To elucidate the biological dysregulation underlying two forms of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), we examined global gene expression profiles of ...inflamed colonic tissue using DNA microarrays. Our results identified several genes with altered expression not previously linked to IBD. In addition to the expected upregulation of various cytokine and chemokine genes, novel immune function-related genes such as IGHG3, IGLL2 and CD74, inflammation-related lipocalins HNL and NGAL, and proliferation-related GRO genes were over-expressed in UC. Certain cancer-related genes such as DD96, DRAL and MXI1 were differentially expressed only in UC. Other genes over-expressed in both UC and CD included the REG gene family and the calcium-binding S100 protein genes S100A9 and S100P. The natural antimicrobial defensin DEFA5 and DEFA6 genes were particularly over-expressed in CD. Overall, significant differences in the expression profiles of 170 genes identified UC and CD as distinct molecular entities. The genomic map locations of the dysregulated genes may identify novel candidates for UC and CD genetic susceptibility.
Aliment Pharmacol Ther 2011; 33: 185–193
Summary
Background Treatment options for fistulizing Crohn’s disease (CD) are limited.
Aim To examine whether fistula closure is maintained at week 26 ...following treatment with certolizumab pegol.
Methods Patients with draining fistulas at baseline from PRECiSE 2 (n = 108) received open‐label induction with certolizumab pegol 400 mg at weeks 0 (baseline), 2 and 4. Response was defined as ≥100‐point decrease from baseline in the Crohn’s Disease Activity Index. Nonresponders (50/108) were excluded. At week 6, responders with draining fistulas (N = 58) were randomised to certolizumab pegol 400 mg (n = 28) or placebo (n = 30) every 4 weeks across weeks 8–24. Fistula closure was evaluated throughout the study, with a final assessment at week 26.
Results The majority of patients (55/58) had perianal fistula. At week 26, 36% of patients in the certolizumab pegol group had 100% fistula closure compared with 17% of patients receiving placebo (P = 0.038). Protocol‐defined fistula closure (≥50% closure at two consecutive post‐baseline visits ≥3 weeks apart) was not statistically significant (P = 0.069) with 54% and 43% of patients treated with certolizumab pegol and placebo achieving this end point, respectively.
Conclusion Continuous treatment with certolizumab pegol improves the likelihood of sustained perianal fistula closure compared with placebo.
Bowel-cleansing studies are frequently underpowered, poorly designed, and use subjective bowel cleansing assessments. Consensus on efficacy, tolerability, and preparation-induced mucosal ...abnormalities is lacking. This study aimed to clarify the differences in efficacy and preparation-induced mucosal inflammation of sodium phosphate (NaP), colonLYTLEY (PEG), and Picoprep (Pico).
This was a prospective randomized single-blinded trial of ambulatory patients to assess the efficacy of bowel preparation and preparation-induced mucosal inflammation. Proceduralists who were blinded to the preparation taken, assessed both bowel cleansing by using the Ottawa bowel preparation assessment tool and preparation-induced mucosal inflammation.
Of the 634 patients, 98 % ingested more than 75 % of the bowel preparation and data were complete for colonic preparation scoring in 99 %. The preparation used, time of procedure, and patient sex all independently impacted on bowel cleansing. NaP was less efficacious than PEG ( P < 0.001) and Pico ( P < 0.001) for morning procedures whereas all bowel preparations were equally efficacious for afternoon procedures. Preparation-induced mucosal inflammation was 10-fold greater with NaP ( P = 0.03) and Pico ( P = 0.03) compared with PEG.
This is the largest published prospective randomized blinded study on this topic and the first to evaluate the three major classes of preparation with a validated tool. The bowel preparation used, time of procedure, and patient sex all independently impacted on bowel cleansing. NaP gave the worst preparation for morning procedures whereas all preparations were equally effective for afternoon procedures. NaP and Pico induced mucosal inflammation 10-fold more frequently than PEG, a finding that requires further investigation.
Summary
Background
Crohn's disease recurs in the majority of patients after intestinal resection.
Aim
To compare the relative efficacy of thiopurines and anti‐TNF therapy in patients at high risk of ...disease recurrence.
Methods
As part of a larger study comparing post‐operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine‐intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment.
Results
A total of 101 patients 50% male; median (IQR) age 36 (25–46) years were included. There were no differences in disease history between thiopurine‐ and adalimumab‐treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2–i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab‐treated patients intention‐to‐treat (ITT); P = 0.028 or 24 of 62 (39%) vs. 3 of 24 (13%) respectively per‐protocol analysis (PPA); P = 0.020. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab).
Conclusions
In Crohn's disease patients at high risk of post‐operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.
Summary
Background
Acute severe ulcerative colitis (ASUC) is a potentially life‐threatening complication of ulcerative colitis.
Aim
To develop consensus statements based on a systematic review of the ...literature of the management of ASUC to improve patient outcome.
Methods
Following a literature review, the Delphi method was used to develop the consensus statements. A steering committee, based in Australia, generated the statements of interest. Three rounds of anonymous voting were carried out to achieve the final results. Acceptance of statements was pre‐determined by ≥80% votes in ‘complete agreement’ or ‘agreement with minor reservation’.
Results
Key recommendations include that patients with ASUC should be: hospitalised, undergo unprepared flexible sigmoidoscopy to assess severity and to exclude cytomegalovirus colitis, and be provided with venous thromboembolism prophylaxis and intravenous hydrocortisone 100 mg three or four times daily with close monitoring by a multidisciplinary team. Rescue therapy such as infliximab or ciclosporin should be started if insufficient response by day 3, and colectomy considered if no response to 7 days of rescue therapy or earlier if deterioration. With such an approach, it is expected that colectomy rate during admission will be below 30% and mortality less than 1% in specialist centres.
Conclusion
These evidenced‐based consensus statements on acute severe ulcerative colitis, developed by a multidisciplinary group, provide up‐to‐date best practice recommendations that improve and harmonise management as well as provide auditable quality assessments.
Summary
Background Resistant ulcerative proctitis can be extremely difficult to manage. Oral tacrolimus can be effective, but may have numerous adverse effects. Topically administered tacrolimus, ...however, may also be effective in proctitis.
Aim To undertake a pilot study to assess a potential role for topical tacrolimus in the management of resistant ulcerative proctitis.
Methods Patients with resistant ulcerative proctitis were assessed prospectively by the colitis activity index (CAI) and Modified Mayo score. Topical rectal tacrolimus ointment was commenced at 0.3 mg/mL 3 mL b.d. and increased depending on clinical response. CAI and modified Mayo scores were assessed at 0 and 8 weeks, as were steroid usage and adverse effects.
Results Eight patients (five male/three female) with inflammation to a maximum of 30 cm from the anus were included. All patients had failed disease control with 5‐aminosalicylic acids, steroids, immunosuppressants and infliximab therapy. The mean initial CAI was 12.1 (range 9–16) and the mean modified Mayo score was 8.0 (range 6–9). After 8 weeks, six of eight patients achieved remission with steroids reduced or ceased in five of six. There were no significant adverse effects.
Conclusions This prospective pilot study demonstrated that topical rectal tacrolimus ointment can be effective in ulcerative proctitis. The preparation was well tolerated with no significant adverse effects. Further controlled studies are required.
Summary
Background
Many patients with active Crohn's disease do not adequately respond to therapies, highlighting the need for new treatments.
Aims
To conduct a randomised, double‐blind, ...placebo‐controlled phase 3 study to assess the efficacy and safety of vercirnon, an oral inhibitor of CC chemokine receptor‐9, for the treatment of patients with moderately‐to‐severely active Crohn's disease.
Methods
Patients with a Crohn's Disease Activity Index (CDAI) of 220–450, plus evidence of active disease (endoscopically confirmed or elevation of both C‐reactive protein and faecal calprotectin), who had failed corticosteroid or immunosuppressant therapy were enrolled. Patients were equally randomised to receive placebo, vercirnon 500 mg once daily or vercirnon 500 mg twice daily. The primary endpoint was clinical response, defined as a 100‐point decrease in CDAI from baseline to week 12.
Results
Six hundred and eight patients were randomised. Patient characteristics and baseline demographics were similar among the groups. The proportions of patients achieving a clinical response were 25.1%, 27.6% and 27.2% for placebo, once daily and twice daily respectively; treatment differences were not significant (2.5%; 95% confidence interval, CI −6.1% to 11.0%, P = 0.546 for once daily vs. placebo, and 2.1%; 95% CI −6.5% to 10.7%, P = 0.648 for twice daily vs. placebo). Adverse events were reported in 69.8%, 73.3% and 78.1% with serious adverse events in 8.9%, 5.9%, and 6.0% of patients in the placebo, once‐daily and twice‐daily groups, respectively.
Conclusions
We did not demonstrate efficacy of vercirnon as an induction therapy in patients with moderately‐to‐severely active Crohn's disease; its effect in maintenance therapy was not addressed.
The advent of the biological era has seen many improvements in the management of inflammatory bowel disease (IBD). These agents, however, are not a ubiquitous panacea as they are neither universally ...available nor are they universally efficacious in the short or long-term. There is, therefore, still a need for other therapies and it is important to remember about the medications that have been effective in the past. The use of azathioprine and 6-mercoptopurine has been the mainstay of long-term therapy for many IBD patients for many years. Their role as steroid sparing agents and in the maintenance of remission is well recognized, and with the advent of metabolite testing their use has been refined. Methotrexate is a second line immunomodulator with less impressive data but still with observed benefits in Crohn's disease (CD) and two newer immunosuppressive agents, mycophenylate mofetil and tacrolimus have sparked some interest as they appear to be efficacious in some patients. As IBD is a chronic incurable condition that primarily presents in young patients, the treating clinician's goal is to induce and maintain long-term remission. So when one agent is ineffective, or unavailable, other agents need to be considered. This review aims to provide clinicians with practical and up to date knowledge about the use of the immunomodulators in the management of IBD, which is vital in order to offer the best management for their patients.
Background and Study Aims
Bowel-cleansing studies are frequently underpowered, poorly designed, and with subjective assessments. Consensus on tolerability of the bowel-cleansing agents is thus ...lacking. This study developed and validated a bowel-preparation tolerability questionnaire and used it to assess the tolerability of three bowel-cleansing agents, sodium phosphate (NaP), polyethylene glycol (PEG), and sodium picosulphate (Pico), in a prospective randomized single-blinded trial of ambulatory patients.
Patients and Methods
The bowel-preparation tolerability questionnaire was validated in 125 consecutive patients and then bowel-preparation agent tolerability was assessed in 634 patients in a prospective randomized single-blinded trial.
Results
The questionnaire’s internal consistency was satisfactory with good to excellent “test–retest” reliability for aggregate tolerability and visual analogue scores. Validity assessment confirmed it as reliable and accurate. Of 634 patients, 97.8 % took >75 % of the allocated preparation and 98.9 % completed the questionnaire. Overall, Pico was better tolerated than PEG (
p
< 0.001) and NaP (
p
< 0.001). NaP was better tolerated than PEG (
p
< 0.001). Regardless of the bowel-preparation agent used, males tolerated them better than females (
p
= 0.009) as did patients having their procedure in the AM. Older patients, however, tolerated all preparations better than younger patients (
p
= 0.006).
Conclusions
This study used the first validated bowel-preparation tolerability questionnaire and identified that age, sex, and procedure time all impacted tolerability. Overall, Pico was best tolerated, but PEG’s tolerability in patients ≥60 years was equal to that of Pico and NaP, suggesting that PEG can be recommended for older patients to avoid the electrolyte disturbances associated with the osmotic preparations.
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