How to manage type 1 pulmonary arterial hypertension (PAH) from mixed connective tissue disease (MCTD)?

Management of Type 1 Pulmonary Arterial Hypertension from Mixed Connective Tissue Disease

Initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 inhibitor (PDE5i) is the recommended first-line treatment for PAH associated with mixed connective tissue disease (MCTD). 1

Diagnostic Confirmation

Before initiating treatment, confirm the diagnosis with:

• Right heart catheterization (essential for definitive diagnosis) 2, 1
• Vasoreactivity testing using short-acting agents (IV epoprostenol, adenosine, or inhaled nitric oxide) 2
• Ventilation-perfusion scanning to rule out chronic thromboembolic pulmonary hypertension 2

Treatment Algorithm

Step 1: Risk Assessment

Classify patient according to WHO Functional Class (FC) and risk stratification:

• Low risk: WHO FC I-II, 6MWD >440m, no RV dysfunction, BNP <50 ng/L
• Intermediate risk: WHO FC III, 6MWD 165-440m, moderate RV dysfunction, BNP 50-300 ng/L
• High risk: WHO FC IV, 6MWD <165m, severe RV dysfunction, BNP >300 ng/L 1

Step 2: Initial Therapy Based on Risk Assessment

For WHO FC II-III (Low to Intermediate Risk):

• First choice: Combination therapy with ambrisentan and tadalafil 2, 1
• If combination therapy is not tolerated:
  • ERA monotherapy (bosentan, ambrisentan, or macitentan) 2
  • PDE5i monotherapy (sildenafil or tadalafil) 2
  • Soluble guanylate cyclase stimulator (riociguat) 2

For WHO FC IV (High Risk):

• First choice: Intravenous epoprostenol (starting dose 2 ng/kg/min, titrated based on clinical response) 1
• Alternative: Subcutaneous or intravenous treprostinil 3

Step 3: Follow-up and Treatment Escalation

• Assess response every 3-6 months 1
• For inadequate response (patient remains symptomatic or fails to improve to low-risk status):
  • Escalate to triple combination therapy (ERA + PDE5i + prostacyclin analogue) 1
  • Consider adding inhaled iloprost or treprostinil to oral therapy 2, 1
  • Consider selexipag (oral prostacyclin receptor agonist) to delay disease progression 4

Special Considerations for MCTD-Associated PAH

1. Immunosuppressive Therapy:

   • Consider immunosuppressive agents in addition to PAH-specific therapy, as inflammation and autoimmune mechanisms play a role in MCTD-PAH 5
   • Particularly beneficial in early stages of MCTD-PAH 6

2. Anticoagulation:

   • Should be considered on an individual basis for CTD-PAH patients 2
   • Use with caution in MCTD due to increased risk of bleeding 2

3. Supportive Care:

   • Supplemental oxygen to maintain saturations >90% 1
   • Supervised exercise training for deconditioned patients 1
   • Immunizations against influenza and pneumococcal pneumonia 1

4. Pregnancy Counseling:

   • Pregnancy should be avoided due to high maternal and fetal mortality risk (30-50%) 1
   • Effective contraception is strongly recommended 1

Monitoring and Long-term Management

• Regular follow-up assessments every 3-6 months with comprehensive evaluation 1
• Monitor for liver function abnormalities with ERA therapy (monthly liver function tests) 7
• Assess treatment goals: improvement to WHO FC I-II, 6MWD >440m, normalization of RV function 1
• Consider referral to specialized centers for:
  • Inadequate response to maximal medical therapy
  • Need for complex combination therapy
  • High-risk features
  • Consideration for surgical options 1

Prognosis and Advanced Options

The prognosis of CTD-associated PAH is worse than other forms of PAH, with 1-year and 3-year survival rates of approximately 81% and 52%, respectively 8. For patients with progressive disease despite optimal medical therapy:

• Consider lung transplantation evaluation for eligible patients 2, 1
• Atrial septostomy may be considered as a bridge to transplantation 2

Early diagnosis and aggressive treatment with combination therapy are essential to improve outcomes in this challenging form of PAH.