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Biomedical subjects

Stephen B Hanauer

Publications and source records attributed to Stephen B Hanauer.

At least 19 recordsLinked to original sources
PubMed2007

Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab.

BACKGROUND: Natalizumab, a humanized monoclonal IgG(4) antibody to alpha4 integrin, was investigated as a treatment of active Crohn's disease (CD). The safety of natalizumab given in combination with infliximab has not previously been studied. METHODS: Seventy-nine adult patients with active CD (Crohn's Disease Activity Index [CDAI] score > or = 150) despite ongoing infliximab treatment were randomized 2:1 to receive 3 intravenous infusions of natalizumab (300 mg; n = 52) or placebo (n = 27) every 4 weeks. Patients received infliximab (5 mg/kg) every 8 weeks for at least 10 weeks before randomization and throughout the study. The primary objective was to assess the short-term safety and tolerability of natalizumab in patients concurrently receiving infliximab. Secondary and tertiary objectives included measures of efficacy, health-related quality of life (HRQoL), and effects on inflammatory markers. A subset of patients also participated in a pharmacokinetic/pharmacodynamic (PK/PD) analysis of the effects of concurrent treatment. RESULTS: Incidence of adverse events (AEs) was similar in the treatment groups. AEs frequently reported in both groups were headache, CD exacerbation, nausea, and nasopharyngitis. No patient had a hypersensitivity-like reaction to natalizumab, whereas 4 patients (5%) experienced reactions to infliximab. Two patients (4%) developed anti-natalizumab antibodies; 10 patients (14%) developed anti-infliximab antibodies. The mean CDAI score decreased with natalizumab plus infliximab but was unchanged with infliximab alone (-37.7 versus +3.5; P = 0.084). Patients in both groups showed small increases in HRQoL (P = 0.811). No drug-drug interactions were noted. CONCLUSIONS: The combination of natalizumab plus infliximab was well tolerated. Several positive trends suggested that treating patients not in remission with infliximab plus natalizumab had greater efficacy than treatment with infliximab alone.

Adult↗
PubMed2007

Fragile egos.

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Colonoscopy↗
PubMed2006

Aminosalicylate therapy in the prevention of dysplasia and colorectal cancer in ulcerative colitis.

BACKGROUND & AIMS: Aminosalicylates have been suggested as chemopreventive agents for colorectal cancer (CRC) in ulcerative colitis (UC). We studied the effect of aminosalicylate use on dysplasia and CRC risk in chronic UC. METHODS: UC patients with dysplasia or CRC were matched with controls by disease duration, extent, and age at diagnosis. The total amount of aminosalicylates over the duration of the disease and the mean daily amount of drug was calculated. Conditional logistic regression was used to examine the relationship of aminosalicylates to the risk of neoplasia; potential confounders were controlled in a multivariable model. RESULTS: Twenty-six cases (8 CRC, 18 dysplasia) were matched with 96 controls. Cases and controls were similar in age (median, 43 vs 42.5 y), age at diagnosis of UC (median, 29.5 vs 30.5 y), duration of UC (median, 11.5 vs 9 y), and extent of disease (58% pancolitis), sex, family history of UC, history of primary sclerosing cholangitis, and smoking history. Cases were more likely to have a family history of CRC than controls (27% of cases, 9% of controls, P = .036). Conditional logistic regression adjusted for disease duration, age at diagnosis, and family history of CRC showed that aminosalicylate use of 1.2 g/day or more was associated with a 72% reduction in the odds of dysplasia/CRC (odds ratio, 0.28; 95% confidence interval, 0.09-0.85). As the total dose of aminosalicylates increased, the odds of dysplasia/CRC decreased (P = .056). CONCLUSIONS: This case-control study shows a significant risk reduction of dysplasia and CRC in UC patients exposed to aminosalicylate therapy.

Adult↗
PubMed2006

Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease.

BACKGROUND: The endoscopic substudy of the ACCENT I (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen) Crohn's disease trial examined the effects of infliximab on mucosal inflammation and mucosal healing, and assessed their impact on outcomes. DESIGN: ACCENT I was a randomized, double-blind, parallel group study. SETTING: This study took place at multiple centers in North America, Europe, and Israel. MAIN OUTCOME MEASUREMENTS: Ileocolonoscopic examinations were performed at weeks 0, 10, and 54. Complete mucosal healing was defined as the absence of all mucosal ulcerations. The end point of principal interest was the proportion of patients randomized as responders with mucosal healing at week 10. The proportion of responders who demonstrated mucosal healing at week 54 or at both weeks 10 and 54 is also summarized. Changes in Crohn's disease endoscopic index of severity (CDEIS) scores from baseline to week 10 and 54 were calculated for all patients in this substudy. RESULTS: Complete mucosal healing by week 10 occurred in significantly more week 2 responders who had received 3 doses of infliximab compared with a single dose (31% vs. 0%, p = 0.010). A significantly higher proportion of week 2 responders in the combined scheduled maintenance group had complete mucosal healing at week 54 compared with the episodic group (50% vs. 7%, p = 0.007). The results for all patients are consistent with those for week 2 responders only. Significantly greater improvement in the CDEIS occurred with scheduled maintenance compared with episodic treatment at week 10 (p </= 0.001) and week 54 (p = 0.026). Notably, no strong relationship between clinical remission and complete mucosal healing was found. Overall, mucosal healing appeared to correlate with fewer hospitalizations, although these results were not statistically significant. CONCLUSIONS: Scheduled infliximab maintenance therapy resulted in more improvement in mucosal ulceration and in higher rates of mucosal healing. There was a numerical trend for patients with better mucosal healing to have a lower rate of Crohn's disease-related hospitalizations.

Adult↗
PubMed2006

General principles and pharmacology of biologics in inflammatory bowel disease.

The pharmacology of each biologic agent is important regarding the dose required to achieve benefits, duration of therapeutic effect, and the induction of immunogenicity. Comprehension of the individual pharmacology, pharmacodynamics, and pharmacokinetics, in addition to the impact of concomitant immunomodulation on immunogenicity allows optimization of each biologic agent in the appropriate inductive or maintenance setting of IBD.

Adalimumab↗
PubMed2006

Fertile ground.

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Evidence-Based Medicine↗
PubMed2006

A generic problem.

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Conflict of Interest↗
PubMed2006

Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial.

BACKGROUND & AIMS: Tumor necrosis factor blockade has been shown to be an effective treatment strategy in Crohn's disease (CD). Adalimumab is a human immunoglobulin G1 (IgG(1)) monoclonal antibody targeting tumor necrosis factor (TNF). A randomized, double-blind, placebo-controlled, dose-ranging trial was performed to evaluate the efficacy of adalimumab induction therapy in patients with CD. METHODS: A total of 299 patients with moderate to severe CD naive to anti-TNF therapy were randomized to receive subcutaneous injections at weeks 0 and 2 with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg or placebo. The primary endpoint was demonstration of a significant difference in the rates of remission at week 4 (defined as a Crohn's Disease Activity Index score <150 points) among the 80 mg/40 mg, 160 mg/80 mg, and placebo groups. RESULTS: The rates of remission at week 4 in the adalimumab 40 mg/20 mg, 80 mg/40 mg, and 160 mg/80 mg groups were 18% (P = .36), 24% (P = .06), and 36% (P = .001), respectively, and 12% in the placebo group. Adverse events occurred at similar frequencies in all 4 treatment groups except injection site reactions, which were more common in adalimumab-treated patients. CONCLUSIONS: Adalimumab was superior to placebo for induction of remission in patients with moderate to severe Crohn's disease naive to anti-TNF therapy. The optimal induction dosing regimen for adalimumab in this study was 160 mg at week 0 followed by 80 mg at week 2. Adalimumab was well tolerated.

Adalimumab↗
PubMed2006

Pilot feasibility studies of leukocytapheresis with the Adacolumn Apheresis System in patients with active ulcerative colitis or Crohn disease.

GOALS: Two uncontrolled, multicenter feasibility studies evaluated safety and pilot efficacy of selective granulocyte and monocyte adsorption apheresis (GMA) with the Adacolumn Apheresis System for treatment of moderate-to-severe ulcerative colitis (UC) and Crohn disease (CD) patients refractory/intolerant to conventional pharmacologic therapy. BACKGROUND: Patients with UC and CD, characterized by elevations in peripheral blood granulocytes, monocytes/macrophages, and proinflammatory mediators, may benefit from reductions in activated granulocytes and monocytes by selective apheresis. METHODS: Patients underwent weekly Adacolumn sessions for 5 weeks. Pilot efficacy assessments used disease activity index (DAI) for UC (0-12) or CD activity index (CDAI; 0-600) for CD. RESULTS: Eleven of 15 UC patients completed all 5 treatments. Mean DAI scores fell from 8.4+/-1.3 (baseline) to 5.2+/-2.9 (week 7). Five patients had DAI reductions of > or = 3 points at week 7. Fourteen of 15 CD patients completed all 5 treatments. Mean CDAI scores fell from 308.0+/-76.5 (baseline) to 200.6+/-117.4 (week 7). Nine CD patients responded (CDAI reductions > or = 70 points) at week 7. Remission (CDAI score < or = 150 at week 7) was observed in 6 patients. There were no device-related serious adverse effects. CONCLUSIONS: Treatment with Adacolumn may be feasible and effective in patients with moderate-to-severe refractory inflammatory bowel disease. Larger sham-controlled studies are ongoing.

Adolescent↗
PubMed2006

Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities.

Ulcerative colitis (UC) and Crohn's disease (CD), the primary constituents of inflammatory bowel disease (IBD), are precipitated by a complex interaction of environmental, genetic, and immunoregulatory factors. Higher rates of IBD are seen in northern, industrialized countries, with greater prevalence among Caucasians and Ashkenazic Jews. Racial gaps are closing, indicating that environmental factors may play a role. IBD is multigenic, with the most clearly established genetic link between certain NOD2 variants and CD. Regardless of the underlying genetic predisposition, a growing body of data implicates a dysfunctional mucosal immune response to commensal bacteria in the pathogenesis of IBD, especially CD. Possible triggers include a chronic inflammatory response precipitated by infection with a particular pathogen or virus or a defective mucosal barrier. The characteristic inflammatory response begins with an infiltration of neutrophils and macrophages, which then release chemokines and cytokines. These in turn exacerbate the dysfunctional immune response and activate either TH1 or TH2 cells in the gut mucosa, respectively associated with CD and, less conclusively, with UC. Elucidation of immunological and genetic factors indicate multiple points at which the inflammatory cascade may be interrupted, yielding the possibility of precise, targeted therapies for IBD.

Animals↗