Dataset Information

Emergent high fatality lung disease in systemic juvenile arthritis.

ABSTRACT:

Objective

To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).

Methods

In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.

Results

LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.

Conclusions

A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

SUBMITTER: Saper VE

PROVIDER: S-EPMC7065839 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

Emergent high fatality lung disease in systemic juvenile arthritis.

Saper Vivian E VE Chen Guangbo G Deutsch Gail H GH Guillerman R Paul RP Birgmeier Johannes J Jagadeesh Karthik K Canna Scott S Schulert Grant G Deterding Robin R Xu Jianpeng J Leung Ann N AN Bouzoubaa Layla L Abulaban Khalid K Baszis Kevin K Behrens Edward M EM Birmingham James J Casey Alicia A Cidon Michal M Cron Randy Q RQ De Aliva A De Benedetti Fabrizio F Ferguson Ian I Fishman Martha P MP Goodman Steven I SI Graham T Brent TB Grom Alexei A AA Haines Kathleen K Hazen Melissa M Henderson Lauren A LA Ho Assunta A Ibarra Maria M Inman Christi J CJ Jerath Rita R Khawaja Khulood K Kingsbury Daniel J DJ Klein-Gitelman Marisa M Lai Khanh K Lapidus Sivia S Lin Clara C Lin Jenny J Liptzin Deborah R DR Milojevic Diana D Mombourquette Joy J Onel Karen K Ozen Seza S Perez Maria M Phillippi Kathryn K Prahalad Sampath S Radhakrishna Suhas S Reinhardt Adam A Riskalla Mona M Rosenwasser Natalie N Roth Johannes J Schneider Rayfel R Schonenberg-Meinema Dieneke D Shenoi Susan S Smith Judith A JA Sönmez Hafize Emine HE Stoll Matthew L ML Towe Christopher C Vargas Sara O SO Vehe Richard K RK Young Lisa R LR Yang Jacqueline J Desai Tushar T Balise Raymond R Lu Ying Y Tian Lu L Bejerano Gill G Davis Mark M MM Khatri Purvesh P Mellins Elizabeth D ED

Annals of the rheumatic diseases 20190927 12

<h4>Objective</h4>To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).<h4>Methods</h4>In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.<h4>Results</h4>LD was associated with distinctive features, including acute erythematous clubbing and a high frequenc ...[more]

PMID: 31562126

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Project description:ObjectiveSystemic 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).MethodsClinical 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.ResultsEighteen 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.ConclusionPulmonary 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.

Project description:Systemic juvenile idiopathic arthritis is a chronic pediatric inflammatory disease of unknown etiology, characterized by fever, rash, hepatosplenomegaly, serositis, and arthritis. We hypothesized that intercellular communication, mediated by extracellular vesicles, contributes to systemic juvenile idiopathic arthritis pathogenesis and that the number and cellular sources of extracellular vesicles would differ between inactive and active states of systemic juvenile idiopathic arthritis and healthy controls. We evaluated plasma from healthy pediatric controls and patients with systemic juvenile idiopathic arthritis with active systemic flare or inactive disease. We isolated extracellular vesicles by size exclusion chromatography and determined total extracellular vesicle abundance and size distribution using microfluidic resistive pulse sensing. Cell-specific extracellular vesicle subpopulations were measured by nanoscale flow cytometry. Isolated extracellular vesicles were validated using a variety of ways, including nanotracking and cryo-electron microscopy. Extracellular vesicle protein content was analyzed in pooled samples using mass spectrometry. Total extracellular vesicle concentration did not significantly differ between controls and patients with systemic juvenile idiopathic arthritis. Extracellular vesicles with diameters <200 nm were the most abundant, including the majority of cell-specific extracellular vesicle subpopulations. Patients with systemic juvenile idiopathic arthritis had significantly higher levels of extracellular vesicles from activated platelets, intermediate monocytes, and chronically activated endothelial cells, with the latter significantly more elevated in active systemic juvenile idiopathic arthritis relative to inactive disease and controls. Protein analysis of isolated extracellular vesicles from active patients showed a proinflammatory profile, uniquely expressing heat shock protein 47, a stress-inducible protein. Our findings indicate that multiple cell types contribute to altered extracellular vesicle profiles in systemic juvenile idiopathic arthritis. The extracellular vesicle differences between systemic juvenile idiopathic arthritis disease states and healthy controls implicate extracellular vesicle-mediated cellular crosstalk as a potential driver of systemic juvenile idiopathic arthritis disease activity.

Project description:Background: Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) is a rare disease associated with dysregulated interleukin (IL)-1 activity. Objectives: To assess the efficacy and safety of Anakinra, an IL-1 receptor antagonist in SJIA and its effects on gene expression profiling. Methods: We conducted a multicenter, randomized, double-blind placebo-controlled trial. The primary objective was to compare the efficacy of a one-month treatment with anakinra (2 mg/kg subcutaneoulsy daily, maximum 100 mg) to a placebo between 2 groups of 12 SJIA patients each. Response was defined by a 30% improvement of the pediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared to baseline. An intention-to-treat analyze was performed. After Month 1 (M1), patients taking placebo were switched to Anakinra. Secondary objectives included tolerance and efficacy assessment for 12 months. Results: At M1, concluding the randomized trial, there was a significant difference in the response rate between patients treated with Anakinra (8/12 responders) and placebo (1/12) (p=0.003). The number of adverse events, mainly pain to injections, was similar between both groups. Ten patients from the placebo group switched to Anakinra at M1; nine were responders at M2. Between M1 and M12, six patients stopped treatment for an adverse event (Crohn’s disease, hepatitis), a lack of efficacy or a disease flare (2 cases each). Blood gene expression profiling at enrollment and upon follow-up allowed us to identify one set of dysregulated genes that reverted to normal values in the clinical responders and a second set, including interferon-inducible genes, that was induced by Anakinra. Conclusion: Anakinra is an effective treatment of SJIA. Its effect is associated with normalization of blood gene expression profiles in clinical responders and de novo induction of an interferon signature. (Clinical trials registration number: NCT00339157)

Project description:ObjectiveRecent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high-mortality interstitial lung disease often characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA-LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA-LD.MethodsWe used SOMAscan to measure ~1,300 analytes in sera from healthy controls and patients with systemic JIA, MAS, SJIA-LD, or other related diseases. We verified selected findings by enzyme-linked immunosorbent assay and lung immunostaining. Because the proteome of a sample may reflect multiple states (systemic JIA, MAS, or SJIA-LD), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort.ResultsProteome alterations in active systemic JIA and MAS overlapped substantially, including known systemic JIA biomarkers such as serum amyloid A and S100A9, and novel elevations in the levels of heat-shock proteins and glycolytic enzymes. Interleukin-18 levels were elevated in all systemic JIA groups, particularly MAS and SJIA-LD. We also identified an MAS-independent SJIA-LD signature notable for elevated levels of intercellular adhesion molecule 5 (ICAM-5), matrix metalloproteinase 7 (MMP-7), and allergic/eosinophilic chemokines, which have been previously associated with lung damage. Immunohistochemistry localized ICAM-5 and MMP-7 in the lungs of patients with SJIA-LD. The ability of ICAM-5 to distinguish SJIA-LD from systemic JIA/MAS was independently validated.ConclusionSerum proteins support a systemic JIA-to-MAS continuum; help distinguish systemic JIA, systemic JIA/MAS, and SJIA-LD; and suggest etiologic hypotheses. Select biomarkers, such as ICAM-5, could aid in early detection and management of SJIA-LD.

Dataset Information

Emergent high fatality lung disease in systemic juvenile arthritis.

Objective

Methods

Results

Conclusions

Publications

Emergent high fatality lung disease in systemic juvenile arthritis.

Similar Datasets

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