What is the treatment approach for patients with systemic sclerosis and associated lung pathologies, such as interstitial lung disease and pulmonary hypertension?

Treatment of Systemic Sclerosis-Associated Lung Pathologies

Start mycophenolate mofetil (MMF) 2-3g daily as first-line therapy for SSc-ILD, and initiate combination therapy with phosphodiesterase-5 inhibitors plus endothelin receptor antagonists for SSc-PAH. 1, 2, 3

Interstitial Lung Disease (SSc-ILD) Management

First-Line Immunosuppressive Therapy

• MMF 2-3g daily is the preferred initial treatment for SSc-ILD, having surpassed cyclophosphamide due to superior tolerability and comparable efficacy 1, 2, 3
• Cyclophosphamide (600mg/m² IV monthly or 100-150mg daily oral) remains an alternative option, particularly for patients with more severe disease (baseline FVC <70% predicted or extensive HRCT involvement), though it carries more adverse effects 1, 2
• The treatment effect of cyclophosphamide is greatest in patients with ≥50% lung zone involvement on HRCT and/or modified Rodnan skin score ≥23, showing 9.81% FVC improvement at 18 months 1

Anti-Fibrotic Therapy for Progressive Disease

• Add nintedanib 150mg twice daily when progressive pulmonary fibrosis develops despite immunosuppressive therapy 1, 2
• Nintedanib reduces annual FVC decline based on the SENSCIS trial, and combination therapy with MMF demonstrates less FVC worsening than either agent alone 1, 2
• A 3% decline in FVC is associated with 43% higher hospitalization and mortality risk, making early intervention critical 1

Alternative Biologic Therapies

• Rituximab (two IV infusions 2 weeks apart, then every 6 months) is an effective alternative to cyclophosphamide with fewer adverse events, supported by multiple RCTs showing improvement in lung function 1, 2
• Tocilizumab (162mg subcutaneously weekly or 4-8mg/kg IV monthly) slows declining lung function in early diffuse SSc with ILD, particularly in patients with elevated acute-phase reactants 1, 2, 3
• Tocilizumab may prevent ILD changes in early dcSSc, though reimbursement limitations restrict access in many jurisdictions 1

Supportive Interventions

• Aggressively treat gastroesophageal reflux disease (GERD) with high-dose proton pump inhibitors, promotility agents, sleeping with head elevated, and avoiding eating after dinner to prevent aspiration-related ILD worsening 1
• Consider fundoplication surgery for severe reflux with symptoms of aspiration or nocturnal choking 1
• Ensure vaccination status is current: Pneumovax 23, Prevnar 13 or 20, influenza vaccine, and COVID-19 vaccine 1, 3
• Prescribe Pneumocystis jirovecii prophylaxis (sulfamethoxazole-trimethoprim) in patients with significant immunosuppression or high-dose glucocorticoids 1
• Provide supplemental oxygen if hypoxia is present to reduce dyspnea and mitigate pulmonary hypertension development 1, 3
• Pulmonary rehabilitation and regular cardiovascular exercise improve symptoms and quality of life in SSc-ILD 1

Advanced Therapies

• Autologous hematopoietic stem cell transplantation (AHSCT) should be considered for rapidly progressive early dcSSc at high risk of organ failure and mortality, performed only in experienced centers 1, 3
• Lung transplantation is the only treatment that improves long-term outcomes for end-stage lung fibrosis, with survival rates of 81% at 1 year and 66% at 5 years 1, 3
• Outcomes after lung transplantation in SSc are comparable to other chronic diseases in age- and sex-matched patients 1
• Reflux is a particular concern post-transplantation as it predisposes to bronchiolitis 1

Pulmonary Hypertension (PH) and Pulmonary Arterial Hypertension (PAH) Management

Classification and Screening

• PH occurs in 15-18% of SSc patients and is classified into WHO groups: Group 1 (PAH), Group 2 (left heart disease), Group 3 (ILD with hypoxia), Group 4 (pulmonary embolism), and Group 5 (unknown causes) 1
• SSc-PAH (Group 1) accounts for two-thirds of PH cases in SSc, occurring in 8-15% of all patients 1
• Echocardiography is the first-line screening test for SSc-associated PH 1
• Very low DLCO (<46% with parenchymal lung disease or <73% without) and decreasing DLCO are suggestive of PAH 1

Non-Pharmacological Management

• Counsel patients against smoking tobacco and marijuana 1
• Encourage regular exercise as tolerated and maintain ideal body weight 1
• Discuss contraception, as pregnancy is dangerous in SSc-PAH due to increased cardiac output and worsening hypoxia 1
• Recommend reduced-salt diet for patients with right ventricular overload and fluid retention 1
• Do not routinely anticoagulate SSc-PAH patients due to lack of survival benefit and high bleeding risk from erosive esophagitis and gastric antral vascular ectasia 1

PAH-Specific Pharmacological Therapy

• Initiate combination therapy at diagnosis with phosphodiesterase-5 (PDE5) inhibitors plus endothelin receptor (ETR) antagonists 1, 3
• ETR antagonists (bosentan, ambrisentan, or macitentan) improve exercise capacity and hemodynamics; require monitoring of liver enzymes and hemoglobin for hepatotoxicity and anemia 1
• PDE5 inhibitors (sildenafil, tadalafil, or vardenafil) enhance the nitric oxide-cGMP pathway, providing pulmonary vasodilatory and anti-proliferative effects 1
• Soluble guanylate cyclase stimulator riociguat (initial 0.5-1mg three times daily, titrated to maximum 2.5mg three times daily) is an alternative pathway targeting agent 1
• Prostacyclin analogues and receptor agonists include epoprostenol (continuous IV), treprostinil (subcutaneous, IV, or inhaled), iloprost (inhaled), and selexipag (oral) 1

Group 3 PH (PH Secondary to ILD)

• Group 3 PH has very poor prognosis as it is associated with hypoxia and lung disease 1
• Treat the underlying ILD with nintedanib for progressive pulmonary fibrosis 1
• Add inhaled treprostinil 18μg four times daily for PH treatment, which improved exercise capacity (6-minute walk distance), reduced NT-proBNP levels, and delayed time to clinical worsening in RCT 1
• Use pulmonary vasodilators judiciously despite concerns about ventilation-perfusion mismatch aggravation 1

Risk Stratification and Treatment Targets

• Treat to target using risk stratification to estimate mortality and guide therapy toward low-risk parameters 1
• Treatment targets include improving 6-minute walk distance, NT-proBNP levels, symptoms, WHO functional class, echocardiogram findings, right heart catheterization parameters, and preventing heart failure 1
• Combination treatment with PAH-specific therapies at diagnosis has improved outcomes, though 5-year mortality remains high 1

Surgical Options for End-Stage Disease

• Consider double-lung or heart-lung transplantation for end-stage lung disease with progressive disease despite therapy 1
• Survival post-transplantation has improved to approximately 93% at 1 year 1
• Right-to-left shunt or atrial septostomy is rarely performed, typically only for severe right heart failure while awaiting transplantation 1

Common Pitfalls and Caveats

• Avoid overtreatment of limited, nonprogressive SSc-ILD: Initial observation with close monitoring ("masterful inactivity with cat-like observation") is appropriate for patients without extensive disease or progression 4
• Do not use beta-blocker monotherapy for PAH, as it only controls peripheral manifestations without addressing central dysregulation 5
• Early intervention is critical: The risk of developing ILD is greatest in the first few years after SSc diagnosis, requiring close monitoring during this period 1, 6
• Combination therapies addressing multiple pathogenic mechanisms are likely needed to impact long-term survival, as single-agent approaches have limited effect 1, 3
• Case stratification is essential for balancing benefits and adverse effects of therapies and ensuring appropriate use of high-cost drugs 1
• Investigate causes of significant hypoxia in SSc-PAH patients (PVOD, ILD, pulmonary emboli), as PAH alone typically causes hypoxia only at end-stage 1