Ανασκόπηση Βιβλιογραφίας στο Άσθμα: Τα 5 κορυφαία άρθρα σχετικά με τους φαινοτύπους του άσθματος του τελευταίου έτους

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1 Ανασκόπηση Βιβλιογραφίας στο Άσθμα: Τα 5 κορυφαία άρθρα σχετικά με τους φαινοτύπους του άσθματος του τελευταίου έτους Στυλιανός Κ. Βιττωράκης MD, PhD. Πνευμονολόγος, Χανιά Ερέτρια, 16 Μαρτίου 2014

2 Exploring the Effects of Omalizumab in Allergic Asthma: An Analysis of Biomarkers in the EXTRA Study Nicola A. Hanania, Sally Wenzel, Karin Rose n, Hsin-Ju Hsieh, Sofia Mosesova, David F. Choy, Preeti Lal, Joseph R. Arron, Jeffrey M. Harris, and William Busse AJRCC 2013; 187:

3 Exploring the Effects of Omalizumab in Allergic Asthma: An Analysis of Biomarkers in the EXTRA Study AIM OF THE STUDY: The identification of biomarkers (of Th 2 inflammation) that predict response to therapy with omalizumab Fractional exhaled nitric oxide (FE NO ), Peripheral blood eosinophil count Serum periostin (generated by airway epithelial cells in response to IL-13,) Note: Serum IgE (total or ag-specific) is not particularly predictive of response to anti- IgE therapy. Other biomarkers can not be measured reliably in blood due to very low levels (IL-1, IL-13). Response to anti-ige treatment can only be assessed after 4 months of therapy. AJRCC 2013; 187:

4 Exploring the Effects of Omalizumab in Allergic Asthma: An Analysis of Biomarkers in the EXTRA Study METHODS EXTRA study: prospective, multicenter, randomized, parallel-group, double-blind, placebo-controlled study (48 weeks). Patients (12-75 yo) were randomized in a 1:1 ratio to receive: high-dose ICS and LABA( ± additional controller medications) + placebo high-dose ICS and LABA( ± additional controller medications) + omalizumab AJRCC 2013; 187:

5 Exploring the Effects of Omalizumab in Allergic Asthma: An Analysis of Biomarkers in the EXTRA Study Cut-off levels for biomarkers: median value Two subgroups: Low FE NO / eosinophil/periostin High FE NO / eosinophil/periostin Low High post hoc analysis: FE NO <19,5ppb 19,5ppb <24ppb 24ppb (ATS 2011) Blood Eosinophils <260μL 260μL Serum Periostin <50ng/ml 50ng/ml Primary Endpoint: number of observed protocol defined exacerbations treatment with systemic corticosteroids >3 days increase of >20 mg in the average daily OCS dose Secondary Endpoints: total asthma symptom score, albuterol use, Asthma quality of life questionnaire (AQLQ), % predicted FEV1 AJRCC 2013; 187:

6 Exploring the Effects of Omalizumab in Allergic Asthma: An Analysis of Biomarkers in the EXTRA Study randomization, groups and study completion AJRCC 2013; 187:

7 Exploring the Effects of Omalizumab in Allergic Asthma: An Analysis of Biomarkers in the EXTRA Study RESULTS: Primary Endpoint Substantial reduction from placebo in exacerbation rate for patients on omalizumab was observed in each biomarkers high subgroup. AJRCC 2013; 187:

8 Exploring the Effects of Omalizumab in Allergic Asthma: An Analysis of Biomarkers in the EXTRA Study STEPP analysis was used to explore alternative thresholds. Post hoc analysis with higher cut-off value (24 ppb) for FeNO. AJRCC 2013; 187:

9 Exploring the Effects of Omalizumab in Allergic Asthma: An Analysis of Biomarkers in the EXTRA Study Time to 1 st exacerbation FeNO Eosinophils The Kaplan-Meier curves and the hazard ratios of the exacerbation-free rate in each of the three biomarker-high subgroups favored the omalizumab group over placebo; In each of the biomarker-low subgroups, the difference between the omalizumab and placebo group was minimal Periostin

10 Exploring the Effects of Omalizumab in Allergic Asthma: An Analysis of Biomarkers in the EXTRA Study Secondary endpoints AJRCC 2013; 187:

11 Observational study in severe asthmatic patients after discontinuation of omalizumab for good asthma control M. Molimard, L. Mala, I. Bourdeix, V. Le Gros Respir Med Feb 12. [Epub ahead of print]

12 Observational study in severe asthmatic patients after discontinuation of omalizumab for good asthma control AIM OF THE STUDY: To investigate (retrospectively) what happens when omalizumab is discontinued in patients with severe, persistent allergic asthma who have responded well to omalizumab treatment. Time to loss of asthma control (after discontinuation of omalizumab) What happens after reintroduction of treatment Notes: No optimal duration treatment is known for omalizumab. There are no guidelines regarding possible discontinuation of omalizumab in responders. Treatment with omalizumab downregulates FcεRI expression on blood basophils and plasmacytoid DCs=> possible disease modifying potential Respir Med Feb 12. [Epub ahead of print]

13 Observational study in severe asthmatic patients after discontinuation of omalizumab for good asthma control METHODS: observational, descriptive, cross-sectional, retrospective study 24 centers in France 61 responder patients (who discontinued omalizumab) Good asthma control: physicians judgment (absence of exacerbation, OS use, symptoms, rescue medication, lung function) Patients medical records showed: either loss of control at some point after the discontinuation of omalizumab or at least 6 months of sustained control post-withdrawal Mean duration of treatment: 22,7±13,1 (range 2,5-59,5) months Respiratory Medicine 2014

14 Observational study in severe asthmatic patients after discontinuation of omalizumab for good asthma control time to lose asthma control after omalizumab discontinuation exacerbation requiring treatment OCS with failure to reestablish control within 1 month after the last dose of OCS Two exacerbations requiring OCS treatment within 1 year Guideline-based criteria of poor control for over a month. 3 GINA criteria and/or increase in ACQ score of over 1.5 and/or ACT score 19 Respiratory Medicine 2014

15 Observational study in severe asthmatic patients after discontinuation of omalizumab for good asthma control SUBJECTS: Respiratory Medicine 2014

16 Observational study in severe asthmatic patients after discontinuation of omalizumab for good asthma control RESULTS Median follow up time: 9,3 months (time to lose control or last date with available data for sustained control) Loss of control: 34 (55.7%) Median time to loss of control: 13 months (mean=20,4±2,6) No correlation was detected between time to loss of control and duration of treatment. Control tended to be sustained for longer in patients whose response had been classified as excellent as opposed to good (median: 17.0 vs months; NS). Respiratory Medicine 2014

17 Observational study in severe asthmatic patients after discontinuation of omalizumab for good asthma control RESUMPTION OF OMALIZUMAB In 20 (of the 34 patients-58.8%) were re-prescribed omalizumab. Excellent response : 6 (30%)patients Good response : 8 (40%) patients. No response: 4 (20%) Short follow-up: 2 patients Limitations of the study: 1. Patients with shorter durations of treatment also had longer follow-up times 2. Observational study 3. No control arm Respiratory Medicine 2014

18 Observational study in severe asthmatic patients after discontinuation of omalizumab for good asthma control Respiratory Medicine 2014

19 N Engl J Med 2013; 368: Dupilumab in Persistent Asthma with Elevated Eosinophil Levels Sally Wenzel, M.D., Linda Ford, M.D., David Pearlman, M.D., Sheldon Spector, M.D., Lawrence Sher, M.D., Franck Skobieranda, M.D.,Lin Wang, Ph.D., Stephane Kirkesseli, M.D., Ross Rocklin, M.D., Brian Bock, D.O., Jennifer Hamilton, Ph.D., Jeffrey E. Ming, M.D., Ph.D., Allen Radin, M.D., Neil Stahl, Ph.D., George D. Yancopoulos, M.D., Ph.D., Neil Graham, M.D., and Gianluca Pirozzi, M.D., Ph.D.

20 Dupilumab in Persistent Asthma with Elevated Eosinophil Levels Dupilumab (SAR231893/REGN668): human monoclonal antibody to IL4Ra (the alpha subunit of the interleukin-4 receptor)- inhibits both IL-4 and IL13 signaling METHODS Randomized, double-blind, placebo-controlled, parallel-group, phase 2A 104 patients (18-65yo) Persistent, moderate-to-severe asthma Elevated blood eosinophil levels 300/μL or sputum eosinophils >3% Medium-dose to high-dose inhaled glucocorticoids plus long-acting betaagonists (Fluticasone 250mcg /Salmetero 50mcgl) 52 patients: dupilumab 300mg subcutaneously once weekly. 52 patients: placebo Wenzel S, N Engl J Med 2013; 368:

21 Dupilumab in Persistent Asthma with Elevated Eosinophil Levels Wenzel S, N Engl J Med 2013; 368:

22 Dupilumab in Persistent Asthma with Elevated Eosinophil Levels STYDY DESIGN Week 4: LABA discontinuation Weeks 6-9: ICS discontinuation 2w 12w 8w Wenzel S, N Engl J Med 2013; 368:

23 Dupilumab in Persistent Asthma with Elevated Eosinophil Levels Primary endpoint : protocol defined exacerbation Reduction of 30% or more in morning PEF from baseline on 2 consecutive days, At least six additional reliever inhalations in a 24-hour period relative to baseline on 2 consecutive days, Exacerbation of asthma requiring systemic glucocorticoid treatment, an increase in inhaled glucocorticoids of at least four times the most recent dose, hospitalization for asthma Secondary endpoints: time to an asthma exacerbation change from baseline at each visit and at week 12 in FEV1, morning and evening PEF, ACQ5 score, Nocturnal awakenings number of albuterolor- levalbuterol inhalations per day. Wenzel S, N Engl J Med 2013; 368:

24 Dupilumab in Persistent Asthma with Elevated Eosinophil Levels RESULTS Wenzel S, N Engl J Med 2013; 368:

25 Dupilumab in Persistent Asthma with Elevated Eosinophil Levels RESULTS-PRIMARY ENDPOINT Patients received the study drug for12 weeks or until an exacerbation occurred. N=23 N=3 The most frequent event qualifying as an exacerbation was reduction in morning PEF and increased use of reliever medication. Wenzel S, N Engl J Med 2013; 368:

26 Dupilumab in Persistent Asthma with Elevated Eosinophil Levels RESULTS- SECONDARY ENDPOINTS A. Time to Exacerbation Wenzel S, N Engl J Med 2013; 368:

27 Dupilumab in Persistent Asthma with Elevated Eosinophil Levels A. Lung Function over time Significant increase from baseline at FEV1 - FEV1% at week 2, which is maintained through week 12 at Dupilumab arm. (despite discontinuation of LABAs and inhaled glucocorticoids) Wenzel S, N Engl J Med 2013; 368:

28 Dupilumab in Persistent Asthma with Elevated Eosinophil Levels B. Asthma Symptoms ACQ5 The ACQ5 score was improved in both study groups at week 1. Subsequently, the ACQ5 score in the dupilumab group continued to improve, with a significant between-group difference by week 3 that was maintained through week 12. Wenzel S, N Engl J Med 2013; 368:

29 Dupilumab in Persistent Asthma with Elevated Eosinophil Levels C. Nocturnal Awakenings Nocturnal awakenings decreased with dupilumab by week 1, and the reduction was maintained and awakenings remained less frequent versus baseline through week 12. Nocturnal awakenings were stable with placebo through week 6, then increased between weeks 6 and 12. Wenzel S, N Engl J Med 2013; 368:

30 Dupilumab in Persistent Asthma with Elevated Eosinophil Levels RESULTS Wenzel S, N Engl J Med 2013; 368:

31 Dupilumab in Persistent Asthma with Elevated Eosinophil Levels BIOMARKERS Wenzel S, N Engl J Med 2013; 368:

32 87% reduction: Is this the magic bullet for difficult-to-control asthma? Limited subpopulation (21% of screened patients)- persistent symptoms+ eosinophilia +treatment with ICS In clinical practice, physicians do not withdraw therapy to induce exacerbations. The first 4 weeks (before withdrawal) - no significant changes in exacerbation rate but only a slight improvement in FEV1 and some biomarkers. The definition of an exacerbation was weighted towards changes in PEFR The study was not designed to show a beneficial ADJUVANT effect of dupilumab on patients with moderate-to-severe asthma.. Safety concern: 4 patients with large increases in eosinophils in dupilumab group Wenzel S, N Engl J Med 2013; 368:

33 Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis Wendy C. Moore, MD, Annette T. Hastie, PhD, Xingnan Li, PhD, MS, Huashi Li, MS, William W. Busse, MD, Nizar N. Jarjour, MD, Sally E. Wenzel, MD Stephen P. Peters, MD, PhD, Deborah A. Meyers, PhD and Eugene R. Bleecker, MD for the National Heart, Lung, and Blood Institute s Severe Asthma Research Program Moore W, JACI 2013

34 Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis The Severe Asthma Research Program (SARP) identified 5 asthma subphenotypes using 34 clinical variables These 5 clinical phenotypes could not be associated with any pathobiologic mechanism due to limited biomarker data AIM OF THE STUDY: To integrate inflammatory cellular measures (sputum counts) with clinical variables. Moore W, JACI 2013

35 Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis METHODS: 423 SARP patients with sputum specimens 2 groups of nonsmoking asthmatic patients : severe non severe (mild to moderate) 15 variables selected for cluster analysis Baseline and max FEV1 and Pred EOS and NEUT % in blood and sputum sex, race, age, age of onset, asthma duration, body mass index (BMI) total number of asthma controllers, dose of corticosteroids, HCU in the past year7 Moore W, JACI 2013

36 Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis 4 groups (clusters A,B,C,D) of severe asthmatics were identified differentiated by inflammatory cell patterns and clinical characteristics. FEV 1 and Sputum neutrophils were the most influential variables for cluster assignment Moore W, JACI 2013

37 Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis Inflammatory Cell Patterns in the 4 clusters Between the clusters, differences in sputum neutrophils percentages were more significant than eosinophils and had greater impact on cluster assignment. Subjects were classified into 4 inflammatory subgroups less or more than median value for each granulocyte: Eosinophils >2%, Eosinophils<2% Neutrophils > 40%, Neutrophils <40% Moore W, JACI 2013

38 Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis Inflammatory Cell Patterns in the 4 clusters As asthma severity increases (clusters C and D), sputum neutrophil percentages increase in nearly all subjects cluster A : low or paucigranulocytic sputum cell pattern (<2% eosinophils and <40% neutrophils, cluster B: eosinophil-predominant pattern (>2% eosinophils and <40% neutrophils) was most frequent(41% of subjects). clusters C and D: increased sputum neutrophil percentages- some subjects showing concurrent increases in sputum eosinophil percentages. Moore W, JACI 2013

39 Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis Clinical characteristics of the 4 clusters Moore W, JACI 2013

40 Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis Clinical characteristics of the 4 clusters Moore W, JACI 2013

41 Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis 4 clusters represent the range of asthma severity, (from mild allergic asthma with to progressively more severe asthma) There is a marked shift in cellular inflammation from eosinophil-predominant to neutrophil-predominant or mixed granulocytic patterns between clusters B and C that appear clinically similar. The neutrophil-predominant and mixed granulocytic patterns were the most frequent patterns observed in the severe asthma clusters The presence of atopy does not exclude a neutrophilic phenotype in subjects with severe asthma. Lung function measures remain the most important variables for the identification of clinical asthma subphenotypes Clinical implications: Severe asthma is associated with sputum neutrophilia with or without eosinophilia, suggesting that new biologic therapies for these patients might need to target both inflammatory cell types. Moore W, JACI 2013

42 Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised doubleblind placebo-controlled trial Guy G Brusselle, Christine VanderStichele, Paul Jordens, René Deman,Hans Slabbynck, Veerle Ringoet, Geert Verleden, Ingel K Demedts,Katia Verhamme, Anja Delporte, Bénédicte Demeyere, Geert Claeys, Jerina Boelens, Elizaveta Padalko, Johny Verschakelen, Georges Van Maele, Ellen Deschepper, Guy F P Joos Brusselle GG, Thorax 2013;68:

43 Azithromycin for prevention of exacerbations in severe asthma (AZISAST) HYPOTHESIS: Does maintenance treatment with low-dose azithromycin decrease the rate of exacerbations in adult patients with severe asthma and frequent exacerbations? Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects Macrolides are used in chronic neutrophilic airway diseases including cystic fibrosis, bronchiectasis and diffuse panbronchiolitis ATS/ ERS Severe asthma Guidelines 2014 Brusselle GG, Thorax 2013;68:

44 Azithromycin for prevention of exacerbations in severe asthma (AZISAST) METHODS: Randomised double-blind placebo-controlled parallel-group multicenter study Severe asthma patients 54 patients 55 patients PRIMARY ENDPOINT: Rate of severe asthma exacerbations (hospitalization; ER visit; and/or need for OCS for at least 3 days) and/or LRTI (requiring antibiotics) SECONDARY OUTCOMES: FEV1, morning PEF, quality of life (AQLQ score) and asthma control (ACQ score). Brusselle GG, Thorax 2013;68:

45 Azithromycin for prevention of exacerbations in severe asthma (AZISAST) RESULTS: Primary endpoints: severe asthma exacerbations and/or LRTI AZ PL Primary Exacer LTRI Hospit. 2 2 Brusselle GG, Thorax 2013;68:

46 Azithromycin for prevention of exacerbations in severe asthma (AZISAST) RESULTS: Subgroup analysis: (blood eosinophilia 200/ml) Azithromycin significantly reduced the rate of primary endpoints and of severe exacerbations compared with placebo in non-eosinophilic severe asthma patients Brusselle GG, Thorax 2013;68:

47 Azithromycin for prevention of exacerbations in severe asthma (AZISAST) RESULTS: Secondary endpoints: At 26 weeks there was a significant improvement in the AQLQ score in the azithromycin group compared with placebo There were no significant between-group differences in the changes in ACQ, FEV1, PEF, use of rescue medication and FeNO Safety: No significant differences in adverse events Brusselle GG, Thorax 2013;68:

48 Azithromycin for prevention of exacerbations in severe asthma (AZISAST) Resistance to macrolides Increase in the proportion of macrolide resistant streptococci at day 30 and day 180 compared to baseline (P=0 01 and P=0.0004), and compared to the placebo group (P=0 002 at Day 180). There is no evidence suggesting that colonisation with macrolideresistant organisms increased the risk of LRTI or pneumonia. Brusselle GG, Thorax 2013;68:

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