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Emergent high fatality lung disease in systemic juvenile arthritis
  1. Vivian E Saper1,
  2. Guangbo Chen2,
  3. Gail H Deutsch3,4,
  4. R Paul Guillerman5,
  5. Johannes Birgmeier6,
  6. Karthik Jagadeesh6,
  7. Scott Canna7,
  8. Grant Schulert8,9,
  9. Robin Deterding10,11,
  10. Jianpeng Xu1,
  11. Ann N Leung12,
  12. Layla Bouzoubaa13,
  13. Khalid Abulaban14,15,
  14. Kevin Baszis16,
  15. Edward M Behrens17,18,
  16. James Birmingham19,20,
  17. Alicia Casey21,22,
  18. Michal Cidon23,24,
  19. Randy Q Cron25,26,
  20. Aliva De27,
  21. Fabrizio De Benedetti28,
  22. Ian Ferguson29,
  23. Martha P Fishman21,22,
  24. Steven I Goodman30,
  25. T Brent Graham31,
  26. Alexei A Grom8,9,
  27. Kathleen Haines32,33,
  28. Melissa Hazen21,22,
  29. Lauren A Henderson21,22,
  30. Assunta Ho34,35,
  31. Maria Ibarra36,37,
  32. Christi J Inman38,
  33. Rita Jerath39,40,
  34. Khulood Khawaja41,
  35. Daniel J Kingsbury42,
  36. Marisa Klein-Gitelman43,
  37. Khanh Lai38,
  38. Sivia Lapidus32,33,
  39. Clara Lin10,11,
  40. Jenny Lin44,45,
  41. Deborah R Liptzin10,11,
  42. Diana Milojevic46,
  43. Joy Mombourquette47,
  44. Karen Onel48,49,
  45. Seza Ozen50,
  46. Maria Perez51,
  47. Kathryn Phillippi52,53,
  48. Sampath Prahalad54,55,
  49. Suhas Radhakrishna56,57,
  50. Adam Reinhardt58,
  51. Mona Riskalla59,60,
  52. Natalie Rosenwasser48,49,
  53. Johannes Roth61,
  54. Rayfel Schneider62,63,
  55. Dieneke Schonenberg-Meinema64,65,
  56. Susan Shenoi4,66,
  57. Judith A Smith67,
  58. Hafize Emine Sönmez50,
  59. Matthew L Stoll25,26,
  60. Christopher Towe8,9,
  61. Sara O Vargas22,68,
  62. Richard K Vehe59,60,
  63. Lisa R Young17,18,
  64. Jacqueline Yang2,
  65. Tushar Desai69,
  66. Raymond Balise13,
  67. Ying Lu70,
  68. Lu Tian70,
  69. Gill Bejerano6,
  70. Mark M Davis71,
  71. Purvesh Khatri2,
  72. Elizabeth D Mellins1
  73. the Childhood Arthritis and Rheumatology Research Alliance Registry Investigators
    1. 1 Pediatrics, Stanford University, Stanford, California, USA
    2. 2 Institute for Immunity, Transplantation and Infection, Center for Biomedical Informatics Research, Medicine, Stanford University, Stanford, California, USA
    3. 3 Pathology, Seattle Children's Hospital, Seattle, Washington, USA
    4. 4 University of Washington School of Medicine, Seattle, Washington, USA
    5. 5 Radiology, Baylor College of Medicine, Houston, Texas, USA
    6. 6 Genetics, Stanford University, Stanford, California, USA
    7. 7 Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
    8. 8 Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
    9. 9 Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
    10. 10 Children's Hospital Colorado, Aurora, Colorado, USA
    11. 11 University of Colorado School of Medicine, Aurora, Colorado, USA
    12. 12 Radiology, Stanford University, Stanford, California, USA
    13. 13 Public Health Services, Biostatistics, University of Miami School of Medicine, Miami, Florida, USA
    14. 14 Helen DeVos Children's Hospital, Grand Rapids, Michigan, USA
    15. 15 Michigan State University, East Lansing, Michigan, USA
    16. 16 Pediatrics, Washington University in Saint Louis, Saint Louis, Missouri, USA
    17. 17 Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
    18. 18 University of Pennsylvania, Philadelphia, Pennsylvania, USA
    19. 19 Medicine, Metro Health Hospital, Wyoming, Michigan, USA
    20. 20 University of Michigan, Ann Arbor, Michigan, USA
    21. 21 Boston Children's Hospital, Boston, Massachusetts, USA
    22. 22 Harvard Medical School, Boston, Massachusetts, USA
    23. 23 Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California, USA
    24. 24 University of Southern California, Los Angeles, California, USA
    25. 25 Children's of Alabama, Birmingham, Alabama, USA
    26. 26 University of Alabama at Birmingham, Birmingham, Alabama, USA
    27. 27 Pediatrics, Columbia University Medical Center, New York, New York, USA
    28. 28 Rheumatology, Ospedale Pediatrico Bambino Gesu, Roma, Italy
    29. 29 Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
    30. 30 Arthritis Associates of South Florida, Delray Beach, Florida, USA
    31. 31 Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    32. 32 Joseph M Sanzari Children's Hospital, Hackensack, New Jersey, USA
    33. 33 Hackensack University Medical Center, Hackensack, New Jersey, USA
    34. 34 Pediatrics, Prince of Wales Hospital, New Territories, Hong Kong
    35. 35 Faculty of Medicine, Chinese University of Hong Kong, New Territories, Hong Kong
    36. 36 Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA
    37. 37 School of Medicine, University of Missouri Kansas City, Kansas City, Missouri, USA
    38. 38 Pediatrics, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
    39. 39 Children's Hospital of Georgia, Augusta, Georgia, USA
    40. 40 Augusta University, Augusta, Georgia, USA
    41. 41 Pediatrics, Al Mafraq Hospital, Abu Dhabi, Abu Dhabi, United Arab Emirates
    42. 42 Randall Children's Hospital at Legacy Emanuel, Portland, Oregon, USA
    43. 43 Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
    44. 44 Children's Hospital at Montefiore, Bronx, New York, USA
    45. 45 Yeshiva University Albert Einstein College of Medicine, Bronx, New York, USA
    46. 46 Johns Hopkins All Children's Hospital, Saint Petersburg, Florida, USA
    47. 47 Pediatrics, Kaiser Permanente Roseville Medical Center, Roseville, California, USA
    48. 48 Pediatrics, Hospital for Special Surgery, New York, New York, USA
    49. 49 Weill Cornell Medical College, New York, New York, USA
    50. 50 Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey
    51. 51 Cook Children's Medical Center, Fort Worth, Texas, USA
    52. 52 Akron Children's Hospital, Akron, Ohio, USA
    53. 53 Northeast Ohio Medical University, Rootstown, Ohio, USA
    54. 54 Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
    55. 55 Children's Healthcare of Atlanta, Atlanta, Georgia, USA
    56. 56 Rady Children's Hospital, San Diego, California, USA
    57. 57 Pediatrics, University of California San Diego, La Jolla, California, USA
    58. 58 Pediatrics, University of Nebraska Medical Center College of Medicine, Omaha, Nebraska, USA
    59. 59 Pediatrics, University of Minnesota Medical School Twin Cities, Minneapolis, Minnesota, USA
    60. 60 University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota, USA
    61. 61 Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
    62. 62 Hospital for Sick Children, Toronto, Ontario, Canada
    63. 63 Pediatrics, University of Toronto, Toronto, Ontario, Canada
    64. 64 Emma Children's Hospital AMC, Amsterdam, The Netherlands
    65. 65 University of Amsterdam, Amsterdam, Noord-Holland, The Netherlands
    66. 66 Pediatrics, Seattle Children's Hospital, Seattle, Washington, USA
    67. 67 Pediatrics, University of Wisconsin Madison School of Medicine and Public Health, Madison, Wisconsin, USA
    68. 68 Pathology, Boston Children's Hospital, Boston, Massachusetts, USA
    69. 69 Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA
    70. 70 Biomedical Data Science, Stanford University, Stanford, California, USA
    71. 71 Institute for Immunity, Transplantation and Infection, Microbiology and Immunology, Stanford University, Stanford, California, USA
    1. Correspondence to Dr Elizabeth D Mellins, Pediatrics, Stanford University, Stanford, CA 94305, USA; mellins{at}


    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.

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

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    • VES and GC are joint first authors.

    • PK and EDM are joint senior authors.

    • Handling editor Josef S Smolen

    • GHD and RPG contributed equally.

    • JoB and KJ contributed equally.

    • SC and GS contributed equally.

    • Collaborators CARRA registry site principal investigators and research coordinators: 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, P Weiss, A Wolverton, J Woo, A Yalcindag, Q Yu, A Zeft, L Zemel, A Zhu and J Zwerling.

    • Contributors VES, GC, GHD, RPG, ANL, JoB, KJ, JX, RB, LB, YL, LT, TD, GB, MMD, PK, EDM: collection, analysis, discussion and interpretation of data. VES, GC: wrote the manuscript. EDM, PK: checked and revised the manuscript. SC, GS, RD, KA, KB, EMB, JaB, AC, MC, RQC, AD, FDB, TBG, AAG, IF, MF, SIG, LRY, MLS, AH, KH, MH, LAH, MI, CJI, RJ, KK, DJK, MK-G, KL, SL, CL, JL, DRL, DM, JM, KO, SO, MP, KP, SP, SR, AR, MR, NR, JR, RS, DS-M, SS, JAS, HES, CT, SOV, RKV, JY: provided data, and checked and approved the manuscript.

    • Funding This work was supported by the sJIA Foundation (EDM), the Lucile Packard Foundation for Children’s Health (EDM), CARRA-Arthritis Foundation grant (EDM, VES), Life Sciences Research Foundation (GC), Bio-X Stanford Interdisciplinary Graduate Fellowship (JoB), Stanford Graduate Fellowship and the Computational Evolutionary Human Genetics Fellowship (KJ), Bill & Melinda Gates Foundation (PK), and NIH 1U19AI109662 (PK), U19AI057229 (PK) and RO1 AI125197 (PK).

    • 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.

    • Patient and public involvement statement Patients were not involved in the research process of this study. Results will be shared via CARRA patient communication mechanisms.

    • Patient consent for publication Not required.

    • Ethics approval Ethics approval was obtained through the Stanford University School of Medicine institutional review board. Contributing case reporters obtained approval per local institutional review board requirements. Institutional review board permission was obtained at each institution according to local requirements.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request.

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