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1.
Inflamm Bowel Dis ; 19(2): 363-9, 2013 Feb.
Article in English | MEDLINE | ID: mdl-22605661

ABSTRACT

BACKGROUND: Thiopurines are the mainstay of conventional maintenance therapy in inflammatory bowel disease (IBD). Unfortunately, up to 50% of patients discontinue immunosuppressive therapy within 2 years due to intolerance or lack of efficacy. Allopurinol with low-dose thiopurine can optimize thiopurine metabolism for IBD patients with preferential shunting toward 6-methyl mercaptopurine (6-MMP) formation. The aim of this study was to assess long-term maintenance effectiveness and tolerability of allopurinol-thiopurine therapy in a larger multicenter cohort of IBD patients. METHODS: Enrolled patients who failed monotherapy with thiopurines due to a skewed metabolism were subsequently treated with a combination therapy of allopurinol and low-dose thiopurine. Adverse events were monitored and therapeutic adherence was assessed. Seventy-seven IBD patients were enrolled with a mean follow-up of 19 months. RESULTS: The median 6-thioguanine nucleotide concentration increased from 145 during monotherapy to 271 pmol/8 × 10(8) red blood cell (RBC) after at least 8 weeks of combination therapy while reducing the thiopurine dosage (P < 0.001). In contrast, median 6-MMP concentrations decreased from 10,110 to 265 pmol/8 × 10(8) RBC (P < 0.001). Leukopenia occurred in 12 patients (16%), requiring dose adaptation. Liver test abnormalities normalized in 81% of patients after the addition of allopurinol. Sixteen (21%) patients had to discontinue combination therapy. The percentage of patients still using combination therapy at 6, 12, 24, and 60 months was 87%, 85%, 76%, and 65%, respectively. CONCLUSIONS: Long-term combination therapy with allopurinol and low-dose thiopurines is an effective and well-tolerated treatment in IBD patients with a skewed thiopurine metabolism.


Subject(s)
Allopurinol/therapeutic use , Azathioprine/therapeutic use , Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Immunosuppressive Agents/therapeutic use , Mercaptopurine/therapeutic use , Adolescent , Adult , Allopurinol/metabolism , Azathioprine/metabolism , Colitis, Ulcerative/metabolism , Crohn Disease/metabolism , Drug Administration Schedule , Drug Therapy, Combination , Female , Humans , Immunosuppressive Agents/metabolism , Maintenance Chemotherapy , Male , Medication Adherence , Mercaptopurine/metabolism , Middle Aged , Treatment Outcome , Young Adult
2.
PLoS One ; 7(2): e32545, 2012.
Article in English | MEDLINE | ID: mdl-22389708

ABSTRACT

BACKGROUND & AIMS: Past studies of the human intestinal microbiota are potentially confounded by the common practice of using bowel-cleansing preparations. We examined if colonic lavage changes the natural state of enteric mucosal-adherent microbes in healthy human subjects. METHODS: Twelve healthy individuals were divided into three groups; experimental group, control group one, and control group two. Subjects in the experimental group underwent an un-prepped flexible sigmoidoscopy with biopsies. Within two weeks, subjects were given a standard polyethylene glycol-based bowel cleansing preparation followed by a second flexible sigmoidoscopy. Subjects in control group one underwent two un-prepped flexible sigmoidoscopies within one week. Subjects in the second control group underwent an un-prepped flexible sigmoidoscopy followed by a second flexible sigmoidoscopy after a 24-hour clear liquid diet within one week. The mucosa-associated microbial communities from the two procedures in each subject were compared using 16S rRNA gene based terminal restriction fragment length polymorphism (T-RFLP), and library cloning and sequencing. RESULTS: Clone library sequencing analysis showed that there were changes in the composition of the mucosa-associated microbiota in subjects after colonic lavage. These changes were not observed in our control groups. Standard bowel preparation altered the diversity of mucosa-associated microbiota. Taxonomic classification did not reveal significant changes at the phylum level, but there were differences observed at the genus level. CONCLUSION: Standard bowel cleansing preparation altered the mucosal-adherent microbiota in all of our subjects, although the degree of change was variable. These findings underscore the importance of considering the confounding effects of bowel preparation when designing experiments exploring the gut microbiota.


Subject(s)
Colon/microbiology , Intestinal Mucosa/microbiology , Adult , Humans , Metagenome/genetics , Middle Aged , Polymorphism, Restriction Fragment Length/genetics , RNA, Ribosomal, 16S/genetics , Sigmoidoscopy
3.
Inflamm Bowel Dis ; 18(1): 10-6, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21456032

ABSTRACT

BACKGROUND: Pivotal trials for adalimumab (ADA) demonstrated effectiveness versus placebo for induction and maintenance of remission in moderate to severely active Crohn's disease (CD). Although the approved maintenance regimen in the U.S. is 40 mg subcutaneously every 14 days, some patients require dose-escalation ([DE] either an increase in the delivered dose or decrease in the interval of treatment). Our objective was to determine which patient-, disease-, and therapy-related factors were associated with DE in CD patients treated with ADA. METHODS: This retrospective medical record review of patients included all patients treated with ADA for CD at the University of Chicago Inflammatory Bowel Disease Center between 2003 and 2008. Patient-related factors, disease-related factors, and therapy-related factors were analyzed. Survival and logistic regression analyses were performed. RESULTS: In all, 75 patients treated with ADA between December 2003 and June 2008 were identified. Thirty-one subjects (41%) required DE (32% male, median age 37.6, median disease duration 22.7 years) after a median 20 weeks of therapy (range 2-75). Patient-, clinical-, and therapy-related factors were similar between DE and non-DE. Need for DE was predicted by a family history of inflammatory bowel disease (IBD) (P = 0.0187). Time to DE was predicted by male gender, isolated colonic disease, and smoking history (all P < 0.05); however, only male gender was an independent predictor of time to DE. CONCLUSIONS: In all, 41% of CD patients required ADA DE, with shorter time to DE in smokers, men, and patients with isolated colonic disease. Patients, caregivers, and insurers should anticipate DE when utilizing ADA in CD.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Crohn Disease/drug therapy , Adalimumab , Adolescent , Adult , Crohn Disease/mortality , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Remission Induction , Retrospective Studies , Survival Rate , Time Factors , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Young Adult
4.
Curr Gastroenterol Rep ; 12(6): 479-84, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20890737

ABSTRACT

Inflammatory bowel disease (IBD), which includes ulcerative colitis, Crohn's disease, and indeterminate colitis, is characterized by chronic inflammation of the digestive tract and has a significant impact on quality of life. Coupled with clinical history, physicians rely on invasive tests (e.g. endoscopy and radiologic examinations) to diagnose IBD. Patients with other gastrointestinal illnesses (e.g. irritable bowel syndrome and celiac disease) may present with symptoms similar to those of an IBD patient. Therefore, a need exists for rapid and noninvasive measures to indicate the presence of IBD. The identification of potential biomarkers associated with IBD has expanded rapidly in the past decade. This article reviews the role of recently studied serologic and fecal markers in the diagnosis of IBD, and differentiation between subtypes of IBD.


Subject(s)
Biomarkers/analysis , Colitis, Ulcerative/diagnosis , Crohn Disease/diagnosis , Algorithms , Antibodies, Anti-Idiotypic/analysis , Antibodies, Antineutrophil Cytoplasmic/blood , Feces/chemistry , Humans , Lactoferrin/analysis , Leukocyte L1 Antigen Complex/analysis , Polysaccharides/immunology , Saccharomyces cerevisiae/immunology , Sensitivity and Specificity
5.
Appl Microbiol Biotechnol ; 88(6): 1333-42, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20931185

ABSTRACT

Metagenomic analysis of colonic mucosa-associated microbes has been complicated by technical challenges that disrupt or alter community structure and function. In the present study, we determined the feasibility of laser capture microdissection (LCM) of intact regional human colonic mucosa-associated microbes followed by phi29 multiple displacement amplification (MDA) and massively parallel sequencing for metagenomic analysis. Samples were obtained from the healthy human subject without bowel preparation and frozen sections immediately prepared. Regional mucosa-associated microbes were successfully dissected using LCM with minimal contamination by host cells, their DNA extracted and subjected to phi29 MDA with a high fidelity, prior to shotgun sequencing using the GS-FLX DNA sequencer. Metagenomic analysis of approximately 67 million base pairs of DNA sequences from two samples revealed that the metabolic functional profiles in mucosa-associated microbes were as diverse as those reported in feces, specifically the representation of functional genes associated with carbohydrate, protein, and nucleic acid utilization. In summary, these studies demonstrate the feasibility of the approach to study the structure and metagenomic profiles of human intestinal mucosa-associated microbial communities at small spatial scales.


Subject(s)
Biodiversity , Colon/microbiology , Intestinal Mucosa/microbiology , Metagenome , Microdissection/methods , Cluster Analysis , DNA, Bacterial/chemistry , DNA, Bacterial/genetics , DNA, Ribosomal/chemistry , DNA, Ribosomal/genetics , High-Throughput Nucleotide Sequencing , Human Experimentation , Humans , Molecular Sequence Data , Nucleic Acid Amplification Techniques , Phylogeny , RNA, Ribosomal, 16S/genetics , Sequence Analysis, DNA
6.
Clin Gastroenterol Hepatol ; 8(8): 655-9, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20451665

ABSTRACT

BACKGROUND & AIMS: There is no consensus on the appropriateness of concomitant immunomodulators with anti-tumor necrosis factor (TNF) therapy for Crohn's disease. Some patients benefit from concomitant immunomodulators, but concerns related to infections and lymphoma risk have dampened enthusiasm for this approach. We applied the RAND/University of California Los Angeles Appropriateness Method toward establishing appropriateness of concomitant immunomodulators and anti-TNF therapies for Crohn's disease. METHODS: A literature review was conducted regarding efficacy and safety of concomitant immunomodulators in the setting of anti-TNF therapy for Crohn's disease and presented to the Building Research in Inflammatory Bowel Disease Globally group, a globally diverse panel of 13 gastroenterologists clinically experienced in inflammatory bowel disease. A total of 134 scenarios were constructed using several clinical variables. Panelists used a modified Delphi method to rate the appropriateness of concomitant immunomodulators, and met to discuss and re-rate appropriateness. Disagreement was assessed using a validated index. RESULTS: Concomitant immunomodulators were generally rated appropriate for 63 scenarios, uncertain for 60 scenarios, and inappropriate for 11 scenarios. In general, concomitant immunomodulators were appropriate for those with extensive disease, shorter duration of disease, perianal involvement, prior surgery, females, and older patients (>26 y). Concomitant immunomodulators were generally rated inappropriate for young males, and in some scenarios involving uncomplicated disease. Smoking and the particular anti-TNF medication did not influence ratings. Disagreement was observed in 6 of 134 scenarios. CONCLUSIONS: The appropriateness of concomitant immunomodulators with anti-TNF therapy for Crohn's disease was determined through a modified Delphi panel approach based on expert interpretation of the available literature. Clinicians should consider multiple factors when considering concomitant immunomodulators with anti-TNF treatment.


Subject(s)
Crohn Disease/drug therapy , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Certolizumab Pegol , Crohn Disease/complications , Female , Humans , Immunoglobulin Fab Fragments/administration & dosage , Immunoglobulin Fab Fragments/adverse effects , Infections/chemically induced , Infliximab , Lymphoma/chemically induced , Male , Middle Aged , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/adverse effects , Treatment Outcome
7.
Liver Int ; 28(7): 1026-33, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18397235

ABSTRACT

INTRODUCTION: One of the proposed second hit mechanisms in the pathophysiology of non-alcoholic steatohepatitis (NASH) is hepatic oxidative stress triggered by elevated levels of endotoxin. We investigated one possible mechanism for the endotoxaemia--disruption of intestinal barrier integrity. METHODS: We enrolled 16 subjects with fatty liver (10 NASH; 6 steatosis) and 12 healthy subjects. Steatosis and NASH were diagnosed by liver biopsy using the Brunt criteria. Gastrointestinal permeability was measured using urinary excretion of 5-h lactulose/mannitol (L/M) ratio and 24-h sucralose. Permeability testing was repeated after aspirin challenge. RESULTS: Groups had similar baseline urinary 0-5 h L/M ratio (small bowel permeability) and 0-24 h sucralose (whole-gut permeability). Aspirin increased 0-5 h urinary L/M in most subjects. In contrast, aspirin significantly increased whole-gut permeability only in NASH subjects. In fact, the major increase in the urinary sucralose occurred in the 6-24 h samples, which points towards the colon as the major site responsible for aspirin-induced leakiness in NASH patients. Serum endotoxin levels were significantly higher in NASH subjects. DISCUSSION: Our findings suggest that aspirin acts on the colon to unmask a susceptibility to gut leakiness in patients with NASH. This effect may be the underlying mechanism for increased serum endotoxin, which is the second hit (after altered lipid metabolism) that is required to initiate a necroinflammatory cascade in hepatocytes which are already primed with obesity-induced abnormal lipid homoeostasis.


Subject(s)
Endotoxemia/physiopathology , Fatty Liver/physiopathology , Intestinal Absorption/physiology , Intestines/physiopathology , Adult , Anti-Inflammatory Agents, Non-Steroidal , Aspirin , Endotoxemia/complications , Endotoxemia/metabolism , Fatty Liver/complications , Fatty Liver/metabolism , Female , Humans , Intestinal Absorption/drug effects , Intestinal Mucosa/metabolism , Intestines/drug effects , Lactulose/urine , Liver/metabolism , Liver/pathology , Male , Mannitol/urine , Middle Aged , Oxidative Stress , Permeability/drug effects , Sucrose/analogs & derivatives , Sucrose/urine
8.
Gastroenterol Hepatol (N Y) ; 4(10): 713-20, 2008 Oct.
Article in English | MEDLINE | ID: mdl-21960891

ABSTRACT

In March 2008, a roundtable discussion was convened by the inflammatory bowel disease (IBD) specialist panel the BRIDGe (Building Resources and Research in IBD Globally) group, which consists of junior faculty gastroenterologists who have undergone advanced fellowship training at IBD referral centers in the United States, Canada, the United Kingdom, and Australia. An agenda was formulated to discuss three current controversies in Crohn's disease management: the role of 5-aminosalicylates, the use of biologic combination therapy versus monotherapy, and the use of step-up therapy versus top-down therapy for Crohn's disease. The aim of the meeting was three-fold: to review the data pertaining to each topic; to collect opinions from the participants as to their analysis of the literature and their current practice; and, where possible, to formulate recommendations of current best practice given the available evidence. This manuscript summarizes the discussions on these three areas of controversy in the current management of Crohn's disease.

9.
Inflamm Bowel Dis ; 13(8): 975-83, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17427244

ABSTRACT

BACKGROUND: The NIDDK IBD Genetics Consortium (IBDGC) collects DNA and phenotypic data from inflammatory bowel disease (IBD) subjects to provide a resource for genetic studies. No previous studies have been performed on the reliability and validity of phenotypic determinations in either Crohn's disease (CD) or ulcerative colitis (UC) using primary records. Our aim was to determine the reliability and validity of these phenotypic assessments. METHODS: The de-identified records of 30 IBD patients were reviewed by 2 phenotypers per center using a standard protocol for phenotypic assessment. Each phenotyper evaluated 10 charts on 2 occasions 5 months apart. Reliability was expressed as the kappa (kappa) statistic. Performance characteristics were determined by comparison to a consensus-derived "gold standard" and by generation of receiver operating characteristic (ROC) curves. RESULTS: Agreement for diagnosis was excellent (kappa = 0.82; 95% confidence interval [CI]: 0.71-0.92). Agreement for CD location was good for jejunal, ileal, colorectal, and perianal disease with kappa between 0.60 and 0.74 but was fair for esophagogastroduodenal (kappa = 0.36). Agreement for UC extent (kappa = 0.67; 95% CI: 0.48-0.85), and CD behavior (kappa = 0.67; 95% CI: 0.49-0.83) were very good. Area under the ROC curves was greater than 0.84 for diagnosis, CD behavior, UC extent, and ileal and colonic CD location. CONCLUSIONS: IBD phenotype classification using a standard protocol exhibited very good to excellent inter- and intrarater agreement and validity. This study highlights the importance of standard protocols in generating reliable and valid phenotypic assessments. The data will facilitate estimates of phenotyping misclassification rates that should be considered when making inferences from IBD genotype-phenotype studies.


Subject(s)
Inflammatory Bowel Diseases/genetics , Phenotype , Colitis, Ulcerative/genetics , Crohn Disease/genetics , Humans , Inflammatory Bowel Diseases/classification , Observer Variation , ROC Curve , Reproducibility of Results , Sensitivity and Specificity
10.
Gastroenterol Hepatol (N Y) ; 3(7): 535-7, 2007 Jul.
Article in English | MEDLINE | ID: mdl-21960861
12.
Gastroenterol Clin North Am ; 33(2): 303-17, ix-x, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15177540

ABSTRACT

The role of the aminosalicylates for induction therapy of mild moderate ulcerative colitis and as maintenance treatment has been substantiated by a large series of controlled clinical trials and confirmatory meta-analyses. Both sulfasalazine and newer derivatives are effective in preventing relapses. It remains to be determined whether certain high-risk groups of patients may benefit from higher doses of mesalamine induction or maintenance therapy. Mesalamine derivatives are also of benefit in the treatment of Crohn's disease. Sulfasalazine is likely not effective in the maintenance of Crohn's disease, although other mesalamine formulations continue to show some prophylactic activity after mesalamine induced remissions and for patients with disease of the ileum who have undergone surgical resection.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Crohn Disease/drug therapy , Mesalamine/therapeutic use , Humans
13.
Nat Clin Pract Gastroenterol Hepatol ; 1(2): 113-6; quiz 1 p following 116, 2004 Dec.
Article in English | MEDLINE | ID: mdl-16265073

ABSTRACT

BACKGROUND: A 34-year-old gravid woman with a history of ileal Crohn's disease presented at 30 weeks' gestation with a 2-week history of fever and right upper quadrant pain. An intra-abdominal abscess was suspected. Ultrasound and MRI failed to demonstrate the suspected abscess. Owing to ongoing pain and fever, the risk to the fetus of a CT scan were discussed with the patient, obstetricians and radiologists, with considerable debate about the possibility of other explanations for her symptoms. Ultimately, a CT scan revealed marked thickening of the distal ileum and confirmed diagnosis of an abscess in continuity with the inflamed bowel. INVESTIGATIONS: Ultrasound, MRI, CT scan, urinalysis, urine culture and liver function tests. DIAGNOSIS: Crohn's disease flare complicated by an intra-abdominal abscess. MANAGEMENT: Antibiotics (ceftizoxime, metronidazole and amoxicillin/clavulanate potassium), parenteral nutrition and ileocecectomy.


Subject(s)
Abdominal Abscess/diagnosis , Abdominal Abscess/etiology , Crohn Disease/complications , Ileal Diseases/complications , Abdominal Abscess/therapy , Abdominal Pain/etiology , Adult , Anti-Bacterial Agents/therapeutic use , Diagnosis, Differential , Digestive System Surgical Procedures/methods , Drainage/methods , Female , Fever/etiology , Humans , Pregnancy , Pregnancy Trimester, Third , Tomography, X-Ray Computed
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