4 results on '"Gram, Hermann"'
Search Results
2. Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy
- Author
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Infection & Immunity, Regenerative Medicine and Stem Cells, Child Health, Immuno/reuma patientenzorg, Brachat, Arndt H, Grom, Alexei A, Wulffraat, Nico, Brunner, Hermine I, Quartier, Pierre, Brik, Riva, McCann, Liza, Ozdogan, Huri, Rutkowska-Sak, Lidia, Schneider, Rayfel, Gerloni, Valeria, Harel, Liora, Terreri, Maria, Houghton, Kristin, Joos, Rik, Kingsbury, Daniel, Lopez-Benitez, Jorge M, Bek, Stephan, Schumacher, Martin, Valentin, Marie-Anne, Gram, Hermann, Abrams, Ken, Martini, Alberto, Lovell, Daniel J, Nirmala, Nanguneri R, Ruperto, Nicolino, Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG), Infection & Immunity, Regenerative Medicine and Stem Cells, Child Health, Immuno/reuma patientenzorg, Brachat, Arndt H, Grom, Alexei A, Wulffraat, Nico, Brunner, Hermine I, Quartier, Pierre, Brik, Riva, McCann, Liza, Ozdogan, Huri, Rutkowska-Sak, Lidia, Schneider, Rayfel, Gerloni, Valeria, Harel, Liora, Terreri, Maria, Houghton, Kristin, Joos, Rik, Kingsbury, Daniel, Lopez-Benitez, Jorge M, Bek, Stephan, Schumacher, Martin, Valentin, Marie-Anne, Gram, Hermann, Abrams, Ken, Martini, Alberto, Lovell, Daniel J, Nirmala, Nanguneri R, Ruperto, Nicolino, and Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG)
- Published
- 2017
3. Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy.
- Author
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Brachat AH, Grom AA, Wulffraat N, Brunner HI, 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 JM, Bek S, Schumacher M, Valentin MA, Gram H, Abrams K, Martini A, Lovell DJ, Nirmala NR, and Ruperto N
- Subjects
- Adolescent, Antibodies, Monoclonal, Humanized, Child, Child, Preschool, Down-Regulation, Female, Gene Expression Profiling, Humans, Immunoassay, Male, Oligonucleotide Array Sequence Analysis, Young Adult, Antibodies, Monoclonal therapeutic use, Arthritis, Juvenile drug therapy, Interleukin-18 biosynthesis, Interleukin-6 biosynthesis, Transcriptome drug effects
- 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.
- Published
- 2017
- Full Text
- View/download PDF
4. The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis.
- Author
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Alten R, Gram H, Joosten LA, van den Berg WB, Sieper J, Wassenberg S, Burmester G, van Riel P, Diaz-Lorente M, Bruin GJ, Woodworth TG, Rordorf C, Batard Y, Wright AM, and Jung T
- Subjects
- Adult, Aged, Animals, Antibodies, Monoclonal physiology, Arthralgia pathology, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid pathology, Cohort Studies, Double-Blind Method, Humans, Inflammation immunology, Inflammation therapy, Inflammation Mediators physiology, Mice, Mice, Inbred DBA, Middle Aged, NIH 3T3 Cells, Antibodies, Monoclonal therapeutic use, Arthralgia immunology, Arthralgia therapy, Arthritis, Rheumatoid therapy, Disease Models, Animal, Inflammation Mediators therapeutic use, Interleukin-1beta immunology
- Abstract
Introduction: IL-1beta is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production., Methods: ACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1beta, was generated to study the potent and long-lasting neutralization of IL-1beta in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA)., Results: The mouse IL-1 receptor cross-reacts with human IL-1beta, and it was demonstrated that ACZ885 can completely suppress IL-1beta-mediated joint inflammation and cartilage destruction in mice. This observation prompted us to study the safety, tolerability and pharmacodynamic activity of ACZ885 in RA patients in a small proof-of-concept study--the first to be conducted in humans. Patients with active RA despite treatment with stable doses of methotrexate were enrolled in this dose escalation study. The first 32 patients were split into four cohorts of eight patients each (six were randomly assigned to active treatment and two to placebo). ACZ885 doses were 0.3, 1, 3 and 10 mg/kg, administered intravenously on days 1 and 15. To explore efficacy within 6 weeks of treatment, an additional 21 patients were randomly assigned to the 10 mg/kg cohort, resulting in a total of 20 patients dosed with 10 mg/kg and 15 patients treated with placebo. There was clinical improvement (American College of Rheumatology 20% improvement criteria) at week 6 in the 10 mg/kg treatment group; however, this did not reach statistical significance (P = 0.085). A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group. Onset of action was rapid, because most responders exhibited improvement in their symptoms within the first 3 weeks. C-reactive protein levels decreased in patients treated with ACZ885 within 1 week. ACZ885 was well tolerated. Three patients receiving ACZ885 developed infectious episodes that required treatment. No anti-ACZ885 antibodies were detected during the study., Conclusion: ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients. Additional studies to characterize efficacy in RA and to determine the optimal dose regimen appear warranted., Trial Registration: ClinicalTrials.gov identifier NCT00619905.
- Published
- 2008
- Full Text
- View/download PDF
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