Is connective tissue disease a likely etiology for primary pulmonary hypertension in a female patient over 65 years old?

Connective Tissue Disease as Etiology for Pulmonary Arterial Hypertension in Women Over 65

Yes, connective tissue disease (CTD) should be a high consideration as the etiology for pulmonary arterial hypertension in a female patient over 65 years old, as CTD represents the leading cause of associated PAH and patients with CTD-PAH are now frequently diagnosed at older ages (mean age 50-65 years), with systemic sclerosis being particularly prevalent in this demographic. 1

Epidemiologic Rationale

CTD is the most common cause of associated PAH (APAH) among all secondary forms, accounting for the majority of cases in this category, with systemic sclerosis (particularly the limited cutaneous form/CREST variant) being the predominant CTD subtype. 1

The age profile of PAH has shifted dramatically over recent decades:

• While the original NIH registry in 1981 showed a mean age of 36 years for idiopathic PAH, current registries demonstrate PAH is now more frequently diagnosed in elderly patients, with mean age at diagnosis between 50-65 years. 1
• The traditional female predominance may not be present in elderly patients, making sex less discriminatory in this age group. 1

Specific CTD Considerations in This Population

Systemic sclerosis (SSc) is the most important CTD to consider, as it:

• Accounts for 75% of all CTD-associated PAH cases 2
• Has a prevalence of PAH between 7-12% in large cohorts, though 65-80% show histopathological changes at autopsy 1, 3
• Occurs most commonly in the limited cutaneous form (formerly CREST syndrome) 1
• Patients with CTD-PAH are predominantly female (4:1 ratio) and older (mean age 66 years at diagnosis) compared to idiopathic PAH 1

Other CTDs to consider include:

• Systemic lupus erythematosus (SLE) 1, 2
• Mixed connective tissue disease (MCTD) 1, 2
• Rheumatoid arthritis (less common) 1, 2
• Dermatomyositis and Sjögren's syndrome (rare) 2, 4

Critical Differential Diagnosis Caveat

However, in patients over 65, left heart disease (Group 2 PH) is actually the most common overall cause of pulmonary hypertension, though it typically does not cause severe PAH. 1 This creates a diagnostic challenge requiring careful evaluation:

Clinical features favoring left ventricular diastolic dysfunction over CTD-PAH include:

• Age >65 years (which applies here) 1
• Elevated systolic/pulse pressure 1
• Obesity, metabolic syndrome 1
• Hypertension, coronary artery disease, diabetes 1
• Atrial fibrillation 1

Echocardiographic features suggesting Group 2 PH include:

• Left atrial enlargement 1
• Concentric LV remodeling (relative wall thickness >0.45) 1
• LV hypertrophy 1
• Elevated LV filling pressures 1

Diagnostic Algorithm for This Patient

The evaluation must distinguish between CTD-PAH (Group 1) and left heart disease (Group 2), as this fundamentally changes management:

1. Screen for CTD manifestations: Look for Raynaud's phenomenon, sclerodactyly, telangiectasias, esophageal dysfunction, calcinosis, arthritis, rashes, or sicca symptoms 1

2. Obtain serologic testing: ANA, anti-Scl-70, anti-centromere antibodies, anti-RNP, anti-dsDNA, RF, anti-CCP 2, 3

3. Perform echocardiography to assess:

   • Tricuspid regurgitation velocity and estimated pulmonary artery systolic pressure 1
   • Left heart structure and function to exclude Group 2 PH 1
   • Right ventricular size and function 1

4. Right heart catheterization is mandatory for definitive diagnosis, particularly to:

   • Confirm PAH hemodynamics (mean PA pressure ≥25 mmHg, pulmonary capillary wedge pressure ≤15 mmHg, PVR >3 Wood units) 1
   • Exclude occult left heart disease with fluid challenge if wedge pressure is borderline 1
   • Assess vasoreactivity 1

5. Evaluate for concurrent interstitial lung disease with high-resolution CT chest, as this commonly coexists with CTD and affects classification and prognosis 3, 5

Prognostic Implications

CTD-PAH carries a worse prognosis than idiopathic PAH, with SSc-PAH having particularly poor outcomes. 1, 2, 3, 5 This is due to:

• Extrapulmonary CTD manifestations (renal disease, GI involvement) 3
• Concurrent interstitial lung disease 3, 5
• Differences in right ventricular response to increased afterload 3
• Multiple comorbidities affecting exercise tolerance beyond PAH itself 5

Patients with CTD-PAH, especially SSc-PAH, should be referred early for lung transplant evaluation given the inferior outcomes. 3

Treatment Considerations

The treatment algorithm for CTD-PAH mirrors that of idiopathic PAH, using the same PAH-specific vasodilator therapies (endothelin receptor antagonists, phosphodiesterase-5 inhibitors, prostacyclin pathway agents). 2, 3, 4

However, immunosuppressive therapy may provide additional benefit in SLE-PAH and MCTD-PAH based on case series, though this is not established for SSc-PAH. 2

Screening Recommendations

Annual transthoracic echocardiography is recommended for asymptomatic SSc patients as a screening test for PAH. 2, 3 For other CTDs, screening is only advised when symptoms suggestive of PH develop. 2