What is the role of Rituximab (a monoclonal antibody) in treating patients with interstitial lung disease (ILD), particularly those with autoimmune-related forms such as rheumatoid arthritis (RA)-associated ILD or systemic sclerosis-associated ILD?

Rituximab in Interstitial Lung Disease

Rituximab is conditionally recommended as a treatment option for systemic autoimmune rheumatic disease-associated ILD (SARD-ILD), serving as either an alternative first-line therapy or as a second-line option when disease progresses despite initial treatment. 1

First-Line Treatment Considerations

Mycophenolate remains the preferred first-line therapy across all SARD-ILD subtypes, with rituximab ranking as an alternative first-line option. 1 The 2023 ACR/CHEST guidelines establish a clear treatment hierarchy where mycophenolate is conditionally recommended over rituximab based on head-to-head voting, though the choice depends on specific clinical situations and patient factors. 1

When to Consider Rituximab as First-Line Therapy

Rituximab may be preferred over mycophenolate in specific clinical contexts: 1

• Active inflammatory arthritis in rheumatoid arthritis-associated ILD (RA-ILD) 1
• Myositis requiring treatment for both pulmonary and muscular manifestations 1
• Sjögren neuropathy where rituximab addresses multiple disease manifestations 1
• Patient preference or contraindications to mycophenolate 1

The evidence supporting rituximab as first-line therapy comes from four trials and observational studies in SSc, RA, and idiopathic inflammatory myopathies (IIM), demonstrating FVC improvement or stabilization. 1

Second-Line Treatment for Progressive Disease

For patients with SARD-ILD progression despite first-line therapy, rituximab is conditionally recommended alongside mycophenolate, cyclophosphamide, and nintedanib as treatment options. 1

Switching vs. Adding Rituximab

The decision to switch to rituximab or add it to existing therapy depends on the current treatment regimen: 1

• Some clinicians add rituximab to mycophenolate for SSc-ILD and IIM-ILD 1
• Others switch to rituximab monotherapy, particularly when considering patient risk factors and preferences 1
• Cyclophosphamide is typically not combined with other therapies, whereas rituximab may be used individually or in combination 1

The evidence supporting rituximab for progressive disease includes indirect evidence from four trials and observational studies across multiple SARD-ILD subtypes (SSc-ILD, MCTD-ILD, IIM-ILD, RA-ILD, and SjD-ILD), showing FVC stabilization or improvement. 1

Rapidly Progressive ILD

For patients with SARD and rapidly progressive ILD (RP-ILD), rituximab is conditionally recommended as a first-line treatment option alongside cyclophosphamide, IVIG, mycophenolate, calcineurin inhibitors, and JAK inhibitors. 1

Treatment Intensity for RP-ILD

The severity of rapidly progressive disease dictates treatment intensity: 1

• Dual combination therapy (pulse IV methylprednisolone plus one immunosuppressant) is conditionally recommended over monotherapy for SARD with RP-ILD (excluding SSc-ILD) 1
• Triple therapy is conditionally recommended for confirmed or suspected MDA-5 positive RP-ILD 1
• Rituximab and cyclophosphamide are recommended over IVIG, though IVIG may be preferred if there is high concern for infection 1

Important caveat: For SSc patients with RP-ILD, the panel could not reach consensus on glucocorticoid use due to scleroderma renal crisis risk; if used, close monitoring for renal crisis is essential. 1

Disease-Specific Considerations

Systemic Sclerosis-Associated ILD (SSc-ILD)

Rituximab demonstrates particular utility in SSc-ILD: 2

• Meta-analysis shows rituximab significantly improved FVC% predicted (mean difference 3.13; 95% CI 0.37-5.90) and modified Rodnan skin score at 24-48 weeks 2
• Retrospective data from 13 patients showed stabilization of pulmonary function at 12 months, with mean FVC increasing by 2.57% 3
• Patients with longer disease duration and worse baseline pulmonary function (median disease duration 9.1 years) showed improvement or stabilization in most cases 4

The quality of evidence remains very low by GRADE criteria, but clinical experience supports its use in progressive or refractory SSc-ILD. 2

Mixed Connective Tissue Disease (MCTD-ILD)

For MCTD-ILD, rituximab serves as an alternative first-line option after mycophenolate and azathioprine. 5 Tocilizumab is also listed as an additional first-line option, particularly for patients with an SSc phenotype. 5

Rheumatoid Arthritis-Associated ILD (RA-ILD)

Rituximab ranks as an alternative first-line option after mycophenolate and azathioprine for RA-ILD. 1 It may be particularly valuable when treating concurrent inflammatory arthritis. 1

Dosing and Administration

Standard rituximab dosing for SARD-ILD follows the rheumatoid arthritis protocol: 6

• Two 1000 mg IV infusions separated by 2 weeks 6
• Repeat courses every 6 months based on clinical response and B-cell reconstitution 6
• Alternative dosing of 500 mg IV every 6 months has been used in some studies 6

Pharmacodynamics and Monitoring

Rituximab depletes peripheral B-lymphocytes within 2 weeks, with most patients showing near-complete depletion (CD19 counts <20 cells/µL). 6 The majority of patients maintain B-cell depletion for at least 6 months, though approximately 4% experience prolonged depletion lasting more than 3 years. 6

Monitor for immunoglobulin reductions: 6

• At 6 months post-treatment, 10% of patients show decreased IgM, 2.8% decreased IgG, and 0.8% decreased IgA below normal limits 6
• With repeated treatment, 23.3% develop low IgM, 5.5% low IgG, and 0.5% low IgA at any time point 6

Safety Considerations

The safety profile of rituximab in SARD-ILD is generally acceptable, though specific concerns exist: 7

• Increased infectious disease risk in patients with ILD, particularly given underlying immunosuppression 7
• Possible lung toxicity, though rare 7
• Increased rate of immune-mediated reactions in patients with connective tissue diseases 7
• Pneumocystis jirovecii pneumonia (PJP) prophylaxis should be considered with significant immunosuppression (trimethoprim-sulfamethoxazole double-strength three times weekly) 1

Common Pitfalls and How to Avoid Them

Do not use rituximab as monotherapy for RP-ILD without glucocorticoids or combination therapy. The guidelines conditionally recommend combination therapy over monotherapy for rapidly progressive disease. 1

Do not delay switching or adding therapy in progressive disease. If patients show progression on first-line therapy with declining FVC or worsening HRCT findings, consider adding or switching to rituximab rather than continuing ineffective treatment. 1

Do not use long-term glucocorticoids with rituximab for chronic SARD-ILD. The guidelines strongly recommend against long-term glucocorticoids (>3 months) for SSc-ILD and conditionally recommend against them for other SARD-ILD. 1 Short-term glucocorticoids (≤3 months) may serve as a bridge when initiating therapy. 1

Do not overlook the need for vaccination and infection prophylaxis. Given B-cell depletion and immunoglobulin reduction, ensure patients receive appropriate vaccinations (influenza, COVID-19, pneumococcal, RSV) before initiating rituximab when possible. 1