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.
- juvenile idiopathic arthritis
- adult onset still's disease
- DMARDs (biologic)
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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.