Is hydroxychloroquine (HCQ) effective as a first-line treatment for interstitial lung disease (ILD)?

Hydroxychloroquine is NOT Recommended for Interstitial Lung Disease in Adults with Systemic Autoimmune Rheumatic Diseases

Hydroxychloroquine has no established role in the treatment of ILD in adults with systemic autoimmune rheumatic diseases and is not mentioned as a treatment option in the most recent 2023 ACR/CHEST guidelines. 1

Evidence-Based First-Line Treatment Options for SARD-ILD

The 2023 ACR/CHEST guidelines provide clear recommendations for first-line ILD treatment that do not include hydroxychloroquine 1:

Preferred First-Line Immunosuppressive Agents

• Mycophenolate (1000-1500 mg twice daily) is conditionally recommended as the preferred first-line option across all SARD-ILD subtypes, with favorable adverse effect profile compared to cyclophosphamide 1, 2
• Rituximab is conditionally recommended, particularly when inflammatory arthritis, myositis, or Sjögren neuropathy are present 1
• Azathioprine is conditionally recommended as a first-line option, though considered "additional" rather than "preferred" in SSc-ILD due to limited effectiveness data 1
• Cyclophosphamide is conditionally recommended but relegated to "additional option" status due to significant adverse effects (infection, cytopenias, hemorrhagic cystitis, infertility) 1

Glucocorticoid Recommendations

• Conditionally recommended for SARD-ILD other than SSc-ILD as short-term therapy (≤3 months), typically combined with immunosuppressive agents 1, 2
• Strongly recommended AGAINST in SSc-ILD due to association with scleroderma renal crisis, with moderate certainty of evidence for harm 1

Disease-Specific Biologic Options

• Tocilizumab is conditionally recommended for SSc-ILD and MCTD-ILD, particularly with inflammatory phenotype (elevated CRP, progressive skin thickening, early diffuse disease) 1
• Nintedanib is conditionally recommended for SSc-ILD as first-line option, though immunosuppressive medications are favored due to nintedanib's attenuation rather than stabilization of FVC decline 1

Why Hydroxychloroquine Is Not Recommended

The comprehensive 2023 ACR/CHEST guideline systematically evaluated all available pharmacologic interventions for SARD-ILD through 216 PICO questions and 5,235 records 1. Hydroxychloroquine was conspicuously absent from all 35 treatment recommendations 1.

Medications Explicitly Recommended AGAINST

The guidelines conditionally recommend against leflunomide, methotrexate, TNF inhibitors, and abatacept as first-line ILD treatment options 1. While hydroxychloroquine is not explicitly listed among drugs recommended against, its complete absence from consideration indicates insufficient evidence for efficacy in adult SARD-ILD 1.

Limited Evidence Base for Hydroxychloroquine in ILD

Pediatric Population Only

The only evidence for hydroxychloroquine in ILD exists in pediatric interstitial lung diseases (chILD), which represents a fundamentally different disease entity from adult SARD-ILD 3, 4:

• A 2015 literature review identified 85 case reports and small series in children treated with chloroquine or hydroxychloroquine (5-10 mg/kg/day), with favorable response reported in only 35 cases 3
• A 2020 prospective randomized controlled trial protocol was designed to evaluate hydroxychloroquine in pediatric ILD, but this addresses genetically or histologically defined chILD, not adult SARD-ILD 4
• One small series from 1994 showed chloroquine benefit in 6 children with desquamative interstitial pneumonitis, but this pattern is rare in adults and not typical of SARD-ILD 5

These pediatric data cannot be extrapolated to adult SARD-ILD due to different disease mechanisms, patterns, and natural history 3, 4.

Treatment Algorithm for SARD-ILD

Step 1: Determine Disease Subtype and Severity

• Assess specific SARD diagnosis (SSc, RA, IIM, MCTD, SjD) 1
• Evaluate ILD severity using FVC, DLCO, HRCT chest patterns, and symptoms 1, 2
• Identify rapidly progressive ILD (progression from room air to high oxygen requirement within days to weeks) 1

Step 2: Initiate First-Line Treatment Based on Subtype

For SSc-ILD:

• Start mycophenolate OR tocilizumab (if inflammatory phenotype) 1
• Avoid glucocorticoids due to renal crisis risk 1
• Consider nintedanib as alternative 1

For RA-ILD:

• Start mycophenolate as preferred agent 2
• Add short-term glucocorticoids (≤3 months) 2
• Alternative: azathioprine or cyclophosphamide 2

For IIM-ILD:

• Start mycophenolate with short-term glucocorticoids 1
• Consider JAK inhibitors or calcineurin inhibitors as first-line options 1

For MCTD-ILD or SjD-ILD:

• Start mycophenolate or azathioprine with short-term glucocorticoids 1
• Consider tocilizumab for MCTD-ILD 1

Step 3: Monitor Response Every 3-6 Months

• Perform PFTs (FVC, DLCO) to assess progression 2
• Obtain HRCT annually or with significant PFT changes 2
• Define progression as: FVC decline ≥10% predicted, OR FVC decline 5-10% with worsening symptoms/increased fibrosis, OR worsening symptoms with increased fibrosis over 24 months 1

Step 4: Manage Progressive Disease Despite First-Line Therapy

• Switch to alternative immunosuppressive agent not previously used (mycophenolate, rituximab, cyclophosphamide) 1, 2
• For RA-ILD specifically: add pirfenidone OR nintedanib 1, 2
• For SSc-ILD, MCTD-ILD, or RA-ILD: consider tocilizumab 1
• Avoid long-term glucocorticoids due to adverse effects without proven long-term efficacy 1, 2

Step 5: Manage Rapidly Progressive ILD

• Initiate pulse IV methylprednisolone 1, 2
• Add 1-2 additional agents: rituximab, cyclophosphamide, IVIG, mycophenolate, calcineurin inhibitor, or JAK inhibitor 1, 2
• For confirmed/suspected MDA-5 RP-ILD: use triple combination therapy 1
• Consider early lung transplant referral 1

Critical Pitfalls to Avoid

• Do not use hydroxychloroquine for adult SARD-ILD—it lacks evidence and is not guideline-recommended 1
• Do not use glucocorticoids in SSc-ILD at any dose due to scleroderma renal crisis risk 1
• Do not rely on long-term glucocorticoids for maintenance therapy in any SARD-ILD 1, 2
• Do not delay lung transplant evaluation in patients with advanced ILD, resting hypoxia, or rapidly deteriorating function 1
• Do not continue methotrexate, leflunomide, or TNF inhibitors if ILD develops while on these agents 1

Co-Management Requirements

Collaboration with pulmonologists is essential for initiation of ILD treatment, particularly to determine need for treatment in asymptomatic patients with stable, mild ILD 1. Management decisions must balance control of extrapulmonary SARD manifestations with ILD progression 2.