What is the role of MAS-825 (targeting Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18)) in treating Systemic Juvenile Idiopathic Arthritis (SJIA) with Interstitial Lung Disease (ILD)?

MAS-825 for SJIA with Interstitial Lung Disease

MAS-825, a bispecific monoclonal antibody targeting both IL-1β and IL-18 simultaneously, represents a promising therapeutic option for SJIA-associated interstitial lung disease (SJIA-ILD), particularly given that standard IL-1 and IL-6 inhibitors must be immediately discontinued in these patients due to their strong association with this life-threatening complication. 1

Critical First Step: Discontinue Standard Biologics

Immediately stop all IL-1 inhibitors (anakinra, canakinumab) and IL-6 inhibitors (tocilizumab) if SJIA-ILD is suspected or confirmed, as most affected children were treated with these agents and they are strongly associated with this complication. 1 This creates a therapeutic dilemma since these are the primary recommended agents for SJIA without lung disease. 2

Rationale for MAS-825 in SJIA-ILD

Mechanistic Advantage

• Dual IL-1β and IL-18 blockade addresses the unique immunopathology of SJIA-ILD, which is characterized by markedly elevated IL-18 levels in both serum (median 27,612 pg/ml vs 5,413 pg/ml in SJIA without LD) and bronchoalveolar lavage fluid. 3

• Patients with SJIA-ILD demonstrate up-regulated type II interferon and T cell activation networks in lung tissue, with elevated interferon-γ-induced chemokines (CXCL9 and CXCL10) in BAL fluid. 3 IL-18 is a key driver of interferon-γ production, making it a logical therapeutic target. 4

• Single-agent blockade of either IL-1 or IL-6 alone is contraindicated in SJIA-ILD, necessitating alternative approaches. 1

Clinical Evidence

• A case report demonstrated marked improvement in refractory SJIA-ILD with MAS-825 treatment, including reduction in total and free IL-18 in serum and BAL, improved baseline oxygen saturation, enhanced exercise tolerance, and better quality of life metrics. 4

• The patient achieved complete steroid and biologic withdrawal after 10 months of MAS-825 therapy with no drug-related adverse effects. 4

• BAL analysis post-treatment showed resolution of pulmonary alveolar proteinosis features and markedly reduced inflammatory infiltrates (decreased CD4 T-cells, CD8 T-cells, and macrophages). 4

Alternative Therapeutic Options When MAS-825 Unavailable

JAK Inhibitors (Preferred Alternative)

• JAK inhibitors represent the next best option for SJIA-ILD given the contraindication to IL-1/IL-6 blockade and should be strongly considered. 1

• These agents can address the interferon-γ-driven pathology characteristic of SJIA-ILD. 5

Glucocorticoids (Bridging Therapy)

• Systemic glucocorticoids are recommended as part of initial treatment for SJIA with lung disease, though they should be used at the lowest effective dose for the shortest duration. 1

• Plan for tapering as other disease-modifying therapies take effect. 1

Calcineurin Inhibitors (Conditional Option)

• Calcineurin inhibitors are conditionally recommended, particularly if macrophage activation syndrome features coexist with lung disease. 1

• These may be combined with other agents in severely ill patients. 2

Agents to Explicitly Avoid in SJIA-ILD

• TNF inhibitors are inappropriate for systemic features and may worsen outcomes. 1

• Abatacept is inappropriate for MAS features in SJIA-ILD. 1

• Conventional synthetic DMARDs alone are ineffective for systemic features. 1

• Rituximab is generally inappropriate for SJIA-ILD. 1

• IVIG is inappropriate unless calcineurin inhibitor plus anakinra have failed (though anakinra itself should be avoided in established ILD). 1

Risk Factors Demanding Heightened Surveillance

Clinicians should maintain high suspicion for SJIA-ILD development in patients with:

• Age <2 years at SJIA onset (OR 6.5). 3

• History of macrophage activation syndrome (OR 14.5). 3, 1

• Previous adverse reactions to tocilizumab (OR 13.6). 3, 1

• Trisomy 21. 1

• Acute digital clubbing (red flag sign demanding immediate evaluation). 2, 1

Clinical Monitoring Considerations

• The interferon-driven transcriptional signature may precede histopathologic findings in lung tissue, suggesting that immunologic activation drives the pathology. 3

• SJIA-ILD has distinct features from primary pulmonary alveolar proteinosis, including less proteinaceous material and fewer lipid-laden macrophages in BAL (mean 10.5% vs 66.1%). 3

• Caution is warranted even with apparent clinical remission on dual IL-1/IL-6 blockade, as interstitial lung disease may progress despite biochemical improvement. 6 This underscores the importance of discontinuing these agents when ILD is present.