1. COPD: Over the Wall of the Second Millennium Bartolome R. Celli, M.D. Brigham and Women’s Hospital Professor of Medicine Harvard Medical School

2. A Trip in Time

3. 2000’s Terrorism increases Gulf War # 2 Espana World Champion!!!! Economic meltdown Pope Francis I Chavez dies

4. # 1 Price # 2 Price # 3 Price 2000’s Social networks High throughtput technology

5. What about COPD? Name recognition. Epidemiology and guidelines The battle against smoking and pollution COPD, not just a lung disease Better treatment. Large pharmacological trials. Different outcomes Phenotypes, comorbidities and complexity The future

6. What about COPD? Name recognition. Epidemiology and guidelines The battle against smoking and pollution COPD, not just a lung disease Better treatment. Large pharmacological trials. Different outcomes Phenotypes, comorbidities and complexity The future

7. Global Burden of Disease Murray and Lopez NEJM 2013;369:448

8. Prevalence of COPD Soriano J et al Lancet

9. Guidelines Many!!!!

10. COPD: Numbers of papers over years PubMed

11. What about COPD? Name recognition. Epidemiology and guidelines The battle against smoking and pollution COPD, not just a lung disease Better treatment. Large pharmacological trials. Different outcomes Phenotypes, comorbidities and complexity The future

12. Smoking: still a problem

13. Vaping E cigarettes Sales in USA in 2013 $ 1 billion

14. Zealots Moderates

15. What about COPD? Name recognition. Epidemiology and guidelines The battle against smoking and pollution COPD, not just a lung disease Better treatment. Large pharmacological trials. Different outcomes Phenotypes, comorbidities and complexity The future

16. FEV1 < 35% “COPD Homogeneity” PT # 1 58 y FEV1: 28 % 1 2 3 4 PT # 2 62 y FEV1: 33% PT # 3 69 y FEV1: 35% PT # 4 72 y FEV1: 34% Cote et al

17. BODE ATS Staging Celli et al. N Engl J Med. 2004;350:1005 #625 #574 #454 #273 #80 #625 #574 #454#273#80 I II III Q1 Q2 Q3 Q4 0.0 0.2 0.4 0.6 0.8 1.0 02652 0.0 0.2 0.4 0.6 0.8 1.0 02652 Probability of Survival

18. RehabilitationUnbeatable Evidence A

19. What about COPD? Name recognition. Epidemiology and guidelines The battle against smoking and pollution COPD, not just a lung disease Better treatment. Large pharmacological trials. Different outcomes Phenotypes, comorbidities and complexity The future

20. B Celli’s Trials type Mega trials > 10,000 Trials 5K to10 K Mini-trials 1K to 5K Pico-trial 100 to 1000 1426Many After 2000

21. FEV1FEV1 QOLQOL EXACERBATIONEXACERBATION St George’s is 3.1 better than placebo and better than baseline 92 ml difference from placebo 25% reduction in exacerbations

22. FEV1FEV1 QOLQOL EXACERBATIONEXACERBATION St George’s is 3.3 units better than placebo and better than baseline 110 ml difference from placebo 16% reduction in exacerbations UPLIFT ®

23. Ultra LABA

25. LAMA Ipratroprium Tiotropium AclidiniumGlycopirroniumUmeclidinium

26. Drug combinations Frequency Development stage Company Formoterol/ aclidinium Twice dailyPhase III*Almirall/Forest Formoterol/ glycopyrrolate Twice dailyPhase II Pearl Therapeutics Olodaterol/ tiotropium Once a dayPhase IIIBI Umeclidinium/ vilanterol Once a dayPhase III*Theravance/GSK Indacaterol/ glycopyrroniu m (QVA149) Once a dayPhase IIINovartis Overview of inhaled LABA/LAMA approved or in development *Detailed data have not been presented publicly

27. SABA SAMA LAMA LABA LABA + LAMA ICS + LABA PDEI 4 How to approach?

28. mMRC 0-1 CAT < 10 mMRC > 2 CAT > 10 Global Strategy for Diagnosis, Management and Prevention of COPD Manage Stable COPD: Pharmacologic Therapy FIRST CHOICE Exacerbations per year > 2 1 0 GOLD 4 GOLD 3 GOLD 2 GOLD 1 SAMA prn or SABA prn LABA or LAMA ICS + LABA or LAMA AB DC ICS + LABA or LAMA

29. > 2 1 0 mMRC 0-1 CAT < 10 GOLD 4 mMRC > 2 CAT > 10 GOLD 3 GOLD 2 GOLD 1 LAMA or LABA or SABA and SAMA LAMA and LABA ICS and LAMA or ICS + LABA and LAMA or ICS + LABA and PDE4-inh or LAMA and LABA or LAMA and PDE4-inh. LAMA and LABA Global Strategy for Diagnosis, Management and Prevention of COPD Manage Stable COPD: Pharmacologic Therapy SECOND CHOICE A DC B Exacerbations per year

30. State of the Art in Hypertension Chobanian A NEJM 2009;361:878

31. Analogy with Hypertension Chobanian A. Shattuck Lecture NEJM 2009; 361:878 “Blood-pressure differences as small as 3/2 mm Hg (2-3 %) between treatment groups have been associated with significant differences in certain outcomes”

32. Analogy with Hypertension “FEV1 differences as small as 100ml (10 %) between treatment groups have been associated with significant differences in certain outcomes”

33. What about COPD? Name recognition. Epidemiology and guidelines The battle against smoking and pollution COPD, not just a lung disease Better treatment. Large pharmacological trials. Different outcomes Phenotypes, complexity and comorbidities The future

34. Inflammation Airflow Limitation Slow declinerFEV 1 Fast decliner Normal or HighBMILow NormalFFMLow NormalLung volumesHigh NormalDLCOLow Slightly impairedExerciseSeverely impaired YesChronic bronchitis No CAD Diabetes Metabolic Syndrome Co-morbiditiesOsteoporosis Skin wrinkling Renal dysfunction Lung Cancer PVD InflammationBiomarkersRepair and ageing Enhanced tissue repair Impaired tissue repair CT scan Significant Emphysema CT scan Minimal or no emphysema CRP IL-6 IL-8 SPD CC-16 SRAGE Genome and Epigenetics

35. Complexity is not new Garden of Earthly Delights Hieronymus Bosch (1450-1516)

36. COPD complexity Agusti A and Vestbo AJRCCM 20122;184:507

37. COPD complexity Agusti A and Vestbo AJRCCM 20122;184:507 Epidemiology Phenotyping OMICS

38. COPD complexity Agusti A and Vestbo AJRCCM 20122;184:507 Epidemiology Phenotyping Genomics Proteomics Metabolomics Visiomics

39. What about COPD? Name recognition. Epidemiology and guidelines The battle against smoking and pollution COPD, not just a lung disease Better treatment. Large pharmacological trials. Different outcomes Phenotypes, comorbidities and complexity The future

40. Genome Transcriptome Proteome Environment Modified from Loscalzo et al Mol Sys Bio 20007;3:124 Metabolome

41. Genome Transcriptome Proteome Environment Inflammation Thrombosis Hemorrhage Fibrosis Immune response Apoptosis Necrosis Cell proliferation Modified from Loscalzo et al Mol Sys Bio 20007;3:124 Metabolome

42. Genome Transcriptome Proteome Environment Inflammation Thrombosis Hemorrhage Fibrosis Immune response Apoptosis Necrosis Cell proliferation Intermediate phenotype Distinct phenotype: Syndrome and clinical disease Modified from Loscalzo et al Mol Sys Bio 20007;3:124 Metabolome

43. Genome Transcriptome Proteome Environment Inflammation Thrombosis Hemorrhage Fibrosis Immune response Apoptosis Necrosis Cell proliferation Abnormal lung function COPD Modified from Loscalzo et al Mol Sys Bio 20007;3:124 Metabolome

44. Predictions The complexity of COPD will be parceled Genes play a role but a significant portion of COPD goes beyond that so epigenetics and the mRNA complex will be researched The “omics” revolution will help Clinical phenotypes are already identifiable. Pathobiological phenotypes will come Smoking cessation and judicious use of current therapies will decrease the impact of COPD The Future is for us to Forge

45. “Querer es poder” Dinorah Croquer “No hay nada como sonar para crear el futuro” Victor Hugo