Systemic juvenile idiopathic arthritis (SJIA) is a chronic, often relapsing and remitting, rheumatic condition of childhood, characterized by fever, rash, arthritis and serositis. Although the etiology is unknown, SJIA complications such as macrophage activation syndrome and amyloidosis support involvement of the innate immune system, as do the paucity of autoantibodies or MHC alleles that predispose to disease. Pro-inflammatory cytokines that are principally monocyte-derived, including IL-18, MIF, IL-6 and IL-1, are implicated in SJIA pathogenesis by transcriptional analysis and other studies. Key roles for IL-1 and IL-6 also are supported by striking clinical responses to their inhibition, at least in subsets of patients, although. The exact nature of the immune dysfunction in SJIA is unknown, however. We have found several novel phenotypes in monocytes that corroborate the idea that monocytes are a central effector cell in SJIA. Monocyte expansion and activation are prominent at SJIA flare. At both flare and quiescence, SJIA monocytes are resistant to apoptotic stimuli, both intrinsic and extrinsic, likely due at least in part to reduced levels of Bid cleavage and surface FasL, respectively. We also observe reduced interferon signaling in SJIA monocytes and increased LPS-stimulated IL-1? secretion. Our findings suggest that aberrant monocyte function may predispose to SJIA, because some abnormal phenotypes are present in SJIA subjects in remission, off medication. The RAPPORT trial offers a unique opportunity to elucidate the role of IL-1 in the generation of these phenotypes. This randomized, placebo-controlled trial of the IL-1 inhibitor Rilanocept will enroll 100 subjects with active SJIA. We will assay monocytes isolated from SJIA subjects before and after IL-1 blockade to assess the role of IL-1 in each phenotype. Also, using clinical information to define level of disease activity, we will assess the correlation of monocyte phenotype with disease activity. This second analysis will provide an important test of conclusions from our prior studies in an independent cohort of SJIA subjects. For selected phenotypes, we will extend our investigation of the underlying cellular mechanisms, using SJIA samples from our collection for initial evaluation of candidate mechanisms. When new features of SJIA monocytes are defined, they will be tested in the RAPPORT samples, and the role of IL-1 in these features will be established by testing samples from Rilonacept-treated subjects. In additional univariate and multivariate analyses, we will determine whether particular abnormal SJIA monocyte phenotype(s) predicts response to Rilonacept treatment.

Public Health Relevance

(provided by applicant): Systemic idiopathic juvenile arthritis (SJIA) is a chronic childhood disease that causes arthritis, fever, rash and other kinds of inflammation (e.g. around the heart and lungs). It is unknown what causes this disease, but some patients respond to medication that inhibits IL-1, an inflammatory mediator made by the body. In conjunction with a trial of the IL-1 inhibitor Rilanocept, we propose to investigate how IL-1 affects a particular immune cell type, the monocyte, which appears to be a key cell in SJIA pathology. We also hope to identify changes in monocytes during disease that predict response to Rilanocept.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR061297-04
Application #
8530018
Study Section
Special Emphasis Panel (ZAI1-PA-I (S1))
Program Officer
Wang, Yan Z
Project Start
2010-09-22
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$295,488
Indirect Cost
$110,808
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Zhang, Yujuan; Gupta, Saloni; Ilstad-Minnihan, Alexandra et al. (2018) Interleukin-1 in monocyte activation phenotypes in systemic juvenile idiopathic arthritis: Observations from a clinical trial of rilonacept, an interleukin-1 inhibitor. Clin Immunol 194:9-18
Arthur, Victoria L; Shuldiner, Emily; Remmers, Elaine F et al. (2018) IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol 70:1319-1330
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Ombrello, Michael J; Arthur, Victoria L; Remmers, Elaine F et al. (2017) Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications. Ann Rheum Dis 76:906-913
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Zhang, Yujuan; Macaubas, Claudia; Gupta, Saloni et al. (2014) A160: role of interleukin-1 in abnormal monocyte phenotype in systemic onset juvenile idiopathic arthritis. Arthritis Rheumatol 66 Suppl 3:S207-8
Prahalad, Sampath; Conneely, Karen N; Jiang, Yunxuan et al. (2013) Susceptibility to childhood-onset rheumatoid arthritis: investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci. Arthritis Rheum 65:1663-7
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