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Emergent high fatality lung disease in systemic juvenile arthritis

Saper, V. E.; Chen, G.; Deutsch, G. H.; Guillerman, R. P.; Birgmeier, J.; Jagadeesh, K.; Canna, S.; Schulert, G.; Deterding, R.; Xu, J.; Leung, A. N.; Bouzoubaa, L.; Abulaban, K.; Baszis, K.; Behrens, E. M.; Birmingham, J.; Casey, A.; Cidon, M.; Cron, R. Q.; De, A.; De Benedetti, F.; Ferguson, I.; Fishman, M. P.; Goodman, S. I.; Graham, T. B.; Grom, A. A.; Haines, K.; Hazen, M.; Henderson, L. A.; Ho, A.; Ibarra, M.; Inman, C. J.; Jerath, R.; Khawaja, K.; Kingsbury, D. J.; Klein-Gitelman, M.; Lai, K.; Lapidus, S.; Lin, C.; Lin, J.; Liptzin, D. R.; 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, J. A.; Sönmez, H. E.; Stoll, M. L.; Towe, C.; Vargas, S. O.; Vehe, R. K.; Young, L. R.; Yang, J.; Desai, T.; Balise, R.; Lu, Y.; Tian, L.; Bejerano, G.; Davis, M. M.; Khatri, P.; Mellins, E. D.

Ann Rheum Dis. 2019 Sep 29; 78(12):1722-1731


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.

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