What can we learn from PAH patients with normalised pulmonary vascular resistance on treatment?

Transcription

1 DHU Thorax Innovation What can we learn from PAH patients with normalised pulmonary vascular resistance on treatment? Marc HUMBERT, MD, PhD UMRS 999 INSERM Université Paris Sud DHU Thorax Innovation (TORINO), LabEx LERMIT Centre National de Référence de l hypertension pulmonaire sévère Hôpitaux Universitaires Paris-Sud, AP-HP, Le Kremlin-Bicêtre, France

2 Presenter Disclosures Marc HUMBERT, MD, PhD The following relationships with commercial interests related to this presentation existed during the past 12 months: Consultancies, Advisory Board, or Lecture Fees: Actelion Aires Bayer BMS GSK Lilly Novartis Pfizer

3 PAH patients with normalised PVR on treatment 1. Idiopathic PAH: chronic vasodilator responders 2. HIV-associated PAH 3. Lupus and mixed connective tissue diseases-associated PAH 4. Porto-pulmonary hypertension (Po-PH) 5. Dasatinib-induced PAH

4 PULMONARY HYPERTENSION UPDATED CLINICAL CLASSIFICATION 1. Pulmonary Arterial Hypertension 1.1. Idiopathic PAH 1.2. Heritable BMPR ALK1, endoglin (with or w/o HHT) Unknown 1.3. Drugs and toxins induced 1.4. Associated with Connective tissue diseases HIV infection Portal hypertension Congenital heart diseases Schistosomiasis Chronic haemolytic anemia 1.5. Persistent PH of the newborn 1. PVOD and PCH 2. PH due to left heart diseases 2.1. Systolic dysfunction 2.2. Diastolic dysfunction 2.3. Valvular disease 3. PH due to lung diseases and/or hypoxia 3.1. COPD 3.2. Interstitial lung diseases 3.3. Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4. Sleep-disordered breathing 3.5. Alveolar hypoventilation disorders 3.6. Chronic exposure to high altitude 3.7. Developmental abnormalities 4. Chronic Thrombo-Embolic PH (CTEPH) 5. PH with unclear and/or mulifactorial mechanisms 5.1. Haematological disorders : myeloproliferative disorders, splenectomy 5.2. Systemic disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis, LAM, neurofibromatosis, vasculitis 5.3. Metabolic disorders : Glycogen storage disease, Gaucher disease, thyroid disorders 5.4. Others : tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis Simonneau G, et al. J Am Coll Cardiol 2009

5 Acute vasoreactivity testing in PAH PAH DIAGNOSIS PAH Basic therapy Oral anticoagulants, Diuretics, O 2, Digoxin... Acute vasoreactivity test (NO or PGI2 or adenosine Positive Negative Oral CCB No CCB +++ Sustained Response Yes Fall in mpap > 10 mmhg + mpap < 40 mmhg + Normal CO Close monitoring of long-term clinical and hemodynamic effects Continue CCB Sitbon O, et al. Circulation. 2005;111: rd World PAH Symposium. J Am Coll Cardiol 2004;43:1S-90S. ACCP Guidelines. Chest 2004;126:1S-92S. Galiè N, et al. ESC Guidelines. Eur Heart J 2004;25: Sitbon et al. Eur Resp J 1998 & Circulation 2005

6 A case of acute vasodilator response Baseline NO 10 ppm mpap = 58 mmhg mpap = 25 mmhg

7 A very small minority of acute vasodilator responder nomalise PVR acutely (near-normalisation) mpap (mmhg) 90 Long-term CCB responders Long-term CCB failure Baseline Acute testing Baseline Acute testing Sitbon et al. Circulation 2005

8 Idiopathic PAH Long-term effects of calcium channel blockers Rich et al. N Engl J Med 1992; Sitbon et al. Circulation 2005

9 The vasoconstrictive component remains unchanged after long-term CCB therapy mpap (mmhg) PVR (Wood Units) Baseline Acute testing (NO) Diltiazem for 2 years Acute testing (NO) Diltiazem stopped for 24h Acute testing (NO) 0 Sitbon et al. Circulation 2005

10 Long-term CCB Responders (Percent - 95% CI) Idiopathic PAH 7.5% Anorexigens-PAH 7.9% CTD-PAH 1.2% HIV-PAH Po-PH 0.7% 1.6% (%) Familial PAH, Congenital Heart Diseases and PVOD/PCH : 0 % Montani et al. Eur Heart J 2010

11 Pulmonary vasoconstriction Abnormal balance of tone Humbert et al. JACC 2004

12 What can be learned from vasodilator responders Some patients with idiopathic and anorexigen-induced PAH have an acutely reversible pulmonary vasoconstriction Such patients can be identified with an acute vasodilator test Only half of the acute responders will respond to long-term CCB therapy Very few patients with other causes of PAH such as heritable or SSc-PAH respond to chronic CCB therapy, highlighting the different pathomechanisms involved in these PAH variants In chronic vasodilator responders, an abnormal balance of tone promotes PAH, but there is no cure as PAH recurs when CCB therapy is stopped

13 HIV-associated PAH 10/59 HIV-PAH patients had reversible disease Degano B, et al. Eur Respir J 2009

14 HIV-associated PAH can reversible n = 10 Baseline 32 ± 22 mo. NYHA I : II : III : IV (n) 0 : 3 : 5 : 2 10 : 0 : 0 : 0 * 6MWD (m) 375 ± ± 52* mpap (mmhg) 51 ± ± 4* CI (L.min -1.m -2 ) 3.3 ± ± 0.8* PVR (dyn.s.cm -5 ) 713 ± ± 76* CD4+ (cells.ml) 304 ± ± 180* * p<0.05 vs baseline Degano B, et al. Eur Respir J 2009

15 HIV-associated PAH: reversible PAH in 10/59 patients Tcherakian et al. Eur Resp J 2012.

16 HIV-associated PAH: reversible PAH in 10/59 patients Montani et al. Eur Respir J 2005

17 PAH associated with HIV infection Incidence seems to go down PAH prevention? Incidence of PAH-HIV as a function of time and CD4+ cells count Opravil et al. AIDS 2008; 22: S35-S40.

18 Is there a role for HIV protease inhibitors in PAH? HAART Immunologic and virologic control Direct effect of PIs on pulmonary vascular remodeling? Gary-Bobo G, et al. Circulation ;122:

19 HIV-associated PAH HIV-infected patients may develop severe PAH Antiretroviral drugs and vasodilators improve survival and sometimes normalise pulmonary pressures Inflammatory cell infiltrates have been detected in patients displaying severe HIVrelated PAH These inflammatory cells produce cytokines and growth factors Humbert, et al. Eur Resp J 1998

20 HIV-ASSOCIATED PAH: HYPOTHESES tat protein gp-120 HIV: indirect role Macrophages/monocytes Lymphocytes ET-1, PDGF, TNFα, VEGF, IL6, IL1β Endothelial cell Endothelial cell SMC Proliferation Reduction of NO & PgI 2 synthesis Increased ET-1 Proliferation, migration Vasoconstriction

21 What can be learned from HIV-associated PAH A subgroup of PAH patients with HIV infection have reversible pulmonary vascular disease PAH cure has been reported in HIV-associated PAH Case series indicate that antiretroviral drugs and pulmonary vasodilators such as ERA contribute to this effect In responders, a role for viral-induced pathomechanisms, as well as inflammatory/proliferative effects is likely

22 SOME PAH PATIENTS IMPROVED WITH ANTI-INFLAMMATORY AGENTS ESPECIALLY IN THE SETTING OF CTD-PAH Retrospective monocenter study (French PAH Reference Center) patients with CTD-PAH Limited SSc n = 5 Diffuse SSc n = 1 SLE n = 13 MCTD n = 8 Rheumatoid arthritis n = 1 First line immunosuppressive therapy Monthly IV cyclophosphamide pulses (600mg/m 2 ) Steroids (prednisone 0.5 à 1mg/kg/j).

23 IMMUNOSUPPRESSIVE THERAPY IN CTD-PAH 8/28 patients (32%) were responders No patient with SSc responded Some SLE and MCTD patients responded after 7 ± 6 CYC pulses [3-20] SLE n = 5 / 13 MCTD n = 3 / 8 SSc n = 0 / 6 Sanchez et al. Chest 2006

24 Cumulative. Survival IMMUNOSUPPRESSIVE THERAPY IN CTD-PAH Responders 0.6 p = Non responders 0 Months Sanchez et al. Chest 2006

25 IMMUNOSUPPRESSIVE THERAPY IN CTD-PAH Retrospective monocenter study n = 22 (SLE, n = 12, MCTD, n =10) Clinical and hemodynamic evaluation after 6±2 CYC pulses, corticosteroids, and PAH specific therapy if needed (ERA and/or prostanoids) Responders = NYHA FC class I-II and hemodynamic improvement at 6 months

26 IMMUNOSUPPRESSIVE THERAPY IN CTD-PAH Immunosuppressive therapy is effective in some CTD- PAH patients, corresponding to SLE and MCTD patients presenting with a better NYHA FC and preserved baseline cardiac output Sanchez et al. Chest 2006; Jais et al. Arthritis Rheum 2008

27 Immunopathology of human and experimental PH Lymphoid Neogenesis F Perros, AJRCCM, 2012 F Perros, ERJ, 2007 O Sanchez, AJRCCM, 2007 M Humbert, AJRCCM, 1995 E Soon, Circulation, 2010 Cytokine and chemokine production in IPAH (IL-1, IL-6, MCP-1, CX3CL1, CCL5 ) T regs reduce pulmonary vascular remodeling and prevent PH R Tamosiuniene, Circ Res, 2011 Mast cells promote pulmonary vascular remodeling BK Dahal, Resp Res, 2011 J Hoffmann, ERJ, 2010 GCS prevent and reverse experimental PH in rats (MCT) Autoantibody production LC Price, ERJ, 2010 N Kherbeck, Clin Rev Allerg Immunol, 2011 DCs recruitment Th2 type inflammation promotes pulmonary vascular remodeling E Daley, JEM, 2008 F Perros, ERJ, 2007

28 What can be learned from CTD-associated PAH A proportion of PAH patients with CTD-PAH have reversible pulmonary vascular disease PAH cure has been reported in SLE and MCTD-associated PAH, but not in SSc Case series indicate that corticosteroids and immunosuppresants may be efficacious in SLE/MCTDassociated PAH In responders, a role for a reversible inflammatory component is likely

29 Distribution of PVR in portal hypertension Hepatopulmonary syndrome Portopulmonary hypertension Pulmonary vasodilatation Precapillary pulmonary hypertension Right-to-left intrapulmonary shunt Vascular remodelling Diffusion impairment Herve P, et al. Eur Respir J 1998

30 Porto-pulmonary hypertension Some patients may near-normalise PVR with therapy Savale et al. Int J Clin Practice 2011

31 Porto-pulmonary Pathophysiology hypertension Hypothesis Genetic factors? Pulmonary vascular remodelling Activation/modulation of various genes in endothelial and smooth muscle cells Vasocontrictive and proliferative agents Circulating bacteria and endotoxins from GI tract Vascular wall shear stress Systemic inflammatory changes Portosystemic Shunts Cardiac output Volume overload

32 What can be learned from Po-PH In portal hypertension, PVR is less tightly regulated than in healthy individuals: major vasodilatation results in low PVR (causing hepatopulmonary syndrome), while vasoconstriction/ remodeling increases PVR (causing Po-PH) A subset of Po-PH patients have reversible pulmonary vascular disease with long-term IV epoprostenol, although they do not present with initial acute vasodilator response In patients who normalize PVR with IV epoprostenol vasodilatation is likely to play a key role in the pathophysiology of PAH Vasodilator therapy may improve patients who may become eligible for liver transplantation (if indicated for liver disease)

33 DASATINIB-INDUCED PAH 8 Lowest estimate of PH incidence 13 / 2900 treated patients = 0.45% 4 No case reported with imatinib or nilotinib 1 Montani et al. Circulation 2012

34 DASATINIB-INDUCED PAH Reversible component after stopping drug exposure Montani et al. Circulation 2012

35 DASATINIB-INDUCED PAH Reversible component after stopping drug exposure Dumitrescu et al. Eur Resp J 2011

36 Targets of tyrosine kinases approved in CML Imatinib (1 st line) Nilotinib (2 nd line) Dasatinib (2 nd line) ABL ABL TXK LIMK2 ARG ARG DDR1 MYT1 BCR-ABL BCR-ABL DDR2 PTK6/Brk KIT KIT ACK QIK PDGFR PDGFR ACTR2B QSK DDR1 SRC ACVR2 RAF1 NQO2 YES BRAF RET FYN EGFR/ERBB1 RIPK2 LYN EPHA2 SLK HCK EPHA3 STK36/ULK LCK EPHA4 SYK FGR EPHA5 TA03 BLK FAK TESK2 FRK GAK TYK2 CSK GCK ZAK BTK HH498/TNNI3K TEC ILK BMX LIMK1 Montani et al. Circulation 2012

37 DASATINIB-INDUCED PAH - Dasatinib Vasoconstriction Partial reversibility after withdrawal of dasatinib Montani et al. Circulation 2012; Nagaraj et al. Eur Resp J 2012

38 What can be learned from dasatinib-induced PAH At least 0.5% of patients exposed long-term to dasatinib will develop PAH Tyrosine kinase inhibition may promote pulmonary vasoconctriction/remodeling Dasatinib-induced PAH is at least partially reversible in most patients Src could be one of the many targets promoting reversible PAH Pharmacovigilance is of utmost importance to detect pulmonary vascular effects of drugs

39 Conclusion There is no medical cure for PAH However, rare cases of reversible PAH have been described Vasoconstriction and response to vasodilators is key in some patients (CCB responders, Po-PH, dasatinib-induced PAH) Inflammation and infection is another key driver of reversible PAH (lupus, MCTD, HIV, etc ) A better understanding of the pathomechanisms contributing to reversible PAH will help designing novel concepts to ultimately cure this devastating disease

40 DHU Thorax Innovation What can we learn from PAH patients with normalised pulmonary vascular resistance on treatment? Marc HUMBERT, MD, PhD UMRS 999 INSERM Université Paris Sud DHU Thorax Innovation (TORINO), LabEx LERMIT Centre National de Référence de l hypertension pulmonaire sévère Hôpitaux Universitaires Paris-Sud, AP-HP, Le Kremlin-Bicêtre, France