What is the recommended treatment for interstitial lung disease associated with perinuclear anti‑neutrophil cytoplasmic antibody (p‑ANCA)‑associated vasculitis?

Treatment of Interstitial Lung Disease in p-ANCA Vasculitis

For ILD associated with p-ANCA vasculitis, treat with glucocorticoids (prednisone 1 mg/kg/day, maximum 80 mg) combined with either rituximab or cyclophosphamide for remission induction, as this represents organ-threatening disease requiring the same aggressive approach used for other severe manifestations of ANCA-associated vasculitis. 1

Disease Classification and Treatment Rationale

ILD in the context of p-ANCA vasculitis (typically MPO-ANCA positive microscopic polyangiitis) constitutes organ-threatening disease and should be managed with the same intensity as other severe AAV manifestations such as rapidly progressive glomerulonephritis or pulmonary hemorrhage. 1

• ILD prevalence is substantially higher in MPO-ANCA (p-ANCA) positive disease, occurring in up to 45% of MPA patients compared to 23% in GPA, with anti-MPO antibodies present in 46-71% of AAV-ILD cases. 2
• ILD significantly impacts mortality, increasing death risk 2-4 fold, particularly when pulmonary fibrosis is present. 2

Induction Therapy Protocol

First-Line Immunosuppression Options

Rituximab (preferred for most patients):

• Dose: 375 mg/m² IV weekly for 4 weeks 1
• Level of evidence 1B for GPA and MPA; Grade A recommendation 1
• Advantages include preservation of reproductive potential and superior efficacy in relapsing disease 1
• A recent case report demonstrated successful treatment of PR3-ANCA-positive IP with moderate-dose glucocorticoid plus rituximab, with complete resolution of symptoms and inflammatory markers 3

Cyclophosphamide (alternative option):

• Oral: 2 mg/kg/day (maximum 200 mg/day) 1
• IV pulse: 15 mg/kg at weeks 0,2,4,7,10,13 (preferred to reduce cumulative dose) 1
• Level of evidence 1A for GPA and MPA; Grade A recommendation 1

Glucocorticoid Regimen

• Initial dose: Prednisone 1 mg/kg/day (maximum 80 mg daily) 1
• Taper schedule over 4-5 months: reduce to 20-30 mg/day at weeks 2-4, then 15-20 mg/day at months 2-3, then 5 mg/day at months 4-5 1
• Avoid pulse IV methylprednisolone: A 2019 multicenter study found that adding pulse methylprednisolone to standard therapy provided no benefit in survival or renal recovery but increased infection risk (HR 2.7) and diabetes incidence (HR 6.33) 4

Essential Supportive Care

Infection Prophylaxis (Mandatory)

• Pneumocystis jirovecii prophylaxis with trimethoprim/sulfamethoxazole (800/160 mg on alternate days or 400/80 mg daily) for all patients receiving cyclophosphamide or rituximab 1
• Alternative agents if contraindicated: dapsone or atovaquone 1

Cyclophosphamide-Specific Precautions

• MESNA administration (oral or IV) to neutralize acrolein and prevent hemorrhagic cystitis 1
• High fluid intake (oral or IV) on infusion days to dilute urinary metabolites 1
• Monitor CBC weekly; adjust or discontinue for leucopenia <4000/μL 1

Maintenance Therapy After Remission

Once remission is achieved (typically 3-6 months):

Rituximab maintenance (preferred):

• 500 mg × 2 doses at complete remission, then 500 mg at months 6,12, and 18 1

Azathioprine (alternative):

• 1.5-2 mg/kg/day 1
• Caution: Azathioprine hypersensitivity syndrome can mimic infection or disease relapse with fever and inflammatory response; consider this diagnosis if unexplained exacerbations occur during maintenance therapy 5

Mycophenolate mofetil (alternative):

• 1 g/day, particularly useful if azathioprine is not tolerated 5

• Continue low-dose glucocorticoids (5-7.5 mg/day) during maintenance, tapering by 1 mg every 2 months 1

Monitoring Requirements

• Clinical assessment with urinalysis at each visit to detect disease activity 2
• Regular monitoring of renal function, inflammatory markers (CRP, KL-6), and ANCA titers 3, 2
• High-resolution CT to assess ILD progression, as ground glass opacities, reticulations, and interlobular septal thickening are common findings 2

Critical Pitfalls to Avoid

• Do not use plasma exchange routinely: The 2020 PEXIVAS trial demonstrated no benefit of plasma exchange for death or ESKD in severe AAV (HR 0.86; 95% CI 0.65-1.13; P=0.27) 6
• Do not delay immunosuppression: Early aggressive treatment is essential given the 2-4 fold increased mortality with AAV-ILD 2
• Do not rely on ANCA titers alone for treatment decisions; clinical assessment should guide therapy 2