What is the best treatment approach for a patient with connective tissue disease (CTD) experiencing an exacerbation of interstitial lung disease (ILD)?

Treatment of CTD-ILD Exacerbation

For an acute exacerbation of CTD-ILD, initiate pulse-dose IV methylprednisolone (1000 mg daily for 3 days) followed by moderate-dose oral prednisone (up to 60 mg daily) with rapid taper, while simultaneously escalating immunosuppression with mycophenolate, rituximab, or cyclophosphamide—except in systemic sclerosis where glucocorticoids carry significant risk of scleroderma renal crisis. 1, 2

Immediate Assessment and Stabilization

Determine the severity and pace of progression:

• Rapidly progressive ILD requires urgent intervention with IV glucocorticoids and upfront combination immunosuppression 1, 3
• Moderate progression allows for sequential therapy escalation without high-dose steroids 1
• Rule out alternative etiologies (infections, lymphoproliferative disorders) before initiating high-dose steroids 2

Disease-Specific Acute Management

For Systemic Sclerosis-ILD Exacerbation:

• Avoid glucocorticoids entirely if possible due to strong evidence of scleroderma renal crisis risk, particularly at prednisone doses >15 mg daily 1, 4
• If glucocorticoids are absolutely necessary for rapidly progressive disease, use the lowest effective dose with close monitoring for renal crisis 1, 2
• Immediately escalate to definitive immunosuppression: switch to or add mycophenolate (preferred), rituximab, or nintedanib 1, 4
• Consider tocilizumab 162 mg subcutaneously weekly for progressive disease 4

For Other CTD-ILD Exacerbations (Myositis, MCTD, RA, Sjögren's):

• For rapidly progressive disease: pulse IV methylprednisolone 1000 mg daily for 3 days, then oral prednisone up to 60 mg daily with rapid taper over weeks 2, 5
• Simultaneously initiate 1-2 additional immunosuppressive agents rather than relying on steroids alone 1, 3
• Preferred agents: rituximab, cyclophosphamide, or IVIG (if infection concern exists) 1

Definitive Immunosuppression Strategy

First-line escalation options (in order of preference):

1. Mycophenolate (preferred across all CTD-ILD subtypes): Start at 500-1000 mg twice daily, target 1500 mg twice daily 1, 3

2. Rituximab: 1000 mg IV on days 1 and 15, or 375 mg/m² weekly for 4 weeks 1, 3

3. Cyclophosphamide: 500-750 mg/m² IV every 4 weeks for 6 months (preferred over oral due to lower toxicity) 1

4. Disease-specific additions:

   • IIM-ILD: Add calcineurin inhibitors (tacrolimus preferred) or JAK inhibitors, particularly for anti-MDA-5 positive patients 1, 5
   • SSc-ILD: Add nintedanib 150 mg twice daily for progressive fibrosing disease 1, 4
   • RA-ILD: Consider adding pirfenidone for progressive disease 3

Combination Therapy for Severe Exacerbations

For rapidly progressive ILD with respiratory failure:

• Use upfront combination therapy (2 agents) rather than monotherapy 1, 3
• Typical combinations: rituximab + cyclophosphamide, or mycophenolate + calcineurin inhibitor 1, 5
• Exception: Cyclophosphamide is typically not combined with other agents except in life-threatening situations 1

Monitoring During Acute Treatment

Daily assessments:

• Respiratory status and oxygen requirements 2
• Blood pressure monitoring (especially SSc patients on any steroids) 2, 4
• Blood glucose and electrolytes 2

Serial testing:

• Pulmonary function tests every 3-6 months 2
• CBC with differential 2-3 weeks after starting immunosuppression, then every 3 months 1
• Liver function tests with same frequency 1

Critical Pitfalls to Avoid

Never use long-term glucocorticoids (>3-6 months) as maintenance therapy:

• Strong recommendation against in SSc-ILD due to renal crisis risk 1, 4
• Conditional recommendation against in other CTD-ILD due to lack of efficacy and toxicity 1, 3

Do not delay immunosuppression while tapering steroids:

• Steroids serve only as a bridge to definitive therapy 2, 4
• Early immunosuppression prevents irreversible fibrosis 1, 6

Avoid monotherapy in rapidly progressive disease:

• Combination therapy is conditionally recommended over monotherapy for rapidly progressive ILD 1, 3

Do not combine nintedanib with mycophenolate upfront:

• Add nintedanib only if documented progression on mycophenolate alone 4

Steroid Taper Protocol

After initial pulse therapy:

• Taper prednisone from 60 mg daily by 10 mg every 1-2 weeks to reach 20 mg daily 2
• Then taper by 5 mg every 2-4 weeks to reach 10 mg daily 2, 5
• Target maintenance dose ≤10 mg daily or discontinuation within 3-6 months 2, 5

When to Consider Transplant Referral

Early referral for lung transplantation evaluation if:

• Rapidly progressive ILD despite maximal medical therapy 1, 3
• Presenting with advanced disease (FVC <50% predicted or DLCO <40% predicted) 1
• SSc-ILD with progression despite combination therapy—consider stem cell transplantation at experienced centers 1, 3