Sarcoidosis Associated Pulmonary Hypertension H. James Ford MD Assistant Professor of Medicine Director, Pulmonary Hypertension Program University of North Carolina at Chapel Hill
Disclosures Consultant for Actelion and United Therapeutics Research grants from Actelion, United Therapeutics, and Gilead.
Case 40 y/o female with biopsy proven sarcoidosis (EBUS of mediastinal node) PFTs normal spirometry, normal lung volumes, DLCO 55% predicted. Having progressive dyspnea on exertion, LE edema. Echo suggests PH and RV dysfunction. CXR with clear lung fields, +hilar and med lymphadenopathy. History of sarcoid liver disease as well with bilirubin 3.1 at baseline and evidence of gastric varices on recent imaging.
Case contd. RHC done: RA 9, mean PA 52, PAWP 8, CO 4.6 L/min, CI 2.7, PVR 9.6 WU Does this patient have: 1) Sarcoidosis and Idiopathic PAH (WHO Grp 1) 2) Sarcoidosis associated PH (WHO Grp 5) 3) Portopulmonary Hypertension and Sarcoidosis (WHO Grp 1) 4) Your guess is as good as mine
Sarcoidosis Sarcoidosis is a disease characterized by noncaseating granulomatous tissue inflammation. Can affect nearly any organ system (CNS, skin, myocardium, liver, kidney, lung, eye). The lung is the most commonly affected organ. Demographics Northern European Caucasians, and African-Americans (large population in southeastern U.S., particularly in the Carolinas) Thomas KW, Hunninghake GW. JAMA. 2003;289(24):3300.
Sarcoidosis and the Lung Manifestations in the lung can include: Lymphadenopaty Inflammatory (ground glass) process Fibrotic lung disease with associated sequelae Cyst/cavity formation Traction bronchiectasis Obstructive airways disease (endobronchial sarcoid) Pulmonary Hypertension Secondary PH Granulomatous vascular lesions PAH? Immunomodulatory therapy is the standard of care.
Stages of Sarcoidosis stage I: hilar or mediastinal nodal enlargement only stage III: parenchymal disease only stage II: nodal enlargement and parenchymal disease stage IV: end-stage lung (pulmonary fibrosis)
How Does Sarcoid Fit in the Classification of PH?(2008 Dana Point) 5. Pulmonary hypertension with unclear multifactorial mechanisms 5.1. Hematologic disorders: myeloproliferative disorders, splenectomy 5.2. Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, 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
Pulmonary Hypertension in Sarcoidosis Can be present with varying degrees of restrictive and obstructive lung disease. Difficulty lies in determining the relative contributor of PH and parenchymal or obstructive lung disease to clinical presentation. How much PAH vs. WHO Group 3 or 2 disease? Phenomenon of disproportionate PVD Increased levels of endothelin (ET)-1 in plasma and bronchoalveolar lavage of some sarcoid patients. This suggests ET-1 may be driving pulmonary fibrosis and sarcoidosis-associated pulmonary hypertension. PVOD can also be seen in sarcoid. Baughman, B. Arthritis Res Ther. 2007; 9(Suppl 2): S8.
The Importance of RHC in Sarcoid Retrospective analysis of 130 patients with sarcoid and persistent DOE despite immunomodulator therapy. Underwent RHC at least 18 months prior to analysis 50 pts with PH and PCWP < 15 mm Hg 20 pts with PH and PCWP > 15 mmhg Hazard ratio for dying for PH with PCWP < 15 mmg vs PH with PCWP > 15 was 3.1. 29% of patients with PH had LV dysfunction (PCWP > 15 mmhg) Baughman, RP et al Chest. 2010 Nov;138(5):1078-85
Treatment of SAPH Two-center experience with 22 patients Retrospective (JHU and Inova Fairfax) Patients with PAH hemodynamics Any PAH therapy in context of sarcoid Median follow up = 11 months Improvement in 6MWD related to baseline FVC. 12 patients with hemodynamic data showed improvement in mpap and PVR. Barnett, CF et al. CHEST.June 2009;135(6):1455-1461
Treatment of SAPH A few early small case series and case reports suggest bosentan is efficacious in select sarcoid patients. Sharma et al: 1 patient treated with bosentan, improved 6MWD and functional class. Foley et al: 1 patient treated with bosentan, improved functional class and hemodynamics. Baughman: 4 patients treated with bosentan with improved hemodynamics. Pitsiou: 1 patient treated with bosentan with functional class and 6MWT improvement. Sharma S, Kashour T, Philipp R. Tex Heart Inst J. 2005;32(3):405-10. Foley, RJ. Respiration 2008;75:211-214. Baughman, B. Arthritis Res Ther. 2007; 9(Suppl 2): S8. Pitsiou et al. Ther Adv Respir Dis (2009) 3(3).
Ambrisentan for Sarcoid Associated PH 24 week prospective, open-label trial of ambrisentan in sarcoid patients with PH Primary endpoint = 6 MWD Secondary endpoints = modified Borg scale, serum brain naturetic peptide, diffusing capacity, and quality of life as measured by the Short Form-36 5 mg daily ambrisentan for 4 weeks, followed by 10 mg daily ambrisentan for 20 weeks. M.A. Judson et al. SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2011; 28; 139-145
Ambrisentan for Sarcoid Associated PH Inclusion criteria Biopsy proven sarcoidosis MPAP > 25 mmhg at rest or > 30 mmhg with exercise by RHC within 1 year Pulmonary capillary wedge pressure 15 mmhg PVR >3.0 Woods units Forced vital capacity (FVC) >40% WHO functional class II or III Stable sarcoidosis treatment regimen for three months prior to entry into study 6 minute walk distance between 150-450 meters Stable dose of antihypertensive medications. No other PAH meds. Exclusion Criteria Exercise limitation related to a noncardiopulmonary reason (e.g. arthritis) Severe systemic hypertension > 170/95 Patients with congestive heart failure (left ventricular dysfunction) or primary right ventricular dysfunction Anticipation by the investigator for escalation in sarcoidosis treatment during the course of the study Pulmonary hypertension related to etiology other than sarcoidosis (i.e. HIV, scleroderma, etc.) Use within 1 month of an endothelin receptor antagonists (bosentan, sitaxsentan). WHO functional class IV status Significant left ventricular dysfunction Significant liver dysfunction not due to sarcoidosis. Patients with severe other organ disease felt by investigators to impact on survival during the course of the study. Pregnant females
Ambrisentan for Sarcoid Associated PH 21 patients enrolled. MPAP (mmhg): 35 + 6 CO (L/min) 4.4 + 0.9 PVR (Woods Units): 6.0 + 2.3 No change in 6MWD (mean change between week 0 and 24: 9.8 ± 54.6 meters, p: NS) No significant change in secondary endpoints. High dropout rate (11/21; 52%) 10/21 that completed study: Improvement in WHO functional class --NS Improvement in HRQOL as per SF 36--NS
Bosentan for SAPH 16 week, double-blind, placebo controlled trial of bosentan in SAPH (2:1) 35 patients completed study (23 active treatment, 12 placebo) No change in 6 MWD Significant improvement in hemodynamics Baughman et al
Bosentan for SAPH Baughman et al
Prostacyclins for SAPH One case series published from BU. Retrospective followed 5 patients on epoprostenol for mean of 29 months. Mild to moderate restrictive lung disease Most with severe DLCO reduction Fisher et al. CHEST.June 2009;135(6):1455-1461
Prostacyclins for SAPH Long term outcomes Mean dose epo = 55 ng/kg/min Fisher et al. CHEST.June 2009;135(6):1455-1461
Iloprost for SAPH Iloprost is an inhaled prostacyclin Theoretically less risk of increasing v/q mismatch. Open-label, prospective study, 16 weeks of iloprost therapy. Pre and post RHC, 6MWD, SGRQ 22 patients with SAPH enrolled, 15 completed (cough and compliance) 6 pts with 20% or greater decrease in PVR Significant improvement in SGRQ score Baughmand RP et al. Sarcoidosis Vasc Diffuse Lung Dis. 2009 Jul;26(2):110-20.
PDE-5 inhibitors for SAPH Single center, retrospective study 25 patients with stage 4 sarcoid referred for transplant. 79% had PH on RHC (mpap > 25 mmhg) Sildenafil administered over median of 4 months duration. Repeat RHC improvements in mpap, PVR, and CO/CI. No consistent changes in 6MWD. Milman et al. J Heart Lung Tsplt. 2008 Mar;27(3):329-34.
Tadalafil for SAPH 24 week prospective, open-label, two-center trial of tadalafil in sarcoid patients with PH Primary endpoint = 6 MWD Secondary endpoints = modified Borg scale, serum brain naturetic peptide, diffusing capacity, and quality of life as measured by the Short Form-36 20 mg daily tadalafil for 4 weeks, followed by 40 mg daily for 20 weeks. Inclusion and Exclusion Criteria same as ambrisentan study
Tadalafil for SAPH 12 patients enrolled. MPAP (mmhg): 35 + 8 (25-49) PAWP (mmhg): 10.3 ± 3.6 (3-15) PVR (Woods Units): 6.2 + 3.6 No change in 6MWD (mean change between week 0 and 24: NS) No significant change in secondary endpoints. High dropout rate (5/12; 42%)
PH in the Setting of Lung Disease Underlying Lung Disease COPD with FEV1 60% predicted IPF with FVC 70% predicted mpap < 25 mmhg 25 mpap < 35 mmhg No PH No PAH tx recommended Meets criteria for IPAH PAH treatment guidelines may apply mpap > 35 mmhg Meets criteria for IPAH PAH treatment guidelines may apply Minimal parenchymal or airway abnl on CT COPD with FEV1 < 60% predicted IPF with FVC < 70% predicted Combined pulm fibrosis and emphysema on CT No PH No PAH tx recommended PH-COPD, PH-IPF, PH- CPFE No data support treatment according to PAH tx guidelines Severe PH-COPD, PH- IPF, PH-CPFE Refer to center with expertise in both PH and chronic lung disease Potential use of PAH tx as a bridge to LT in end stage disease
Conclusions Sarcoidosis associated PH remains a challenge to define and treat. Some patients exhibit clearly disproportionate hemodynamic perturbations, while most have concomitant moderate lung disease and PVD. There is a paucity of data regarding the treatment approach to these patients. Larger, controlled trials needed to determine the broader utility of PAH therapies in SAPH.