Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy

Background: Canakinumab is a human anti-interleukin-1 beta (IL-1 beta) monoclonal antibody neutralizing IL-1 beta-mediated pathways. We sought to characterize the molecular response to canakinumab and evaluate potential markers of response using samples from two pivotal trials in systemic juvenile idiopathic arthritis (SJIA). Methods: Gene expression was measured in patients with febrile SJIA and in matched healthy controls by Affymetrix DNA microarrays. Transcriptional response was assessed by gene expression changes from baseline to day 3 using adapted JIA American College of Rheumatology (aACR) response criteria (50 aACR JIA). Changes in pro-inflammatory cytokines IL-6 and IL-18 were assessed up to day 197. Results: Microarray analysis identified 984 probe sets differentially expressed (>= 2-fold differenceP = 50 aACR JIA were recognizable by baseline expression values. Analysis of gene expression profiles from patients achieving = 50 aACR JIA response at day 15 identified 102 probe sets differentially expressed upon treatment (>= 2-fold differenceP = 8-fold declineP = 1.5-fold decline, P <= 0.002). Conclusions: Treatment with canakinumab in SJIA patients resulted in downregulation of innate immune response genes and reductions in IL-6 and clinical symptoms. Additional research is needed to investigate potential differences in the disease mechanisms in patients with heterogeneous gene transcription profiles.Novartis PharmaNorvartis Inst Biomed Res, Basel, SwitzerlandPRCSG, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USAWilhelmina Childrens Hosp, Dept Pediat Immunol & Rheumatol, Utrecht, NetherlandsUniv Paris 05, Unite Immunol Hematol & Rhumatol Pediat, Hop Necker Enfants Malad, Ctr Reference Natl Arthrit Juveniles,IMAGINE Inst, Paris, FranceRambam Med Ctr, Dept Pediat B, Haifa, IsraelAlder Hey Childrens NHS Fdn Trust, Liverpool, Merseyside, EnglandCerrahpasa Tip Fak, Ic Hastaliklari ABD, Romatol BD, Istanbul, TurkeyInst Rheumatol, Paediat Clin, Warsaw, PolandHosp Sick Children, Div Rheumatol, Toronto, ON, CanadaIst Gaetano Pini, Div Reumatol, Milan, ItalySchneider Childrens Med Ctr, Pediat Rheumatol Unit, Petah Tiqwa, IsraelUniv Fed Sao Paulo, Pediat, Sao Paulo, BrazilBritish Columbia Childrens Hosp, Vancouver, BC, CanadaUniv Ziekenhuis Gent, Ctr Kinderreumatol, Ghent, BelgiumRandall Children’s Hospital at Legacy Emanuel, Portland, OR, USAFloating Hosp Children, Rheumatol NEMC 286, Boston, MA USANovartis Pharmaceut, E Hanover, NJ USAUniv Genoa, Genoa, ItalyPediat II PRINTO, Ist Giannina Gaslini, Genoa, ItalyNovartis Inst Biomed Res, Cambridge, MA USAUniv Fed Sao Paulo, Pediat, Sao Paulo, BrazilWeb of Scienc