SLE with Interstitial Lung Disease (ILD) — Complete 15-Mark Answer

1. INTRODUCTION

2. SPECTRUM OF PULMONARY MANIFESTATIONS IN SLE

3. ILD IN SLE — PATHOGENESIS

• Autoantibodies (anti-dsDNA, anti-Sm, anti-Ro/SSA, anti-U1-RNP) → immune complex deposition in alveolar walls and vessels
• Complement activation (↓ C3, ↓ C4) → neutrophil and macrophage recruitment
• Cytokine cascade — IL-8, TNF-α, TGF-β → amplified alveolar inflammation
• T-cell dysregulation — imbalance of Th1/Th2 cytokines shifts toward fibrogenesis
• Type I interferon excess — drives ongoing epithelial injury
• Pulmonary capillaritis — immune complex deposits detectable by direct immunofluorescence (in contrast to pauci-immune ANCA vasculitis)

4. HISTOLOGICAL PATTERNS OF ILD IN SLE

5. CLINICAL FEATURES

A. Acute Lupus Pneumonitis

• Fever, severe dyspnoea, hypoxaemia, dry cough
• Rapid onset, often in the context of active SLE
• Pulmonary infiltrates indistinguishable from infection on imaging → always exclude infection first
• Haemoptysis may occur with DAH component

B. Chronic ILD

• Insidious progressive dyspnoea and dry cough
• Usually presents years after SLE diagnosis
• Fine bibasal Velcro crackles on auscultation
• Digital clubbing is rare
• Risk is increased in SLE patients with features of mixed connective tissue disease

C. Shrinking Lung Syndrome

• Diaphragmatic weakness (not true ILD)
• Elevated hemi-diaphragms, subsegmental atelectasis, restrictive physiology
• Diffusing capacity (DLCO) corrected for alveolar volume is normal (distinguishes from ILD)
• Associated with pleuritis, anti-dsDNA, anti-RNP seropositivity
• Resistant to standard immunosuppression

D. Diffuse Alveolar Haemorrhage (DAH)

• Abrupt onset, often not the first SLE manifestation
• Fever + rapid-onset bilateral infiltrates; haemoptysis absent in up to 50%
• Diagnosis confirmed by BAL (increasingly haemorrhagic aliquots)
• Mortality 0–90%, overall survival ~61% in systematic reviews

6. INVESTIGATIONS

A. Serology

• ANA (>95% sensitive), anti-dsDNA (highly specific), anti-Sm
• Anti-U1-RNP — associated with MCTD overlap and higher ILD risk
• ↓ C3, ↓ C4 correlate with disease activity
• Anti-Ro/SSA (also found in LIP subtype)
• ANCA may co-exist in capillaritis

B. Pulmonary Function Tests (PFTs)

• Restrictive pattern: ↓ FVC, ↓ TLC, normal or ↑ FEV1/FVC ratio
• ↓ DLCO — most sensitive marker; reflects alveolar–capillary membrane damage
• Exercise-induced hypoxaemia
• Serial PFTs monitor disease progression and treatment response

C. HRCT Chest (Key Exam Point)

• Ground-glass opacification (GGO) — active alveolitis; most reversible finding
• Irregular linear / band-like opacities (interlobular septal thickening)
• Intralobular reticulation
• Consolidation — in acute lupus pneumonitis or DAH
• Traction bronchiectasis — with established fibrosis
• Honeycombing — extremely rare; signifies UIP pattern
• Bilateral pleural effusions often coexist
• Decreasing lung volumes → shrinking lung syndrome

D. Bronchoscopy + BAL

• Excludes infection (mandatory before escalating immunosuppression)
• Confirms DAH (serial increasingly haemorrhagic BAL aliquots, haemosiderin-laden macrophages)

E. Surgical Lung Biopsy

• Rarely required; indicated when diagnosis uncertain and pattern will change management
• NSIP and OP patterns → more responsive to treatment
• UIP pattern → poor prognosis

7. MANAGEMENT

Principles

1. Exclude infection before starting/escalating immunosuppression
2. Not all patients require treatment — decision based on disease severity, rate of progression, PFT trajectory, histological pattern
3. Goal: maximise lung function, minimise symptom burden; stability = success in many cases

A. ACUTE LUPUS PNEUMONITIS / DAH (Severe/Life-threatening)

Step 1 — High-dose IV Methylprednisolone (Pulse therapy)

• Methylprednisolone 500–1000 mg IV daily × 3–5 days
• Followed by oral prednisone 1–2 mg/kg/day
• Taper by 10% every 7–10 days once disease controlled; do NOT taper too fast → risk of relapse

Step 2 — Cyclophosphamide (for severe/non-responding cases, especially DAH)

• Cyclophosphamide IV pulse: 0.5–1 g/m² IV once monthly × 6 months (NIH protocol)
  OR oral 2.0 mg/kg/day (avoid in young women due to gonadotoxicity)
• Used in ~55% of SLE-DAH patients
• Negative prognostic factors in DAH: mechanical ventilation, infection, cyclophosphamide therapy (reflect disease severity)

Step 3 — Plasmapheresis (PLEX)

• Used in ~31% of SLE-DAH cases in systematic reviews
• No proven survival benefit but may be used as adjunct in catastrophic disease
• 5 sessions of plasma exchange over 10 days

Rituximab

• 375 mg/m² IV weekly × 4 doses OR 1000 mg IV × 2 doses, 2 weeks apart
• Used in refractory/severe SLE not responding to conventional therapy; conflicting RCT data but effective in observational studies
• Increasingly used for DAH and refractory ILD

B. CHRONIC ILD IN SLE

First-line: Hydroxychloroquine (for all SLE patients)

• Dose: 5 mg/kg/day orally (maximum 400 mg/day)
• Duration: Long-term / indefinitely
• Reduces flares, disease progression, thrombotic events (particularly with antiphospholipid antibodies)
• Not effective for major organ manifestations alone but is background therapy for all SLE patients
• Monitor: annual ophthalmology (retinal toxicity after >5 years or >5 mg/kg/day)

Corticosteroids

• Prednisone 0.5–1 mg/kg/day orally for active ILD
• Taper to lowest effective dose (aim ≤7.5 mg/day for maintenance)
• NSIP and OP patterns respond better than UIP

Immunosuppressants (Steroid-sparing, Maintenance)

Anti-fibrotic Therapy (Progressive ILD refractory to immunosuppression)

• Nintedanib 150 mg orally twice daily — approved for progressive fibrosing ILD of any CTD; attenuates decline in FVC; can be used alone or added to MMF

Belimumab (B-lymphocyte stimulator inhibitor)

• 10 mg/kg IV monthly after 3 loading doses, OR 200 mg SC weekly
• FDA approved 2012 for SLE; 2020 for lupus nephritis
• Added to standard therapy → increased response rate, prevents worsening renal disease
• Used for active, autoantibody-positive SLE on background standard therapy

C. PULMONARY ARTERIAL HYPERTENSION in SLE

• Vasodilators: endothelin receptor antagonists (bosentan), PDE-5 inhibitors (sildenafil)
• Anticoagulation (especially with APS)
• Immunosuppression (cyclophosphamide)
• Transplantation in refractory cases

8. DRUG MONITORING SUMMARY

9. PROGNOSIS

• Cases with NSIP or OP pattern → better treatment response; partial to complete resolution possible
• Cases with UIP pattern or honeycombing → progressive fibrosis, poor prognosis
• Shrinking lung syndrome — generally resistant to all immunosuppression
• DAH — mortality 0–90%; overall survival ~61%; poor prognostic factors: mechanical ventilation, secondary infection
• Overall, ILD in SLE carries a worse prognosis than ILD in other CTDs such as polymyositis/dermatomyositis
• Up to 20% of patients with CTD-ILD may initially be labelled as idiopathic ILD → serological re-testing at follow-up is important (seroconversion in 51% in Chinese cohort study)

10. KEY EXAM POINTS (Viva Tips)

• HRCT detects ILD in 38% of SLE patients with normal CXR — HRCT is far more sensitive
• The most common SLE pulmonary manifestation is pleuritis, not ILD
• Always exclude infection before diagnosing acute lupus pneumonitis (both look identical on imaging)
• Shrinking lung syndrome = diaphragmatic weakness; DLCO corrected for alveolar volume is normal (key differentiating point from true ILD)
• Histology predicts response: NSIP/OP → respond; UIP → poor response
• MMF is now preferred first-line steroid-sparing agent over cyclophosphamide for chronic CTD-ILD (better side-effect profile)
• Methotrexate is avoided in ILD (can itself cause drug-induced pneumonitis)
• Hydroxychloroquine 5 mg/kg/day is background therapy for ALL SLE patients
• Nintedanib (anti-fibrotic) is now an option for progressive fibrosing SLE-ILD
• Belimumab → first biologic approved specifically for SLE (2012)