Predictive Model for the Outcome of Infliximab Therapy in Crohn's Disease Based on Apoptotic Pharmacogenetic Index and Clinical Predictors

Background: Infliximab (IFX) is an effective therapy for refractory luminal and fistulizing Crohn's disease (CD). Predictors of response could improve selection of patients with a higher probability of favorable outcomes and could improve the safety profile. We aimed to develop a predictive model for the response to infliximab in CD. Methods: Genetic and clinical data collected in a previous pharmacogenetic study of apoptosis genes were analyzed using SAS Enterprise miner modeling software and SPSS 12.0. We proposed a novel apoptotic pharmacogenetic index (API) with a score ranging from 0 (low apoptotic response) to 3 (high apoptotic response) and subsequently developed a decision tree model. Results: Response and remission rates significantly increased with API score (P = 0.005 in the group of patients with luminal CD, P = 0.02 in the group of patients with fistulizing CD). Patients with an API ≤ 1 (n = 59) had the lowest response and remission rates in both the luminal CD (50% and 39.5%, respectively) and fistulizing CD (61.9% and 28.6%, respectively) groups, compared to those with an API of 2 (n = 158), whose response and remission rates were 73.8% and 56.1%, respectively, in the luminal CD group and 85.7% and 44.9%, respectively, in the fistulizing CD group; and those with an API of 3 (n = 10), whose response and remission rates were 100% and 85.7%, respectively, in the luminal CD group and 100% and 0% in the fistulizing CD group. Response in patients with an API ≤ 1 was significantly influenced by concurrent azathioprine therapy in the luminal CD (21.4% versus 78.9%, P < 0.001) and in the fistulizing CD (46.6% versus 100%, P = 0.04) groups. In patients with an API of 2, we saw an interaction with age older than 40 years and location of disease (response 52.2% versus 83.9%, P = 0.008) in the luminal CD group and with baseline CRP greater than 5 mg/L (73.9% versus 93.9%, P = 0.04) in the fistulizing CD group. Conclusions: From our newly proposed apoptotic pharmacogenetic index and clinical predictors, we developed a model for prediction of low, medium, and high responses to the first infusion of IFX in patients with CD. Further studies are needed to confirm the hypothesis generated by our study.

[1]  J. Mary,et al.  Infliximab plus azathioprine for steroid-dependent Crohn's disease patients: a randomized placebo-controlled trial. , 2006, Gastroenterology.

[2]  Paul Rutgeerts,et al.  Infliximab for induction and maintenance therapy for ulcerative colitis. , 2005, The New England journal of medicine.

[3]  P. Rutgeerts,et al.  Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn's disease , 2005, Alimentary pharmacology & therapeutics.

[4]  S. Schreiber,et al.  A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. , 2005, Gastroenterology.

[5]  P. Rutgeerts,et al.  The impact of major depressive disorder on the short‐ and long‐term outcome of Crohn's disease treatment with infliximab , 2005, Alimentary pharmacology & therapeutics.

[6]  M. Bala,et al.  Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease. , 2005, Gastroenterology.

[7]  G. Lichtenstein,et al.  Are there predictors of Remicade treatment success or failure? , 2005, Advanced drug delivery reviews.

[8]  G. Radford-Smith,et al.  CDP571, a humanised monoclonal antibody to tumour necrosis factor α, for moderate to severe Crohn’s disease: a randomised, double blind, placebo controlled trial , 2004, Gut.

[9]  P. Rutgeerts,et al.  Tumour necrosis factor‐α receptor 1 and 2 polymorphisms in inflammatory bowel disease and their association with response to infliximab , 2004, Alimentary pharmacology & therapeutics.

[10]  P. Hellström,et al.  Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County , 2004, Gut.

[11]  J. Belaiche,et al.  Association between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn's disease , 2004, Alimentary pharmacology & therapeutics.

[12]  P. Rutgeerts,et al.  Infliximab maintenance therapy for fistulizing Crohn's disease. , 2004, The New England journal of medicine.

[13]  G. Corazza,et al.  Defective mucosal T cell death is sustainably reverted by infliximab in a caspase dependent pathway in Crohn’s disease , 2003, Gut.

[14]  J. Satsangi,et al.  An analysis of factors influencing short‐term and sustained response to infliximab treatment for Crohn's disease , 2003, Alimentary pharmacology & therapeutics.

[15]  D. Hommes,et al.  Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease. , 2003, Gastroenterology.

[16]  M. Neurath,et al.  CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. , 2003, The Journal of clinical investigation.

[17]  M. Peppercorn,et al.  Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: a randomized controlled trial. , 2003, Gastroenterology.

[18]  An Carbonez,et al.  Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. , 2003, The New England journal of medicine.

[19]  G. Cooper,et al.  A Novel Polymorphic CAAT/Enhancer-Binding Protein β Element in the FasL Gene Promoter Alters Fas Ligand Expression: A Candidate Background Gene in African American Systemic Lupus Erythematosus Patients1 , 2003, The Journal of Immunology.

[20]  J. Hampe,et al.  Response to infliximab treatment in Crohn's disease is not associated with mutations in the CARD15 (NOD2) gene: an analysis in 534 patients from two multicenter, prospective GCP-level trials. , 2002, Pharmacogenetics.

[21]  J. Belaiche,et al.  Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn's disease , 2002, American Journal of Gastroenterology.

[22]  J. Achkar,et al.  Predictors of response to infliximab in patients with Crohn's disease. , 2002, Gastroenterology.

[23]  J. Belaiche,et al.  NOD2/CARD15 does not influence response to infliximab in Crohn's disease. , 2002, Gastroenterology.

[24]  J. Belaiche,et al.  Serological markers for prediction of response to anti-tumor necrosis factor treatment in Crohn's disease , 2002, American Journal of Gastroenterology.

[25]  S. Hanauer,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group , 2022 .

[26]  S. Deventer,et al.  Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease , 2002, Gut.

[27]  J. Belaiche,et al.  Inflammatory Bowel Disease A Positive Response to Infliximab in Crohn Disease: Association with a Higher Systemic Inflammation Before Treatment But Not With -308 TNF Gene Polymorphism , 2002, Scandinavian journal of gastroenterology.

[28]  W Domschke,et al.  Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway. , 2001, Gastroenterology.

[29]  S. Targan,et al.  ANCA pattern and LTA haplotype relationship to clinical responses to anti-TNF antibody treatment in Crohn's disease. , 2001, Gastroenterology.

[30]  W. Selby,et al.  Early Australian experience with infliximab, a chimeric antibody against tumour necrosis factor‐α, in the treatment of Crohn’s disease: is its efficacy augmented by steroid‐sparing immunosuppressive therapy? , 2001 .

[31]  J. Lord,et al.  Ageing and the neutrophil: no appetite for killing? , 2000, Immunology.

[32]  P. Rutgeerts,et al.  Endoscopic and histologic healing of Crohn's (ileo-) colitis with azathioprine. , 1999, Gastrointestinal endoscopy.

[33]  E. Vasiliauskas,et al.  Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. , 1999, Gastroenterology.

[34]  P. Rutgeerts,et al.  Infliximab for the treatment of fistulas in patients with Crohn's disease. , 1999, The New England journal of medicine.

[35]  S. Targan,et al.  A Short-Term Study of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor α for Crohn's Disease , 1997 .

[36]  N. Manolios,et al.  Identification and characterization of polymorphisms in the promoter region of the human Apo-1/Fas (CD95) gene. , 1997, Molecular immunology.

[37]  A. Zinsmeister,et al.  The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients. , 2004, Gastroenterology.

[38]  J. Hampe,et al.  Pharmacogenetic investigation of the TNF/TNF-receptor system in patients with chronic active Crohn's disease treated with infliximab , 2002, The Pharmacogenomics Journal.

[39]  W. Selby,et al.  Early Australian experience with infliximab, a chimeric antibody against tumour necrosis factor-alpha, in the treatment of Crohn's disease: is its efficacy augmented by steroid-sparing immunosuppressive therapy? The Infliximab User Group. , 2001, Internal medicine journal.

[40]  S. Targan,et al.  A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. , 1997, The New England journal of medicine.