Initial Treatment for ILD with UIP Pattern

Diagnosis and Treatment Approach

The American College of Rheumatology recommends that the treatment approach for ILD with UIP pattern depends critically on whether the patient has an underlying systemic autoimmune rheumatic disease (SARD) or idiopathic pulmonary fibrosis (IPF) 1, 2, 3
The European Respiratory Society suggests screening for connective tissue disease markers, including rheumatoid factor, anti-CCP antibodies, ANA, anti-Scl-70, anti-Jo-1, and other myositis-specific antibodies, to differentiate between SARD-associated ILD and IPF 3, 4
The American Thoracic Society recommends evaluating for environmental/occupational exposures, including organic antigens, silica, asbestos, and drug toxicity, to exclude other causes of ILD 3, 4

The American College of Rheumatology recommends mycophenolate as the preferred first-line immunosuppressive therapy across all SARD-ILD subtypes, including those with UIP pattern 1, 2, 5
The European League Against Rheumatism suggests rituximab as a conditionally recommended alternative for SARD-ILD with UIP pattern 1, 2, 5
The American College of Rheumatology conditionally recommends cyclophosphamide, typically not combined with other agents, for SARD-ILD with UIP pattern 1, 2, 6
The American College of Rheumatology conditionally recommends azathioprine for most SARD-ILD, except systemic sclerosis, with UIP pattern 1, 2, 5

The European Respiratory Society recommends antifibrotic therapy with either pirfenidone or nintedanib for IPF with definite UIP pattern, as immunosuppressive therapy is not effective and may be harmful 3
The American Thoracic Society suggests that pirfenidone and nintedanib have similar efficacy in slowing disease progression in IPF 3

The American College of Rheumatology recommends monitoring for progressive pulmonary fibrosis (PPF) phenotype, including ≥10% decline in FVC, worsening respiratory symptoms, and/or radiographic progression within the past year despite treatment 7, 8
The European Respiratory Society suggests considering adding nintedanib to ongoing immunosuppressive therapy if PPF develops in SARD-ILD 1, 2, 7
The American Thoracic Society recommends early recognition of PPF, as progression to irreversible fibrosis significantly worsens prognosis 5, 8

The American College of Rheumatology recommends mycophenolate as the preferred first-line immunosuppressive therapy for Connective Tissue Disease-Associated ILD (CTD-ILD) across all SARD-ILD subtypes 9
For systemic sclerosis-ILD specifically, nintedanib is conditionally recommended as an additional first-line option by the American College of Rheumatology 9, 10

No subsequent randomized controlled trials have been conducted to validate the preliminary findings of a single small pilot study on losartan in ILD, representing very low-quality evidence 10

Accurate classification of ILD as inflammatory (requiring immunosuppression) versus fibrotic (requiring antifibrotic therapy) is essential before initiating treatment, because therapeutic strategies differ fundamentally between these phenotypes. 11
Patients with suspected systemic autoimmune rheumatic disease‑associated ILD (SARD‑ILD) should be screened for underlying connective‑tissue diseases such as systemic sclerosis, rheumatoid arthritis, idiopathic inflammatory myopathies, mixed connective‑tissue disease, and Sjögren syndrome. [11][12]

Mycophenolate is the preferred first‑line immunosuppressive agent for all SARD‑ILD subtypes, including cases that display a usual interstitial pneumonia (UIP) radiologic pattern. 11

In systemic sclerosis‑associated ILD, glucocorticoids are strongly recommended against both as initial therapy and after disease progression. [11][13]
For all other connective‑tissue disease‑associated ILDs, glucocorticoids are conditionally recommended (i.e., may be used when benefits outweigh risks). [11][12]

A systematic work‑up for alternative causes of cough should be performed before attributing the symptom to ILD itself; gastro‑esophageal reflux disease (GERD) is a common reversible contributor that must be assessed. 14

Mycophenolate is the preferred first‑line immunosuppressive therapy for CTD‑associated UIP, irrespective of radiologic pattern, as recommended by the 2023 American College of Rheumatology/American College of Chest Physicians guidelines (conditionally recommended) 15.
The preference for mycophenolate is based on substantial clinical experience and trial data showing favorable efficacy and tolerability compared with alternative agents, despite limited head‑to‑head comparisons (conditionally recommended) 16.
In systemic‑sclerosis‑related ILD, mycophenolate achieved outcomes comparable to cyclophosphamide but with a more favorable adverse‑effect profile (conditionally recommended) 16.

Rituximab may be used as an alternative first‑line agent for CTD‑associated UIP (conditionally recommended) 15.
Cyclophosphamide is conditionally recommended as a first‑line monotherapy (i.e., not combined with other immunosuppressants) for CTD‑associated UIP (conditionally recommended) 15.
Azathioprine is conditionally recommended for most CTD‑ILD with a UIP pattern, except in systemic sclerosis where it is considered an adjunct rather than a preferred option (conditionally recommended) 16.

Glucocorticoids are strongly recommended against as first‑line therapy because of the risk of scleroderma renal crisis, especially at higher daily doses (strongly recommended against) 15.
If glucocorticoids are unavoidable, they should be given at the lowest effective dose (ideally below the high‑dose threshold) and patients should be closely monitored for renal complications (conditionally recommended) 15.
Nintedanib is conditionally recommended as an additional first‑line option specifically for systemic‑sclerosis‑ILD (conditionally recommended) 17.

Short‑term glucocorticoids (≤ 3 months) are conditionally recommended for CTD‑ILD other than systemic sclerosis, useful during disease flares or as a bridge when switching immunosuppressive agents (conditionally recommended) 15.

Leflunomide, methotrexate, TNF‑inhibitors, and abatacept should not be used as first‑line ILD treatments because of insufficient efficacy data and potential for harm (conditionally recommended against) 17.
Long‑term glucocorticoid monotherapy should be avoided across all CTD‑ILD subtypes; glucocorticoids should be limited to short courses or combined with steroid‑sparing immunosuppressants (conditionally recommended) 15.

When PPF develops despite first‑line immunosuppression, adding nintedanib to the existing regimen is conditionally recommended rather than switching to a different immunosuppressive agent (conditionally recommended) 16.
The decision to add nintedanib versus changing immunosuppression should consider the speed of disease progression, the extent of fibrotic involvement, and the presence of a UIP pattern on CT imaging (conditionally recommended) 16.