Sonia Friedman

Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine.

Background : Many non‐responders to azathioprine or mercaptopurine (6‐mercaptopurine) have high normal thiopurine methyltransferase activity and preferentially metabolize mercaptopurine to produce 6‐methylmercaptopurine instead of the active 6‐tioguanine (6‐tioguanine) metabolites.

Pediatric patients with untreated ulcerative colitis may present initially with unusual morphologic findings.

Background: Anecdotal observations by the authors of this study, together with the results of a few previous smaller studies, suggest that children with new-onset (previously untreated) ulcerative colitis (UC) may occasionally present with discontinuous disease, relative or absolute rectal sparing, and may lack histologic features of chronicity. Therefore, the objectives of this study were to determine the clinical and pathologic features of new-onset UC in children and to compare the initial presentation of UC in this group with a control group of adults. Design: Routinely processed rectal and colonic mucosal biopsies from 73 pediatric (male/female ratio 33/40, mean age 11.5 years, range 2.5–18 years) and 38 adult patients (male/female ratio 15/23, mean age 41.5 years, range 27–64 years) who presented with new-onset UC were evaluated for a variety of clinical and pathologic features, including duration of symptoms prior to presentation, crypt architectural (e.g., atrophy, branching) and nonarchitectural (e.g., basal plasmacytosis, Paneth cell metaplasia) features of chronicity, degree of active inflammation, and distribution and extent of disease. Results: A significant proportion of children with new-onset UC had patchiness of microscopic features of chronicity (21% of patients), relative (23%), or absolute (3%), rectal sparing, and had little or no crypt architectural distortion in their rectal biopsies (8%). These features were not observed in adult patients with UC. In addition, a higher proportion of children with UC initially presented with subtotal or with pancolitis compared with the adults (42% vs. 11%; P < 0.002). Conclusions: A significant proportion of children with new-onset UC may show unusual patterns of disease. Pathologists should be aware of these findings since they have significant implications for the differential diagnosis of pediatric inflammatory bowel disease.

Are patients with inflammatory bowel disease receiving optimal care

OBJECTIVES:Guidelines have been published as a framework for therapy of patients with inflammatory bowel disease (IBD). The purpose of this study was to determine whether patients referred for a second opinion were receiving therapy in accordance with practice guidelines.METHODS:Patients with luminal IBD under the care of a gastroenterologist who sought a a second opinion at Brigham and Womens Hospital between January 2001 and April 2003 were enrolled in this study. Clinical information was obtained by direct patient interview at the time of initial patient visit and by a review of prior records. Data obtained included the diagnosis, clinical symptoms, prior medical therapy, preventive measures for metabolic bone disease, and colon-cancer screening.RESULTS:The study population consisted of 67 consecutive patients: 21 with ulcerative colitis, 44 with Crohns disease and 2 in whom the diagnosis of IBD could not be confirmed. Of the 65 patients with confirmed IBD, 56 patients had symptoms of active disease and 9 were asymptomatic. All analyses were carried out on the 56 patients with active disease. Of the 33 patients treated with aminosalicylates, 21 (64%) were not receiving maximal doses. Nine of 12 (75%) patients with distal ulcerative colitis were not receiving rectal aminosalicylate therapy. Within 6 months of their clinic visit, 35 patients had received corticosteroid therapy, and 27 (77%) patients had been treated with corticosteroids for greater than 3 months. In 16 of 27 (59%) there was no attempt to start steroid sparing medications such as 6-mercaptopurine (6MP), azathioprine, or infliximab. Of the 11 patients treated with either 6MP or azathioprine, 9 (82%) were suboptimally dosed without an attempt to increase dosage. Of the 27 patients on prolonged corticosteroid therapy 21 (78%) received inadequate treatment to prevent metabolic bone disease. Three of 9 patients (33%) meeting indications for surveillance colonoscopy for dysplasia had not undergone colonoscopy at the appropriate interval.CONCLUSIONS:Patients with IBD often do not receive optimal medical therapy. In particular, there is suboptimal dosing of 5-ASA and immunomodulatory medications, prolonged use of corticosteroids, failure to use steroid-sparing agents, inadequate measures to prevent metabolic bone disease, and inadequate screening for colorectal cancer.

5‐Aminosalicylate therapy is associated with higher 6‐thioguanine levels in adults and children with inflammatory bowel disease in remission on 6‐mercaptopurine or azathioprine

Background: Small uncontrolled trials have suggested that 5‐aminosalicylate (5‐ASA) medications increase 6‐thioguanine nucleotide (6‐TGn) levels in adults with Crohns disease (CD) on azathioprine (AZA) or 6‐mercaptopurine (6‐MP), presumably through the inhibition of thiopurine methyltransferase (TPMT). We tested the theory that coadministration of 5‐ASA agents with AZA/6‐MP results in higher 6‐TGn levels in a large cohort of children and adults with CD or ulcerative colitis (UC). Methods: A retrospective cohort study identified all children and adults treated for IBD with AZA/6‐MP at 2 tertiary medical centers. Patients were included if their TPMT genotype was known and 6‐TGn and 6‐methymercaptopurine (6‐MMP) levels had been obtained after 3 months of clinical remission at a stable dose of AZA/6‐MP. 6‐TGn and 6‐MMP levels were compared between patients taking and those not taking 5‐ASA medications through the use of linear regression models to identify and adjust for potentially confounding variables. Results: Of the 126 patients included, 88 were taking 5‐ASA medications. Patients on 5‐ASA agents had higher mean 6‐TGn levels after adjustment for confounding variables (&Dgr;6‐TGn, 47.6 ± 21.8 pmol/8 × 108 red blood cells; P = 0.03). CD and TPMT heterozygosity was independently associated with higher 6‐TGn levels (P = 0.01 and P = 0.03, respectively). 5‐ASA exposure was not associated with a change in 6‐MMP levels. Conclusions: We found that 5‐ASA therapy is associated with higher 6‐TGn levels in children and adults with IBD on 6‐MP/AZA. TPMT inhibition may not explain this effect because 5‐ASA exposure did not affect 6‐MMP levels. The observed association of CD with higher 6‐TGn levels is novel and needs to be verified in prospective studies.

Efficacy of Vedolizumab as Induction Therapy in Refractory IBD Patients: A Multicenter Cohort.

Background:Vedolizumab (VDZ) demonstrated efficacy in Crohns disease (CD) and ulcerative colitis (UC) in the GEMINI trials. Our aim was to evaluate the efficacy of VDZ at week 14 in inflammatory bowel disease in a multicenter cohort of patients. Methods:Patients at Massachusetts General Hospital and Brigham and Womens Hospital were considered for inclusion. VDZ (300 mg) was administered at weeks 0, 2, 6, and 14. Efficacy was assessed using the Harvey–Bradshaw index for CD, the simple clinical colitis activity index for UC and physician assessment, along with C-reactive protein and decrease of corticosteroid therapy. Clinical response was defined as decrease in Harvey–Bradshaw index ≥3 and simple clinical colitis activity index ≥3 and remission as Harvey–Bradshaw index ⩽4, simple clinical colitis activity index ⩽2 and physician assessment of response and remission. Results:Our study included 172 patients (107 CD, 59 UC, 6 inflammatory bowel disease-unclassified, men 48.3%, mean age 40 years and disease duration 14 years). Fourteen patients had ostomy and 9 ileoanal pouch, and only 35.5% fulfilled eligibility for the GEMINI trials. Previous treatment failures with ≥ 2 anti-TNFs occurred in 70.9%, one-third were on an immunomodulator and 46% systemic steroids at baseline. In CD, 48.9% and 23.9% and in UC, 53.9% and 29.3% had clinical response and clinical remission at week 14, respectively. Adverse events occurred in 10.5%. Conclusions:VDZ is safe and well tolerated in refractory inflammatory bowel disease patients in a clinical practice with efficacy in UC and CD with responses similar to what was seen in clinical trials.

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.

Screening and surveillance colonoscopy in chronic Crohn's colitis: results of a surveillance program spanning 25 years.

BACKGROUND & AIMS Since 1980, we have followed 259 patients with chronic Crohns colitis in a prospective colonoscopic surveillance program. Our initial results through August 1998 showed a 22% chance of developing definite dysplasia or cancer by the fourth surveillance examination. We now update the results of all examinations since September 1998 until April 2005. METHODS All patients had at least 7 years of Crohns colitis affecting at least one third of the colon. Patients were recalled every 1 to 2 years or sooner if dysplasia was found. Pathology was classified as normal, dysplasia (indefinite, low-grade [LGD], or high-grade [HGD]), or carcinoma. Lesions were classified as flat, polyp, or mass. RESULTS A total of 1424 examinations were performed on 259 patients. Ninety percent had extensive colitis. The median age at diagnosis was 22 years (range, 2-61 y), and the median disease duration was 18 years (range, 7-49 y). On screening examination, definite dysplasia or cancer was found in 18 patients (7%). Thirteen had LGD, 2 had HGD, and 3 had cancer. On surveillance examinations, a first finding of definite dysplasia or cancer was found in an additional 30 patients (14%). Twenty-two had LGD, 4 had HGD, and 4 had cancer. The cumulative risk of detecting an initial finding of any definite dysplasia or cancer after a negative screening colonoscopy was 25% by the 10th surveillance examination. The cumulative risk of detecting an initial finding of flat HGD or cancer after a negative screening colonoscopy was 7% by the ninth surveillance examination. CONCLUSIONS Periodic surveillance colonoscopy should be part of the routine management of chronic extensive Crohns colitis.

SYSTEMIC AMYLOIDOSIS AND THE GASTROINTESTINAL TRACT

Systemic amyloidosis is caused by a variety of different diseases and frequently involves the gastrointestinal tract. Each type of amyloid affects the gastrointestinal tract differently. This article reviews the unique pathogenesis, pattern of gastrointestinal disposition, diagnosis, and treatment of the five systemic amyloidoses, and discusses the gastrointestinal diseases that cause systemic amyloidosis: inflammatory bowel disease and familial Mediterranean fever.

Management of neoplastic polyps in inflammatory bowel disease.

Dysplasia-associated lesions or masses (DALMs) are a heterogeneous population of lesions with different endoscopic and morphologic features. Non-adenoma-like DALMs should be removed via colectomy. Adenoma-like DALMs that occur outside areas of colitis can be treated like sporadic adenomas and removed by polypectomy. Recent data suggest that adenoma-like DALMs located within areas of colitis should be removed by polypectomy with complete excision and multiple biopsies of the site. As long as there is no flat dysplasia or adenocarcinoma elsewhere in the colon, a colectomy is not required. However, this group of patients requires increased colonoscopic surveillance.

Low-Dose 18F-FDG PET/CT Enterography: Improving on CT Enterography Assessment of Patients with Crohn Disease

The purpose of this study was to evaluate the diagnostic efficacy of low-dose, combined 18F-FDG PET/CT enterography (PET/CTE), compared with CT enterography (CTE) alone, in the assessment of patients with Crohn disease. Methods: Thirteen patients with Crohn disease were prospectively enrolled in this pilot study and underwent abdominal–pelvic 18F-FDG PET/CTE using neutral oral and intravenous contrast medium. The effective dose from PET/CTE was 17.7 mSv for the first 4 patients and 8.31 mSv for the last 9 patients. Six patients underwent surgical resection of the bowel, and 7 patients underwent colonoscopy with biopsies within 27 d (mean, 12 d) of PET/CTE. PET/CTE and CTE images were each visually assessed for Crohn disease involvement in 54 bowel segments with pathology correlation. Extraintestinal findings were recorded. A CTE severity score, maximum standardized uptake value (SUVmax), SUVmax ratio, simplified endoscopic score, and clinical parameters were correlated with pathology inflammation grade, on a per-patient basis and on a per-bowel-segment basis, using Spearman correlation. Results: In 3 (23.1%) of 13 patients, 18F-FDG uptake using PET/CTE revealed active inflammation in a bowel segment not evident using CTE (n = 2) or revealed an enterocolic fistula missed with CTE (n = 1). Visual interpretation of both PET/CTE and CTE images detected the presence of disease in all bowel segments with more than mild inflammation (sensitivity, 100%; specificity, 89.7%; positive predictive value, 78.9%; and negative predictive value, 100%). Correlation to inflammation grade per patient was the strongest for the SUVmax ratio (0.735, P = 0.004) and SUVmax (0.67, P = 0.013), as compared with the CTE score (0.62, P = 0.024). Correlation with inflammation per bowel segment was higher for the CTE score (0.79, P < 0.0001) than the SUVmax ratio (0.62, P < 0.0001) or SUVmax (0.48, P < 0.0001). SUVmax correlated strongly with serum C-reactive protein (0.82, P = 0.023), but CTE score did not. Conclusion: Low-dose 18F-FDG PET/CTE, compared with CTE, may improve the detection and grading of active inflammation in patients with Crohn disease. PET/CTE also may reveal clinically significant findings, such as enterocolic fistula, not evident on PET or CTE alone.