What is the medication of choice for managing Scleroderma-associated Interstitial Lung Disease (ILD)?

Medication of Choice for Scleroderma-Associated ILD

Mycophenolate is the preferred first-line medication for managing scleroderma-associated interstitial lung disease (SSc-ILD), with tocilizumab, rituximab, and cyclophosphamide as additional first-line options depending on clinical circumstances. 1, 2

First-Line Treatment Hierarchy

The 2023 ACR/CHEST guidelines establish a clear treatment hierarchy for SSc-ILD based on head-to-head voting by expert panels 1:

Preferred First-Line Agent

• Mycophenolate is conditionally recommended as the preferred immunosuppressive therapy across all systemic autoimmune rheumatic disease-associated ILD, including SSc-ILD 1, 2
• Mycophenolate demonstrates comparable efficacy to cyclophosphamide but with superior tolerability 2, 3
• Real-world evidence shows mycophenolate stabilizes or improves forced vital capacity (FVC) and slows ILD progression, even at doses lower than 3 g/day 3

Additional First-Line Options

The following agents are conditionally recommended as first-line alternatives, listed in hierarchical order 1:

• Tocilizumab: Conditionally recommended specifically for SSc-ILD and MCTD-ILD 1, 2
• Rituximab: Conditionally recommended as a first-line option, particularly valuable when concurrent inflammatory arthritis or myositis is present 1, 2
• Cyclophosphamide: Conditionally recommended, particularly for induction therapy in patients at high risk for progression 1, 2
• Azathioprine: Conditionally recommended but considered an "additional option" rather than "preferred" due to limited evidence of effectiveness relative to other therapies in SSc-ILD 1, 2
• Nintedanib: Conditionally recommended as a first-line option for SSc-ILD, though it should not be combined upfront with mycophenolate 1, 2

Critical Glucocorticoid Caveat

The ACR/CHEST guidelines strongly recommend AGAINST glucocorticoids as first-line treatment in SSc-ILD 1, 2. This is a strong recommendation (not conditional) due to:

• Association with scleroderma renal crisis (SRC), particularly at prednisone doses >15 mg daily 1
• Negative trends in FVC with glucocorticoid use 2
• This contrasts sharply with other systemic autoimmune rheumatic disease-associated ILD where short-term glucocorticoids are conditionally recommended 1

Important exception: In the rare occurrence of rapidly progressive SSc-ILD, there was no panel consensus on glucocorticoid use, and an individualized approach may be warranted given the life-threatening nature, despite SRC risk 1

Agents to Avoid as First-Line Therapy

The guidelines conditionally recommend AGAINST the following as first-line therapy in SSc-ILD 1, 2:

• Leflunomide
• Methotrexate
• TNF inhibitors
• Abatacept
• Pirfenidone
• JAK inhibitors
• IVIG or plasma exchange

Management of Progressive Disease Despite First-Line Treatment

When SSc-ILD progresses despite initial therapy, the approach depends on whether progression is due to intolerance or true treatment failure 1:

Treatment Options for Progression

• Continue to strongly avoid long-term glucocorticoids 1, 2
• Switch to or add: mycophenolate, rituximab, cyclophosphamide, or nintedanib 1, 2
• The decision to switch versus add therapy depends on the current medication and which therapy is being initiated 1
• Cyclophosphamide is typically not used in combination with other therapies, whereas others may be used individually or in combination 1

Antifibroticsfor Progressive Disease

• Nintedanib is conditionally recommended for SSc-ILD progression 1
• The decision to use nintedanib versus immunosuppression depends on the pace of progression, amount of fibrotic disease, and presence of usual interstitial pneumonia pattern on CT chest 1
• Do NOT add nintedanib or pirfenidone to mycophenolate unless there is evidence of ILD progression on mycophenolate alone 1, 2

Advanced Therapies

• Referral for stem cell transplantation and/or lung transplantation is conditionally recommended for SSc-ILD progression despite first-line treatment 1, 2
• Lung transplant referral should occur before deterioration renders the patient ineligible 1

Rapidly Progressive SSc-ILD

For the rare presentation of rapidly progressive SSc-ILD, a more aggressive approach is warranted 1:

• Pulse intravenous methylprednisolone is conditionally recommended as first-line treatment (despite the general prohibition on glucocorticoids in SSc-ILD) 1, 2
• Combination therapy (double or triple therapy) is conditionally recommended over monotherapy 1
• First-line options include: rituximab, cyclophosphamide, IVIG, mycophenolate, calcineurin inhibitors, or JAK inhibitors 1, 2
• Early lung transplant referral should be considered 1

Practical Treatment Algorithm

1. Initial diagnosis of SSc-ILD: Start mycophenolate as preferred first-line agent 1, 2
2. Consider alternative first-line agents (tocilizumab, rituximab, cyclophosphamide) based on:
   • Concurrent manifestations (e.g., rituximab for inflammatory arthritis) 1
   • Risk of progression (cyclophosphamide for high-risk patients) 2
   • Patient-specific factors (e.g., infection concerns, cost, fertility) 1
3. If progression occurs: Switch to or add rituximab, cyclophosphamide, or nintedanib 1, 2
4. If rapidly progressive: Use IV methylprednisolone with combination immunosuppression 1, 2
5. If refractory to medical management: Refer for stem cell or lung transplantation 1, 2

Evidence Quality and Clinical Context

All treatment recommendations carry low to very low certainty of evidence, reflecting the challenges in conducting high-quality trials in this population 1, 2. The hierarchical ranking was established through head-to-head voting by expert panels, acknowledging that decisions depend on specific clinical situations and patient factors 1. Despite the conditional nature of most recommendations, mycophenolate consistently emerged as the preferred agent across all voting scenarios 1.