Identification of Distinct Inflammatory Programs and Biomarkers in Systemic Juvenile Idiopathic Arthritis and Related Lung Disease by Serum Proteome Analysis
The SOMAscan assay was supported by a grant to the Intramural Research Program of the National Institute of Allergy and Infectious Diseases from the Systemic JIA Foundation. Dr. Chen is an Eli Lilly Fellow of the Life Science Research Foundation. Dr. Jang's work was supported by a Dean's Postdoctoral Fellowship, School of Medicine, Stanford. Drs. Macaubas and Mellins’ work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH (grants R01-AR-066551 and AR-061297) and the Arthritis Foundation Great West Region Arthritis Center of Excellence. Drs. Schneider and Canna's work was supported by the RK Mellon Institute for Pediatric Research and the National Institute of Allergy and Infectious Diseases, NIH (grants K22-AI-123366, NICHD-R01, and HD-098428). Drs. Saper and Mellins’ work was supported by the Lucille Packard Foundation for Children's Health and the Childhood Arthritis and Rheumatology Research Alliance/Arthritis Foundation. Drs. de Jesus and Goldbach-Mansky's work was supported by the National Institute of Allergy and Infectious Diseases intramural research program. Dr. Khatri's work was supported by the Bill and Melinda Gates Foundation (grant OPP1113682), the National Institute of Allergy and Infectious Diseases, NIH (grants 1U19-AI-109662, U19-AI-057229, and 5R01-A-I125197), the Department of Defense (contracts W81XWH-18-1-0253 and W81XWH1910235), and the Ralph and Marian Falk Medical Research Trust.
Drs. Khatri, Mellins, and Canna contributed equally to this work.
Author disclosures are available at https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fart.42099&file=art42099-sup-0001-Disclosureform.pdf.
Abstract
Objective
Recent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high-mortality interstitial lung disease often characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA-LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA-LD.
Methods
We used SOMAscan to measure ~1,300 analytes in sera from healthy controls and patients with systemic JIA, MAS, SJIA-LD, or other related diseases. We verified selected findings by enzyme-linked immunosorbent assay and lung immunostaining. Because the proteome of a sample may reflect multiple states (systemic JIA, MAS, or SJIA-LD), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort.
Results
Proteome alterations in active systemic JIA and MAS overlapped substantially, including known systemic JIA biomarkers such as serum amyloid A and S100A9, and novel elevations in the levels of heat-shock proteins and glycolytic enzymes. Interleukin-18 levels were elevated in all systemic JIA groups, particularly MAS and SJIA-LD. We also identified an MAS-independent SJIA-LD signature notable for elevated levels of intercellular adhesion molecule 5 (ICAM-5), matrix metalloproteinase 7 (MMP-7), and allergic/eosinophilic chemokines, which have been previously associated with lung damage. Immunohistochemistry localized ICAM-5 and MMP-7 in the lungs of patients with SJIA-LD. The ability of ICAM-5 to distinguish SJIA-LD from systemic JIA/MAS was independently validated.
Conclusion
Serum proteins support a systemic JIA–to-MAS continuum; help distinguish systemic JIA, systemic JIA/MAS, and SJIA-LD; and suggest etiologic hypotheses. Select biomarkers, such as ICAM-5, could aid in early detection and management of SJIA-LD.
