Ulcerative Colitis: Probert CS

Orchard T, Probert CS, Keshav S. · St Mary's Hospital & Imperial College, London, UK. · Aliment Pharmacol Ther. · Pubmed #16939425 No free full text.

Abstract: British Society of Gastroenterology guidelines recommend that all patients with ulcerative colitis should receive long-term therapy with a 5-aminosalicylic acid compound to maintain remission. Recent studies have shown that time spent in remission is longer when the maintenance dose is increased from 1.2 to 2.4 g/day, with patients with extensive disease benefiting most from an increase with dosage. A retrospective analysis also found that the frequency of relapse was lower in patients taking more than the median dose of 5-aminosalicylic acid (1.6 g/day) compared with those taking less than the median dose. Similarly, when 5-aminosalicylic acids are used to induce remission, continuing the induction dosage for an extra 4 weeks prolongs remission and reduces the frequency of relapse. However, patients rarely comply fully with the prescribed dose regimen, which can lead to effective under-dosing. The recent discovery that 5-aminosalicylic acids may act in ulcerative colitis by activating peroxisome proliferator-activated receptor-gamma, a nuclear receptor that plays a role in the control of cell proliferation and apoptosis, has given new impetus to the idea that long-term therapy with 5-aminosalicylic acid may reduce the risk of colorectal cancer. Epidemiological studies are beginning to provide evidence to support this view. Accumulating evidence suggests that the next revision of the clinical guidelines should suggest life-long doses of 5-aminosalicylic acid of > or =2 g/day for maintenance of remission in patients with ulcerative colitis.

Creed TJ, Probert CS, Norman MN, Moorghen M, Shepherd NA, Hearing SD, Dayan CM, Anonymous00230. · Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Dorothy Hodgkin Building, Bristol, UK. · Aliment Pharmacol Ther. · Pubmed #16669958 No free full text.

Abstract: 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: <or=2). RESULTS: Within 8 weeks, 10 of 20 (50%) patients achieved clinical remission (seven of 13 moderate, and three of seven severe). At 24 weeks, 13 of 20 (65%) patients were in clinical remission. Five patients required colectomy (four severe, one moderate ulcerative colitis) and one required rescue ciclosporin (moderate ulcerative colitis). Two patients developed herpes zoster, but treatment was generally well tolerated. CONCLUSIONS: Basiliximab appears to promote prolonged remission after a single treatment. Taken in combination with previously reported data, basiliximab shows particular promise in moderate steroid-resistant ulcerative colitis.

Marteau P, Probert CS, Lindgren S, Gassul M, Tan TG, Dignass A, Befrits R, Midhagen G, Rademaker J, Foldager M. · Gastroenterology, Hopital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris cedex 15, France. · Gut. · Pubmed #15951542 links to  free full text

Abstract: BACKGROUND AND AIMS: Oral aminosalicylates are well established in the treatment of active mild/moderate ulcerative colitis (UC) when the disease is extensive (that is, beyond the splenic flexure). The majority of clinical symptoms relate to disease activity in the distal part of the colon and therefore this study was designed to investigate if adding a mesalazine enema to oral mesalazine has additional benefit for patients with extensive mild/moderate active UC. METHODS: A randomised double blind study was performed in 127 ambulatory patients. All received 4 g/day (twice daily dosing) oral mesalazine for eight weeks. During the initial four weeks, they additionally received an enema at bedtime containing 1 g of mesalazine or placebo. Disease activity was assessed using the ulcerative colitis disease activity index, with clinical and endoscopic signs at four and eight weeks. RESULTS: Remission was obtained in 44% (95% confidence interval (CI) 31%, 58%) of the mesalazine enema group (Me) and in 34% (95% CI 21%, 49%) of the placebo enema group (Pl) at four weeks (p = 0.31) and in 64% (95% CI 50%, 76%) of the Me group versus 43% (95% CI 28%, 58%) of the Pl group at eight weeks (p = 0.03). Improvement was obtained in 89% (95% CI 78%, 96%) of the Me group versus 62% (95% CI 46%, 75%) of the Pl group at four weeks (p = 0.0008) and in 86% (95% CI 75%, 94%) of the Me group versus 68% (95% CI 53%, 81%) of the Pl group at eight weeks (p = 0.026). CONCLUSION: In patients with extensive mild/moderate active UC, the combination therapy is superior to oral therapy. It is safe, well accepted, and may be regarded as firstline treatment.

Creed TJ, Norman MR, Probert CS, Harvey RF, Shaw IS, Smithson J, Anderson J, Moorghen M, Gupta J, Shepherd NA, Dayan CM, Hearing SD. · University Research Centre for Neuroendocrinology, Bristol Royal Infirmary, Bristol, UK. · Aliment Pharmacol Ther. · Pubmed #12848627 links to  free full text

Abstract: 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.

Probert CS, Hearing SD, Schreiber S, Kühbacher T, Ghosh S, Arnott ID, Forbes A. · University Division of Medicine, Bristol Royal Infirmary, Marlborough Street, Bristol BS2 8HW, UK. · Gut. · Pubmed #12801957 links to  free full text

Abstract: BACKGROUND: Tumour necrosis factor production is increased in the mucosa of patients with active ulcerative colitis. The benefits of infliximab in Crohn's disease are established. We investigated its efficacy in ulcerative colitis. METHODS: We conducted a randomised placebo controlled trial of infliximab (5 mg/kg) in the treatment of glucocorticoid resistant ulcerative colitis. Infusions were given at weeks 0 and 2. Disease activity and quality of life were recorded over eight weeks of follow up. Remission was defined as an ulcerative colitis symptom score (UCSS) of < or =2 and/or Baron score of 0 at week 6. Patients not in remission were offered open label infliximab 10 mg/kg and reviewed two weeks later. RESULTS: After two weeks, there was no statistically significant difference between the infliximab and placebo groups in the proportion of patients with a Baron score of 0 (13% (3/23) v 5% (1/19) (95% confidence interval (CI) -9% to 24%); p=0.74). After six weeks, remission (UCSS < or =2) rates were 39% (9/23) versus 30% (6/20) (95% CI -19 to 34%; p=0.76). The median improvement in UCSS was 3 for the infliximab group and 2.5 for the placebo group (p=0.82, Mann-Whitney U test). A Baron score of 0 was likely in either group (26% (6/23) v 30% (6/20) (95% CI -30% to 23%); p=0.96). Improvement in the IBDQ and EuroQol was not significantly different between the groups (p=0.22 and 0.3, respectively, Mann-Whitney U test). Twenty eligible patients were given open labelled infusions. Remission was achieved in 3/11 (27%) patients initially treated with infliximab and in 1/9 (11%) patients treated with placebo. CONCLUSION: These data do not support the use of infliximab in the management of moderately active glucocorticoid resistant ulcerative colitis.

Probert CS. · University of Bristol, Bristol, UK. · Nat Clin Pract Gastroenterol Hepatol. · Pubmed #18797443 No free full text.

This publication has no abstract.

Garner CE, Smith S, de Lacy Costello B, White P, Spencer R, Probert CS, Ratcliffe NM. · Clinical Science at South Bristol, Bristol Royal Infirmary, Marlborough St., Bristol BS2 8HW, UK. · FASEB J. · Pubmed #17314143 links to  free full text

Abstract: Little is known about the volatile organic compounds (VOCs) in feces and their potential health consequences. Patients and healthcare professionals have observed that feces often smell abnormal during gastrointestinal disease. The aim of this work was to define the volatiles emitted from the feces of healthy donors and patients with gastrointestinal disease. Our hypotheses were that i) VOCs would be shared in health; ii) VOCs would be constant in individuals; and iii) specific changes in VOCs would occur in disease. Volatile emissions in health were defined in a cohort and a longitudinal study. Subsequently, the pattern of volatiles found in the cohort study were compared to that found from patients with ulcerative colitis, Campylobacter jejuni, and Clostridium difficile. Volatiles from feces were collected by solid-phase microextraction and analyzed by gas chromatography/mass spectrometry. In the cohort study, 297 volatiles were identified. In all samples, ethanoic, butanoic, pentanoic acids, benzaldehyde, ethanal, carbon disulfide, dimethyldisulfide, acetone, 2-butanone, 2,3-butanedione, 6-methyl-5-hepten-2-one, indole, and 4-methylphenol were found. Forty-four compounds were shared by 80% of subjects. In the longitudinal study, 292 volatiles were identified, with some inter and intra subject variations in VOC concentrations with time. When compared to healthy donors, volatile patterns from feces of patients with ulcerative colitis, C. difficile, and C. jejuni were each significantly different. These findings could lead the way to the development of a rapid diagnostic device based on VOC detection.

Tsironi E, Feakins RM, Probert CS, Roberts CS, Rampton DS, Phil D. · Academic Departments of Adult and Paediatric Gastroenterology and of Histopathology, Barts and The London, Queen Mary School of Medicine and Dentistry, London, UK. · Am J Gastroenterol. · Pubmed #15330914 No free full text.

Abstract: OBJECTIVES: Ulcerative colitis (UC) and Crohn's disease (CD) were previously thought to be uncommon and abdominal tuberculosis (TB) common in patients from Bangladesh. We have reevaluated their incidence in Bangladeshis resident in East London. METHODS: Bangladeshis resident in Tower Hamlets presenting between 1997 and 2001 were identified from pathology, endoscopy, and medical records. Demographic, clinical, and management details were recorded. Incidences were calculated and compared with those from 1981 to 1989. RESULTS: Sixteen Bangladeshi patients with UC, 19 with CD, and 5 with abdominal TB were identified. Between 1997 and 2001, the age-standardized incidence of UC was 8.2/10(5)/yr (95% CI 2.5-13.9) compared with 2.4 (95% CI 0.8-3.8) in 1981-1989, and that of CD was 7.3/10(5)/yr (95% CI 2.0-12.6) (2.3, 95% CI 0.7-3.7 in 1981-1989). The standardized ratios for the incidences of UC and CD in recent periods compared with previous periods were 2.1 (95% CI 0.9-3.9) and 2.5 (1.2-4.6), respectively. There was a significant increase in the number of Bangladeshis developing CD by age <20 yr between the earlier and more recent periods (p < 0.02). The standardized incidence of abdominal TB was 2.5/10(5)/yr (95% CI 0.2-4.8) in 1997-2001, and 7.4 (95% CI 2.1-12.7) in 1985-1989 (p < 0.05). The standardized ratio for the incidence of TB in the two periods was 0.22 (95% CI 0.07-0.53). CONCLUSIONS: In Bangladeshis in East London, the incidence of IBD has increased and of abdominal TB has fallen over the last decade; CD has become a more likely diagnosis than abdominal TB. Clinicians in the Western world need to be aware of the changing incidences of IBD and abdominal TB in South Asians.

Haslam N, Standen GR, Probert CS. · Bury General Hospital, England, UK. · Inflamm Bowel Dis. · Pubmed #11383586 No free full text.

Abstract: BACKGROUND: A thrombotic etiology for inflammatory bowel disease (IBD) has been proposed as a result of its association with thromboembolic complications, smoking, the oral contraceptive pill, and the response of ulcerative colitis (UC) patients to heparin. We have previously demonstrated an increased prevalence of the Factor V Leiden mutation in UC and wished to investigate the frequency of the recently discovered prothrombin G20210A gene mutation in IBD. The aim of the study was to investigate the hypothesis that the prothrombic state associated with the prothrombin G20210A gene mutation is involved in the etiology of IBD. PATIENTS AND METHODS: A prospective cohort study of patients attending the Bristol Royal Infirmary and Gloucestershire Royal Hospital's IBD clinics was performed. Thirty-nine patients with IBD (24 with Crohn's disease and 15 with UC) and 100 historical controls were screened for the presence of the prothrombin gene mutation using a heteroduplex-based polymerase chain reaction technique. None of the patients with IBD had a personal history of thromboembolism, while three of them had a family history. RESULTS: No IBD patients had the prothrombin gene mutation compared with four (4%) controls (allelic frequency 2%). CONCLUSION: There does not appear to be an association of the prothrombin gene mutation with IBD and therefore it is unlikely to be involved in the etiology of IBD.

Probert CS, Chott A, Saubermann LJ, Stevens AC, Balk SP, Blumberg RS. · Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · J Clin Immunol. · Pubmed #11332651 No free full text.

Abstract: The normal human intestinal mucosa contains clonal T cell expansions. Clonal populations of T cells can be determined through evaluation of the idiotypic, hypervariable region of their T cell receptor (TCR). We have previously reported that there exists a highly conserved TCR pattern among intestinal CD8+ T cells in the majority of ulcerative colitis (UC) patients undergoing colectomy that was not present in normal control individuals. This TCR pattern, or motif, was characterized by particular beta-chain usage (TCRBV3 and TCRBJ1S6) and a defined length in the hypervariable third complementarity determining region (CDR3). The aim of this study was to assess the motif's relationship to disease activity. Subjects were 66 with UC, 19 with Crohn's disease, 14 inflammatory controls, and 6 normal controls. cDNA and gDNA were prepared from colonic biopsies and paraffin blocks, respectively, obtained from study subjects and used to assess TCRBV CDR3 region length and usage, as well as for cloning and sequencing of TCRs. The TCRBV CDR3 region was present in 25 of a series of 48 UC subjects but only 3 of 19 Crohn's disease patients and 3 of 14 inflammatory controls. The motif was more common in UC than either Crohn' s disease or inflammatory controls (chi2 = 7.5, P = 0.006, and chi2 = 4.1, P = 0.04, respectively). The motifs presence was not dependent upon histologic disease activity (either active or inactive UC). Clinical UC disease activity was also not significantly associated with an increased presence of the motif in 14 paired biopsies, which were taken during times of clinical activity or inactivity. There was a trend toward persistence of the motif, as it was present in 6 of 14 subjects over a 3- to 6-month time period. The previously described UC-associated TCRBV CDR3 region motif located in the intestinal CD8+ T-cell subset is found in a significant proportion of UC subjects. The TCR motif does not significantly discriminate active from inactive disease states. The persistent and diffuse nature of this TCR-associated motif in UC suggests that an ongoing T-cell response to a particular antigen(s) is occuring in this disorder.

Haslam N, Hearing SD, Probert CS. · Dept of Gastroenterology, Gloucestershire Royal Hospital, UK. · Eur J Gastroenterol Hepatol. · Pubmed #10912486 No free full text.

Abstract: BACKGROUND: The failure of standard treatments for inflammatory bowel disease (IBD) has led to the use of immuno-modulatory therapy. Most reports of the use of cyclosporin are from single specialist centres. AIM: To survey the use of cyclosporin in IBD in Bristol's three teaching hospitals. PATIENTS AND METHODS: Over a 4-year period, all patients receiving cyclosporin for IBD were identified and the following data recorded: diagnosis, duration of disease, initial treatment, date initiated, dose of cyclosporin, side-effects, initial clinical response, and current patient status. RESULTS: Thirty-three patients were identified, of whom 26 had ulcerative colitis (UC), six had Crohn's disease and one had indeterminant colitis. The most frequent indication was as 'rescue' therapy in acute severe UC. The overall initial response rate was 63%, but this was only maintained in 30% long-term patients, with over half of them reporting side-effects. Four patients had life threatening side-effects. CONCLUSION: Although the initial response rates are encouraging, the long-term results are poor and at the expense of a high incidence of side-effects. We feel that the use of cyclosporin in IBD should be reconsidered until more information from randomized controlled studies becomes available.

Haslam N, Standen GR, Probert CS. · Department of Gastroenterology, Gloucestershire Royal Hospital, Gloucester, UK. · Eur J Gastroenterol Hepatol. · Pubmed #10563542 No free full text.

Abstract: BACKGROUND: A thrombotic aetiology for inflammatory bowel disease (IBD) has been proposed as a result of its association with thrombo-embolic complications, smoking, the oral contraceptive pill and the response of ulcerative colitis (UC) patients to heparin. The factor V Leiden (FVL) mutation is the commonest inherited risk factor for thrombo-embolism. AIM: The aim of the study was to investigate the hypothesis that the pro-thrombotic state associated with the FVL mutation is involved in the aetiology of IBD. PATIENTS AND METHODS: A prospective cohort study of patients attending the Bristol Royal Infirmary IBD outpatient clinic was performed. Fifty-four patients with IBD (30 with Crohn's disease (CD) and 24 with UC) and 55 historical controls were screened for the presence of FVL using the activated protein C (APC) ratio. Abnormal APC ratios were confirmed to be due to FVL using a heteroduplex-based polymerase chain reaction (PCR) technique. RESULTS: Five patients had the FVL mutation, compared to two controls. One of the patients was homozygous. Two of the patients had CD and three UC. The differences between controls and IBD patients was significant when the allelic frequency of the FVL mutation in patients with UC was compared with controls, with a risk ratio of 2.27, but with limited data. CONCLUSION: There appears to be a weak association between FVL and UC. This association is not strong enough to imply a causal relationship, but may be responsible for some of the thrombo-embolic complications.

Hearing SD, Norman M, Probert CS, Haslam N, Dayan CM. · University of Bristol, Division of Medicine, Bristol Royal Infirmary, Bristol, UK. · Gut. · Pubmed #10446106 links to  free full text

Abstract: BACKGROUND: Up to 29% of patients with severe ulcerative colitis (UC) fail to respond to steroid treatment and require surgery. Previous studies have failed to show a clear correlation between failure of steroid treatment in severe UC and measures of disease severity. The reasons for treatment failure therefore remain unknown. AIM: To investigate the hypothesis that patients with severe UC who fail to respond to steroid treatment have steroid resistant T lymphocytes. METHODS: Eighteen patients with severe UC were studied. After seven days' treatment with high dose intravenous steroids they were classified as complete responders (CR), incomplete responders (IR), or treatment failures (TF). Within 48 hours of admission blood was taken and the antiproliferative effect of dexamethasone on phytohaemagglutinin stimulated peripheral blood T lymphocytes was measured. Maximum dexamethasone induced inhibition of proliferation (I(max)) was measured. RESULTS: In vitro T lymphocyte steroid sensitivity of TF and IR patients was significantly less than that of CR patients. Both TF and 3/5 IR patients had an I(max) of less than 60%; all CR patients had an I(max) of greater than 60%. No significant correlation was seen between response to treatment and disease severity on admission. When in vitro T lymphocyte steroid sensitivity was remeasured three months later, there was no difference between the groups. CONCLUSIONS: Results suggest that T lymphocyte steroid resistance is an important factor in determining response to steroid treatment in patients with severe UC and may be more predictive of outcome than disease severity.

Saubermann LJ, Probert CS, Christ AD, Chott A, Turner JR, Stevens AC, Balk SP, Blumberg RS. · Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Am J Physiol. · Pubmed #10070037 links to  free full text

Abstract: T cell activation, as defined by expression of relevant cell surface molecules, such as the interleukin-2 receptor (CD25), is increased in many chronic relapsing diseases, including inflammatory bowel disease (IBD). These T cells are generally activated through contact of their clonotypic T cell receptor (TCR) with a peptide antigen presented by a major histocompatibility complex molecule. One of the putative antigenic contact sites for the TCR is the third complementarity determining region (CDR3) of the TCR beta-chain variable region (TCRBV). Therefore, analysis of the TCRBV CDR3 provides insight into the diversity of antigens encountered by a given T cell population. This study evaluated the TCRBV CDR3 usage of the activated intestinal lymphocytes from human subjects with IBD, diverticulitis (inflammatory control), and a normal tissue control. Public patterns, as demonstrated by shared TCRBV CDR3 amino acid sequences of activated intestinal T cell subpopulations, were observed. In particular, a public pattern of TCRBV22, a conserved valine in the fifth position, and use of TCRBJ2S1 or TCRBJ2S5 was present in three of four Crohn's disease subjects while not present in the ulcerative colitis subjects. However, the private patterns of TCRBV CDR3 region amino acid sequences were far more striking and easily demonstrated in all individuals studied, including a normal noninflammatory control. Thus we conclude that selective antigenic pressures are prevalent among an individual's activated intestinal lymphocytes.