Distinct Gene Expression Signatures Characterize Strong Clinical Responders Versus Nonresponders to Canakinumab in Children With Systemic Juvenile Idiopathic Arthritis

Autor: Alex V. Pickering, Grant S. Schulert, Alexei A. Grom, Emely L Verweyen
Rok vydání: 2020
Předmět:
0301 basic medicine
Oncology
Isoantigens
Chemokine CXCL1
Interleukin-1beta
Arthritis
Neutrophil Activation
0302 clinical medicine
Interferon
Gene expression
Immunology and Allergy
Prospective cohort study
Child
Toll-Like Receptors
Up-Regulation
DNA-Binding Proteins
Treatment Outcome
Caspases
medicine.drug
Signal Transduction
medicine.medical_specialty
Immunology
Antigens
Differentiation
Myelomonocytic
Receptors
Cell Surface
Antibodies
Monoclonal
Humanized
GPI-Linked Proteins
Article
03 medical and health sciences
Rheumatology
Antigens
CD
Internal medicine
medicine
Humans
Glycoproteins
030203 arthritis & rheumatology
Receptors
Interleukin-1 Type I
business.industry
Tumor Necrosis Factor-alpha
Calcium-Binding Proteins
medicine.disease
Arthritis
Juvenile
Blockade
CARD Signaling Adaptor Proteins
Canakinumab
Interleukin 1 Receptor Antagonist Protein
030104 developmental biology
Gene Ontology
business
Interleukin-1 Receptor Accessory Protein
Transcriptome
CD163
Zdroj: Arthritis Rheumatol
ISSN: 2326-5205
Popis: OBJECTIVE Canakinumab is a human anti-interleukin-1β (anti-IL-1β) blocking agent that effectively neutralizes IL-1β-mediated signaling for treatment of systemic juvenile idiopathic arthritis (JIA). While many patients have dramatic clinical response to IL-1 blockade, approximately one-third fail to respond, but there are currently no validated clinical or immunologic predictors of response. We undertook this study to characterize distinct gene signatures for treatment response and nonresponse to canakinumab in systemic JIA patients. METHODS We performed a secondary analysis of whole-blood gene expression microarrays using blood samples obtained from healthy controls and systemic JIA patients at baseline and on day 3 after canakinumab treatment (GEO accession no. GSE80060). Patients were considered strong clinical responders if they met the ACR90 response (exhibited ≥90% improvement in the American College of Rheumatology [ACR] JIA response criteria; nonresponders were those who met ACR30 [exhibiting ≤30% improvement in the ACR JIA response criteria]). A random-effects model with patient identity as the random variable was used for differential expression analysis. RESULTS We identified a distinct gene expression signature in patients with a strong clinical response to canakinumab treatment as compared to nonresponders, mediated by up-regulation of neutrophil- and IL-1-associated genes and characterized by increasing divergence from control transcriptomes with increasing clinical response. We also identified a signature including up-regulated CD163 expression that was associated with canakinumab nonresponse. Intriguingly, canakinumab treatment induced either up- or down-regulation of type I interferon (IFN) genes, independent of clinical response. CONCLUSION Here, we identify a gene signature in systemic JIA patients prior to receiving treatment that distinguishes strong responders to canakinumab from nonresponders. Further prospective studies are needed to assess the utility of these insights for treatment decisions in systemic JIA and to track the association of up-regulated type I IFN signatures with systemic JIA complications.
Databáze: OpenAIRE
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