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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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Selective local anesthesia versus corticosteroid infiltration on low back pain: a randomized clinical trial.
Valencia Moya, A, Navarro Suay, R, Fernández González, JA, Gutiérrez Ortega, C, Panadero Useros, T, Mestre Moreiro, C
Revista espanola de anestesiologia y reanimacion. 2020;(1):1-7
Abstract
ANTECEDENTS AND OBJECTIVE Local infiltrations are second line therapy in the treatment of chronic low back pain, although their use is controversial in the literature. Our objective was to compare the effectiveness of 2 types of infiltration at the paravertebral lumbar level in two groups of patients diagnosed with low back pain: corticosteroids, and selective local anaesthetic administered using segmental neural therapy (SNT). MATERIAL AND METHODS Double-blind clinical trial in 55 patients diagnosed with low back pain in the neurosurgery department of the Hospital Central de la Defensa Gómez Ulla. Patients were randomised to 2 treatment groups to receive either paravertebral injections of corticosteroids or SNT. Outcomes were measured using a visual analogue scale, the Oswestry Disability Index, the Short Form-36, and patient satisfaction at the start of treatment (baseline) and at 3 and 12 months post intervention. RESULTS The combined treatment group showed a statistically significant improvement in Oswestry Disability Index at 3 months. The SNT group showed a statistically significant improvement in baseline visual analogue scale vs. visual analogue scale at 3 (1.398cm, p=0.001) and 12 months (0.791cm, p=0.007). No differences were observed in the remaining variables measured. The percentage of patients that would repeat the treatment was 81% and 83%, respectively. CONCLUSIONS Significant pain relief was achieved with SNT, and disability improved with the combined treatment. Although clinical improvement was limited, patients were satisfied. Local infiltrations should be considered as an alternative treatment for chronic low back pain. CLINICAL TRIAL REGISTRATION This clinical trial was registered at the European Union Clinical Trials Register with EUDRA-CT number 2015-001146-29.
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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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Copeptin levels upon corticosteroid treatment in acute community-acquired pneumonia.
Popovic, M, Blum, CA, Christ-Crain, M
Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2019;(2):e1
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Comparison between montelukast and tiotropium as add-on therapy to inhaled corticosteroids plus a long-acting β2-agonist in for patients with asthma.
Hoshino, M, Akitsu, K, Ohtawa, J
The Journal of asthma : official journal of the Association for the Care of Asthma. 2019;(9):995-1003
Abstract
Objective: Asthma often remains uncontrolled despite treatment with inhaled corticosteroids (ICS) alone or with ICS plus a long-acting β2-agonist (LABA). The recommended alternative is the addition of either montelukast or tiotropium. The aim of this study was to compare the effects of montelukast and tiotropium on airway inflammation and remodeling in persistent asthma. Methods: Eighty-seven patients with asthma were treated with budesonide and formoterol (640/18 μg); then, the patients were randomly allocated to three groups to receive oral montelukast (10 mg/day), inhaled tiotropium (5 μg/day), or no add-on to the maintenance therapy for 48 weeks. Fractional exhaled nitric oxide (FeNO) and pulmonary function were measured, and quantitative computed tomography was performed. Results: Compared to the maintenance therapy, add-on montelukast significantly decreased FeNO (p < 0.05) and improved airflow obstruction (p < 0.05), whereas airway dimensions remained unchanged. Changes in FeNO were significantly correlated with changes in FEV1 (r = -0.71, p < 0.001). In contrast, the addition of tiotropium significantly decreased airway wall area corrected for body surface area (WA/BSA) (p < 0.05), decreased wall thickness (T/√BSA) (p < 0.05) and improved airflow obstruction (p < 0.05) with no change in FeNO. Changes in WA/BSA and T/√BSA were significantly correlated with the change in percentage predicted FEV1 (r = -0.84, p < 0.001 and r = -0.59, p < 0.01, respectively). Conclusions:Adding either montelukast or tiotropium to ICS/LABA may provide additive benefits with respect to the pulmonary function and airway inflammation or remodeling in patients with 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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Mucosal Healing and Bacterial Composition in Response to Enteral Nutrition Vs Steroid-based Induction Therapy-A Randomised Prospective Clinical Trial in Children With Crohn's Disease.
Pigneur, B, Lepage, P, Mondot, S, Schmitz, J, Goulet, O, Doré, J, Ruemmele, FM
Journal of Crohn's & colitis. 2019;(7):846-855
Abstract
AIMS: Exclusive enteral nutrition [EEN] is as efficacious as corticosteroids [CS] to induce remission in Crohn's disease [CD], without their adverse effects. EEN seems to be more efficient than steroids to induce mucosal healing, but the underlying molecular mechanisms are only sparsely understood. We aimed in the present work to study the anti-inflammatory effects of EEN with Modulen IBD® vs CS in active paediatric CD, and to assess its modulatory effects on the intestinal microbiota as compared with steroids. MATERIALS AND METHODS Nineteen patients with new-onset active CD (Harvey-Bradshaw index [HBI] >5), aged from 6 to 17 years, were included in this prospective randomised induction trial with CS [n = 6] or EEN [n = 13]. Patients were assessed at Weeks 0 and 8 using clinical parameters HBI, endoscopic findings (Crohn's Disease Endoscopic Index of Severity [CDEIS] score) and analysis of faecal microbiota composition. RESULTS At 8 weeks, clinical remission [HBI <5] was achieved in 13/13 patients on EEN and 5/6 patients on steroids; the mucosal healing rate was significantly higher in the EEN [89%] compared with steroid group [17%]. There were no significant differences between groups regarding biological markers, but the intestinal microbiota profiles shifted upon EEN-induced remission to a higher proportion of Ruminococcus bacteria compared with steroid-induced remission [p = 0.049], and with higher proportions of bacteria belonging to Clostridium in EEN-treated patients. CONCLUSIONS Both steroid and EEN induced clinical remission. However, patients with EEN-induced remission showed a higher rate of mucosal healing and this was associated with a different gut microbiota compositional shift in these children.
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Residual endogenous corticosteroid production in patients with adrenal insufficiency.
Vulto, A, Bergthorsdottir, R, van Faassen, M, Kema, IP, Johannsson, G, van Beek, AP
Clinical endocrinology. 2019;(3):383-390
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Abstract
OBJECTIVE This study aimed at comparing precursors of endogenous corticosteroid production in patients with primary adrenal insufficiency and in secondary adrenal insufficiency. DESIGN Twenty patients with primary adrenal insufficiency and matched controls and 19 patients with secondary adrenal insufficiency participated in this ancillary analysis of two different studies. PATIENTS AND MEASUREMENTS Patients with primary adrenal insufficiency were on stable hydrocortisone and fludrocortisone therapy. Patients with secondary adrenal insufficiency received two different doses of hydrocortisone in a randomized crossover study. Main outcome measures were concentrations of precursors of cortisol and aldosterone measured by LC-MS/MS RESULTS Compared to controls, progressively lower concentrations of the glucocorticoid precursors 11-deoxycortisol, 11-deoxycorticosterone and corticosterone concentrations were found in patients with secondary adrenal insufficiency on lower hydrocortisone dose, secondary adrenal insufficiency on higher hydrocortisone dose and primary adrenal insufficiency, respectively. Half of the primary adrenal insufficient patients showed evidence of residual endogenous cortisol or aldosterone synthesis, as determined by quantifiable 11-deoxycortisol, 11-deoxycorticosterone and corticosterone conce ntrations. In secondary adrenal insufficient patients with higher endogenous cortisol production, as indicated by 11-deoxycortisol concentrations above the median, no increased cortisol exposure was observed both by plasma pharmacokinetic parameters and 24-hour free cortisol excretion in urine. CONCLUSIONS Adrenal corticosteroid production is likely to continue during treatment in a considerable percentage of patients with both primary and secondary adrenal insufficiency. In patients with secondary adrenal insufficiency, this synthesis appears to be sensitive to the dose of hydrocortisone. However, the residual corticosteroid concentrations were quantitatively low and its clinical significance remains therefore to be determined.
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Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial.
Devereux, G, Cotton, S, Fielding, S, McMeekin, N, Barnes, PJ, Briggs, A, Burns, G, Chaudhuri, R, Chrystyn, H, Davies, L, et al
JAMA. 2018;(15):1548-1559
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IMPORTANCE Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD. OBJECTIVE To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD. DESIGN, SETTING, AND PARTICIPANTS The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites. INTERVENTIONS Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787). MAIN OUTCOMES AND MEASURES The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period. RESULTS Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%). CONCLUSIONS AND RELEVANCE Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN27066620.
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Effect of Different Volumes on Pain Relief in Patient Receiving Fluoroscopic Guided Interlaminar Lumbar Epidural Steroid Injection.
Makkar, JK, Kumar, B, Jain, K, Dhutt, SS, Batra, YK, Singh, PM
Pain physician. 2018;(3):243-250
Abstract
BACKGROUND Epidural steroids injections (ESI) are frequently used to treat lumbar radicular pain. Although different volume have been used for interlaminar ESI in adults, there is no controlled trial comparing the effect of different volumes on pain relief for the same dose of steroid . OBJECTIVE To compare the effect of increase in volume of epidural drug on pain relief in lumbar ESI. STUDY DESIGN Randomized double blind trial SETTING Pain OR of a tertiary care centre METHODS Sixty patients were randomly allocated to 1 of 3 groups: Group A (4 mL), Group B (6 mL), and Group C (8 mL). Pain was evaluated using visual analog scale (VAS) and improvement in disability using modified Oswestry Disability Questionnaire scores (MODQS) at 2, 4, 8, 12, and 24 weeks. Patients having less than 50% pain relief from baseline received an additional epidural injection of the same volume with a maximum of 3 injections at least 15 days apart. The primary objective of the study was incidence of patients attaining more than 50% pain relief at 6 months. Secondary outcome included MODQS and pattern of spread of iodinated contrast on fluoroscopy. RESULTS At the end of 6 months, there was no significant difference in the effective pain relief between the 3 groups (Group A-16/22 (72.7%), Group B-15/20 (75%), Group C-13/18 (72.2%); P = 0.98, chi- square test). All groups demonstrated a significant reduction in mean VAS scores. There was no significant intergroup difference in VAS sores and MODQS at all the time intervals. The pattern of contrast spread did not differ between the 3 groups. LIMITATION Not a placebo controlled trial. CONCLUSIONS An increase in volume of the injectate from 4 mL to 8 mL did not increase the efficacy of interlaminar ESI. KEY WORDS Epidural steroid, volume, low back pain, interlaminar.