Sjögren’s-Associated Interstitial Lung Disease

Notes

Inflammatory and Autoimmune Conditions | Pulmonary Disease in Rheumatology | Pulmonology | Rheumatology

Overview

Sjögren’s-associated interstitial lung disease (Sjögren’s-ILD) is a significant extra-glandular manifestation of primary Sjögren’s disease (pSS), occurring in ~9–20% of patients clinically, with subclinical involvement detectable in up to 50% on HRCT. It may precede sicca symptoms or develop late in the disease course. The most common ILD pattern is nonspecific interstitial pneumonia (NSIP), followed by usual interstitial pneumonia (UIP), organizing pneumonia (OP), and lymphocytic interstitial pneumonia (LIP). Risk factors include older age, male sex, smoking, anti-Ro/SSA positivity, and high disease activity. The most important complication is progressive pulmonary fibrosis leading to respiratory failure.

Definition

Primary Sjögren’s Disease (pSS): Chronic autoimmune disorder characterized by lymphocytic infiltration of exocrine glands, leading to sicca symptoms and systemic manifestations.
Interstitial Lung Disease (ILD): Group of disorders involving inflammation and/or fibrosis of the lung interstitium.
Nonspecific Interstitial Pneumonia (NSIP): ILD pattern with uniform interstitial inflammation and fibrosis, common in Sjögren’s-ILD.
Lymphocytic Interstitial Pneumonia (LIP): Rare ILD pattern with diffuse infiltration of alveolar septa by lymphocytes and plasma cells.

Anatomy and Physiology

Alveolar-capillary unit: Interface for gas exchange between alveolar air and pulmonary capillary blood.
Type I pneumocytes: Flat epithelial cells specialized for gas exchange.
Type II pneumocytes: Produce surfactant and regenerate alveolar epithelium.
Interstitial space: Contains fibroblasts, extracellular matrix, and immune cells; normally minimal to allow efficient diffusion.
Pulmonary lymphatics: Important in immune surveillance and clearance of interstitial fluid.

Aetiology and Risk Factors

Aetiology

Autoimmune-mediated injury to alveolar epithelium and interstitium
Lymphocytic infiltration driven by B-cell hyperactivity and autoantibodies (anti-Ro/SSA, anti-La/SSB)
Aberrant fibroblast activation and collagen deposition

Risk Factors

Age >50 years
Male sex
Smoking
Anti-Ro/SSA positivity
High systemic disease activity
Longer disease duration
Raynauds
Lymphopenia
Dental caries

Remember

ILD can be the first manifestation of pSS, especially in older male patients.

Side note

Raynaud’s phenomenon, lymphopenia, and rampant dental caries have been linked to higher ILD prevalence.

Pathophysiology

Genetic susceptibility + environmental triggers → autoimmune activation
Lymphocytic infiltration of exocrine glands and lung interstitium
Cytokine release (IL-6, BAFF, IFN-γ) → chronic inflammation
Fibroblast activation → extracellular matrix deposition
Progressive interstitial thickening → impaired gas exchange
Fibrosis → irreversible architectural distortion

Think

LIP pattern reflects intense lymphoid proliferation, sometimes linked to lymphoma risk.

Clinical Manifestations

Progressive exertional dyspnea
Nonproductive cough
Bibasilar “Velcro” crackles
Fatigue, low-grade fever
Sicca symptoms: dry eyes, dry mouth
Arthralgia, myalgia
Hypoxemia in advanced disease

Diagnosis

Key Investigations

HRCT: NSIP (most common), LIP, UIP, OP
PFTs: restrictive defect, ↓ FVC, ↓ DLCO
Serology: ANA, anti-Ro/SSA, anti-La/SSB
Minor salivary gland biopsy: lymphocytic sialadenitis (for pSS diagnosis)
BAL: lymphocytosis in LIP

Differential Diagnoses

Condition	Differentiating Feature
IPF	Older age, no sicca symptoms, UIP pattern
Sarcoidosis	Noncaseating granulomas, hilar lymphadenopathy
Hypersensitivity pneumonitis	Exposure history, centrilobular nodules
Lymphoma	Mass lesions, monoclonal lymphoid proliferation

Classification

ILD Classification Patterns

Pattern	HRCT Features	Common in Sjögren’s?	Prognosis
NSIP (Nonspecific Interstitial Pneumonia)	Bilateral, symmetric ground‑glass opacities ± fine reticulation; subpleural sparing common	Yes – most common	Better than UIP
UIP (Usual Interstitial Pneumonia)	Basal/subpleural reticulation, honeycombing, traction bronchiectasis; heterogeneous	Less common	Poorer prognosis
LIP (Lymphocytic Interstitial Pneumonia)	Diffuse ground‑glass opacities, thin‑walled cysts, septal thickening, scattered nodules	Characteristic but rare	Variable
OP (Organizing Pneumonia)	Patchy, peripheral or peribronchial consolidations; “reverse halo” sign possible	Occasional	Good with treatment
DAD (Diffuse Alveolar Damage)	Diffuse ground‑glass opacities, consolidation; ARDS‑like	Rare	Poor; acute presentation

Remember

In primary Sjögren’s, NSIP is most common, LIP is characteristic but less frequent, and UIP is less common but carries a worse prognosis.

Treatment

Immunosuppressants:
- Mycophenolate mofetil, azathioprine
- Cyclophosphamide for severe/progressive disease
Biologics:
- Rituximab (especially in LIP or refractory disease)
Glucocorticoids:
- Moderate to high dose for induction, taper to maintenance
Supportive:
- Oxygen therapy
- Pulmonary rehabilitation
- Vaccinations

Remember

LIP may respond better to immunosuppression than fibrotic UIP.

Complications and Prognosis

Complications

Progressive pulmonary fibrosis
Respiratory failure
Pulmonary hypertension
Lymphoma (especially in LIP)
Opportunistic infections

Prognosis

NSIP and OP: better prognosis
UIP: poorer prognosis
Poor prognostic factors:
- Older age
- Male sex
- Extensive fibrosis on HRCT
- Rapid FVC decline

References

Flament T et al. Pulmonary manifestations of Sjögren’s syndrome. Eur Respir Rev. 2016;25(140):110–123.
Maleki-Fischbach M et al. Manifestations and management of Sjögren’s disease. Arthritis Res Ther. 2024;26:43.
Parambil JG et al. Interstitial lung disease in primary Sjögren’s syndrome. Chest. 2006;130:1489–1495.
Roca F et al. ILD in primary Sjögren’s syndrome. Autoimmun Rev. 2017;16:48–54.
Ramos-Casals M et al. Primary Sjögren’s syndrome: immunologic and clinical predictors of major organ involvement. Arthritis Rheum. 2002;46:1585–1594.