Emergent high fatality lung disease in systemic juvenile arthritis

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

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107 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)1722-1731
Number of pages10
JournalAnnals of the rheumatic diseases
Issue number12
Publication statusPublished - 1 Jan 2019


  • DMARDs (biologic)
  • adult onset still's disease
  • inflammation
  • juvenile idiopathic arthritis
  • treatment

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