ObjectiveTo investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).MethodsIn a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.ResultsLD 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.ConclusionsA 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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Objective To investigate characteristics and risk factors of a novel parenchymal lung disease, increasingly detected in systemic juvenile idiopathic arthritis (sJIA). Methods In a multi-center retrospective study, 61 cases were investigated, using physician-reported clinical information and centralized analyses of radiologic, pathologic and genetic data. Results Lung disease (LD) was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the IL-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes +/- ground glass opacities. Predominant pathology (23/36) 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. 5-year survival was 42%. Whole-exome sequencing (20/61) did not identify a novel monogenic defect PAP-related or macrophage activation syndrome (MAS)-related mutations as likely primary cause. Trisomy 21 (T21) increased LD risk, as did young sJIA onset. Refractory sJIA was not required for LD development. Exposure to interleukin (IL)-1 and IL-6 inhibitors (46/61) 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 it was not associated with LD features. Conclusions A rare, life-threatening LD 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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