Emergent high fatality lung disease in systemic juvenile arthritis

Childhood arthritis and Rheumatology Research alliance Registry investigators

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134 Scopus citations


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
Issue number12
StatePublished - 2019

Bibliographical note

Funding Information:
LD in sJIA was characterised by young age at sJIA onset and unusual clinical features, including acute erythematous clubbing, atypical rash and anaphylaxis to tocilizumab; severe tocilizumab reaction in sJIA with pulmonary disease was also noted in the data from the PharmaChild registry. 50 The most prevalent finding on chest CT was peripheral septal thickening ± ground-glass opacities. Crazy-paving, consolidation and hyperenhancing lymph nodes were also observed. On tissue diagnosis, this group showed primarily PAP/ELP-like pathology. Compared with PAP/ELP in other settings, the LD pathology was distinctive for its patchiness and associated vascular changes. The proportion of LD cases with PAP/ELP-like tissue diagnosis has increased since 2010, coinciding with increasing use of IL-1/IL-6 inhibitors. 40 Pre-exposure to these inhibitors was characteristic of the predominant phenotypic subtype in our series. It is possible that this association is confounded by concomitant reduction in steroids with inhibitor use or by treatment of severe inflammation; our data do not conclusively rule out these possibilities. However, severe disease has been observed since the initial description of sJIA in 1897, 51 whereas the LD with associated features described here appears to be new and increasing in frequency. Among biopsied cases, PAP/ELP was found in 80% with pre-exposure (includes one with mostly pleural sample and limited PAP foci) vs 36% not pre-exposed (OR=7 (95% CI 1.45 to 33.7), Fisher’s p=0.015; online supplementary figure S5E ) and was independent of PAP/ELP association with young age ( online supplementary figure S9 ). Thus, IL-1/IL-6 inhibitor exposure may promote development of PAP/ELP-like disease and may qualitatively influence LD-associated features in a subset of patients with sJIA, among the substantially larger group of patients who derive striking benefit from these inhibitors. Autopsy RNA sequencing data from the Genotype-Tissue Expression project show the lung is a major physiological producer of IL-1 and IL-6 in adults ( online supplementary figure S10 ), 52 and cytokine profiling suggests that circulating IL-1RA levels (reflecting the IL-1 activity) in young (<4 years) healthy children are 2× higher than in older healthy children. 53 In addition, NFκB, a key transcription factor downstream of IL-1, stimulates angiogenesis and alveolarisation in the postnatal, developing lung. 54 These observations raise the possibility of a physiological role of IL-1/IL-6 in the lung, particularly in early childhood. The striking enhancement of LD risk by early age of sJIA onset suggests developmental vulnerabilities that may interact with the inhibitors. A specific relationship between reduced IL-1 and PAP development is described in mice. IL-1α −/− mice (but not IL-1β −/− mice) challenged with inhaled silicone, an inflammasome (NLRP3) activator, 55 develop PAP-like LD. 56 In the lung, IL-1 regulates granulocyte-macrophage colony-stimulating factor (GM-CSF) levels 57 58 and macrophage function 56 57 ; disruption of either can lead to surfactant accumulation and PAP. 59 60 These findings imply a link between reduced IL-1 and PAP, but also suggest that additional triggers may be required for disease development, in line with the rarity of severe parenchymal LD among the overall population of patients with sJIA treated with IL-1/IL-6 inhibitors. The association of PAP and paediatric haematological malignancies, especially myeloid leukaemia, can be ascribed in some cases to dysregulation of the GM-CSF/GM-CSF receptor axis and consequent macrophage dysfunction. 61 We found an outsized risk of LD in children with T21 and sJIA. T21 carries increased susceptibility to adverse drug reactions 62 and to viral pneumonia. 63 Another contributing factor may be underlying type 1 interferonopathy, recently described in T21. 64 An association of T21 and PAP in the context of haematological malignancy also has been reported. 65 Drug hypersensitivity reactions can occur in children treated with biologic drugs for rheumatic disease. 66 A subset of LD cases met the criteria for DReSS ( online supplementary tables S1 and S8 ), a delayed form of severe drug-related hypersensitivity with organ involvement that can include lung. 17 67 68 DReSS findings included dramatic eosinophilia, often despite concurrent steroids, together with extensive, persistent rash, frequently involving the face, which is uncommon in sJIA. 18 Altered drug metabolism in childhood may increase risk of hypersensitivity reactions. 69 Another consideration is drug-induced interstitial lung disease (DiILD), previously reported in children with rheumatic disease on biologics. 70 DiILD has overlapping chest CT findings with LD in sJIA. 71 No pathological findings are pathognomonic of DiILD, 71 72 but PAP has been described. 24 Drug cessation is indicated when DReSS or DiILD is recognised. 68 Infection may exacerbate LD, trigger its detection or be causally linked. Pathogens identified at initial lung evaluation ( online supplementary table S3 ) included rhinovirus (a cause of severe lower respiratory infection in young children 73 ), herpes viruses and pneumocystis, all of which require IL-1 for optimal host defence. 55 74 75 Pneumocystis pneumonia (PCP) is a recognised cause of PAP 25 and is associated with high mortality in immunocompromised individuals. 76 PCP risk is also elevated in DReSS. 77 At least four of our cases had PCP; these were diagnosed by PCR of BAL, the preferred test in non-HIV immunosuppressed patients. 76 It seems prudent to consider prophylaxis for patients with sJIA with lymphopaenia or steroid use (consistent with recommendations 78 ) or T21. LD in sJIA has been associated with MAS. 13 79 In 23 out of 61 cases in our series, LD detection occurred with concurrent MAS. Out of these 23, 19 had their first MAS episode at or after LD diagnosis, suggesting that LD may trigger systemic inflammation. Consistent with this possibility, 4 of 11 cases with MAS co-occurred with initial detection of LD during three treatment trials of the inhibitors (n=331 subjects in total). 4–6 PH with a range of severity was observed with or without pre-exposure to inhibitors and with or without PAP/ELP pathology. Out of 20 subjects, 2 lacked substantial parenchymal LD at PH detection. Together, these observations argue that PH in this LD cohort has heterogeneous biology. Persistent arthritis ( figure 4F ) was less frequent in the pre-exposed LD cohort than in the sJIA cohort in the CARRA legacy registry (2010–2013), 42 and of comparable frequency to children treated with IL-1 inhibition as first-line sJIA therapy. Inhibitor therapy may attenuate arthritis when given early or the LD cohort may be enriched for children with systemic inflammation-predominant disease. 18 80 Over 50 additional LD cases in sJIA have been reported to us since closing this series. The Food and Drug Administration (FDA) adverse event website (FDA Adverse Event Reporting System) shows 39 adults (rheumatoid arthritis (23), AOSD (11), other (5)) developing alveolar disease or PH on IL-1/IL-6 inhibitors and 4 DReSS cases (second quarter, 2019). An apparent discrepancy between adverse event reports and the frequency of sJIA-LD reported here may reflect its underdiagnosis or under-reporting. 81 The association between cytokine inhibition and sJIA-LD and related mechanistic hypotheses demand further investigation. We acknowledge the limitations of retrospective data, use of historical/published data for controls, possible biases as mentioned and false discovery issues associated with multiple hypothesis testing in a large data set. With these limitations, one cannot assign causality to cytokine inhibition in LD in sJIA. Likewise, it is premature to make treatment recommendations solely on the basis of our findings. Therapeutic decision making for patients with sJIA-associated LD is challenging, and currently individualised management is appropriate. However, in children with risk factors, close attention to subtle pulmonary symptoms is advised, and approaches for early detection of altered pulmonary function, guided by a pulmonary specialist, should be considered. In light of high fatality, efforts to determine LD prevalence, uncover molecular mechanism(s), and devise treatment and prevention approaches are urgently needed. The CARRA registry has been supported by the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the Arthritis Foundation. We thank all participants and hospital sites that recruited patients for the CARRA registry. The authors thank Drs Joseph A Kovacs, Jay K Kolls and Sergio Vargas for their expert input on pneumocystis pneumonia, Dr James Verbsky for contributing unidentified genetic data, and Dr Xuan Qin for PCP staining of a subset of biopsies. The authors also thank Dr Yuki Kimura for critical reading of the manuscript, Dr Claudia Macaubas for statistical assistance and Ms Melinda Hing for assistance with the manuscript. 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.

Funding Information:
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).

Publisher Copyright:
© © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.


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


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