Ulcerative Colitis: Tremaine WJ

Tremaine WJ. · No affiliation provided · Clin Gastroenterol Hepatol. · Pubmed #17368229 No free full text.

This publication has no abstract.

Tremaine WJ, Camilleri M. · Division of Gastroenterology and Hepatology, Fiterman Center, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Inflamm Bowel Dis. · Pubmed #17352385 links to  free full text

Abstract: Physicians often take on responsibilities beyond medical care regarding their patients with ulcerative colitis and Crohn's disease: they serve as the patients' advocates to nonmedical entities and individuals, including insurance companies, schools, employers, companions, and family members. These responsibilities create a more complex relationship between the patient and their IBD physician. In addition, these responsibilities may accentuate ethical issues for the physician who is also engaged in clinical treatment trials for inflammatory bowel disease (IBD). Ethical issues include therapeutic misconception, clinical equipoise, and financial and nonfinancial conflicts of interest. Physicians who refer patients with IBD to enroll in treatment trials, as well as clinician investigators who conduct studies should consider measures to clarify the separation between clinical care and participation in a therapeutic study, and to ensure the ethical treatment of patients. These precautionary measures may include payment of participants to emphasize that the research study is different from clinical care, consent by an investigator other than the treating physician, and care to disclose conflicts of interest to the patient and the medical community in presentations and publications. If the financial conflict is too great, a physician should not participate in the clinical trial.

Tremaine WJ. · Mayo Clinic, Rochester, Minnesota 55905, USA. · J Clin Gastroenterol. · Pubmed #10777181 No free full text.

Abstract: The most recently recognized and least understood forms of inflammatory bowel disease are two types of idiopathic microscopic colitis-collagenous colitis and lymphocytic colitis. These disorders share many clinical and histologic features, but they have a few notable differences. Whether these are two distinct entities or different presentations of the same disease remains controversial. Bismuth subsalicylate is effective in some patients and treatment is symptomatic and empirical in others. Unlike ulcerative colitis and Crohn's disease, these forms of inflammatory bowel disease rarely require surgery. Ileostomy with or without colectomy is curative for the rare patient with severe symptoms that are refractory to medical measures. Collagenous and lymphocytic colitis are not associated with an increased risk of malignancy.

Tremaine WJ, Brzezinski A, Katz JA, Wolf DC, Fleming TJ, Mordenti J, Strenkoski-Nix LC, Kurth MC, Anonymous00162. · Mayo Clinic, Rochester, MN 55905, USA. · Aliment Pharmacol Ther. · Pubmed #11876693 links to  free full text

Abstract: BACKGROUND: Mast cells isolated from the colonic mucosa in active ulcerative colitis appear to be partially degranulated, suggesting the release of tryptase. AIM: To investigate the safety and activity of APC 2059, a highly specific tryptase inhibitor, in the treatment of ulcerative colitis. METHODS: This was an open-label, Phase 2, multicentre pilot study in patients with mildly to moderately active ulcerative colitis, with a disease activity index of 6-9 on a 12-point scale. Fifty-six adults received 20 mg APC 2059 subcutaneously twice daily and 53 completed 28 days of treatment. The primary end-point was response, defined as a final disease activity index of < or = 3. Supplementary analyses were also performed. RESULTS: Sixteen (29%) of 56 patients responded. Five (9%) showed complete remission (disease activity index=0). Twenty-seven (49%) improved, with a final disease activity index of < or = 3 or a four-point reduction. Improvement or normalization in each category of the disease activity index was as follows: stool frequency, 64%; bleeding, 64%; endoscopy, 50%; physicians' rating, 63%. There were no significant relationships between outcome and pharmacokinetics. The most common adverse events were related to the injection site (32.1%). CONCLUSIONS: In this pilot study, the tryptase inhibitor APC 2059 was safe and there was evidence of activity in the treatment of ulcerative colitis.

Sands BE, Tremaine WJ, Sandborn WJ, Rutgeerts PJ, Hanauer SB, Mayer L, Targan SR, Podolsky DK. · Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston 02114, USA. · Inflamm Bowel Dis. · Pubmed #11383595 No free full text.

Abstract: We report the experience of 11 patients (of 60 planned patients) enrolled in a double-blind, placebo-controlled clinical trial of infliximab in patients with severe, active steroid-refractory ulcerative colitis. The study was terminated prematurely because of slow enrollment. Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5, 10, or 20 mg/kg body weight. The primary endpoint used in this study was treatment failure at 2 weeks after infusion. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. Safety evaluations included physical examination, clinical chemistry and hematology laboratory tests, and occurrence of adverse experiences. Four of 8 patients (50%) who received infliximab were considered treatment successes at 2 weeks, compared with none of 3 patients who received placebo. Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab. Infusion with infliximab produced no significant adverse events. Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory ulcerative colitis.

Mahadevan U, Tremaine WJ, Johnson T, Pike MG, Mays DC, Lipsky JJ, Sandborn WJ. · Division of Gastroenterology and Hepatology, University of California, San Francisco, USA.) · Am J Gastroenterol. · Pubmed #11151878 No free full text.

Abstract: OBJECTIVE: Azathioprine use in acute ulcerative colitis has been limited by its perceived long onset of action. The aim of this study was to determine the safety and clinical effect of an i.v. loading dose of azathioprine in the setting of severe steroid refractory ulcerative colitis. METHODS: Nine hospitalized patients with severe steroid refractory ulcerative colitis were enrolled. Patients 1-3 received 20 mg/kg i.v. azathioprine over 36 h. Patients 4-6 received 40 mg/kg i.v. azathioprine over 36 h. Patients 7-9 received 40 mg/kg i.v. azathioprine as three 8-h infusions over 3 days. Clinical remission was defined as steroid withdrawal and an Ulcerative Colitis Disease Activity Index score of 0. The Inflammatory Bowel Disease Questionnaire was obtained at each visit. White blood cell concentrations and erythrocyte concentrations of 6-thioguanine were obtained. RESULTS: Five of nine patients (56%) had a response and avoided colectomy. Three of nine patients (33%) met the definition for clinical remission. Response was seen within 4 wk. The mean 6-thioguanine concentration for those five patients at 12 wk after infusion was 148.2 pmol/8 x 10(8). Two patients had transient leukopenia and one had transient hepatotoxicity. CONCLUSIONS: Intravenous azathioprine appears to be safe and of clinical benefit in inducing response and avoiding colectomy in severe steroid refractory ulcerative colitis. Data from an i.v. azathioprine trial in Crohn's disease suggests oral dosing alone may obtain the same results. The role of oral dosing alone in severe ulcerative colitis and the role of azathioprine metabolite levels in monitoring efficacy should be investigated further.

Egan LJ, Sandborn WJ, Tremaine WJ, Leighton JA, Mays DC, Pike MG, Zinsmeister AR, Lipsky JJ. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA. · Aliment Pharmacol Ther. · Pubmed #10594394 links to  free full text

Abstract: BACKGROUND AND AIMS: The optimum initial dose of methotrexate for steroid-requiring inflammatory bowel disease is not known. AIM: To compare directly the efficacy and toxicity of methotrexate 15 and 25 mg/week, and to explore the value of methotrexate blood levels as predictors of outcome. METHODS: A 16-week randomized single-blind comparison of subcutaneous methotrexate 15 or 25 mg/week was performed in 32 patients with steroid-requiring Crohn's disease or ulcerative colitis. Patients who did not respond to methotrexate 15 mg/week were further studied for an additional 16 weeks on methotrexate 25 mg/week. Blood was drawn every 2 weeks for methotrexate levels. RESULTS: After 16 weeks, 17% of patients in each group achieved remission; 39% of patients randomized to 15 mg/week and 33% of patients randomized to 25 mg/week improved (P=N.S. ). Clinical status improved in four out of 11 patients after methotrexate dose escalation from 15 to 25 mg/week. Toxicity was not different between the treatment groups. Methotrexate blood levels did not predict efficacy or toxicity. CONCLUSIONS: For induction of remission in steroid-requiring inflammatory bowel disease, subcutaneous methotrexate at initial doses of 15 and 25 mg/week are equally efficacious. At these doses, response is not associated with blood methotrexate concentrations.

Louvet B, Buisine MP, Desreumaux P, Tremaine WJ, Aubert JP, Porchet N, Capron M, Cortot A, Colombel JF, Sandborn WJ. · Laboratoire de recherche sur les MICI (CRI 4U004B), Centre Hospitalier Universitaire (CHU), Lille, France. · Inflamm Bowel Dis. · Pubmed #10453373 No free full text.

Abstract: Our goal was to determine the effect of transdermal nicotine on cytokine and mucin gene transcription in ulcerative colitis (UC). Sixty-four nonsmoking patients with active UC were randomly assigned to transdermal nicotine (maximum dose 22 mg/day) or placebo for 4 weeks. Clinical assessment and colonic mucosal biopsies were obtained at entry and after 4 weeks. Inflammatory and immunoregulatory cytokines were assessed by qualitative reverse transcriptase-polymerase chain reaction (RT-PCR). Based on this initial screen. IL-8 mRNA levels were measured by RT-competitive PCR. MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, and MUC6 mRNA concentrations were measured by quantitative dot blot analysis. Cytokine mRNA expression, except for IL-8, was similar in all patients. IL-8 mRNA levels were significantly decreased in the colonic mucosa of nicotine-treated patients who improved (p = 0.04). IL-8 mRNA values were similar before and after treatment in nonresponding nicotine-treated patients and in all placebo-treated patients. Mucin gene expression was similar in all patient groups. Beneficial effects of transdermal nicotine in active UC may result from decrease of IL-8 expression at the transcriptional level. Transdermal nicotine has no effect on mucin gene transcription.

Pardi DS, Loftus EV, Tremaine WJ, Sandborn WJ, Alexander GL, Balm RK, Gostout CJ. · Inflammatory Bowel Disease Clinic and GI Bleeding Team, Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota, USA. · Gastrointest Endosc. · Pubmed #9925691 No free full text.

Abstract: BACKGROUND: Acute major gastrointestinal hemorrhage is uncommon in inflammatory bowel disease. METHODS: We characterized the clinical features and course of such hemorrhage in patients at our institution from 1989 to 1996. RESULTS: Thirty-one patients had acute lower gastrointestinal bleeding from inflammatory bowel disease and one had upper gastrointestinal bleeding from duodenal Crohn's disease. Three patients had ulcerative colitis and 28 had Crohn's disease, representing 0.1% of admissions for ulcerative colitis and 1.2% for Crohn's disease. In addition, another patient bled from an ileal J-pouch. In patients with Crohn's disease, the site of bleeding was duodenal in 1, small intestinal in 9, ileocolonic in 8, and colonic in 10. All ulcerative colitis patients had pancolitis. Medical therapy was initiated in 27 patients, including endoscopic therapy in 3. Five patients underwent surgery immediately, and 7 medically treated patients eventually required surgery for ongoing or recurrent bleeding. CONCLUSIONS: Acute major gastrointestinal bleeding is uncommon in inflammatory bowel disease. Most cases are due to Crohn's disease, without a predilection for site of involvement. The presence of an endoscopically treatable lesion is uncommon, and surgery is required in less than half of cases during the initial hospitalization. Recurrent hemorrhage is not rare, and for these cases surgery may be the most appropriate treatment.

Tremaine WJ, Timmons LJ, Loftus EV, Pardi DS, Sandborn WJ, Harmsen WS, Thapa P, Zinsmeister AR. · Division of Gastroenterology and Hepatology, Fiterman Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Aliment Pharmacol Ther. · Pubmed #17539983 No free full text.

Abstract: BACKGROUND: There is conflicting data regarding the response to medical and surgical therapy for inflammatory bowel disease with respect to age at disease onset. AIM: To determine if the age at onset of Crohn's disease and ulcerative colitis is a risk factor for surgery for non-neoplastic bowel disease. METHODS: This was a case-control study of patients evaluated between 1998 and 2001. Cases had undergone an initial operation for bowel disease. Controls were matched 1:1 for gender, disease subtype, date of first visit (+/-2 years), time from diagnosis prior to first visit (+/-3 years) and duration of follow-up. Association with age, disease extent, smoking history, medication use and co-morbidities vs. case/control status was assessed using multiple variable conditional logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (CI) for undergoing surgery. RESULTS: Among 132 Crohn's patients, older patients had lower odds for surgery (OR per 5 years, 0.86; 95% CI: 0.75-0.98). The rate of surgery for non-neoplastic bowel disease was not significantly associated with disease distribution, co-morbidities or cigarette smoking. Among 234 ulcerative colitis patients, the rate of surgery was unrelated to age, disease extent, co-morbidities or cigarette smoking, CONCLUSIONS: For Crohn's disease, but not ulcerative colitis, the risk of surgery for non-neoplastic bowel disease decreases with increasing age at diagnosis, irrespective of disease distribution and history of cigarette smoking.

Loftus CG, Loftus EV, Harmsen WS, Zinsmeister AR, Tremaine WJ, Melton LJ, Sandborn WJ. · Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. · Inflamm Bowel Dis. · Pubmed #17206702 links to  free full text

Abstract: BACKGROUND: We previously reported that the prevalence of Crohn's disease (CD) and ulcerative colitis (UC) in Olmsted County, Minnesota, had risen significantly between 1940 and 1993. We sought to update the incidence and prevalence of these conditions in our region through 2000. METHODS: The Rochester Epidemiology Project allows population-based studies of disease in county residents. CD and UC were defined by previously used criteria. County residents newly diagnosed between 1990 and 2000 were identified as incidence cases, and persons with these conditions alive and residing in the county on January 1, 2001, were identified as prevalence cases. All rates were adjusted to 2000 US Census figures for whites. RESULTS: In 1990-2000 the adjusted annual incidence rates for UC and CD were 8.8 cases per 100,000 (95% confidence interval [CI], 7.2-10.5) and 7.9 per 100,000 (95% CI, 6.3-9.5), respectively, not significantly different from rates observed in 1970-1979. On January 1, 2001, there were 220 residents with CD, for an adjusted prevalence of 174 per 100,000 (95% CI, 151-197), and 269 residents with UC, for an adjusted prevalence of 214 per 100,000 (95% CI, 188-240). CONCLUSION: Although incidence rates of CD and UC increased after 1940, they have remained stable over the past 30 years. Since 1991 the prevalence of UC decreased by 7%, and the prevalence of CD increased about 31%. Extrapolating these figures to US Census data, there were approximately 1.1 million people with inflammatory bowel disease in the US in 2000.

Laing AW, Pardi DS, Loftus EV, Smyrk TC, Kammer PP, Tremaine WJ, Schleck CD, Harmsen WS, Zinsmeister AR, Melton LJ, Sandborn WJ. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Inflamm Bowel Dis. · Pubmed #16917225 No free full text.

Abstract: BACKGROUND: Microscopic colitis is a common cause of chronic watery diarrhea of unknown origin. Some patients develop diarrhea after cholecystectomy, and some patients with microscopic colitis have evidence of bile acid malabsorption. However, the association between cholecystectomy and microscopic colitis has not been studied. A protective effect of appendectomy on the development of ulcerative colitis also has been reported, but its relationship with microscopic colitis has not been studied. The aim of this study was to assess cholecystectomy and appendectomy as potential risk factors for the development of microscopic colitis in a nested case-control study. MATERIALS AND METHODS: Using the Rochester Epidemiology Project, we identified all Olmsted County (Minnesota) residents with an initial diagnosis of microscopic colitis between January 1, 1985, and December 31, 2001. Rates of antecedent cholecystectomy or appendectomy in patients with microscopic colitis were compared with age-, gender-, and calendar year-matched community controls through conditional logistic regression. RESULTS: Microscopic colitis was identified in 130 cases. Cholecystectomy preceded the diagnosis of microscopic colitis in 12 cases (9%) compared with 17 (13%) in the control group (odds ratio [OR] 0.7; 95% CI 0.3-1.5). Appendectomy preceded the diagnosis of microscopic colitis in 39 subjects (30%) compared with 28 (22%) in the control group (OR 1.6; 95% CI 0.9-2.7). Similar results were obtained when the analysis was restricted to microscopic colitis subtype (lymphocytic colitis or collagenous colitis). CONCLUSIONS: In this population-based nested case-control study, no significant association was seen between cholecystectomy or appendectomy and the development of microscopic colitis or its subtypes.

Jess T, Loftus EV, Velayos FS, Harmsen WS, Zinsmeister AR, Smyrk TC, Tremaine WJ, Melton LJ, Munkholm P, Sandborn WJ. · Department of Medical Gastroenterology, Herlev University Hospital, Herlev, Denmark. · Inflamm Bowel Dis. · Pubmed #16917220 No free full text.

Abstract: BACKGROUND AND AIMS: The risk, fate, and ideal management of colorectal dysplasia in inflammatory bowel disease (IBD) remain debated. We estimated the incidence, long-term outcome, and risk factors for progression of colorectal dysplasia (adenomas [adenoma-associated lesions or masses (ALMs)], flat dysplasia, and dysplasia-associated lesions or masses [DALMs]) in a population-based IBD cohort from Olmsted County, Minnesota. MATERIALS AND METHODS: The Rochester Epidemiology Project was used to identify cohort patients with colorectal dysplasia. Medical records were reviewed for demographic and clinical characteristics. Histology slides were reviewed by a pathologist blinded to previous pathology reports. The cumulative incidence of dysplasia was estimated, and the association between patient characteristics and recurrence/progression of dysplasia was assessed using proportional hazards regression. RESULTS: Twenty-nine (4%) IBD patients developed flat dysplasia (n = 8), DALMs (n = 1), ALMs in areas of IBD (n = 18), or ALMs outside areas of IBD (n = 2). Among 6 patients with flat low-grade dysplasia (fLGD) who did not undergo colectomy, none progressed during a median of 17.8 (range 6-21) years of observation with a median of 3 (range 0-12) surveillance colonoscopies. Four (22%) patients with ALMs in areas of IBD who did not undergo surgery developed LGD or DALMs. Primary sclerosing cholangitis and dysplasia located proximal to the splenic flexure were significantly associated with risk for recurrence/progression of dysplasia. CONCLUSIONS: This population-based cohort study from Olmsted County, Minnesota did not confirm an increased risk of cancer related to fLGD, whereas 22% of patients with ALMs in areas of IBD developed fLGD or DALMs.

Velayos FS, Loftus EV, Jess T, Harmsen WS, Bida J, Zinsmeister AR, Tremaine WJ, Sandborn WJ. · Division of Gastroenterology and Hepatology, University of California San Francisco, San Francisco, California, USA. · Gastroenterology. · Pubmed #16762617 No free full text.

Abstract: BACKGROUND & AIMS: Predictive and protective factors associated with colorectal cancer in chronic ulcerative colitis are not well described. Surveillance colonoscopy and 5-aminosalicylic acid therapy may mitigate cancer risk, but there is debate because these variables have not been evaluated in the same study. The presence of postinflammatory pseudopolyps and use of other anti-inflammatory medications may be important variables that influence risk, but data are sparse. METHODS: Variables associated with colorectal cancer were registered in 188 patients with ulcerative colitis-related cancer and matched controls. Conditional logistic regression, adjusted for age at colitis diagnosis and colitis duration, identified a final set of variables independently associated with colorectal cancer. RESULTS: In the final multiple variable model, the most important factors associated with colorectal cancer were a history of pseudopolyps (OR, 2.5; 95% CI: 1.4-4.6), 1 or 2 surveillance colonoscopies (OR, 0.4; 95% CI: 0.2-0.7), smoking (OR, 0.5; 95% CI: 0.2-0.9) and use of corticosteroids (OR, 0.4; 95% CI: 0.2-0.8), aspirin (OR, 0.3; 95% CI: 0.1-0.8), nonsteroidal anti-inflammatory drugs (OR, 0.1; 95% CI: 0.03-0.5), and 5-aminosalicylic acid agents (OR, 0.4; 95% CI: 0.2-0.9), although the latter was not statistically significant after 5 years. Primary sclerosing cholangitis and immunosuppressive use were not statistically significant. CONCLUSIONS: These results suggest that, in a population matched for extent and duration of chronic ulcerative colitis, surveillance colonoscopy and use of anti-inflammatory medications may reduce the risk of colorectal cancer. A history of postinflammatory pseudopolyps appears to be a predictive factor for cancer.

Jess T, Loftus EV, Velayos FS, Harmsen WS, Zinsmeister AR, Smyrk TC, Schleck CD, Tremaine WJ, Melton LJ, Munkholm P, Sandborn WJ. · Department of Medical Gastroenterology, Herlev University Hospital, Herlev, Denmark. · Gastroenterology. · Pubmed #16618397 No free full text.

Abstract: BACKGROUND & AIMS: The risk for colorectal cancer in Crohn's disease and ulcerative colitis patients from the United States currently is unknown. We estimated the risk for small-bowel and colorectal cancer in a population-based cohort of 692 inflammatory bowel disease patients from Olmsted County, Minnesota, from 1940 to 2001. METHODS: The Rochester Epidemiology Project was used to identify cohort patients with colorectal and small-bowel cancer. The cumulative probability of cancer and standardized incidence ratios (SIR) were estimated using expected rates from Surveillance, Epidemiology, and End Results, white patients from Iowa, from 1973 to 2000, and Olmsted County, from 1980 to 1999. RESULTS: Colorectal cancer was observed in 6 ulcerative colitis patients vs 5.38 expected (SIR, 1.1; 95% confidence interval [CI], 0.4-2.4), but 4 of these occurred among those with extensive colitis or pancolitis (SIR, 2.4; 95% CI, 0.6-6.0). Six Crohn's disease patients (vs 3.2 expected) developed colorectal cancer (SIR, 1.9; 95% CI, 0.7-4.1). Three Crohn's disease patients developed small-bowel cancer vs 0.07 expected (SIR, 40.6; 95% CI, 8.4-118). CONCLUSIONS: The risk for colorectal cancer was not increased among ulcerative colitis patients overall, but appeared to be increased among those with extensive colitis. The colorectal cancer risk was increased slightly among Crohn's disease patients, who also had a 40-fold excess risk for small-bowel cancer.

Jess T, Loftus EV, Harmsen WS, Zinsmeister AR, Tremaine WJ, Melton LJ, Munkholm P, Sandborn WJ. · Department of Medical Gastroenterology C, Herlev University Hospital, Denmark. · Gut. · Pubmed #16423890 No free full text.

Abstract: BACKGROUND AND AIMS: We followed a population based cohort of patients with inflammatory bowel disease (IBD) from Olmsted County, Minnesota, in order to analyse long term survival and cause specific mortality. Material and METHODS: A total of 692 patients were followed for a median of 14 years. Standardised mortality ratios (SMRs, observed/expected deaths) were calculated for specific causes of death. Cox proportional hazards regression was used to determine if clinical variables were independently associated with mortality. RESULTS: Fifty six of 314 Crohn's disease patients died compared with 46.0 expected (SMR 1.2 (95% confidence interval (CI) 0.9-1.6)), and 62 of 378 ulcerative colitis (UC) patients died compared with 79.2 expected (SMR 0.8 (95% CI 0.6-1.0)). Eighteen patients with Crohn's disease (32%) died from disease related complications, and 12 patients (19%) died from causes related to UC. In Crohn's disease, an increased risk of dying from non-malignant gastrointestinal causes (SMR 6.4 (95% CI 3.2-11.5)), gastrointestinal malignancies (SMR 4.7 (95% CI 1.7-10.2)), and chronic obstructive pulmonary disease (COPD) (SMR 3.5 (95% CI 1.3-7.5)) was observed. In UC, cardiovascular death was reduced (SMR 0.6 (95% CI 0.4-0.9)). Increased age at diagnosis and male sex were associated with mortality in both subtypes. In UC but not Crohn's disease, a diagnosis after 1980 was associated with decreased mortality. CONCLUSIONS: In this population based study of IBD patients from North America, overall survival was similar to that expected in the US White population. Crohn's disease patients were at increased risk of dying from gastrointestinal disease and COPD whereas UC patients had a decreased risk of cardiovascular death.

Chopra A, Pardi DS, Loftus EV, Tremaine WJ, Egan LJ, Faubion WA, Hanson KA, Johnson TA, Sandborn WJ. · Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Inflamm Bowel Dis. · Pubmed #16374255 No free full text.

Abstract: BACKGROUND: Delayed release budesonide was approved by the FDA for the treatment of mildly to moderately active Crohn's disease involving the ileum and ascending colon. Controlled trials have demonstrated that budesonide is effective in inducing remission and for maintenance of remission, with less frequent steroid side effects than conventional steroids. We sought to determine the benefit of this medication in clinical practice and to identify any non-FDA-approved uses that may warrant further study. METHODS: Patients in whom oral budesonide was prescribed between November 1, 2001 and October 31, 2002, were identified and medical records were reviewed. Patients were categorized by indication for therapy: ileocolonic Crohn's disease (group 1), Crohn's disease elsewhere (group 2), and other conditions (group 3). RESULTS: A total of 225 patients were identified (108 in group 1, 62 in group 2, and 55 in group 3). Group 3 included patients with microscopic colitis (n = 28), pouchitis (n = 13), ulcerative colitis (n = 12), and celiac disease (n = 2). A favorable outcome occurred in 61% of group 1 patients but only 24% of patients in group 2. In group 3, only microscopic colitis patients and pouchitis patients experienced response rates >50% (77% and 60%, respectively). CONCLUSION: Budesonide is effective in a majority of patients with ileocolonic Crohn's disease and microscopic colitis, which is consistent with results reported from clinical trials. A majority of patients with pouchitis also benefit from budesonide therapy, but prospective controlled trials are necessary to clarify the benefit in this group.

Dozois EJ, Wolff BG, Tremaine WJ, Watson WJ, Drelichman ER, Carne PW, Bakken JL. · Division of Colon and Rectal Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA. · Dis Colon Rectum. · Pubmed #16320006 No free full text.

Abstract: PURPOSE: Previous studies have reported high morbidity and mortality in mothers and their offspring after colectomy for ulcerative colitis during pregnancy. This study was designed to assess the maternal and fetal outcomes of pregnant females undergoing colectomy for ulcerative colitis in the current era. METHODS: A retrospective analysis was performed at our institution of all pregnant females undergoing operation for ulcerative colitis between 1980 and 2004. To compare this data to that of past literature, a MEDLINE search from 1951 to 2004 reviewed all cases reported on this topic. RESULTS: Between 1980 and 2004, five females underwent an operation at our institution for fulminant ulcerative colitis while pregnant. All five patients underwent subtotal colectomy with Brooke ileostomy. Postoperative maternal morbidity included a superficial wound infection and a small asymptomatic intra-abdominal abscess. All females had successful pregnancies, and no maternal or fetal deaths occurred. Two patients went on to have an ileal pouch-anal anastomosis, one had a completion proctectomy and end ileostomy, one is scheduled for an ileal pouch-anal anastomosis, and one patient is lost to follow-up. The literature review revealed 37 cases. The overall fetal and maternal mortality was 49 and 22 percent respectively. Postoperative maternal morbidity was reported in 24 percent. CONCLUSIONS: In contrast to historic data, the maternal and fetal mortality from our series was zero and maternal morbidity was low. Subtotal colectomy and Brooke ileostomy for ulcerative colitis during pregnancy is safe. A multidisciplinary team that includes a gastroenterologist, high-risk obstetrician, and experienced surgeon is necessary for an optimal outcome.

Solem CA, Loftus EV, Tremaine WJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. · Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Inflamm Bowel Dis. · Pubmed #16043984 No free full text.

Abstract: INTRODUCTION: We sought to examine the relationship between C-reactive protein (CRP) and clinical, endoscopic, histologic, and radiographic activity in inflammatory bowel disease (IBD). METHODS: All IBD patients at our institution between January 2002 and August 2003 who had a CRP, colonoscopy, and either small bowel follow-through (SBFT) or CT enterography (CTE) performed within 14 days were identified. Clinical activity was assessed retrospectively through review of the medical record. Logistic regression was used in Crohn's disease (CD) patients to estimate the odds ratio (OR) with 95% confidence intervals for an elevated CRP. Associations were assessed using Fisher exact test in ulcerative colitis (UC) patients due to small sample size. RESULTS: One-hundred four CD patients (46% males) and 43 UC and indeterminate colitis patients (44% males) were identified. In CD patients, moderate-severe clinical activity (OR, 4.5; 95% CI, 1.1-18.3), active disease at colonoscopy (OR, 3.5; 95% CI, 1.4-8.9), and histologically severe inflammation (OR, 10.6; 95% CI; 1.1-104) were all significantly associated with CRP elevation. Abnormal small bowel radiographic imaging was not significantly associated with CRP elevation. In UC patients, CRP elevation was significantly associated with severe clinical activity, elevation in sedimentation rate, anemia, hypoalbuminemia, and active disease at ileocolonoscopy, but not with histologic inflammation. CONCLUSIONS: CRP elevation in IBD patients is associated with clinical disease activity, endoscopic inflammation, severely active histologic inflammation (in CD patients), and several other biomarkers of inflammation, but not with radiographic activity.

Loftus EV, Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS, Zinsmeister AR, Jewell DA, Sandborn WJ. · Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA. · Gut. · Pubmed #15591511 links to  free full text

Abstract: BACKGROUND: Inflammatory bowel disease associated with primary sclerosing cholangitis (PSC-IBD) may have a high prevalence of rectal sparing, backwash ileitis, and colorectal neoplasia. AIMS: To describe the clinical features and outcomes of PSC-IBD and compare these to a group of chronic ulcerative colitis (CUC) patients. METHODS: The medical records of all patients with PSC-IBD evaluated at the Mayo Clinic Rochester between 1987 and 1992 were abstracted for information on endoscopic and histological features, colorectal neoplasia, surgery, and other clinical outcomes. Patients referred for colorectal neoplasia and those who did not undergo colonoscopy with biopsies were excluded. A control group of CUC patients matched for sex, duration of IBD at first clinic visit, and calendar year of first clinic visit was identified, and similar information was abstracted. RESULTS: Seventy one PSC-IBD patients and 142 CUC patients without PSC were identified. Rectal sparing and backwash ileitis were more common in the PSC-IBD group (52% and 51%, respectively) than in controls (6% and 7%, respectively). Overall, colorectal neoplasia developed in 18 cases and 15 controls, including 11 cancers (seven cases and four controls). An increased risk of colorectal neoplasia or death was not detected in a matched analysis. Although the cumulative incidence of colorectal neoplasia was higher in cases (33%) than in controls (13%) at five years, this was of borderline statistical significance (p=0.054, unmatched log rank test). Overall survival from first clinic visit was significantly worse among cases (79% v 97%) at five years (p<0.001, unmatched log rank test). CONCLUSION: PSC-IBD is frequently characterised by rectal sparing and backwash ileitis. Colorectal neoplasia develops in a substantial fraction and overall survival is worse. PSC-IBD may represent a distinct IBD phenotype.

Loftus EV, Achenbach SJ, Sandborn WJ, Tremaine WJ, Oberg AL, Melton LJ. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA. · Clin Gastroenterol Hepatol. · Pubmed #15017646 No free full text.

Abstract: BACKGROUND & AIMS: Osteopenia is common in patients with ulcerative colitis (UC), but less is known about fracture risk. Previously we were unable to demonstrate increased fractures in a population-based cohort with Crohn's disease. METHODS: Medical records of 273 Olmsted County, Minnesota residents initially diagnosed with UC in 1940-1993 were reviewed for evidence of subsequent fractures, as were records of a control cohort of county residents matched on age and gender. Cumulative fracture incidence after diagnosis was estimated by using the Kaplan-Meier method. The hazard ratio of fracture in cases relative to control subjects was estimated by Cox proportional hazards regression, which was also used to evaluate potential risk factors for fracture. RESULTS: Median follow-up was 13 years (range, 1 day-53 years). The cumulative incidence of any fracture from time of diagnosis was 40% at 25 years versus 42% in control subjects (P=0.615). The hazard ratio in cases compared to control subjects was 1.1 (95% confidence interval, 0.8-1.6) for any fracture and 1.3 (95% confidence interval, 0.6-2.8) for any osteoporotic fracture (hip, spine, or wrist as a result of moderate trauma). Other causes of secondary osteoporosis were associated with increased fracture risk, whereas estrogen use was protective. One hundred three cases received any corticosteroids (38%), and 34 (12%) had taken corticosteroids for 6 months or longer. Corticosteroids and bowel resection were not associated with fracture risk. CONCLUSIONS: In this population-based cohort of patients with UC, fracture risk was not elevated relative to matched community control subjects. Use of corticosteroids did not appear to significantly influence the risk of fracture.

Solem CA, Loftus EV, Tremaine WJ, Sandborn WJ. · Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. · Am J Gastroenterol. · Pubmed #14687149 No free full text.

Abstract: OBJECTIVES: Venous thromboembolism has been associated with inflammatory bowel disease (IBD). We sought to describe the clinical features, acquired and congenital risk factors, and outcomes of venous thromboembolism in IBD. METHODS: All patients with confirmed IBD and deep venous thrombosis (DVT) or pulmonary embolism (PE) at our institution between 1991 and 2000 were identified. Medical records were abstracted for clinical features, risk factors, treatment, and outcomes. RESULTS: Fifty-nine ulcerative colitis (UC) patients (68% males) and 39 Crohn's disease (CD) patients (41% males) were identified. UC extent was pancolonic in 76%, and CD extent was ileocolonic in 56%, colonic in 23%, and ileal in 21%. Eighty percent of CD patients and 79% of UC patients had active disease. Thrombophilia was present in 33% of the 40 patients tested. Most patients (87%) had other risk factors for DVT/PE. Long-term treatment included warfarin alone (62%), warfarin and IVC filter (18%), and IVC filter alone (7%). Five CD patients (13%) had recurrent DVT/PE. Among the 16 UC patients who underwent proctocolectomy following DVT/PE, there were two recurrences (13%), similar to the three recurrences (10%) seen among the 29 patients who had intact colons. Mortality rate was 22% after a median follow-up of 1.8 yr. CONCLUSIONS: Venous thromboembolism is a serious complication of IBD that may lead to death. Thrombophilia evaluations have a relatively high diagnostic yield overall, although specific genetic abnormalities are individually uncommon. Other DVT/PE risk factors are usually present. Proctocolectomy is not protective of recurrent DVT/PE.

Colombel JF, Ricart E, Loftus EV, Tremaine WJ, Young-Fadok T, Dozois EJ, Wolff BG, Devine R, Pemberton JH, Sandborn WJ. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA. · Am J Gastroenterol. · Pubmed #14572574 No free full text.

Abstract: OBJECTIVES: The occurrence of Crohn's disease (CD) in a patient with an ileal-pouch anastomosis (IPAA) often results in severe morbidity and significant chance of reservoir loss. We report our experience of the use of infliximab in these patients. METHODS: Medical records of 26 patients with an IPAA and CD-related complications were reviewed. The median time between the IPAA and the diagnosis of CD was 4.5 yr (range 0.1-16 yr). The main reasons for changing the original ulcerative colitis diagnosis to CD were complex perianal or pouch fistulizing disease in 14 patients (54%), prepouch ileitis in five (19%), and both prepouch ileitis and complex fistula in seven (27%). Patients received one to three doses of infliximab over 8 wk as induction therapy. Subsequently the patients received a variable number of maintenance infusions. RESULTS: At a short term follow-up, 16/26 patients (62%) had a complete response, six of 26 (23%) had a partial response, and four of 26 (15%) had no response. Information regarding long term follow-up was available in 24 patients. After a median follow-up of 21.5 months (range 3-44 months), eight patients (33%) either had their pouch resected or had a persistent diverting ileostomy. The pouch was functional in 16/24 (67%) patients, with either good (n = 7) or acceptable (n = 7) clinical results in 14/24 (58%). Of those 14 patients, 11 were under long term, on demand, or systematic maintenance treatment with infliximab. CONCLUSIONS: Infliximab is beneficial in both the short and long term treatment of patients with an IPAA performed for a presumed diagnosis of ulcerative colitis who subsequently develop CD-related complications. Good pouch function requires long term treatment with infliximab in most patients.

Mahadevan U, Loftus EV, Tremaine WJ, Pemberton JH, Harmsen WS, Schleck CD, Zinsmeister AR, Sandborn WJ. · Division of Gastroenterology, University of California, San Francisco, USA. · Inflamm Bowel Dis. · Pubmed #12479645 No free full text.

Abstract: AIM: To determine whether the use of azathioprine/6-mercaptopurine before colectomy is associated with an increased rate of postoperative complications. METHODS: All patients who underwent colectomy with ileal pouch-anal anastomosis for ulcerative colitis between 1997 and 1999 were identified. Medical records were abstracted for demographics, extent and duration of disease, dose and duration of corticosteroids and azathioprine/6-mercaptopurine, albumin, and Truelove/Witts score. Early (30-day) and late (6-month) complications were identified. Noncorticosteroid immunosuppressive use was coded as none, azathioprine/6-mercaptopurine within 1 week of surgery, or therapy with other immunosuppressive agents within 1 month of surgery. A logistic regression analysis assessed the association between these variables and complications. RESULTS: Early complications occurred in 49 of 151 (32%) patients not treated with immunosuppressive agents, 12 of 46 (26%) azathioprine/6-mercaptopurine-treated patients, and 4 of 12 (33%) patients treated with other immunosuppressive agents (p = 0.71). Late complications occurred in 72 of 148 (49%), 20 of 46 (43%), and 8 of 12 (67%) patients in these same groups, respectively. Intravenous or oral steroids at doses of 40 mg/d or greater (p < 0.01) and severe or fulminant disease (p = 0.0094) were associated with greater early complication rates. CONCLUSION: Early complications after restorative proctocolectomy for ulcerative colitis are associated with high dose steroids and severe disease but not use of azathioprine/6-mercaptopurine.

Ricart E, Taylor WR, Loftus EV, O'Kane D, Weinshilboum RM, Tremaine WJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. · Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA. · Am J Gastroenterol. · Pubmed #12135032 No free full text.

Abstract: OBJECTIVES: 5-Aminosalicylate is metabolized in colonic mucosa by N-acetyltransferase 1 (NAT1), and sulfapyridine is metabolized in the liver by N-acetyltransferase 2 (NAT2). Common genetic polymorphisms in these enzymes result in rapid and slow acetylation. We determined the association between NAT1 genotype and response to mesalamine and sulfasalazine, as well as between NAT2 genotype and toxicity to sulfasalazine, in a population-based cohort of patients with ulcerative colitis. METHODS: DNA was obtained from 77 white patients with ulcerative colitis from Olmsted County, MN. NAT1 and NAT2 genotyping was performed using microelectronic array devices. Phenotypes were deduced from previously published genotype/phenotype correlations. Clinical response to mesalamine and sulfasalazine, and toxicity to sulfasalazine, were determined by medical record review and associated with NAT1 and NAT2 genotypes. RESULTS: The clinical response rates among 52 patients treated with mesalamine were 67% (31 of 46) for rapid acetylators and 83% (five of six) for slow acetylators (odds ratio = 0.4, 95% CI = < 0.1-3.9, p = 0.65). Similarly, the clinical response rates among 64 patients treated with sulfasalazine were 74% (43 of 58) for rapid acetylators and 67% (four of six) for slow acetylators (odds ratio = 1.4, 95% CI = 0.2-8.6, p = 0.65). The toxicity rates among the 64 patients treated with sulfasalazine were 34% (12 of 35) for slow acetylators and 45% (13 of 29) for rapid acetylators (odds ratio = 0.6, 95% CI = 0.2-1.8, p = 0.65). CONCLUSIONS: NAT1 and NAT2 genotypes did not predict response to mesalamine or sulfasalazine, or toxicity to sulfasalazine.