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Biomedical subjects

W J Sandborn

Publications and source records attributed to W J Sandborn.

At least 73 records · Page 4Linked to original sources
PubMed2000

Risk of lymphoma in inflammatory bowel disease.

OBJECTIVE: Inflammatory bowel disease with a subsequent diagnosis of non-Hodgkin's lymphoma has been reported. There is concern that the risk of developing lymphoma will rise with increasing use of immune modifier therapy. We determined the risk of non-Hodgkin's lymphoma in an U.S. population-based inception cohort, and evaluated the association between inflammatory bowel disease and lymphoma in our referral practice. METHODS: The records of all incidence cases of inflammatory bowel disease in Olmsted County, Minnesota, between 1950 and 1993 were reviewed for the diagnosis of lymphoma. Standardized incidence ratios (observed/expected) were used to estimate relative risk. In addition, the clinical features and outcomes of all patients with inflammatory bowel disease and lymphoma seen at Mayo Clinic between 1976 and 1997 were reviewed. RESULTS: Among 454 county residents diagnosed with inflammatory bowel disease, a single non-Hodgkin's lymphoma occurred in a patient with Crohn's disease. No cases were seen with ulcerative colitis. The estimated relative risk of lymphoma was 2.4 in Crohn's disease (95% confidence interval, 0.1-13), 0 in ulcerative colitis (0-6), and 1.0 in inflammatory bowel disease overall (0.03-6). Between 1976 and June 1997, 61 patients with inflammatory bowel disease and lymphoma (approximately 0.41%) were seen in the referral practice. In four patients with Crohn's disease (13%), potential neoplastic risk factors were identified-therapeutic radiation in 1, and use of purine analogs in 3 (median length of use, 11 months). CONCLUSIONS: Our population-based cohort study demonstrated that the absolute risk of non-Hodgkin's lymphoma remains quite small (0.01% per person-year). This risk may not exceed that in the general population. In our referral practice, immune modifier therapy could be potentially implicated in only 5% of cases of lymphoma occurring in the setting of inflammatory bowel disease.

Cohort Studies↗
PubMed2000

Fecal calprotectin levels predict colorectal inflammation among patients with chronic diarrhea referred for colonoscopy.

OBJECTIVE: Chronic diarrhea is a relatively common condition with multiple diverse etiologies. Stool testing may serve as a diagnostic aid to discriminate the presence or absence of organic pathology, such as colorectal inflammation. Calprotectin (a leukocyte-derived protein) and hemoglobin can be measured quantitatively from stool and represent candidate inflammation biomarkers. The aim of this study was to assess and compare the screening performance of fecal calprotectin and fecal hemoglobin among colonoscopy referral patients with chronic diarrhea of unknown origin or chronic colitis of unknown activity. METHODS: All subjects were identified prospectively and each submitted a single stool sample before purgation. Fecal calprotectin (PhiCal; Nycomed Pharma, Oslo, Norway) and fecal hemoglobin (HemoQuant; Mayo Medical Laboratories, Rochester, MN) assays were performed in separate laboratories by masked technicians. Colonoscopic and histological findings served as criterion standards for establishing the presence or absence of colorectal inflammation. RESULTS: Among 110 subjects who provided complete fecal assay data, 29 (26%) had and 81 (74%) did not have colorectal inflammation. Increased fecal calprotectin levels were significantly (p = 0.0001) associated with the presence of colorectal inflammation, whereas fecal hemoglobin levels were not (p = 0.61). Direct comparison of the fecal assays revealed that calprotectin was a more sensitive biomarker for colorectal inflammation at all specificity levels (p = 0.0001). CONCLUSIONS: In this study of colonoscopy referral patients, colorectal inflammation was reflected by fecal calprotectin but not by fecal hemoglobin levels. Assay of fecal calprotectin holds promise as a triage tool to identify inflammatory causes of chronic diarrhea.

Adolescent↗
PubMed2000

Intravenous azathioprine in severe ulcerative colitis: a pilot study.

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.

Adult↗
PubMed2000

Ulcerative colitis in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival.

BACKGROUND: There is significant geographic variation in the reported incidence of ulcerative colitis. AIMS: To update the incidence and prevalence of ulcerative colitis in Olmsted County, Minnesota, examine temporal trends, and determine overall survival. PATIENTS: All Olmsted County residents diagnosed with ulcerative colitis between 1940 and 1993 (incidence cases), and all residents with ulcerative colitis alive on 1 January 1991 (prevalence cases). METHODS: Incidence and prevalence rates were adjusted using 1990 US census figures for whites. The effects of age, sex, and calendar year on incidence rates were evaluated using Poisson regression. Survival from diagnosis was compared with that expected for US north-central whites. RESULTS: Between 1940 and 1993, 278 incidence cases were identified, for an adjusted incidence rate of 7.6 cases per 100 000 person years (95% confidence interval (CI), 6.7 to 8.5). On 1 January 1991, there were 218 residents with definite or probable ulcerative colitis, for an adjusted prevalence rate of 229 cases per 100 000 (95% CI, 198 to 260). Increased incidence rates were associated with later calendar years (p<0.002), younger age (p<0.0001), urban residence (p<0.0001), and male sex (p<0.003). Overall survival was similar to that expected (p>0.2). CONCLUSIONS: The overall incidence rate of ulcerative colitis in Olmsted County increased until the 1970s, and remained stable thereafter. Incidence rates among men and urban residents were significantly higher. The prevalence rate in Rochester in 1991 was 19% higher than that in 1980. Overall survival was similar to that of the general population.

Adolescent↗
PubMed2000

Steroid-dependent Crohn's disease.

Placebo controlled trials have demonstrated that a tapering course of corticosteroids is an effective therapy for active Crohn's disease. A population-based study of 109 patients with Crohn's disease undergoing their first course of corticosteroids showed that, at the end of one year, 44% of patients were steroid responsive, 36% were steroid dependent and 20% were steroid refractory. Side effects occur frequently during a four-month tapering course of corticosteroids, including moon face, acne, infection, ecchymoses, hypertension, hirsutism, petechial bleeding and striae. More serious side effects occur with long term use, including hypertension, diabetes, infection, osteonecrosis, osteoporosis, myopathy, cataracts, glaucoma and psychosis. Low dose corticosteroids, alternate-day corticosteroids and mesalamine (5-aminosalicylate) are not effective steroid-sparing agents in patients with Crohn's disease. Controlled ileal release budesonide, 6 mg/day, is an effective steroid-sparing agent, but it does result in some decrease in adrenal function. Azathioprine, 6-mercaptopurine and methotrexate are all effective steroid-sparing agents, as is the humanized, anti-tumour necrosis factor monoclonal antibody, CDP571. A preliminary, uncontrolled study has suggested that the mouse/human chimeric monoclonal antibody infliximab may also be steroid sparing. Surgical resection is an effective strategy to reduce steroid use in the short to intermediate term, but postoperative reoccurrence of Crohn's disease occurs frequently. Given the morbidity associated with prolonged corticosteroid use, medical and surgical treatment strategies to reduce steroid use should be employed routinely.

Anti-Inflammatory Agents↗
PubMed1999

Inhibition of interleukin-1-stimulated NF-kappaB RelA/p65 phosphorylation by mesalamine is accompanied by decreased transcriptional activity.

Nuclear factor kappaB (NF-kappaB) is an inducible transcription factor that regulates genes important in immunity and inflammation. The activity of NF-kappaB is highly regulated: transcriptionally active NF-kappaB proteins are sequestered in the cytoplasm by inhibitory proteins, IkappaB. A variety of extracellular signals, including interleukin-1 (IL-1), activate NF-kappaB by inducing phosphorylation and degradation of IkappaB, allowing nuclear translocation and DNA binding of NF-kappaB. Many of the stimuli that activate NF-kappaB by inducing IkappaB degradation also cause phosphorylation of the NF-kappaB RelA (p65) polypeptide. The transactivating capacity of RelA is positively regulated by phosphorylation, suggesting that in addition to cytosolic sequestration by IkappaB, phosphorylation represents another mechanism for control of NF-kappaB activity. In this report, we demonstrate that mesalamine, an anti-inflammatory aminosalicylate, dose-dependently inhibits IL-1-stimulated NF-kappaB-dependent transcription without preventing IkappaB degradation or nuclear translocation and DNA binding of the transcriptionally active NF-kappaB proteins, RelA, c-Rel, or RelB. Mesalamine was found to inhibit IL-1-stimulated RelA phosphorylation. These data suggest that pharmacologic modulation of the phosphorylation status of RelA regulates the transcriptional activity of NF-kappaB, independent of nuclear translocation and DNA binding. These findings highlight the importance of inducible phosphorylation of RelA in the control of NF-kappaB activity.

Base Sequence↗
PubMed1999

Misdiagnosis of specific cytomegalovirus infection of the ileoanal pouch as refractory idiopathic chronic pouchitis: report of two cases.

PURPOSE: Chronic nonspecific reservoir ileitis (pouchitis) occurs in 5 to 10 percent of patients who undergo ileal pouch-anal anastomosis for ulcerative colitis. Specific infection of the ileal pouch-anal anastomosis with cytomegalovirus has not been reported. AIM: We report two patients with specific cytomegalovirus infection of the ileal pouch-anal anastomosis, initially misdiagnosed as idiopathic chronic pouchitis. CASE SERIES: Patient 1 had ileal pouch-anal anastomosis for ulcerative colitis. Three years later she had diarrhea, fever, pelvic pain, and pouch inflammation at endoscopy consistent with pouchitis. She had no response to medical therapy. Repeat endoscopy showed persistent inflammation and biopsies showed cytomegalovirus. She had symptomatic improvement after treatment with intravenous ganciclovir, 10 mg/kg/day for ten days (stopped for rash). Repeat pouch biopsies were negative for cytomegalovirus. Patient 2 had ileal pouch-anal anastomosis for ulcerative colitis. Nine years later she had resection of obstructing stricture at previous loop ileostomy site. She underwent reoperation with ileostomy and pouch defunctionalization for peritonitis. Four weeks later she had fever and bloody discharge from the diverted pouch. Pouch endoscopy with biopsy showed inflammation consistent with pouchitis. She had no response to medical therapy. Re-examination of pouch biopsies with a specific monoclonal immunofluorescent stain showed cytomegalovirus. She had symptomatic improvement after treatment with intravenous ganciclovir, 10 mg/kg/day for 21 days. Repeat pouch biopsies were negative for cytomegalovirus. CONCLUSIONS: Specific cytomegalovirus infection of the ileal pouch-anal anastomosis may be misdiagnosed as idiopathic refractory chronic pouchitis. Cytomegalovirus must be excluded before immune modifier therapy or pouch excision in these patients.

Adult↗
PubMed1999

Systemic and intestinal pharmacokinetics of methotrexate in patients with inflammatory bowel disease.

BACKGROUND: The pharmacokinetics of low-dose subcutaneous methotrexate have not been determined throughout the standard weekly dosing interval. It is not known whether methotrexate concentrations in the gastrointestinal tract are sufficient for pharmacologic activity in inflammatory bowel disease. METHODS: Ten patients with inflammatory bowel disease participated in the study. After the patients started taking 15 or 25 mg subcutaneous methotrexate once a week, erythrocyte methotrexate concentration was measured every 2 weeks. The absorption, rectal distribution, metabolism, and elimination of methotrexate were measured. The effect of methotrexate on proliferation of an intestinal epithelial cell line was determined. RESULTS: After weekly subcutaneous administration of methotrexate was begun, trough erythrocyte concentration rose to reach a plateau after 6 to 8 weeks, ranging from 150 to 300 nmol/L. More than 90% of subcutaneously administered methotrexate was rapidly excreted in the urine. The methotrexate plasma time course after subcutaneous administration fit a 2-compartment first-order model with biphasic elimination and trough concentration of about 1 nmol/L. Trough and peak methotrexate concentrations (mean value +/- SD) were 64 +/- 33 and 206 +/- 64 fmol/mg in the rectal mucosa and 4 +/- 3 and 51 +/- 26 nmol/L in the rectal lumen. These methotrexate concentrations were in the range found to be pharmacologically active against Caco-2 cell growth, that is, a 50% inhibitory concentration from 10 to 46 nmol/L. CONCLUSION: Subcutaneous methotrexate was well absorbed and distributed to the site of the lesions in patients with inflammatory bowel disease. Methotrexate was concentrated intracellularly in blood and in the rectum. The methotrexate concentration in the rectal mucosa remained within a pharmacologically active range throughout the dosing interval. The findings represent a pharmacologic explanation for the sustained efficacy of weekly methotrexate therapy.

Adult↗
PubMed1999

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group.

BACKGROUND & AIMS: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. METHODS: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of </=150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. RESULTS: At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups. CONCLUSIONS: A loading dose does not decrease the time to response in patients with steroid-treated Crohn's disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Administration, Oral↗
PubMed1999

Clinical course and costs of care for Crohn's disease: Markov model analysis of a population-based cohort.

BACKGROUND & AIMS: Crohn's disease results in substantial morbidity and high use of health services. The aim of this study was to describe the lifetime clinical course and costs of Crohn's disease in a 24-year population-based inception cohort of patients with Crohn's disease in Olmsted County, Minnesota. METHODS: Disease states were defined by medical and surgical treatment. A Markov model analysis calculated time in each disease state and present value of excess lifetime costs in comparison with an age- and sex-matched cohort. RESULTS: For a representative patient, projected lifetime costs were $39,906 per patient using median charges and $125,404 using mean charges. There were 29.1 years (63% of total) without medications. There were 12.7 years (27%) on aminosalicylate therapy, generating $11,467 (29%) in charges, and 3.2 years (7%) on corticosteroid or immunosuppressive therapy, generating $5147 (13%) in charges. Surgery generated $17,526 (44%) in charges. CONCLUSIONS: Most of the clinical course is spent in remission, either medical or surgical. Aminosalicylate therapy accounts for 29% of the costs of care. Surgery has the highest charges but the longest remissions. Treatment strategies that induce remission in mild disease and maintain remission with lower-cost maintenance therapy will have the largest effect on patient outcomes and costs.

Adolescent↗
PubMed1999

Acute major gastrointestinal hemorrhage in inflammatory bowel disease.

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.

Acute Disease↗