An emergent, high-fatality lung disease in systemic juvenile arthritis
Authors: Saper Vivian E. , Chen Guangbo , Deutsch Gail H. , Guillerman R Paul. , Birgmeier Johannes , Jagadeesh Karthik , Canna Scott , Schulert Grant , Deterding Robin , Xu Jianpeng , Leung Ann N. , Bouzoubaa Layla , Abulaban Khalid , Baszis Kevin , Behrens Edward M. , Birmingham James , Casey Alicia , Cidon Michal , Cron Randy , De Aliva , De Benedetti Fabrizio , Ferguson Ian , Fishman Martha P. , Goodman Steven I. , Graham Brent , Grom Alexei , Haines Kathleen , Hazen Melissa , Henderson Lauren A. , Ho Assunta , Ibarra Maria , Inman CJ , Jerath Rita , Khawaja Khulood Walid , Kingsbury Daniel J , Klein-Gitelman Marisa , Lai Khan , Lapidus Sivia , Lin Clara , Lin Jenny , Liptzin Deborah R. , Milojevic Diana , Mombourquette Joy , Onel Karen , Ozen Seza , Perez Maria , Phillippi Kathryn , Prahalad Sampath , Radhakrishna Suhas , Reinhardt Adam , Riskalla Mona , Rosenwasser Natalie , Roth Johannes , Schneider Rayfel , Schonenberg-Meinema Dieneke , Shenoi Susan , Smith Judith A , Sonmez Hafize Emine , Stoll Matthew L. , Towe Christopher , Vargas Sara O. , Vehe Richard K , Young Lisa R. , Yang Jacqueline , Desai Tushar , Balise Raymond , Lu Ying , Tian Lu , Bejerano Gil , Davis Mark M. , Khatri Purvesh , Mellins Elizabeth D. ,   the Childhood Arthritis and Rheumatology Research Alliance Registry Investigators
Published: August 2019

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.