{"doi":"10.1002/art.42099","title":"Identification of Distinct Inflammatory Programs and Biomarkers in Systemic Juvenile Idiopathic Arthritis and Related Lung Disease by Serum Proteome Analysis","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.","journal":"Arthritis & Rheumatology","year":2022,"id":239674,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":48,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9579,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":298923,"name":"Gail Deutsch","orcid":"0000-0002-0571-0285","position":1,"is_corresponding":false},{"id":297410,"name":"Grant S. Schulert","orcid":"0000-0001-5923-7051","position":2,"is_corresponding":false},{"id":280919,"name":"Hong Zheng","orcid":"0000-0002-8884-8211","position":3,"is_corresponding":false},{"id":74025,"name":"SoRi Jang","orcid":"0000-0002-9156-552X","position":4,"is_corresponding":false},{"id":311312,"name":"Bruce C. Trapnell","orcid":"0000-0003-2817-6254","position":5,"is_corresponding":false},{"id":230129,"name":"Pui Y. Lee","orcid":"0000-0002-5779-4193","position":6,"is_corresponding":false},{"id":865883,"name":"Claudia Macaubas","orcid":"0000-0002-5472-8086","position":7,"is_corresponding":false},{"id":866680,"name":"Katherine Ho","orcid":null,"position":8,"is_corresponding":false},{"id":466767,"name":"Corinne Schneider","orcid":null,"position":9,"is_corresponding":false},{"id":635910,"name":"Vivian E Saper","orcid":"0000-0001-9043-3229","position":10,"is_corresponding":false},{"id":104156,"name":"Adriana A. de Jesus","orcid":"0000-0001-8966-8362","position":11,"is_corresponding":false},{"id":104362,"name":"Mark A. Krasnow","orcid":"0000-0002-1976-5471","position":12,"is_corresponding":false},{"id":286641,"name":"Alexei A. Grom","orcid":"0000-0001-5717-136X","position":13,"is_corresponding":false},{"id":104223,"name":"Raphaela Goldbach‐Mansky","orcid":"0000-0001-7865-5769","position":14,"is_corresponding":false},{"id":4851,"name":"Purvesh Khatri","orcid":"0000-0002-4143-4708","position":15,"is_corresponding":false},{"id":350837,"name":"Elizabeth Mellins","orcid":"0000-0003-2577-139X","position":16,"is_corresponding":false},{"id":231234,"name":"Scott Canna","orcid":"0000-0003-3837-5337","position":17,"is_corresponding":false},{"id":865882,"name":"Guangbo Chen","orcid":"0000-0003-2179-1174","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T00:22:41.699779Z","pmid":"35189047","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}