Cheifetz Laboratory


Adam S. Cheifetz, MD cheifetz
Associate Professor of Medicine, Harvard Medical School
Clinical Director, Center for Inflammatory Bowel Disease

Project 1

Title: Long-term outcome of optimizing infliximab therapy to overcome immunogenicity in patients with inflammatory bowel disease.

Hypothesis to be tested or rationale: Anti-drug antibodies against anti-tumor necrosis factor (TNF) therapy have been associated with lower drug concentrations, secondary loss of response (SLR) and infusion reactions in patients with inflammatory bowel disease (IBD). Preliminary data suggest that anti-TNF therapy optimization can increase drug concentration, reverse immunogenicity and regain response in patients with SLR due to anti-drug antibodies. However, data regarding the long-term outcome of these patients are scarce. The aim of the study is to investigate drug retention and variables associated with drug retention in patients with IBD of whom infliximab was optimized to overcome immunogenicity.

Methods to be used: Retrospective, observational, multi-center study of consecutive IBD patients with antibodies to infliximab (ATI), based on either proactive or reactive therapeutic drug monitoring, who underwent infliximab optimization (increasing dose, shortening interval, adding an IMM, or combination) to overcome immunogenicity. Drug retention is defined as no need for drug discontinuation due to SLR or serious adverse event. Kaplan-Meier survival analysis (Log-rank test) will be used to estimate drug retention. Univariable and multivariable Cox proportional hazards regression analysis will be also performed to determine the independent effects of variables associated with drug retention.

Project 2

Title: Defining a therapeutic drug window in patients treated with infliximab for fistulizing Crohn’s disease.

Hypothesis to be tested or rationale: Anti-tumor necrosis factor (TNF) therapy is effective for the treatment of fistulizing CD. Recent exposure-response relationship studies have revealed a positive correlation between high serum anti-TNF drug concentration and favorable therapeutic outcomes, although there are only limited data regarding fistulizing CD. The aim of the study is to define the therapeutic window for adequate infliximab concentration associated with favorable therapeutic outcomes in patients with fistulizing CD both during induction and maintenance therapy including fistula response, defined as a reduction of at least 50 percent from base line in the number of draining fistulas and complete fistula response, defined as the absence of draining fistulas.

Methods to be used: Post-hoc analysis of the ACCENT II study, a randomized, double-blind, placebo-controlled trial of anti-TNFα chimeric monoclonal antibody (Infliximab, REMICADE®) in the long-term treatment of patients with fistulizing Crohn’s disease.

Source of data if project does not involve direct patient contact: Yale University Open Data Access (YODA)

Project 3

Title: Serum infliximab concentration and prevention of clinical or endoscopic post-operative recurrence in patients with Crohn’s disease and an ileocolonic resection.

Hypothesis to be tested or rationale: Anti-tumor necrosis factor (TNF) therapy is effective for preventing endoscopic or clinical post-operative recurrence (POR) in patients with Crohn’s disease (CD) and an ileocolonic resection. Recent exposure-response relationship studies have revealed a positive correlation between high serum anti-TNF drug concentration and positive clinical outcomes. The aim of the study is to define the therapeutic window for adequate infliximab concentration associated with favorable therapeutic outcomes, including post-operative endoscopic, sustained clinical or deep remission in CD patients who receive prophylactic infliximab therapy after an ileocolonic resection for prevention of clinical or endoscopic POR.

Methods to be used: Post-hoc analysis of the PREVENT study, a prospective, multicenter, randomized, double-Blind, placebo-controlled trial comparing infliximab and placebo in the prevention of recurrence in CD patients undergoing surgical resection who are at an increased risk of recurrence.

Source of data if project does not involve direct patient contact: Yale University Open Data Access (YODA).

Project 4

Title: Infliximab and adalimumab concentration associated with endoscopic and histological remission in IBD

Hypothesis to be tested or rationale: Several therapeutic drug monitoring (TDM) exposure-response relationship studies have shown a positive correlation between infliximab and adalimumab trough concentration and favorable therapeutic outcomes in inflammatory bowel diseases (IBD); Crohn’s disease (CD) and ulcerative colitis (UC). However, trough concentration cut-offs may vary depending on the assay used and the outcome of interest. The aim of the study is to investigate the association of infliximab and adalimumab trough concentration during maintenance phase with biological, endoscopic and histological remission in IBD and variables associated with these outcomes.

Methods to be used: Retrospective, observational, multicenter study. Biological remission is defined as CRP≤5 mg/L. Endoscopic remission is defined as absence of any ulceration or erosion for CD, a Rutgeerts score of i0 for CD patients with an ileocolonic resection and a Mayo endoscopic score of 0 for patients with UC. Histological remission is defined as absence of any sign of active inflammation. Per event analysis will be performed i.e. a patient could be analyzed more than once provided that at least 3 months elapsed between colonoscopy procedures and that each procedure correlated with an adjacent serum sample. A receiver-operating characteristic (ROC) analysis will be performed for infliximab and adalimumab trough concentration to trace thresholds associated with therapeutic outcomes of interest, based on the Youden Index.

Project 5

Title: Long-term outcomes of proactive versus reactive therapeutic drug monitoring for adalimumab optimization in inflammatory bowel disease.

Hypothesis to be tested or rationale: Therapeutic drug monitoring (TDM) of anti-tumor necrosis factor (TNF) therapy in inflammatory bowel disease (IBD) is performed either for loss of response (reactive TDM) or in patients in clinical remission with drug titration to a target concentration (proactive TDM). The aim of this study is to evaluate the long-term outcomes of IBD patients undergoing proactive or reactive TDM of adalimumab and variables associated with these outcomes.

Methods to be used: Retrospective, observational, multicenter study. Time-to-event analysis for treatment failure, first IBD-related surgery and hospitalization, serious infusion reaction (SIR) and antibodies to adalimumab will be performed. Treatment failure is defined as drug discontinuation for loss of response or serious adverse event, or need for surgery.