Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy
- Creators
- Brachat A. H.
- Grom A. A.
- Wulffraat N.
- Brunner H. I.
- Quartier P.
- Brik R.
- McCann L.
- Ozdogan H.
- Rutkowska-Sak L.
- Schneider R.
- Gerloni V.
- Harel L.
- Terreri M.
- Houghton K.
- Joos R.
- Kingsbury D.
- Lopez-Benitez J. M.
- Bek S.
- Schumacher M.
- Valentin M. -A.
- Gram H.
- Abrams K.
- Martini A.
- Lovell D. J.
- Nirmala N. R.
- Ruperto N.
- Cuttica R.
- Emminger W.
- Lauwerys B.
- Wouters C.
- Goffin L.
- Sztajnbok F.
- Radominski S.
- Oliveira S.
- Haddad E.
- Kone-Paut I.
- Desjonqueres M.
- Fischbach M.
- Thon A.
- Foell D.
- Weibarth-Riedel E.
- Horneff G.
- Trauzeddel R.
- Berner R.
- Kallinich T.
- Trachana M.
- Constantin T.
- Barash J.
- Berkun Y.
- Uziel Y.
- Corona F.
- Alessio M.
- Cimaz R.
- Viola S.
- Flato B.
- Ferrandiz M.
- Calvo I.
- Anton J.
- Robledillos J. C.
- Gamir M. L.
- Magnusson B.
- Hofer M.
- Unsal E.
- Erguven M.
- Ozen S.
- Wilkinson N.
- Chieng A.
- Ramanan A.
- Foster H.
- Nistala K.
- Higgins G.
- Marzan K.
- Schikler K.
- Morris P.
- Others:
- Brachat, A. H.
- Grom, A. A.
- Wulffraat, N.
- Brunner, H. I.
- Quartier, P.
- Brik, R.
- Mccann, L.
- Ozdogan, H.
- Rutkowska-Sak, L.
- Schneider, R.
- Gerloni, V.
- Harel, L.
- Terreri, M.
- Houghton, K.
- Joos, R.
- Kingsbury, D.
- Lopez-Benitez, J. M.
- Bek, S.
- Schumacher, M.
- Valentin, M. -A.
- Gram, H.
- Abrams, K.
- Martini, A.
- Lovell, D. J.
- Nirmala, N. R.
- Ruperto, N.
- Cuttica, R.
- Emminger, W.
- Lauwerys, B.
- Wouters, C.
- Goffin, L.
- Sztajnbok, F.
- Radominski, S.
- Oliveira, S.
- Haddad, E.
- Kone-Paut, I.
- Desjonqueres, M.
- Fischbach, M.
- Thon, A.
- Foell, D.
- Weibarth-Riedel, E.
- Horneff, G.
- Trauzeddel, R.
- Berner, R.
- Kallinich, T.
- Trachana, M.
- Constantin, T.
- Barash, J.
- Berkun, Y.
- Uziel, Y.
- Corona, F.
- Alessio, M.
- Cimaz, R.
- Viola, S.
- Flato, B.
- Ferrandiz, M.
- Calvo, I.
- Anton, J.
- Robledillos, J. C.
- Gamir, M. L.
- Magnusson, B.
- Hofer, M.
- Unsal, E.
- Erguven, M.
- Ozen, S.
- Wilkinson, N.
- Chieng, A.
- Ramanan, A.
- Foster, H.
- Nistala, K.
- Higgins, G.
- Marzan, K.
- Schikler, K.
- Morris, P.
Citation
Description
Background: Canakinumab is a human anti-interleukin-1β (IL-1β) monoclonal antibody neutralizing IL-1β-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 difference; P < 0.05) in patients versus controls. Over 50% of patients with ≥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 difference; P < 0.05) on day 3 versus baseline, including IL-1β, IL-1 receptors (IL1-R1 and IL1-R2), IL-1 receptor accessory protein (IL1-RAP), and IL-6. The strongest clinical response was observed in patients with higher baseline expression of dysregulated genes and a strong transcriptional response on day 3. IL-6 declined by day 3 (≥8-fold decline; P < 0.0001) and remained suppressed. IL-18 declined on day 57 (≥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. Trial registration: Clinicaltrials.gov: NCT00886769(trial 1). Registered on 22 April 2009; NCT00889863(trial 2). Registered on 21 April 2009.
Additional details
- URL
- http://hdl.handle.net/11567/965179
- URN
- urn:oai:iris.unige.it:11567/965179
- Origin repository
- UNIGE