James Rochon

Methotrexate for the Treatment of Crohn's Disease

BACKGROUND Although corticosteroids are highly effective in improving symptoms of Crohns disease, they may have substantial toxicity. In some patients, attempts to discontinue corticosteroids are unsuccessful. METHODS We conducted a double-blind, placebo-controlled multicenter study of weekly injections of methotrexate in patients who had chronically active Crohns disease despite a minimum of three months of prednisone therapy. Patients were randomly assigned to treatment with intramuscular methotrexate (25 mg once weekly) or placebo for 16 weeks. The patients also received prednisone (20 mg once a day), which was tapered over 10 weeks unless their condition worsened. The primary outcome measure was clinical remission at the end of the 16-week trial. Remission was defined by the discontinuation of prednisone and a score of < or = 150 points on the Crohns Disease Activity Index. RESULTS A total of 141 patients were randomly assigned in a 2:1 ratio to methotrexate (94 patients) or placebo (47 patients). After 16 weeks, 37 patients (39.4 percent) were in clinical remission in the methotrexate group, as compared with 9 patients (19.1 percent) in the placebo group (P = 0.025; relative risk, 1.95; 95 percent confidence interval, 1.09 to 3.48). The patients in the methotrexate group received less prednisone overall than those in the placebo group (P = 0.026). The mean (+/- SE) score on the Crohns Disease Activity Index after 16 weeks of treatment was significantly lower in the methotrexate group (162 +/- 12) than in the placebo group (204 +/- 17, P = 0.002). The changes in quality-of-life scores and serum orosomucoid concentrations were similar. In the methotrexate group, 16 patients (17 percent) withdrew from treatment because of adverse events (including asymptomatic elevation of serum aminotransferase in 7 and nausea in 6), as compared with 1 patient (2 percent) in the placebo group. CONCLUSIONS In a group of patients with chronically active Crohns disease, methotrexate was more effective than placebo in improving symptoms and reducing requirements for prednisone.

Quality of life: A valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease

BACKGROUND/AIMS Quality of life (QOL), a subjective index of health perception and function, embraces physical, social, and emotional performance but has not had a prominent role in clinical trials of inflammatory bowel disease (IBD). To test the robustness of the Inflammatory Bowel Disease Questionnaire (IBDQ), a disease-specific QOL index, this study assessed its validity, reliability, and responsiveness during a multicenter trial. METHODS Three hundred five patients with stable Crohns disease received cyclosporin or placebo for 18 months. IBDQ and dimensional scores (bowel, social, systemic, and emotional) were correlated with disease activity (Crohns disease activity index [CDAI] and Harvey-Bradshaw index). Concordance of IBDQ scores was tested in 280 stable subjects. Linear regression evaluated change in IBDQ scores over time. RESULTS IBDQ scores correlated highly with CDAI (r = -0.67; P < 0.0001). The reliability coefficient for IBDQ score was 0.70 vs. 0.66 for CDAI and 0.55 for Harvey-Bradshaw index. Regression line slopes of IBDQ scores were significantly different in patients who deteriorated from those who remained stable ([b] < 0.15; P < 0.0001). QOL scores were lower in patients who required surgery. CONCLUSIONS The IBDQ is a valid reliable assessment tool that reflects important changes in the health status of patients with IBD. The IBDQ is a robust measure of therapeutic efficacy and should be used in future clinical trials in IBD.

Low-Dose Cyclosporine for the Treatment of Crohn's Disease

BACKGROUND Long-term corticosteroid therapy for Crohns disease is associated with important types of morbidity, such as osteoporosis. Safe and effective alternative treatments are required. Although a short-term benefit of cyclosporine in active Crohns disease has been suggested, the long-term safety and efficacy of this treatment have not been established. METHODS We conducted a randomized, double-blind, placebo-controlled evaluation of the effect of 18 months of low-dose cyclosporine treatment on the course of Crohns disease. Adult patients whose disease had been active within the previous two years were randomly assigned to receive cyclosporine (151 patients) or placebo (154 patients) in addition to their usual therapy. Randomization was stratified according to center and score on the Crohns Disease Activity Index (193 patients had scores of 150 or less, and 112 had scores greater than 150). The primary outcome measure was clinically important worsening of Crohns disease, defined as a 100-point increase in the Crohns Disease Activity Index from the patients base-line value. Secondary outcomes were the use of prednisone and 5-amino-salicylates, mean score on the Crohns Disease Activity Index and mean quality-of-life score, and the need for surgery. RESULTS The condition of more patients worsened with cyclosporine than with placebo (91 of 151, or 60.3 percent, vs. 80 of 154, or 51.9 percent; P = 0.10). The median time to worsening of disease in patients receiving cyclosporine was 338 days, as compared with 492 days in patients receiving placebo (P = 0.25; relative risk, 1.22; 95 percent confidence interval, 0.86 to 1.72). Analyses of the mean Crohns Disease Activity Index and quality-of-life scores and of the use of prednisone and 5-aminosalicylates also failed to demonstrate benefit. CONCLUSIONS In our patient population, the addition of low-dose cyclosporine to conventional treatment for Crohns disease did not improve symptoms or reduce requirements for other forms of therapy.

Survival of cadaveric renal transplant grafts from young donors and in young recipients

Evidence from multicenter registries has suggested that cadaveric renal graft survival is poorer when either the recipient or the donor is very young. We therefore analyzed our results from a single pediatric center. There was a significant correlation between greater recipient age and improved cadaveric graft (P=0.002) and patient (P=0.0009) survival. The age of the donor also appeared important, particularly in very young children, but became less so as donor age rose. Forty-four percent of recipients under 3 years old who received cadaveric kidneys from donors less than 4 years old lost their grafts as a result of renal thrombosis, ischemia, or technical problems, compared with only 3% of recipients over 9 years of age, whose grafts came from donors who were also over 9 years. The 1-year first cadaveric graft survival rates for these two age groups were 33% and 82% respectively. Our experience confirms the poor findings reported in very young recipients and with very young donors.

Supplementing the Intent-to-Treat Analysis: Accounting for Covariates Observed Postrandomization in Clinical Trials

Abstract A problem that arises frequently in the analysis of clinical trials is accounting for covariates observed postrandomization. Two examples are patient compliance measured through pill counts and the dose of a concomitant medication. Typically these are measured concurrently with the primary endpoint at the regularly scheduled follow-ups during the course of the study. To account for these effects, the confounders are sometimes introduced as time-dependent covariates into the statistical model. But there are conceptual and statistical difficulties with this approach. In this article we adopt the view that because the confounder is observed postrandomization, it must be considered as an endpoint in its own right. A seemingly unrelated regression (SUR) model is proposed to relate the two sets of repeated measures to important explanatory variables, and a vector autoregressive moving average (ARMA) time series model is used to characterize the disturbance terms within and across the two series. This a...

ARMA Covariance Structures with Time Heteroscedasticity for Repeated Measures Experiments

Abstract Rochon and Helms (1989) presented a model for analyzing repeated measures experiments. The general linear model was used to assess the influence of covariate information, and ARMA time series models were put forward to characterize the covariance matrix among the repeated measures. Practical experience has suggested, however, that the ARMA assumption of constant variances and autocovariances over time is too restrictive for many applications. For example, observations may be relatively stable toward the beginning of the study but become more variable toward the end. This article presents a modification to this structure, which provides for heteroscedasticity over time. Maximum likelihood (ML) estimation procedures are considered, and the estimators are found to enjoy optimal large sample properties. A scoring algorithm is described for iterating to a solution of the ML equations. The model is illustrated with data from a clinical trial investigating human erythropoietin for treating anemia in end...

Length of stay, short stay units and psychiatric emergency admissions.

Length of stay information was collected from 1,364 individuals over a one year period for five general hospitals in a major metropolitan area. The current set of data represents homogeneity in the nature of admissions and the type of facilities examined. Three of the hospitals operated short stay units. Significant differences in the total length of stay were observed according to age, sex and presence of psychosis but there were no unequivocal distinctions between short stay and conventional hospitals.

A Genome-Wide Association Study Identifies Potential Susceptibility Loci for Hepatotoxicity Due to Various Drugs

Idiosyncratic drug-induced liver injury (DILI) is a leading cause of morbidity and mortality due to medication use yet is poorly studied, in part, due to its low incidence in the general population. Identification of genetic variants associated with these uncommon and difficult to diagnose adverse events could provide clues to underlying mechanisms. Hypothesis: Common genetic variants exist that contribute to DILI susceptibility from multiple drugs. Methods: DNA obtained from 783 individuals of European ancestry who experienced DILI attributed to >200 individual drugs were genotypedwith the Illumina 1Mor 1Mduo beadchip. Source of DNA samples included the following DILI registries: DILIN (401), DILIGEN (242), EUDRAGENE (89), and Malaga (51). Genome Wide Association (GWA) was performed using population controls (n=3001). Potential associations were tested for replication in 190 independent cases from DILIN. Results: GWA revealed a strong association within the MHC region (p 108), which did not replicate in validation cohorts composed of sufficient cases due to the same drug or class. Conclusion: Our replicated association between hepatocellular DILI and STAT4 supports the emerging role of the immune system in DILI susceptibility and suggests that common genetic variation may contribute to DILI susceptibility from multiple drugs. However, the generally negative GWA results suggest that there may be a preponderance of drug-specific genetic risk factors and/or rare genetic variation underlying DILI susceptibility. Therefore, we have begun whole exome and whole genome sequencing of DILI cases caused by the most frequent drugs in our cohorts in search of rarer, high-penetrance drug-specific risk factors.

S1590 Immuno-Allergic (I-a) Manifestations of Drug-Induced Liver Injury (DILI) in the USA. Results from the Prospective Study of the DILI Network

Aim: Cytochrome P450 3A is the most important drug metabolizing enzyme in humans and nearly 40% of its activity is located in the small bowel. We have previously shown that intestinal CYP3A activity is markedly diminished in cirrhotics with transjugular intrahepatic portasystemic shunts (TIPS) and this leads to markedly increased bioavailability of orally administered CYP3A substrates and may lead to adverse effects. We conducted a study to test the hypothesis that oral CYP3A substrates with QT prolonging effect cause abnormal prolongation of QT interval in cirrhotics with TIPS. Methods: 23 subjects (9 controls, 8 cirrhotics with TIPS and 6 cirrhotics without TIPS) participated in this study. Subjects with cirrhosis and TIPSS were matched for age, gender, race and BMI. The mean age ± SD was 52 ± 9 years, 9 females and 6 African American. Oral erythromycin (ERY), a CYP3A substrate known to prolong QT interval in humans, was administered to test the relationship between diminished small bowel CYP3A activity and QT prolongation by oral medications. It was dosed at 500 mg PO BID for 7 days. EKGs (n=32) were obtained from each subject at baseline and after administration of ERY on day 1 and day 7 at scheduled intervals (over 24 hours) on each study day. QT intervals were measured in 3 consecutive beats in two leads and corrected QT interval (QTc) was obtained by fredericia correction and simple regression analysis. Primary outcome measure is maximal QTc change (QTc Max δ) after ERY administration on day 1 and day 7 in comparison to pre-drug administration baseline. The changes in QTc are compared among the three patient groups using ANOVA according to day 1 and day 7. Results: There was no statistically significant difference among the three groups in QTc Max δ following the first dose of ERY (p=0.8) on day 1. However, cirrhotics with TIPS had significantly greater QTc Max δ than other two groups following 7-days of oral ERY administration (p= 0.0271), irrespective of correction formula. Summary: Cirrhotic Patients with TIPS had significantly greater prolongation in QTc following multiple doses of erythromycin than cirrhotics without TIPS. Conclusion: Cirrhotics with TIPS are more prone for adverse events such QT prolongation by oral medications that are metabolized by small bowel CYP3A. The maximal QTc change (mean± SE) (QTc Max δ) milliseconds in each group on day 1 and on day 7 of oral erythromycin 500 mg twice daily.