Initial Treatment for Interstitial Lung Disease
Idiopathic Pulmonary Fibrosis (IPF)
For patients with IPF, initiate antifibrotic therapy with either nintedanib or pirfenidone immediately upon diagnosis, as disease progression is linear and irreversible regardless of baseline lung function. 1, 2, 3
First-Line Antifibrotic Therapy
Pirfenidone is FDA-approved for IPF treatment at a dose of 2,403 mg/day (801 mg three times daily with food), demonstrating a statistically significant reduction in FVC decline compared to placebo (mean treatment difference 193 mL at 52 weeks) 2
Nintedanib is equally effective as first-line therapy, slowing annual FVC decline by approximately 44-57% in IPF patients 1, 4
Both antifibrotic agents reduce the risk of acute respiratory deteriorations and likely improve life expectancy based on pooled trial data and observational studies, though individual trials were not powered for mortality endpoints 2, 3
Critical Treatment Principles
Do not delay treatment waiting for disease progression - FVC decline in IPF is nearly linear, with patients having well-preserved baseline FVC experiencing the same rate of decline as those with advanced disease 3
Treatment should begin regardless of baseline FVC, as long as FVC ≥50% and DLCO ≥30-35% (typical trial inclusion criteria) 2
Managing Adverse Effects
Pirfenidone most commonly causes gastrointestinal symptoms (nausea, dyspepsia, vomiting) and photosensitivity/skin rashes 1, 5
Nintedanib causes gastrointestinal adverse effects including diarrhea (2.8 times placebo), nausea (3.1 times), vomiting (3.6 times), and elevated liver enzymes (3.2-3.6 times) 1
Dose adjustment is effective at reducing side effects without compromising efficacy - most patients can tolerate antifibrotic therapy with appropriate management 3
If severe adverse effects occur with first-line therapy, switching to the alternative antifibrotic is a feasible strategy, with significantly fewer severe adverse effects observed after switching (43.9% before vs 12.1% after, p<0.001) 6
Connective Tissue Disease-Associated ILD (CTD-ILD)
Systemic Sclerosis-ILD (SSc-ILD)
For SSc-ILD, mycophenolate is the preferred first-line immunosuppressive agent, with nintedanib conditionally recommended as an additional first-line option. 1, 7, 8
Mycophenolate 1000-1500 mg twice daily is the preferred first-line agent per the American College of Rheumatology, with monitoring of complete blood count every 2-4 months 1, 7
Nintedanib is conditionally recommended as first-line therapy specifically for SSc-ILD (unlike other CTD-ILDs where it is recommended against as first-line) 1
Tocilizumab is conditionally recommended as a first-line option for SSc-ILD 1
HRCT screening should be performed even in asymptomatic SSc patients due to high ILD prevalence and its status as the leading cause of death in this population 1
Rheumatoid Arthritis-ILD (RA-ILD)
For RA-ILD, initiate mycophenolate as the preferred first-line immunosuppressive therapy, with rituximab particularly beneficial when active inflammatory arthritis coexists. 1, 7, 8
Mycophenolate is the preferred first-line agent per the American College of Rheumatology 1, 7, 8
Rituximab is conditionally recommended as first-line, particularly beneficial for patients with concurrent active inflammatory arthritis 1, 8
Azathioprine and cyclophosphamide are alternative first-line options 1, 7, 8
Short-term glucocorticoids (≤3 months) are conditionally recommended as part of initial combination therapy 1, 7
The American College of Rheumatology could not reach consensus on nintedanib as first-line therapy for RA-ILD, though it is conditionally recommended for progressive disease 1
Pirfenidone is conditionally recommended against as first-line therapy for RA-ILD due to limited evidence (TRAIL1 study terminated early for futility) 1
Inflammatory Myopathy-ILD (IIM-ILD)
For IIM-ILD, mycophenolate remains the preferred first-line agent, with calcineurin inhibitors (particularly tacrolimus) and JAK inhibitors as additional first-line options for severe or MDA-5 positive disease. 1
Mycophenolate, azathioprine, rituximab, and cyclophosphamide are all conditionally recommended first-line options 1
Calcineurin inhibitors (tacrolimus preferred over cyclosporine) are conditionally recommended as first-line therapy, particularly for MDA-5-ILD or severe presentations, due to rapid onset of action 1
JAK inhibitors are conditionally recommended as first-line options for IIM-ILD based on observational data showing lower mortality with tofacitinib compared to tacrolimus in anti-MDA-5 ILD 1
Progressive Pulmonary Fibrosis (PPF) Despite Initial Therapy
For IPF Progression
- Switch to the alternative antifibrotic if on first-line therapy (pirfenidone to nintedanib or vice versa) 6
For CTD-ILD Progression
For progressive RA-ILD despite first-line immunosuppression, add pirfenidone as the preferred antifibrotic agent. 1, 7, 8
Pirfenidone is conditionally recommended specifically for progressive RA-ILD (not as first-line) 1, 7, 8
Nintedanib is conditionally recommended for progressive SARD-ILD including RA-ILD 1, 7, 8
Tocilizumab is conditionally recommended for progressive SSc-ILD, MCTD-ILD, and RA-ILD 1, 7, 8
Mycophenolate, rituximab, or cyclophosphamide should be used if not already tried as first-line agents 1, 7
Avoid adding glucocorticoids for progressive disease - the American College of Rheumatology conditionally recommends against this, with a strong recommendation against glucocorticoids specifically in progressive SSc-ILD 1
Rapidly Progressive ILD
For rapidly progressive RA-ILD or IIM-ILD, initiate upfront combination therapy (double or triple therapy) with pulse intravenous methylprednisolone plus immunosuppressive agents. 7
Pulse IV methylprednisolone is conditionally recommended as first-line treatment 7
Upfront combination therapy is conditionally recommended over monotherapy 7
Combination options include rituximab, cyclophosphamide, IVIG, mycophenolate, calcineurin inhibitors, or JAK inhibitors 7
Monitoring Strategy
Pulmonary function tests (FVC and DLCO) every 3-6 months to assess disease progression 1, 7, 8
Short-term repeat PFTs within 3 months and HRCT within 6 months of initial diagnosis to determine rate of progression 1, 8
A 5% decline in FVC over 12 months is associated with approximately 2-fold increase in mortality compared to stable FVC 4
Annual HRCT or with significant PFT changes to evaluate radiographic progression 7
Critical Pitfalls to Avoid
Do not withhold antifibrotic therapy in IPF based on perceived disease stability - progression is inevitable and linear, and treatment preserves lung function that cannot be recovered once lost 3
Do not rely on long-term glucocorticoids for CTD-ILD management - substantial adverse effect profile without proven long-term efficacy 1, 7
Do not use pirfenidone as first-line therapy for non-IPF ILD (except progressive RA-ILD where it can be added) - evidence is insufficient and the American College of Rheumatology conditionally recommends against it 1
Do not add antifibrotics to stable mycophenolate therapy without evidence of progression - cost and adverse effects outweigh benefits in non-progressive disease 1
Do not overlook RA-ILD screening in high-risk patients (male gender, smoking history, high RF/anti-CCP titers, longer disease duration) - RA-ILD is substantially underdiagnosed 1, 8