W1304 Durability of Infliximab Dose Intensification in Crohn's Disease

Division of Gastroenterology, Department of Internal Medicine, University of California at San Francisco, San Francisco, CA, USA.
Digestive Diseases and Sciences (Impact Factor: 2.61). 11/2011; 57(4):1013-9. DOI: 10.1007/s10620-011-1969-3
Source: PubMed


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.

9 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and aim: 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 · 3.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cigarette smoking may be associated with the augmentation of pro-inflammatory cytokines including Tumor Necrosis Factor-alpha (TNF-α), which may affect the outcomes of pharmacological agents such as TNF-α inhibitors. The purpose of this study was to investigate the impact of smoking on the effectiveness of TNF-α inhibitors in patients with rheumatoid arthritis (RA) or Crohn's disease (CD). We used systematic literature review methods. A total of 1,147 articles were selected after exclusion of duplicates through a database search. Among them, 28 articles were finally selected through a review of titles and abstracts and a subsequent review of full articles. The effectiveness of TNF-α inhibitors in patients with RA or CD among the selected articles was summarized by their smoking status. Meta-analysis was performed with random effect model. When current smokers were compared with non-smokers for response after adjustments through meta-analysis among patients with RA, current smokers had 59% less response than non-smokers with statistical significance (Pooled adjusted OR=0.41, 95% CI=0.17-0.95). In patients with CD, current smokers tended to have lower clinical response than non-smokers, but statistical significance was not shown. In subgroup analyses for luminar CD or fistulizing CD, current smokers tended to have a lower response in luminar CD (Pooled OR=0.62, 95% CI=0.34-1.14), but smoking status was not associated with drug response in fistulizing CD. This study raises awareness of the adverse effects of smoking in terms of clinical response in patients treated with TNF-α inhibitors.
    01/2014; 22(2):92. DOI:10.12793/tcp.2014.22.2.92
  • [Show abstract] [Hide abstract]
    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 · 4.46 Impact Factor
Show more