The appropriateness of concomitant immunomodulators with anti-tumor necrosis factor agents for Crohn's disease: one size does not fit all.

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.

Assessment of reliability and validity of IBD phenotyping within the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) IBD Genetics Consortium (IBDGC).

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.

Fever and right upper quadrant pain in a pregnant woman at 30 weeks' gestation.

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.

Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease.

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.

Predictors of adalimumab dose escalation in patients with Crohn's disease at a tertiary referral center.

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.

Current Controversies in Crohn's Disease: A Roundtable Discussion of the BRIDGe Group.

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.

Mesalamine derivatives in the treatment of Crohn's disease.

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.