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Biomedical subjects

Bruce E Sands

Publications and source records attributed to Bruce E Sands.

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↗
PubMed2006

Risks and benefits of infliximab for the treatment of Crohn's disease.

BACKGROUND & AIMS: Infliximab is effective for the treatment of active Crohn's disease. However, rare but serious complications related to infliximab therapy including lymphoma, sepsis, and death have been reported. The purpose of this study was to analyze the risks and benefits of infliximab for the treatment of Crohn's disease with the goal of providing data to aid both physicians and patients in the process of making a decision about treatment. METHODS: A decision analytic model was constructed to determine the risks and benefits of infliximab when compared with standard therapy. The analysis simulated 2 cohorts of 100,000 patients each, with one arm receiving infliximab while the other remained on standard therapy. RESULTS: Model results showed that in 100,000 patients at 1 year, infliximab will lead to 12,216 more patients in remission, 4255 fewer surgeries, and 33 fewer deaths from flares of disease. This is at the cost of 201 more lymphomas and 249 more deaths related to complications from infliximab. Overall, the infliximab strategy resulted in more quality-adjusted life years (QALYs/patient) than the standard therapy strategy (.77 QALYs/patient vs .75 QALYs/patient). CONCLUSIONS: Despite an increased risk of lymphoma and death associated with use of infliximab, the substantial clinical improvement and fewer surgeries as a result of infliximab result in an increase in QALYs. In properly selected patients, the benefits of infliximab could outweigh its risks. These data should help guide decision making and the informed consent process when considering the use of infliximab for the treatment of Crohn's disease.

Adult↗
PubMed2006

Algorithms to identify colonic ischemia, complications of constipation and irritable bowel syndrome in medical claims data: development and validation.

PURPOSE: A challenge in the use of insurance claims databases for epidemiologic research is accurate identification and verification of medical conditions. This report describes the development and validation of claims-based algorithms to identify colonic ischemia, hospitalized complications of constipation, and irritable bowel syndrome (IBS). METHODS: From the research claims databases of a large healthcare company, we selected at random 120 potential cases of IBS and 59 potential cases each of colonic ischemia and hospitalized complications of constipation. We sought the written medical records and were able to abstract 107, 57, and 51 records, respectively. We established a 'true' case status for each subject by applying standard clinical criteria to the available chart data. Comparing the insurance claims histories to the assigned case status, we iteratively developed, tested, and refined claims-based algorithms that would capture the diagnoses obtained from the medical records. We set goals of high specificity for colonic ischemia and hospitalized complications of constipation, and high sensitivity for IBS. RESULTS: The resulting algorithms substantially improved on the accuracy achievable from a naïve acceptance of the diagnostic codes attached to insurance claims. The specificities for colonic ischemia and serious complications of constipation were 87.2 and 92.7%, respectively, and the sensitivity for IBS was 98.9%. CONCLUSIONS: U.S. commercial insurance claims data appear to be usable for the study of colonic ischemia, IBS, and serious complications of constipation.

Algorithms↗
PubMed2006

New therapies for the treatment of inflammatory bowel disease.

Medical therapy of IBD has made remarkable progress in recent years, driven forward by new knowledge about mechanisms of disease and advances in biotechnology. As we continue to learn about how best to use the agents currently in our hands, the addition of new drugs will further improve outcomes, and will bring new insights into the fundamental causes of these diseases.

Crohn Disease↗
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

Variation in severity assessment and initial mesalamine dose selection for ulcerative colitis in community practice.

BACKGROUND AND AIMS: Ulcerative colitis treatment is based largely on anatomic extent of inflammation and severity. Clinical severity is designated by the terms mild, moderate, or severe. The aims of this study are to assess consistency between: (1) community physicians and established treatment guidelines in their respective operational definitions of severity and (2) clinical severity ratings and resulting treatment. METHODS: Medical records of 411 patients who were successfully treated with mesalamine delayed release tablets without requiring steroids were reviewed. Data recorded included the prescribed dose of mesalamine, clinical symptoms, and physician's global assessment (PGA). RESULTS: Physicians were moderately consistent with the American College of Gastroenterology Guidelines in their assignments of PGA (kappa=0.57, P<0.001). An alternative decision rule, which deviated from the guidelines by placing a higher proportion of patients in the mild category, yielded a significantly higher kappa of 0.69 (P<0.001). The associations between severity measures and mesalamine dose yielded tau statistics of 0.13, 0.16, and 0.14 (all P<0.001), respectively for PGA, number of stools per day and percentage of stools with blood. CONCLUSIONS: Ulcerative colitis treatment quality may be enhanced by promoting a more consistent terminology for disease severity and reducing the unexplained variation in treatment dosing.

Adolescent↗
PubMed2006

Risk factors for colorectal cancer in Crohn's colitis: a case-control study.

BACKGROUND: Few data exist regarding exposures associated with colorectal cancer (CRC) in patients with Crohn's colitis. The aim of this study was to identify exposures that alter the risk of CRC in patients with Crohn's colitis. METHODS: The Research Patient Database Registry at Massachusetts General Hospital was searched to identify cases and controls. Cases had a confirmed diagnosis of Crohn's disease involving at least one third of the colon and a confirmed diagnosis of colorectal adenocarcinoma. Matched controls were randomly chosen from the same source population. Paired univariate analysis was performed to develop an odds ratio (OR) for each exposure. RESULTS: Twenty-seven patients were found to have Crohn's colitis and CRC. Colonoscopy performed for screening or surveillance was associated with an OR of 0.21 (95% CI 0.04-0.77; P=0.02). Nonsignificant trends for a protective effect included prior appendectomy (OR 0.30; 95% CI 0.05-1.17; P=0.10) and regular 5-aminosalicylate use (OR 0.30; 95% CI 0.05-1.17; P=0.10). Smoking history was associated with a 4-fold-increased risk for CRC, but this was not statistically significant (OR 4.00; 95% CI 0.80-38.67; P=0.11). CONCLUSIONS: We found that having a colonoscopy for an indication of surveillance or screening is associated with decreased risk of CRC in the setting of Crohn's colitis. These data underscore the importance of CRC surveillance for Crohn's colitis in addition to ulcerative colitis and should prompt further study in this area.

Adolescent↗
PubMed2006

Prevention and treatment of osteoporosis in inflammatory bowel disease.

The following are guidelines for evaluation and consideration for treatment of patients with inflammatory bone disease (IBD) after bone mineral density (BMD) measurements. The Crohn's & Colitis Foundation of America (CCFA) has indicated that its recommendations are intended to serve as reference points for clinical decision-making, not as rigid standards, limits, or rules. They should not be interpreted as quality standards.

Absorptiometry, Photon↗
PubMed2006

Possible association between isotretinoin and inflammatory bowel disease.

OBJECTIVES: The Physician's Desk Reference lists inflammatory bowel disease (IBD) as a possible adverse event associated with the use of isotretinoin, a popular acne prescription medication. Our aim was to perform a systematic examination of reports of IBD associated with isotretinoin use. METHODS: All reports filed with the Food and Drug Administration (FDA) via the MedWatch system were requested and reviewed. Strength of causality was determined using the Naranjo adverse drug reaction (ADR) probability scale. RESULTS: All of the adverse reports filed with the FDA between 1997 and 2002 were accessed and reviewed. Eighty-five cases of IBD associated with isotretinoin use were reported. According to the Naranjo ADR probability scale, 4 cases (5%) scored in the "highly probable" range for isotretinoin as the cause of IBD, 58 cases (68%) were "probable," 23 cases (27%) were "possible," and no cases were "doubtful." CONCLUSIONS: In a subgroup of patients, isotretinoin might serve as a trigger for IBD.

Acne Vulgaris↗
PubMed2006

Outcome of surgical versus percutaneous drainage of abdominal and pelvic abscesses in Crohn's disease.

OBJECTIVE: Abdominal and pelvic abscesses are a common complication of Crohn's disease. We studied the effect of the initial choice of therapy on time to resolution of abdominal and pelvic abscesses. METHODS: We recorded clinical, laboratory, and radiographic data on all adult patients with Crohn's disease and abdominal or pelvic abscesses treated at our institution from 1991 to 2001 and followed > or = 1 yr. Univariate analysis identified variables associated with initial choice of drainage modality. These variables were included in a Cox regression model to identify factors independently associated with time to resolution. RESULTS: Of 66 episodes identified, surgery was the initial modality in 29 and percutaneous drainage in 37. Median time to resolution was not different between surgical drainage (25.0 days, range 0-240) and percutaneous drainage (21.5 days, range 0-182) (p = 0.084). Older age, longer duration of symptoms prior to drainage, no fistula identified radiographically, immune modulator use, no rebound tenderness, and admission to the medical service were factors associated with percutaneous drainage as initial modality. These factors, when incorporated in a Cox regression model, did not significantly affect the time to resolution. Days from onset of symptoms to radiographic diagnosis or drainage were independently associated with time to resolution of the abscess. CONCLUSION: Time to resolution of abdominal or pelvic abscesses in Crohn's disease is similar with percutaneous drainage and surgery. One-third of patients treated with percutaneous drainage required surgery within 1 yr. Earlier intervention for abdominal and pelvic abscesses is associated with shorter time to resolution.

Abdominal Abscess↗
PubMed2005

Infliximab for induction and maintenance therapy for ulcerative colitis.

BACKGROUND: Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, is an established treatment for Crohn's disease but not ulcerative colitis. METHODS: Two randomized, double-blind, placebo-controlled studies--the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)--evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. RESULTS: In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P<0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P< or =0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P<0.001 for both comparisons). CONCLUSIONS: Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo. (ClinicalTrials.gov numbers, NCT00036439 and NCT00096655.)

Adult↗
PubMed2005

Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease.

BACKGROUND & AIMS: Infliximab is effective in closing fistulas in patients with Crohn's disease. We examined the effect of infliximab maintenance treatment on hospitalizations, surgeries, and procedures in patients with fistulizing Crohn's disease enrolled in the ACCENT II study. METHODS: After 5 mg/kg infliximab at weeks 0, 2, and 6, a total of 282 patients were separately randomized at week 14 as responders (at least a 50% reduction from baseline in the number of draining fistulas at both weeks 10 and 14) or nonresponders to receive placebo or 5 mg/kg infliximab maintenance every 8 weeks. At week 22 and later, patients who lost response could be treated with a maintenance dose 5 mg/kg higher. Data on Crohn's disease-related hospitalizations, surgeries, and procedures were compared between the treatment groups for responders and all randomized patients. RESULTS: A total of 282 patients were randomized at week 14, of whom 195 were randomized as responders. Among patients randomized as responders, those who received infliximab maintenance had significantly fewer mean hospitalization days (0.5 vs. 2.5 days; P < .05), mean numbers (per 100 patients) of hospitalizations (11 vs. 31; P < .05), all surgeries and procedures (65 vs. 126; P < .05), inpatient surgeries and procedures (7 vs. 41; P < .01), and major surgeries (2 vs. 11; P < .05), compared with those who received placebo maintenance. CONCLUSIONS: In patients with fistulizing Crohn's disease, infliximab 5 mg/kg every 8 weeks significantly reduced hospitalizations, surgeries, and procedures compared with placebo.

Adult↗
PubMed2005

A survey of methodological variation in the Crohn's disease activity index.

BACKGROUND: The Crohn's disease activity index (CDAI) is the most widely used Crohn's disease activity instrument, yet little is known about the methodological variation in its use. METHODS: A MEDLINE search was performed to identify authors of articles published from 1976 to 1997 in which the CDAI was used. A multiple-choice questionnaire was sent to all of the authors identified. Questions covered investigators' practice and research characteristics, and details of definitions and techniques applied in scoring the CDAI. RESULTS: A total of 208 authors were identified, and 100 valid responses were obtained. The respondents were experienced investigators, with 63% of the authors having used the CDAI for > or =7 years. Of these authors, 70% characterized themselves as working in an academic clinical practice, and 72% had participated in industry-sponsored drug studies in which the CDAI was used as an end point. Considerable variation was noted in the administration and scoring of the CDAI, including disagreement on the definition of "liquid or very soft stools," the recording of the number of stools, the recording of pain ratings, and the scoring of extraintestinal manifestations and fistulas. The recording of fever, the scoring for the use of opiates, and the standard for the weight variable also varied widely among respondents. CONCLUSION: Considerable variation exists in the administration and implementation of the CDAI score among the pool of experienced researchers who were surveyed. This variation may affect the comparability of studies and may introduce random error into the measurement of the CDAI.

Crohn Disease↗
PubMed2005

Design issues and outcomes in IBD clinical trials.

Successful clinical trials in inflammatory bowel disease are based on precise definitions of study populations, standardized and well-defined interventions, reliable indices of disease activity, and clearly stipulated outcome measures. Interpretation of research results is often complicated by the differentiation of goals of therapy (remission induction and maintenance, quality of life) and the multitude of patient subsets. Choosing the correct patient subtype to enroll in a clinical trial is critical to the results of a study, its conclusions, and its applicability to the clinical setting. Validated, easy-to-use disease activity indices allow interpretation of results across trials. The use of biomarkers as surrogate clinical endpoints provides reproducibility, ease of statistical handling as a continuous variable, and consistent measurement of response to treatment. Despite these potential advantages, biomarkers of disease activity lack specificity and will need to be validated against clinically meaningful outcomes. Careful subject selection, standardization of disease activity indices, and precise outcome measurement are the keys to continued improvement of the inflammatory bowel disease research process.

Biomarkers↗
PubMed2005

State of the art: IBD therapy and clinical trials in IBD.

Inflammatory bowel diseases (IBD) encompass Crohn's disease and ulcerative colitis, which are diseases characterized by chronic intestinal inflammation. IBD is believed to result from predisposing genetic and environmental factors (specific antigens and pathogen-associated molecular patterns) acting on the immunoregulatory system and causing inflammation of the gastrointestinal mucosa. IBD may be the result of an imbalance of effector (proinflammatory) and regulatory T-cell responses. Three scenarios indicative of the outcome of this balance exist in animal models: balanced effector and regulatory T cells resulting in a normal controlled inflammation; overactive effector T cells resulting in inflammation and disease; and an absence of regulatory T cells resulting in uncontrolled inflammation and severe, aggressive disease. The number of products under study for the treatment of IBD has increased from 3 products and 1 target in 1993 to more than 30 products and more than 10 targets in 2005. The number of products under development and continued investigations into the pathogenesis of IBD emphasize the need to expand clinical research efforts in IBD.

Animals↗
PubMed2004

Infliximab maintenance therapy for fistulizing Crohn's disease.

BACKGROUND: Infliximab, a monoclonal antibody against tumor necrosis factor, is an effective maintenance therapy for patients with Crohn's disease without fistulas. It is not known whether infliximab is an effective maintenance therapy for patients with fistulas. METHODS: We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least three months' duration. Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6. A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54. The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent randomization. RESULTS: The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, P<0.001). At week 54, 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36 percent of patients in the infliximab maintenance group (P=0.009). CONCLUSIONS: Patients with fistulizing Crohn's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.

Adult↗
PubMed2004

Long-term treatment of rectovaginal fistulas in Crohn's disease: response to infliximab in the ACCENT II Study.

BACKGROUND & AIMS: The ACCENT II study (A Crohn's Disease Clinical Trial Evaluating Infiximab in a New Long-term Treatment Regimen in Patients With Fistulizing Crohn's Disease) evaluated the efficacy and safety of infliximab maintenance treatment in patients with fistulizing Crohn's disease. This post hoc analysis was conducted to determine the efficacy and safety of infliximab therapy in women with rectovaginal fistulas. METHODS: All patients received 5 mg/kg infliximab intravenously at weeks 0, 2, and 6. Patients who achieved response at weeks 10 and 14 then were randomized as responders if they had at least 50% of baseline fistulas closed, or as nonresponders, to receive placebo or infliximab 5 mg/kg every 8 weeks through week 54. RESULTS: Of 282 patients in the ACCENT II study, 25 of 138 (18.1%) women had a total of 27 draining rectovaginal fistulas at baseline. After infusions of infliximab at weeks 0, 2, and 6, 60.7% (17 of 28) and 44.8% (13 of 29) of rectovaginal fistulas were closed at weeks 10 and 14, respectively. Among responders, 72.2% (13 of 18) of rectovaginal fistulas were no longer draining at week 14. The duration of rectovaginal fistula closure was longer in the infliximab 5-mg/kg maintenance group (median, 46 wk) than in the placebo group (33 wk). CONCLUSIONS: Infliximab is effective in short-term closure of rectovaginal fistulas and maintenance treatment was more effective than placebo in prolonging rectovaginal fistula closure.

Abdominal Abscess↗