Kevin McHugh

Experimental colitis alters myenteric nerve function at inflamed and noninflamed sites in the rat

BACKGROUND & AIMS Studies in inflammatory bowel disease have shown extensive structural abnormalities in the enteric nervous system of inflamed and noninflamed gut; however, functional correlates are lacking. The aim of this study was to determine the effect of colitis on myenteric nerve function at inflamed and noninflamed sites in rat intestine. METHODS Tritiated noradrenaline release was measured from longitudinal muscle myenteric plexus preparations from the distal and transverse colon and terminal ileum of rats with colitis induced by trinitrobenzene sulfonic acid or Trichinella spiralis larvae. RESULTS As characterized by myeloperoxidase activity and histology, both models induced inflammation restricted to the distal colon. In distal colon in trinitrobenzene sulfonic acid colitis, KCl- or electrical field stimulation-evoked 3H release was suppressed by 56% and 60%, respectively; in T. spiralis-infected rats, the KCl-evoked release was suppressed by 58%. 3H release was also suppressed by similar magnitudes in noninflamed transverse colon and terminal ileum of each model. CONCLUSIONS Experimental distal colitis alters myenteric nerve function in inflamed distal colon and noninflamed gut regions. These changes are independent of the manner in which colitis is induced and provide a basis for the extensive disruption of physiological function observed in inflammatory bowel disease.

Previous inflammation alters the response of the rat colon to stress

BACKGROUND & AIMS Patients with inflammatory bowel disease have symptoms of irritable bowel syndrome (IBS) with a higher than expected prevalence. Stress is an important factor in the pathogenesis of IBS. Thus, previous inflammation may predispose to IBS by rendering the bowel more susceptible to the impact of stress. The aim of this study was to examine the effect of previous colitis on stress-induced responses in rats. METHODS Acute colitis was induced in rats by intrarectal administration of trinitrobenzene sulfonic acid (TNBS), and the rats were allowed to recover for 6 weeks before application of mild restraint stress for 3 consecutive days. In vitro measurements included myeloperoxidase activity, plasma corticosterone levels, interleukin 1 beta messenger RNA expression, and [3H]noradrenaline release from the myenteric plexus. RESULTS Six weeks after administration of TNBS, stress caused a significant increase in myeloperoxidase activity in TNBS-treated rats but not in stressed controls; plasma corticosterone responses were similar. Stress also caused an exaggerated and significant suppression of [3H]noradrenaline release in TNBS-treated stressed rats compared with stressed controls. This was accompanied by a significant decrease in interleukin 1 beta messenger RNA expression in the colon. CONCLUSIONS Previous colitis rendered the colon more susceptible to effects of stress on enteric nerve function and also increased some parameters of inflammation in response to stress.

On the specificity of altered muscle function in experimental colitis in rats.

BACKGROUND Studies on muscle contraction in colitis yield conflicting data that may reflect differences in the manner in which colitis is induced. Therefore, we compared distal colonic longitudinal muscle contraction in four models of colitis in the rat. METHODS Distal colitis was induced by intrarectal administration of trinitrobenzene sulfonic, acetic acid, or Trichinella spiralis larvae, or by intraperitoneal injection of mitomycin C. Colonic myeloperoxidase activity was used to monitor acute inflammation. RESULTS Myeloperoxidase activity increased in each model of colitis. In trinitrobenzene-treated rats, contractile responses to carbachol, substance P, and KCl decreased by 64%, 76%, and 58%, respectively. In acetic acid treated rats, responses induced by carbachol, substance P, or KCl were each significantly decreased by 73%, 68%, and 55% and were similarly reduced by 42%, 77%, and 46%, respectively, in rats with T. spiralis colitis. In mitomycin-induced colitis, these respective responses also decreased significantly by 71%, 55%, and 54%. CONCLUSION Decreased contractility of longitudinal muscle in acute colitis in rats is independent of the manner in which the colitis is induced and is mediated at a receptor-independent locus on the muscle cell.

The mechanism of altered neural function in a rat model of acute colitis

BACKGROUND & AIMS Distal colitis induced in rats by trinitrobenzene sulfonic acid (TNBS) causes a suppression of [3H]noradrenaline release from the myenteric plexus, of inflamed distal colon, as well as in noninflamed regions of colon and ileum. The aim of this study was to explore the mechanisms underlying these neural changes in TNBS colitis. METHODS Colitis was induced by intrarectal administration of TNBS, and the animals were killed on day 5. Inflammation was assessed by measuring myeloperoxidase (MPO) activity, and noradrenaline release was measured as 3H release from rats myenteric plexus preparations preloaded with [3H]noradrenaline. These end points were examined: (1) after administration of the locally active steroid budesonide; (2) in congenitally athymic rats; and (3) in rats treated with the interleukin 1 receptor antagonist (IL-1ra) to interleukin 1 beta. RESULTS In colitis, both topical budesonide and systemic IL-1ra treatments attenuated the suppression of KCl-evoked 3H release from longitudinal muscle myenteric plexus in both inflamed and noninflamed segments. However, neither of these treatments altered MPO activity. A similar suppression of [3H]noradrenaline release was observed in athymic rats after TNBS, although there was a substantially greater increase in MPO activity compared with euthymic rats with colitis. CONCLUSIONS TNBS-induced colitis alters myenteric nerve function at inflamed and noninflamed sites via a steroid-sensitive and interleukin 1-mediated process that does not require T lymphocytes.

Efficacy and safety of adalimumab in Canadian patients with moderate to severe Crohn’s disease: Results of the Adalimumab in Canadian SubjeCts with ModErate to Severe Crohn’s DiseaSe (ACCESS) trial

OBJECTIVE To evaluate open-label adalimumab therapy for clinical effectiveness, fistula healing, patient-reported outcomes and safety in Canadian patients with moderate to severe Crohns disease (CD) who were either naive to or previously exposed to antitumour necrosis factor (anti-TNF) therapy. METHODS Patients with moderate to severe CD (CD activity index [CDAI] score of greater than 220, or Harvey-Bradshaw index [HBI] of 7 or greater) were eligible. Patients received open-label adalimumab as induction (160 mg and 80 mg subcutaneously [sc]) at weeks 0 and 2, respectively and maintenance (40 mg sc every other week) therapy. At or after eight weeks, patients with flare or nonresponse could have their dosage increased to 40 mg sc weekly. Patients were followed for a minimum of six months or until adalimumab was commercially available in Canada. RESULTS Of the 304 patients enrolled, 160 were infliximab experienced, while 144 were anti-TNF naive. HBI remission (HBI score of 4 or lower) at week 24 was achieved by 53% of anti-TNF-naive and 36% of infliximab-experienced patients (P<0.01; P<0.001 for both groups for all visits versus baseline). Fistula healing rates at week 12 were 48% for anti-TNF-naive patients, and 26% for infliximab-experienced patients. At week 24, fistula healing rates were significantly greater for the anti-TNF-naive group (60% versus 28%; P<0.01). Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients. Serious infections occurred in 2% of patients. CONCLUSIONS Adalimumab therapy induced and sustained steroidfree remission in both infliximab-experienced and anti-TNF-naive patients with moderate to severe CD. Clinically meaningful rates of fistula healing were also observed. Improvements in patient-reported outcomes were sustained throughout the 24-week study period.

Self-reported awareness and use of the International Classification of Diseases coding of inflammatory bowel disease services by Ontario physicians.

RATIONALE Population and health services research can be performed by linkage analysis of administrative data. However, the robustness of study results is determined by the accuracy of the diagnostic coding. OBJECTIVES To estimate the awareness, use and accuracy of the International Classification of Diseases, Ninth Revision (ICD-9) coding by physicians providing services for patients with Crohns disease (CD) and ulcerative colitis (UC). METHODS All Ontario gastroenterologists and a 10% random sample of internists, pediatricians, pediatric or general surgeons, and family physicians were surveyed by postal questionnaire to estimate the frequency and 95% CI of using codes 555 or 556 when billing for CD- and UC-related services, respectively. c2 tests were used for between-group comparisons. RESULTS Of the physicians who were surveyed, 67.7% (416 of 614) responded; 258 of 391 (66%) who were still practising in Ontario saw patients with inflammatory bowel disease (IBD), and 54% had more than 10 IBD patients; 86.5% (95% CI 82.4% to 90.6%) were familiar with ICD-9 codes, and 91.4% (95% CI 88.1% to 95.6%) used the codes 555 (CD) or 556 (UC) for billing. Rates of ICD-9 use did not differ by sex but were used more frequently by those graduating after 1981 (P<0.02). Gastroenterologists used ICD-9 IBD codes 555 or 556 significantly more often than all other physicians (P=0.001). Most (more than 75%) Ontario physicians used ICD-9 IBD codes always or frequently when billing for IBD-related services. Few (10%) used these codes to bill for non-IBD-related problems. CONCLUSIONS These data suggest that there is acceptable use and accuracy of ICD-9 diagnostic coding for CD and UC services - comparable with results from studies of other diseases. Administrative data may thus be used to undertake epidemiological studies in IBD in Ontario.

The establishment of a national tissue bank for inflammatory bowel disease research in Canada.

The Crohns and Colitis Foundation of Canada (CCFC) has established a national bank for tissue, serum and blood from patients with inflammatory bowel disease (IBD). Investigators from across the country submit material to the bank together with clinical data. Investigators may access their own patient information from the bank for their own study purposes, but the distribution of tissue is restricted to specific CCFC-funded projects. Currently, tissues are being collected from newly diagnosed, untreated IBD patients to support a recent initiative aimed at characterizing microbes in colonic and ileal biopsies from such patients. In the future, criteria for the submission of tissue will be tailored to specific research questions. This bank is believed to be the first national bank of its kind dedicated to research in Crohns disease and ulcerative colitis

W1097 Steroid-Free Remission and Fistula Closure in Adalimumab-Treated Patients with Moderate to Severe Crohn's Disease: the Access Trial

BACKGROUND: Natalizumab (NAT), a monoclonal antibody to α4-integrin, was recently approved by the FDA for use in the treatment of moderate to severe Crohns disease (CD). AIM: To prospectively report the clinical outcomes and safety in patients (pts) treated with NAT at a tertiary care IBD center. METHODS: Eighteen pts with moderate to severe CD treated in clinical practice with intravenous NAT every 4 weeks were enrolled in a registry. Patients were assessed for clinical response to NAT (categorized as complete response [CR], partial response [PR], or no response [NR]), steroid reduction, and adverse events (AE). RESULTS: The median age of this group was 43.5 years (range 20-63) with median disease duration of 13 years (range 3-43). All patients had failed prior anti-TNF therapy (median of 2 agents). Twelve pts (67%) had ileocolonic CD at diagnosis and 5 (28%) had undergone colectomy prior to NAT. The median follow-up was 88 days (range 3-219). Two pts had screening brain MRI or CT prior to NAT. Pts received one to eight infusions of NAT for a total of 77 infusions. In total, 2 pts (11%) had CR, 13 (72%) had PR and 3 (17%) had NR. Two pts achieved complete mucosal healing as documented by radiography. There were 6 pts on corticosteroids; 4 prior to NAT and 2 initiated during treatment. One pt successfully completed prednisone taper and 2 pts are currently tapering (mean dose change 7.5 mg). Sixteen pts (89%) had a total of 55 AE. Clinically significant AE included 1 ileocolonic resection due to active CD with high-grade dysplasia found in surgical specimen, 1 abdominal wall abscess, 1 Epstein Barr virus febrile infection, 3 infusion reactions characterized by rash, pruritus or throat irritation and 4 hospitalizations secondary to volume depletion (2), abscess drainage (1) and fever work-up (1). Eight pts (44%) complained of headache following infusions and 1 of loss of balance and tinnitus. Two patients with neurologic symptoms underwent brain CT or MRI evaluations, which were negative. Minor infectious AE included 4 upper respiratory tract infections and 1 each of conjunctivitis, sinus infection, cystitis and otitis. Only 1 pt discontinued NAT due to an infusion reaction and acute infectious colitis. CONCLUSIONS: In this initial clinical practice experience, NAT was a clinically beneficial and well-tolerated option for patients with CD who had lost their response to, or who could not tolerate, anti-TNF agents.

The gut—brain axis in IBD: an investigator’s perspective

The gut—brain axis is a neurohumoral bidirectional communication network that integrates behavior and intestinal function. Brain-to-gut communication is evident in many demonstrations of central nervous system (CNS) control of intestinal physiology, including motility and acid secretion. This may be relevant to the pathogenesis of functional bowel disease and stress-induced peptic ulceration. Gut-to-brain communication is reflected in studies on feeding behavior which have identified satiety signals originating from the upper and lower gut to influence appetitive behavior. With growing acceptance of neuroimmune interactions it is possible to extrapolate our knowledge of brain—gut interactions to increase our understanding of the pathophysiology of inflammatory bowel disease (IBD).