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Author Notes:

Correspondence: Dr Elizabeth D Mellins, Pediatrics, Stanford University, Stanford, CA 94305, USA; mellins@stanford.edu

Author contributions: VES, GC, GHD, RPG, ANL, JoB, KJ, JX, RB, LB, YL, LT, TD, GB, MMD, PK, EDM: collection, analysis, discussion and interpretation of data. VES, GC: wrote the manuscript. EDM, PK: checked and revised the manuscript.

SC, GS, RD, KA, KB, EMB, JaB, AC, MC, RQC, AD, FDB, TBG, AA G, IF, MF, SI G, LRY, MLS, AH, KH, MH, LA H, MI, CJI, RJ, KK, DJK, MK-G, KL, SL, CL, JL, DRL, DM, JM, KO, SO, MP, KP, SP, SR, AR, MR, NR, JR, RS, DS-M, SS, JAS, HES, CT, SOV, RKV, JY: provided data, and checked and approved the manuscript.

We thank all participants and hospital sites that recruited patients for the CARRA registry. The authors thank Drs Joseph A Kovacs, Jay K Kolls and Sergio Vargas for their expert input on pneumocystis pneumonia, Dr James Verbsky for contributing unidentified genetic data, and Dr Xuan Qin for PCP staining of a subset of biopsies.

The authors also thank Dr Yuki Kimura for critical reading of the manuscript, Dr Claudia Macaubas for statistical assistance and Ms Melinda Hing for assistance with the manuscript.

Disclosures: VES reports personal fees from Novartis. GD reports personal fees from Novartis. SC reports personal fees from Novartis and grants from AB2 Bio. GS reports personal fees from Novartis. KB reports personal fees from Novartis. RQC is co-PI of an investigator-initiated clinical trial funded by SOBI.

RD reports personal fees from Boehringer Ingelheim, other from NowVitals, personal fees and other from Triple Endoscopy, other from Earables, and NowVitals with patents and lung-related device development. AAG reports grants and personal fees from Novartis and grants from NovImmune. SL reports personal fees from Novartis.

RS reports personal fees from Novartis, NovImmune and SOBI. SS reports personal fees from Novartis. MLS reports personal fees from Novartis. LRY reports other from Up-To-Date and other from Boehringer Ingelheim, outside the submitted work. EDM reports grants from Novartis.


Research Funding:

This work was supported by the sJIA Foundation (EDM), the Lucile Packard Foundation for Children’s Health (EDM), CARRA-Arthritis Foundation grant (EDM, VES), Life Sciences Research Foundation (GC), Bio-X Stanford Interdisciplinary Graduate Fellowship (JoB), Stanford Graduate Fellowship and the Computational Evolutionary Human Genetics Fellowship (KJ), Bill & Melinda Gates Foundation (PK), and NIH 1U19AI109662 (PK), U19AI057229 (PK) and RO1 AI125197 (PK).

The CARRA registry has been supported by the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the Arthritis Foundation.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Rheumatology
  • Pulmonary alveolar proteinosis
  • Intraalveolar cholesterol granulomas
  • Macrophage activation syndrome
  • Endogenous lipoid pneumonia
  • GM-CSF Autoantibodies
  • Idiopathic arthritis
  • Bronchoalveolar lavage
  • Rheumatoid arthritis
  • ABCA3 Mutations
  • Children

Emergent high fatality lung disease in systemic juvenile arthritis


Journal Title:

Annals of the Rheumatic Diseases


Volume 78, Number 12


, Pages 1722-1731

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/).
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