What is the treatment approach for a patient with systemic sclerosis and associated pulmonary arterial hypertension (PAH)?

Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension

For treatment-naive patients with systemic sclerosis-associated PAH (SSc-PAH) at low or intermediate risk, initiate oral combination therapy with an endothelin receptor antagonist (ambrisentan 10 mg daily) plus a PDE5 inhibitor (tadalafil 40 mg daily), as this approach improves exercise capacity and delays clinical worsening compared to monotherapy. 1, 2

Risk Stratification Framework

Risk assessment must be performed using the REVEAL 2.0 calculator before initiating therapy 1:

• Low risk: REVEAL score ≤6
• Intermediate risk: REVEAL score 7-8
• High risk: REVEAL score ≥9

The assessment should include WHO functional class, 6-minute walk distance, NT-proBNP levels, echocardiographic findings (right ventricular function), and hemodynamic parameters from right heart catheterization 1, 3.

Initial Treatment Algorithm Based on Risk and Functional Class

Low to Intermediate Risk Patients (WHO Functional Class II-III)

First-line therapy is oral combination treatment with an endothelin receptor antagonist plus a PDE5 inhibitor 1:

• Ambrisentan 5-10 mg once daily (start at 5 mg, increase to 10 mg if tolerated) 1, 2
• Tadalafil 40 mg once daily 1, 2

Alternative combination options include 1:

• Bosentan 62.5-125 mg twice daily plus sildenafil 20 mg three times daily
• Macitentan 10 mg daily plus tadalafil 40 mg daily

Monotherapy is reserved only for very specific situations 1:

• Very mild PAH (WHO functional class I, pulmonary vascular resistance 3-4 Wood units, mean pulmonary arterial pressure <30 mmHg, normal right ventricle on echocardiography)
• Suspicion of pulmonary veno-occlusive disease (where combination therapy may cause pulmonary edema)
• Combination therapy unavailable or contraindicated due to severe liver disease

High Risk Patients (WHO Functional Class IV)

Initiate combination therapy including intravenous prostacyclin analogue 1, 3:

• Continuous IV epoprostenol starting at 2 ng/kg/min, titrated based on clinical response and tolerability 1, 4
• Add oral endothelin receptor antagonist and PDE5 inhibitor as tolerated
• Consider referral for lung transplantation evaluation 1

Epoprostenol has demonstrated mortality benefit in SSc-PAH, with improvements in 6-minute walk distance (median increase 108 meters), NYHA functional class (38% improved vs 0% in controls), and hemodynamics 1, 4.

Reassessment and Treatment Escalation

Reassess all patients at 3-6 months after initiating therapy 1:

• If low-risk status achieved: continue structured follow-up with current regimen
• If intermediate or high risk persists: escalate to triple combination therapy with endothelin receptor antagonist, PDE5 inhibitor, and prostacyclin analogue 1

The goal is treating to target—achieving and maintaining low-risk status across multiple parameters including 6-minute walk distance, NT-proBNP, functional class, and hemodynamics 1.

Specific Drug Classes and Mechanisms

Endothelin Receptor Antagonists

Three oral agents are available targeting elevated endothelin-1 levels 1:

• Bosentan: 62.5-125 mg twice daily (requires monthly liver function monitoring due to hepatotoxicity risk) 1
• Ambrisentan: 5-10 mg once daily (requires monthly liver function tests and hemoglobin monitoring) 1, 2
• Macitentan: 10 mg once daily 1

All endothelin receptor antagonists are teratogenic and require reliable contraception; hormonal contraceptives may be less effective when co-administered with bosentan due to cytochrome P450 interference 1.

PDE5 Inhibitors

These enhance the nitric oxide-cGMP pathway, providing pulmonary vasodilation and anti-proliferative effects 1:

• Tadalafil: 40 mg once daily 1, 2
• Sildenafil: 20 mg three times daily 1

Prostacyclin Analogues

Reserved for high-risk patients or those failing oral combination therapy 1:

• Epoprostenol IV: 1-12 ng/kg/min continuous infusion via central venous catheter (average dose 9.2 ng/kg/min) 1, 4
• Iloprost inhaled: 2.5-5 μg per dose, 6-9 times daily 1
• Treprostinil subcutaneous/IV: 0.625-1.25 ng/kg/min continuous infusion 1
• Selexipag oral: 200-1600 μg twice daily 1

Soluble Guanylate Cyclase Stimulators

• Riociguat: 0.5-2.5 mg three times daily, titrated every 2 weeks 1

Critical Supportive Care Measures

Anticoagulation is NOT routinely recommended in SSc-PAH, unlike idiopathic PAH, due to high bleeding risk from gastrointestinal complications (erosive esophagitis, gastric antral vascular ectasia) without proven survival benefit 1.

Diuretics should be used for right ventricular overload and fluid retention 1, 3.

Supplemental oxygen is indicated to maintain oxygen saturation >90% 1, 3.

Reduced-salt diet is recommended for patients with right ventricular overload 1.

Vaccinations against influenza and pneumococcal pneumonia should be administered 3.

Important Caveats and Pitfalls

Rule out other causes of pulmonary hypertension before diagnosing PAH 1:

• Pulmonary veno-occlusive disease (suggested by severe hypoxia, pleural effusions, interlobular septal thickening on CT—occurs in ~11% of SSc-PAH cases)
• Interstitial lung disease with hypoxia (group 3 PH)
• Left heart disease (group 2 PH)
• Chronic thromboembolic pulmonary hypertension (rare in SSc but must be excluded)

Echocardiography is the first-line screening test, but right heart catheterization is required for definitive diagnosis and hemodynamic assessment before initiating PAH-specific therapy 1.

SSc-PAH has worse prognosis than idiopathic PAH, with more progressive disease and higher mortality despite treatment 1. Five-year survival remains poor even with current therapies 1.

Monitor for adverse effects 1:

• Endothelin receptor antagonists: hepatotoxicity (monthly liver function tests required), anemia, peripheral edema
• PDE5 inhibitors: headache, hypotension, contraindicated with nitrates
• Prostacyclins: jaw pain, diarrhea, flushing, hypotension, catheter-related infections (0.3 infections/patient/year for IV epoprostenol)

Combination therapy at diagnosis is now standard, as historical monotherapy approaches have been superseded by evidence showing superior outcomes with upfront combination treatment 1.

Emerging Therapies

Rituximab (B-cell depletion) added to standard PAH therapy showed possible benefit in improving functional exercise capacity at 48 weeks in an underpowered trial, though the primary endpoint at 24 weeks was not met 1, 5. More data are needed before recommending immunosuppression as standard treatment for SSc-PAH 1.

Surgical Options

Lung transplantation (double-lung or heart-lung) should be considered for end-stage disease with progressive deterioration despite maximal medical therapy, with current 1-year survival post-transplant at 93% 1.