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“Linee Guida Internazionali su Asma e Rinite” Prof. Leonardo M. Fabbri Department of Pulmonary Diseases University of M

Università degli Studi di Modena e Reggio Emilia. “Linee Guida Internazionali su Asma e Rinite” Prof. Leonardo M. Fabbri Department of Pulmonary Diseases University of Modena & Reggio Emilia, Italy http//pneumologia.unimo.it. Modena 07/05/2004. TREATMENT OPTIONS IN ASTHMA.

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“Linee Guida Internazionali su Asma e Rinite” Prof. Leonardo M. Fabbri Department of Pulmonary Diseases University of M

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  1. Università degli Studi di Modena e Reggio Emilia “Linee Guida Internazionali su Asma e Rinite” Prof. Leonardo M. Fabbri Department of Pulmonary Diseases University of Modena & Reggio Emilia, Italy http//pneumologia.unimo.it Modena 07/05/2004

  2. TREATMENT OPTIONS IN ASTHMA CURRENT OPTIONS Inhaled corticosteroids Long acting beta2-agonists Leukotriene receptor antagonists FUTURE OPTIONS Better corticosteroids and bronchodilators Phosphodiesterase inhibitors Anti-IgE FUTURISTIC OPTIONS Mediator antagonists Non-steroidal antiinflammatory agents Chemokine and chemokine receptor antagonists Gene therapy

  3. TREATMENT OPTIONS IN ASTHMA CURRENT OPTIONS Inhaled corticosteroids Long acting beta2-agonists Leukotriene receptor antagonists FUTURE OPTIONS Better corticosteroids and bronchodilators Phosphodiesterase inhibitors Anti-IgE FUTURISTIC OPTIONS Mediator antagonists Non-steroidal antiinflammatory agents Chemokine and chemokine receptor antagonists Gene therapy

  4. Management of asthma:updating the GINA guidelines Mild Intermittent Avoidance of risk factors, immunotherapy Short-acting beta-2 agonists as needed Mild Persistent Low-dose inhaled steroids Combination of long-acting beta2 agonists with low dose inhaled steroids Moderate Persistent Asthma severity Combination with higher doses inhaled corticosteroids, theophylline, antileukotrienes Moderate Persistent Severe Persistent Systemic steroids

  5. TREATMENT OPTIONS IN ASTHMA CURRENT OPTIONS Inhaled corticosteroids Long acting beta2-agonists Leukotriene receptor antagonists FUTURE OPTIONS Better corticosteroids and bronchodilators Phosphodiesterase inhibitors Anti-IgE FUTURISTIC OPTIONS Mediator antagonists Non-steroidal antiinflammatory agents Chemokine and chemokine receptor antagonists Gene therapy

  6. “Soft steroids” Butixicort Tipredane Prodrug Ciclesonide Active drug released in the airways Lung metabolism (esterases) Systemic circulation REDUCING SYSTEMIC EFFECTS OF CORTICOSTEROIDS BDP Triamcinolone Flunisolide Budesonide Fluticasone Mometasone NOT EFFECTIVE EFFECTIVE

  7. NEW BRONCHODILATORS • Improvement in existing drugs • Long-acting ß2-agonists: salmeterol, formoterol • once daily • Anticholinergics: tiotropium bromide • (once daily, COPD) • Novel classes • Potassium channel openers (levcromakalim) • VIP analogues (Ro 25-1553) • Nitrovasodilators

  8. PHOSPHODIESTERASE 4 INHIBITORS Mast cell Airway smooth muscle cells Eosinophil Epithelial cells T-cell Macrophage NANC nerves Neutrophil PDE4 INHIBITORS Cilomilast Roflumilast CP 80633 CDP-840 etc

  9. Anti-inflammatory Nausea PDE 4 INHIBITORS: SIDE EFFECTS • Nausea and vomiting • Diarrhoea • Headaches • (N.B. side effects of theophylline) • Central or peripheral effect? • Subtype selective inhibitors? • - human PDE4A, 4B, 4C, 4D

  10. *** *** T0 Roflumilast Tlast Roflumilast T0 BDP Tlast BDP Roflumilast vs low-dose Beclomethasone(BDP) in moderate persistent asthma Rescue Medication – Diary

  11. Roflumilast 250µg / 500µg is safe and well tolerated Roflumilast may have antiflammatory properties - dose-dependent reduction of early and late asthmatic reactions - ongoing sputum and biopsy studies In Phase II/III clinical trials Roflumilast showed A dose response effect, with 250µg and 500µg being effective doses Superiority over Montelukast Equivalence to 400 µg BDP Efficacy already after 1 week of treatment Constant efficacy over at least 1 year Clinically relevant improvement of lung function Roflumilast in Asthma

  12. POSITION OF ANTI-IgE IN THE TREATMENT OF ASTHMA • Patients with more severe asthma • steroid-dependent, steroid-resistant, brittle • Patients with severe concomitant allergic • diseases • Poor compliance with existing therapy ? • Cover for immunotherapy ?

  13. TREATMENT OPTIONS IN ASTHMA CURRENT OPTIONS Inhaled corticosteroids Long acting beta2-agonists Leukotriene receptor antagonists FUTURE OPTIONS Better corticosteroids and bronchodilators Phosphodiesterase inhibitors Anti-IgE FUTURISTIC OPTIONS Mediator antagonists Non-steroidal antiinflammatory agents Chemokine and chemokine receptor antagonists Gene therapy

  14. MEDIATOR ANTAGONISTS MEDIATOR ANTAGONIST/INHIBITOR Histamine Prostaglandins Thromboxane Leukotriene B4 cys-Leukotrienes PAF Bradykinin Tachykinins Adenosine Reactive oxygen species Endothelin-1 Nitric oxide loratadine, cetirizine indomethacin ozagrel LY293111 montelukast, zileuton apafant, modipafant icatibant CP 999994 theophylline N-acetyl cysteine bosentan iNOS inhibitors

  15. NEW ANTI-INFLAMMATORY TREATMENTS FOR ALLERGIC DISEASES New steroids • ‘Soft steroids’ • ‘Dissociated steroids’ Anti-eosinophil drugs • IL-5 inhibition • VLA4 inhibitors • CCR3 antagonists Non-steroidal anti-inflammatory agents • PDE4 inhibitors • NF-B inhibitors • p38 MAP kinase inhibitors Anti-allergic drugs • Anti-IgE • Anti-IL-4 • IL-12, IL-18, IFN-

  16. Th1 and Th2 balance W. Busse and R. Lemanske. Immunology of asthma NEJM 2001: 344:350

  17. Preferential expression of chemokine receptors in Th1 vs Th2 cells Sinigaglia et al, Am J Respir Crit Care Med 2001; 164: 1266-1275

  18. normal control non-challenged allergen-challenged CD3/CCR4 T cells/mm2 CCR4+ P<0.05 5000 4000 NON CHALLENGED 3000 ALLERGEN CHALLENGED 2000 1000 0 CCR4 expression in asthma P. Panina-Bordignon, A. Papi et al. J Clin Invest 107:1357, 2001

  19. Up-regulation of MDC and TARC after allergen challenge non-challenge allergen-challenge control MDC TARC P. Panina-Bordignon et al. J Clin Invest 107:1357, 2001

  20. Non-challenged Normal control CD3/CCR3 CD3/CCR3 CD3/CCR3 EG2/CCR3 allergen-challenged allergen-challenged CCR3 is not expressed by lung T cells but only by eosinophils in asthma

  21. Chemokines-cytokines expression in T cells infiltrating the central airways of asthmatics vs COPD patients L L ASTHMA ASTHMA e L e CXCR3/IFN-g CCR4/IL-4 L L COPD COPD e e CCR4/IL-4 CXCR3/IFN-g Panina Bordignon, Papi A et al J Clin Invest 2001; 107:1357

  22. Differences between asthma and COPD ASTHMA Sensitizing agent COPD Smoking Asthmatic airway inflammation CD4+ T-lymphocytes Eosinophils COPD airway inflammation CD8+ T-lymphocytes Marcrophages Neutrophils Completely reversible Completely irreversible Airflow limitation

  23. CHEMOKINE ANTAGONISTS IN ALLERGY MCP1-5 MDC TARC CCR2 CCR4 Monocyte Mast cell T cell Th2 cell CCR3 antagonists Met-RANTES UCB35625 SB-328437 CCR2 antagonists CCR4 antagonists Eotaxin, Eotaxin-2 RANTES MCP-4 CCR3 CCR8 CXCR4 Eosinophil Th2 cell Mast cell

  24. Chemokine receptors in the clinic

  25. BEYOND STEROIDS • Non-steroidal anti-inflammatory agents • Anti-eosinophil strategies • Anti-TNF • NF-B inhibitors • p38 MAP kinase inhibitors

  26. Chromosomal regions involved in the pathogenesis of asthma Modified from Parè et al, 1999 T-cell-receptor (14q) Activated Tcell IL-4 Antigens CD4 Th APC CD4 Th2 Class II HLA MOLECULES (6p) IL4 IL13 (5q) IL5 GMCSF (5q) Y IgE IL-4R (16p) Y B-cell Y Y Eosinophils IgE-receptor (11q) Y Y v Mast cells v 2-receptor (5q) Inflammatory mediators LTC4 LTD4 Histamine, PAF Beta-2-agonists Airway smooth muscle cell chronic airway inflammation-bronchoconstriction-airway hyperrsponsiveness

  27. Association between genetic polymorphisms of the 2-adrenoreceptor and response to albuterol in children with and without a history of wheezing When compared to homozygotes for Gly-16, homozygotes for Arg-16 were 5.3 and heterozygotes for 2AR-16 were 2.3 times more likely to respond to albuterol. Martinez FD et al, J Clin Invest 1997;100:3184-3188

  28. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment Day 8 Day 16 25 Wild type ABT-761 Wild type placebo 20 Mutant ABT-761 15 FEV1 change from baseline 10 5 0 Drazen J et al, Nature Genetics 1999;2:168-170

  29. CONCLUSIONS Room for improvement of current treatment options Ciclesonide, phosphodiesterase inhibitors and anti-IgE available soon Very few new treatments likely over next 15 years Studies on genetics of asthma may contribute to improve characterization and treatment of asthma

  30. In collaboration with the World Health Organization

  31. The ARIA initiative was developed as a state-of-the-art for the specialist, the general practitioner and for health care workers: to update their knowledge of allergic rhinitis, to highlight the impact of allergic rhinitis on asthma, to provide an evidence-based documented revision on the diagnosis methods, to provide an evidence-based revision on the treatments available, to propose a stepwise approach to the management of the disease, to assess the magnitude of the problem in developing countries and to implement guidelines (with IUATLD)

  32. ARIA programme First phase: Development of evidence-based guidelines during a workshop held at WHO in December 1999 (J Allergy Clin Immunol, suppl, Nov 2001). Document has been endorsed by several allergy, respiratory, ENT and paediatric associations.

  33. ARIA programme First phase: Development of evidence-based guidelines during a workshop held at WHO in December 1999 (J Allergy Clin Immunol, suppl, Nov 2001). Document has been endorsed by several allergy, respiratory, ENT and paediatric associations. Second phase: To produce materials to help improve delivery of care to those with rhinitis. In particular a pocket guide To implement ARIA guidelines To update the workshop report

  34. 1- Why ARIA ? 2- New classification of rhinitis 3- Importance of nasal inflammation 4- Treatment based on evidence 5- Impact of rhinitis on asthma

  35. Dalla Rinite all’Asma “Linee Guida Internazionali su Asma e Rinite” Prof. Leonardo M. Fabbri Department of Pulmonary Diseases University of Modena & Reggio Emilia, Italy http//pneumologia.unimo.it Modena, 07/05/2004

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