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One decade after the emergence of biologic therapy for Crohn's disease (CD), our treatment algorithms are beginning to change. Once reserved for patients with refractory disease, disease unresponsive to conventional therapies, or those requiring multiple courses of corticosteroids, there is increasing evidence that early, aggressive interventions with immunosuppressants or biologic therapies targeting tumor necrosis factor-alpha or alpha-4 integrins can alter the natural history of CD by reducing the transmural complications of structuring and fistulization and the nearly inevitable requisite for surgical resections. More recent trials are beginning to suggest that intervention with combination therapy for selected patients with a poor prognosis may modify the long-term course of CD. Selection of patients with features predicting a complex or progressive course and early, combined intervention is now possible. Future studies are still needed to best identify predictors of response to individual agents with differing mechanisms of action, as well as to optimize the risk-benefit of long-term maintenance therapy.

Background & Aims: The efficacy of infliximab for treating patients with ulcerative colitis has been established., Methods: The Active Ulcerative Colitis Trial (ACT)-1 and ACT-2 randomized, double-blind, placebo-controlled studies evaluated infliximab induction and maintenance therapy in moderately to severely active ulcerative colitis. Overall, 728 patients received placebo or infliximab (5 or 10 mg/kg) intravenously at weeks 0, 2, and 6, then every 8 weeks through week 46 (ACT-1) or 22 (ACT-2). Colectomy, hospitalization, and surgery/procedure data through 54 weeks after the first infusion were obtained from ACT-1, ACT-2, and associated data sources. In the prespecified analysis, all data were combined to ascertain time to colectomy. Kaplan-Meier product-limit method was used to estimate the cumulative incidence of colectomy, and log-rank test was used to compare the combined infliximab group and placebo., Results: Eighty-seven percent (630 of 728) of patients had complete colectomy follow-up; 13% (98 of 728) of patients had a median follow-up of 6.2 months. The cumulative incidence of colectomy through 54 weeks was 10% for infliximab and 17% for placebo (P = .02), yielding an absolute risk reduction of 7%. Compared with placebo, fewer ulcerative colitis-related hospitalizations and surgeries/procedures per 100 patient-years of treatment occurred with infliximab therapy: 40 vs 20 (P = .003) and 34 vs 21 (P = .03), respectively. Serious adverse events occurring in infliximab-treated patients included serious infections, tuberculosis, histoplasmosis, listeriosis, and malignancy., Conclusions: Patients with moderately to severely active ulcerative colitis treated with infliximab were less likely to undergo colectomy through 54 weeks than those receiving placebo.

Background: The aim of this study was to assess the clinical benefit and tolerability of adalimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF), in patients with ulcerative colitis (UC)., Methods: Patients with active UC, including those who had lost response or developed intolerance to the chimeric anti-TNF antibody infliximab, were enrolled in a 24-week uncontrolled trial. Patients were treated with subcutaneous adalimumab 160 mg at week 0, 80 mg at week 2, and 40 mg every other week starting at week 4. After week 8 the dose could be escalated to 40 mg weekly for incomplete response. Outcome measures included clinical response and remission and mucosal healing., Results: Twenty patients were enrolled, of whom 13 had previously received infliximab. Seven patients had dose escalation of adalimumab between weeks 8 and 16, from 40 mg every other week to 40 mg weekly, due to incomplete response. The rates of clinical response were 25% at week 8 and 50% at week 24. The rates of clinical remission were 5% at week 8 and 20% at week 24. The rate of mucosal healing was 30% at week 8. The rates of clinical response and remission and mucosal healing were similar in infliximab-naïve and previously exposed patients. None of the patients experienced hypersensitivity reactions during treatment with adalimumab., Conclusions: Adalimumab is well tolerated and appears to be a clinically beneficial option for patients with UC, including those who have previously lost their response to or cannot tolerate infliximab.

Background and Aims: We previously reported that IBD patients who are non-responders to thiopurines with preferential shunting of metabolites to hepatotoxic 6-methylmercaptopurine ribonucleotides compared to 6-thioguanine nucleotides can reverse the ratio of 6-MMP/6-TGN and respond to thiopurines with the addition of allopurinol. The objective of this study is to report long term efficacy and safety, along with results for an additional 11 patients., Methods: Retrospective chart review of patients at the University of Chicago IBD Center treated with allopurinol in addition to thiopurines., Results: Twenty five patients with Crohn's disease or ulcerative colitis were enrolled. Within the first month of therapy 6-TGN metabolite levels increased from a mean of 186.5±17.4 (SE) to 352.8±37.8 pmol/8×10(8) (p=0.0001). Over the same period 6-MMP levels decreased from a mean of 11,966±1697 to 2004±536 pmol/8×10(8) (p<0.0001). The mean daily dosage of prednisone decreased from 19.8±3.8 mg to 5.3±2.7 mg (p=0.03). Thirteen patients have a minimum of one year follow-up. Nine of these thirteen patients have continued on therapy for at least 2 years. All thirteen of these patients continue to be in clinical remission at the last follow-up visit. No patients have had evidence of sustained thrombocytopenia or abnormal liver enzymes., Conclusions: In AZA/6-MP non-responders with increased 6-MMP/6-TGN ratios, addition of allopurinol continues to demonstrate safety and efficacy for long-term maintenance and steroid-sparing in IBD.

Objectives: To evaluate the efficacy and safety of purine analogs (azathioprine, 6-mercaptopurine (6-MP)) in the prevention of postoperative recurrence in Crohn's disease (CD)., Methods: We searched MEDLINE, the Cochrane Library, and EMBASE. The primary end points, clinical and endoscopic recurrence at 1 and 2 years, and safety were analyzed by the methods of Peto and Der Simonian and Laird., Results: Four controlled trials enrolled 433 patients and compared azathioprine (n=3) or (6-MP) (n=1) with control arms (placebo with or without antibiotic induction therapy or mesalamine). In the overall analysis, purine analogs were more effective than control arms in preventing clinical recurrence at 1 year (mean difference, 95% confidence interval (CI): 8, 1-15%, P=0.021, number needed to treat (NNT)=13) and 2 years (mean difference, 95% CI: 13%, 2-24%, P=0.018, NNT=8). In sensitivity analyses, the efficacy of purine analogs was superior to that of placebo for the prevention of clinical and endoscopic recurrence at 1 year (mean differences, 95% CI: 13, 1.8-25%, P=0.025, NNT=7, and 23%, 9-37%, P=0.0016, NNT=4, respectively). At 1 year, in the overall analysis, purine analogs were more effective than control arms were in preventing severe (i2-4) endoscopic recurrence (mean difference, CI 95%: 15, 1.8-29%, P=0.026, NNT=7), but they were not effective in the prevention of very severe (i3-4) recurrence. The rate of adverse events leading to drug withdrawal was higher in thiopurine-treated patients than in control arms (17.2 vs. 9.8%, respectively, P=0.021)., Conclusions: Purine analogs are more effective than placebo in preventing both clinical and endoscopic postoperative recurrence in CD, but they are associated with a higher rate of adverse events leading to drug withdrawal.

Two 8-week, randomized, placebo-controlled parent studies, SPD476-301 (by Lichtenstein and associates) and SPD476-302 (by Kamm and colleagues), of MMX Multi Matrix System (MMX) mesalamine have evaluated the induction of remission in ulcerative colitis patients, and a third study has evaluated the maintenance of remission in patients from these parent studies. Here, we examine data only from patients who received MMX mesalamine 2.4 g or 4.8 g daily in these trials. In total, 63.6% of patients (220/346) achieved remission following 8-16 weeks of MMX mesalamine therapy. Among these 220 eligible patients, 218 entered the 12-month maintenance phase, and of this group, 89.9% (196/218) were relapse-free at study end. Overall, 56.6% (196/346) of patients who started MMX mesalamine therapy both achieved and maintained remission for 12 months. The adverse-event profile of MMX mesalamine was similar to the profile of the parent studies' placebo arms at all doses and frequencies. Therefore, the majority of patients with active, mild-to-moderate ulcerative colitis can achieve remission, including complete symptom resolution and mucosal healing, and remain relapse-free for at least 1 year with MMX mesalamine., (Copyright © 2009, Gastro-Hep Communications, Inc.)

Although the use of concomitant immunosuppressants (IS) with biologics has been demonstrated to reduce the immunogenicity of chimeric (infliximab), humanized (natalizumab), human (adalimumab) antibodies and antibody fragments (certolizumab pegol), to date concomitant IS with biologics has not impacted on the short or intermediate responses in the treatment of Crohn's disease in most induction and maintenance trials. The optimal strategy to reduce antibodies to infliximab is to use an induction and maintenance strategy rather than episodic therapy. Any potential benefit of concomitant IS use with biologic agents needs to be balanced against the risk of combination therapy including serious infections and the risk of neoplasia. The discovery of genetic polymorphism for production of thiopurine methyltransferase (TPMT), a key enzyme in the metabolism of thiopurine antimetabolites, has made it possible to rationalize therapy in terms of patient and dosage selection. TPMT screening prior to initiation of thiopurine antimetabolites is currently recommended to avoid treating patients with low or absent TPMT activity with potentially toxic doses of thiopurines. Routine monitoring of blood counts and liver enzymes is recommended even in individuals with normal TPMT activity. The ability to monitor thiopurine metabolites may make it possible to optimize therapeutic response by guiding clinicians on dose escalation., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

Background: Crohn's disease (CD) and multiple sclerosis (MS) share common pathogenic processes. Interferon (IFN) beta-1a is effective and generally well tolerated in patients with MS and has been shown to down-regulate the expression of interleukin-12, a cytokine that is thought to be involved in mucosal degeneration in CD. IFN beta-1a therefore offers promise as a treatment for CD., Methods: In this multicentre, double-blind, placebo-controlled, phase II, dose-finding study, patients with steroid-induced clinical remissions of CD were randomized 1:1:1:1 to subcutaneous IFN beta-1a: 66 mcg three times weekly (tiw), 44 mcg tiw, 44 mcg twice weekly (biw), or matching placebo tiw with steroid tapering. The primary endpoint was the proportion of patients relapse-free at Week 26. Safety was also assessed., Results: This study was terminated early following a planned interim analysis at 26 weeks. Of the planned 192 patients, 67 were randomized to treatment: placebo (n = 16), or IFN beta-1a 44 mcg biw (n = 17), 44 mcg tiw (n = 16) or 66 mcg tiw (n = 18). In total, 20/67 patients (29.9%) completed 26 weeks and 7 patients (10.4%) completed 52 weeks. The proportion of patients who remained relapse-free at Week 26 did not differ significantly between the placebo group (5/16, 31%) and the IFN beta-1a 44 mcg biw (6/17, 35%; p = 0.497), 44 mcg tiw (7/16, 44%; p = 0.280) or 66 mcg tiw (2/18, 11%; p = 0.333) groups. There was little difference between treatment groups in secondary efficacy endpoints. IFN beta-1a was generally well tolerated at all doses. Adverse events (AEs) were generally mild or moderate in IFN beta-1a-treated patients, with the most common AEs (influenza-like symptoms, headache, injection-site reactions) being similar to those reported with IFN beta-1a in MS., Conclusion: There was no difference in efficacy between patients with CD receiving IFN beta-1a or placebo. However, these results should be considered in the context of the low patient numbers and high dropout rate. Overall, IFN beta-1a was generally well tolerated, with a safety profile that was consistent with previous experience in MS., Trial Registration: ClinicalTrials.gov NCT00304252.

Guidelines for clinical practice are intended to suggest preferable approaches to particular medical problems as established by interpretation and collation of scientifically valid research, derived from extensive review of published literature. When data that will withstand objective scrutiny are not available, a recommendation may be made based on a consensus of experts. Guidelines are intended to apply to the clinical situation for all physicians without regard to specialty. Guidelines are intended to be flexible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are inflexible and rarely violated. Given the wide range of choices in any health-care problem, the physician should select the course best suited to the individual patient and the clinical situation presented. These guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee. Expert opinion is solicited from the outset for the document. The quality of evidence upon which a specific recommendation is based is as follows: Grade A: Homogeneous evidence from multiple well-designed randomized (therapeutic) or cohort (descriptive) controlled trials, each involving a number of participants to be of sufficient statistical power. Grade B: Evidence from at least one large well-designed clinical trial with or without randomization, from cohort or case-control analytic studies, or well-designed meta-analysis. Grade C: Evidence based on clinical experience, descriptive studies, or reports of expert committees. The Committee reviews guidelines in depth, with participation from experienced clinicians and others in related fields. The final recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientific developments at a later time.

There has been a continual evolution of therapy for Crohn's disease (CD) over the past decade since the introduction of biological therapies targeting tumor necrosis factor-alpha. Conventional agents continue to be safe and effective for patients with mild to moderately active CD and, in population series, less than half of the patients with CD require corticosteroid therapy. In contrast, patients presenting at young ages, those with extensive disease, deep ulcerations, transmural complications or extraintestinal complications that require corticosteroid therapy have a poor prognosis. Introduction of immunosuppressives late in the course or for patients with steroid-dependent or steroid-refractory disease have not changed the 'natural history' of CD or the need for eventual surgical resections. There is increasing evidence that early intervention with immunosuppressives or biologic agents at the same time as corticosteroids, or biologic agents targeting tumor necrosis factor or adhesion molecules, can have rapid and prolonged benefits, including steroid sparing, reductions in hospitalizations and, perhaps, reductions in the need for surgery. Treatment should be optimized according to the patient status and response with whichever level of therapy is introduced and maintained.

Objectives: The Crohn's Disease Activity Index (CDAI) is used to judge efficacy in clinical trials. We explored the effect of CDAI response definitions for induction on study efficiency., Methods: We analyzed primary CDAI data from induction studies in patients with mildly to moderately active Crohn's disease, not receiving concomitant aminosalicylates, corticosteroids, or immunomodulator therapy, and without fistulizing or stricturing complications. The 12 definitions of clinical response included: CDAI decrease from baseline by 50, 70, 100, or 150 points; decrease by 25% from baseline and by 70 or 100 points; CDAI <100 or 150 points; CDAI <150 points plus decrease by 70 or 100 points; CDAI <150 points at any time sustained for the duration of the trial; or decrease in the CDAI by 70 points for the last two consecutive visits. Response definitions were ranked according to ability to optimize the effect difference between treatment arms. The effect of time, baseline disease activity (CDAI 200-299 or > or =300 points), and previous surgical resections on response definitions were evaluated and ranked. Multivariate analysis on additional factors of age (<40 or > or =40 yr), gender and duration of disease (<2 or > or =2 yr) were performed to determine predictors of response when applied to these CDAI definitions., Results: Treatment effect differences in placebo-controlled studies were maximized by response definitions that incorporated either a decrease CDAI > or =70 points for the last two consecutive visits or decrease in baseline CDAI > or =100 points, and remained optimal when evaluated for the composite effect of time, baseline activity, and prior resections. A decrease in baseline CDAI > or =100 points had some advantages over a decrease CDAI > or =70 points over two visits in terms of study efficiency, as it produced a lower control response rate and was not influenced by any of the baseline factors., Conclusion: Clinical trial efficiency for induction studies in patients with mildly to moderately active Crohn's disease can be improved by using either a decrease in CDAI by > or =70 points for the last two consecutive visits or a decrease in baseline CDAI by > or =100 points as the primary end point for the trial. These findings are valid for patients with ileocecal Crohn's disease not refractory to aminosalicylates, corticosteroids, immunomodulators, and biologics, and patients who do not have stricturing or penetrating complications. It is unclear if these CDAI response criteria would similarly increase study efficiency in trials that recruited patients with moderately to severely active disease, patients refractory to aminosalicylates, corticosteroids, immunomodulators, and biologics, and patients with stricturing or penetrating complications.

Loperamide is an effective therapy for a variety of diarrheal syndromes, including acute, nonspecific (infectious) diarrhea; traveler's diarrhea; and chemotherapy-related and protease inhibitor?associated diarrhea. Loperamide is effective for the "gut-directed" symptom of diarrhea in patients with painless diarrhea or diarrhea-predominant irritable bowel syndrome. Loperamide and diphenoxylate are commonly used to treat diarrhea in numerous settings of inflammatory bowel disease. Loperamide has also been observed to increase anal sphincter tone, which may lead to improvement of fecal continence in patients with and without diarrhea. Loperamide is generally well tolerated at recommended nonprescription doses, with the most common side effects related to the impact on bowel motility (abdominal pain, distention, bloating, nausea, vomiting, and constipation).

With the introduction of biologic therapies for inflammatory bowel disease, significant questions have arisen regarding their best optimization. Although initial recommendations were to combine immunosuppressives with biologics to reduce immunogenicity, trials with 3 different anti-tumor necrosis factor agents (infliximab, adalimumab, and certolizumab) and a humanized monoclonal antibody that targets alpha-4 integrins (natalizumab) have failed to demonstrate the clinical superiority of combination therapy when high-dose induction and scheduled maintenance therapy was prescribed for up to 1 year. However, immunosuppressive agents should be considered with episodic biologic therapy to decrease immunogenicity and secondary loss of response. The issue of whether induction with biologics and maintenance therapy with immunosuppressives as monotherapy is as safe and effective as induction and maintenance with biologics alone still remains to be addressed. Further, with the use of concomitant immunosuppressives and biologics, evolving data raise concerns for an increase in adverse events, including opportunistic infections, neurological disorders, and cancer. Specific therapeutic decisions need to be individualized and the clinician must help the patient weigh quality-of-life issues with readiness to assume possible risks.

Background: More than two-thirds of ulcerative colitis patients experience at least one relapse over a period of 10 years. Treatments that reduce the likelihood of relapses also reduce the risk of long-term complications., Aim: To review three topics: the current standard of treatment for ulcerative colitis, evolving concepts in treatment, and disease modification as a treatment goal of the future., Results: Currently, 5-aminosalicylates are the standard treatment for the induction and maintenance of remission in mild-to-moderate ulcerative colitis patients. Evidence suggests that patients who take oral 5-aminosalicylates regularly are nearly six times more likely to experience regression in disease severity than those who do not. Additional treatment options such as corticosteroids, immunomodulators, biological therapies and ciclosporin are available for moderate-to-severe ulcerative colitis patients, or those who do not respond to 5-aminosalicylate. Surgery becomes pertinent for more than one-third of ulcerative colitis patients during the course of their disease. With the availability of a variety of therapies, advances in surgery and improved management strategies, a better understanding of patient treatment expectations can help improve the quality of care for ulcerative colitis patients., Conclusions: Disease modification is increasingly becoming a treatment goal in the management of ulcerative colitis. However, long-term studies are needed to examine further the disease modifying role of 5-aminosalicylates.

Background & Aims: Thiazolidinedione ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARgamma), widely used to treat type 2 diabetes mellitus, have been proposed as novel therapies for ulcerative colitis (UC)., Methods: This multicenter, randomized, double-blind, placebo-controlled clinical trial compared the efficacy of rosiglitazone (Avandia; GlaxoSmithKline, Philadelphia, PA) 4 mg orally twice daily vs placebo twice daily for 12 weeks in 105 patients with mild to moderately active UC. Disease activity was measured with the Mayo score. The primary end point was clinical response (>/=2-point reduction) at week 12. Clinical remission (Mayo score

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor (TNF) alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non-systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine (6-MP) and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn's disease, and infliximab is also approved for the treatment of UC.

Background: Delayed-release oral mesalamine 2.4 g/day to 4.8 g/day has been shown to be effective in treating mildly to moderately active ulcerative colitis (UC), but it is unknown whether an initial dose of 4.8 g/day is more effective than 2.4 g/day in patients with mildly to moderately active UC and in the subgroup with moderate disease., Patients and Methods: A six-week, multicentre, randomized, double-blind, controlled trial assessing the safety and clinical efficacy of a new dose (ASCEND I) of medication randomly assigned 301 adults with mildly to moderately active UC to delayed-release oral mesalamine 2.4 g/day (400 mg tablet [n=154]) or 4.8 g/day (800 mg tablet [n=147]). The primary efficacy end point was overall improvement (ie, treatment success), defined as complete remission or response to therapy from baseline to week 6. Primary safety end points were adverse events and laboratory evaluations. Data were also analyzed separately for the prespecified subgroup of patients with moderate UC at baseline., Results: Treatment success was not statistically different between the treatment groups at week 6; 51% of the group (77 of 150) who received delayed-release oral mesalamine 2.4 g/day and 56% of the group (76 of 136) who received 4.8 g/day reached the efficacy end point (P=0.441). Among the moderate disease subgroup, however, the higher initial dose was more effective; 57% of patients (53 of 93) given delayed-release oral mesalamine 2.4 g/day and 72% of patients (55 of 76) given 4.8 g/day achieved treatment success (P=0.0384). Both regimens were well tolerated., Conclusions: Delayed-release oral mesalamine is an effective and well-tolerated initial therapy in patients with mildly to moderately active UC, and a 4.8 g/day dose may enhance treatment success rates in patients with moderate disease compared with mesalamine 2.4 g/day.

Background: The efficacy of the nonabsorbable antibiotic rifaximin in patients with active acute or chronic pouchitis is unknown., Methods: We performed a placebo-controlled pilot trial to evaluate the efficacy and safety of rifaximin in patients with active pouchitis. Eighteen patients with active pouchitis were randomized to receive oral rifaximin 400 mg or placebo 3 times daily for 4 weeks. Active pouchitis was defined as a total Pouchitis Disease Activity Index (PDAI) score = 7 points. Clinical remission was defined as a PDAI score <7 points and a decrease in the baseline PDAI score = 3 points. The primary analysis was clinical remission at week 4., Results: Eight patients were randomized to rifaximin and 10 patients were randomized to placebo. One patient in the placebo group did not have a post-baseline efficacy evaluation and was excluded from the efficacy analysis. Two of 8 patients (25%) treated with rifaximin were in clinical remission at week 4 compared to 0 of 9 patients (0%) treated with placebo (P = 0.2059). None of 8 patients in the rifaximin group withdrew from the trial prior to week 4. Two of 9 patients in the placebo group withdrew prior to week 4 due to lack of efficacy and were categorized as treatment failures., Conclusions: Clinical remission occurred more frequently in patients treated with rifaximin 400 mg 3 times daily but the difference was not significant in this pilot study. A larger trial would be required to determine if rifaximin is effective for the treatment of active pouchitis. Rifaximin was well tolerated.