Multicenter Study

. 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

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, Affiliations

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 mellins@stanford.edu.

^# Contributed equally.

PMID: 31562126
PMCID: PMC7065839
DOI: 10.1136/annrheumdis-2019-216040

Multicenter Study

Emergent high fatality lung disease in systemic juvenile arthritis

Vivian E Saper et al. Ann Rheum Dis. 2019 Dec.

. 2019 Dec;78(12):1722-1731.

doi: 10.1136/annrheumdis-2019-216040. Epub 2019 Sep 27.

Authors

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 mellins@stanford.edu.

^# Contributed equally.

PMID: 31562126
PMCID: PMC7065839
DOI: 10.1136/annrheumdis-2019-216040

Erratum in

Correction: Emergent high fatality lung disease in systemic juvenile arthritis.
[No authors listed] [No authors listed] Ann Rheum Dis. 2022 Feb;81(2):e35. doi: 10.1136/annrheumdis-2019-216040corr1. Ann Rheum Dis. 2022. PMID: 35022191 No abstract available.

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.

PubMed Disclaimer

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.

Figures

**Figure 1**
Distinctive clinical features in systemic juvenile idiopathic arthritis (sJIA) with lung disease (LD) and survival outcome. (A) Acute erythematous digital clubbing; (B, C) bulbous deformity with erythematous clubbing of fingers (B) and toes (C); (D) typical salmon-coloured, macular sJIA rash (evanescent); and (E, F) atypical rashes that occur before LD detection: (E) oedematous, urticarial, non-evanescent rash (knee) and (F) serpiginous, eczematous, non-evanescent rash with hyperpigmented borders. (G) Mean±SE blood ferritin values of propensity-matched (online supplementary figure S3) sJIA controls (blue) and LD cases (red) across time points relative to LD diagnosis. n.s., p>0.1, *p<0.05, **p<0.01, ***p<0.001, by Wilcoxon rank-sum test.

**Figure 2**
Distinctive radiological and pathological features. Panels A–E: representative axial chest CT images: (A) multilobar, predominantly peripheral septal thickening, most marked in the lower lung, parahilar and/or anterior upper lobes with or without adjacent ground-glass opacities; (B) crazy-paving; (C) peripheral consolidations; (D) peribronchovascular consolidations; (e) predominantly ground-glass opacities; and (F) hyperenhancing lymph nodes on contrast-enhanced CT. Panels G–H: histopathological findings (H&E staining) along the pulmonary alveolar proteinosis/endogenous lipoid pneumonia (PAP/ELP) spectrum. Alveolar filling with eosinophilic proteinaceous material (G, left), admixed with a variable degree of ELP, indicated by cholesterol clefts (arrowheads) and foamy (lipid-containing) macrophages (G, middle and right), as described. Regions of PAP/ELP accompanied by type II alveolar epithelial cell hyperplasia (G, right insert, arrow), mild to moderate interstitial infiltration by inflammatory cells and lobular remodelling (airspace widening with increased interstitial smooth muscle). Typically, PAP/ELP findings were patchy, with involved areas juxtaposed to the normal lung (G, left, arrow). Pulmonary arterial wall thickening; a, artery (G, right). In A–G, the number of cases with pattern/number of assessable cases are indicated. (H) Electron micrograph showing normal lamellar bodies within type II cells (arrows) and macrophage (centre), containing lamellar debris, lipid (*) and cholesterol clefts (arrowhead). Original magnification ×7000. Four PAP/ELP cases (one each: ABCA3 and CSF2RB variants), stained for surfactant proteins (SP-B, proSP-C, SP-D, ABCA3, TTF-1), demonstrated robust immunoreactivity (not shown).

**Figure 3**
Annual number of reported cases of LD and PAP/ELP pathology. (A) Annual number of LD cases in this series (total n=61). (B) Percentage of biopsied LD cases (n=36) with PAP/ELP pathology, grouped by year of LD diagnosis. (C) Annual incidence of LD, indicating proportions exposed (black) or not (grey) to anti-IL-1/IL-6 inhibitors. ABCA-3, ATP binding cassette subfamily A member 3; IL, interleukin; LD, lung disease; PAP/ELP, pulmonary alveolar proteinosis/endogenous lipoid pneumonia; proSP-C, prosurfactant D; SP-B, surfactant protein B; SP-D, surfactant protein D; TTF-1, thyroid transcription factor 1.

**Figure 4**
Association between unusual features and pre-exposure to anti-IL-1/IL-6 or MAS at sJIA onset. (A) Heat map indicating occurrence of unusual clinical and radiological features (rows) by subjects (columns), grouped by pre-exposure status. (B) Statistical analysis for panel A, indicating p values, FDR and OR with 95% CI. Inf, infinite, #p<0.1, *p<0.05, **p<0.01, ***p<0.001. (C–F) Comparison of severity-related features in pre-exposed LD cases versus published sJIA cohorts. (C) Pre-exposed LD cases compared with Janow *et al* (D) Pre-exposed LD cases with sJIA onset <1.5 years, compared with comparable age group in Russo and Katsicas; cut-off at <1.5 years was chosen by Russo and Katsicas, based on developmental difference before versus after 18 months. (E) Pre-exposed LD cases with sJIA onset >1.5 years, compared with comparable age group in Russo and Katsicas. (F) Pre-exposed LD cases treated with IL-1/IL-6 inhibitors for ≥6 months compared with comparable groups in Pardeo *et al* and Nigrovic *et al.* No bar indicates unavailable data. For details on definitions and published cohorts, see online supplementary table S6. (G) Statistical analysis of associations between MAS at sJIA onset and unusual clinical features of LD in sJIA, indicating p values, FDR and OR with 95% CI. FDR, false discovery rate; HELN, hyperenhancing lymph nodes; IL, interleukin; LD, lung disease; MAS, macrophage activation syndrome; PAP/ELP, pulmonary alveolar proteinosis/endogenous lipoid pneumonia; sJIA, systemic juvenile idiopathic arthritis.

**Figure 5**
Survival outcome in systemic juvenile idiopathic arthritis cohort with lung disease (LD). The number of survivors at a given time point after LD diagnosis is shown (strata).

See this image and copyright information in PMC

Comment in

Storm Warning: Lung Disease in Systemic Juvenile Idiopathic Arthritis.
Nigrovic PA. Nigrovic PA. Arthritis Rheumatol. 2019 Nov;71(11):1773-1775. doi: 10.1002/art.41071. Epub 2019 Sep 22. Arthritis Rheumatol. 2019. PMID: 31390168 Free PMC article. No abstract available.
Response to: 'Effectiveness and safety of ruxolitinib for the treatment of refractory systemic idiopathic juvenile arthritis like associated with interstitial lung disease: case report' by Bader-Meunier et al.
Saper VE, Chen G, Khatri P, Mellins ED. Saper VE, et al. Ann Rheum Dis. 2022 Feb;81(2):e21. doi: 10.1136/annrheumdis-2020-217000. Epub 2020 Feb 13. Ann Rheum Dis. 2022. PMID: 32054603 No abstract available.
Effectiveness and safety of ruxolitinib for the treatment of refractory systemic idiopathic juvenile arthritis like associated with interstitial lung disease : a case report.
Bader-Meunier B, Hadchouel A, Berteloot L, Polivka L, Béziat V, Casanova JL, Lévy R. Bader-Meunier B, et al. Ann Rheum Dis. 2022 Feb;81(2):e20. doi: 10.1136/annrheumdis-2020-216983. Epub 2020 Feb 13. Ann Rheum Dis. 2022. PMID: 32054604 No abstract available.
Successful treatment of plasma exchange for refractory systemic juvenile idiopathic arthritis complicated with macrophage activation syndrome and severe lung disease.
Sato S, Hosokawa T, Kawashima H. Sato S, et al. Ann Rheum Dis. 2022 Apr;81(4):e61. doi: 10.1136/annrheumdis-2020-217390. Epub 2020 Apr 3. Ann Rheum Dis. 2022. PMID: 32245894 No abstract available.
Response to: 'Successful treatment of plasma exchange for refractory systemic juvenile idiopathic arthritis complicated with macrophage activation syndrome and severe lung disease' by Sato et al.
Saper VE, Chen G, Guillerman RP, Khatri P, Cron RQ, Mellins ED. Saper VE, et al. Ann Rheum Dis. 2022 Apr;81(4):e62. doi: 10.1136/annrheumdis-2020-217426. Epub 2020 Apr 21. Ann Rheum Dis. 2022. PMID: 32317313 No abstract available.

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1. Gurion R, Lehman TJA, Moorthy LN. Systemic arthritis in children: a review of clinical presentation and treatment. Int J Inflam 2012;2012:1–16. - PMC - PubMed
1. Gerfaud-Valentin M, Cottin V, Jamilloux Y, et al. Parenchymal lung involvement in adult-onset still disease: a STROBE-compliant case series and literature review. Medicine 2016;95:e4258. - PMC - PubMed
1. Minoia F, Davì S, Horne A, et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol 2014;66:3160–9. - PubMed
1. Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2396–406. - PubMed
1. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2385–95. - PubMed

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Emergent high fatality lung disease in systemic juvenile arthritis

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Emergent high fatality lung disease in systemic juvenile arthritis

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