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

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.

doi:10.1186/s13075-016-1212-x

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.

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

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.

2017-01-01

Abstract

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.