Background/Purpose: Systemic Juvenile Idiopathic Arthritis (SJIA) is associated with a recently recognized albeit poorly defined and characterized lung disease (LD). Our objective is to describe clinical characteristics, risk factors, histopathologic and immunologic features of SJIA-associated LD (SJIA-LD).

Methods: This was a prospective cohort study; patients were identified upon lung disease detection or referral to Cincinnati Children’s Hospital for consultation or second opinion. This study was approved by the Institutional Review Board, and written informed consent was obtained from all patients and/or their legal guardians. Clinical data was abstracted from medical records, and epidemiologic, cellular, biochemical, genomic analysis, and transcriptional profiling analyses were performed.

Results: Twenty-two patients with SJIA-LD have been evaluated since 2010. Typical radiographic findings included diffuse ground-glass opacities, subpleural reticulation, peribronchovascular and/or septal thickening, and lymphadenopathy. Pathologic findings included patchy but extensive lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia (ELP). Compared to SJIA patients without LD, children with SJIA-LD were younger at SJIA diagnosis, had prior episodes of macrophage activation syndrome (MAS), have had adverse reactions to biologic therapy, and have higher serum IL-18. PAP is classically associated with primary or secondary dysfunction of alveolar macrophages leading to accumulation of pulmonary surfactant in alveolar spaces. However, SJIA-LD patients lacked genetic, serologic, or functional evidence of GM-CSF pathway dysfunction typical of primary familial or autoimmune PAP. Additionally, bronchoalveolar lavage (BAL) rarely demonstrated proteinaceous material and had less lipid-laden macrophages than seen in primary PAP. Instead, SJIA-LD BAL fluid contained elevated levels of IL-18 and IFNγ-induced chemokines CXCL9-10. Finally, multiplex transcriptional profiling of SJIA-LD lung tissue identified upregulated type II interferon and T-cell activation networks, including a STAT1 transcriptional network. Two of the most highly upregulated non-HLA genes were CXCL10 (9-fold increase) and CXCL9 (7-fold increase), IFN-induced chemokines whose serum levels are strongly associated with MAS. This signature was also present in SJIA-LD lung tissue sections lacking substantial histopathological findings, suggesting it may precede and may even drive lung pathology. Taken together, this gene expression analysis supports significant IFNγ-induced pulmonary inflammation in children with SJIA-LD.

Conclusion: Pulmonary disease in SJIA has distinct clinical and immunologic features and represents an uncharacterized inflammatory lung disease. MAS may constitute a risk factor for SJIA-LD development. Both BAL cytokine analysis and gene expression profiling of lung tissue revealed substantial inflammation including elevated IL-18, IFNγ pathway activation and T cell function.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/systemic-juvenile-idiopathic-arthritis-lung-disease-characterization-and-risk-factors/