Faculty Bibliography

BACKGROUND AND AIMS: Our understanding of malignancy associated with immunosuppression in patients with inflammatory bowel disease (IBD) comes from studies of individuals with no history of cancer. We investigated whether patients with IBD and a history of cancer who were subsequently immunosuppressed have an increased risk of developing incident cancer. METHODS: We performed a retrospective analysis of data from 333 patients with IBD treated at 7 academic medical centers who developed cancer and subsequently received treatment with anti-tumor necrosis factor (TNF), anti-TNF with an anti-metabolite (thiopurines, methotrexate), anti-metabolites, or no subsequent exposure to immunosuppressive agents (controls). We collected data on their primary outcomes of incident cancers (new or recurrent). Hazard ratios (HRs) were calculated using Cox proportional hazards and Kaplan-Meier survival curves; study groups were compared using the Log-Rank test. RESULTS: During the follow-up period, 90 patients (27%) developed an incident cancer. Patient characteristics between groups differed, but matching was not possible due to the relatively small sample sizes. There was no difference in time to (p=0.14) or type of (p= 0.61) incident cancer among the 4 groups. After adjusting for recurrence risk for type of prior cancer, there was no difference in risk of incident cancer (HR for anti-TNF=0.32; 95% confidence interval [CI], 0.09-1.09; HR for anti-TNF with an anti-metabolite=0.64; 95% CI, 0.26-1.59; HR for an anti-metabolite=1.08; 95% CI, 0.54-2.15) or time to subsequent cancer between study arms (p=.22). CONCLUSION: Based on a retrospective study, in patients with IBD and a history of cancer, exposure to an anti-TNF agent or an anti-metabolite following cancer was not associated with an increased risk of incident cancer, compared to patients who did not receive immunosuppression. Larger, matched, prospective studies are needed to confirm these findings.

Purpose This study was designed to describe a polyp or cluster of polyps limited to the sigmoid as a marker of ileo-sigmoid fistulae (ISF) in patients with ileitis. These fistulas are frequently undiagnosed prior to surgery and this novel finding will increase a gastroenterologist's opportunity to detect them pre-operatively and their prognostic implication of worsening ileitis. Method The medical records of patients with Crohn's disease and ISF were reviewed to determine whether colonoscopy had revealed polyposis limited to the sigmoid and its frequency. Results Thirty-seven patients (18 men) with Crohn's ileitis were identified from our database with ISF. Twenty had one or more sigmoid polyps without polyps elsewhere in the colon suggesting the site of fistula exit. Fifteen of the patients had ISF and 5 ileo-rectal fistula (IRF). Detection of the fistula was made by various means including colonoscopy, sigmoidoscopy, small bowel x-ray series, barium enema, CT scan or MRE. The ISF was generally diagnosed prior to the recognition and significance of the segmental polyps. These polyps were inflammatory or hyperplastic on pathologic review. Conclusion Most ISF and IRF are now found pre-operatively by imaging and some are incidental surgical findings. The segmental sigmoid polyps that we describe should help the gastroenterologist to be suspicious of ISF. The polyps are a surrogate marker for the progression of the fistulas and the underlying ileitis as they tend to appear after the fistula has matured and lead to increased intensity of medical therapy well before surgical intervention is required.

Two large studies concluded that AZA started early after diagnosis of Crohn's disease have no late maintenance value. This is contrary to previous studies on 6MP for Crohn's disease and could lead to negating the value of two of the few drugs that have been proven successful. We here outline the many reasons why 6MP remains a valuable drug in the treatment of Crohn's disease.

AIM: To search for the answer in extensive ulcerative colitis as to whether histological inflammation persisting despite endoscopic mucosal healing serves to increase the risk of colon cancer (CC) or high grade dysplasia (HGD). METHODS: This is a single center (Lenox Hill Hospital) retrospective cohort and descriptive study of extensive ulcerative colitis (UC) for 20 years or more with a minimum of 3 surveillance colonoscopies and biopsies performed after the first 10 years of UC diagnosis. Data analyzed included: duration of UC, date of diagnosis of (CC) or (HGD), number of surveillance colonoscopies, and biopsies showing histological inflammation and its severity in each of 6 segments when endoscopic appearance is normal. Two subgroups of patients were compared: group 1 patients who developed CC/HGD and group 2 patients who did not develop CC/HGD. RESULTS: Of 115 patients with longstanding UC reviewed, 68 patients met the inclusion criteria. Twenty patients were in group 1 and 48 in group 2. We identified the number of times for each patient when the endoscopic appearance was normal but biopsies nevertheless showed inflammation. Overall, histological disease activity in the absence of gross/endoscopic disease was found in 31.2% (95%CI: 28%-35%) of colonoscopies performed on the entire cohort of 68 patients. Histological disease activity when the colonoscopy showed an absence of gross disease activity was more common in group 1 than group 2 patients, 88% (95%CI: 72%-97%) vs 59% (95%CI: 53%-64%). Only 3/20 (15%) of patients in group 1 ever had a colonoscopy completely without demonstrated disease activity (i.e., no endoscopic or histological activity) as compared to 37/48 (77%) of patients in group 2, and only 3.3% (95%CI: 0.09%-8.3%) of colonoscopies in group 1 had no histological inflammation compared to 23% (95%CI: 20%-27%) in group 2. CONCLUSION: Progression to HGD or CC in extensive ulcerative colitis of long standing was more frequently encountered among those patients who demonstrate persistent histological inflammation in the absence of gross mucosal disease. Our findings support including the elimination of histological inflammation in the definition of mucosal healing, and support this endpoint as an appropriate goal of therapy because of its risk of increasing dysplasia and colon cancer.

Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immunosuppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corticosteroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn's disease as well. Not much was ever made of the role of sulfasalazine for Crohn's disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-aminosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn's colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in patients with ulcerative colitis, but its placebo controlled trial for Crohn's disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless clinicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn's disease. What changes have taken place utilizing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960's and 1970's and its trial for Crohn's disease published in the New England Journal of Medicine in 1980?

BACKGROUND: : Patients with ulcerative colitis and Crohn's colitis have an increased risk of colon cancer influenced by the duration, extent, and severity of disease. Surveillance colonoscopy serves to detect cancer and precancerous dysplasia at the earliest possible time. Reduction of inflammation should theoretically reduce the development of cancer. Immunosuppressives should do so, but there is a fear that indeed the risk of cancer might be increased with their use. Our study was conducted to determine whether a relationship exists between receiving treatment with 6-MP for ulcerative and Crohn's colitis and increasing or decreasing the incidence of colorectal cancer (CRC). METHODS: : We conducted a single-center, retrospective cohort study of patients with long standing colitis (ulcerative and Crohn's) using the database of the senior investigator (B.I.K.). Two groups were matched based on their propensity to receive treatment with 6-MP; one group received 6-MP treatment, the other did not. Both groups were compared on the incidence of colon cancer. RESULTS: : No significant differences existed between the two cohorts with regard to type of disease, duration, extent, age, and sex. Six out of 27 patients not on 6-MP and seven out of 27 patients on 6-MP developed CRC (P= 1). CONCLUSIONS: : We conclude that there is neither sufficient evidence currently to state that 6-MP is associated with an increased development of CRC, nor that it has a chemopreventive effect.