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1.  The epidemiology of microscopic colitis: a population based study in Olmsted County, Minnesota 
Gut  2006;56(4):504-508.
Although the epidemiology of microscopic colitis has been described in Europe, no such data exist from North America. We studied the incidence, prevalence and temporal trends of microscopic colitis in a geographically defined US population.
Design and setting
In this population based cohort study, residents of Olmsted County, Minnesota, with a new diagnosis of microscopic colitis, and all who had colon biopsies for evaluation of diarrhoea, between 1 January 1985 and 31 December 2001 were identified. Biopsies were reviewed for confirmation (cases) and to identify missed cases (diarrhoea biopsies).
Main outcome measures
Incidence rates, age and sex adjusted to the 2000 US white population. Poisson regression assessed the association of calendar period, age and sex with incidence.
We identified 130 incident cases for an overall rate of 8.6 cases per 100 000 person‐years. There was a significant secular trend, with incidence increasing from 1.1 per 100 000 early in the study to 19.6 per 100 000 by the end (p<0.001). Rates increased with age (p<0.001). By subtype, the incidence was 3.1 per 100 000 for collagenous colitis and 5.5 per 100 000 for lymphocytic colitis. Collagenous colitis was associated with female sex (p<0.001) but lymphocytic colitis was not. Prevalence (per 100 000 persons) on 31 December 2001 was 103.0 (39.3 for collagenous colitis and 63.7 for lymphocytic colitis).
The incidence of microscopic colitis has increased significantly over time, and by the end of the study, the incidence and prevalence were significantly higher than reported previously. Microscopic colitis is associated with older age, and collagenous colitis is associated with female sex.
PMCID: PMC1856874  PMID: 17135309
Background & Aims
We sought to estimate the need for surgery in an American population-based cohort of Crohn’s disease.
The medical records of 310 incident cases of Crohn’s disease from Olmsted County, Minnesota, diagnosed between 1970 and 2004, were reviewed through March 2009. Cumulative incidence was estimated using the Kaplan-Meier method, and associations between baseline factors and time to first event were assessed using proportional hazards regression and expressed as hazard ratios (HR) with 95% confidence intervals (95% CI).
Median follow-up per patient was 12.0 years. One hundred fifty-two patients underwent at least one major abdominal surgery, 65 had at least two surgeries, and 32 had at least three. The cumulative probability of major abdominal surgery was 38%, 48% and 58% at 5, 10 and 20 years after diagnosis, respectively. Baseline factors significantly associated with time to major abdominal surgery were: ileocolonic (HR, 3.3), small bowel (HR, 3.4) and upper gastrointestinal (HR, 4.0) extent, relative to colonic alone; current cigarette smoking (HR, 1.7), male gender (HR, 1.6), penetrating disease behavior (HR, 2.7), and early corticosteroid use (HR=1.6). Major abdominal surgery rates remained stable, with 5-year cumulative probabilities in 1970–74 and 2000–04 of 37.5% and 35.1%, respectively.
The cumulative probability of major abdominal surgery in this population-based cohort of Crohn’s disease approached 60% after 20 years of disease, and many patients required second or third surgeries. Non-colonic disease extent, current smoking, male gender, penetrating disease behavior, and early steroid use were significantly associated with major abdominal surgery.
PMCID: PMC3572861  PMID: 22945286
Crohn’s disease; surgery; natural history; risk factors
3.  Outcomes of Patients with Microscopic Colitis Treated with Corticosteroids: A population-based study 
To evaluate the outcomes of corticosteroid-treated microscopic colitis in a population-based cohort, and to compare these outcomes in patients treated with prednisone or budesonide
A historical cohort study of Olmsted County, Minnesota residents diagnosed with collagenous colitis or lymphocytic colitis from 1986 to 2010 was performed using the resources of the Rochester Epidemiology Project.
Of 315 patients, 80 (25.4%) were treated with corticosteroids. The median age was 66.5 years (range: 16 – 95) and 78.7% were female. Forty patients (50%) had lymphocytic colitis and 40 (50%) had collagenous colitis. Six patients were lost to follow-up. The remaining 74 had a median follow-up of 4 years (range: 0.2 – 14); 56 (75.6%) had complete response and 15 (20.3%) had partial response. Fifty patients out of 71 who responded (70.4%) had a recurrence after corticosteroid discontinuation. After 397 person years of follow-up in the 73 patients with long-term data, 47 (64.4%) required maintenance with corticosteroids.
Prednisone was used in 17 patients (21.2%) and budesonide in 63 (78.8%). Patients treated with budesonide had a higher rate of complete response than those treated with prednisone (82.5% vs 52.9%; odds ratio, 4.18; 95% CI, 1.3 – 13.5) and were less likely to recur (hazard ratio, 0.38; 95% CI, 0.18 – 0.85; p=0.02).
Patients with microscopic colitis often respond to corticosteroid therapy, but with a high relapse rate. Budesonide had a higher response rate and a lower risk of recurrence than prednisone.
PMCID: PMC3575108  PMID: 23295275
microscopic colitis; corticosteroid; outcomes; response; recurrence
Inflammatory Bowel Diseases  2011;18(1):43-48.
Background and aims
The cumulative incidence of and risk factors for perianal Crohn’s disease for findings other than fistulas are unknown.
The medical records of 310 incident cases of Crohn’s disease from Olmsted County, Minnesota, diagnosed between 1970 and 2004, were reviewed for evidence of perianal disease findings other than fistulas. Cumulative incidence was estimated using the Kaplan-Meier method, and associations between baseline factors and time to first event were assessed using proportional hazards regression. Four types of lesions were studied: anorectal strictures, deep anal canal ulcers, anal fissures, and perianal skin tags.
The 10-year cumulative probability from time of diagnosis was 5.8% (95% confidence interval [CI], 2.6%-8.8%) for anorectal strictures, 6.6% (3.6%-9.6%) for deep anal canal ulcers, 10.5% (6.8%-14.1%) for anal fissures, and 18.7% (13.9%-23.3%) for perianal skin tags. The cumulative probability for any perianal lesion other than fistulas was 21.3% (16.5%-25.8%) at 5 years and 29.2% (23.5%-34.5%) at 10 years. Baseline factors associated with time to first perianal lesion other than fistulas were age (hazard ratio [HR] per 10 years, 0.9; 95% CI, 0.8-0.98; p=0.026), female gender (HR, 1.7; 95% CI, 1.1-2.7; p=0.013), and presence of extraintestinal manifestations (HR, 1.7; 95% CI, 1.03-2.8; p=0.038).
Perianal lesions other than fistulas occurred frequently during the clinical course of Crohn’s disease. Female gender and extraintestinal manifestations were associated with increased risks for perianal lesions other than fistulas, while older age at diagnosis was associated with a slightly decreased risk.
PMCID: PMC3352677  PMID: 21351216
Crohn’s disease; natural history; anorectal strictures; anal ulcers; perianal tags; anal fissures
5.  Strategies for the Care of Adults Hospitalized for Active Ulcerative Colitis 
Ulcerative colitis is a chronic inflammatory disease of the colon; as many as 25% of patients with this disease require hospitalization. The goals of hospitalization are to assess disease severity, exclude infection, administer rapidly acting and highly effective medication regimens, and determine response. During the hospitalization, patients should be given venous thromboembolism prophylaxis and monitored for development of toxic megacolon. Patients who do not respond to intravenous corticosteroids should be considered for rescue therapy with infliximab or cyclosporine. Patients who are refractory to medical therapies or who develop toxic megacolon should be evaluated promptly for colectomy. Patients who do respond to medical therapies should be discharged on an appropriate maintenance regimen when they meet discharge criteria. We review practical evidence-based management principles and propose a day-by-day algorithm for managing patients hospitalized for ulcerative colitis.
PMCID: PMC4226798  PMID: 22835577
7.  Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study 
Gut  2013;63(3):442-450.
Interferon-γ-inducible protein-10 (IP-10 or CXCL10) plays a role in inflammatory cell migration and epithelial cell survival and migration. It is expressed in higher levels in the colonic tissue and plasma of patients with ulcerative colitis (UC). This phase II study assessed the efficacy and safety of BMS-936557, a fully human, monoclonal antibody to IP-10, in the treatment of moderately-to-severely active UC.
In this 8-week, phase II, double-blind, multicentre, randomised study, patients with active UC received placebo or BMS-936557 (10 mg/kg) intravenously every other week. The primary endpoint was the rate of clinical response at Day 57; clinical remission and mucosal healing rates were secondary endpoints. Post hoc analyses evaluated the drug exposure–response relationship and histological improvement.
109 patients were included (BMS-936557: n=55; placebo: n=54). Prespecified primary and secondary endpoints were not met; clinical response rate at Day 57 was 52.7% versus 35.2% for BMS-936557 versus placebo (p=0.083), and clinical remission and mucosal healing rates were 18.2% versus 16.7% (p=1.00) and 41.8% versus 35.2% (p=0.556), respectively. However, higher BMS-936557 steady-state trough concentration (Cminss) was associated with increased clinical response (87.5% vs 37.0% (p<0.001) for patients with Cminss 108–235 μg/ml vs placebo) and histological improvements (73.0% vs 41.0%; p=0.004). Infections occurred in 7 (12.7%) BMS-936557-treated patients and 3 (5.8%) placebo-treated patients. 2 (3.6%) BMS-936557 patients discontinued due to adverse events.
Anti-IP-10 antibody, BMS-936557, is a potentially effective therapy for moderately-to-severely active UC. Higher drug exposure correlated with increasing clinical response and histological improvement. Further dose–response studies are warranted.
Clinical Trial Registration Number: NCT00656890.
PMCID: PMC3933070  PMID: 23461895
Antibody Targeted Therapy; Ulcerative Colitis
8.  Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study 
Gut  2013;63(3):433-441.
Budesonide MMX is a novel oral formulation of budesonide that uses Multi-Matrix System (MMX) technology to extend release to the colon. This study compared the efficacy of budesonide MMX with placebo in patients with active, mild-to-moderate ulcerative colitis (UC).
Patients were randomised 1:1:1:1 to receive budesonide MMX 9 mg or 6 mg, or Entocort EC 9 mg (budesonide controlled ileal-release capsules; reference arm) or placebo once daily for 8 weeks. The primary endpoint was combined clinical and endoscopic remission, defined as UC Disease Activity Index score ≤1 with a score of 0 for rectal bleeding and stool frequency, no mucosal friability on colonoscopy, and a ≥1-point reduction in endoscopic index score from baseline.
410 patients were evaluated for efficacy. Combined clinical and endoscopic remission rates with budesonide MMX 9 mg or 6 mg, Entocort EC and placebo were 17.4%, 8.3%, 12.6% and 4.5%, respectively. The difference between budesonide MMX 9 mg and placebo was significant (OR 4.49; 95% CI 1.47 to 13.72; p=0.0047). Budesonide MMX 9 mg was associated with numerically higher rates of clinical (42.2% vs 33.7%) and endoscopic improvement (42.2% vs 31.5%) versus placebo. The rate of histological healing (16.5% vs 6.7%; p=0.0361) and proportion of patients with symptom resolution (23.9% vs 11.2%; p=0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Adverse event profiles were similar across groups.
Budesonide MMX 9 mg was safe and more effective than placebo at inducing combined clinical and endoscopic remission in patients with active, mild-to-moderate UC.
PMCID: PMC3933176  PMID: 23436336
Inflammatory Bowel Disease; IBD; Ulcerative Colitis
9.  Stool DNA Testing for the Detection of Colorectal Neoplasia in Patients with Inflammatory Bowel Disease 
Alimentary pharmacology & therapeutics  2013;37(5):10.1111/apt.12218.
Current approaches to the detection of colorectal neoplasia associated with inflammatory bowel disease (IBD-CRN) are suboptimal.
We tested the feasibility of using stool assay of exfoliated DNA markers to detect IBD-CRN.
This investigation comprised tissue and stool studies. In the tissue study, gene sequencing and methylation assays were performed on candidate genes using tissue DNA from 25 IBD-CRNs and from 25 IBD mucosae without CRN. Mutations on P53, APC, KRAS, BRAF or PIK3CA genes were insufficiently informative, but several aberrantly methylated genes were highly discriminant. In the stool study, we evaluated candidate methylated genes (vimentin, EYA4, BMP3, NDRG4) in a prospective blinded study on buffered stools from 19 cases with known IBD-CRN and 35 age- and sex-matched IBD controls without CRN. From stool-extracted DNA, target genes were assayed by quantitative allele-specific real-time target and signal amplification method.
IBD-CRN cases included 17 with ulcerative colitis (UC) and 2 with Crohn’s disease (CD); 9 had cancer and 10 had dysplasia. Controls included 25 with UC and 10 with CD. Individually, BMP3, vimentin, EYA4, and NDRG4 markers showed high discrimination in stools with respective areas under the ROC curve of 0.91, 0.91, 0.85, and 0.84 for total IBD-CRN and of 0.97, 0.97, 0.95, and 0.85 for cancer. At 89% specificity, the combination of mBMP3 and mNDRG4 detected 9/9 (100%) of CRC and 80% of dysplasia, 4/4 (100%) of high grade and 4/6 (67%) of low grade.
These findings demonstrate feasibility of stool DNA testing for noninvasively detecting IBD-CRN.
PMCID: PMC3869396  PMID: 23347191
Stool DNA; inflammatory bowel disease; cancer surveillance; colorectal neoplasms; DNA methylation
10.  Development of the first disability index for inflammatory bowel disease based on the international classification of functioning, disability and health 
Gut  2011;61(2):241-247.
The impact of inflammatory bowel disease (IBD) on disability remains poorly understood. The World Health Organization's integrative model of human functioning and disability in the International Classification of Functioning, Disability and Health (ICF) makes disability assessment possible. The ICF is a hierarchical coding system with four levels of details that includes over 1400 categories. The aim of this study was to develop the first disability index for IBD by selecting most relevant ICF categories that are affected by IBD.
Relevant ICF categories were identified through four preparatory studies (systematic literature review, qualitative study, expert survey and cross-sectional study), which were presented at a consensus conference. Based on the identified ICF categories, a questionnaire to be filled in by clinicians, called the ‘IBD disability index’, was developed.
The four preparatory studies identified 138 second-level categories: 75 for systematic literature review (153 studies), 38 for qualitative studies (six focus groups; 27 patients), 108 for expert survey (125 experts; 37 countries; seven occupations) and 98 for cross-sectional study (192 patients; three centres). The consensus conference (20 experts; 17 countries) led to the selection of 19 ICF core set categories that were used to develop the IBD disability index: seven on body functions, two on body structures, five on activities and participation and five on environmental factors.
The IBD disability index is now available. It will be used in studies to evaluate the long-term effect of IBD on patient functional status and will serve as a new endpoint in disease-modification trials.
PMCID: PMC3245899  PMID: 21646246
Antibacterial peptide; azathioprine; bacterial translocation; Crohn's colitis; Crohn's disease; disability; gut immunology; IBD basic research; IBD clinical; IBD models; ICF; immunology; inflammatory bowel disease; infliximab; lamina proprial lymphocytes; mucosal immunology; 6-mercaptopurine; thiopurine methyltransferase; ulcerative colitis
11.  Risk of Biologic Therapy-Associated Progressive Multifocal Leukoencephalopathy: Use of the JC Virus Antibody Assay in the Treatment of Moderate-to-Severe Crohn’s Disease 
Gastroenterology & Hepatology  2012;8(11 Suppl 8):1-20.
For treatment of moderate-to-severe active Crohn’s disease, clinicians generally rely on immunosuppressants (including azathioprine and 6-mercaptopurine), corticosteroids, and antibodies against tumor necrosis factor α. However, a significant proportion of patients do not respond to these therapies, lose response over time, or are intolerant to these therapies. In such cases, one of the only remaining pharmacologic treatment options is natalizumab, an α4 integrin-targeted antibody. Unfortunately, 3 cases of progressive multifocal leukoencephalopathy (PML) were reported in natalizumab-treated patients in 2005, shortly after natalizumab’s approval by the US Food and Drug Administration (FDA). Natalizumab was subsequently withdrawn from the market but was then reintroduced in 2006 under close supervision by the FDA. Careful review of postmarketing data revealed 3 major risk factors for the development of natalizumab-associated PML, the most significant of which is prior exposure to the JC virus (JCV). To help identify patients who may be at higher risk for developing natalizumab-associated PML, a JCV antibody assay was developed that can detect anti-JCV antibodies in patients’ blood. Clinicians can now consider a patient’s anti-JCV antibody status together with the other major risk factors for natalizumab-associated PML—duration of natalizumab therapy and prior immunosuppressant use—to more accurately gauge the risks and benefits of natalizumab therapy in a particular patient.
PMCID: PMC4027896  PMID: 24847181
12.  Mucosal Healing with Infliximab 
Gastroenterology & Hepatology  2012;8(2):117-119.
PMCID: PMC3317509  PMID: 22485079
13.  Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) 
Gut  2011;61(4):535-542.
Variability in endoscopic assessment necessitates rigorous investigation of descriptors for scoring severity of ulcerative colitis (UC).
To evaluate variation in the overall endoscopic assessment of severity, the intra- and interindividual variation of descriptive terms and to create an Ulcerative Colitis Endoscopic Index of Severity which could be validated.
A two-phase study used a library of 670 video sigmoidoscopies from patients with Mayo Clinic scores 0–11, supplemented by 10 videos from five people without UC and five hospitalised patients with acute severe UC. In phase 1, each of 10 investigators viewed 16/24 videos to assess agreement on the Baron score with a central reader and agreed definitions of 10 endoscopic descriptors. In phase 2, each of 30 different investigators rated 25/60 different videos for the descriptors and assessed overall severity on a 0–100 visual analogue scale. κ Statistics tested inter- and intraobserver variability for each descriptor. A general linear mixed regression model based on logit link and β distribution of variance was used to predict overall endoscopic severity from descriptors.
There was 76% agreement for ‘severe’, but 27% agreement for ‘normal’ appearances between phase I investigators and the central reader. In phase 2, weighted κ values ranged from 0.34 to 0.65 and 0.30 to 0.45 within and between observers for the 10 descriptors. The final model incorporated vascular pattern, (normal/patchy/complete obliteration) bleeding (none/mucosal/luminal mild/luminal moderate or severe), erosions and ulcers (none/erosions/superficial/deep), each with precise definitions, which explained 90% of the variance (pR2, Akaike Information Criterion) in the overall assessment of endoscopic severity, predictions varying from 4 to 93 on a 100-point scale (from normal to worst endoscopic severity).
The Ulcerative Colitis Endoscopic Index of Severity accurately predicts overall assessment of endoscopic severity of UC. Validity and responsiveness need further testing before it can be applied as an outcome measure in clinical trials or clinical practice.
PMCID: PMC3292713  PMID: 21997563
Ulcerative colitis; endoscopy; disease severity; activity index; instrument development; inflammatory bowel disease; Crohn's disease; infliximab; 5-aminosalicylic acid (5-ASA); clinical trials; TNF-alpha; IBD; 6-mercaptopurine; probiotics; prebiotic; intestinal bacteria; chronic IBD; antibody targeted therapy; IBD clinical; chronic ulcerative colitis; cell migration; cellular immunity
14.  Risk Factors Associated With Progression to Intestinal Complications of Crohn's Disease in a Population-Based Cohort 
Gastroenterology  2010;139(4):1147-1155.
Background and Aims
We sought to assess the evolution of Crohn's disease behavior in an American population-based cohort.
The medical records of all Olmsted County, Minnesota residents who were diagnosed with Crohn's disease from 1970 to 2004 were evaluated for their initial clinical phenotype, based on the Montreal classification. The cumulative probabilities of developing structuring and/or penetrating complications were estimated using the Kaplan-Meier method. Proportional hazards regression was used to assess associations between baseline risk factors and changes in behavior.
Among 306 patients, 56.2% were diagnosed between the ages of 17 and 40 years. Disease extent was ileal in 45.1%, colonic in 32.0%, and ileocolonic in 18.6%. At baseline, 81.4% had non-stricturing non-penetrating disease, 4.6% had stricturing disease, and 14.0% had penetrating disease. The cumulative risk of developing either complication was 18.6% at 90 days, 22.0% at 1 year, 33.7% at 5 years, and 50.8% at 20 years after diagnosis. Among 249 patients with non-stricturing, non-penetrating disease at baseline, 66 changed their behavior after the first 90 days from diagnosis. Relative to colonic extent, ileal, ileocolonic, and upper gastrointestinal extent were significantly associated with changes in behavior, whereas the association with perianal disease was barely significant.
In a population-based cohort study, 18.6% of patients with Crohn's disease experienced penetrating or stricturing complications within 90 days after diagnosis; 50% experienced intestinal complications 20 years after diagnosis. Factors associated with development of complications were the presence of ileal involvement and perianal disease.
PMCID: PMC2950117  PMID: 20637205
Crohn's disease; complications; stricture; fistula; abscess; natural history
15.  Diagnostic Ionizing Radiation Exposure in a Population-Based Cohort of Patients with Inflammatory Bowel Disease 
For diagnosis, assessing disease activity, complications and extraintestinal manifestations, and monitoring response to therapy, patients with inflammatory bowel disease undergo many radiological studies employing ionizing radiation. However, the extent of radiation exposure in these patients is unknown.
A population-based inception cohort of 215 patients with inflammatory bowel disease from Olmsted County, Minnesota, diagnosed between 1990 and 2001, was identified. The total effective dose of diagnostic ionizing radiation was estimated for each patient. Linear regression was used to assess the median total effective dose since symptom onset.
The number of patients with Crohn's disease and ulcerative colitis was 103 and 112, with a mean age at diagnosis of 38.6 and 39.4 yr, respectively. Mean follow-up was 8.9 yr for Crohn's disease and 9.0 yr for ulcerative colitis. Median total effective dose for Crohn's disease was 26.6 millisieverts (mSv) (range, 0–279) versus 10.5 mSv (range, 0–251) for ulcerative colitis (P < 0.001). Computed tomography accounted for 51% and 40% of total effective dose, respectively. Patients with Crohn's disease had 2.46 times higher total effective dose than ulcerative colitis patients (P = 0.001), adjusting for duration of disease.
Annualizing our data, the radiation exposure in the inflammatory bowel disease population was equivalent to the average annual background radiation dose from naturally occurring sources in the U.S. (3.0 mSv). However, a subset of patients had substantially higher doses. The development of imaging management guidelines to minimize radiation dose, dose-reduction techniques in computed tomography, and faster, more robust magnetic resonance techniques are warranted.
PMCID: PMC2831296  PMID: 18564113
16.  MMX Mesalamine for Induction and Maintenance Therapy in Mild-to-Moderate Ulcerative Colitis 
Gastroenterology & Hepatology  2009;5(7):494-500.
Two 8-week, randomized, placebo-controlled parent studies, SPD476-301 (by Lichtenstein and associates) and SPD476-302 (by Kamm and colleagues), of MMX Multi Matrix System (MMX) mesalamine have evaluated the induction of remission in ulcerative colitis patients, and a third study has evaluated the maintenance of remission in patients from these parent studies. Here, we examine data only from patients who received MMX mesalamine 2.4 g or 4.8 g daily in these trials. In total, 63.6% of patients (220/346) achieved remission following 8–16 weeks of MMX mesalamine therapy. Among these 220 eligible patients, 218 entered the 12-month maintenance phase, and of this group, 89.9% (196/218) were relapse-free at study end. Overall, 56.6% (196/346) of patients who started MMX mesalamine therapy both achieved and maintained remission for 12 months. The adverse-event profile of MMX mesalamine was similar to the profile of the parent studies’ placebo arms at all doses and frequencies. Therefore, the majority of patients with active, mild-to-moderate ulcerative colitis can achieve remission, including complete symptom resolution and mucosal healing, and remain relapse-free for at least 1 year with MMX mesalamine.
PMCID: PMC2886429
MMX mesalamine; 5-aminosalicylic acid; ulcerative colitis
17.  Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared with 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I trial 
Delayed-release oral mesalamine 2.4 g/day to 4.8 g/day has been shown to be effective in treating mildly to moderately active ulcerative colitis (UC), but it is unknown whether an initial dose of 4.8 g/day is more effective than 2.4 g/day in patients with mildly to moderately active UC and in the subgroup with moderate disease.
A six-week, multicentre, randomized, double-blind, controlled trial assessing the safety and clinical efficacy of a new dose (ASCEND I) of medication randomly assigned 301 adults with mildly to moderately active UC to delayed-release oral mesalamine 2.4 g/day (400 mg tablet [n=154]) or 4.8 g/day (800 mg tablet [n=147]). The primary efficacy end point was overall improvement (ie, treatment success), defined as complete remission or response to therapy from baseline to week 6. Primary safety end points were adverse events and laboratory evaluations. Data were also analyzed separately for the prespecified subgroup of patients with moderate UC at baseline.
Treatment success was not statistically different between the treatment groups at week 6; 51% of the group (77 of 150) who received delayed-release oral mesalamine 2.4 g/day and 56% of the group (76 of 136) who received 4.8 g/day reached the efficacy end point (P=0.441). Among the moderate disease subgroup, however, the higher initial dose was more effective; 57% of patients (53 of 93) given delayed-release oral mesalamine 2.4 g/day and 72% of patients (55 of 76) given 4.8 g/day achieved treatment success (P=0.0384). Both regimens were well tolerated.
Delayed-release oral mesalamine is an effective and well-tolerated initial therapy in patients with mildly to moderately active UC, and a 4.8 g/day dose may enhance treatment success rates in patients with moderate disease compared with mesalamine 2.4 g/day.
PMCID: PMC2658575  PMID: 18080055
Delayed release; Inflammatory bowel disease; Mesalamine; Ulcerative colitis
20.  Development of the Crohn's disease digestive damage score, the Lémann score 
Inflammatory Bowel Diseases  2010;17(6):1415-1422.
Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be “diagnostic modality driven”: for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. (Inflamm Bowel Dis 2011)
PMCID: PMC3116198  PMID: 21560202
Crohn's disease; illness index severity; magnetic resonance imaging
21.  A Pooled Analysis of Infections, Malignancy, and Mortality in Infliximab- and Immunomodulator-Treated Adult Patients With Inflammatory Bowel Disease 
The objective of this study was to analyze the safety of long-term infliximab treatment, with/without concomitant immunomodulators, across Crohn's disease (CD) and ulcerative colitis (UC) clinical trials.
To maximize sample size, we pooled primary safety data across 10 CD or UC trials, including five randomized, controlled trials contributing data from patients who received intravenous infliximab 5 or 10 mg/kg (n=1,713; ±azathioprine) or placebo (n=406; ±azathioprine). Pooled incidences and 95% confidence intervals (CIs) were determined for mortality, infection, and malignancy. Standardized incidence ratios and 95% CIs were also determined for malignancies using the Surveillance, Epidemiology, and End Results database.
We observed no increase in infections, serious infections, or malignancy with infliximab vs. placebo in these patients with inflammatory bowel disease (IBD). In patients with UC, but not CD, immunomodulator treatment (vs. treatment without immunomodulator) yielded a higher incidence (95% CI) of infections (120.07 (110.66, 130.08)/100 patient-years (pt-yrs) vs. 92.47 (84.54, 100.94)/100 pt-yrs). Among placebo-treated patients with CD, but not UC, those with immunomodulator use demonstrated a higher incidence (95% CI) of malignancy vs. no immunomodulator treatment (1.84 (0.22, 6.66)/100 pt-yrs vs. 0.00 (0.00, 0.00)/100 pt-yrs). Mortality and infection-related mortality appeared unaffected by infliximab or immunomodulator treatment.
Infliximab treatment of IBD did not appear to affect incidences of infection, mortality, or malignancy. Relative to patients with no immunomodulator use, immunomodulator-treated UC patients demonstrated a higher incidence of infection and immunomodulator-plus-placebo-treated CD patients demonstrated a higher incidence of malignancy.
PMCID: PMC3390465  PMID: 22613901
22.  Serious Infection and Mortality in Patients With Crohn's Disease: More Than 5 Years of Follow-Up in the TREAT™ Registry 
The objective of this study was to contribute long-term safety data for infliximab and other therapies in Crohn's disease (CD).
We prospectively evaluated CD patients enrolled in the large, observational Crohn's Therapy, Resource, Evaluation, and Assessment Tool registry, established to compare infliximab safety with conventional nonbiological medications in CD.
A total of 6,273 patients were enrolled and evaluated on or before 23 February 2010; 3,420 received infliximab (17,712 patient-years; 89.9% received ≥2 infusions) and 2,853 received other-treatments-only (13,251 patient-years). Mean length of patient follow-up was 5.2 years. More infliximab- than other-treatments-only-treated patients had moderate-to-severe (30.6% vs. 10.7%) or severe-to-fulminant (2.5% vs. 0.6%) disease severity (P<0.001). In the year before enrollment, more infliximab- than other-treatments-only-treated patients required surgical intervention (17.4% vs. 13.6%), medical hospitalization (14.2% vs. 8.8%), prednisone (47.8% vs. 31.4%), immunomodulators (52.0% vs. 32.1%), and narcotic analgesics (17.3% vs. 9.1%). Patient mortality was similar for infliximab- and other-treatments-only-treated patients (0.58 vs. 0.59/100 patient-years). In multivariate logistic regression analyses, treatment with prednisone (hazard ratio (HR)=2.14, 95% confidence interval (CI)=1.55, 2.95; P<0.001) or narcotic analgesics (HR=1.79, 95% CI=1.29, 2.48; P<0.001) and age (HR=1.08, 95% CI=1.07, 1.09; P<0.001) were associated with increased mortality risk. Neither infliximab nor immunomodulator treatment was associated with increased mortality risk. Factors independently associated with serious infections included moderate-to-severe disease activity (HR=2.24, 95% CI=1.57, 3.19; P<0.001), narcotic analgesic treatment (HR=1.98, 95% CI=1.44, 2.73; P<0.001), prednisone therapy (HR=1.57, 95% CI=1.17, 2.10; P=0.002), and infliximab treatment (HR=1.43, 95% CI=1.11, 1.84; P=0.006).
Mortality was similar between infliximab- and other-treatments-only-treated CD patients. An increased risk of serious infection with infliximab was observed, although CD severity and use of prednisone or narcotic analgesics carried higher risks.
PMCID: PMC3438468  PMID: 22890223
23.  Andrographis paniculata Extract (HMPL-004) for Active Ulcerative Colitis 
Andrographis paniculata has in vitro inhibitory activity against TNF-α, IL-1β and NF-κB. A pilot study of A. paniculata extract (HMPL-004) suggested similar efficacy to mesalamine for ulcerative colitis.
A randomized, double-blind, placebo-controlled trial evaluated the efficacy of A. paniculata extract (HMPL-004) in 224 adults with mild-to-moderate ulcerative colitis. Patients were randomized to A. paniculata extract (HMPL-004) 1,200 mg or 1,800 mg daily or placebo for 8 weeks.
In total, 45 and 60% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical response at week 8, compared with 40% of those who received placebo (P=0.5924 for 1,200 mg vs. placebo and P=0.0183 for 1,800 mg vs. placebo). In all, 34 and 38% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical remission at week 8, compared with 25% of those who received placebo (P=0.2582 for 1,200 mg vs. placebo and P=0.1011 for 1,800 mg vs. placebo). Adverse events developed in 60 and 53% of patients in the A. paniculata 1,200 mg and 1,800 mg daily groups, respectively, and 60% in the placebo group.
Patients with mildly to moderately active ulcerative colitis treated with A. paniculata extract (HMPL-004) at a dose of 1,800 mg daily were more likely to achieve clinical response than those receiving placebo.
PMCID: PMC3538174  PMID: 23044768
24.  Four-Year Maintenance Treatment With Adalimumab in Patients with Moderately to Severely Active Ulcerative Colitis: Data from ULTRA 1, 2, and 3 
The safety and efficacy of adalimumab for patients with moderately to severely active ulcerative colitis (UC) has been reported up to week 52 from the placebo-controlled trials ULTRA (Ulcerative Colitis Long-Term Remission and Maintenance with Adalimumab) 1 and 2. Up to 4 years of data for adalimumab-treated patients from ULTRA 1, 2, and the open-label extension ULTRA 3 are presented.
Remission per partial Mayo score, remission per Inflammatory Bowel Disease Questionnaire (IBDQ) score, and mucosal healing rates were assessed in adalimumab-randomized patients from ULTRA 1 and 2 up to week 208. Corticosteroid-free remission was assessed in adalimumab-randomized patients who used corticosteroids at lead-in study baseline. Maintenance of remission per partial Mayo score and mucosal healing was assessed in patients who entered ULTRA 3 in remission per full Mayo score and with mucosal healing, respectively. As observed, last observation carried forward (LOCF) and nonresponder imputation (NRI) were used to report efficacy. Adverse events were reported for any adalimumab-treated patient.
A total of 600/1,094 patients enrolled in ULTRA 1 or 2 were randomized to receive adalimumab and included in the intent-to-treat analyses of the studies. Of these, 199 patients remained on adalimumab after 4 years of follow-up. Rates of remission per partial Mayo score, remission per IBDQ score, mucosal healing, and corticosteroid discontinuation at week 208 were 24.7%, 26.3%, 27.7% (NRI), and 59.2% (observed), respectively. Of the patients who were followed up in ULTRA 3 (588/1,094), a total of 360 patients remained on adalimumab 3 years later. Remission per partial Mayo score and mucosal healing after ULTRA 1 or 2 to year 3 of ULTRA 3 were maintained by 63.6% and 59.9% of patients, respectively (NRI). Adverse event rates were stable over time.
Remission, mucosal healing, and improved quality of life were maintained in patients with moderately to severely active UC with long-term adalimumab therapy, for up to 4 years. No new safety signals were reported.
PMCID: PMC4223868  PMID: 25155227

Results 1-24 (24)