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Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.
Reich, K, Teixeira, HD, de Bruin-Weller, M, Bieber, T, Soong, W, Kabashima, K, Werfel, T, Zeng, J, Huang, X, Hu, X, et al
Lancet (London, England). 2021;(10290):2169-2181
Abstract
BACKGROUND Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis. METHODS In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18-75 years) and adolescents (aged 12-17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting. FINDINGS Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8-45·4] for the upadacitinib 15 mg group and 50·6% [43·8-57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1-34·9] for the upadacitinib 15 mg group and 47·6% [41·1-54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group. INTERPRETATION Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit-risk profile in adults and adolescents with moderate-to-severe atopic dermatitis. FUNDING AbbVie.
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Association of Antenatal Corticosteroids and Magnesium Sulfate Therapy With Neurodevelopmental Outcome in Extremely Preterm Children.
Gentle, SJ, Carlo, WA, Tan, S, Gargano, M, Ambalavanan, N, Chawla, S, Bell, EF, Bann, CM, Hintz, SR, Heyne, RJ, et al
Obstetrics and gynecology. 2020;(6):1377-1386
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Abstract
OBJECTIVE To test the primary hypothesis that extremely preterm children antenatally exposed to both magnesium sulfate and antenatal corticosteroids have a lower rate of severe neurodevelopmental impairment or death compared with those exposed to antenatal corticosteroids alone. METHODS This was a prospective observational study of children born at 22 0/7-26 6/7 weeks of gestation from 2011 to 2014 at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network hospitals (N=3,093). The primary outcome was severe neurodevelopmental impairment or death at 18-26 months of corrected age follow-up based on exposure to antenatal corticosteroids and magnesium sulfate or antenatal corticosteroids alone. Secondary outcomes included components of severe neurodevelopmental impairment by exposure group and comparisons of severe neurodevelopmental impairment or death between children exposed to both antenatal corticosteroids and magnesium sulfate with those exposed to magnesium sulfate alone or to neither antenatal corticosteroids nor magnesium sulfate. Logistic regression models adjusted for background characteristics. RESULTS Children exposed to both antenatal corticosteroids and magnesium sulfate had a lower rate of severe neurodevelopmental impairment or death (813/2,239, 36.3%) compared with those exposed to antenatal corticosteroids alone (225/508, 44.3%; adjusted odds ratio [aOR] 0.73; 95% CI 0.58-0.91), magnesium sulfate alone (47/89, 53%; aOR 0.49; 95% CI 0.29-0.82), or neither therapy (121/251; 48.2%; aOR 0.66, 95% CI 0.49-0.89). Similarly, children exposed to both antenatal corticosteroids and magnesium sulfate had a lower rate of death compared with either or neither therapy, but the rate of severe neurodevelopmental impairment among survivors did not differ between exposure groups. CONCLUSION In children born between 22 0/7 and 26 6/7 weeks of gestation, exposure to both antenatal corticosteroids and magnesium sulfate was associated with lower rates of severe neurodevelopmental impairment or death and death compared with exposure to antenatal corticosteroids alone. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT00063063.
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Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients.
Rohmer, J, Couteau-Chardon, A, Trichereau, J, Panel, K, Gesquiere, C, Ben Abdelali, R, Bidet, A, Bladé, JS, Cayuela, JM, Cony-Makhoul, P, et al
American journal of hematology. 2020;(11):1314-1323
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FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.
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DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics.
Wang, AL, Gruzieva, O, Qiu, W, Kebede Merid, S, Celedón, JC, Raby, BA, Söderhäll, C, DeMeo, DL, Weiss, ST, Melén, E, et al
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019;(9):1225-1234
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BACKGROUND Response to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known. OBJECTIVE To examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma. METHODS Epigenome-wide DNA methylation was analysed in individuals on inhaled corticosteroids in three independent and ethnically diverse cohorts-Childhood Asthma Management Program (CAMP); Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE); and Genetic Epidemiology of Asthma in Costa Rica Study (GACRS). Treatment response was evaluated using two definitions, the absence of emergency department visits and/or hospitalizations and the absence oral corticosteroid use while on inhaled corticosteroid therapy. CpG sites meeting nominal significance (P < 0.05) for each outcome were combined in a three-cohort meta-analysis with adjustment for multiple testing. DNA methylation was correlated with gene expression using Pearson and partial correlations. RESULTS In 154 subjects from CAMP, 72 from BAMSE, and 168 from GACRS, relative hypomethylation of cg00066816 (171 bases upstream of IL12B) was associated with the absence of emergency department visits and/or hospitalizations (Q = 0.03) in all cohorts and lower IL12B expression (ρ = 0.34, P = 0.01) in BAMSE. Relative hypermethylation of cg04256470 (688 bases upstream of CORT) was associated with the absence of oral corticosteroid use (Q = 0.04) in all cohorts and higher CORT expression (ρ = 0.20, P = 0.045) in CAMP. CONCLUSION AND CLINICAL RELEVANCE Differential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics. Pharmaco-methylation can identify novel markers of treatment sensitivity in asthma.
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Randomized, Open-Label, Phase IV, Korean Study of Kidney Transplant Patients Converting From Cyclosporine to Prolonged-Release Tacrolimus Plus Standard- or Reduced-Dose Corticosteroids.
Baek, CH, Kim, CD, Lee, DR, Kim, YH, Yang, J, Kim, BS, Lee, JS, Han, SY, Kim, SW, Lee, S, et al
Transplantation proceedings. 2019;(3):749-760
Abstract
BACKGROUND This 24-week, multicenter, randomized, exploratory, comparative, open-label, phase-IV study assessed the safety and efficacy of prolonged-release tacrolimus (PR-T) with reduced-dose versus standard-dose corticosteroids in stable kidney transplant recipients in Korea after converting from cyclosporine-based therapy. METHODS At baseline, patients were converted from cyclosporine-based to PR-T-based immunosuppression and randomized (1:1) to receive either corticosteroids maintained at prestudy dose (standard-dose group) or tapered from week 4 to 50% of the prestudy dose by week 12 (reduced-dose group). Patients were seen at baseline and weeks 1, 4, 12, and 24. The primary endpoint was change in estimated glomerular filtration rate (Modification-of-Diet-in-Renal-Disease-4) between baseline and week 24. Secondary endpoints included either acute rejection or patient-reported satisfaction with PR-T. Adverse events (AEs) were recorded. RESULTS Overall, 150 patients were randomized into a reduced-dose group (n = 73) and a standard-dose group (n = 77). At week 24, mean ± standard deviation for corticosteroid dose was 2.5 ± 0.9 mg and 5.0 ± 1.3 mg, respectively. Mean change in estimated glomerular filtration rate from baseline to week 24 was +1.5 ± 9.1 mL/min/1.73 m2 (P = .1567) and +3.4 ± 10.6 mL/min/1.73 m2 (P = .0065), respectively, and not significantly different between groups. There were no acute rejection episodes. Most respondents (>70%) considered PR-T more convenient than cyclosporine. AE incidence was similar between groups. The most common AEs experienced by ≥3% of patients in either treatment group were gastrointestinal events (20.8% and 28.6% of patients receiving reduced- and standard-dose corticosteroids, respectively). Most AEs in both treatment groups were mild or moderate in severity. CONCLUSION Renal function was maintained following conversion from cyclosporine to PR-T, irrespective of corticosteroid regimen; PR-T enables reduced corticosteroid dosage.
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Treatment, outcomes and costs of asthma exacerbations in Chilean children: a prospective multicenter observational study.
Herrera, AM, Brand, P, Cavada, G, Koppmann, A, Rivas, M, Mackenney, J, Sepúlveda, H, Wevar, ME, Cruzat, L, Soto, S, et al
Allergologia et immunopathologia. 2019;(3):282-288
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OBJECTIVE To describe potential regional variations in therapies for severe asthma exacerbations in Chilean children and estimate the associated health expenditures. METHODS Observational prospective cohort study in 14 hospitals over a one-year period. Children five years of age or older were eligible for inclusion. Days with oxygen supply and pharmacological treatments received were recorded from the clinical chart. A basic asthma hospitalization basket was defined in order to estimate the average hospitalization cost for a single patient. Six months after discharge, new visits to the Emergency Room (ER), use of systemic corticosteroids and adherence to the controller treatment were evaluated. RESULTS 396 patients were enrolled. Patients from the public health system and from the north zone received significantly more days of oxygen, systemic corticosteroids and antibiotics. Great heterogeneity in antibiotic use among the participating hospitals was found, from 0 to 92.3% (ICC 0.34, 95% CI 0.16-0.52). The use of aminophylline, magnesium sulfate and ketamine varied from 0 to 36.4% between the different Pediatric Intensive Care Units (ICC 0.353, 95% CI 0.010-0.608). The average cost per inpatient was of $1910 USD. 290 patients (73.2%) completed the follow-up six months after discharge. 76 patients (26.2%) were not receiving any controller treatment and nearly a fourth had new ER visits and use of systemic corticosteroids due to new asthma exacerbations. CONCLUSIONS Considerable practice variation in asthma exacerbations treatment was found among the participating hospitals, highlighting the poor outcome of many patients after hospital discharge, with an important health cost.
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A multinational observational study identifying primary care patients at risk of overestimation of asthma control.
Kritikos, V, Price, D, Papi, A, Infantino, A, Ställberg, B, Ryan, D, Lavorini, F, Chrystyn, H, Haughney, J, Lisspers, K, et al
NPJ primary care respiratory medicine. 2019;(1):43
Abstract
Factors related to the discrepancy between patient-perceived and actual disease control remain unclear. Identifying patients at risk of overestimation of asthma control remains elusive. This study aimed to (i) investigate the relationship between patient-reported and actual level of asthma control (ii), compare the characteristics between patients who believe their asthma is well controlled that accurately report 'well-controlled' asthma with those that do not, and (iii) identify factors associated with inaccurately reported 'well-controlled' asthma. A historical, multinational, cross-sectional study using data from the iHARP (initiative Helping Asthma in Real-life Patients) review service for adults with asthma prescribed fixed-dose combination therapy. Data from 4274 patients were analysed. A major discrepancy between patient-reported and Global Initiative for Asthma defined asthma control was detected; 71.1% of patients who reported 'well-controlled' asthma were inaccurate in their perception despite receiving regular maintenance therapy. Significant differences were noted in age, gender, body mass index, education level, medication use, side effects, attitudes to preventer inhaler use, inhaler technique review and respiratory specialist review between patients who accurately reported 'well-controlled' asthma and those who did not. Independent risk factors associated with inaccurately reported 'well-controlled' asthma were: having taken a maximum of 5-12 puffs or more of reliever inhaler on at least one day within the previous 4 weeks; being female; having seen a respiratory specialist more than a year ago (rather than in the previous year); and having required oral corticosteroids for worsening asthma in the previous year. The study highlighted the significant hidden burden associated with under-recognition of poor asthma control, on the part of the patient and the need for targeted interventions designed to address the continuing discrepancy between perceived and actual disease control.
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FCER2 T2206C variant associated with FENO levels in asthmatic children using inhaled corticosteroids: The PACMAN study.
Karimi, L, Vijverberg, SJH, Farzan, N, Ghanbari, M, Verhamme, KMC, Maitland-van der Zee, AH
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019;(11):1429-1436
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BACKGROUND The FCER2 gene, via encoding of the CD23 receptor, plays an important role in the regulation of IgE responses. A genetic variant of the FCER2 gene (T2206C) was previously shown to be associated with IgE levels in asthmatic children. IgE sensitization has also been linked to increased levels of fractional exhaled nitric oxide (FENO). OBJECTIVE To investigate whether the FCER2 T2206C variant influences FENO levels in asthmatic children with a reported use of inhaled corticosteroids (ICS). METHODS This cross-sectional study involved 593 asthmatic children with a reported use of ICS, availability of FENO measurements and genotyping data on the FCER2 T2206C variant (rs28364072). An additive genetic model was assumed, and the association between the FCER2 T2206C variant and the log-transformed (ln) FENO levels was evaluated using linear regression analysis, adjusted for age, sex, adapted British Thoracic Society (BTS) treatment steps and atopy. RESULTS The mean age of the population was 9.1 ± 2.2 years, and the median of FENO levels was 13.0 ppb with an interquartile range (IQR) of (8.0-27.5 ppb). The minor allele (G) frequency of rs28364072 was 29.6%, and each extra copy of the G allele was significantly associated with a lower level of the geometric mean of FENO (log scale, β = -0.12, 95% CI: -0.23, -0.02). CONCLUSION AND CLINICAL RELEVANCE Our results showed that the FCER2 T2206C variant was significantly associated with lower FENO levels in carriers of the G allele. Nevertheless, this SNP contributed little to the variability in FENO levels in this patient population. Our findings contribute to the present knowledge on FENO in asthmatic children; however, future replication studies are required to establish the role of this gene in relation to FENO.
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An Open-Label, Multi-Institutional, Randomized Study to Evaluate the Additive Effect of a Leukotriene Receptor Antagonist on Cough Score in Patients with Cough-Variant Asthma Being Treated with Inhaled Corticosteroids.
Miwa, N, Nagano, T, Ohnishi, H, Nishiuma, T, Takenaka, K, Shirotani, T, Nakajima, T, Dokuni, R, Kawa, Y, Kobayashi, K, et al
The Kobe journal of medical sciences. 2018;(4):E134-E139
Abstract
Cough-variant asthma is one of the most common reasons for chronic cough. It is important to treat appropriately cough-variant asthma because 30% to 40% of cough-variant asthma becomes a typical asthma. However, little is known about the treatment of cough-variant asthma except for inhaled corticosteroid (ICS). The aim of this study was to validate the additive efficacy of a leukotriene receptor antagonist (LTRA) on cough score and respiratory function in patients with cough-variant asthma being treated with ICS. A total 28 patients were randomly assigned to either an ICS + LTRA group or an ICS group. There were statistically significant improvements in cough scores in the ICS + LTRA group from 0 weeks (6.7 ± 4.4) to 2 weeks (2.9 ± 3.2) (P < 0.05), 4 weeks (0.7 ± 1.1) (P < 0.001), and 8 weeks (0.8 ± 1.2) (P < 0.001). However similar improvements were not evident in the ICS group from 0 weeks (6.7 ± 4.4) to 2 weeks (5.6 ± 10.0) (P = 0.59), 4 weeks (4.6 ± 7.6) (P = 0.32), and 8 weeks (2.9 ± 5.2) (P = 0.08). On the other hand, no significant changes were evident in the forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC). In conclusion, the LTRA was useful in improving cough in patients with cough-variant asthma, even though it appeared to be ineffective in improving respiratory function.
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Vitamin D3 therapy in patients with asthma complicated by sinonasal disease: Secondary analysis of the Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma trial.
Jiao, J, King, TS, McKenzie, M, Bacharier, LB, Dixon, AE, Codispoti, CD, Dunn, RM, Grossman, NL, Lugogo, NL, Ramratnam, SK, et al
The Journal of allergy and clinical immunology. 2016;(2):589-592.e2