What is the etiology of Sjögren's (Sjögren's syndrome) Interstitial Lung Disease (ILD)?

Sjögren's Syndrome-Associated Interstitial Lung Disease: Etiology

Sjögren's-associated ILD is an autoimmune-mediated inflammatory process resulting from lymphocytic infiltration of the lung parenchyma, occurring as part of the systemic autoimmune exocrinopathy that characterizes Sjögren's syndrome. 1

Pathophysiologic Mechanism

The etiology of Sjögren's-ILD stems from the same autoimmune dysregulation that drives the systemic disease:

• Lymphocytic infiltration of lung tissue represents the primary pathologic mechanism, mirroring the lymphocytic infiltration seen in exocrine glands 2, 3
• The disease represents a complex autoimmune exocrinopathy with multifactorial pathogenesis that extends beyond glandular tissue to affect multiple organ systems including the lungs 2
• Diffuse lymphocytic infiltration characterizes the tracheobronchial and parenchymal involvement 3

Temporal Relationship and Disease Progression

The onset of ILD in Sjögren's syndrome demonstrates significant variability:

• ILD prevalence increases over time: 10% within the first year of Sjögren's diagnosis and 20% after 5 years 1
• ILD can precede systemic disease: 10-51% of patients develop ILD years before the onset of clinical Sjögren's syndrome 4
• This temporal variability suggests that pulmonary autoimmune inflammation may be an early or even initial manifestation of the systemic autoimmune process 4

Histopathologic Patterns

The autoimmune process manifests in distinct histopathologic patterns, with varying frequencies:

• Nonspecific interstitial pneumonia (NSIP): 45% - the most common pattern 1, 4, 3
• Respiratory bronchiolitis: 25% 1
• Usual interstitial pneumonia (UIP): 16% 1
• Lymphoid interstitial pneumonia (LIP): 15% - highly typical for Sjögren's but occurs in only a few cases 1, 2, 4
• Organizing pneumonia: 7% 1
• Amyloid: 6% 1
• Lymphoma: 4% 1

Unique Features in Sjögren's-ILD

Cystic lung disease occurs more commonly in Sjögren's compared with other connective tissue diseases 1:

• Associated with older age, secondary Sjögren's, and elevated anti-SSA (Ro) antibody 1
• Higher frequency of anti-SSB (La) antibody has also been reported 1
• Most commonly secondary to lymphoid interstitial pneumonia/follicular bronchiolitis but may suggest amyloid or MALT lymphoma, especially with concomitant nodules 1

Clinical Course and Prognosis

The natural history reflects the underlying autoimmune etiology:

• Most ILDs in Sjögren's follow an indolent course 1
• UIP pattern portends worse prognosis and can be progressive 1
• Acute exacerbations of NSIP and UIP can precipitate respiratory failure and death 1
• Mortality correlates with decreased baseline PaO2 and presence of microscopic honeycombing 1

Important Caveat: Drug-Induced ILD

Clinicians must distinguish between disease-related and iatrogenic lung injury, as medications used to treat Sjögren's can themselves cause drug-induced ILD 1:

• TNF-alpha inhibitors
• Sulfasalazine
• Cyclophosphamide
• Rituximab
• Leflunomide
• Methotrexate
• Sulfonamides

While the risk is approximately 1% for most agents, drug-induced ILD must be considered in patients who are progressive or refractory to therapies 1. This requires distinguishing treatment-related complications from progression of the underlying autoimmune lung disease.