Gary Wild

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.

Patient nonadherence to medication in inflammatory bowel disease

OBJECTIVE:The aim of this study was to identify determinants of nonadherence to medication in outpatients with established inflammatory bowel disease (IBD).METHODS:Ten gastroenterologists and 153 of their IBD patients participated in this prospective study. Demographic, clinical, and psychosocial characteristics, as well as patient-physician discordance, were assessed at an office visit. Nonadherence to medication was assessed 2 wk later. Separate generalized estimating equations were used to identify determinants of nonadherence.RESULTS:Physicians averaged 47.9 yr in age (range 30.1–57.5 yr), and 90% were male. Patients averaged 37.0 yr (SD = 15.1), and 87 (56.9%) were female. In all, 63 patients (41.2%) were nonadherent to medication; of these, 51 (81.0%) indicated unintentional nonadherence, 23 (36.5%) intentional nonadherence, and 11 (17.5%) both. Overall nonadherence was predicted by disease activity (OR = 0.55, p = 0.0022), new patient status (OR = 2.14, p = 0.0394), disease duration (OR = 0.50, p = 0.0001), and scheduling a follow-up appointment (OR = 0.30, p = 0.0059), whereas higher discordance on well-being was predictive only in psychologically nondistressed patients (p = 0.0026 for interaction). Unintentional nonadherence was predicted by age (OR = 0.97, p = 0.0072), new patient status (OR = 2.80, p = 0239), and higher discordance on well-being in psychologically nondistressed patients (p = 0.0504). Intentional nonadherence was predicted by disease duration (OR = 0.55, p = 0032), scheduling a follow-up appointment (OR = 0.12, p = 0.0001), certainty that medication would be helpful (OR = 0.99, p = 0.0409), and total patient-physician discordance (OR = 1.59, p = .0120).CONCLUSIONS:These findings suggest that the therapeutic relationship, as well as individual clinical and psychosocial characteristics, influence adherence to medication.

CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure.

The caspase recruitment domain gene (CARD15) was recently identified as the underlying gene associated with the IBD1 locus that confers susceptibility to Crohn disease (CD). CARD15 is related to the NOD1/Apaf-1 family of apoptosis regulators, and three sequence variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) in the gene were demonstrated to be associated with CD. We collected a cohort of 231 patients with CD and 71 healthy control individuals from the Canadian province of Quebec, to determine the prevalence of these sequence variants in an independent population. Clinical records of all patients were systematically reviewed, and detailed phenotypic information was obtained. All patient DNA samples were genotyped for the three variants, thus enabling an analysis of genotype-phenotype correlations. In this cohort, 45.0% of patients with CD carried at least one variant in the CARD15 gene, compared with 9.0% of control individuals (P<10-7). Allele frequencies of Arg702Trp, Gly908Arg, and Leu1007fsinsC were 12.9%, 5.2%, and 10.3% in patients with CD, compared with 4.2%, 0.7%, and 0.7% in control individuals, respectively. Importantly, CARD15 mutants were seen with equal frequency in patients with familial and sporadic CD. Analysis of the relationship between genotype and phenotype convincingly demonstrates that CARD15 variants are significantly associated with ileal disease involvement, as opposed to strictly colonic disease (P<.001). Moreover, we were able to determine the haplotype structure surrounding this disease gene by genotyping 45 single-nucleotide polymorphisms (SNPs) in a 177-kb region that contained the CARD15 gene. This structure helps clarify the history of these causal mutations. Finally, this analysis shows that CARD15 involvement with CD is detectable by use of publicly available SNPs alone.

Treatment of Active Crohn's Disease With MLN0002, a Humanized Antibody to the α4β7 Integrin

BACKGROUND & AIMS Selective blockade of lymphocyte-vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the alpha4beta7 integrin, in patients with active Crohns disease. METHODS Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (>or=70-point decrement in the Crohns Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score <or=150) and with an enhanced clinical response (>or=100-point decrement in CDAI). Human anti-human antibody levels were measured. RESULTS Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively (P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohns disease. CONCLUSIONS This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohns disease.

Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic Whites: characterization of a large North American cohort.

OBJECTIVES:Inflammatory bowel disease (IBD), comprising primarily of Crohns disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population.METHODS:Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions.RESULTS:African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4–5.5), colorectal disease (OR = 1.9; 95% CI: 1.1–3.4), perianal disease (OR = 1.7; 95% CI: 1.03–2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32–0.96). They were also at higher risk for uveitis (OR = 5.5; 95% CI: 2.3–13.0) and sacroiliitis (OR = 4.0; 95% CI: 1.55–10.1). Hispanics had higher prevalence of perianal CD (OR = 2.9; 95% CI: 1.8–4.6) and erythema nodosum (3.3; 95% CI: 1.7–6.4). Among UC patients, Hispanics had more proximal disease extent. Both African American and Hispanic CD patients, but not UC patients, had lower prevalences of family history of IBD than their white counterparts.CONCLUSIONS:There are racial differences in IBD family history, disease location, and EIMs that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. These findings underscore the need for further studies in minority populations.

Predicting relapse in Crohn’s disease: a biopsychosocial model

Background: Crohn’s disease (CD) is a chronic relapsing inflammatory bowel disorder. Both biological and psychosocial factors may modulate the illness experience. Aim: The aim of this study was to identify clinical, biological and psychosocial parameters as predictors of clinical relapse in quiescent CD. Methods: Patients in medically induced remission were followed prospectively for 1 year, or less if they relapsed. Disease characteristics were determined at baseline. Serum cytokines, anti-Saccharomyces cerevisiae antibodies, C-reactive protein (CRP), erythrocyte sedimentation rate and intestinal permeability were measured every 3 months. Psychological distress, perceived stress, minor life stressors and coping strategies were measured monthly. A time-dependent multivariate Cox regression model determined predictors of time to relapse. Results: 101 patients (60 females, 41 males) were recruited. Fourteen withdrew and 37 relapsed. CRP (HR = 1.5 per 10 mg/l, 95% CI 1.1 to 1.9, p = 0.007), fistulising disease (HR = 3.2, 95% CI, 1.1 to 9.4, p = 0.04), colitis (HR = 3.5 95% CI 1.2 to 9.9, p = 0.02) and the interaction between perceived stress and avoidance coping (HR = 7.0 per 5 unit increase for both scales, 95% CI 2.3 to 21.8, p = 0.003) were predictors of earlier relapse. Conclusions: In quiescent CD, a higher CRP, fistulising disease behaviour and disease confined to the colon were independent predictors of relapse. Moreover, patients under conditions of low stress and who scored low on avoidance coping (ie, did not engage in social diversion or distraction) were least likely to relapse. This study supports a biopsychosocial model of CD exacerbation.

Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial.

Background: An uncontrolled pilot study demonstrated that daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), might be effective for the treatment of active ulcerative colitis. Methods: A randomised, double blind, placebo controlled trial was conducted to evaluate the efficacy of daclizumab induction therapy in patients with active ulcerative colitis. A total of 159 patients with moderate ulcerative colitis were randomised to receive induction therapy with daclizumab 1 mg/kg intravenously at weeks 0 and 4, or 2 mg/kg intravenously at weeks 0, 2, 4, and 6, or placebo. The primary end point was induction of remission at week 8. Remission was defined as a Mayo score of 0 on both endoscopy and rectal bleeding components and a score of 0 or 1 on stool frequency and physician’s global assessment components. Response was defined as a decrease from baseline in the Mayo score of at least 3 points. Results: Two per cent of patients receiving daclizumab 1 mg/kg (p = 0.11 v placebo) and 7% of patients receiving 2 mg/kg (p = 0.73) were in remission at week 8, compared with 10% of those who received placebo. Response occurred at week 8 in 25% of patients receiving daclizumab 1 mg/kg (p = 0.04) and in 33% of patients receiving 2 mg/kg (p = 0.30) versus 44% of those receiving placebo. Daclizumab was well tolerated. The most frequently reported adverse events in daclizumab treated patients compared with placebo treated patients were nasopharyngitis (14.6%) and pyrexia (10.7%). Conclusion: Patients with moderate ulcerative colitis who are treated with daclizumab are not more likely to be in remission or response at eight weeks than patients treated with placebo.

Psychological distress, social support, and disease activity in patients with inflammatory bowel disease.

OBJECTIVES:The objectives of this study were to compare the psychological status of patients in active and inactive disease states, to assess social support, and to identify correlates of psychological distress in patients with inflammatory bowel disease (IBD).METHODS:This cross-sectional study was conducted in 200 patients (mean age 36.7 yr [SD = 14.8], 119 [59.5%] female) with long-standing IBD who were seen in tertiary care. Psychosocial assessments included psychological distress (Symptom Checklist-90R), social support (Social Support Questionnaire-6), perceived stress (Perceived Stress Scale-10), and recent minor stressful events (Weekly Stress Inventory). Disease activity was assessed with the Harvey Bradshaw Index.RESULTS:Patients reported higher levels of satisfaction with social support and smaller network sizes compared with normative values. Using multiple linear regression, the independent correlates of psychological distress (p = 0.0001; adjusted R2= 0.62) were as follows: active disease (p = 0.0234), less time since diagnosis (p = 0.0012), and greater number (p = 0.0001) and impact of stressful events (p = 0.0003). A statistically significant interaction term (p = 0.0171) revealed that the relationship between psychological distress and perceived stress changes depending on the level of satisfaction with social support. For patients with low levels of perceived stress, satisfaction with social support did not affect levels of psychological distress. However, for patients who experienced moderate to high levels of perceived stress, high satisfaction with social support decreased the level of psychological distress.CONCLUSIONS:These findings suggest that strategies aimed at improving social support can have a favorable impact on psychological distress and, ultimately, can improve health outcomes in patients with IBD.

Short-Chain Fatty Acids Increase Proglucagon and Ornithine Decarboxylase Messenger RNAs After Intestinal Resection in Rats

BACKGROUND Intestinal adaptation is a complex physiological process that is not completely understood. Systemic administration of short-chain fatty acids (SCFAs) has been shown to facilitate adaptation to small bowel resection; however the mechanisms underlying this phenomena are unknown. METHODS Forty-six male Sprague-Dawley rats underwent an 80% jejunoileal resection and jugular catheterization. After surgery, rats were randomly assigned to receive standard total parenteral nutrition (TPN) or an isoenergetic, isonitrogenous TPN supplemented with SCFAs. On day 3 or 7 after surgery, ileal samples were removed for determination of mucosal wet weight, DNA, RNA, and protein concentrations. Total cellular RNA was extracted for use in Northern blot analysis to quantify proglucagon and ornithine decarboxylase messenger RNAs (mRNAs). RESULTS Total, mucosal, and submucosal weights were increased (p < .05) in the SCFA group both 3 and 7 days after surgery. Ileal DNA and RNA concentrations were increased (p < .05) in the SCFA group at both time points; however ileal protein concentration did not differ between groups until 7 days after resection. Levels of proglucagon and ornithine decarboxylase messenger RNAs were higher (p < .05) in the SCFA group at both time points. CONCLUSION The upregulation of proglucagon and ornithine decarboxylase gene expression may be the mechanism by which SCFAs facilitate intestinal adaptation.

Scalloped Valvulae Conniventes: An Endoscopic Marker of Celiac Sprue

The finding, in a patient with celiac sprue, of a characteristic change at endoscopy (scalloping of the valvulae conniventes, event on close inspection, but forming only a mosaic pattern from a distance) led to an endoscopic survey designed to define its incidence. In a series of 28 sequential patients found to have microscopic changes characteristic of sprue on biopsy, distinctive endoscopic changes were found in 22 (in 6 of 9 with sprue in relapse, and 16 of 19 presenting with initial symptoms). The finding of the distinctive appearance provides an endoscopically recognizable pattern that can be associated with sprue. It also provides the potential for early recognition of the process in patients in whom the diagnosis might otherwise have been delayed due to a lack of substantial evolution of the usually associated symptom complex.