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 De; Fabrizio 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; Childhood Arthritis and Rheumatology Research Alliance Registry Investigators

doi:10.1136/annrheumdis-2019-216040

Emergent high fatality lung disease in systemic juvenile arthritis

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

Authors

Vivian E Saper¹, Guangbo Chen², Gail H Deutsch^#^{3

4}, R Paul Guillerman^#⁵, Johannes Birgmeier^#⁶, Karthik Jagadeesh^#⁶, Scott Canna^#⁷, Grant Schulert^#^{8

9}, Robin Deterding^{10

11}, Jianpeng Xu¹, Ann N Leung¹², Layla Bouzoubaa¹³, Khalid Abulaban^{14

15}, Kevin Baszis¹⁶, Edward M Behrens^{17

18}, James Birmingham^{19

20}, Alicia Casey^{21

22}, Michal Cidon^{23

24}, Randy Q Cron^{25

26}, Aliva De²⁷, Fabrizio De Benedetti²⁸, Ian Ferguson²⁹, Martha P Fishman^{21

22}, Steven I Goodman³⁰, T Brent Graham³¹, Alexei A Grom^{8

9}, Kathleen Haines^{32

33}, Melissa Hazen^{21

22}, Lauren A Henderson^{21

22}, Assunta Ho^{34

35}, Maria Ibarra^{36

37}, Christi J Inman³⁸, Rita Jerath^{39

40}, Khulood Khawaja⁴¹, Daniel J Kingsbury⁴², Marisa Klein-Gitelman⁴³, Khanh Lai³⁸, Sivia Lapidus^{32

33}, Clara Lin^{10

11}, Jenny Lin^{44

45}, Deborah R Liptzin^{10

11}, Diana Milojevic⁴⁶, Joy Mombourquette⁴⁷, Karen Onel^{48

49}, Seza Ozen⁵⁰, Maria Perez⁵¹, Kathryn Phillippi^{52

53}, Sampath Prahalad^{54

55}, Suhas Radhakrishna^{56

57}, Adam Reinhardt⁵⁸, Mona Riskalla^{59

60}, Natalie Rosenwasser^{48

49}, Johannes Roth⁶¹, Rayfel Schneider^{62

63}, Dieneke Schonenberg-Meinema^{64

65}, Susan Shenoi^{4

66}, Judith A Smith⁶⁷, Hafize Emine Sönmez⁵⁰, Matthew L Stoll^{25

26}, Christopher Towe^{8

9}, Sara O Vargas^{22

68}, Richard K Vehe^{59

60}, Lisa R Young^{17

18}, Jacqueline Yang², Tushar Desai⁶⁹, Raymond Balise¹³, Ying Lu⁷⁰, Lu Tian⁷⁰, Gill Bejerano⁶, Mark M Davis⁷¹, Purvesh Khatri², Elizabeth D Mellins⁷²; Childhood Arthritis and Rheumatology Research Alliance Registry Investigators

Collaborators

Childhood Arthritis and Rheumatology Research Alliance Registry Investigators:
K Abulaban, R Agbayani, S Akoghlanian, E Anderson, M Andrew, B Badwal, L Barillas-Arias, K Baszis, M Becker, H Bell-Brunson, H Benham, S Benseler, T Beukelman, J Birmingham, M Boncek, H Brunner, A Bryson, H Bukulmez, L Cerracchio, E Chalom, J Chang, N Chowdhury, K Chundru, T Davis, J Dean, F Dedeoglu, V Dempsey, M Dionizovik-Dimanovski, L Dolinsky, J Drew, B Feldman, P Ferguson, B Ferreira, C Fleming, L Franco, I Goh, D Goldsmith, B Gottlieb, T Graham, T Griffin, M Hance, D Helfrich, K Hickey, M Hollander, J Hsu, A Huber, A Hudson, C Hung, A Huttenlocher, L Imundo, C Inman, J Jaquith, R Jerath, J Jones, S Jones, L Jung, P Kahn, D Kingsbury, K Klein, M Klein-Gitelman, S Kramer, A Kufen, S Lapidus, D Latham, S Linehan, B Malla, M Malloy, A Martyniuk, T Mason, K McConnell, D McCurdy, K McKibben, C McMullen-Jackson, K Moore, L Moorthy, E Muscal, W Norris, J Olson, K O'Neil, K Onel, K Phillips, L Ponder, S Prahalad, C Rabinovich, S Rauch, S Ringold, M Riordan, S Roberson, A Robinson, E Rojas, M Rosenkranz, B Rosolowski, N Ruth, K Schikler, A Sepulveda, C Smith, H Stapp, K Stewart, R Syed, A Tangarone, M Tesher, A Thatayatikom, R Vehe, E von Scheven, D Wahezi, C Wang, C Wassink, M Watson, A Watts, J Weiss

Affiliations

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 [email protected].

^# 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.

Publication types

Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Arthritis, Juvenile / complications*
Biopsy
Child
Child, Preschool
Female
Follow-Up Studies
Humans
Incidence
Infant
Lung / diagnostic imaging*
Lung Diseases / diagnosis
Lung Diseases / epidemiology*
Lung Diseases / etiology
Male
Prognosis
Retrospective Studies
Survival Rate / trends
Tomography, X-Ray Computed
United States / epidemiology

Supplementary concepts

Rheumatoid Arthritis, Systemic Juvenile

Abstract

Publication types

MeSH terms

Supplementary concepts

Grants and funding