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Ann Rheum Dis. 2019 Dec;78(12):1722-1731. doi: 10.1136/annrheumdis-2019-216040. Epub 2019 Sep 27.

Emergent high fatality lung disease in systemic juvenile arthritis.

Author information

1
Pediatrics, Stanford University, Stanford, California, USA.
2
Institute for Immunity, Transplantation and Infection, Center for Biomedical Informatics Research, Medicine, Stanford University, Stanford, California, USA.
3
Pathology, Seattle Children's Hospital, Seattle, Washington, USA.
4
University of Washington School of Medicine, Seattle, Washington, USA.
5
Radiology, Baylor College of Medicine, Houston, Texas, USA.
6
Genetics, Stanford University, Stanford, California, USA.
7
Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
8
Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
9
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
10
Children's Hospital Colorado, Aurora, Colorado, USA.
11
University of Colorado School of Medicine, Aurora, Colorado, USA.
12
Radiology, Stanford University, Stanford, California, USA.
13
Public Health Services, Biostatistics, University of Miami School of Medicine, Miami, Florida, USA.
14
Helen DeVos Children's Hospital, Grand Rapids, Michigan, USA.
15
Michigan State University, East Lansing, Michigan, USA.
16
Pediatrics, Washington University in Saint Louis, Saint Louis, Missouri, USA.
17
Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
18
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
19
Medicine, Metro Health Hospital, Wyoming, Michigan, USA.
20
University of Michigan, Ann Arbor, Michigan, USA.
21
Boston Children's Hospital, Boston, Massachusetts, USA.
22
Harvard Medical School, Boston, Massachusetts, USA.
23
Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California, USA.
24
University of Southern California, Los Angeles, California, USA.
25
Children's of Alabama, Birmingham, Alabama, USA.
26
University of Alabama at Birmingham, Birmingham, Alabama, USA.
27
Pediatrics, Columbia University Medical Center, New York, New York, USA.
28
Rheumatology, Ospedale Pediatrico Bambino Gesu, Roma, Italy.
29
Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
30
Arthritis Associates of South Florida, Delray Beach, Florida, USA.
31
Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
32
Joseph M Sanzari Children's Hospital, Hackensack, New Jersey, USA.
33
Hackensack University Medical Center, Hackensack, New Jersey, USA.
34
Pediatrics, Prince of Wales Hospital, New Territories, Hong Kong.
35
Faculty of Medicine, Chinese University of Hong Kong, New Territories, Hong Kong.
36
Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA.
37
School of Medicine, University of Missouri Kansas City, Kansas City, Missouri, USA.
38
Pediatrics, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
39
Children's Hospital of Georgia, Augusta, Georgia, USA.
40
Augusta University, Augusta, Georgia, USA.
41
Pediatrics, Al Mafraq Hospital, Abu Dhabi, Abu Dhabi, United Arab Emirates.
42
Randall Children's Hospital at Legacy Emanuel, Portland, Oregon, USA.
43
Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
44
Children's Hospital at Montefiore, Bronx, New York, USA.
45
Yeshiva University Albert Einstein College of Medicine, Bronx, New York, USA.
46
Johns Hopkins All Children's Hospital, Saint Petersburg, Florida, USA.
47
Pediatrics, Kaiser Permanente Roseville Medical Center, Roseville, California, USA.
48
Pediatrics, Hospital for Special Surgery, New York, New York, USA.
49
Weill Cornell Medical College, New York, New York, USA.
50
Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
51
Cook Children's Medical Center, Fort Worth, Texas, USA.
52
Akron Children's Hospital, Akron, Ohio, USA.
53
Northeast Ohio Medical University, Rootstown, Ohio, USA.
54
Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
55
Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
56
Rady Children's Hospital, San Diego, California, USA.
57
Pediatrics, University of California San Diego, La Jolla, California, USA.
58
Pediatrics, University of Nebraska Medical Center College of Medicine, Omaha, Nebraska, USA.
59
Pediatrics, University of Minnesota Medical School Twin Cities, Minneapolis, Minnesota, USA.
60
University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota, USA.
61
Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
62
Hospital for Sick Children, Toronto, Ontario, Canada.
63
Pediatrics, University of Toronto, Toronto, Ontario, Canada.
64
Emma Children's Hospital AMC, Amsterdam, The Netherlands.
65
University of Amsterdam, Amsterdam, Noord-Holland, The Netherlands.
66
Pediatrics, Seattle Children's Hospital, Seattle, Washington, USA.
67
Pediatrics, University of Wisconsin Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
68
Pathology, Boston Children's Hospital, Boston, Massachusetts, USA.
69
Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.
70
Biomedical Data Science, Stanford University, Stanford, California, USA.
71
Institute for Immunity, Transplantation and Infection, Microbiology and Immunology, Stanford University, Stanford, California, USA.
72
Pediatrics, Stanford University, Stanford, California, USA mellins@stanford.edu.
#
Contributed equally

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.

KEYWORDS:

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

Conflict of interest statement

Competing interests: 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.

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