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. 2019 Nov;71(11):1943-1954.
doi: 10.1002/art.41073. Epub 2019 Oct 1.

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

Grant S Schulert  1 , Shima Yasin  1 , Brenna Carey  2 , Claudia Chalk  2 , Thuy Do  2 , Andrew H Schapiro  1 , Ammar Husami  2 , Allen Watts  2 , Hermine I Brunner  1 , Jennifer Huggins  1 , Elizabeth D Mellins  3 , Esi M Morgan  1 , Tracy Ting  1 , Bruce C Trapnell  1 , Kathryn A Wikenheiser-Brokamp  1 , Christopher Towe  2 , Alexei A Grom  1
Affiliations

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

Grant S Schulert et al. Arthritis Rheumatol. 2019 Nov.

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.

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Conflict of interest statement

All other authors declare no conflicts of interest.

Figures

Figure 1:
Figure 1:
High-resolution Chest CT images from SJIA-LD patients. A, Focal areas of pleural thickening and bronchovascular centric tree-in-bud opacities in a mild case. B, More extensive pleural thickening with associated interlobular septal thickening in a moderately severe case. C, Ground-glass opacities with interlobular septal thickening and peripheral areas of consolidation in a severe case.
Figure 2:
Figure 2:
SJIA-LD histopathogy includes ELP/PAP features, vasculopathy, chronic inflammation & fibrosis. Gross focal lesions (A,*, **) are histologically comprised of peribronchiovascular (A,*) and subpleural (A**) air space filling with an associated inflammatory infiltrate. Disease distribution in other cases include patchy but extensive regions of lung involvement with intervening areas of normal lung (B, arrow), and diffuse involvement with marked interstitial, pleural and interlobular septal collagenous fibrosis (C, arrow; Trichrome stain). Vasculopathy includes intimal hyperplasia and fibrosis of veins (C, arrowhead) and mild arterial medial and/or intimal thickening (D, arrowhead and inset; Movat pentachrome stain) to marked occlusive mural thickening of small arteries (E, arrowhead and inset, Trichrome-VVG stain). Features in the spectrum of ELP and PAP include airspace filling with foamy macrophages (F, inset; G, arrowhead) and eosinophilic proteinaceous material (G-H,*) with a variable abundance of cholesterol clefts (F-H, arrows) including cholesterol cleft aggregates associated with a granulomatous reaction and surrounding interstitial fibrosis (F-G, arrows). The ELP/PAP features are associated with Type II alveolar epithelial cell hyperplasia (F, arrowhead) and a mild to marked lymphoplasmacytic infiltrate present in all cases. a=artery; b=bronchiole. Original magnification 20x (A), 40x (B-C), 200x (D-F), H), 400x (F insert; G). (I), Ultrastructural features of SJIA-ILD. High-resolution view of a surgical lung biopsy showing cholesterol clefts (double asterisks), collagen fibrils (arrowheads) comprising interstitial fibrosis, and an alveolar macrophage containing lipid droplets (single asterisks) and engorged with numerous intracytoplasmic lamellar structures typical of internalized surfactant (arrows). Uranyl acetate-lead citrate staining, original magnification 6000x.
Figure 3:
Figure 3:
SJIA-LD has a lymphocyte predominant infiltrate with a predominance of CD4+ helper T-cells. Lung biopsies from two patients with SJIAlung (A-B) with lymphocyte predominant inflammation distributed diffusely as single cells as well as aggregates, some with follicle formation (B, arrow). The inflammatory infiltrate is CD3+ T-cell predominant (C-D) admixed with fewer CD20+ B-cells (E-F). CD4+ helper T-cells (G-H) predominant over CD8+ cytotoxic T-cells (I-J). Original magnification 200x (left panel) and 100x (right panel).
Figure 4:
Figure 4:
SJIA-LD patients lack characteristic features seen in PAP. A, serum titers of anti-GM-CSF antibodies detected in patients with autoimmune PAP (n=5), hereditary PAP (n=1), or SJIA-LD (n=6). B, representative flow cytometry detection of P-STAT5 in monocytes from control patient (top) and patient with SJIA-LD (bottom) before or after simulation with GM-CSF. C, dose response of P-STAT5 in monocytes from healthy controls (blue) and SJIA-LD patients (red) to GM-CSF. Data are expressed as mean fluorescence index (MFI at 10ng/ml ÷ MFI at 0 ng/ml x100. D-F, Analysis of BAL fluid obtained from patients with SJIA-LD (n=6) and hereditary or autoimmune PAP (n=7). (D) shows percent of lipid-laden macrophages detected by ORO staining, (E) shows BAL fluid cell count differential. (F) shows cytokine levels as determined by specific ELISA or luminex as described.
Figure 5:
Figure 5:
IFNγ response and T cell activation gene expression is upregulated in SJIA-LD lungs. (A), unsupervised clustering of samples based upon differentially expressed genes between SJIA-LD samples (blue) and controls (green) (corrected p<0.05). (B), Log relative expression of significantly upregulated genes involved in HLA-D (left), IFNγ response pathways (center) and T cells (right). (C), principle component analysis of Nanostring gene expression data. (D), H&E sections of lung samples from two simultaneously obtained lung biopsies from radiographically and grossly affected and unaffected regions from two patients used to determine SJIA-LD associated transcriptome. Original magnification 40x.
Figure 6:
Figure 6:
Proposed mechanism of SJIA-LD. The cytokine storm during acute MAS, where IFNγ and IL-18 play a pivotal role, activates resident immune cells in the lungs including macrophages. These cells subsequently release chemokines which may include CXCL9–10 and initiate recruitment of Th1 cells into the lung interstitium. Accumulation of immune cells then promotes persistent and self-sustained inflammatory response. The inflammatory milieu associated with this response deviates polarization of macrophages away from the phenotype necessary for recycling surfactant leading to the emergence of PAP-like features. The role of biologic therapy and/or other environmental and genetic factors in this process remains unclear.
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