Abstract Background Despite the advancement in pharmacological management of Inflammatory Bowel Disease (IBD), the efficacy and the side effects of the biologics are rarely studied in the elderly population. Our aim was to evaluate retrospectively the drug sustainability, efficacy, and safety of the biologic therapies in the elderly IBD population. Methods Consecutive elderly (> 60 years old) IBD patients, treated with biologics (infliximab, adalimumab, vedolizumab, ustekinumab) followed at the McGill University IBD Center were included between January 2000 and 2020. The efficacy of treatment was measured using clinical and biochemical parameters. Response and remission variables were measured at three distinct time points from the start date of the biologic agent, as in 3, 6–9 and 12–18 months. Patients required a minimal follow-up period of three months. Adverse events (AE) or serious adverse events (SAE) occurring within three months of the last biologic dose were considered to be related to the biologic agent. Results We identified a total of 147 elderly patients with IBD treated with biologic agents (109 Crohn’s disease (CD) and 38 ulcerative colitis (UC)). Disease location was predominantly ileocolonic (47.7%) in CD and pancolitis(63.2%) in UC. 47.6% of elderly IBD patients had attempted at least 1 biologic agent (Table1). The mean duration of biologic treatment was 157.5 (SD:148)weeks. Steroid exposure varied from 34% at the start of biologic therapy to 19% at 3 months, 16.3% at 6–9 months and 6.5% at 12–18 months.’ The remission rates at 3, 6–9 and 12–18 month were not significant between the biologic therapies. Kaplan-Meyer analysis did not show statistical difference for drug sustainability (p=0.195)(Figure1), time to adverse event (p=0.158) (Figure2) or infection rates (p=0.973) (Figure3) between all four biologics studied. The most common AEs led to discontinuation were loss of response, infusion or injection reaction and infection. Conclusion Current biologic therapies were not different with regards to drug sustainability and safety in the elderly IBD population. Based on these results, we are not able to suggest a preferred sequencing order among biologicals.

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.

Gastrointestinal mucosal polyamines influence enterocyte proliferation and differentiation during small intestinal maturation in the rat. Studies in postnatal rats have shown that ornithine decarboxylase (ODC) protein and mRNA peak before the maximal expression of brush-border membrane (BBM) sucrase-isomaltase (SI) and the sugar transporters sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter 2 (GLUT2). This study was undertaken to test the hypothesis that the oral administration of spermidine in postnatal rats upregulates the expression of ODC, thereby enhancing the expression of SI and SGLT1 in the brush-border membrane as well as basolateral membrane-facilitative GLUT2 and Na(+)-K(+)-ATPase. Northern and Western blot analyses were performed with antibodies and cDNA probes specific for SI, SGLT1, GLUT2, alpha(1)- and beta(1)-subunits of Na(+)-K(+)-ATPase, and ODC. Postnatal rats fed 6 mumol spermidine daily for 3 days from days 7 to 9 were killed either on postnatal day 10 (Sp10) or day 13 following a 3-day washout period (Sp13). Sp10 rats showed a precocious increase in the abundance of mRNAs for SI, SGLT1, and GLUT2 and Na(+)-K(+)-ATPase activity and alpha(1)- and beta(1)-isoform gene expression compared with controls. ODC activity and protein and mRNA abundance were also increased in Sp10 animals. The increased expression of these genes was not sustained in Sp13 rats, suggesting that these effects were transient. Thus, 3 days of oral polyamine administration induces the precocious maturation of glucose transporters in the postnatal rat small intestine, which may be mediated by alterations in ODC expression.

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.

Glucocorticosteroids enhance absorptive functions of the intestine. This study was undertaken to assess the influence of budesonide (BUD), prednisone (PRED), or control vehicle in rats fed either a saturated fatty acid diet (SFA) or a polyunsaturated fatty acid diet (PUFA), on the uptake of sugars. Steroids increased the uptake of fructose, and these effects were greater with SFA than PUFA. No effect on the abundance or the expression of the mRNAs of SGLT1, GLUT5, or GLUT2 was observed, and yet immunohistochemistry staining in the jejunum for SGLT1 and GLUT5 was greater in SFA than in PUFA. The early response genes and proglucagon expression was enhanced in the ileum of animals fed SFA and given control vehicle. Steroids increased the ileal proglucagon mRNA. In summary, (1) PRED and BUD enhance the uptake of fructose, (2) this enhancement may be increased further by feeding SFA, and (3) signaling may involve early response genes and proglucagon.

Glucocorticosteroids enhance digestive and absorptive functions of the intestine of weaning and adult rats. This study was undertaken to assess the influence of treatment of weaning male rats with budesonide (Bud), prednisone (Pred), or control vehicle on the in vitro jejunal and ileal uptake of glucose and fructose. Bud and Pred had no effect on the uptake of D-glucose by sodium glucose transporter-1. In contrast, the uptake of D-fructose by GLUT-5 was similarly increased with Bud and with Pred. The increases in the uptake of fructose were not due to variations in the weight of the intestinal mucosa, food intake, or in GLUT-5 protein or mRNA expression. There were no steroid-associated changes in mRNA expression of c-myc, c-jun, c-fos, proglucagon, or selected cytokines. However, the abundance of ileal ornithine decarboxylase mRNA was increased with Pred. Giving postweaning rats 4 wk of Bud or Pred in doses equivalent to those used in clinical practice increases fructose but not glucose uptake. This enhanced uptake of fructose was likely regulated by posttranslational processes.

In the past year there have been many advances in the area of small bowel physiology and pathology and therapy. In preparation for this review, over 1500 papers were assessed. The focus is on presenting clinically useful information for the practicing gastroenterologist. Selected important clinical learning points include the following: (1) glutamine may restore the AIDs-associated increased intestinal permeability to normal; (2) substance P is a major mediator of diarrhea caused by Costridium difficile toxin A, acting by binding to a G-protein-coupled receptor, and represents a possible 2therapeutic target; (3) the serological diagnosis of celiac disease has been greatly enhanced with the use of anti-endomysial antibody testing, and the recent antitransglutaminase; (4) a quarter of patients with celiac disease may have secondary pancreatic insufficiency and require enzyme replacement therapy; (5) in the patient with unexplained elevation in the serum transaminase concentration, consider celiac disease as an obscure possibility; (6) bosentan and endothelin receptor agonist may prove to be useful in reducing gut ischemia in patients with septic shock; and (7) the administration of recombinant human fibroblast growth factor-2 may prove to be useful to prevent radiation damage to the gastrointestinal tract.

In the past year there have been many advances in the area of small bowel physiology and pathology and therapy. In preparation for this review, over 1500 papers were assessed. The focus is on presenting clinically useful information for the practising gastroenterologist. Selected important clinical learning points include the following: (1) numerous peptides are being identified which stimulate the proliferation and functional response of the small intestine to disease or resection, and may in time find a clinical use; (2) under usual in vivo conditions, absorption of nutrients has little effect on the paracellular movement of water; (3) the permeability of the intestine is modified by the function of the tight junctions, and measuring intestinal permeability may be useful to reflect the presence of disease; (4) the release of serotonin is influenced by cholinergic, adrenergic, and nonadrenergic, noncholinergic mechanisms, and serotonin agonists and antagonists may play an important future role in the treatment of motility disorders; (5) the use of endothelin receptor antagonists may be useful for the treatment of intestinal anaphylaxis; (6) the alterations in intestinal pH and motility in patients with Crohn's disease may influence the action of pH- or time-dependent release medications; and (7) patients with irritable bowel syndrome may also have abnormalities in gastric and small intestinal motility.

In the past year there have been many advances in the area of small bowel physiology and pathology and therapy. In preparation for this review, over 1500 papers were assessed. The focus is on presenting clinically useful information for the practising gastroenterologist. Selected important clinical learning points include the following: (1) glucose absorption mediated by SGLT1 is controlled by mRNA abundance, as well as by posttranscriptional processes including protein trafficking; (2) inducers of cytochrome P-450 decrease glucose and fructose absorption and increase glucose consumption in the intestine; (3) the regulated release of nutrients from the stomach into the upper intestine ensures that the modest intestinal transport reserve capacity is not exceeded; (4) hepatocyte growth factor and short-chain fatty acids may enhance intestinal adaptation and prevent the atrophy seen when total parenteral nutrition is infused; (5) inhibitors of pancreatic lipase and phospholipase H2 may be useful clinically to reduce absorption as part of a treatment program for obesity and hyperlipidemia; (6) several membrane-bound and cytosolic proteins have been identified in the enterocyte as well as in the hepatocyte and may be the target for the future therapeutic manipulation of bile acid metabolism and control of hyperlipidemia; (7) suspect bile acid malabsorption in the patient with otherwise unexplained chronic diarrhea; (8) a proportion of lipid absorption is protein-mediated, and this opens the way to targeting these proteins and thereby therapeutically modifying lipid absorption; (9) a high protein diet may be useful to increase the intestinal absorption of drugs transported by the H+/dipeptide cotransporter; (10) a metal transporter DCT1 has been identified, and this may open the way to a better understanding of disorders of, for example, iron and zinc metabolism; (11) the nutrient transporters such as SGLT1 are responsible for a portion of the intestinal absorption of water; (12) the influence of nitric oxide on intestinal water absorption and secretion depends on its concentration; (13) a trial of bile acid-sequestering agent may prove useful in the treatment of the patient who experiences diarrhea while taking an enteral diet; (14) a proteolytic extract from pineapple stems may prove to be useful to treat diarrhea, although the mechanism of this effect remains to be established; and (15) the antisecretory effect of the new peptide, sorbin, needs to be tested in a clinical situation on patients with diarrhea. Other new and promising antidiarrheal agents include bromelain, an extract from pineapple stems, and igmesine, a final sigma ligand.

Our knowledge base pertaining to the pathogenesis of inflammatory bowel disease (IBD) has greatly expanded over the past decade, owing to dramatically improved animal models of enterocolitis and major advances in mucosal immunology and recombinant DNA technology. The current model pertaining to the pathogenesis of IBD emphasizes the important interactions among genetic, immune and environmental factors and underscores the observation that each mucosal cell type functions as effector and target cells. The identification of differentially expressed genes in the intestine has added to our understanding of the cellular mechanisms associated with the regulation of gene expression in this biological system. Abnormal intestinal cell gene products and responses play a central role in the pathogenesis of IBD. However, the identification and differential expression of potentially aberrant genes remains to be defined. Of the estimated 100 000 genes encoded by the genome of higher eukaryotic cells, approximately 10-20

The Na+,K+-ATPase plays akey role in the absorption of electrolytes, water, andnutrients from the small intestine. The effect ofstreptozotocin-induced diabetes mellitus (STZ-DM) on theactivity and expression of Na+,K+-ATPase in therat small intestine was examined in the present study.Diabetes mellitus was induced by a singleintraperitoneal injection of STZ (75 mg/kg) and controland STZ-DM rats were killed at day 30 (chronic diabetic state). Levels ofNa+,K+-ATPase activity and numbersof sodium pumps were increased two- to threefold in thejejunum and ileum. Sodium pump kinetics were unalteredin STZ-DM. The levels ofNa+,K+-ATPase alpha1 and beta1isoform protein, corresponding mRNAs, and levels oftranscription were increased in the jejunal and ilealmucosa of the chronically diabetic rat. The increases in Na+,K+-ATPasefunctional activity, protein expression, and mRNA weremost marked at the level of the ileal mucosa. While aproximal to distal gradient inNa+,K+ATPase activity and subunitisoform protein levels were observed in both control anddiabetic rats, levels of subunit isoform mRNA abundancewere similar in both regions of the small intestine inboth groups of rats. The alterations in small intestinal Na+,K+-ATPase expressionin the chronic diabetic state appear to involvealterations in transcriptional and posttranscriptionalevents and may likely represent an adaptive responsethat leads to increased Na+-coupled monosaccharideabsorption in the context of a perceived state ofnutrient depletion.

The effect of fasting on mucosal Na-K-ATPase activity in various regions of rat small intestine was investigated. Fasting (17--48 h) was associated with a consistent decrease in specific and total activity of Na-K-ATPase in the jejunum, the levels tending to rise more distally. No effect on the specific activities of Mg-ATPase or alkaline phosphatase was found. Fasting was also associated with incresed adrenocortical activity and with decreases in mucosal mass, protein content, and histological dimensions of the jejunum, no similar changes being found in the distal small intestine. Glucose ingestion prevented the decrease in jejunal enzyme activity associated with fasting and elevated levels in the mid and terminal small intestine of fed animals. These effects suggest that Na-K-ATPase activity in small intestinal mucosa may be, in part, inducible.