Daniel H. Present

Early Mucosal Healing With Infliximab Is Associated With Improved Long-term Clinical Outcomes in Ulcerative Colitis

BACKGROUND & AIMS In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergo remission, and have mucosal healing. We investigated the association between early improvement (based on endoscopy) and subsequent clinical outcome. METHODS Patients underwent endoscopic evaluations at weeks 0, 8, 30, and 54 (ACT-1 only), and were categorized into 4 subgroups by week 8 (Mayo endoscopy subscore, 0-3). The association of week 8 endoscopy subscores, subsequent colectomy risk, symptoms and corticosteroid use outcomes were analyzed. Mucosal healing was defined as a Mayo endoscopy subscore of 0 (normal) or 1 (mild). RESULTS Infliximab-treated patients with lower week 8 endoscopy subscores were less likely to progress to colectomy through 54 weeks of follow-up evaluation (P=.0004). This trend was not observed among patients given placebo (P=.47). Patients with lower endoscopy subscores achieved better symptomatic and corticosteroid use outcomes at weeks 30 and 54 (P<.0001, infliximab; P<.01, placebo). Among patients who achieved clinical response at week 8, trends in subsequent clinical outcomes by week 8 endoscopy subscores were generally consistent with that for the overall patient population; no trends were observed among patients who achieved clinical remission. CONCLUSIONS The degree of mucosal healing after 8 weeks of infliximab was correlated with improved clinical outcomes including colectomy. Similar trends were observed for all outcomes except colectomy among the subgroup with clinical response at week 8. The degree of mucosal healing at week 8 among those in clinical remission did not predict subsequent disease course.

Colectomy Rate Comparison After Treatment of Ulcerative Colitis With Placebo or Infliximab

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.

Colonoscopic polypectomy in chronic colitis: Conservative management after endoscopic resection of dysplastic polyps

BACKGROUND & AIMS Adenomatous polyps are by definition dysplastic and pathologically indistinguishable from the dysplasia-associated lesion or mass (DALM) described in 1981. Yet, adenomatous polyps in noncolitic colons are usually removed definitively endoscopically, whereas DALMs are regarded as harbingers of colon cancer, mandating colectomy. METHODS Since 1988, all of our patients with chronic ulcerative or Crohns colitis and dysplastic polyps and no coexistent dysplasia in flat mucosa underwent colonoscopic polypectomy. Biopsy specimens were obtained also adjacent to polypectomy sites, from strictures, and throughout the colon at 10-cm intervals. Follow-up colonoscopies and biopsies were performed within 6 months after polypectomy and yearly thereafter. RESULTS Colonoscopy in 48 patients with chronic colitis (mean duration, 25.4 years) resected 70 polyps (60 in colitic and 10 in noncolitic mucosa). Polyps were detected on screening colonoscopies (29%) and on surveillance (71%). Pathology was tubular adenoma in all polyps from noncolitic mucosa and low-grade dysplasia (57), high-grade dysplasia (2), or carcinoma (1) in polyps from colitic mucosa. Subsequent colonoscopies (mean follow-up, 4.1 years) revealed additional polyps in 48% but no carcinomas. Surgical resection (6 patients) for recurrent polyps confirmed colonoscopic findings. No dysplasia or cancers in flat mucosa were found at surgery or on follow-up colonoscopies. CONCLUSIONS In patients with chronic colitis who have no dysplasia in flat mucosa, colonoscopic resection of dysplastic polyps can be performed effectively, just as in noncolitic colons.

Cyclosporine and Infliximab as Rescue Therapy for Each Other in Patients With Steroid-Refractory Ulcerative Colitis

BACKGROUND & AIMS In patients with severe corticosteroid-refractory ulcerative colitis, cyclosporine or infliximab may be added in an effort to induce remission. If the patient then fails either of these drugs, it is unknown whether success can be achieved by using the other agent. The aim of this study was to assess outcomes of using cyclosporine after failure of infliximab, and vice versa. METHODS We retrospectively reviewed the charts of 19 patients with corticosteroid-refractory ulcerative colitis who received either infliximab after failed cyclosporine or cyclosporine after failed infliximab. Acute salvage therapy was defined as having received the alternate drug within 4 weeks of discontinuing the first agent. RESULTS Ten patients received infliximab after failing cyclosporine; 9 patients received cyclosporine after failing infliximab. Four patients (40%) in the infliximab-salvage group achieved remission, as did 3 (33%) in the cyclosporine-salvage group. Remission lasted a mean of 10.4 months (range, 4.4-17.03 mo) and 28.5 months (range, 5.0-41.5 mo), respectively. Severe adverse events included one patient who developed sepsis and died after receiving infliximab salvage. One patient who received cyclosporine salvage developed herpetic esophagitis, and another patient who received cyclosporine salvage developed pancreatitis and bacteremia. CONCLUSIONS In patients with severe corticosteroid-refractory ulcerative colitis who fail treatment with either cyclosporine or infliximab, remission rates using acute salvage therapy by crossing over to the other drug occur in approximately one third of patients and have limited duration. Serious adverse events occurred in 16%, including 1 death, suggesting that the risks of acute salvage therapy may outweigh the benefits.

Long-term infliximab maintenance therapy for ulcerative colitis: the ACT-1 and -2 extension studies.

Background: The aim was to evaluate long‐term efficacy, quality of life, and safety in ulcerative colitis patients who received infliximab during the ACT‐1 and ‐2 extension studies. Methods: Adults with moderate‐to‐severely active ulcerative colitis in the 54‐week ACT‐1 and 30‐week ACT‐2 studies who achieved benefit from infliximab were eligible to participate in extension studies and receive up to 3 additional years of therapy. Patients received randomized study medication until all sites were unblinded; placebo‐treated patients were discontinued. Patients receiving 5 or 10 mg/kg infliximab continued to receive open‐label infliximab every 8 weeks. Patients receiving infliximab 10 mg/kg could decrease to 5 mg/kg; patients receiving infliximab 5 mg/kg could increase to 10 mg/kg if response was lost. Results: A total of 229 of 484 infliximab‐treated patients from the ACT‐1 and ACT‐2 main studies entered the long‐term extensions. Overall, 70 (30.6%) patients discontinued infliximab infusions for adverse events (24 [10.5%]), lack of efficacy (11 [4.8%]), required a colectomy (1 [0.4%]), or for other reasons (34 [14.8%]). Proportions of patients whose Physicians Global Assessment scores were indicative of no or mild disease (score = 0 or 1) were maintained during the extension studies; 76.5% at Extension week 0 and ranged between 90.0% and 94.3% through Extension week 152. Improvement in Inflammatory Bowel Disease Questionnaire scores observed in the main studies was maintained. During the long‐term extension, the infliximab safety profile was consistent with that of the main studies; no new or unexpected safety signals were observed. Conclusions: Long‐term treatment with infliximab for up to 3 additional years was effective and well tolerated. (Inflamm Bowel Dis 2011;)

Nature and course of pancreatitis caused by 6-mercaptopurine in the treatment of inflammatory bowel disease

6-Mercaptopurine (6-MP) has an important role in the treatment of inflammatory bowel disease. Its most frequent short-term complication has proven to be pancreatitis, which we have now seen in 13 of 400 (3.25%) patients (12 Crohns disease, 1 ulcerative colitis) and which we here describe. The timing of the pancreatitis was such that it could not be attributed to sulfasalazine, which was also being taken by 9 patients, or corticosteroids, which were being taken by 7 patients. The dosage of 6-MP ranged from 50 to 100 mg daily, and the pancreatitis, which was uncomplicated in all cases, occurred within 8-32 days with one exception (6.5 mo). Symptoms included epigastric pain, back pain, fever, and nausea. The serum amylase was elevated in 12 patients. The average elevation was 5.9 times normal. In all cases, the 6-MP was discontinued and symptoms and signs returned to normal over a period of 1-11 days. No other complications of 6-MP occurred; there was no leukopenia. Of 7 patients rechallenged with 6-MP, all developed recurrent pancreatitis, including 4 in less than 24 h. In 3 patients, desensitization attempted by a gradual increase in dose from 1/8 tablet (approximately 6 mg) daily also led to recurrence. The timing of the initial pancreatitis and the recurrence at rechallenge are best explained by an allergic reaction. 6-Mercaptopurine should not be reinstituted once it has caused pancreatitis.

Relapses of Inflammatory Bowel Disease During Pregnancy: In-Hospital Management and Birth Outcomes

BACKGROUND:There are few studies that describe the medical treatment and colitis response rates among patients with a severe relapse of inflammatory bowel disease (IBD) during pregnancy, and few studies of the effect of such a relapse on birth outcomes in these patients.OBJECTIVES:To describe the treatment and response rates of severe colitis in pregnancy, and to assess the effects of a severe relapse of colitis during pregnancy on birth outcomes.METHODS:We performed a case control study of pregnant patients with IBD hospitalized for a disease relapse at two large treatment centers between 1989 and 2001. Details of management of disease relapse and maternal and fetal outcomes were recorded.RESULTS:Eighteen patients (11 ulcerative colitis, 6 Crohns disease, 1 indeterminate colitis), mean age 28.6 yr (range 19–38) formed the study group; 41 age-matched pregnant IBD patients without disease relapse formed the control group. Study patients were hospitalized at a mean of 15.9-wk gestation (range 8–35) for a mean of 10.4 days (range 3–31). All 18 patients received IV hydrocortisone (mean dose 199 mg/day) and 7 patients (39%) either continued taking or were commenced on immunomodulators: IV cyclosporine (5 patients) and azathioprine/6-MP (3 patients). Fifteen patients (83%) had a clinical response to these medical treatments, 3 patients required colectomy. There were significant differences between study and control groups in gestation period (35.0 wk vs 38.7 wk, respectively, P = 0.0001) and birth weight (2,001 g vs 3,018 g, respectively, P < 0.0001).CONCLUSIONS:Treatment with IV hydrocortisone and IV cyclosporine appears effective at inducing remission of colitis but their use must continue to be confined to severely ill patients being treated at specialized centers. Severe relapses of colitis during pregnancy increase the risk of preterm birth and low birth weight.

The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn’s disease who failed prior infliximab therapy

Aliment Pharmacol Ther 2010; 32: 1228–1239

How to do without steroids in inflammatory bowel disease.

This review covers the use of steroids in the treatment of both ulcerative colitis and Crohns disease. It looks at controlled trials and uncontrolled trials as to the benefits of this agent in both inducing and maintaining remission. The review also stresses the high incidence of toxicity with prolonged use of steroids and the fact that controlled trials have clearly shown that steroids do not maintain remission in either disorder. Alternatives to initiating steroids in mild to moderately active ulcerative colitis and Crohns disease are presented. The use of steroids in fistulizing versus nonfistulizing Crohns is also covered. Finally, there is a review of data and discussion of the role of antibiotics, immunosuppressives, and combination therapy for both ulcerative colitis and Crohns disease. The expectation is that the reader will consider alternatives to initiating and maintaining steroids for prolonged periods of time in the treatment of inflammatory bowel disease.

Intravenous cyclosporine in refractory pyoderma gangrenosum complicating inflammatory bowel disease

BackgroundPyoderma gangrenosum complicates inflammatory bowel disease in 2–3% of patients and often fails to respond to antibiotics, steroids, surgical debridement or even colectomy. MethodsWe performed a retrospective chart analysis of 11 consecutive steroid-refractory pyoderma patients (5 ulcerative colitis, 6 Crohns disease) referred to our practice and then treated with intravenous cyclosporine. Pyoderma gangrenosum was present on the extremities in 10 patients, the face in 2, and stomas in 2. At initiation of intravenous cyclosporine, bowel activity was moderate in 3 patients, mild in 4, and inactive in 4. All patients received intravenous cyclosporine at a dose of 4 mg/kg/d for 7–22 days. They were discharged on oral cyclosporine at a dose of 4–7 mg/kg/d. ResultsAll 11 patients had closure of their pyoderma with a mean time to response of 4.5 days and a mean time to closure of 1.4 months. All seven patients with bowel activity went into remission. Nine patients were able to discontinue steroids, and nine were maintained on 6-mercaptopurine or azathioprine. One patient who could not tolerate 6-mercaptopurine had a recurrence of pyoderma. No patient experienced significant toxicity. ConclusionIntravenous cyclosporine is the treatment of choice for pyoderma gangrenosum refractory to steroids and 6-mercaptopurine should be used as maintenance therapy.