1 / 40

Treatment of PAH Associated with IPF/SSc

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

lynley
Download Presentation

Treatment of PAH Associated with IPF/SSc

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Treatment of PAH Associated with IPF/SSc Dr.Özlem Özdemir Kumbasar

  2. 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

  3. 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

  4. 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

  5. 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

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

  7. Pulmonary manifestations of scleroderma • Most common manifestations: • Interstitial lung disease • Pulmonary hypertension • Others: • Pleural disease • Chronic aspiration • Airway disease • Lung cancer • Extrinsic restriction

  8. 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)

  9. 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%)

  10. 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

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

  12. 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

  13. Clinical features • Symptoms are often nonspecific: • dyspnea • fatigue • chest pain • syncope • In the early stages symptoms are evident only on exertion.

  14. Diagnosis-baseline • History • Examination • Blood tests • Autoantibodies • Chest x-ray • PFT (spirometry, DLCO, ABG) • Doppler Echo

  15. 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

  16. Doppler Echo • sPAP>35mmHg ? - >40mmHg • N-terminal proBNP • CT-pericardial disease, main pA daimeter >29mm • Right heart catheterization-gold standard

  17. 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.

  18. 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.

  19. 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.

  20. 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)

  21. Treatment • PAH specific agents: • Prostanoids • Endothelin antagonists • Phosphodiesterase inhibitors

  22. 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.

  23. 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.

  24. 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.

  25. 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.

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

  27. 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.

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

  29. 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.

  30. 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.

  31. Prognostic factors in IPF • 10% decrements in FVC • Exercise capacity • 6 MW distance • Desaturation during 6 MWT • PH

  32. PH in IPF • Prevalence: 32-85% • Serial progression in PAP • Retrospective studies: • Initial prevelance: 33-41% • Follow-up prevalence:85-90%

  33. 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

  34. 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.

  35. Treatment • Supplemental oxygen-beneficial effects on survival? • CCB-no role • Anticoagulation-better outcomes with long term anticoagulation??

  36. 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.

  37. 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

  38. 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?

  39. Treatment • Sildenafil • A sigle dose of sildenafil decreased mPAP and shunt flow • A study with 14 patients: sildenafil improved 6MWD

  40. 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.

More Related