Raymond K. Cross

Nitric oxide in inflammatory bowel disease.

Nitric oxide (NO) is a pleiotropic free radical messenger molecule. There is a large body of evidence that the inducible form of the NO synthase enzyme (iNOS) that is responsible for high-output production of NO from l-arginine is up-regulated in various forms of mucosal inflammation. Consistent with this, multiple detection strategies have demonstrated that iNOS expression, enzymatic activity, and NO production are increased in human inflammatory bowel disease tissues. There is also evidence that the level of iNOS-derived NO correlates well with disease activity in ulcerative colitis, while for Crohns disease, the results are more variable. A substantial number of animal studies have assessed the role of inducible NO production. While the majority of studies have shown improvement in experimental inflammatory bowel disease with iNOS inhibition, there are also a significant number of reports of exacerbation of disease with inhibitors. Similarly, studies using iNOS-deficient mice in colitis models have shown improvement, worsening, or no effect on disease. The authors suggest that additional studies to assess the role of the competing biochemical pathway, namely the conversion of l-arginine to polyamines via the actions of arginase and ornithine decarboxylase, may provide important new insights into understanding the regulation of mucosal inflammation and inflammatory bowel disease.

Antecedent Nonbladder Syndromes in Case-Control Study of Interstitial Cystitis/Painful Bladder Syndrome

OBJECTIVES Probing for clues to the pathogenesis of interstitial cystitis/painful bladder syndrome (IC/PBS), we sought antecedent nonbladder syndromes that distinguished incident IC/PBS cases from matched controls. METHODS Female incident IC/PBS cases were recruited nationally, and their IC/PBS onset date (index date) was established. The controls were recruited by national random digit dialing and matched to the cases by sex, age, region, and interval between the (assigned) index date and interview. The prevalence of 24 nonbladder syndromes before the index date was assessed, 7 by multiple methods. RESULTS The cases with IC/PBS had greater antecedent prevalence of 11 syndromes, and 243 of 313 cases (78%) vs 145 of 313 controls (45%) had multiple syndromes (P < .001). Fibromyalgia-chronic widespread pain (FM-CWP), chronic fatigue syndrome, sicca syndrome, and irritable bowel syndrome were associated with each other by pairwise and factor analyses using numerous assumptions. Cases with FM-CWP, chronic fatigue syndrome, sicca syndrome, and/or irritable bowel syndrome (n = 141, 45%) were more likely to have other syndromes (ie, migraine, chronic pelvic pain, depression, and allergy). Three other syndrome clusters were identified; each was associated with this FM-CWP cluster. CONCLUSIONS Eleven antecedent syndromes were more often diagnosed in those with IC/PBS, and most syndromes appeared in clusters. The most prominent cluster comprised FM-CWP, chronic fatigue syndrome, sicca syndrome, and irritable bowel syndrome; most of the other syndromes and identified clusters were associated with it. Among the hypotheses generated was that some patients with IC/PBS have a systemic syndrome and not one confined to the bladder.

Protective Role of Arginase in a Mouse Model of Colitis

Arginase is the endogenous inhibitor of inducible NO synthase (iNOS), because both enzymes use the same substrate, l-arginase (Arg). Importantly, arginase synthesizes ornithine, which is metabolized by the enzyme ornithine decarboxylase (ODC) to produce polyamines. We investigated the role of these enzymes in the Citrobacter rodentium model of colitis. Arginase I, iNOS, and ODC were induced in the colon during the infection, while arginase II was not up-regulated. l-Arg supplementation of wild-type mice or iNOS deletion significantly improved colitis, and l-Arg treatment of iNOS−/− mice led to an additive improvement. There was a significant induction of IFN-γ, IL-1, and TNF-α mRNA expression in colitis tissues that was markedly attenuated with l-Arg treatment or iNOS deletion. Treatment with the arginase inhibitor S-(2-boronoethyl)-l-cysteine worsened colitis in both wild-type and iNOS−/− mice. Polyamine levels were increased in colitis tissues, and were further increased by l-Arg. In addition, in vivo inhibition of ODC with α-difluoromethylornithine also exacerbated the colitis. Taken together, these data indicate that arginase is protective in C. rodentium colitis by enhancing the generation of polyamines in addition to competitive inhibition of iNOS. Modulation of the balance of iNOS and arginase, and of the arginase-ODC metabolic pathway may represent a new strategy for regulating intestinal inflammation.

Narcotic use in patients with Crohn's disease.

OBJECTIVES:Despite advances in treatment for Crohns disease (CD), some patients suffer from chronic pain. We sought to characterize the prevalence of narcotic use and contributing factors in CD patients at a referral center.METHODS:A retrospective analysis of 291 CD patients followed over a 5-yr period was performed. Clinical status was evaluated with the Harvey–Bradshaw index (HBI) of disease activity and the short inflammatory bowel disease questionnaire (SIBDQ).RESULTS:Narcotic use was identified in 13.1% of patients. Narcotic users were more likely to be female, 72% versus 49% (p = 0.01), had higher rates of disability, 15.4% versus 3.6% (p = 0.001), and a longer duration of disease, 17.0 versus 12.9 yr (p = 0.03). In addition, they took more medications 6.97 versus 4.7 (p < 0.001) and had a higher prevalence of neuropsychiatric drug use, 37% versus 19% (p = 0.01). CD patients receiving narcotics had worse disease activity (HBI 9.1 vs 5.0, p < 0.001) and diminished quality of life (SIBDQ 44.2 vs 51.6 (p = 0.04)). However, logistic regression analysis found that active disease [HBI score of ≥ 4 (OR 3.9)], polypharmacy [use of ≥ 5 drugs (OR 5.5)], and smoking (OR 2.8) were associated with narcotic use.CONCLUSIONS:Narcotic use may be an indicator of more severe disease since it is associated with increased disease activity and decreased quality of life. Factors correlating with narcotic use include smoking and PP. Our data emphasize the need for further work to characterize chronic pain in CD patients.

Randomized, controlled trial of home telemanagement in patients with ulcerative colitis (UC HAT)

Background: Outcomes are suboptimal in ulcerative colitis (UC). Telemedicine for UC is feasible and improves outcomes. Our goals were to evaluate a home telemanagement system for UC (UC HAT) on disease activity, quality of life (QoL), and adherence compared to best available care (BAC) in a randomized, controlled trial. Methods: Adults with UC were randomly assigned to receive UC HAT or BAC for 12 months. UC HAT recruits answered questions regarding disease activity, adherence, side effects, and measured their weight weekly. An educational curriculum was delivered after each session. Alerts and action plans were generated based on the results. BAC underwent routine follow‐up, received written action plans, and were given educational fact sheets. Seo Index scores, Inflammatory Bowel Disease Questionnaire (IBDQ) scores, and adherence rates were compared between UC HAT and BAC at 1 year. Results: Twenty‐five patients were randomized to UC HAT and 22 to BAC. After 12 months, 11 withdrew in UC HAT compared to 5 in BAC. Disease activity, QoL, and adherence were not different between groups at any timepoint postbaseline. Adjusted analyses of trial completers using all available data demonstrated decreased Seo Index (11.9 in UC HAT (P = 0.08) versus 1.2 in BAC (P = 0.84) and increased IBDQ scores (12.5 in UC HAT (P = 0.04) versus to −3.8 in BAC (P = 0.47) from baseline in UC HAT compared to BAC. Conclusions: UC HAT did not improve disease activity, QoL, or adherence compared to BAC after 1 year. After adjustment for baseline disease knowledge, UC HAT trial completers experienced significant gains in disease‐specific QoL from baseline compared to BAC trial completers. Our results suggest a potential benefit of UC HAT. Further research is indicated to determine if telemedicine improves outcomes in patients with IBD. (Inflamm Bowel Dis 2012;)

Feasibility and Acceptance of a Home Telemanagement System in Patients with Inflammatory Bowel Disease: A 6-Month Pilot Study

Our purpose was to assess the acceptance and feasibility of a home telemanagement system (HAT) in inflammatory bowel disease (IBD). The HAT consists of a laptop and a scale. Subjects were required to complete weekly self-testing for 6 months. Disease activity, quality of life, and knowledge were assessed at baseline and 6 months. Attitudinal surveys were completed at 6 months. Twenty-five subjects completed the study. Ninety-one percent of patients thought that self-testing was not complicated. Eighty-six percent said that self-testing did not interfere with their usual activities. Ninety-one percent of patients would consider using a HAT in the future. Adherence with self-testing was 91%. Improvements in disease activity and quality of life, and significant improvements in knowledge, were observed after implementation of the HAT. The HAT is feasible and accepted in IBD. We predict that the HAT will positively affect adherence, monitoring, and patient education, resulting in improved disease activity and quality of life.

Anti-Tumor Necrosis Factor Therapy Is Associated With Infections after Abdominal Surgery in Crohn's Disease Patients

OBJECTIVES:Anti-tumor necrosis factor (anti-TNF) therapy effects on postoperative complications in Crohns disease (CD) patients are unclear. We examined a retrospective cohort to clarify this relationship.METHODS:CD patients followed at a referral center between July 2004 and May 2011 who underwent abdominal surgery were identified. Postoperative complications (major infection, intra-abdominal abscess, peritonitis, anastomotic leak, wound infection, dehiscence, fistula, thrombotic, and death) were compared in patients exposed and unexposed to anti-TNF ≤8 weeks preoperatively. Demographics, surgical history, comorbidities, corticosteroid (CS) and immunomodulator use, Montreal classification, operative details, and preoperative nutritional status were assessed. Multivariate analysis measured the independent effect of preoperative anti-TNF on postoperative complications.RESULTS:Overall, 325 abdominal surgeries were performed; 150 (46%) with anti-TNF ≤8 weeks before surgery. The anti-TNF group developed overall infectious (36% vs. 25%, P=0.05) and a trend toward surgical site complications (36% vs. 25%, P=0.10) more frequently. Major postoperative and intra-abdominal septic complications did not differ between groups. Multivariable analysis showed that preoperative anti-TNF was an independent predictor of overall infectious (odds ratio (OR) 2.43; 95% confidence interval (CI) 1.18–5.03) and surgical site (OR 1.96; 95% CI 1.02–3.77) complications.CONCLUSIONS:In a tertiary referral center, use of anti-TNF therapy in CD patients ≤8 weeks before intestinal resection or any intra-abdominal surgery was independently associated with increases in infectious and surgical complications.

Vedolizumab for the treatment of ulcerative colitis and Crohn’s disease

Crohns disease and ulcerative colitis are chronic, relapsing inflammatory disorders of the GI tract. In both Crohns disease and ulcerative colitis, leukocytic infiltration of the mucosa is associated with epithelial damage. Recently, monoclonal antibodies directed against cell adhesion molecules (CAMs) involved in leukocyte extravasation have been developed. Natalizumab, the first drug brought to market targeting CAMs, is clinically effective but is associated with serious adverse effects including the uncommon, but often fatal, neurological disease progressive multifocal leukoencephalopathy. Vedolizumab targets a subset of the CAMs blocked by natalizumab and is currently in Phase III trials to study its efficacy and safety in patients with inflammatory bowel disease. Here, we discuss the current treatment options available for patients with Crohns disease or ulcerative colitis, the history of CAM inhibitors, the current state of development of vedolizumab and its future role in inflammatory bowel disease, if approved by regulatory agencies.

Acceptance of telemanagement is high in patients with inflammatory bowel disease.

Goals Assess acceptance and attitudes regarding telemanagement (HAT) in patients with inflammatory bowel disease (IBD). Background Noncompliance is a barrier to successful outcomes in patients with IBD. Novel methods for monitoring and assessing compliance are needed. Study HAT consists of a laptop connected to a weight scale. HAT prompts patients to respond to questions about symptoms, medication side effects, and compliance. Ten consecutive adult patients with IBD were trained to use HAT. Attitudinal surveys and structured qualitative interviews were performed at the end of the session. Results Twenty percent of patients had never used a computer at home. All patients reported that use of the computer and self-testing was not complicated. All patients reported that the symptom diary and questions on side effects were easy to answer. All patients reported that self-testing took little time. Eighty percent said that testing would not interfere with usual activities, that they could comply with testing 3 times/wk, and that they would agree to use the system in the future. Conclusions Improved methods of monitoring are needed for patients with IBD. Patients with IBD can be easily trained to use HAT, and patient acceptance is high. Further studies are needed to determine the clinical impact of HAT in IBD.

Racial differences in disease phenotypes in patients with Crohn's disease

Background: Our objectives were to assess the differences in perforating disease behavior, disease severity, and extraintestinal manifestations (EIM) in patients with Crohns disease (CD) by race. Materials and Methods: We identified outpatients with CD evaluated at the University of Maryland Gastroenterology Faculty Practice office or the Baltimore Veterans Affairs Maryland Health Care System, from 1997 to 2005. We assessed age at diagnosis, disease behavior, disease location, need for surgery and EIM. Results: Race was not associated with perforating disease behavior (relative risk [RR] 0.79, 95% confidence interval [CI] 0.46‐1.35), need for surgery (RR 0.89, 95% CI 0.56‐1.12), and EIM of CD (RR 0.77, 95% CI 0.46‐1.27). White patients were significantly more likely to have ileal disease, whereas African American patients were significantly more likely to have ileocolonic and colonic disease. Age at diagnosis younger than 40 years (odds ratio [OR] 4.41, 95% CI 1.84‐10.56) and ileocolonic disease (OR 2.39, 95% CI 1.24‐4.63) were independent risk factors for perforating disease behavior. Similarly, age at diagnosis younger than 40 (OR 2.79, 95% CI 1.45‐5.33), ileal disease (OR 3.76, 95% CI 1.66‐8.48), and ileocolonic disease (OR 2.57, 95% CI1.21‐5.46) were associated with the need for surgery. Female gender (OR 4.23, 95% CI 1.87‐9.58) and a positive family history of CD (OR 3.45, 95% CI 1.49‐8.0) were associated with joint manifestations of CD. Discussion: We did not detect differences in disease behavior, severity, or joint EIM by race. Although African American patients were more likely to have ileocolonic or colonic disease, these factors did not affect disease behavior or severity.