Durability of Infliximab Dose Intensification in Crohn's Disease
ABSTRACT Dose intensification is a common approach to treat Crohn's disease (CD) patients who lose response to infliximab maintenance therapy. Few studies have reported upon its long-term efficacy or predictors of response.
The goal of this study is to investigate durability and predictors of response to dose intensification-including method of dose intensification, combination immunomodulator therapy, and premedication with intravenous hydrocortisone.
We performed a retrospective study of dose-intensified CD patients at our institution. Dose intensification was defined as an increase in dose from 5 to 10 mg/kg, an increase in frequency of infusions from every 8 weeks to every 6 weeks or less, or both an increase in dose and frequency.
Thirty CD patients (mean age, 39.9 years) met study criteria and underwent dose intensification. Ten (33.3%) patients remained on dose intensification at the end of our study or returned to their former infliximab dose or schedule (median follow-up, 41 months). Fourteen patients (46.7%) eventually lost response to dose intensification, but dose intensification extended infliximab therapy by a median duration of 9 months. Six patients (20%) didn't respond to dose intensification. Neither method of dose intensification, combination immunomodulator therapy, nor premedication with intravenous hydrocortisone predicted initial or durable response to dose intensification. However, analysis of predictors was limited by the small sample size of our study.
The majority of CD patients respond to dose intensification, and a substantial portion will experience durable response such that infliximab therapy is successfully extended by one or more years.
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ABSTRACT: BACKGROUND: Crohn's disease treatments available today are not quite satisfactory. N-(3', 4'-dimethoxycinnamonyl) anthranilic acid (3, 4-DAA) has been proved to be effective in many autoimmune diseases. Therefore, we investigated the immunologic function of 3, 4-DAA on trinitrobenzene sulfonic acid (TNBS) colitis and human Crohn's disease. METHODS: Mice with TNBS-induced colitis were treated with 3, 4-DAA or 1-methyl-tryptophan (1- MT). Colitis severity was assessed with clinical and histological scores. Cell proliferation, cytokine expression, and the percentage of CD4(+) CD25(+) T cells were measured in both mice and human samples. RESULTS: In mice treated with 3, 4-DAA, the clinical and histological scores were decreased (P<0.05); the proliferation of mesenteric lymph nodes (MLNs) cells and lamina propria mononuclear cells (LPMCs) were inhibited (P<0.05); Th1 cytokine expressions were decreased (P <0.05), and Th2 cytokine levels were increased (P<0.05). 3, 4-DAA also induced CD4(+) CD25(+) T cells expression (5.88±2.1 vs 11.03±2.93, P<0.05) in mice MLNs. Transfer of these cells into TNBS colitis mice resulted in the reduction of the disease activity index (DAI) and histological scores. In LPMCs isolated from human Crohn's disease, 3, 4-DAA had the same effect. It can inhibit the cell proliferation, decrease Th1 cytokine expressions (P <0.05), and increase Th2 cytokine levels (P<0.05). The percentage of CD4(+) CD25(+) T cells were also increased (1.60±0.14 vs 2.45±0.50, P<0.05). 1-MT treatment led to opposite outcomes. CONCLUSION: 3, 4-DAA can alleviate the severity of colitis through inhibiting Th1 cells response, promoting Th2 cytokines expression and inducing CD4(+) CD25(+) T cells expression.Journal of Gastroenterology and Hepatology 05/2013; 28(8). DOI:10.1111/jgh.12266 · 3.63 Impact Factor
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ABSTRACT: Despite increasing use of infliximab (IFX) in children with Crohn's disease (CD) and ulcerative colitis (UC), long-term durability and safety of IFX beyond 1 year is limited in pediatric inflammatory bowel disease. We performed a 10-year single-center retrospective cohort study of 188 patients initiating IFX at <21 years of age with 1-year minimum follow-up. Data were retrieved from medical records. IFX outcomes were defined as sustained remission in the absence of dose modification (sustained durable remission), recaptured response, and treatment failure. Adverse events, anti-infliximab antibodies (ATI), and role of concomitant low-dose oral methotrexate (<10 mg/wk) on IFX durability were analyzed. Univariate associations and survival analysis were performed. As of the last follow-up, 39% of patients with CD and 29% of patients with UC achieved sustained durable remission and another 60% recaptured and maintained response. For CD, 88% remained on IFX at 1 year, 80% at 2 years, and 82% at 5 years. In UC, 70% avoided colectomy at 1 year. Of IFX failures, 25% with CD and 11% with UC developed ATI. The most common adverse event causing cessation of therapy was infusion reactions. Treatment limiting recurrent infections occurred in <1%, and 1 patient developed lymphoproliferative disease. Low-dose methotrexate did not influence any IFX outcomes. IFX is safe and effective for long-term maintenance therapy in pediatric patients with inflammatory bowel disease. IFX dose intensification can optimize durability and overcome loss of response. Loss of response is likely affected by development of ATI. Higher doses of oral methotrexate may be needed to optimize IFX.Inflammatory Bowel Diseases 02/2014; 20(4). DOI:10.1097/MIB.0000000000000003 · 5.48 Impact Factor
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ABSTRACT: Background: Infliximab, a monoclonal antibody tumor necrosis factor-alpha inhibitor, is an effective therapy that is indicated for the treatment of patients with Crohn’s disease. Although dose escalation from 5 mg/kg to 10 mg/kg is allowed according to the prescribing label of infliximab, conflicting results exist regarding the rate at which this escalation may occur, which may affect payers and providers. Objective: The goal of this exploratory study was to characterize and quantify the rate of infliximab dose escalation in a sample of patients with Crohn’s disease. Methods: Administrative claims data from patients with Crohn’s disease in a large mid-Atlantic managed care organization were collected and used to target and recruit providers into a chart review study of infliximab dosing. Data from the charts of 161 patients with Crohn’s disease who were receiving infliximab between 2006 and 2010 were extracted. Patients were grouped into an infliximab dose-escalation group or a dose-stable group based on these data. The evidence of any infliximab dose ≥7.5 mg/kg or evidence of a mean maintenance interval of 42 days or less resulted in the placement of a patient in the dose-escalation group, with the balance of patients comprising the stable-dose group. Results: A total of 925 infliximab infusions were captured from 161 patients. Of the 161 patients identified, 110 had at least 4 infusions, and 4 had missing data; therefore, only 106 (66%) patients were qualified for the final infliximab dosing analysis. A total of 18 (17%) of these patients had evidence of infliximab dose escalation (dose-escalation group), and the remaining 88 (83%) patients had a consistent 5-mg/kg dose and schedule (stable-dose group). Of the 18 patients in the dose-escalation group, 9 (50%) had a decrease in maintenance interval, whereas 12 (66.7%) patients had an increase in their dosage. A total of 3 (16.7%) patients had both an increase in dose and a reduction in maintenance interval. Conclusions: Infliximab has been shown to be a cost-effective treatment for patients with Crohn’s disease. The rate of infliximab dose escalation in this study was within the lower range of published estimates for this medication. Studies using larger sample sizes are needed to validate the findings of the current study. In addition, studies that are focused on quantifying and describing the nature of infliximab dose escalation may be useful in the development of successful patient–treatment matching algorithms.American Health and Drug Benefits 04/2014; 7(2):87-93.