Connective Tissue Disease–Associated Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling of pulmonary arterioles that leads to increased pulmonary vascular resistance, right heart failure, and death. It is associated with connective tissue diseases, including systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. PAH is characterized by dyspnea on exertion and fatigue. Syncopal events suggest severe disease. Patients may present with signs of right heart failure. One- and 3-year survival rates are approximately 81% and 52%, respectively. Given the high prevalence and mortality, algorithms for screening are currently under investigation and will hopefully lead to earlier diagnosis and improved survival.

Key points

•

Systemic sclerosis is the most common underlying disease associated with connective tissue disease–associated pulmonary arterial hypertension (CTD-PAH), and has the poorest prognosis.
•

Patients with suspected PAH should undergo a complete evaluation, including right heart catheterization (RHC) and testing to rule out other possible causes of pulmonary hypertension.
•

Patients with RHC-confirmed PAH should be treated with PAH-specific therapies. However, the role of immunosuppression for the treatment of CTD-PAH is unclear.
•

The development of robust screening algorithms may lead to earlier diagnosis and improved survival in systemic sclerosis-PAH.

Introduction

Pulmonary hypertension (PH) is a disease that is strictly defined by having a resting mean pulmonary artery pressure (mPAP) of 25 mm Hg or greater as measured by right heart catheterization (RHC). The causes of PH are diverse, but regardless of the cause, chronic elevation of pulmonary arterial pressures can lead to right ventricular strain, dilatation, dysfunction, and ultimately right heart failure. Historically, PH was classified as either primary or secondary PH. However, it was recognized that this classification scheme was insufficient for distinguishing between different types of PH. At the second World Symposium on PH in 1998, the causes of PH were categorized into 5 groups: group 1, pulmonary arterial hypertension (PAH); group 2, PH secondary to left heart disease; group 3, PH owing to chronic lung disease and/or hypoxia; group 4, chronic thromboembolic PH; and group 5, PH owing to unclear multifactorial mechanisms. Over the years, the classification scheme has been updated to reflect the growing understanding of the pathophysiology of different types of PH ( Box 1 ).

Box 1

1.

PAH
- 1.1
  
  Idiopathic PAH
- 1.2
  
  Heritable PAH
  - 1.2.1
    
    BMPR2
  - 1.2.2
    
    ALK-1, ENG, SMAD9, CAV1, KCNK3
- 1.3
  
  Drug and toxin induced
- 1.4
  
  Associated with
  - 1.4.1
    
    Connective tissue disease
  - 1.4.2
    
    Human immunodeficiency virus
  - 1.4.3
    
    Portal hypertension
  - 1.4.4
    
    Congenital heart disease
  - 1.4.5
    
    Schistosomiasis
1’. Pulmonary venoocclusive disease and/or pulmonary capillary hemangiomatosis
1’’. Persistent PH of the newborn (PPHN)
2.

PH owing to left heart disease
- 2.1
  
  Left ventricular systolic dysfunction
- 2.2
  
  Left ventricular diastolic dysfunction
- 2.3
  
  Valvular disease
- 2.4
  
  Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies
3.

PH owing to lung disease and/or hypoxia
- 3.1
  
  Chronic obstructive pulmonary disease
- 3.2
  
  Interstitial lung disease
- 3.3
  
  Other pulmonary diseases with mixed restrictive and obstructive patterns
- 3.4
  
  Sleep-disordered breathing
- 3.5
  
  Alveolar hypoventilation disorders
- 3.6
  
  Chronic exposure to high altitude
- 3.7
  
  Developmental lung diseases
4.

Chronic thromboembolic PH (CTEPH)
5.

PH with unclear multifactorial mechanisms
- 5.1
  
  Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy
- 5.2
  
  Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis
- 5.3
  
  Metabolic disorders: glycogen storage disorders, Gaucher disease, thyroid disorders
- 5.4
  
  Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

Abbreviations: PAH, pulmonary arterial hypertension; PH, pulmonary hypertension.

From Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62:D36; with permission.

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