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Treatment of PAH Associated with IPF/SSc

Dr.Özlem Özdemir Kumbasar

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Clinical Classification of Pulmonary Hypertension

1-Pulmonary arterial hypertension 2-Pulmonary hypertension associated

with left heart diseases 3-Pulmonary hypertension associated

with respiratory diseases and/or hypoxia 4-Pulmonary hypertension due to chronic

thrombotic and/or embolic disease 5-Miscellaneaus

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1.Pulmonary Arterial Hypertension

1.1.Idiopathic 1.2.Familial 1.3.Associated with

1.3.1.Connective tissue diseases 1.3.2.Congenital systemic to pulmonary shunts 1.3.3.Portal hypertension 1.3.4.HIV infection 1.3.5.Drugs and toxins 1.3.6.Other (tyroid disorders, hematological problems….)

1.4.Associated with significant venous or capillary involvement

1.5.Persistant pulmonary hypertension of the newborn

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3.Pulmonary hypertension associated with respiratory diseases and/or hypoxia

3.1.Chronic obstructive pulmonary diseases

3.2.Interstitial lung diseases 3.3.Sleep disordered breathing 3.4.Alveolar hypoventilation disorders 3.5.Chronic exposure to high altitude 3.6.Developmental abnormalities

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Systemic sclerosis-Scleroderma

American Rheumatism Association (American College of Rheumatology):Major criterion or two or more minor criterion

Major criterion: symmetrical thickening, thightening and induration of the skin of the fingers and skin proximal to the metacarpophalangeal, or metatarsophalengeal joints

Minor criteria: Sclerodactily: the changes of the major criterion, but

limited to the fingers Digital pitting scars or loss of substance from the finger

pad: depressed areas at tips of fingers or loss of digital pad tissue as a result of ischemia

Bibasilar pulmonary fibrosis

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SSc has two subgroups according to the extent of skin involvement: Diffuse SSc-dSSc Limited SSc-lSSc

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Pulmonary manifestations of scleroderma

Most common manifestations: Interstitial lung disease Pulmonary hypertension

Others: Pleural disease Chronic aspiration Airway disease Lung cancer Extrinsic restriction

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PH in SSc ILD hypoxemia PH ILD+PH (PH out of proportion to the degree of

fibrosis) Isolated PH Myocardial inflammation and fibrosis

left and right ventricular disfunctionPH

-PH due to unrelated lung disease (COPD, CTEPH)

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PAH is a leading cause of mortality in SSC.

SSc-associated PAH has got a worse prognosis than idiopathic PAH.

PAH related to SSc is common but its true prevelance is not known (4.9-38%)

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Risk factors for PAH in SSc Genetic???: HLA-B*13; HLA-B*65 Increased age of SSc onset;

postmenopausal age Severe Raynaud phenomenon and

digital tip ulcers Absence of anti-Scl-70 Predominance of nucleolar auto-

antibodies

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A decrease of DLCO during the early stages of the disease is a predictor of subsequent development of PAH during the course of SSc.

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Pathogenesis Pathogenesis of SSc-PAH resemble those

of iPAH: Endothelial injury dysfunction

activated myofibroblasts Overproduction of endothelin Decreased production of vasodilators Vascular smooth muscle cell proliferation and

hypertrophy Inflammation and adventitial fibrosis in

medium sized to small sized pulmonary arteries

Vasoconstriction and hypertrophic changes increased pulmonary vascular resistance

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Clinical features

Symptoms are often nonspecific: dyspnea fatigue chest pain syncope

In the early stages symptoms are evident only on exertion.

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Diagnosis-baseline

History Examination Blood tests Autoantibodies Chest x-ray PFT (spirometry, DLCO, ABG) Doppler Echo

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Scleroderma patient with respiratory symptoms

PFT : spirometry, DLCO, ABG Isolated reduction in DLCO or a

proggressive decline in DLCO suggest PAH A ratio of percentage of predicted FVC and

the percentage of predicted DLCO >1.4 is a predictor of PAH; and a value >2 predicts worse survival.

Normal PFT results do not rule out PAH. Serial DLCO testing has been recommended

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Doppler Echo sPAP>35mmHg ? - >40mmHg

N-terminal proBNP CT-pericardial disease, main pA

daimeter >29mm Right heart catheterization-gold

standard

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Treatment Patients with combined PAH and diastolic

dysfunction and/or interstitial lung disease are often exclude from clinical trials. Therefore it is not known how best to treat them.

Treatment may be complicated with worsening hypoxemia due to increased ventilation-perfusion mismatch or pulmonary edema in patients with severe honeycombing or diastolic dysfunction.

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Treatment

There are no specific guidelines for the treatment of SSc-PAH.

Treatment guidelines for iPAH cover PAH associated with connective tissue diseases; most experts use these recommendations.

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Treatment All patients with documented

hypoxemia should be on supplemental oxygen to maintain SaO2 above 90%.

Patients with evidence of right ventricular failure should be given diuretics.

Oral anticoagulant- can be given if complication risk is low. Bleeding complications are more frequent in SSc.

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Treatment CCB:

Less than 10% of patients with iPAH are true responders to high dose calcium channel blokers.

Even fewer patients with SSc-PAH are true responders.

Acute vasoreactivity testing for Patients with SSc-PAH (weak recommendation based on expert opinion only)

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Treatment

PAH specific agents: Prostanoids Endothelin antagonists Phosphodiesterase inhibitors

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Treatment

Prostanoids: Epoprostenol:

Continuous iv epoprostenol improved exercise capacity, symptoms and hemodynamics in patients with SSc-PAH, in a multicenter, randomised, controlled, open label study . A survival advantage was not demonstrated.

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Treatment

Prostanoids: Treprostinil:

Sc infusion of treprostinil improved symptoms, exercise capacity and hemodynamics in patients with CTD related PAH

Inhaled iloprost: Inhaled iloprost trial included patients with

CTD, but subgroup analysis for thie group was not reported.

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Treatment

Endothelin antagonists: Bosentan:

It is approved for the treatment of iPAH and CTD-PAH.

Bosentan prevented walk distance deterioration in patients with SSc when compared with placebo. But exercise improvement was less marked than that seen in iPAH population.

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Treatment Bosentan:

In a retrospective single center study of iPAH and SSc-PAH patients, firs-line bosentan monotherapy was associated with long term improvement in functional class and good overall survival in patients with class III iPAH. Bur SSc-PAH patients showed stability or decline in functional class and tended to have a higher mortality.

In a second retrospective study of SSc-PAH patients bosentan was associated with an early improvement in functional class, but this benefit was lost after 9 months.

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Treatment

Efficacy of selective ETA receptor antagonists sitaxsentan and ambrisentan in SSc-PAH patients remains to be determined

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Treatment

Phosphodiesterase inhibitors: Sildenafil:

In a randomised, double-blind, placebo controlled study of 278 patients with PAH sildenafil improved exercise capacity, functional class and hemodynamics. 30% of these patients had CTD, mainly SSc; but subgroup analysis was not reported.

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Updated ACCP Guideline-Chest 2007:131:1917-1928

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PAH is a leading cause of mortality in patients with SSc.

In the current treatment era, 1 year survival for patients with SSc-PAH improved from 68 to 81%; and 2 year survival from 47 to 71%.

But SSc-PAH is associated with a poorer response to therapy and worse outcome when compared with iPAH.

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Idiopathic Pulmonary Fibrosis

IPF has a poor prognosis. Median survival is 2-5 years. Mortality is usually related to

progressive restriction or acute exacerbations.

PH may complicate the course of IPF and potentially impact prognosis.

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Prognostic factors in IPF

10% decrements in FVC Exercise capacity

6 MW distance Desaturation during 6 MWT

PH

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PH in IPF

Prevalence: 32-85% Serial progression in PAP Retrospective studies:

Initial prevelance: 33-41% Follow-up prevalence:85-90%

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PH in IPF Lung volumes PH Exercise capacity PH Interstitial remodeling Vascular remodeling

Down-regulation of prostanoid synthases in the interstitium and pulonary arteries of patients with IPF???

IPF lungs show increased ET-1 and ET converting enzyme as compared with normal lungs

PDGF TGF-beta

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PH in IPF Presence of PH correlated with lower DLCO

and requirement for supplemental oxygen. PH appears to be an important prognostic

factor in IPF. sPAP>50mmHg was found correlated with

poorer survival. Patients with mean PAP>35 had 1.5 fold

increased post lung transplant mortality.

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Treatment

Supplemental oxygen-beneficial effects on survival?

CCB-no role Anticoagulation-better outcomes

with long term anticoagulation??

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Treatment Bosentan

BUILD-1:A randomized placebo controlled trial of bosentan in idiopathic pulmonary fibrosis

No improvment over placebo with respect to 6MWD

A trend to delayed time to death or disease progression

Patients with echocardiographic evidence of severe PH (sPAP>50) were excluded.

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Treatment

iv epoprostenol: Decreases mPAP but increases

pulmonary shunt flow Current data do not support the use

of iv epoprostenol in PH related to IPF

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Treatment

Inhaled iloprost Decreases mPAP without changes in

shunt flow in patients with PH related to lung fibrosis. (8 patients, only one of them IPF).

Inhaled iloprost in IPF+PH-this study was completed (www.clinicaltrials.gov) Results?

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Treatment

Sildenafil A sigle dose of sildenafil decreased

mPAP and shunt flow A study with 14 patients: sildenafil

improved 6MWD

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Treatment There are potential therapies: Et

antagonists, inhaled prostanoids, phosphodiesterase inhibitors

But long term randomized, controlled trials are necessary to make strict conclusions.

Supplemental oxygen (when necessary) the most important therapy according to current data.