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 & 52 others 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

Research output: Contribution to journalArticleAcademicpeer-review

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
JournalAnnals of the Rheumatic Diseases
Volume78
DOIs
Publication statusPublished - 1 Jan 2019
Externally publishedYes

Cite this

Saper, V. E., Chen, G., Deutsch, G. H., Guillerman, R. P., Birgmeier, J., Jagadeesh, K., ... Mellins, E. D. (2019). Emergent high fatality lung disease in systemic juvenile arthritis. Annals of the Rheumatic Diseases, 78. https://doi.org/10.1136/annrheumdis-2019-216040
Saper, Vivian E. ; Chen, Guangbo ; Deutsch, Gail H. ; Guillerman, R. Paul ; Birgmeier, Johannes ; Jagadeesh, Karthik ; Canna, Scott ; Schulert, Grant ; Deterding, Robin ; Xu, Jianpeng ; Leung, Ann N. ; Bouzoubaa, Layla ; Abulaban, Khalid ; Baszis, Kevin ; Behrens, Edward M. ; Birmingham, James ; Casey, Alicia ; Cidon, Michal ; Cron, Randy Q. ; de, Aliva ; de Benedetti, Fabrizio ; Ferguson, Ian ; Fishman, Martha P. ; Goodman, Steven I. ; Graham, T. Brent ; Grom, Alexei A. ; Haines, Kathleen ; Hazen, Melissa ; Henderson, Lauren A. ; Ho, Assunta ; Ibarra, Maria ; Inman, Christi J. ; Jerath, Rita ; Khawaja, Khulood ; Kingsbury, Daniel J. ; Klein-Gitelman, Marisa ; Lai, Khanh ; Lapidus, Sivia ; Lin, Clara ; Lin, Jenny ; Liptzin, Deborah R. ; Milojevic, Diana ; Mombourquette, Joy ; Onel, Karen ; Ozen, Seza ; Perez, Maria ; Phillippi, Kathryn ; Prahalad, Sampath ; Radhakrishna, Suhas ; Reinhardt, Adam ; Riskalla, Mona ; Rosenwasser, Natalie ; Roth, Johannes ; Schneider, Rayfel ; Schonenberg-Meinema, Dieneke ; Shenoi, Susan ; Smith, Judith A. ; Sönmez, Hafize Emine ; Stoll, Matthew L. ; Towe, Christopher ; Vargas, Sara O. ; Vehe, Richard K. ; Young, Lisa R. ; Yang, Jacqueline ; Desai, Tushar ; Balise, Raymond ; Lu, Ying ; Tian, Lu ; Bejerano, Gill ; Davis, Mark M. ; Khatri, Purvesh ; Mellins, Elizabeth D. / Emergent high fatality lung disease in systemic juvenile arthritis. In: Annals of the Rheumatic Diseases. 2019 ; Vol. 78.
@article{c5633bfe962b477cb815f9f3fced7113,
title = "Emergent high fatality lung disease in systemic juvenile arthritis",
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.",
author = "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 Adam Reinhardt and Mona Riskalla and Natalie Rosenwasser and Johannes Roth and Rayfel Schneider and Dieneke Schonenberg-Meinema and Susan Shenoi and Smith, {Judith A.} and S{\"o}nmez, {Hafize Emine} and Stoll, {Matthew L.} and Christopher Towe and Vargas, {Sara O.} and Vehe, {Richard K.} and Young, {Lisa R.} and Jacqueline Yang and Tushar Desai and Raymond Balise and Ying Lu and Lu Tian and Gill Bejerano and Davis, {Mark M.} and Purvesh Khatri and Mellins, {Elizabeth D.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1136/annrheumdis-2019-216040",
language = "English",
volume = "78",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group",

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Saper, VE, Chen, G, Deutsch, GH, Guillerman, RP, Birgmeier, J, Jagadeesh, K, Canna, S, Schulert, G, Deterding, R, Xu, J, Leung, AN, Bouzoubaa, L, Abulaban, K, Baszis, K, Behrens, EM, Birmingham, J, Casey, A, Cidon, M, Cron, RQ, de, A, de Benedetti, F, Ferguson, I, Fishman, MP, Goodman, SI, Graham, TB, Grom, AA, Haines, K, Hazen, M, Henderson, LA, Ho, A, Ibarra, M, Inman, CJ, Jerath, R, Khawaja, K, Kingsbury, DJ, Klein-Gitelman, M, Lai, K, Lapidus, S, Lin, C, Lin, J, Liptzin, DR, Milojevic, D, Mombourquette, J, Onel, K, Ozen, S, Perez, M, Phillippi, K, Prahalad, S, Radhakrishna, S, Reinhardt, A, Riskalla, M, Rosenwasser, N, Roth, J, Schneider, R, Schonenberg-Meinema, D, Shenoi, S, Smith, JA, Sönmez, HE, Stoll, ML, Towe, C, Vargas, SO, Vehe, RK, Young, LR, Yang, J, Desai, T, Balise, R, Lu, Y, Tian, L, Bejerano, G, Davis, MM, Khatri, P & Mellins, ED 2019, 'Emergent high fatality lung disease in systemic juvenile arthritis' Annals of the Rheumatic Diseases, vol. 78. https://doi.org/10.1136/annrheumdis-2019-216040

Emergent high fatality lung disease in systemic juvenile arthritis. / Saper, Vivian E.; Chen, Guangbo; Deutsch, Gail H.; Guillerman, R. Paul; Birgmeier, Johannes; Jagadeesh, Karthik; Canna, Scott; Schulert, Grant; Deterding, Robin; Xu, Jianpeng; Leung, Ann N.; Bouzoubaa, Layla; Abulaban, Khalid; Baszis, Kevin; Behrens, Edward M.; Birmingham, James; Casey, Alicia; Cidon, Michal; Cron, Randy Q.; de, Aliva; de Benedetti, Fabrizio; Ferguson, Ian; Fishman, Martha P.; Goodman, Steven I.; Graham, T. Brent; Grom, Alexei A.; Haines, Kathleen; Hazen, Melissa; Henderson, Lauren A.; Ho, Assunta; Ibarra, Maria; Inman, Christi J.; Jerath, Rita; Khawaja, Khulood; Kingsbury, Daniel J.; Klein-Gitelman, Marisa; Lai, Khanh; Lapidus, Sivia; Lin, Clara; Lin, Jenny; Liptzin, Deborah R.; Milojevic, Diana; Mombourquette, Joy; Onel, Karen; Ozen, Seza; Perez, Maria; Phillippi, Kathryn; Prahalad, Sampath; Radhakrishna, Suhas; Reinhardt, Adam; Riskalla, Mona; Rosenwasser, Natalie; Roth, Johannes; Schneider, Rayfel; Schonenberg-Meinema, Dieneke; Shenoi, Susan; Smith, Judith A.; Sönmez, Hafize Emine; Stoll, Matthew L.; Towe, Christopher; Vargas, Sara O.; Vehe, Richard K.; Young, Lisa R.; Yang, Jacqueline; Desai, Tushar; Balise, Raymond; Lu, Ying; Tian, Lu; Bejerano, Gill; Davis, Mark M.; Khatri, Purvesh; Mellins, Elizabeth D.

In: Annals of the Rheumatic Diseases, Vol. 78, 01.01.2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Emergent high fatality lung disease in systemic juvenile arthritis

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 - Reinhardt, Adam

AU - Riskalla, Mona

AU - Rosenwasser, Natalie

AU - Roth, Johannes

AU - Schneider, Rayfel

AU - Schonenberg-Meinema, Dieneke

AU - Shenoi, Susan

AU - Smith, Judith A.

AU - Sönmez, Hafize Emine

AU - Stoll, Matthew L.

AU - Towe, Christopher

AU - Vargas, Sara O.

AU - Vehe, Richard K.

AU - Young, Lisa R.

AU - Yang, Jacqueline

AU - Desai, Tushar

AU - Balise, Raymond

AU - Lu, Ying

AU - Tian, Lu

AU - Bejerano, Gill

AU - Davis, Mark M.

AU - Khatri, Purvesh

AU - Mellins, Elizabeth D.

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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85072920713&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31562126

U2 - 10.1136/annrheumdis-2019-216040

DO - 10.1136/annrheumdis-2019-216040

M3 - Article

VL - 78

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

ER -