6 th International Meeting on Pulmonary Rare Diseases and Orphan Drugs. Milano, Febbraio 2015 RARE DISEASES IN ITALY: TIME FOR A NEW PERSECTIVE

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1 6 th International Meeting on Pulmonary Rare Diseases and Orphan Drugs Milano, Febbraio 2015 RARE DISEASES IN ITALY: TIME FOR A NEW PERSECTIVE NSIP: quale terapia? Carlo Albera Università di Torino, Scuola di Medicina Polo San Luigi Gonzaga Dipartimento di Scienze Cliniche e Biologiche Centro Interstiziopatie Polmonari / Malattie Rare

2 Disclosure Statement Dr Carlo Albera has served as investigator in clinical trials, consultant, speaker, Steering Committee or Scientific Advisory Board member for : Actelion Bayer Centocor Eli-Lilly Gilead GSK InterMune Roche

3 NSIP: the disease

4 Raghu G, et al. Am J Respir Crit Care Med. 2011;183:

5 The introduction of NSIP among IIPs was made by Katzenstein and Myers in Several studies have been focused on the fact that some cases of interstitial pneumonias did not match with UIP, DIP or AIP on the basis of the histopathological features. These pneumonias have been reported as non-specific interstitial pneumonias by Travis et al. NSIP was before cosidered as provisional The revision 2002 ATS/ERS IIPs statement classifies idiopathic NSIP as a specific clinicopathological entity Am J Respir Crit Care Med Vol 165. pp , 2002

6 HISTOLOGIC FEATURES OF NSIP Key Histologic Features Cellular pattern Mild to moderate interstitial chronic inflammation Type II pneumocyte hyperplasia in areas of inflammation Fibrosing pattern Dense or loose interstitial fibrosis lacking the temporal heterogeneity pattern and/or patchy features of UIP Lung architecture may appear lost on examination of H&Estained sections, but relatively preserved with elastic stains Interstitial chronic inflammation mild or moderate Am J Respir Crit Care Med 165.,277, 2002

7 CLINICAL CONDITIONS ASSOCIATED WITH NONSPECIFIC INTERSTITIAL PNEUMONIA HISTOLOGIC PATTERN No detectable cause (idiopathic NSIP) Collagen vascular disease (SSC) Hypersensitivity pneumonitis Drug-induced pneumonitis Infection Immunodeficiency including HIV infection Modif for Am J Respir Crit Care Med 165.,277, 2002

8 Pattern is not a disease We must treat a disease not a pattern PATTERN UIP NSIP condition DISEASE IPF (if idiopathic UIP) NSIP (cellular/fibrosing) Idiopathic Associated with specific clinical UIP: we have strong data on treatment the disease NSIP: we have some data on treament of different dsease with the same pattern

9 IPF prognosis is far worse compared with non-specific interstitial pneumonia and other IIPs UIP pattern 100 Non-specific interstitial pneumonia Other IIPs p < rank sum test Survival (%) InterMune, Inc., 2012 Time after diagnosis (years) UIP: Usual interstitial pneumonia is the histological pattern usually seen in the clinical diagnosis of IPF IIPs: Idiopathic interstitial pneumonias PRC-1383 Bjoraker JA et al. Am J Respir Crit Care Med 1998;157:

10 Survival in patients with usual interstitial pneumonia (- - -) and nonspecific interstitial pneumonia ( ). Eur Respir J 2002; 19:

11 Natural history of IPF Disease progression is inevitable yet unpredictable Acute exacerbations of IPF often have no identifiable cause and result in high mortality Acute exacerbations Respiratory function / symptoms Rapidly progressive Episodes of acute respiratory worsening Slowly progressive Median survival following diagnosis (years) Kim DS et al. Proc Am Thorac Soc 2006;3: PRC-1383

12 Park IN et al, CHEST 2007; 132: ) Among 74 patients with surgical lung biopsy confirmed fibrotic I-NSIP, the estimated 1-year frequency of AE was 4.2%. The estimated 1-year AE frequency was 3.3% in surgical lung biopsy-confirmed CVD-IP 5.6% among the patients with CVD-UIP 11.1% in RA-UIP

13 1-year frequency of AE among all the patients with biopsy-proven I-NSIP (n 74) and CVD-IP (n 93) at Asan Medical Center Park IN et al, CHEST 2007; 132: )

14 NSIP: the treatment.

15 THE TREATMENT OF NSIP: PROBLEMS Case definition needs biopsy Pattern and disease definition coincident Cellular and fibrosing forms Idiopathic and associated forms Different outcome NSIP and UIP : two entities (always? sometime?) No significant EBM data -> no approved drug No RCS availale (up to date)

16 83 patients who were classified with idiopathic NSIP (72 fibrotic, 11 Cellular fibrotic NSIP 16 (22%) patients died of NSIP-related causes with a median (range) followup of 53 ( ) months. Despite the favourable survival (5-yr 74%), patients with fibrotic NSIP were frequently hospitalised with recurrence rate of 36%. Initial Treatment : Cellular : Fibrotic : steroid alone steroid + cytotoxic agent Eur Respir J 2009; 33: 68 76

17 Clinical courses and final outcomes of the patients with fibrotic nonspecific interstitial pneumonia after initial treatment. Among the initial improvement group, forced vital capacity (FVC) improved to normal range (.80%predicted) in 25 (69%) patients.

18 27 patients with IPF and 12 patients with fibrosing NSIP All patients were treated with : intermittent pulse therapy with methylprednisolone for 4 weeks followed by cyclophosphamide with low-dose prednisolone Eur Respir J 2005; 25:

19 Changes in mean vital capacity (VC) ± SD. One-way repeatedmeasures ANOVA revealed a significant difference between IPF and NSIP (fibrosing)

20 Kaplan-Meier survival curves in IPF and fibrosing NSIP f NSIP IPF In idiopathic pulmonary fibrosis, combination of corticosteroid and immunosuppressive therapy has only limited efficacy. In contrast, the favourable therapeutic responsiveness and survival in the authors fibrosing nonspecific interstitial pneumonia patients may suggest the efficacy of immunosuppressive therapy for fibrosing nonspecific interstitial pneumonia.

21 The aim of the present study was to assess if insip might represent an early lung manifestation of an autoimmune disease 27 cases with insip In 50% of patients diagnosed with insip, evidence of autoimmune diseases develops within 2 yrs, suggesting a probable link between the clinical entity of insip and autoimmune disorders Eur Respir J 2011; 38:

22 37 patients with idiopathic nonspecific interstitial pneumonia (insip)

23 35 patients with pathologically proven NSIP In patients who show sustained disease progression despite treatment, the progression is associated with various systemic conditions such as CVD, malignancy, or exposure to drugs or chemicals. A lower dose of initial steroids is significantly associated with relapse.

24 Most of the patients were treated with corticosteroid orccorticosteroid plus immunosuppressive agents UCTD-NSIP 15 patients [77%] Non-UCTD-NSIP 20 patients [80%] Among the immunosuppressive agents, cyclosporine was most commonly given to the both groups. There was no significant difference in the percentage of patients receiving immunosuppressive agents or duration of the therapy between the two groups.

25 Survival curves of NSIP patients. Patients fulfilling the criteria of undifferentiated connective tissue disea (UCTD- NSIP) have a significantly better survival rate than those who do not fulfill (Non-UCTD-NSIP)

26 SUGGESTIONS, PROPOSAL, QUESTIONS ON THE POSSIBLE TREATMENT OF NSIP: PRESENT AND FUTURE Idiopathic NSIP Cellular: steroids ± immuno suppressant/cytotoxic (or tripl therapy) Re-evaluation -> response -> continue -> no response -> antifibroric drugs Fibrosing : as UIP-> antifibrotic drugs as first line therapy

27 SUGGESTIONS, PROPOSAL, QUESTIONS ON THE POSSIBLE TREATMENT OF NSIP: PRESENT AND FUTURE NSIP associated with specific clinical condition SSC* RA (and other CVD) Immunosuppressants or cytotoxic drugs ± steroids MMF ± steroids Re-evaluation -> response -> continue -> no response -> antifibrotic drugs * Phase II Pirfenidone trial (LOTUSS) Pilot study on Rituximab (Mab Thera)

Position Statement from the Irish Thoracic Society on the treatment of Idiopathic Pulmonary Fibrosis

BACKGROUND Position Statement from the Irish Thoracic Society on the treatment of Idiopathic Pulmonary Fibrosis Idiopathic Pulmonary Fibrosis (IPF) is a rare, chronic and fatal disease characterised by