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Background: Most colorectal cancers (CRC) arise sporadically from precursor lesions: colonic polyps. Polyp resection prevents progression to CRC. Risk of future polyps is proportional to the number and size of polyps detected at screening, allowing identification of high-risk individuals who may benefit from effective chemoprophylaxis. We aimed to investigate the potential of 5-aminosalicylic acid (5-ASA), a medication used in the treatment of ulcerative colitis, as a possible preventative agent for sporadic CRC., Methods: Human colorectal adenoma (PC/AA/C1, S/AN/C1 and S/RG/C2), transformed adenoma PC/AA/C1/SB10 and carcinoma cell lines (LS174T and SW620) were treated with 5-ASA. The effect on growth in two- and three-dimensional (3D) culture, β-catenin transcriptional activity and on cancer stemness properties of the cells were investigated., Results: 5-ASA was shown, in vitro, to inhibit the growth of adenoma cells and suppress β-catenin transcriptional activity. Downregulation of β-catenin was found to repress expression of stem cell marker LGR5 (leucine-rich G protein-coupled receptor-5) and functionally suppress stemness in human adenoma and carcinoma cells using 3D models of tumorigenesis., Conclusions: 5-ASA can suppress the cancer stem phenotype in adenoma-derived cells. Affordable and well-tolerated, 5-ASA is an outstanding candidate as a chemoprophylactic medication to reduce the risk of colorectal polyps and CRC in those at high risk.

Background: There is no gold standard index in the measurement of ulcerative colitis (UC) disease activity in clinical trials. Mucosal healing has been described as an important clinical endpoint requiring endoscopic assessment, which is unpleasant for the patient and may hamper recruitment to trials. The aim of this study was to determine whether endoscopy is necessary in the assessment of UC disease activity and whether a noninvasive disease activity index (partial Mayo score) could be used to predict the Mayo score., Methods: In all, 149 subjects with moderate to severe UC enrolled in a clinical trial were assessed using total and partial Mayo scores. Histologic assessment of biopsies was performed. A regression model was constructed to predict total Mayo score from the partial Mayo score and histology score from the Mayo score. A Bland-Altman test of agreement was performed., Results: The partial Mayo score correlated closely with the total Mayo score at week 4 (rho = 0.97) and week 8 (rho = 0.98). The model to predict total from partial Mayo score showed excellent correlation (rho = 0.97) and good agreement with the total Mayo score at week 4 and the week 8 validation set (rho = 0.97) and accurately classified disease severity (kappa = 0.82). The model to predict histology score from the Mayo score correlated only moderately with the actual histology score at week 4 (rho = 0.59) and week 8 (rho = 0.36)., Conclusions: The Mayo score can be accurately predicted from the partial Mayo score. A noninvasive index can replace the Mayo score in future clinical trials., (Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.)

Background & Aims: Basiliximab is a chimeric monoclonal antibody that binds CD25 and thereby inhibits interleukin (IL)-2-mediated proliferation of lymphocytes. IL-2 might contribute to the resistance of T cells to corticosteroids. We investigated the efficacy and safety of basiliximab as a corticosteroid-sensitizing agent in patients with corticosteroid-refractory ulcerative colitis (UC)., Methods: We studied 149 patients with moderate to severe UC (Mayo score ≥6 and endoscopic subscore ≥2) despite treatment for at least 14 days with oral prednisone (40-50 mg/day). Subjects were randomly assigned to groups that were given 20 mg (n = 46) or 40 mg (n = 52) basiliximab or placebo (n = 51) at weeks 0, 2, and 4. All subjects received 30 mg/day prednisone through week 2; the dose was reduced by 5 mg each week to 20 mg/day, which was maintained until week 8. At week 8, we compared the rates of clinical remission (Mayo score ≤2, no subscore >1) for patients given basiliximab with the rate for patients given placebo., Results: Twenty-eight percent of patients given placebo, 29% of those given the 40-mg dose of basiliximab, and 26% of those given the 20-mg dose of basiliximab achieved clinical remission (P = 1.00 vs placebo for each dose). Basiliximab was generally well tolerated. Six subjects who received basiliximab had serious adverse events (6.1%) compared with 2 who received placebo (3.9%; P = .72). In subjects given basiliximab, incomplete saturation of CD25 (<50%) on peripheral T cells was associated with the presence of anti-basiliximab antibodies (odds ratio, 21; 95% confidence interval, 2.4-184)., Conclusions: Basiliximab does not increase the effect of corticosteroids in the induction of remission in outpatients with corticosteroid-resistant moderate to severe UC., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Methotrexate is an immunosuppressant used in the treatment of patients with Crohn's disease who are intolerant or refractory to azathioprine., Aim: To present clinical experience in terms of response, side effects and reason for cessation of methotrexate treatment as well as adherence to monitoring regimens., Design: Retrospective review of case records of 37 patients taking methotrexate for Crohn's disease at the Bristol Royal Infirmary, a large UK teaching hospital. Thirty-five patients used oral methotrexate., Results: Response rate to methotrexate was 78% at 3 months. Adverse events were uncommon and rarely dangerous. Monitoring of treatment did not adhere to British Society of Gastroenterology guidelines., Conclusion: Oral methotrexate is effective and safe in the treatment of Crohn's disease. This is in contrast to findings of previous series, which have mainly reported on intramuscular methotrexate use. Monitoring of treatment is currently inadequate and consensus should be sought for a pragmatic monitoring schedule to resolve this important governance issue.

Objectives: To determine the 3 year mortality of patients admitted to hospital for the treatment of ulcerative colitis (UC)., Design: Retrospective case note review of all patients admitted to hospital for treatment of active UC over a 6 year period from 1 January 2000., Setting: Teaching hospital with a tertiary referral practice for the management of infiammatory bowel disease., Patients: 106 patients (134 admissions) met the inclusion criteria., Interventions: Elective and emergency colectomy was undertaken in 16 and 26 patients, respectively., Main Outcome Measures: Mortality at 3 years., Results: There were six deaths after 3 years. Case fatality at 30 days, 1, 2 and 3 years was 1.0% (95% CI 0.2 to 5.1), 1.9% (95% CI 0.2 to 6.6), 2.9% (95% CI 5.9 to 8.0) and 5.7% (95% CI 2.1 to 11.9), respectively. There were no deaths in either surgical group. One patient (89 years, female) died while awaiting emergency colectomy. Patients who died were significantly older at the time of admission (79 years (95% CI 71 to 88 years) vs 41.2 years (95% CI 38 to 45 years)) and were more likely to have comorbid illness (p<0.001). Severity of disease, prior immunosuppressive use, first presentation and smoking status were not associated with increased mortality., Conclusions: Three year mortality following admission for treatment of UC was 5.7% (95% CI 2.1 to 11.9), significantly lower than that reported previously. Mortality was significantly associated with increasing age and the presence of comorbid disease. Disease specific factors such as severity, extent and first presentation were associated with emergency colectomy but not mortality., Competing Interests: Competing interests: None.

Summary: We performed a randomised controlled trial (RCT) to determine whether risedronate 35 mg once weekly prevents bone loss following an 8-week reducing course of prednisolone given for an exacerbation of inflammatory bowel disease (IBD). The greatest change in bone mineral density (BMD) was at Ward's triangle (WT), which fell by 2.2% in the placebo group, compared with a reduction of 0.8% in the risedronate group., Introduction: Whether bisphosphonates can prevent bone loss associated with intermittent glucocorticoid (GC) therapy is unknown, reflecting the difficulty in performing RCTs in this context., Method: To explore the feasibility of RCTs to examine this question, lumbar spine (LS; L2-4) and hip dual X-ray absorptiometry (DXA) scans were performed in 78 patients commencing a GC therapy course for a relapse of IBD. They were then randomised to receive placebo or risedronate 35 mg weekly for 8 weeks, after which the DXA scan was repeated., Results: For LS BMD, there was no change in the placebo group (0.1 +/- 0.4, p = 0.9), but there was an increase after risedronate (0.8 +/- 0.4, p = 0.04; mean% +/- SEM by paired Student's t test). There were small decreases in both groups at the total hip (-0.5 +/- 0.3, p = 0.04; -0.5 +/- 0.3, p < 0.05, placebo and risedronate, respectively). At WT, BMD fell after placebo (-2.2 +/- 0.5, p = 0.001) but not risedronate (-0.8 +/- 0.5, p = 0.09; p = 0.05 for between-group comparison)., Conclusion: RCTs can be used to examine whether bisphosphonates prevent bone loss associated with intermittent GC therapy, providing metabolically active sites such as WT are employed as the primary outcome.

Treatment failure occurs in up to 30% of patients treated with steroids for inflammatory diseases. The aim of this study was to explore the potential role of 21 cytokines in steroid-resistant inflammatory disease and to develop methods to restore steroid sensitivity through cytokine manipulation. The dexamethasone inhibition of lymphocyte proliferation assay correlates with the outcome of steroid therapy in ulcerative colitis (UC) and other inflammatory diseases. Using this assay, PBMC production of 21 cytokines, assayed by cytokine bead array, was correlated with percentage of suppression of proliferation by 10(-6) M dexamethasone (Imax) in 26 healthy volunteers. Effects of the addition of exogenous cytokines to induce steroid resistance in PBMCs from healthy volunteers and cytokine blockade to improve steroid sensitivity in PBMCs from patients with steroid-resistant UC were then explored. Production of IL-1alpha, IL-10, IL-17, IFN-gamma, G-CSF, GM-CSF, TNF-alpha, and IFN-inducible protein 10 (IP-10) correlated significantly with in vitro steroid sensitivity; however, only IL-2 and TNF-alpha reduced steroid sensitivity when added exogenously. Addition of IL-10 enhanced steroid suppression. Immunoneutralization or receptor blockade of IL-2, but not TNF-alpha, IFN-gamma, IL-4, IL-17, or IP-10 increased steroid sensitivity in cells from steroid-resistant UC patients. Neutralization of IL-10 reduced steroid sensitivity. Of the large panel of cytokines studied, IL-2 appears to have the greatest antagonistic effect on the antiproliferative effect of steroids. These data suggest that IL-2 inhibition in vivo may improve the response to steroids in steroid-resistant individuals.

Up to 30% of patients with autoimmune, allergic, and lymphoproliferative diseases are refractory to glucocorticoid therapy. The present study was undertaken to investigate whether such steroid resistance (SR) is limited to a subpopulation of CD4(+) T cells and, as IL-2 is a putative driver of SR, whether T cell SR is associated with CD25 expression. We show that SR patients have a characteristic subgroup of activated CD4(+) T cells that continue to proliferate despite exposure to high-dose Dexamethasone (Dex), demonstrate that CD4(+)CD25(-) cells are exquisitely sensitive to Dex whereas CD4(+)CD25(int) cells are highly SR, and further find that the combination of an anti-CD25 mAb with Dex enhances suppression of T cell proliferation compared with each agent alone. We therefore conclude that SR is not a general property of all lymphocytes but resides in T cell subpopulations, which are prevalent in SR patients and express intermediary levels of CD25. As a result, we propose a new paradigm for SR disease in which glucocorticoid therapy positively selects SR cells, generating a population of drug-resistant lymphocytes that perpetuate on-going inflammation.

Background: Steroid resistance in inflammatory bowel disease presents a difficult clinical challenge. The advent of biological therapies coupled with an increasing understanding of the pathogenesis of inflammatory bowel disease has provided new therapeutic options., Methods: We review the available literature of the mechanisms behind steroid resistance. In addition, we outline some of the options available for treating those patients who fail to respond adequately to glucocorticoids., Results: Approximately 30% of patients prescribed glucocorticoids will not achieve clinical remission. Many such patients are offered immunosuppressive or, recently, biological agents. However, these agents are ineffective in a large proportion of patients. Immunosuppressive agents only bring 40-60% of patients into remission, and biological agents typically induce remission in just 40% of patients. In this review, the possible explanations for glucocorticoid resistance are discussed. Recent evidence suggests that in many patients it is mediated by interleukin-2. Basiliximab, a biological agent that interrupts interleukin-2 signalling, has shown significant benefit in early clinical studies., Conclusions: Patients who fail to respond to steroid therapy should have alternative agents introduced in a timely fashion. Steroid refractory inflammatory bowel disease remains a difficult condition to treat, but new therapies and managements are emerging.

Background: Preliminary data have suggested that interleukin-2 receptor blockade with basiliximab may increase steroid sensitivity. We have previously reported a small case series demonstrating the potential of basiliximab as a novel agent for the treatment of steroid-resistant ulcerative colitis., Aim: To report further experience of the efficacy and safety of treatment with the interleukin-2 receptor blocking monoclonal antibody basiliximab, in addition to steroids, for the treatment of severe and moderate steroid-resistant ulcerative colitis., Methods: Twenty patients were enrolled - 13 patients with moderate steroid-resistant ulcerative colitis (Ulcerative Colitis Symptom Score: >or=6) and seven patients with severe steroid-resistant ulcerative colitis. All were given a single dose of 40 mg basiliximab plus standard steroid therapy in an open-label, uncontrolled trial. Primary end point was clinical remission within 8 weeks (Ulcerative Colitis Symptom Score:

Background: Steroid resistance represents a major clinical problem in the treatment of ulcerative colitis. In vitro, interleukin-2 renders lymphocytes steroid resistant., Aim: To explore the therapeutic potential of interleukin-2 receptor blockade in steroid-resistant ulcerative colitis with both in vitro measures and a pilot in vivo study., Methods: Ten patients with steroid-resistant ulcerative colitis received a single bolus of 40 mg of intravenous basiliximab plus steroid treatment in an open-label, uncontrolled, 24-week study. The outcome was assessed using the Ulcerative Colitis Symptom Score, rectal biopsy and Inflammatory Bowel Disease Questionnaire. Lymphocyte steroid sensitivity was measured in vitro in 39 subjects in the presence or absence of basiliximab., Results: Nine of the 10 patients achieved clinical remission within 8 weeks. At 24 weeks, seven patients were in clinical remission. Marked improvement in the Ulcerative Colitis Symptom Score was seen by 1 week (P = 0.004) and on rectal biopsy and Inflammatory Bowel Disease Questionnaire by 2 weeks (both P < 0.05). Improvements persisted to 24 weeks (Ulcerative Colitis Symptom Score, Inflammatory Bowel Disease Questionnaire, both P < 0.005). Eight of the nine responders relapsed (median, 9 weeks), but remission was re-achieved with further corticosteroids and the addition of azathioprine. At 24 weeks, seven patients were in full clinical remission, five off all steroid therapy. In vitro measurement of lymphocyte steroid sensitivity demonstrated steroid resistance in 22% of subjects. All were rendered steroid sensitive in the presence of basiliximab., Conclusions: Basiliximab appears to be effective at inducing remission in steroid-resistant ulcerative colitis. In vitro, basiliximab also produced a dramatic increase in lymphocyte steroid sensitivity in healthy subjects. Confirmation in randomized controlled studies is required.