Influence of Corticosteroid Use on Short- and Long-Term Outcomes of Biologic Therapy for Inflammatory Bowel Diseases.

BACKGROUND: Corticosteroids (CS) are widely used to treat Crohn's disease (CD) and ulcerative colitis (UC), but are not recommended as maintenance therapy. Biologic drugs are widely used as an alternative to or in conjunction with CS to induce and maintain remission. This meta-analysis tested the hypothesis that CS use is associated with differential response to biologics. METHODS: We identified published placebo-controlled clinical trials of biologic drugs approved for the treatment of CD or UC. Pooled estimates of the risk difference (RD) and 95% confidence intervals were derived from random effects models for induction of response and remission and maintenance of remission comparing biologic with CS versus biologic alone. Heterogeneity of response was estimated using I2. RESULTS: Fifteen studies met the inclusion criteria. Pooled estimates of the RD and I2 comparing biologic plus CS versus biologic alone were as follows: induction of UC response 0.15 (0.05, 0.25), I2 = 57.29% and CD response 0.02 (- 0.03, 0.06), I2 = 0.01%; induction of UC remission 0.03 (- 0.01, 0.08), I2 = 0.00% and CD remission 0.08(0.02, 0.14), I2 = 7.81%; and maintenance of UC remission - 0.06 (- 0.13, 0.01), I2 = 0.00% and CD remission - 0.06 (- 0.14, 0.03), I2 = 11.24%. Patients in the placebo arm of CD trials who were receiving CS were less likely to achieve remission during the induction phase (pooled RD - 0.05 (- 0.09, - 0.00), I2 = 0.00%). CONCLUSIONS: In this meta-analysis of placebo-controlled trials, CS use was associated with higher biologic response rates for UC and remission rates for CD during the induction phase, but were not associated with improved maintenance of remission.

Indeterminate QuantiFERON-TB Gold Increases Likelihood of Inflammatory Bowel Disease Treatment Delay and Hospitalization.

Background: QuantiFERON-TB Gold (QFTG) is a blood test used to diagnose latent tuberculosis infection (LTBI) prior to TNF-α inhibitor (anti-TNF) initiation. We sought to determine factors associated with indeterminate QFTG results in inflammatory bowel disease (IBD) patients and whether indeterminate results are associated with IBD-related morbidity. Methods: This nested case-control study included IBD patients who underwent QFTG testing. Cases were patients with indeterminate QFTG and controls were those with negative QFTG. The association of demographic and clinical data with indeterminate QFTG result was assessed using logistic regression. We examined the clinical impact of indeterminate QFTG results on risk of hospitalization and delay in anti-TNF initiation using inverse probability-of-treatment weighting (IPTW) regression. Results: We identified 411 patients with QFTG testing (320 negative, 80 indeterminate, and 11 positive results). No patient with an indeterminate result subsequently had LTBI. Systemic corticosteroid use (OR, 4.4; 95% CI, 2.0-9.6) and hospitalization at the time of QFTG (OR, 3.8; 95% CI, 1.9-7.7) were associated with indeterminate QFTG, while immunomodulator use was nearly statistically significant (OR, 3.1; 95% CI, 0.9-9.8) and anti-TNF use was not (OR, 0.9; 95% CI, 0.2-4.6). After IPTW adjustment, indeterminate QFTG was associated with a 23.1% (95% CI, 8.2%-37.9%) greater probability of delay in anti-TNF initiation beyond 30 days and an 11.9% (95% CI, 0.6%-23.1%) greater probability of hospitalization within 60 days. Conclusions: Systemic corticosteroid use and hospitalization were associated with an indeterminate QFTG result. Indeterminate QFTG results were associated with delayed anti-TNF initiation and subsequent hospitalization.

Measurement of Inflammatory Bowel Disease Symptoms: Reliability of an Abbreviated Approach to Data Collection.

BACKGROUND: The Crohn's Disease Activity Index (CDAI) and Mayo score for ulcerative colitis (UC) require symptom recall and/or use of a symptom diary. We examined patients' abilities to recall their symptoms and the day-to-day variability of symptoms. METHODS: Patients with UC or CD completed a questionnaire including items from the short CDAI (sCDAI) and the 6-point Mayo score. Patients were randomized to receive a follow-up questionnaire testing recall of the bowel symptom items between 1 and 7 days later. In a second study, patients completed a 7-day electronic diary recording their symptoms. sCDAI and 6-point Mayo scores were computed. Analyses estimated daily variability in the indices and misclassification rates when using fewer than 7 days of data. RESULTS: 100%, 82%, and 90% of CD participants recalled the same disease activity status (i.e., active versus remission) as reported on the initial survey when the follow-up questionnaire was administered 1 to 2, 3 to 5, and 6 to 8 days later, respectively. Compared with using 7 days of data, when using only day 7 data, 3.7% of patients with CD were misclassified as active or inactive. Disease activity was misclassified in 2.8%, 4.9%, and 3.3% of patients by using the last 2, 3, or 4 days, respectively. Results were similar for patients with UC. CONCLUSIONS: Patients with CD and UC demonstrated good recall of bowel symptoms for up to 8 days. Additionally, bowel symptoms have relatively little variability within a 7-day period allowing for accurate computation of the sCDAI and 6-point Mayo score using 1 to 3 days of data.

Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis.

BACKGROUND & AIMS: Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized controlled trial to investigate whether increasing doses of mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. METHODS: We screened 119 patients with UC in remission on the basis of Simple Clinical Colitis Activity Index scores, FC >50 µg/g, and intake of no more than 3 g/day mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n = 26) or a group that increased its dose by 2.4 g/day for 6 weeks (n = 26). The primary outcome was continued remission with FC <50 µg/g. Secondary outcomes were continued remission with FC <100 µg/g or <200 µg/g (among patients with pre-randomization values above these levels). RESULTS: The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P = .0496). More patients in the dose escalation group reduced FC to below 100 µg/g (P = .04) and 200 µg/g (P = .005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 µg/g compared with those with FC <200 µg/g (P = .01). CONCLUSIONS: Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov number: NCT00652145.

Use of the noninvasive components of the Mayo score to assess clinical response in ulcerative colitis.

BACKGROUND: The Mayo score and a noninvasive 9-point partial Mayo score are used as outcome measures for clinical trials assessing therapy for ulcerative colitis (UC). There are limited data assessing what defines a clinically relevant change in these indices. We sought to assess what constitutes a clinically meaningful change in these indices using data from a recently completed placebo-controlled clinical trial. METHODS: In all, 105 patients were enrolled in a 12-week randomized, placebo-controlled trial assessing rosiglitazone for treatment of mild to moderate UC. We compared the change in the Mayo score, the partial Mayo score, and a 6-point score composed just of the stool frequency and bleeding components of the Mayo score to the patient's perception of disease activity at week 0 and week 12. Optimal cutpoints were calculated as the maximal product of sensitivity and specificity. RESULTS: Each index was strongly correlated with the patient's rating of disease activity at week 12 (Spearman correlations 0.61-0.71, P < 0.0001 for all correlations). The maximal product of sensitivity and specificity to identify patient reported improvement of disease activity was achieved using cutpoints for change of 2.5 for the Mayo score (sensitivity 88%, specificity 80%), 2.5 for the partial Mayo score (sensitivity 88%, specificity 87%), and 1.5 for the 6-point score (sensitivity 88%, specificity 80%). CONCLUSIONS: The partial Mayo score and the 6-point score composed solely of the stool frequency and bleeding components performed as well as the full Mayo score to identify patient perceived clinical response.

Risk for active tuberculosis in inflammatory bowel disease patients.

BACKGROUND & AIMS: The primary aim of this study was to determine the incidence of active tuberculosis in an inflammatory bowel disease population compared with the general population before the availability of infliximab. METHODS: We performed a retrospective cohort study with the General Practice Research Database from January 1988-October 1997. Ulcerative colitis and Crohn's disease subjects with a minimum of 1 year of follow-up were matched to randomly selected subjects from the remaining population on year of birth (+/-5 years), sex, and primary care practice at ratio of 1:4. Active tuberculosis was determined by tuberculosis diagnostic codes. The incidence of active tuberculosis in the inflammatory bowel disease population and the relative risk for active tuberculosis in inflammatory bowel disease population compared with the general population were calculated. Multivariate logistic regression analysis was performed to adjust for confounders. RESULTS: There were 16,213 inflammatory bowel disease subjects and 66,512 control subjects. The annual incidence of active tuberculosis was 20/100,000 in inflammatory bowel disease subjects compared with 9/100,000 in control subjects, yielding an unadjusted relative risk for active tuberculosis of 2.36 (95% confidence interval, 1.17-4.74). Adjusting for confounders, corticosteroid use and smoking, the odds ratio of inflammatory bowel disease for active tuberculosis was 1.88 (95% confidence interval, 0.68-5.20). CONCLUSIONS: During the pre-infliximab era, inflammatory bowel disease subjects appeared to be at higher risk for active tuberculosis than the general population, with immunosuppressant medications likely the main reason for this increased risk.

Infliximab in ulcerative colitis.

Infliximab is effective for treatment of moderate-to-severe UC and is recommended for patients who have had an inadequate response to medical therapy or who are intolerant of or do not desire to take the potential risk of using specific agents including immunomodulators (cyclosporine A, azathioprine, or 6-mercaptopurine), corticosteroids, and, potentially, mesalamine. Future trials are needed to assess the efficacy of infliximab with immunomodulators to see if additional benefit is achieved so that the risk-benefit ratio is positive. Based on the favorable efficacy of infliximab for UC therapy, the ground work has been established for evaluating infliximab and addressing some of the many unanswered questions and also for assessing other anti-TNF agents and streamlining the anti-TNG antibody to improve efficacy, reduce side effects, and ease administration.

Methods to avoid infections in patients with inflammatory bowel disease.

Infections have been reported in patients with inflammatory bowel disease (IBD), especially in association with anti-inflammatory and immunomodulatory medications used to treat IBD. Unfortunately, there is a dearth of information on infectious complication risk in patients with IBD. This review describes infectious complications reported in patients with IBD and provides a framework for future studies to assess potential risk factors and incidence for infection. Recommendations are also provided for prevention of infection.

Antibiotic use and the risk of flare of inflammatory bowel disease.

BACKGROUND & AIMS: Intestinal microbial flora participate in the pathogenesis of inflammatory bowel disease. Because antibiotic therapy alters intestinal microbial flora, we hypothesized that use of antibiotics might decrease the risk of flare. METHODS: We conducted a case-crossover study by using the General Practice Research Database from 1989-1997. Flares of disease were identified by receipt of a new prescription for either corticosteroids or mesalamine medications after an interval of at least 4 months without prescriptions for either class of medication. The primary exposure was receipt of any antibiotics in the 60 days preceding the index date. RESULTS: Among 1205 patients with Crohn's disease, exposure to antibiotics was associated with a reduced risk of flare (adjusted odds ratio [OR], 0.78; 95% confidence interval [CI], 0.64-0.96; P = .019). The effect was strongest with more recent exposure (test for trend, P < .05). Among 2230 patients with ulcerative colitis, use of any antibiotics within 60 days was not associated with flare of disease (adjusted OR, 0.96; 95% CI, 0.82-1.12; P = .581), although a potentially protective effect was observed in those patients with very recent exposure (exposure within 15 days: OR, 0.66; 95% CI, 0.51-0.85). CONCLUSIONS: Antibiotic use within 60 days was associated with a lower risk of flare of Crohn's disease, but not ulcerative colitis. The strength of the protective effect of antibiotics in Crohn's disease wanes over time.

Seasonal variation in flares of inflammatory bowel disease.

BACKGROUND & AIMS: Previous research has yielded conflicting data as to whether the natural history of inflammatory bowel disease follows a seasonal pattern. The purpose of this study was to determine whether relapse of inflammatory bowel disease follows a seasonal pattern either across a cohort of patients or within individual patients. METHODS: We used 1988 to 1997 data from the General Practice Research Database to conduct a retrospective cohort study of 1587 patients with Crohn's disease (mean age at start of follow-up, 41 +/- 17 years) and 2773 patients with ulcerative colitis (mean age at start of follow-up, 48 +/- 16 years). Flares of disease were identified by receipt of a new prescription for either corticosteroids or 5-ASA medications following an interval of at least 4 months without prescriptions for either class of medication. Logistic regression was used to adjust the association of season of the year and flare of disease for potential confounding variables. RESULTS: There was no association between season of the year and flare of Crohn's disease (P = 0.66). Season of the year was only weakly associated with flares of ulcerative colitis (P = 0.02). Compared with winter, spring had very slightly higher rates of flares (OR = 1.13, 95% CI: 1.05-1.23). We did not observe seasonal patterns within individual patients experiencing multiple flares (P > 0.05 for Crohn's disease and ulcerative colitis). CONCLUSIONS: Although we observed a slight increase in exacerbations of ulcerative colitis in the spring, in general, these data do not support an association between season of the year and flares.

Corticosteroids and immunomodulators: postoperative infectious complication risk in inflammatory bowel disease patients.

BACKGROUND & AIMS: Many patients with inflammatory bowel disease receive corticosteroids and 6-mercaptopurine/azathioprine during elective bowel surgery. We investigated the postoperative infection risk for patients undergoing elective bowel surgery who were receiving corticosteroids and/or 6-mercaptopurine/azathioprine before surgery compared with patients not receiving these medications. METHODS: A retrospective cohort study was conducted on 159 patients with inflammatory bowel disease who underwent elective bowel surgery. There were 56 patients receiving corticosteroids alone, 52 patients receiving 6-mercaptopurine/azathioprine alone or with corticosteroids, and 51 patients receiving neither corticosteroids nor 6-mercaptopurine/azathioprine. Postoperative infectious complications to time of discharge were categorized into major and minor complications. RESULTS: Patients receiving corticosteroids had an adjusted odds ratio for any and major infectious complications of 3.69 (95% confidence interval [CI], 1.24-10.97) and 5.54 (95% CI, 1.12-27.26), respectively. The adjusted odds ratio for patients receiving 6-mercaptopurine/azathioprine for any and major infectious complications was 1.68 (95% CI, 0.65-4.27) and 1.20 (95% CI, 0.37-3.94), respectively. CONCLUSIONS: Preoperative use of corticosteroids in patients with inflammatory bowel disease who are undergoing elective bowel surgery is associated with an increased risk of postoperative infectious complications. 6-Mercaptopurine/azathioprine alone and the addition of 6-mercaptopurine/azathioprine for patients receiving corticosteroids was not found to significantly increase the risk of postoperative infectious complications.