CHAPTER 3
Pulmonary Arterial Hypertension in Connective Tissue Disease

https://doi.org/10.1016/S1571-5078(04)02003-3Get rights and content

Publisher Summary

This chapter describes pulmonary arterial hypertension in connective tissue disease. The chapter illustrates that pulmonary hypertension can occur for several reasons and consensus among experts as to the correct terminology and classification has been an important milestone. The mechanisms by which pulmonary hypertension can arise that are relevant to rheumatic disease are addressed in the chapter. These mechanisms need to be considered in the context of the rheumatic disease in which they occur and also in the light of recent classification systems are reviewed briefly. The principles of management of pulmonary hypertension depend upon the underlying disease. In cases of severe interstitial lung fibrosis with hypoxia and pulmonary hypertension, the management is that of the underlying interstitial disease and treatment of hypoxia. Pulmonary veno-occlusive disease is another important cause for pulmonary hypertension that should be excluded during the initial investigation of suspected cases.

Introduction

As with many of the major organ-based complications of rheumatic disease, there has been a substantial growth in understanding of pathogenesis and improvements in management of pulmonary hypertension by drawing upon the considerable progress that has been made addressing this complication in other contexts and in cases of idiopathic or primary pulmonary hypertension (PPH). The first important consideration is one of terminology. Pulmonary hypertension can occur for several reasons and consensus amongst experts as to the correct terminology and classification has been an important milestone. The mechanisms by which pulmonary hypertension can arise that are relevant to rheumatic disease are listed in Table 1. These mechanisms need to be considered in the context of the rheumatic disease in which they occur and also in the light of recent classification systems that have been revised and reviewed.

The principles of management of pulmonary hypertension depend upon the underlying disease. In cases of severe interstitial lung fibrosis with hypoxia and pulmonary hypertension, the management is that of the underlying interstitial disease and treatment of hypoxia. In cases of pulmonary vasculitis, treatments should include immunosuppression and corticosteroids. Thromboembolic disease can arise in a number of ways. Pulmonary embolism can complicate intercurrent illness, venous stasis, and operative procedures, or may be a manifestation of a thrombotic tendency. Of the latter, the most important cases are those with antiphospholipid antibody syndrome. Pulmonary venoocclusive disease is another important cause for pulmonary hypertension that should be excluded during the initial investigation of suspected cases.

Clinically, the most important group of patients with rheumatic disease and pulmonary hypertension are those with systemic sclerosis (SSc). It is now appreciated that many patients with scleroderma appear to have a pulmonary vasculopathy. This may be part of a more general vascular disease and correlates, for example, with the presence of renal hypoperfusion. In SSc-associated pulmonary hypertension, advances in therapy have been made possible by applying treatments developed for PPH to scleroderma-associated disease. This is logical as the pathology of both conditions appears to be very similar, with evidence of fibroproliferative occlusion of the pulmonary arterial tree associated on occasion with vasospasm. The latter appears less frequent than in idiopathic disease but can still, on occasion, be associated with improvements in cardiac output. Many of the studies of new therapies for pulmonary arterial hypertension (PAH) have included patients with SSc-associated disease and so some comparative efficacy data are available. Overall, these results have supported inclusion of such patients but suggest that SSc-associated cases may do less well than those with idiopathic disease.

There have been major clinical advances over the past 5 years in the management of PAH, both within and outside the context of connective tissue diseases (CTDs). In particular, there have now been several clinical trials confirming efficacy for parenteral or inhaled prostacyclin analogues and also for an oral endothelin receptor antagonist. These therapies are now licensed for use in primary or CTD-associated PAH in many countries.

The earliest reports of PAH as a complication of scleroderma are of historical interest (Young and Mark, 1978, Sackner et al., 1966), but it has almost certainly been an under-recognised complication and may well have often been misdiagnosed as interstitial pulmonary fibrosis (IPF). It is likely that cases of cardiac involvement from SSc are, on occasion, attributable to decompensated PAH. There has been an excess of cardiac mortality in almost all published series of SSc survival and a substantial proportion of deaths may have resulted from unrecognised pulmonary vascular disease or secondary cardiac problems.

Section snippets

Prevalence

There is a wide range in reported frequency of PAH in SSc. This probably results from differences in diagnostic criteria and patient populations examined. The best data come from cardiac catheter studies, although these may underdiagnose the prevalence, as most patients must present a clinical suspicion of PAH in order to proceed to this invasive test. Our own data suggest a prevalence of 12–15% in a hospital-based cohort (Mukerjee et al., 2003). This is within the published range of 5–50% of

Survival

Outcome in SSc is largely determined by the pattern and severity of internal organ-based manifestations. For some complications, such as accelerated phase hypertension and scleroderma renal crisis, there are robust clinical tools for diagnosis and the clinical presentation is inevitable relatively soon after onset of the involvement. For others, diagnosis is dependent upon more sophisticated assessment methods and presentation can be insidious. Thus cardiorespiratory involvement from SSc can

Aetiopathogenesis of PAH in CTD

Unlike skin disease, studies of biology and pathogenetic mechanism in PAH are hampered by the relative inaccessibility of lung tissue for histological and cell culture analysis. Moreover, whereas biopsies may be performed in some patients with active interstitial lung disease to aid diagnosis and classification, this cannot be justified in cases of SSc-associated PAH due to the risk of haemorrhage. Direct examination of lesional tissue is, therefore, only possible in surgical resection

Clinical manifestations

The clinical features attributed to pulmonary hypertension are similar in the context of CTD to those in other clinical situations. Thus, breathlessness, especially on exertion, is generally the first symptom. In taking a history it is important to precisely define the nature, duration and severity of dyspnoea and its impact on function. Patients with CTD may have other musculoskeletal or vascular causes for breathlessness or other pathologies such as anaemia, cardiac disease or interstitial

Diagnostic investigations

There are now well-established diagnostic criteria for PAH. Clinical features and simple investigations such as ECG, Doppler-echocardiogram and pulmonary function tests are useful and also assist with important differential diagnoses such as cardiac involvement or interstitial lung fibrosis. Other causes for PHT must be excluded and ventilation:perfusion (V:Q) scans or CT pulmonary angiogram (CTPA) are important. Additional cardiac tests might also be needed to exclude coronary arterial or

Invasive haemodynamic testing: rheumatological perspective

Although RHC remains the definitive tool for diagnosis and assessment of PAH, it has limitations in rheumatology. These relate to its applicability to supplement screening tools that are less invasive. Thus, a subset of patients that are suspected to have PAH based upon clinical, echocardiographic or lung function test data proceeds to RHC. This is an invasive test that may be especially risky in patients with a complex multisystem disease such as SSc or another CTD. A major goal is defining

Treatment of PAH

Treatments for pulmonary hypertension in CTD have progressed in parallel with those for idiopathic pulmonary hypertension and also benefited from more consistent and rigorous methods of classification of PHT. Thus, causes such as thromboembolism or chronic pulmonary veno-occlusive disease require specific treatment. It is suggested that cases of PAH in lupus may respond to treatment with immunosuppression but this is unclear. The benefits of long-term oxygen treatment in cases of PAH associated

Current best-practice management of PAH in SSc

With established therapies and formalised assessment protocols, there is now an accepted standard of practice for SSc-associated PAH and this is summarised in the algorithm shown in Fig. 1. These care pathways are likely to be refined and modified but represent a tremendous advance upon the available approaches of just a few years ago and reflect consensus amongst rheumatologists, cardiologists and respiratory physicians in the UK. A major goal at present is education of patients and the

Monitoring and screening for pulmonary hypertension in scleroderma

Monitoring of all patients with SSc with, at least, annual Doppler-echocardiogram and pulmonary function testing is an appropriate minimum standard of observation of these patients, although this is not yet universally practised. Once the diagnosis has been made, it is important that the disease is monitored. Although some centres perform repeated RHC studies, this is invasive and probably follow-up is most practically done by serial Doppler-echocardiography every 3–6 months depending upon

The future

Despite advances in management of advanced pulmonary hypertension there are still many challenges. It is important that appropriate comparative studies are developed to confirm the benefit of treatments in CTD-associated pulmonary hypertension. Also the place of combination therapies needs to be better defined. There is some promise from preliminary studies in PPH that phosphodiesterase-5 inhibitors may be useful and even synergistic with endothelin receptor antagonists but this remains to be

References (63)

  • N.M. Albert et al.

    Managing patients with primary pulmonary hypertension: prostacyclin therapy

    Am. J. Crit. Care.

    (1997)
  • R.J. Allcock et al.

    Palliation of systemic sclerosis-associated pulmonary hypertension by atrial septostomy

    Arthritis Rheum.

    (2001)
  • D.B. Badesch et al.

    Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial

    Ann. Intern. Med.

    (2000)
  • R.J. Barst et al.

    A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group

    N. Engl. J. Med.

    (1996)
  • D. Bouros et al.

    Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome

    Am. J. Respir. Crit. Care Med.

    (2002)
  • D. Chemla et al.

    Haemodynamic evaluation of pulmonary hypertension

    Eur. Respir. J.

    (2002)
  • J.G. Coghlan et al.

    The heart and pulmonary vasculature in scleroderma: clinical features and pathobiology

    Curr. Opin. Rheumatol.

    (2001)
  • A. Crilly et al.

    Analysis of transforming growth factor beta1 gene polymorphisms in patients with systemic sclerosis

    Ann. Rheum. Dis.

    (2002)
  • G.E. D'Alonzo et al.

    Survival in patients with primary pulmonary hypertension

    Ann. Int. Med.

    (1991)
  • C.P. Denton et al.

    Comparison of Doppler-echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis

    Br. J. Rheumatol.

    (1997)
  • L. Du et al.

    Signaling molecules in nonfamilial pulmonary hypertension

    N. Engl. J. Med.

    (2003)
  • S. Gibbs

    Recommendations on the management of pulmonary hypertension in clinical practice. British Cardiac Society Guidelines and Medical Practice Committee, and approved by the British Thoracic Society and the British Society of Rheumatology

    Heart

    (2001)
  • S.P. Karwatowski et al.

    Effect of systemic sclerosis on left ventricular long-axis motion and left ventricular mass assessed by magnetic resonance

    J. Cardiovasc. Magn. Reson.

    (2000)
  • M. Kobo et al.

    Lung transplantation in patients with scleroderma

    J. Heart Lung Transplant.

    (2001)
  • E.T. Koh et al.

    Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients

    Br. J. Rheumatol.

    (1996)
  • K.B. Lane et al.

    Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium

    Nature Genet.

    (2000)
  • A.J. MacGregor et al.

    Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival

    Rheumatology

    (2001)
  • M. Magdiliano et al.

    Pulmonary hypertension in autoimmune rheumatic diseases

    Arthritis Rheum.

    (2002)
  • M.D. Mayes

    Endothelin and endothelin receptor antagonists in systemic rheumatic disease

    Arthritis Rheum.

    (2003)
  • G.M. Mitri et al.

    A comparison between anti-Th/To- and anticentromere antibody-positive systemic sclerosis patients with limited cutaneous involvement

    Arthritis Rheum.

    (2003)
  • M.Y. Mok et al.

    Pulmonary hypertension secondary to systemic lupus erythematosus: prolonged survival following treatment with intermittent low dose iloprost

    Lupus

    (1999)
  • Cited by (1)

    • Systemic sclerosis refractory disease: From the skin to the heart

      2011, Autoimmunity Reviews
      Citation Excerpt :

      There are reports of imatinib used in association with endothelin antagonists and phosphodiesterase type-5 inhibitors that improves refractory PAH [62–64]. Autologous hematopoietic stem cell transplantation, after high-dose cyclophosphamide or total body irradiation and antithymocyte globulin therapy, is also an option in refractory cases with nearly 50% response rate [65]. While the results of ongoing trials are pending, the high rates of toxicity and mortality compared with other therapeutic options, restrict its use.

    View full text