Increasing Infliximab Dose Based on Symptoms, Biomarkers, and Serum Drug Concentrations Does Not Increase Clinical, Endoscopic, and Corticosteroid-Free Remission in Patients With Active Luminal Crohn's Disease

Background & Aims: A combination of infliximab and immunomodulators is the most efficacious treatment for Crohn's disease (CD). Patients have the best outcomes when their serum concentrations of these drugs are above a determined therapeutic threshold. We performed a prospective, randomized trial to determine whether therapeutic drug monitoring (TDM) to maintain serum levels of infliximab above 3 μg/mL produced higher rates of clinical and endoscopic remission than adapting dose based only on symptoms. Methods: We performed a double-blind trial in which 122 biologic-naïve adult patients with active CD (71 female, median age 29.8 years) received induction treatment with infliximab in combination with an immunosuppressant, from July 2012 through September 2015 at 27 centers in Europe. At week 14 of treatment, patients were randomly assigned (1:1:1) to 3 infliximab maintenance groups: dose increases (2 maximum) in steps of 2.5 mg/kg based on clinical symptoms and biomarker analysis and/or serum infliximab concentrations (dose intensification strategy [DIS]1 group); dose increase from 5 to 10 mg/kg based on the same criteria (DIS2 group); dose increase to 10 mg/kg based on clinical symptoms alone (controls). Patients’ CD activity index scores, levels of C-reactive protein, fecal levels of calprotectin, and serum concentrations of infliximab were determined at baseline and at weeks 2, 4, 6, 12, and 14 of treatment, and then every 4 weeks thereafter until week 54. The primary endpoint was sustained corticosteroid-free clinical remission (CD activity index <150) from weeks 22 through 54 with no ulcers at week 54. Results: The primary endpoint was reached by 15 (33%) of 45 patients in the DIS1 group, 10 (27%) of 37 patients in the DIS2 group, and 16 (40%) of 40 patients in the control group (P =.50). Conclusions: In a prospective randomized exploratory trial of patients with active CD, we found increasing dose of infliximab based on a combination of symptoms, biomarkers, and serum drug concentrations does not lead to corticosteroid-free clinical remission in a larger proportion of patients than increasing dose based on symptoms alone. EUDRACT NUMBER: 2011–003038–14

Increasing Infliximab Dose Based on Symptoms, Biomarkers, and Serum Drug Concentrations Does Not Increase Clinical, Endoscopic, or Corticosteroid-Free Remission in Patients With Active Luminal Crohn's Disease

A combination of infliximab and immunomodulators is the most efficacious treatment for Crohn's disease (CD). Patients have the best outcomes when their serum concentrations of these drugs are above a determined therapeutic threshold. We performed a prospective, randomized trial to determine whether therapeutic drug monitoring (TDM) to maintain serum levels of infliximab above 3 μg/mL produced higher rates of clinical and endoscopic remission than adapting dose based only on symptoms. We performed a double-blind trial in which 122 biologic-naïve adult patients with active CD (71 female, median age 29.8 years) received induction treatment with infliximab in combination with an immunosuppressant, from July 2012 through September 2015 at 27 centers in Europe. At week 14 of treatment, patients were randomly assigned (1:1:1) to 3 infliximab maintenance groups: dose increases (2 maximum) in steps of 2.5 mg/kg based on clinical symptoms and biomarker analysis and/or serum infliximab concentrations (DIS1 group); dose increase from 5 to 10 mg/kg based on the same criteria (DIS2 group); dose increase to 10 mg/kg based on clinical symptoms alone (controls). Patients' CD activity index scores, levels of C-reactive protein, fecal levels of calprotectin, and serum concentrations of infliximab were determined at baseline and at weeks 2, 4, 6, 12, and 14 of treatment, and then every 4 weeks thereafter until week 54. The primary endpoint was sustained corticosteroid-free clinical remission (CD activity index <150) from weeks 22 through 54 with no ulcers at week 54. The primary endpoint was reached by 15/45 patients (33%) in the DIS1 group, 10/37 patients (27%) in the DIS2 group, and 16/40 patients (40%) in the control group (P=.50). In a prospective randomized exploratory trial of patients with active CD, we found increasing dose of infliximab based on a combination of symptoms, biomarkers and serum drug concentrations does not lead to corticosteroid-free clinical remission in a larger proportion of patients than increasing dose based on symptoms alone. 2011-003038-1

Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS: Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589

Excess risk of urinary tract cancers in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study

IF 6.32International audienceBackgroundThe risk of urinary tract cancers, including kidney and bladder cancers, was increased in transplant recipients receiving thiopurines.AimTo assess the risk of urinary tract cancers in patients with inflammatory bowel disease (IBD) receiving thiopurines in the CESAME observational cohort.MethodsBetween May 2004 and June 2005, 19 486 patients with IBD, 30.1% of whom were receiving thiopurines, were enrolled. Median follow‐up was 35 months (IQR: 29–40).ResultsTen and six patients developed respectively kidney and bladder cancer. The incidence rates of urinary tract cancer were 0.48/1000 patient‐years in patients receiving thiopurines (95% CI: 0.21–0.95), 0.10/1000 patient‐years in patients who discontinued thiopurines (95% CI: 0.00–0.56) and 0.30/1000 patient‐years in patients never treated with thiopurines (95% CI: 0.12–0.62) at entry. The standardised incidence ratio of urinary tract cancer was 3.40 (95% CI: 1.47–6.71, P = 0.006) in patients receiving thiopurines, 0.64 (95% CI: 0.01–3.56, P = 0.92) in patients previously exposed to thiopurines and 1.17 (95% CI: 0.47–12.42, P = 0.78) in patients never treated with thiopurines. The multivariate‐adjusted hazard ratio (HR) of urinary tract cancer between patients receiving thiopurines and those not receiving thiopurines was 2.82 (95% CI: 1.04–7.68, P = 0.04). Other significant risk factors were male gender (HR: 3.98, 95% CI: 1.12–14.10, P = 0.03) and increasing age (HR after 65 years (ref <50): 13.26, 95% CI: 3.52–50.03, P = 0.0001).ConclusionPatients with IBD receiving thiopurines have an increased risk of urinary tract cancers. Clinically relevant excess risk is observed in older men