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.
Discussion