEC ≥ 150 cells/µL.
Funding: GSK(ID:205687)
Managing patients with severe asthma and common comorbidities of atopy, obesity, and depression/anxiety: real-world effectiveness of mepolizumab
Nestor Molfino, Thomas Casale, Jared Silver, Michael Bogart, Elizabeth Packnett, Donna McMorrow, Juan Wu, and Beth Hahn
Introduction: Mepolizumab has been shown to improve severe asthma control in clinical trials. However, physicians treat holistically and consider comorbid conditions when selecting therapy. Atopy, obesity, and depression/anxiety affect patients with asthma at an increased rate, yet few studies have examined asthma therapy with these comorbidities. This study examined the impact of mepolizumab in patients with severe asthma and atopy, obesity, or depression/anxiety.
Methods: Retrospective claims data base analysis of patients with commercial and/or Medicare supplemental insurance with asthma, ≥12 years of age at mepolizumab initiation (index date), ≥2 mepolizumab administrations 6 months postindex, ≥12 months of continuous enrollment before (baseline) and after (follow-up) the index date, and a medical claim for one of the prespecified comorbidities during baseline. Asthma exacerbations and OCS use were compared between baseline and follow-up periods for each of the non–mutually exclusive comorbid subgroups.
Results: Patient subgroups were identified with the following comorbidities: atopy (n = 468), obesity (n = 171), depression/anxiety (n = 173). After initiating mepolizumab, the mean rate of exacerbations was reduced in all groups: 48% in atopy, 52% in obesity, 38% in depression/anxiety (p < 0.0001). All subgroups also had significant decreases in mean number of OCS claims (atopic 33%, obesity 38%, depression/anxiety 31%; p < 0.001) and OCS bursts (atopic 40%, obesity 48%, depression/anxiety 37%; p < 0.001) compared with baseline.
Conclusion: This study demonstrates that patients with asthma and atopy, obesity, or depression/anxiety have significantly fewer exacerbations and reduced OCS use in a real-world setting after treatment with mepolizumab. Holistic patient care for severe asthma is critical, and mepolizumab provides tangible clinical benefit, despite the complexities of medical comorbidities.
Funded by GSK-sponsored study 213145
Impact of baseline clinical asthma characteristics on the response to mepolizumab: a post hoc meta-analysis of two phase III trials
M.C. Liu, C. Taillé, J.K. Lee, S.G. Smith, S. Mallett, N. Martin, P. Howarth, S. Yancey, and C. Lemiere
Introduction: Severe asthma is associated with a broad range of phenotypes. We assessed whether select baseline clinical characteristics could influence the efficacy of mepolizumab in patients with severe eosinophilic asthma (SEA).
Methods: This was a post hoc meta-analysis of data from the phase III MENSA and MUSCA studies. Patients ages ≥12 years with SEA and two or more exacerbations were randomized to 4-weekly placebo or mepolizumab 100 mg subcutaneously for 32/24 weeks (MENSA/MUSCA). We assessed annual rates of clinically significant exacerbations (primary end point), proportions of patients achieving complete asthma control (Asthma Control Questionnaire [ACQ] 5 score <0.75), changes from baseline in prebronchodilator forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) total score, and ACQ-5 score. Analyses were performed by age at asthma onset (<18/18–40/≥40 years); lung function (% predicted FEV1 ≤60/60–80/>80%), airway reversibility (≥12/<12% change in FEV1), and asthma control (uncontrolled versus partial or complete control [ACQ-5 score ≥1.5/<1.5]) at baseline.
Results: Overall, 936 patients received mepolizumab or placebo. Across age, lung function, and airway reversibility subgroups, mepolizumab reduced exacerbation rates by 49–63% versus placebo. FEV1, SGRQ total score, and ACQ-5 score were also improved with mepolizumab versus placebo across the majority of age and lung function subgroups. Patients were more likely to achieve complete asthma control with mepolizumab versus placebo, irrespective of baseline asthma control (odds ratio mepolizumab/placebo [95% confidence interval]: 2.28 [1.47-3.54] and 2.31 [1.38-3.87] for baseline ACQ-5 scores ≥1.5 and <1.5).
Conclusion: Mepolizumab is beneficial for patients with SEA who have a broad range of baseline clinical characteristics.
Funded by GSK (meta-analysis: 208115 [MEA115588/NCT01691521; 200862/NCT02281318]).
CAPTAIN Study: Effect of baseline lung function on response to triple therapy in patients with asthma inadequately controlled on inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) therapy
R. Nathan, L.-P. Boulet, H.A. Kerstjens, A. Papi, I.D. Pavord, N.A. Hanania, J. Oppenheimer, D.J. Maselli, M.C. Liu, S. Weinstein, D. Mannino, G. Peachey, A. Zarankaite, N. Sule, A. Fowler, L. Lee, and E. Kerwin
Introduction: The CAPTAIN Study showed that adding umeclidinium (UMEC) to ICS/LABA improves lung function and symptom control for patients with uncontrolled asthma, but the effects of UMEC may vary according to baseline lung function. We investigated the effect of UMEC addition on asthma outcomes according to baseline lung function.
Methods: CAPTAIN Study: Phase IIIA, randomized, double-blind, 24–52-week, parallel-group study in adults with uncontrolled asthma and airflow reversibility at screening. Treatment: fluticasone furoate (FF)/UMEC/vilanterol (VI) 100/31.25/25, 100/62.5/25, 200/31.25/25, 200/62.5/25 μg, or FF/VI 100/25, 200/25 μg QD (ELLIPTA). Outcomes: change from baseline in clinic trough forced expiratory volume in 1 second (FEV1) and asthma control questionnaire (ACQ) 7 response (≥0.5-point decrease from baseline) at week 24, and annualized moderate/severe exacerbation rate according to baseline lung function subgroup: FEV1 <60/≥60% predicted; FEV1 reversibility to SABA <400/≥400 mL; FEV1/forced vital capacity (FVC) ratio <0.7/≥0.7 (prespecified exploratory analyses).
Results: UMEC addition improved trough FEV1 in both FEV1 <60/≥60% predicted subgroups, with FF/UMEC/VI 100/62.5/25 (n = 207/197) resulting in improvements of 72 mL (95% CI, 12–132) and 146 mL (84–209), respectively, versus FF/VI 100/25 (n = 210/192). FF/UMEC/VI 200/62.5/25 (n = 188/219) led to improvements of 95 mL (33–157) and 88 mL (28–147), respectively, versus FF/VI 200/25 (n = 201/200) in these subgroups. Trough FEV1 improvements after UMEC addition to FF/VI 100/25 or 200/25 were also observed in both SABA reversibility and FEV1/FVC subgroups. ACQ-7 responses favoring FF/UMEC/VI versus FF/VI were also observed across subgroups. FF/UMEC/VI 100/62.5/25 was associated with moderate-severe exacerbation rate reductions versus FF/VI 100/25 across subgroups. There was no clear pattern in treatment response on the rate of moderate-severe exacerbations according to baseline lung function for the FF 200 μg dose comparisons.
Conclusion: The improvements observed after addition of UMEC to FF/VI, in both functional and clinical outcomes, were independent of baseline lung function.
Funded by GSK (205715/NCT02924688).
CAPTAIN Study: Effects of smoking status on treatment response to triple therapy in patients with inadequately controlled asthma on inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) therapy
A. Papi, L. Lee, H.A. Kerstjens, L.-P. Boulet, A. Zarankaite, I.D. Pavord, G. Brusselle, N. Barnes, N.A. Hanania, S. Pascoe, J. Oppenheimer, E. Pizzichini, and A. Fowler
Introduction: In patients with uncontrolled asthma despite ICS/LABA, effects of adding a long-acting muscarinic antagonist (LAMA) or increasing ICS dose differ based on treatment outcome and may vary with smoking history. Therefore, we analyzed effects of adding umeclidinium (UMEC) or increasing fluticasone furoate (FF) dose on forced expiratory volume in 1 second (FEV1) and exacerbations by smoking status.
Methods: CAPTAIN: Phase IIIA, randomized, double-blind, 24–52-week, parallel-group study in adults with uncontrolled asthma and airflow reversibility at screening. Treatment: FF/UMEC/vilanterol (VI) 100/31.25/25, 100/62.5/25, 200/31.25/25, 200/62.5/25 μg; or FF/VI 100/25, 200/25 μg QD (ELLIPTA). Outcomes: Change from baseline in trough FEV1 at week 24 and annualized rate of moderate-severe exacerbations in former versus never smokers. Analyses were prespecified, except for the FF/VI 200/25 versus 100/25 comparison (post hoc in the smoking subgroups).
Results: Number of patients overall and for never smokers and former smokers, respectively: FF/UMEC/VI 100/62.5/25: 406, 325, 81; FF/UMEC/VI 200/62.5/25: 408, 315, 93; FF/VI 100/25: 407, 338, 69; FF/VI 200/25: 406, 337, 69. A numerical trend for greater reductions in exacerbation rates in former versus never smokers was seen for FF/UMEC/VI 100/62.5/25 versus FF/VI 100/25 and FF/UMEC/VI 200/62.5/25 versus FF/VI 200/25 (rate ratios [95% CI]: 0.55 (0.31–0.96) versus 0.86 (0.64–1.14), and 0.69 (0.38–1.24) versus 1.06 (0.77–1.45), respectively). Effects of increasing ICS dose on exacerbations did not differ by smoking status. FEV1 was improved by a greater extent in former versus never smokers after addition of UMEC 62.5 μg to FF/VI 100 μg or from doubling the FF dose in dual therapy (mean difference in change from baseline: 186 mL (85–287) and 94 mL (46–141) for FF/UMEC/VI 100/62.5/25 versus FF/VI 100/25; 142 mL (36–247) and 33 mL (–15 to 80) for FF/VI 200/25 versus FF/VI 100/25.
Conclusion: Addition of UMEC was associated with a greater reduction in exacerbations in former versus never smokers, including with FF 200 μg. For FEV1, effects of both treatments were less consistent with smoking history.
Funded by GSK (205715/NCT02924688).
Dupilumab provides early and sustained clinically meaningful responses in a phase 3 trial in adolescents with inadequately controlled moderate-to-severe atopic dermatitis: Results from the overall population and in a subgroup of patients not achieving IGA scores of 0/1
Eric L. Simpson, Andrew Blauvelt, Emma Guttman-Yassky, Melinda Gooderham, Iftikhar Hussain, Zhen Chen, Noah A. Levit, and Ana B. Rossi
Objective: We determined the proportion of atopic dermatitis (AD) patients with clinically meaningful responses after dupilumab treatment for 16 weeks in the overall adolescent population and in a subgroup not achieving IGA scores of 0/1 at week 16 (wk 16) in a double-blinded, phase 3 trial (LIBERTY AD ADOL: NCT03054428).
Methods: Adolescents with inadequately controlled moderate-to-severe AD were randomized 1:1:1 to subcutaneous dupilumab every 4 weeks (q4w; 300 mg), every 2 weeks (q2w; 200 or 300 mg), or placebo for 16 weeks. Clinically meaningful responses were defined as ≥50% improvement in EASI, or a ≥3-point improvement in weekly-averaged Peak daily Pruritus NRS, or a ≥ 6-point improvement in CDLQI from baseline through wk 16. A composite end point was defined as response in ≥ 1 of the above end points.
Results: Patients (N = 251) were randomized to dupilumab q4w, q2w, and placebo. At wk 16, significantly more patients receiving dupilumab achieved the composite end point versus placebo (q4w/q2w versus placebo: 63.1%/80.5% versus 23.5% [p < 0.0001 for both]). Of 214 patients who did not achieve IGA 0/1 at wk 16, significantly more dupilumab-treated patients achieved the composite end point versus placebo (q4w/q2w versus placebo: 55.1%/74.2% versus 21.7% [p < 0.0001 for both]) at wk 16. Clinically meaningful responses were seen as early as wk 2 after first dupilumab dose. Dupilumab was generally well tolerated, with an acceptable safety profile similar to that seen in the adult AD population.
Conclusion: A majority of adolescents treated with dupilumab demonstrated early, progressive, and sustained clinically meaningful responses in ≥ 1 key AD domain compared with placebo.
Funded by Sanofi/Regeneron
Rapid and sustained improvement in itch in children aged 6–11 years with severe atopic dermatitis (AD) treated with dupilumab: analysis from the LIBERTY AD PEDS phase 3 trial
Gil Yosipovitch, Jonathan I. Silverberg, Jashin J. Wu, Zhen Chen, Alvina Abramova, and Randy Prescilla
Background: In LIBERTY AD PEDS phase 3 trial (NCT03345914) in children with severe AD, dupilumab significantly improved AD signs and symptoms. We assess time to onset of improvement in pruritus in a subset of children treated with FDA-approved doses of dupilumab.
Methods: Children aged 6–11 years were randomized to dupilumab 300 mg every 4 weeks (300 mg q4w, loading dose 600 mg), 100 mg/200 mg q2w (loading dose 200 mg/400 mg), or placebo, with concomitant medium-potency topical corticosteroids (TCS). This analysis evaluated the change from baseline in daily and weekly peak pruritus numerical rating scale (PP-NRS) scores up to week 16.
Results: This analysis included 243 patients treated with FDA-approved doses of dupilumab or placebo (<30 kg: 600 mg loading dose, then 300 mg q4w + TCS/placebo + TCS; ≥30kg: 400-mg loading dose then 200 mg q2w + TCS/placebo + TCS; n = 61/61/59/62). The percent decrease in daily PP-NRS score (SE) from baseline of dupilumab + TCS versus placebo + TCS was significant, as early as day 8 in the q4w group after a single dose (−13.8% [2.9] versus −5.1% [2.9]; p < 0.05) and day 16 in the q2w group (−22.1% [3.4] versus −12.6% [3.3]; p < 0.05). At week 16, mean percent change from baseline (SE) in weekly PP-NRS score in the q4w group versus placebo + TCS was −55.0% (4.0) versus −26.6% (4.3) (p < 0.0001) and −58.3% (4.0) versus −25.3% (3.9) (p < 0.0001) in the q2w group versus placebo + TCS. Safety profile was consistent with the known dupilumab safety profile.
Conclusion: Dupilumab + TCS treatment provided rapid and sustained improvement in itch intensity and frequency in children aged 6 − 11 years with severe AD.
Funded by Sanofi/Regeneron
Infections in adults with moderate-to-severe atopic dermatitis treated with dupilumab: long-term data from an open-label extension (OLE) study
Andrew Blauvelt, Andreas Wollenberg, Lawrence Eichenfiel, Zhen Chen, Ainara Rodriguez Marco, Jignesh Vakil, Faisal A. Khokhar, and Sonya L. Cyr
Background: Atopic dermatitis (AD) is associated with immunologic and skin barrier dysfunction, predisposing patients to infections. Here, we report the incidence of infections in adults with moderate-to-severe AD treated with dupilumab for up to 3 years in an OLE study.
Methods: LIBERTY AD OLE (NCT01949311) is an ongoing trial assessing 300 mg dupilumab weekly (higher than the approved adult dose [300 mg every 2 weeks]) in adults with moderate-to-severe AD who participated in previous controlled dupilumab studies. Placebo + topical corticosteroids (TCS) and dupilumab 300 mg weekly + TCS arms of the 52-week CHRONOS trial (NCT02260986) are provided for comparison because OLE lacks a control arm. CHRONOS was selected because it was the largest and longest controlled study when concomitant TCS was used. Infection data are based on the Medical Dictionary for Regulatory Activities search: Primary System Organ Class “Infections and Infestations;” incidence is reported as the number of patients per 100 patient-years (nP/100PY).
Results: A total of 2677 patients were treated in OLE; 315 with placebo + TCS and 315 with dupilumab + TCS in CHRONOS. The overall exposure-adjusted incidence rate (nP/100PY) of infections in OLE (74.1) was lower than in CHRONOS placebo + TCS (107.0) and dupilumab + TCS (93.7) groups. The incidence of infections (nP/100PY) leading to treatment discontinuation (0.4) and serious/severe infections (1.4) in OLE was lower than CHRONOS placebo + TCS (0.9 and 2.1, respectively).
Conclusion: In comparison with the placebo arm of the 52-week CHRONOS trial, dupilumab 300 mg weekly for up to 3 years in adults with moderate-to-severe AD was associated with a lower incidence of overall infections, serious/severe infections, and infections leading to treatment discontinuation.
Funded by Sanofi/Regeneron
5-Period, 5-treatment crossover study to compare the pharmacokinetics of intranasal and intramuscular epinephrine administration in healthy adult participants
David Dworaczyk, Ph.D., and Allen Hunt, M.D.
Introduction: Intramuscular (IM) epinephrine via autoinjector has suboptimal compliance and/or use; alternatives are needed. We compared the bioavailability and cardiovascular effects of intranasal (IN) epinephrine nasal spray versus IM epinephrine.
Methods: This open-label, randomized, 5-treatment, 5-way crossover study included 25 healthy participants aged 19–45 years. Epinephrine administrations were 6.6 mg IN (1 × 6.6-mg), 4.4 mg IN (2 × 2.2 mg), 8.8 mg IN (2 × 4.4 mg), 13.2 mg IN (2 × 6.6 mg), and 0.3 mg IM (1 × 0.3-mg); second IN administration within 10 seconds after first dose (opposite nostril); ≥1 day washout. Epinephrine concentrations and cardiovascular effects were measured (–30 to 360 minutes). Pharmacokinetic (PK) parameters evaluated included the area under the plasma concentration-time curve (AUC) from 0 to 10, 20, 30, 60, and 360 minutes (i.e., AUC0–10, AUC0–20, AUC0–30, AUC0–60, AUC0–360), maximum observed concentration from time 0 to 10 minutes (Cmax[10 minutes]) and Cmax. PK parameters were analyzed by analysis of variance. Safety was assessed.
Results: Aside from AUC0–10, AUCs and Cmax values were greater after 6.6 mg IN versus 0.3 mg IM epinephrine (AUC0–10, 936 versus 979 minutes*pg/mL; AUC0–20, 3054 versus 2273 minutes*pg/mL; AUC0–30, 5291 versus 3756 minutes*pg/mL; AUC0–60, 10,171 versus 7433 minutes*pg/mL; AUC0–360, 25,461 versus 15,163 minutes*pg/mL; Cmax(10 minutes), 277 versus 246; Cmax, 293 versus 238 pg/mL). After 20 minutes, baseline-corrected epinephrine concentrations ≥ 100 pg/mL were reached by 100% (13.2 mg IN), 80% (6.6 mg and 8.8 mg IN, 0.3 mg IM), and 60% (4.4 mg IN) of participants; epinephrine concentrations ≥ 200 pg/mL were reached by 64% (13.2 mg IN), 60% (6.6 mg IN), 56% (8.8 mg IN and 0.3 mg IM), and 32% (4.4 mg IN) of participants. IN epinephrine had no clinically meaningful heart rate/blood pressure effects.
Conclusion: Epinephrine bioavailability and cumulative PK data demonstrate that the single 6.6 mg IN epinephrine dose was comparable with or greater than dosing with the 0.3 mg IM epinephrine autoinjector, with similar cardiovascular effects.
Funded by Bryn Pharma, LLC
Recombinant human C1 esterase inhibitor as short-term prophylaxis during dental surgery in a 5-year-old with hereditary angioedema
Carly Hopkins, P.A.-C., Nami Park, Pharm.D., and S. Reed Shimamoto, M.D.
Introduction: Recombinant human C1 esterase inhibitor (rhC1-INH) is indicated in the United States for the treatment of acute attacks of hereditary angioedema (HAE) in adolescents/adults, and in the European Union for patients aged ≥2 years. rhC1-INH is administered by using weight-based dosing (<84 kg, 50 U/kg; ≥84 kg, 4200 U). HAE attacks, characterized by disabling and painful swelling, are generally unpredictable, but triggers can include dental and medical procedures. A preemptive management plan for patients with HAE can minimize the attack risk. Global HAE guidelines recommend short-term prophylaxis with C1-INH concentrate, administered as close as possible to initiation of the procedure.
Methods: We present the case report of a child with HAE due to C1 inhibitor deficiency who received rhC1-INH as short-term prophylaxis to prevent potential breakthrough HAE attacks during dental surgery.
Results: A male with a paternal history of HAE was diagnosed with type I HAE at age 3 years. He had no other medical conditions and was not receiving long-term prophylaxis. At age 4.8 years, he needed to have several dental crown repairs and/or cavities addressed, which would require undergoing anesthesia and intubation. Given that he had not previously undergone a major medical procedure and the planned procedure invasiveness, including intubation, we recommended short-term prophylaxis to reduce the risk of an HAE attack. The child (weight, ∼17 kg at time of surgery), was prescribed rhC1-INH 50 U/kg (850 U) the night before the procedure and rhC1-INH 50 U/kg (850 U) to be administered 30 − 60 minutes before beginning the outpatient dental procedure. He tolerated the anesthesia and dental procedure well, and no HAE attacks were reported through at least 7 days postprocedure. No adverse effects related to rhC1-INH administration were observed.
Conclusions: Short-term prophylaxis with rhC1-INH before a dental procedure seemed efficacious and safe in a child < 5 years of age with HAE.
Funded by Pharming Healthcare Inc.