Emergent high fatality lung disease in systemic juvenile arthritis

Childhood arthritis and Rheumatology Research alliance Registry investigators

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1722-1731
Number of pages10
JournalAnnals of the Rheumatic Diseases
Volume78
Issue number12
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

Pulmonary diseases
Juvenile Arthritis
Lung Diseases
Macrophages
Macrophage Activation Syndrome
Pulmonary Alveolar Proteinosis
Pathology
Interleukin-6
Pneumonia
Chemical activation
Pharmaceutical Preparations
Exome
Drug Hypersensitivity
Lymphopenia
Opacity
Delayed Hypersensitivity
Anaphylaxis
Ferritins
Down Syndrome
Interleukin-1

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Childhood arthritis and Rheumatology Research alliance Registry investigators (2019). Emergent high fatality lung disease in systemic juvenile arthritis. Annals of the Rheumatic Diseases, 78(12), 1722-1731. https://doi.org/10.1136/annrheumdis-2019-216040

Emergent high fatality lung disease in systemic juvenile arthritis. / Childhood arthritis and Rheumatology Research alliance Registry investigators.

In: Annals of the Rheumatic Diseases, Vol. 78, No. 12, 01.01.2019, p. 1722-1731.

Research output: Contribution to journalArticle

Childhood arthritis and Rheumatology Research alliance Registry investigators 2019, 'Emergent high fatality lung disease in systemic juvenile arthritis', Annals of the Rheumatic Diseases, vol. 78, no. 12, pp. 1722-1731. https://doi.org/10.1136/annrheumdis-2019-216040
Childhood arthritis and Rheumatology Research alliance Registry investigators. Emergent high fatality lung disease in systemic juvenile arthritis. Annals of the Rheumatic Diseases. 2019 Jan 1;78(12):1722-1731. https://doi.org/10.1136/annrheumdis-2019-216040
Childhood arthritis and Rheumatology Research alliance Registry investigators. / Emergent high fatality lung disease in systemic juvenile arthritis. In: Annals of the Rheumatic Diseases. 2019 ; Vol. 78, No. 12. pp. 1722-1731.
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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 = "adult onset still's disease, DMARDs (biologic), inflammation, juvenile idiopathic arthritis, treatment",
author = "{Childhood arthritis and Rheumatology Research alliance Registry investigators} and Saper, {Vivian E.} and Guangbo Chen and Deutsch, {Gail H.} and Guillerman, {R. Paul} and Johannes Birgmeier and Karthik Jagadeesh and Scott Canna and Grant Schulert and Robin Deterding and Jianpeng Xu and Leung, {Ann N.} and Layla Bouzoubaa and Khalid Abulaban and Kevin Baszis and Behrens, {Edward M.} and James Birmingham and Alicia Casey and Michal Cidon and Cron, {Randy Q.} and Aliva De and {De Benedetti}, Fabrizio and Ian Ferguson and Fishman, {Martha P.} and Goodman, {Steven I.} and Graham, {T. Brent} and Grom, {Alexei A.} and Kathleen Haines and Melissa Hazen and Henderson, {Lauren A.} and Assunta Ho and Maria Ibarra and Inman, {Christi J.} and Rita Jerath and Khulood Khawaja and Kingsbury, {Daniel J.} and Marisa Klein-Gitelman and Khanh Lai and Sivia Lapidus and Clara Lin and Jenny Lin and Liptzin, {Deborah R.} and Diana Milojevic and Joy Mombourquette and Karen Onel and Seza Ozen and Maria Perez and Kathryn Phillippi and Sampath Prahalad and Suhas Radhakrishna and Raymond Balise",
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T1 - Emergent high fatality lung disease in systemic juvenile arthritis

AU - Childhood arthritis and Rheumatology Research alliance Registry investigators

AU - Saper, Vivian E.

AU - Chen, Guangbo

AU - Deutsch, Gail H.

AU - Guillerman, R. Paul

AU - Birgmeier, Johannes

AU - Jagadeesh, Karthik

AU - Canna, Scott

AU - Schulert, Grant

AU - Deterding, Robin

AU - Xu, Jianpeng

AU - Leung, Ann N.

AU - Bouzoubaa, Layla

AU - Abulaban, Khalid

AU - Baszis, Kevin

AU - Behrens, Edward M.

AU - Birmingham, James

AU - Casey, Alicia

AU - Cidon, Michal

AU - Cron, Randy Q.

AU - De, Aliva

AU - De Benedetti, Fabrizio

AU - Ferguson, Ian

AU - Fishman, Martha P.

AU - Goodman, Steven I.

AU - Graham, T. Brent

AU - Grom, Alexei A.

AU - Haines, Kathleen

AU - Hazen, Melissa

AU - Henderson, Lauren A.

AU - Ho, Assunta

AU - Ibarra, Maria

AU - Inman, Christi J.

AU - Jerath, Rita

AU - Khawaja, Khulood

AU - Kingsbury, Daniel J.

AU - Klein-Gitelman, Marisa

AU - Lai, Khanh

AU - Lapidus, Sivia

AU - Lin, Clara

AU - Lin, Jenny

AU - Liptzin, Deborah R.

AU - Milojevic, Diana

AU - Mombourquette, Joy

AU - Onel, Karen

AU - Ozen, Seza

AU - Perez, Maria

AU - Phillippi, Kathryn

AU - Prahalad, Sampath

AU - Radhakrishna, Suhas

AU - Balise, Raymond

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - adult onset still's disease

KW - DMARDs (biologic)

KW - inflammation

KW - juvenile idiopathic arthritis

KW - treatment

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U2 - 10.1136/annrheumdis-2019-216040

DO - 10.1136/annrheumdis-2019-216040

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