Your SlideShare is downloading. ×
Update on Pulmonary Arterial Hypertension in Scleroderma
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

Update on Pulmonary Arterial Hypertension in Scleroderma

925
views

Published on

Dr. Roberto Machado from the University of Illinois at Chicago presented an update on PAH at a Patient Education Conference on March 15, 2014 hosted by the Scleroderma Foundation, Greater Chicago …

Dr. Roberto Machado from the University of Illinois at Chicago presented an update on PAH at a Patient Education Conference on March 15, 2014 hosted by the Scleroderma Foundation, Greater Chicago Chapter.

Published in: Health & Medicine

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
925
On Slideshare
0
From Embeds
0
Number of Embeds
3
Actions
Shares
0
Downloads
34
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide
  • More than pathologic pulmonary condition can be present in an individual with SSc.
  • The US Registry to EValuateEArly and Long-term PAH Disease Management (REVEAL) is a multicenter, observational, US-based registry initiated in 2006 and designed to study longitudinal clinical course and disease management in patients with PAH.A recent analysis of the REVEAL baseline database indicated that half of the patients included have associated PAH (APAH), and of these, about half have PAH secondary to connective tissue/collagen vascular disease. Thus, CTDs account for nearly one in four cases of PAH .HIV = human immunodeficiency virusAdapted from Badesch DB et al. Chest. 2010;137:376-387.
  • Renal crisis used to be a dominant cause of death in patients with SSc.With the advent of ACE inhibitors, survival is much improved.On the other hand, lung complications resulting in death have been on the rise, such that PAH and PF are now by far the leading cause of mortality in patients with SSc, accounting for about half of deaths in patients with SSc. ACE = angiotensin-converting enzymePF = pulmonary fibrosisSRC = scleroderma renal crisisSteen VD. Ann Rheum Dis. 2007;66:940-944.
  • ~5% of cohort had PH.Of 17 patients with PH, 9 had significant restrictive lung disease (including 6 with pulmonary fibrosis).Highlights the relevance of PH (in general) in the SSc population.Limitations: only 4 of 17 patients had a right heart catheterization (RHC).Koh ET. Br J Rheumatol. 1996;35:989-993.
  • Need to emphasize risk factors.ANA = antinuclear antibody
  • These next slides summarize the very latest “Recommendations for Screening and Detection of CTD-Associated PAH” just published online a few weeks ago.Here are some of the general evidence-based guidelines.The graded quality of the evidence is noted in parentheses after each recommendationKhanna D et al. Arthritis Rheum. 2013 Sep 10. doi: 10.1002/art.38172. [Epub ahead of print]
  • These are additional recommendations for initial screening evaluations and the frequency of noninvasive testing.Khanna D et al. Arthritis Rheum. 2013 Sep 10. doi: 10.1002/art.38172. [Epub ahead of print]
  • CVD = collagen vascular diseaseFC = functional classBadesch DB et al. Chest. 2010;137:376-387.
  • mPAP = mean pulmonary artery pressuremPAWP = mean pulmonary artery wedge pressurePVRI = pulmonary vascular resistance indexRAP = right atrial pressureHumbert M et al. Arthritis Rheum. 2011;63:3522-3530.
  • Humbert M et al. Arthritis Rheum. 2011;63:3522-3530.
  • Saggar R et al. EurRespir J. 2010;36:893-900. [Epub 2010 Mar 29.]
  • Transcript

    • 1. Update on Pulmonary Arterial Hypertension in Scleroderma Scleroderma Patient Education Conference March 15th 2014 Roberto F. Machado, MD Section of Pulmonary and Critical Care, Allergy and Sleep University of Illinois at Chicago College of Medicine
    • 2. Interstitial Fibrosis Potentially treatable; not currently reversible Recurrent Aspiration Treatable Pulmonary Hypertension Treatable within limits The major clinical issue is defining the relative contribution of each process and choosing the appropriate therapy. Scleroderma and the Lung
    • 3. Badesch D et al. J Am Coll Cardiol. 2009;54:S55-S66. McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619. Hemodynamic Definition of PH/PAH PH PAH Mean PAP ≥25 mm Hg plus PCWP/LVEDP ≤15 mm Hg Mean PAP ≥25 mm Hg ACCF/AHA includes PVR >3 Wood Units
    • 4. Clinical Classification of Pulmonary Hypertension (Dana Point) 1. PAH • Idiopathic PAH • Heritable • Drug- and toxin-induced • Persistent PH of newborn • Associated with: −CTD −HIV infection −portal hypertension −CHD −schistosomiasis −chronic hemolytic anemia 1’. PVOD and/or PCH 2. PH Owing to Left Heart Disease • Systolic dysfunction • Diastolic dysfunction • Valvular disease 3. PH Owing to Lung Diseases and/or Hypoxia • COPD • ILD • Other pulmonary diseases with mixed restrictive and obstructive pattern • Sleep-disordered breathing • Alveolar hypoventilation disorders • Chronic exposure to high altitude • Developmental abnormalities 4. CTEPH 5. PH With Unclear Multifactorial Mechanisms • Hematologic disorders • Systemic disorders • Metabolic disorders • Others Simonneau G et al. J Am Coll Cardiol. 2009;54;S43-S54.
    • 5. LV A LA RA RV PT PVOD ILD Pulmonary Hypertension (PH) in CTD PAH LV systolic or diastolic dysfunction ↑ LAP
    • 6. Vasculopathy in Scleroderma • Masson-Trichrome stain of digital artery from patient with SSc • Striking fibrotic intimal hyperplasia • Adventitial fibrosis • Arterial lumen severely compromised
    • 7. Nearly 25% of PAH Is CTD-related: REVEAL Registry Based on Venice Clinical Classification (2003); 2967 patients. Adapted from Badesch DB et al. Chest. 2010;137:376-387. Overall Associated Associated (50.7%) Idiopathic (46.2%) Heritable (2.7%) Pulmonary veno-occlusive (0.4%) Connective tissue/ collagen vascular (49.9%) Congenital heart disease (19.5%) HIV (4.0%) Other (5.5%) Drugs/Toxins (10.5%) Portopulmonary (10.6%)
    • 8. SRC PAH GI PF Heart Multi-organ 1972- 1976 1977- 1981 1982- 1986 1987- 1991 1992- 1996 1997- 2001 Changing Patterns of Mortality in Scleroderma Steen VD. Ann Rheum Dis. 2007;66:940-944. PAH p=0.05 GI p=0.43 Heart p=0.26 50 40 30 20 10 0 Year of death p<0.001(SRC) p<0.001 (PF) Frequency(%)
    • 9. Impact of Untreated Lung Disease in SSc Koh ET. Br J Rheumatol. 1996;35:989-993. Survival (%) Lung involvement (without PH) (n=73) 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years from diagnosis of PH PH (n=17) No lung disease (n=138)
    • 10. Stupi AM et al. Arthritis Rheum.1986;29:515-524. Steen VD, Medsger TA Jr. Arthritis Rheum. 2003;48:516-522. Stupi AM et al: Average PA pressure: 82/35 (50) mm Hg Average PA resistance: 16 Wood units Average cardiac index: 2.1 L/min/m2 Impact of PAH on Survival in Limited SSc Before PAH Therapy Steen V et al: Average PASP: 76 mm Hg SSc with PAH (n=20) (n=106) SSc without PAH (n=287) (n=106) % cumulative survival Follow-up (yr) 0 20 40 60 80 100 1 2 3 4 5
    • 11. Summary of Risk Factors for PAH in Scleroderma • Long disease duration (usually >8 yr) • Limited scleroderma > diffuse scleroderma • Abnormal pulmonary function tests – low DLCO <55% predicted and FVC %/DLCO % >1.6 • Autoantibody profile – anticentromere antibody – antinucleolar pattern on ANA (anti-U3 antibody, which is not clinically available)
    • 12. Prevalence ~8.0% Screening for PAH in Scleroderma Hachulla E et al. Arthritis Rheum. 2005;52:3792-3800. SSc patients with no severe pulmonary function abnormalities (N=599; n=29 with known PAH) Doppler echocardiography (n=570) VTR <2.5 m/s VTR 2.5–3 m/s VTR >3 m/s NO DYSPNEA (or dyspnea explained by another cause) DYSPNEA (not explained by another cause) Suspected PAH (n=33) No PAH Right heart catheterization mPAP at rest <25 mm Hg mPAP at rest ≥25 mm Hg and PAWP <15 mm Hg mPAP during exercise <30 mm Hg mPAP during exercise ≥30 mm Hg Confirmed PAH (n=18) No PAH (n=15)
    • 13. Latest Recommendations for Screening and Detection of SSC-Associated PAH General Evidence-based Guidelines Khanna D et al. Arthritis Rheum. 2013 Sep 10. doi: 10.1002/art.38172. [Epub ahead of print] • All patients with SSc should be screened for PAH • All SSc and scleroderma-spectrum patients with a positive non-invasive screen should be referred for RHC • RHC is mandatory for diagnosis of PAH
    • 14. Latest Recommendations for Screening and Detection of SSc-Associated PAH Khanna D et al. Arthritis Rheum. 2013 Sep 10. doi: 10.1002/art.38172. [Epub ahead of print] Initial SSc Screening Evaluation • FT with DLCO (high) • Transthoracic echocardiogram (TTE) (high) • NT- Pro BNP (mod) • DETECT algorithm if DLCO% < 60% and >3 yrs disease duration (mod) Frequency of Noninvasive Tests • TTE annually as screening (low); if new signs or symptoms develop (high) • PFT with DLCO annually as screening (low qual); if new signs or symptoms develop (low) • NT-Pro BNP if new signs of symptoms develop (low)
    • 15. Impact of Proactive Screening in Systemic Sclerosis
    • 16. CTD patients are known to be a high-risk patient population. Why aren’t they identified earlier than other PAH patients? *Modified NYHA/WHO functional class. Badesch DB et al. Chest. 2010;137:376-387. CVD/CTD Patients Are Often Diagnosed With More Advanced Symptoms 7.6 36.7 50.0 5.6 0 20 40 60 80 100 I II III IV Patients(%) FC* at Enrollment REVEAL Registry (All Patients) (n=2525) 5.7 32.2 54.9 7.2 0 20 40 60 80 100 I II III IV FC* at Enrollment REVEAL Registry (CVD/CTD) (n=639)
    • 17. Screening Can Help in Diagnosing the Disease in an Early Stage 1 24 63 12 0 20 40 60 80 100 I II III IV Patients(%) NYHA FC (N=674) Humbert M et al. Am J Respir Crit Care Med. 2006;173:1023-1030. Hachulla E et al. Arthritis Rheum 2005: 52:3792-3800. No Screening Without screening, the majority of patients were diagnosed in NYHA FC III or FC IV, and only 24% of patients were in NYHA FC II at diagnosis. 5 44 28 11 0 20 40 60 80 100 I II III IV NYHA FC (N=18) With Screening
    • 18. Values are mean ± SD. Humbert M et al. Arthritis Rheum. 2011;63:3522-3530. Hemodynamics at PAH-SSc Diagnosis: “Routine Practice” and “Detection” Patients Routine Practice (n=16) Detection (n=16) p RAP (mm Hg) 10 ± 5 6 ± 3 0.020 mPAP (mm Hg) 49 ± 11 34 ± 10 0.0004 mPAWP (mm Hg) 9 ± 4 10 ± 3 0.28 Cardiac output (L/min) 3.59 ± 1.10 5.96 ± 1.51 <0.0001 Cardiac index (L/min/m2) 2.37 ± 0.81 3.42 ± 0.92 0.0028 PVRI (dynes.s.cm-5.m-2) 1500 ± 602 613 ± 400 <0.0001
    • 19. Prognosis of “Routine Practice” and “Detection” PAH-SSc Patients 100 80 60 40 20 0 Survival(%) 1 3 5 8 Years of follow-up 100% 75% 31% 25% 17% 81% 73% 64% Routine practice PAH-SSc Detection PAH-SSc p=0.0037 HR=4.15 (95% CI 1.47–11.71) Adapted from Humbert M et al. Arthritis Rheum. 2011;63:3522-3530.
    • 20. Treatment for Scleroderma-associated PAH
    • 21. cGMP cAMP Vasoconstriction and proliferation Endothelin receptor A Exogenous nitric oxide Endothelin- receptor antagonists Endothelin receptor B Phosphodiesterase type 5 inhibitor Vasodilation and antiproliferation Phosphodiesterase type 5 Vasodilation and antiproliferation Prostacyclin derivatives Nitric Oxide Endothelin-1 Pre-proendothelin L-arginine Prostaglandin I2 L-citrulline Nitric Oxide Pathway Endothelin Pathway Prostacyclin PathwayEndothelial cells Proendothelin Endothelial cells Arachidonic acid Smooth muscle cells Prostacyclin (prostaglandin I2) Smooth muscle cells PAH Treatment: Targeting Known Pathophysiological Pathways Prostacyclins Epoprostenol, Treprostinil Iloprost (inhaled) PDE-5 Inhibitors Sildenafil, Tadalafil SGC Stimulator Riociguat Endothelin Receptor Antagonists Bosentan, Ambrisentan , Macitentan Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.
    • 22. Combination Therapy *Half of patients on combination therapy †SERAPHIN, 64% on combination therapy, 5% of patients on prostanoid; PATENT 1, 6%. SGC Stimulators Prostanoids Endothelin Receptor Antagonists Phospho- diesterase Inhibitors TRIUMPH STEP SERAPHIN† TRIUMPH PACES PATENT-1* PATENT-1* ? ? ??? PHIRST* SERAPHIN†
    • 23. Morrell, N. W. et al. JACC 2009; 54(1 Suppl):S20-31. Some Cellular Processes Implicated in the Pathogenesis of PAH
    • 24. Am J Respir Crit Care Med, 2014 http://www.atsjournals.org/doi/abs/10.1164/rccm.201308-1543PP Treatment for PAH: The Pipeline
    • 25. Post-transplant Survival Saggar R et al. Eur Respir J. 2010;36:893-900. [Epub 2010 Mar 29.] 0.00 0.25 0.50 0.75 1.00 Survival proportion Time after lung transplant (mo) 0 12 24 36 48 60 SSc IPF
    • 26. Long-term Management • PH therapies are not curative – long-term progression should be anticipated • Re-assess patients frequently and have high index of suspicion for progression • Escalate level of care if treatment response inadequate or progression encountered
    • 27. Summary • Approximately 1 in 8 SSc patients develops PAH • Early detection of and intervention in PAH are critical to delaying onset of right heart failure • Multiple medical therapies are available but CTD- associated PAH can be less responsive and challenging to treat – combination therapy is becoming the mainstay • We continue to study new targets that we hope will reverse the progressive nature of the disorder

    ×