Treatment of pah associated with ipf ssc
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Treatment of PAH Associated with IPF/SSc. Dr.Özlem Özdemir Kumbasar. 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

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Treatment of PAH Associated with IPF/SSc

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Treatment of pah associated with ipf ssc

Treatment of PAH Associated with IPF/SSc

Dr.Özlem Özdemir Kumbasar


Clinical classification of pulmonary hypertension

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


1 pulmonary arterial hypertension

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


3 pulmonary hypertension associated with respiratory diseases and or hypoxia

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


Systemic sclerosis scleroderma

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


Treatment of pah associated with ipf ssc

  • SSc has two subgroups according to the extent of skin involvement:

    • Diffuse SSc-dSSc

    • Limited SSc-lSSc


Pulmonary manifestations of scleroderma

Pulmonary manifestations of scleroderma

  • Most common manifestations:

    • Interstitial lung disease

    • Pulmonary hypertension

  • Others:

    • Pleural disease

    • Chronic aspiration

    • Airway disease

    • Lung cancer

    • Extrinsic restriction


Ph in ssc

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 disfunction

    PH

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


Treatment of pah associated with ipf ssc

  • 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%)


Risk factors for pah in ssc

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


Treatment of pah associated with ipf ssc

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


Pathogenesis

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


Clinical features

Clinical features

  • Symptoms are often nonspecific:

    • dyspnea

    • fatigue

    • chest pain

    • syncope

  • In the early stages symptoms are evident only on exertion.


Diagnosis baseline

Diagnosis-baseline

  • History

  • Examination

  • Blood tests

  • Autoantibodies

  • Chest x-ray

  • PFT (spirometry, DLCO, ABG)

  • Doppler Echo


Scleroderma patient with respiratory symptoms

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


Treatment of pah associated with ipf ssc

  • Doppler Echo

    • sPAP>35mmHg ? - >40mmHg

  • N-terminal proBNP

  • CT-pericardial disease, main pA daimeter >29mm

  • Right heart catheterization-gold standard


Treatment

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.


Treatment1

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.


Treatment2

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.


Treatment3

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)


Treatment4

Treatment

  • PAH specific agents:

    • Prostanoids

    • Endothelin antagonists

    • Phosphodiesterase inhibitors


Treatment5

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.


Treatment6

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.


Treatment7

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.


Treatment8

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.


Treatment9

Treatment

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


Treatment10

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.


Treatment of pah associated with ipf ssc

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


Treatment of pah associated with ipf ssc

  • 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.


Idiopathic pulmonary fibrosis

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.


Prognostic factors in ipf

Prognostic factors in IPF

  • 10% decrements in FVC

  • Exercise capacity

    • 6 MW distance

    • Desaturation during 6 MWT

  • PH


Ph in ipf

PH in IPF

  • Prevalence: 32-85%

  • Serial progression in PAP

  • Retrospective studies:

    • Initial prevelance: 33-41%

    • Follow-up prevalence:85-90%


Ph in ipf1

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


Ph in ipf2

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.


Treatment11

Treatment

  • Supplemental oxygen-beneficial effects on survival?

  • CCB-no role

  • Anticoagulation-better outcomes with long term anticoagulation??


Treatment12

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.


Treatment13

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


Treatment14

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?


Treatment15

Treatment

  • Sildenafil

    • A sigle dose of sildenafil decreased mPAP and shunt flow

    • A study with 14 patients: sildenafil improved 6MWD


Treatment16

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.


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