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1.  A Population-Based Study of Incidence, Risk Factors, Clinical Spectrum, and Outcomes of Ischemic Colitis 
Background & Aims
Little is known about progression of ischemic colitis (IC) among unselected patients. We aimed to estimate the incidence, risk factors, and natural history of IC in a population-based cohort in Olmsted County, Minnesota.
Methods
We performed a retrospective population-based cohort and nested case–control study of IC. Each IC case was matched to 2 controls from the same population based on sex, age, and closest registration number. Conditional logistic regression, the Kaplan-Meier method, and proportional hazards regression were used to assess comorbidities, estimate survival, and identify characteristics associated with survival, respectively.
Results
Four hundred forty-five county residents (median age, 71.6 years; 67% female) were diagnosed with IC from 1976 through 2009 and were matched with 890 controls. The age- and sex-adjusted incidence rates of IC nearly quadrupled, from 6.1 cases/100,000 person-years in 1976–1980 to 22.9/100,000 in 2005–2009. The odds for IC were significantly higher among subjects with atherosclerotic diseases; odds ratios ranged from 2.6 for individuals with coronary disease to 7.9 for individuals with peripheral vascular disease. Of IC cases, 59% survived for 5 years (95% CI, 54%–64%), compared to 90% of controls (95% CI, 88%–92%). Age >40 years, male sex, right-sided colon involvement, concomitant small bowel involvement, and chronic obstructive pulmonary disease were all independently associated with mortality (P<.05).
Conclusions
The incidence of IC increased over the past 3 decades in a population-based cohort in Minnesota. IC typically presents in older patients with multiple co-morbidities and is associated with high in-hospital mortality (11.5%) and rates of surgery (17%).
doi:10.1016/j.cgh.2014.07.061
PMCID: PMC4326614  PMID: 25130936
COPD; epidemiologic study; cardiovascular disease; intestinal vasculature
2.  CUMULATIVE INCIDENCE AND RISK FACTORS FOR HOSPITALIZATION AND SURGERY IN A POPULATION-BASED COHORT OF ULCERATIVE COLITIS 
Inflammatory bowel diseases  2013;19(9):1858-1866.
Background and Aims
We sought to identify clinical and demographic features influencing hospitalization and colectomy in a population-based inception cohort of ulcerative colitis.
Methods
Between 1970 and 2004, a total of 369 patients (58.5% males) from Olmsted County, Minnesota were followed from diagnosis for 5,401 person-years. The cumulative probability of hospitalization and colectomy were estimated using the Kaplan-Meier method. Cox proportional hazards regression was used to identify factors associated with hospitalization and colectomy.
Results
The cumulative probability of first hospitalization was 29.4% at 5 years (95% confidence interval [CI], 24.5%–34.1%), 38.7% at 10 years (33.1% –43.8%), 49.2% at 20 years (42.7% –55.2%) and 52.3% at 30 years (45.1% –59.7%). The incidence rate of hospitalizations decreased over the last four decades, although cumulative probability of first hospitalization increased with successive decades of diagnosis. Early need for corticosteroids (hazard ratio [HR], 1.8; 95% CI, 1.1–2.7) and early need for hospitalization (HR, 1.5; 1.02–2.4) were independent predictors of hospitalization after 90 days of illness. The cumulative probability of colectomy from time of diagnosis was 13.1% at 5 years (95% CI, 9.4% –16.6%), 18.9% at 10 years (14.4% –23.2%), and 25.4% at 20 years (19.8% –30.8%). Male gender (HR, 2.1; 95% CI, 1.3–3.5), diagnosis in the 1990s (HR, 2.0; 1.01–4.0) and diagnosis in 2000–2004 (HR, 3.7; 1.7–8.2) were significantly associated with colectomy risk.
Conclusion
Colectomy rates were comparable to reports from northern Europe. The numbers of hospitalizations show a decreasing trend. Male gender and being diagnosed in the 2000–04 period predicted colectomy while extensive colitis predicted future hospitalizations.
doi:10.1097/MIB.0b013e31828c84c5
PMCID: PMC4526131  PMID: 23660997
Ulcerative colitis; colectomy; ileal pouch-anal anastomosis; hospitalizations; corticosteroids
3.  The epidemiology of microscopic colitis: a population based study in Olmsted County, Minnesota 
Gut  2006;56(4):504-508.
Objective
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.
Results
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).
Conclusions
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.
doi:10.1136/gut.2006.105890
PMCID: PMC1856874  PMID: 17135309
4.  SURGERY IN A POPULATION-BASED COHORT OF CROHN’S DISEASE FROM OLMSTED COUNTY, MINNESOTA (1970–2004) 
Background & Aims
We sought to estimate the need for surgery in an American population-based cohort of Crohn’s disease.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1038/ajg.2012.298
PMCID: PMC3572861  PMID: 22945286
Crohn’s disease; surgery; natural history; risk factors
5.  Outcomes of Patients with Microscopic Colitis Treated with Corticosteroids: A population-based study 
Objectives
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
Methods
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.
Results
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).
Conclusion
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.
doi:10.1038/ajg.2012.416
PMCID: PMC3575108  PMID: 23295275
microscopic colitis; corticosteroid; outcomes; response; recurrence
6.  PERIANAL CROHN’S DISEASE FINDINGS OTHER THAN FISTULAS IN A POPULATION-BASED COHORT 
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1002/ibd.21674
PMCID: PMC3352677  PMID: 21351216
Crohn’s disease; natural history; anorectal strictures; anal ulcers; perianal tags; anal fissures
7.  Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency 
The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired antigen-induced lymphocyte proliferation, reduced cytokine production by CD8+ T lymphocytes, and decreased numbers of natural killer (NK) cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.
doi:10.4049/jimmunol.1401463
PMCID: PMC4355235  PMID: 25667416
8.  Update on Janus Kinase Antagonists in Inflammatory Bowel Disease 
Janus kinase (JAK) inhibitors have emerged as a novel orally administered small molecule therapy for the treatment of ulcerative colitis and possibly Crohn’s disease. These molecules are designed to selectively target the activity of specific JAKs and offer a targeted mechanism of action without risk of immunogenicity. Based on data from clinical trials in rheumatoid arthritis and phase 2 studies in inflammatory bowel disease, tofacitinib and other JAK inhibitors are likely to become a new form of medical therapy for the treatment of inflammatory bowel disease.
doi:10.1016/j.gtc.2014.05.011
PMCID: PMC4129380  PMID: 25110261
Janus kinase inhibitors; Small molecule therapy; Tofacitinib; Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease
9.  The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease 
Gut  2014;64(10):1539-1545.
Objective
Although low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohn's disease (CD), the clinical relevance of ATI in patients with adequate infliximab concentrations is uncertain. We evaluated this question using an assay sensitive for identification of ATI in the presence of infliximab.
Design
In an observational study, 1487 trough serum samples from 483 patients with CD who participated in four clinical studies of maintenance infliximab therapy were analysed using a fluid phase mobility shift assay. Infliximab and ATI concentrations most discriminant for remission, defined as a C-reactive protein concentration of ≤5 mg/L, were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission.
Results
Based upon analysis of 1487 samples, 77.1% of patients had detectable and 22.9% had undetectable infliximab concentrations, of which 9.5% and 71.8%, respectively, were positive for ATI. An infliximab concentration of >2.79 μg/mL (area under the curve (AUC)=0.681; 95% CI 0.632 to 0.731) and ATI concentration of <3.15 U/mL (AUC=0.632; 95% CI 0.589 to 0.676) were associated with remission. Multivariable analysis showed that concentrations of both infliximab trough (OR 1.8; 95% CI 1.3 to 2.5; p<0.001) and ATI (OR 0.57; 95% CI 0.39 to 0.81; p=0.002) were independent predictors of remission.
Conclusions
The development of ATI increases the probability of active disease even at low concentrations and in the presence of a therapeutic concentration of drug during infliximab maintenance therapy. Evaluation of strategies to prevent ATI formation, including therapeutic drug monitoring with selective infliximab dose intensification, is needed.
doi:10.1136/gutjnl-2014-307883
PMCID: PMC4602247  PMID: 25336114
CROHN'S DISEASE; INFLIXIMAB; PHARMACOKINETICS; PHARMACOLOGY; TNF
10.  Ciprofloxacin for prevention of postoperative recurrence in patients with Crohn’s disease: a randomized, double-blind, placebo-controlled pilot study 
Inflammatory bowel diseases  2013;19(5):1073-1079.
Background
The commensal bacterial flora plays a critical role in postoperative recurrence of Crohn’s disease (CD). We conducted a randomized, double-blind, placebo-controlled 6 months pilot trial of ciprofloxacin for the prevention of endoscopic recurrence in patients with CD who underwent surgery.
Methods
Thirty-three patients with CD, who had undergone surgery with ileo-colonic anastomosis within the previous 2 weeks, were randomized to treatment with ciprofloxacin (500 mg twice daily) or placebo tablets for 6 months. Endpoints were endoscopic recurrence at 6 months and safety and tolerability of long-term ciprofloxacin therapy.
Results
Thirty-three patients were randomized; 14 patients discontinued the study early. Significant endoscopic recurrence was observed in 3 of 9 patients (33%) in the ciprofloxacin group and 5 of 10 patients (50%) in the placebo group at 6 months after surgery (p<0.578). The intention-to-treat analysis demonstrated endoscopic recurrence in 11/17 patients (65%) in the ciprofloxacin group and 11/16 patients (69%) in the placebo group at month 6 (p<0.805). Thirty-six adverse events (AE’s) occurred in 19/33 patients (58%). Possible drug associated AE’s occurred significantly more often in the ciprofloxacin group (p<0.043), leading to study drug discontinuation in 24% (4/17) and 6% (1/16) patients in the ciprofloxacin group and placebo group, respectively (p<0.166).
Conclusion
In this pilot study, ciprofloxacin was not more effective than placebo for the prevention of postoperative recurrence in patients with CD. Long-term ciprofloxacin therapy is limited by drug-associated side effects. Future studies in postoperative prevention of CD should evaluate antibiotic approaches with a more favorable safety profile.
doi:10.1097/01.MIB.0000428910.36091.10
PMCID: PMC4596532  PMID: 23511031
Crohn’s disease/surgery; ciprofloxacin; quinolone; Anti-Infective Agents/adverse effects; inflammatory bowel diseases
11.  Budesonide Foam Has a Favorable Safety Profile for Inducing Remission in Mild-to-Moderate Ulcerative Proctitis or Proctosigmoiditis 
Digestive Diseases and Sciences  2015;60(11):3408-3417.
Background
Budesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis.
Aim
The aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam.
Methods
Data from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam.
Results
A similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0 %, respectively). Adverse events occurred in 41.4 and 36.3 % of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic–pituitary–adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration.
Conclusions
This integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic–pituitary–adrenal axis.
doi:10.1007/s10620-015-3868-5
PMCID: PMC4621699  PMID: 26386854
Ulcerative colitis; Ulcerative proctitis; Ulcerative proctosigmoiditis; Budesonide foam; Safety; Pharmacokinetics
12.  Validated gene expression biomarker analysis for biopsy-based clinical trials in ulcerative colitis Short title: Inflammatory gene expression in ulcerative colitis 
Summary
Background
Accurate and reproducible measurement of expression of pro-inflammatory cytokines in colonic biopsies from patients with ulcerative colitis (UC) is essential for proof-of-concept and mechanism-of-action studies. Few studies have rigorously established the number of biopsies required for accurate and reproducible biomarker measurements.
Aim
To validate methods for measuring changes in gene expression in colonic biopsy samples.
Methods
Twelve colonic biopsies were obtained from each of 6 healthy controls, 6 patients with inactive UC, and 7 patients with active UC. Mayo endoscopic scores were used as a clinical reference standard. Quantitative PCR was used to assess mRNA expression of eight known inflammatory genes. The power to detect a reduction in gene expression in active versus inactive UC was calculated using a linear mixed effect model.
Results
mRNA analysis of colonic biopsies is a sensitive and feasible approach for measuring inflammatory gene expression in colonic biopsies. Inflammatory biomarkers correlate with Mayo endoscopic subscores for each colonic region. For most genes, 3 rectal biopsies from 2–4 patients are required to detect changes in gene expression corresponding to active versus inactive UC to achieve a power of 80% with an alpha of 0.05.
Conclusions
Our data suggest that systematic measurement of inflammatory biomarkers at the mRNA level can be a valuable tool for hypothesis testing and assessment of clinical activity and response to therapy in ulcerative colitis.
doi:10.1111/apt.12862
PMCID: PMC4143528  PMID: 25041724
ulcerative colitis; gene expression; coefficient of variation; sampling error; mRNA; molecular targets; biomarkers; power
13.  Validation of gene expression biomarker analysis for biopsy-based clinical trials in Crohn’s disease 
Inflammatory bowel diseases  2015;21(2):323-330.
Background
The ability to measure the expression of pro-inflammatory cytokines from intestinal biopsies in patients with Crohn’s disease in an accurate and reproducible way is critical for proof-of-concept and mechanism-of-action trials; however, the number of biopsies from a segment of the ileum or colon required to yield reproducible results has not been rigorously evaluated. We examined intestinal biopsies from patients with Crohn’s disease to validate methods for detecting changes in inflammatory gene expression.
Methods
To evaluate the reproducibility of gene expression measurements, intestinal biopsies were obtained from designated segmentsfrom6 healthy controls, 6 patients with active Crohn’s disease, and 6 patients with inactive Crohn’s disease. Disease activity was based on the simple endoscopic score for Crohn’s disease (SES-CD). Expression of 7 pro-inflammatory genes was measured from each biopsy using quantitative PCR. Using a linear mixed effects model, the power to detect transcriptional changes corresponding to active and inactive Crohn’s disease was calculated.
Results
Total SES-CD score corresponds with expression of most inflammatory biomarkers. For most genes, 2 – 5biopsies are needed to reduce sampling error to <25% for most genes. To measure changes in mRNA expression corresponding to active versus inactive Crohn’s disease, one to two intestinal biopsies from 3 patients before and after treatment are needed to yield power of at least 80%.
Conclusion
Measuring pro-inflammatory gene expression from mucosal biopsies from patients with Crohn’s disease is practicable and provides objective biomarkers that can be utilized in proof-of-concept and mechanism-of-action trials to assess response to therapy.
doi:10.1097/MIB.0000000000000264
PMCID: PMC4404151  PMID: 25545378
Crohn’s disease; gene expression; biomarker; coefficient of variation; sampling error; proof-of-concept; power
14.  A phase II study of laquinimod in Crohn's disease 
Gut  2014;64(8):1227-1235.
Objective
Laquinimod is an oral therapeutic agent under investigation for the treatment of Crohn's disease (CD), Huntington's disease, lupus nephritis and multiple sclerosis. This dose escalation study evaluated the safety and efficacy of laquinimod as induction therapy in patients with active moderate–severe CD.
Design
Multicentre, double-blind, sequential-cohort, randomised controlled trial with laquinimod doses of 0.5, 1, 1.5 or 2 mg/day or placebo (n=45 per cohort randomised in a 2:1 ratio) for 8 weeks with 4-week follow-up. Stable concomittant therapies and prior use of anti-tumour necrosis factor agents were permitted. Comprehensive safety assessments were performed and efficacy analyses included the proportions of patients in clinical remission (CD Activity Index (CDAI) <150 and no treatment failure (TF)), and with a clinical response (70 or 100 point CDAI reduction from baseline or remission and no TF).
Results
117 patients received laquinimod and 63 patients received placebo. The overall incidence of adverse events (AEs) in the laquinimod group was similar to the pooled placebo group (86.2%–96.7% vs 82.5%) and most AEs were mild to moderate in severity. Treatment with laquinimod 0.5 mg showed consistent effects on remission (48.3% (CI 31% to 66%) vs 15.9% (CI 9% to 27%)), response 100 (55.2% (CI 37% to 71%) vs 31.7% (CI 22% to 44%)) and response 70 (62.1% (CI 44% to 77%) vs 34.9% (CI 24% to 47%)) versus placebo. Laquinimod 1.0 mg showed less benefit (26.7% remission (CI 14% to 44%) and 53.3% response 70 (CI 36% to 70%)), and no effect was noted on remission/response at higher doses.
Conclusions
Laquinimod was safe and well tolerated, and the effects on remission and response of the 0.5 mg dose suggest a treatment benefit in patients with CD.
Trial registration number
NCT00737932.
doi:10.1136/gutjnl-2014-307118
PMCID: PMC4515993  PMID: 25281416
CROHN'S DISEASE; PHARMACOTHERAPY; IBD CLINICAL; CLINICAL TRIALS; CLINICAL DECISION MAKING
15.  Budesonide MMX for the Induction of Remission of Mild to Moderate Ulcerative Colitis: A Pooled Safety Analysis 
Journal of Crohn's & Colitis  2015;9(9):738-746.
Background and aims:
Cumulative safety and tolerability of budesonide MMX, a once-daily oral corticosteroid for inducing mild to moderate ulcerative colitis remission, was examined.
Methods:
Data from three randomized, double-blind, placebo-controlled, phase II or III studies [budesonide MMX 9mg, 6mg, or 3mg for 8 weeks]; one phase II study [randomisation to budesonide MMX 9mg or placebo for 4 weeks, then open-label budesonide MMX 9mg for 4 weeks]; and one open-label study [budesonide MMX 9mg for 8 weeks] were pooled.
Results:
Patients randomised to budesonide MMX 9mg [n = 288], 6mg [n = 254], or placebo [n = 293] had similar rates of adverse events [AEs] [27.1%, 24.8%, and 23.9%, respectively] and serious AEs [2.4%, 2.0%, and 2.7%, respectively]; treatment-related AEs and serious AEs were reported by 11.8% and 13.5%, and 5.9% and 2.2%, respectively, of patients receiving budesonide MMX 3mg [n = 17] or open-label budesonide MMX 9mg [n = 89]. Mean morning plasma cortisol concentrations were normal from baseline to final visit across randomised groups; in patients receiving open-label budesonide, mean cortisol concentration was 129.9 nmol/l after 4 weeks, returning to normal concentrations at final visit. Budesonide MMX was not associated with an overall increased risk for glucocorticoid-related adverse effects.
Conclusions:
Budesonide MMX 9mg was associated with normal mean cortisol concentrations at final visit and an AE incidence comparable to placebo. Overall, budesonide MMX was safe and well tolerated for inducing remission of patients with mild to moderate ulcerative colitis.
doi:10.1093/ecco-jcc/jjv101
PMCID: PMC4736820  PMID: 26094251
Budesonide MMX; ulcerative colitis; safety; tolerability
16.  Biologic Concentration Testing in Inflammatory Bowel Disease 
Inflammatory Bowel Diseases  2015;21(6):1435-1442.
Article first published online 14 January 2015.
Abstract:
Anti-TNF medications have revolutionized the care of patients with inflammatory bowel disease. However, despite an initial robust effect, loss of response is common and long-term results are disappointing. Much of this lack of durability may be due to inadequate dose optimization, and recent studies suggest a correlation between serum drug concentrations and clinical outcomes. Currently, in clinical practice, measurement of drug concentrations and antibodies to drug are typically performed only when a patient presents with active inflammatory bowel disease symptoms or during a potential immune-mediated reaction to anti-TNF (“reactive” setting). However, proactive monitoring of anti-TNF concentrations with titration to a therapeutic window (i.e., therapeutic concentration monitoring) represents a new strategy with many potential clinical benefits including prevention of immunogenicity, less need for IFX rescue therapy, and greater durability of IFX treatment. This review will cover the salient features of anti-TNF pharmacokinetics and pharmacodynamics and provide a rational approach for the use of anti-TNF concentration testing in both the reactive and proactive settings.
doi:10.1097/MIB.0000000000000312
PMCID: PMC4437804  PMID: 25590953
anti-TNF; therapeutic concentration monitoring; loss of response; pharmacokinetics; pharmacodynamics; inflammatory bowel disease; Crohn's disease; ulcerative colitis; infliximab; adalimumab
17.  Briakinumab for Treatment of Crohn's Disease: Results of a Randomized Trial 
Inflammatory Bowel Diseases  2015;21(6):1329-1340.
Article first published online 29 April 2015.
Background:
This study assessed the efficacy and safety of briakinumab, a human anti-IL-12/23p40 monoclonal antibody, compared with placebo for the induction and maintenance of remission in patients with moderately to severely active Crohn's disease.
Methods:
In this phase 2b, multicenter, double-blind, parallel group study, 246 patients stratified by prior tumor necrosis factor–antagonist use and response, were randomized (1:1:1:3) to 4 intravenous induction regimens: placebo, 200, 400, or 700 mg briakinumab, at weeks 0/4/8. At week 12, responders in the placebo or 400-mg induction groups entered the maintenance phase with the same regimen, whereas responders in the 700-mg induction group were rerandomized (1:1:1) to receive placebo, 200, or 700 mg briakinumab at weeks 12/16/20. At week 24, patients in remission stopped receiving study drug (withdrawal phase) until relapse. Patients experiencing relapse, nonresponders, and nonremitters could enter the open-label phase.
Results:
The primary end point of clinical remission at week 6 was not met. There were numerically greater rates of remission and response at 6, 12, or 24 weeks in patients treated with briakinumab. The safety and tolerability profile of briakinumab was similar in the induction and maintenance phases of the trial.
Conclusions:
Briakinumab showed a similar safety and tolerability profile to placebo in the induction and maintenance phases, and comparable rates of serious adverse events, adverse events leading to discontinuation, and malignancy. These data provide support for the potential efficacy of briakinumab and other IL-12/23 inhibitors in the treatment of moderate-to-severe Crohn's disease.
doi:10.1097/MIB.0000000000000366
PMCID: PMC4450894  PMID: 25989338
IL-12; IL-23; monoclonal antibody
18.  A gp130-Src-YAP Module Links Inflammation to Epithelial Regeneration 
Nature  2015;519(7541):57-62.
Summary
Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members whose expression is elevated in many diseases, including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). We show that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the classic gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signaling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated upon receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signaling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
doi:10.1038/nature14228
PMCID: PMC4447318  PMID: 25731159
19.  The Impact of Clinical Information on the Assessment of Endoscopic Activity: Characteristics of the Ulcerative Colitis Endoscopic Index Of Severity [UCEIS] 
Journal of Crohn's & Colitis  2015;9(8):607-616.
Background and Aims:
To determine whether clinical information influences endoscopic scoring by central readers using the Ulcerative Colitis Endoscopic Index of Severity [UCEIS; comprising ‘vascular pattern’, ‘bleeding’, ‘erosions and ulcers’].
Methods:
Forty central readers performed 28 evaluations, including 2 repeats, from a library of 44 video sigmoidoscopies stratified by Mayo Clinic Score. Following training, readers were randomised to scoring with [‘unblinded’, n = 20, including 4 control videos with misleading information] or without [‘blinded’, n 20] clinical information. A total of 21 virtual Central Reader Groups [CRGs], of three blinded readers, were created. Agreement criteria were pre-specified. Kappa [κ] statistics quantified intra- and inter-reader variability.
Results:
Mean UCEIS scores did not differ between blinded and unblinded readers for any of the 40 main videos. UCEIS standard deviations [SD] were similar [median blinded 0.94, unblinded 0.93; p = 0.97]. Correlation between UCEIS and visual analogue scale [VAS] assessment of overall severity was high [r blinded = 0.90, unblinded = 0.93; p = 0.02]. Scores for control videos were similar [UCEIS: p ≥ 0.55; VAS: p ≥ 0.07]. Intra- [κ 0.47–0.74] and inter-reader [κ 0.40–0.53] variability for items and full UCEIS was ‘moderate’-to-‘substantial’, with no significant differences except for intra-reader variability for erosions and ulcers [κ blinded: 0.47 vs unblinded: 0.74; p 0.047]. The SD of CRGs was lower than for individual central readers [0.54 vs 0.95; p < 0.001]. Correlation between blinded UCEIS and patient-reported symptoms was high [stool frequency: 0.76; rectal bleeding: 0.82; both: 0.81].
Conclusions:
The UCEIS is minimally affected by knowledge of clinical details, strongly correlates with patient-reported symptoms, and is a suitable instrument for trials. CRGs performed better than individuals.
doi:10.1093/ecco-jcc/jjv077
PMCID: PMC4584567  PMID: 25956538
Endoscopic score; ulcerative colitis; disease activity index
20.  Emerging Treatment Options in Mild to Moderate Ulcerative Colitis 
Gastroenterology & Hepatology  2015;11(3 Suppl 1):1-16.
Ulcerative colitis (UC) is a chronic inflammatory condition associated with rectal bleeding and urgency, tenesmus, and diarrhea. Several medical therapies can be used in the treatment of UC. Aminosalicylates are widely used based on their efficacy in the induction and maintenance of remission. Although corticosteroids are effective in patients with more severe disease, systemic use is associated with significant safety concerns. The newer corticosteroid budesonide has lower systemic bioavailability and, consequently, a more favorable safety profile. A budesonide extended-release formulation allows once-daily dosing and delivers the agent locally throughout the colon. Biologic agents used for the treatment of moderate to severe UC include the tumor necrosis factor inhibitors infliximab, adalimumab, and golimumab, and the integrin inhibitor vedolizumab. Rectally administered therapy can also be useful in the treatment of UC. In October 2014, the US Food and Drug Administration approved a budesonide foam formulation for inducing remission in patients with active mild to moderate distal UC extending up to 40 cm from the anal verge. Budesonide foam rapidly distributes to the sigmoid colon and the rectum and avoids some of the drawbacks of suppositories and enemas.
PMCID: PMC4609145  PMID: 26491415
21.  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.
doi:10.1016/j.cgh.2012.07.006
PMCID: PMC4226798  PMID: 22835577
22.  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.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1136/gutjnl-2011-300049
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
24.  Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study 
Gut  2013;63(3):442-450.
Objective
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.
Design
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.
Results
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.
Conclusions
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:
ClinicalTrials.gov NCT00656890.
doi:10.1136/gutjnl-2012-303424
PMCID: PMC3933070  PMID: 23461895
Antibody Targeted Therapy; Ulcerative Colitis
25.  Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study 
Gut  2013;63(3):433-441.
Objective
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).
Design
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.
Results
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.
Conclusion
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.
doi:10.1136/gutjnl-2012-304258
PMCID: PMC3933176  PMID: 23436336
Inflammatory Bowel Disease; IBD; Ulcerative Colitis

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