Systemic Juvenile Idiopathic Arthritis–Associated Lung Disease: Characterization and Risk Factors

Abstract

Objective Systemic juvenile idiopathic arthritis (JIA) is associated with a recently recognized, albeit poorly defined and characterized, lung disease (LD). The objective of this study was to describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA‐LD). Methods Clinical data collected since 2010 were abstracted from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed. Results Eighteen patients with SJIA‐LD were identified. Radiographic findings included diffuse ground‐glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA‐LD were younger at the diagnosis of systemic JIA (odds ratio [OR] 6.5, P = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, P < 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, P < 0.001), and had higher serum levels of interleukin‐18 (IL‐18) (median 27,612 pg/ml versus 5,413 pg/ml; P = 0.047). Patients with SJIA‐LD lacked genetic, serologic, or functional evidence of granulocyte–macrophage colony‐stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA‐LD rarely demonstrated proteinaceous material and had less lipid‐laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA‐LD versus 66.1% in patients with primary PAP; P < 0.001). BAL fluid from patients with SJIA‐LD contained elevated levels of IL‐18 and the interferon‐γ–induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA‐LD identified up‐regulated type II interferon and T cell activation networks. This signature was also present in SJIA‐LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA‐LD. Conclusion Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

“…Similarly, elevated IL-18 levels are also seen in some patients with sJIA and adult Still's disease, and are now recognized as factors predisposing to the development of MAS (15,17,(45)(46)(47). Some of these patients are included in a publication that highlights a larger spectrum of sJIA patients who develop a heterogeneous spectrum of lung diseases that include PAP and interstitial lung fibrosis and are referred to as sJIA-LD (48). Patients with IL-18PAP-MAS share a cytokine signature linked to high expression of IL-18 and originally described in NLRC4-MAS (12), which includes hematopoietic growth factors/cytokines like M-CSF, SCF, and IL-3.…”

Storm Warning: Lung Disease in Systemic Juvenile Idiopathic Arthritis

“…This new report by Schulert et al adds importantly to the initial description of SJIA‐LD. Schulert et al described 18 patients from the Cincinnati Children's Hospital Medical Center, long known as a referral center for children with systemic JIA and now increasingly for children with SJIA‐LD as well.…”

“…A recent case series identified 61 additional cases . In this issue of Arthritis & Rheumatology , Schulert and coworkers report yet more patients matching this case description and provide the first detailed mechanistic look at systemic JIA with lung disease, designated SJIA‐LD . The storm is upon us.…”

“…The fact that most SJIA‐LD patients have a history of MAS and high IL‐18 levels suggests that they are particularly prone to IFNγ excess, and thus potentially to IFNγ‐mediated activation of alveolar macrophages. Evidence for such activation is provided by gene expression studies in SJIA‐LD lung tissue in the study by Schulert et al , where both CXCL9 and CXCL10 were substantially up‐regulated, with corresponding proteins detected in 2 of 6 bronchoalveolar lavage fluid samples. Intriguingly, overexpression of IFNγ and other Th1 cytokines by T lymphocytes can cause PAP‐like disease in mice .…”

Identification of Human Immune Cell Subtypes Most Vulnerable to IL-1β-induced Inflammatory Signaling Using Mass Cytometry

“…Cytokine storm is suspected of producing the overzealous immune response driving the severe cardiopulmonary complications that are fueling the high morbidity and mortality rates in certain COVID-19-infected individuals 1,2 . Cytokine storm or macrophage activation syndrome or secondary haemophagocytic lyphohistocytosis has previously been described as a serious complication in other clinical contexts including individuals with rheumatologic disorders such as systemic onset juvenile inflammatory arthritis also known as Still's disease 3 , sepsis 4 , and CAR-T cell therapy 5 . IL-1β is one of the key inflammatory cytokines implicated in the cytokine storm syndrome 4,6,7 .…”