Two large studies concluded that AZA started early after diagnosis of Crohn’s disease have no late maintenance value. This is contrary to previous studies on 6MP for Crohn’s disease and could lead to negating the value of two of the few drugs that have been proven successful. We here outline the many reasons why 6MP remains a valuable drug in the treatment of Crohn’s disease.

Background: The role of intravenous (IV) cyclosporine in severe Crohn’s colitis (CC) is poorly studied. Aim: Our primary aim was to determine the in-hospital colonic resection rate in patients with severe CC who received IV cyclosporine, and the potential predictors of resection among these patients. Methods: An inpatient pharmacy query of all patients who received IV cyclosporine at Mount Sinai Medical Center for 12.5 years after January 1, 1996 was reviewed. Patients with CC or indeterminate colitis favoring Crohn’s were included and their medical records were reviewed. Subsequent need for colonic surgery was assessed. A Kaplan-Meier plot with log-rank testing was performed to determine the rate of colonic surgery avoidance. Forward stepwise logistic regression was performed to determine independent predictors of surgery. Results: Forty-eight patients met our inclusion criteria. Prior thiopurine and anti-tumor necrosis factor (anti-TNF) use was 85% and 69%, respectively. The median follow-up time was 12 months (range, 1 to 60 mo). 12.5% of patients required colonic resection during their admission for IV cyclosporine. Anti-TNF use in the 4 weeks preceding IV cyclosporine was the only predictor of surgery in this setting (P=0.05). The cumulative colonic surgery avoidance rate was 72±13% at 6 months and 59±15% at 12 months. Conclusions: The use of IV cyclosporine resulted in a low rate of in-hospitalization colonic surgery among CC patients with severe disease, the majority of whom previously failed anti-TNFs and thiopurines.

BACKGROUND:6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective for induction and maintenance therapy of Crohn's disease (CD) and ulcerative colitis (UC). There is an increased risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with 6-MP/AZA. Little, however, is known about the prognosis of IBD patients treated with 6-MP/AZA who develop lymphoma.METHODS:We conducted a retrospective review of 8780 records from three tertiary IBD centers and the records of 600 lymphoma patients from an academic Hematology and Oncology Center. The primary endpoint variable was survival of IBD patients with a lymphoma diagnosis treated or not treated with 6-MP/AZA. A secondary endpoint was the relative survival rate (by gender, race, and ethnicity) extrapolated from the Surveillance Epidemiology and End Results (SEER) database, computed for each subject.RESULTS:Fourteen IBD patients were diagnosed with lymphoma. Twelve had CD and two had UC. Seven patients had treatment with 6-MP/AZA and seven had not. Two patients who received 6-MP/AZA died (both 1 year after diagnosis) and two patients who had not received 6-MP/AZA died (one after 2 years, another 3 years after diagnosis), all from lymphoma. Survival at last follow-up was similar to expected survival based on extrapolated SEER data for both 6-MP/AZA treated and untreated patients.CONCLUSIONS:We found no differences of survival with lymphoma between IBD patients and expected survival for the general population. Also, the prognosis for those IBD patients treated with 6-MP/AZA was not worse than lymphoma patients not treated with 6-MP/AZA. Statistical analysis, however, was limited by the small sample size and heterogeneity of the patients studied.

Background: The aim was to evaluate long-term efficacy, quality of life, and safety in ulcerative colitis patients who received infliximab during the ACT-1 and -2 extension studies.Methods: Adults with moderate-to-severely active ulcerative colitis in the 54-week ACT-1 and 30-week ACT-2 studies who achieved benefit from infliximab were eligible to participate in extension studies and receive up to 3 additional years of therapy. Patients received randomized study medication until all sites were unblinded; placebo-treated patients were discontinued. Patients receiving 5 or 10 mg/kg infliximab continued to receive open-label infliximab every 8 weeks. Patients receiving infliximab 10 mg/kg could decrease to 5 mg/kg; patients receiving infliximab 5 mg/kg could increase to 10 mg/kg if response was lost.Results: A total of 229 of 484 infliximab-treated patients from the ACT-1 and ACT-2 main studies entered the long-term extensions. Overall, 70 (30.6%) patients discontinued infliximab infusions for adverse events (24 [10.5%]), lack of efficacy (11 [4.8%]), required a colectomy (1 [0.4%]), or for other reasons (34 [14.8%]). Proportions of patients whose Physician's Global Assessment scores were indicative of no or mild disease (score 0 or 1) were maintained during the extension studies; 76.5% at Extension week 0 and ranged between 90.0% and 94.3% through Extension week 152. Improvement in Inflammatory Bowel Disease Questionnaire scores observed in the main studies was maintained. During the long-term extension, the infliximab safety profile was consistent with that of the main studies; no new or unexpected safety signals were observed.Conclusions: Long-term treatment with infliximab for up to 3 additional years was effective and well tolerated.

BACKGROUND & AIMS In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergo remission, and have mucosal healing. We investigated the association between early improvement (based on endoscopy) and subsequent clinical outcome. METHODS Patients underwent endoscopic evaluations at weeks 0, 8, 30, and 54 (ACT-1 only), and were categorized into 4 subgroups by week 8 (Mayo endoscopy subscore, 0-3). The association of week 8 endoscopy subscores, subsequent colectomy risk, symptoms and corticosteroid use outcomes were analyzed. Mucosal healing was defined as a Mayo endoscopy subscore of 0 (normal) or 1 (mild). RESULTS Infliximab-treated patients with lower week 8 endoscopy subscores were less likely to progress to colectomy through 54 weeks of follow-up evaluation (P=.0004). This trend was not observed among patients given placebo (P=.47). Patients with lower endoscopy subscores achieved better symptomatic and corticosteroid use outcomes at weeks 30 and 54 (P<.0001, infliximab; P<.01, placebo). Among patients who achieved clinical response at week 8, trends in subsequent clinical outcomes by week 8 endoscopy subscores were generally consistent with that for the overall patient population; no trends were observed among patients who achieved clinical remission. CONCLUSIONS The degree of mucosal healing after 8 weeks of infliximab was correlated with improved clinical outcomes including colectomy. Similar trends were observed for all outcomes except colectomy among the subgroup with clinical response at week 8. The degree of mucosal healing at week 8 among those in clinical remission did not predict subsequent disease course.

BACKGROUND:Cyclosporine (CSA) is effective in the short-term for severe, steroid refractory ulcerative colitis; but its use has been limited by concerns about safety and colectomy-sparing rates. The aim of this study was to assess the long-term colectomy-sparing effects and safety of CSA in patients hospitalized for ulcerative colitis.METHODS:Review of the patients who underwent intravenous CSA for ulcerative colitis between 1989 and 2003.RESULTS:A total of 71 patients with severe ulcerative colitis were treated with IV CSA. The median length of follow-up was 1.5 years (mean=3 y) (range 1 mo to 14 y) (IQR 0.6 to 4.6). Eighty-five percent (60/71) of patients responded to IV CSA and were discharged on oral CSA. Of these 60 patients, 26 were transitioned from CSA to 6MP. Of the 26 patients who were transitioned from CSA to 6MP, only 1 patient (4%) ultimately required colectomy; whereas colectomy was carried out in 76% (26/34) of the patients who were not transitioned from CSA to 6MP. Only concomitant 6MP therapy was associated with a reduced risk of colectomy (OR 0.01, 95% CI 0.001, 0.09, P<0.0001) on long-term follow-up in this group. Cumulative colectomy rates for the entire cohort were 39% (28/71) at 1 year, 42% (30/71) at 2 years, and 46% (33/71) at 5 years. Side effects were noted in two-thirds of the patients, the majority of which were mild.CONCLUSION:CSA is an effective therapy for severe ulcerative colitis. Long-term efficacy is improved with transition to 6MP. Adverse events with CSA are frequent, but most are mild.

Background The US Food and Drug Administration currently approves three types of anti-tumor necrosis factor α (anti-TNFα) therapy for treatment of moderate to severe Crohn’s disease. There are no guidelines to clarify which of the drugs may be better suited to individual clinical scenarios. Aims We gathered national data on the prescribing pattern, comfort levels, and algorithms gastroenterologists use for management of their biologic-requiring Crohn’s disease patients. Methods An internet survey was mailed to members of the American Gastroenterology Association. Responses were separated into “non-expert” and “expert” physician groups on the basis of whether a practice consisted of >50% of patients with inflammatory bowel disease. We compared experts with non-experts with regard to the use of the three anti-TNF agents, attitudes regarding their relative efficacy, and their experience with adverse events. Results Of 3,990 eligible gastroenterologists, 473 replied in full (11.9%). Sixty (12.6%) respondents met the criterion for IBD expert physician. Experts were comfortable using both immunomodulators and anti-TNFα therapy. Community physicians were equally comfortable prescribing 6-mercaptopurine, azathioprine, infliximab, and adalimumab, but less comfortable than experts with methotrexate (56 vs. 86%, P < 0.05) and certolizumab (68 vs. 89%, P < 0.05). Expert physicians were much more likely to have encountered adverse reactions to anti-TNFα therapy. Conclusions Our results suggest that experts are more comfortable using a broader array of medical therapy than non-expert physicians. Although both groups had similar concerns regarding side-effects of anti-TNFα therapy, expert physicians were much more likely to have managed a broad range of complications in their patient population.

BACKGROUND:Adalimumab induces and maintains remission in adults with Crohn's disease.AIM:To evaluate safety, fistula healing, quality of life and work productivity in adalimumab-treated patients who failed infliximab, including primary nonresponders.METHODS:After a ≥8-week infliximab washout, patients with moderate-to-severe Crohn's disease received open-label adalimumab as induction (160/80 mg at weeks 0/2) and maintenance (40 mg every other week) therapies. At/after 8 weeks, patients with flare/nonresponse could receive weekly therapy. Minimum study duration was 8 weeks, continuing until the commercial availability of adalimumab for Crohn's disease.RESULTS:Of 673 patients enrolled, 17% were infliximab primary nonresponders and 83% were initial responders. Three percent of patients had serious infections (mainly abscesses). Complete fistula healing was achieved by 34/88 (39%) patients with baseline fistulas. Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients, as well as the subgroup of primary nonresponders.CONCLUSIONS:Blinded clinical trials have shown adalimumab to be both an effective first-line therapy for anti-TNF-naïve patients and an important treatment option for infliximab-refractory or -intolerant patients. This trial presents open-label experience to support further the safety and effectiveness of adalimumab in patients who failed infliximab therapy, including primary nonresponders (NCT00338650).

Purpose: Background: There are currently three available anti-TNF therapies, infliximab (IFX), adalizumab (ADA), and certolizumab (CZA), for the treatment of moderate-to-severe Crohn's disease. There are no guidelines that clarify which of these drugs may be better suited to individual clinical scenarios. There is little understanding of what criteria physicians use to choose among these medications. AIMS: To gather national data on the prescribing pattern, comfort levels, and algorithms gastroenterologists use in the management of their biologic requiring patients. Methods: An internet survey was emailed to members of the American Gastroenterology Association. Responses were collected and separated into “community” and “expert” physician based on the criteria of >50% patient panel consisting of patients with inflammatory bowel disease (IBD). Chi square and Fischer Exact test were used to determine differences in the responses between groups. Results: Of 3990 eligible surveys distributed, 473 replied in full (11.9%). 64 (12.6%) of these respondents met the criteria of IBD expert physician. Demographic criteria of expert and community physicians are presented in the Table. Experts were comfortable using both immunomodulators (methotrexate (MTX), 6MP, AZA) and Anti-TNF therapies, with no difference among the specific Anti-TNF's. Community physicians were equally comfortable prescribing 6MP, AZA, IFX, ADA, but less comfortable with MTX (56% vs. 86%; p < 0.0001) and CZA (68 vs. 89%; p=0.0007) than experts. When asked whether their choice of initial anti-TNF therapy has changed since the introduction of subcutaneously administered drugs, 41% of experts now offer all three as equal options, compared to 24% of community physicians (p=0.0078). While there was no difference in the proportion of experts and community physicians that still prefer infliximab (38% in both groups, p=0.92), a greater proportion of community physicians now prefer SQ adalimumab (32%) compared to experts (14%, p=0.0055). Conclusion: Our data suggest that experts are more comfortable using a broader array of medical therapies than community physicians.Table: [1244] Demographic and practice-pattern information of respondents

Purpose: To assess whether there is an association between degree of mucosal healing (MH) at wk 8 and clinical outcomes in patients with moderate-to-severe ulcerative colitis (UC) in ACT1 and ACT2. Methods: MH at wk 8 was assessed using the Mayo endoscopic subscore classification (0-normal, 1-mild, 2-moderate, 3-severe disease). A post-hoc logrank test was used to examine the distribution of time to colectomy through wk 54 across the 4 endoscopy subgroups for IFX and PBO-treated patients, respectively (ACT 1 and ACT 2 combined). The proportion of patients with symptomatic remission (stool frequency score of 0/1 and a rectal bleeding score of 0) and corticosteroid-free status were assessed at wk 30 (ACT 1 and ACT 2 combined) and at wk 54 (ACT 1). Results: IFX patients who had endoscopy subscores of 0 or 1 at wk 8 were less likely to progress to colectomy through wk 54 (Table; p=0.0004). Small event numbers in PBO patients precluded a clear conclusion for PBO. IFX patients with lower endoscopy scores at wk 8 were more likely to be in symptomatic remission at wk 30 (71% (0); 51% (1); 23% (2); 10% (3), p<0.0001). Among those receiving corticosteroids prior to starting IFX-treatment, patients were more likely to be corticosteroid-free at wk 30 as their degree of MH improved at wk 8 (62% (0); 46% (1); 20% (2); 10% (3), p<0.0001). Similar trends in symptomatic remission and the attainment of a corticosteroid-free status were observed at wk 54 for IFX patients in ACT 1. Although a lower proportion of PBO patients achieved symptomatic remission or became corticosteroid-free vs. IFX patients, similar trends of improved outcomes at wks 30 and 54 were associated with the degree of MH attained by PBO patients at wk 8.[1200] Table. Kaplan-Meier estimates of time to colectomyConclusion: Patients with moderate-to-severe UC, who achieve early mucosal healing, are less likely to go on to colectomy through 1 year of follow-up. Improved endoscopic outcomes were associated with a greater likelihood of achieving symptomatic remission and eliminating corticosteroids. Disclosure: Dr Sandborn-Investigator, Centocor R&D, Inc Dr Rutgeerts-Investigator, Centocor R&D, Inc Dr Reinisch-Investigator, Centocor R&D, Inc Dr Esser-Employee-Centocor BV Drs Wang and Oddens-Employees-Schering Corp Drs Lang, Marano, Strauss-Employees-Centocor R&D, Inc Dr Feagan-Investigator, Centocor R&D, Inc Dr Hanauer-Investigator, Centocor R&D, Inc Dr Lichtenstein-Investigator, Centocor R&D, Inc Dr Present-Investigator, Centocor R&D, Inc Dr Sands-Investigator, Centocor R&D, Inc Dr Colombel-Investigator, Centocor R&D, Inc. This research was supported by an industry grant from Centocor R&D, Inc.

Purpose: Infliximab (IFX) is effective in inducing and maintaining remission in moderate to severe ulcerative colitis (UC). In practice, a loss of efficacy requires that the IFX dose be increased or the interval between infusions be decreased. Our aim was to describe the frequency with which dose intensification (dose increase or interval decrease) occurs. Methods: Patients (pts) with UC who were seen by a Mount Sinai Medical Center (NY) affiliated gastroenterologist, and for whom IFX infusion records were available were considered eligible. Pts who received > 3 infusions, where any interval between infusions was less than 1 yr, were included. Dose increase was defined by dose doubling in at least 1 infusion. Interval decrease was defined by any 3 consecutive infusions given 6 or fewer weeks apart, not including the first 2 infusions given as induction. Interval decrease was only tabulated among patients who received 5 or more total infusions. Pts were followed through May 2009. Demographics, disease and medication data, as well as follow-up status were recorded for all pts. A Kaplan-Meier plot with log-rank testing was performed to determine the rate of dose intensification over 24 mos. Stepwise logistic regression was calculated using the following variables: age, gender, duration of disease, disease extent, prior and concurrent thiopurine use, elevated pre-IFX CRP or ESR, low pre-IFX Hb or albumin, >6 mo gap between any 2 infusions. Results: A total of 63 pts met the inclusion criteria. Mean age at the initial IFX infusion was 36.9±13.3 yrs; 51% were women; median duration of disease at first IFX infusion was 3 yrs; 67% of pts had pancolitis; pts had a median of 11 total infusions over the course of 18 mos. Overall, 52% of pts required dose intensification over a 24 mo period. Dose intensification rates were 34.8±6.2% at 6 mos and 44.8±6.6% at 12 mos. In the univariate analysis, none of the variables were predictive of dose intensification. At the end of the follow-up period, 68% of patients who underwent dose intensification remained on IFX, while the rate for those who did not undergo dose intensification was 64%. 3/59(5%) pts for whom follow-up was available went on to colectomy (2 received IV cyclosporine prior to surgery). All 3 had gotten dose intensification. Conclusion: About 50% of UC pts started on IFX will require dose intensification over 24 mos; most of these patients are able to continue therapy. These findings are similar to the experience of IFX in Crohn's. Disclosure: Dr Ullman - Speaker's Bureau: Centocor; Dr Mayer - Ext Advisory Board: Centocor.

Background and Aims: Although expression of the di/tripeptide transporter PepT1 has been observed in colon under inflammatory conditions, the inducing factors and underlying mechanisms have not yet been investigated. Here, we addressed the role of pathogenic bacteria in the regulation of colonic PepT1 expression/function and the potential role of PepT1 in bacterial-epithelial interaction. Methods: Colonic HT29-Cl.19A cells were infected with enteropathogenic E. coli (EPEC). PepT1 promoter activity and PepT1 expression/activity were analyzed using the luciferase assay, RT-PCR, nuclear run-on assay, immunoblotting, immunofluorescence staining and uptake experiments. Cdx2-PepT1 promoter binding was assessed by gel-shift and chromatin immunoprecipitation assay. In Vitro experiments were validated by ex vivo and In Vivo infection of wild type and PepT1 over-expressing mice with Citrobacter rodentium. Interleukin (IL)-8 and keratinocyte-derived chemokine (KC) expression levels were quantified by real-time RT-PCR and ELISA. Results: EPEC transcriptionally induced PepT1 expression/activity in HT29-Cl.19A cells. Cdx2 over-expression in HT29-Cl.19A cells induced PepT1 expression and Cdx2 silencing markedly reduced EPECinduced PepT1 expression, indicating the importance of Cdx2 in PepT1 expression. Furthermore, PepT1 expression required intimate adherence of EPEC to host cells through lipid rafts (LRs). Importantly, PepT1 expressed upon EPEC infection is functionally localized in LRs, and PepT1 associated with LRs delayed EPEC-LR binding as monitored in real time by an electric cell-substrate impedance-sensing technique. Remarkably, PepT1 over-expression in HT29-Cl.19A cells reduced EPEC-triggered NF-κB and MAP kinase activation and IL-8 production. In agreement with In Vitro data, ex vivo and In Vivo experiments showed that C. rodentium increased PepT1 mRNA and protein expression levels in mouse colon. Furthermore, PepT1 over-expression in mouse colon reduced C. rodentium adherence and C. rodentium-induced KC production. Conclusions: We demonstrate that i) EPEC transcriptionally induces functional PepT1 expression in LRs of colonocytes by intimately attaching to host cell membranes through LRs, ii) the transcription factor Cdx2 is crucial for EPECinduced PepT1 expression, and iii) PepT1 associated with LRs is involved in bacterialepithelial interaction and intestinal inflammation. Our findings not only reveal a novel mechanism underlying the regulation of colonic epithelial PepT1 expression/function under pathological conditions, but also highlight the potential contribution of this transporter to host defense mechanisms in response to pathogenic attack.

Background and Aims: Although expression of the di/tripeptide transporter PepT1 has been observed in colon under inflammatory conditions, the inducing factors and underlying mechanisms have not yet been investigated. Here, we addressed the role of pathogenic bacteria in the regulation of colonic PepT1 expression/function and the potential role of PepT1 in bacterial-epithelial interaction. Methods: Colonic HT29-Cl.19A cells were infected with enteropathogenic E. coli (EPEC). PepT1 promoter activity and PepT1 expression/activity were analyzed using the luciferase assay, RT-PCR, nuclear run-on assay, immunoblotting, immunofluorescence staining and uptake experiments. Cdx2-PepT1 promoter binding was assessed by gel-shift and chromatin immunoprecipitation assay. In Vitro experiments were validated by ex vivo and In Vivo infection of wild type and PepT1 over-expressing mice with Citrobacter rodentium. Interleukin (IL)-8 and keratinocyte-derived chemokine (KC) expression levels were quantified by real-time RT-PCR and ELISA. Results: EPEC transcriptionally induced PepT1 expression/activity in HT29-Cl.19A cells. Cdx2 over-expression in HT29-Cl.19A cells induced PepT1 expression and Cdx2 silencing markedly reduced EPECinduced PepT1 expression, indicating the importance of Cdx2 in PepT1 expression. Furthermore, PepT1 expression required intimate adherence of EPEC to host cells through lipid rafts (LRs). Importantly, PepT1 expressed upon EPEC infection is functionally localized in LRs, and PepT1 associated with LRs delayed EPEC-LR binding as monitored in real time by an electric cell-substrate impedance-sensing technique. Remarkably, PepT1 over-expression in HT29-Cl.19A cells reduced EPEC-triggered NF-κB and MAP kinase activation and IL-8 production. In agreement with In Vitro data, ex vivo and In Vivo experiments showed that C. rodentium increased PepT1 mRNA and protein expression levels in mouse colon. Furthermore, PepT1 over-expression in mouse colon reduced C. rodentium adherence and C. rodentium-induced KC production. Conclusions: We demonstrate that i) EPEC transcriptionally induces functional PepT1 expression in LRs of colonocytes by intimately attaching to host cell membranes through LRs, ii) the transcription factor Cdx2 is crucial for EPECinduced PepT1 expression, and iii) PepT1 associated with LRs is involved in bacterialepithelial interaction and intestinal inflammation. Our findings not only reveal a novel mechanism underlying the regulation of colonic epithelial PepT1 expression/function under pathological conditions, but also highlight the potential contribution of this transporter to host defense mechanisms in response to pathogenic attack.

Purpose: IV cyclosporine (CSA) is effective in severe steroid resistant UC. Its role in Crohn's colitis (CC) is less well studied. Our primary aim was to determine the colonic resection rate in patients (pts) with severe CC who received IV CSA, and to determine the potential predictors of colonic resection among these pts. Methods: An inpatient pharmacy query of all pts who received IV CSA at Mount Sinai Medical Center between 7/1/96 and 7/1/08 was reviewed. Pts with CC or indeterminate colitis (IC) favoring Crohn's were included in this study and their medical records were reviewed. Pts with IC that did not favor Crohn's, and those treated solely for small bowel, perianal fistulizing disease or pyoderma gangrenosum were excluded. Dates of colonic surgery were recorded. Pts that were discharged without requiring surgery were placed on oral CSA; subsequent need for colonic surgery was assessed. A Kaplan-Meier plot with log-rank testing was performed to determine the rate of colonic surgery avoidance. Forward stepwise logistic regression was performed to determine independent predictors of surgery. Results: 48 pts met our inclusion criteria; 41 had CC and 7 had IC favoring Crohn's. Admission demographics: women - 62%; mean age - 36 ± 14 yrs; prior bowel surgery - 33%; median disease duration - 10 yrs; history of thiopurine use - 85%; thiopurine use on admission for IV CSA - 44%; history of anti-TNF - 69%; anti-TNF in 4 wks preceding IV CSA - 22%; prednisone on admission - 48%. Median follow-up time was 12 mos (range 1 - 60 mos). Overall, 50% pts required a colonic resection, 13% during their admission for IV CSA. The cumulative colonic surgery avoidance rate was 71.8 ± 13.1% at 6 mos and 58.9 ± 14.9% at 12 mos (Fig. 1). In the multivariable analysis, anti-TNF use in the 4 wks preceding IV CSA was predictive of surgery: RR=3.3, 95%CI 1.1-10.0. A higher albumin level (overall median = 3.0 g/dL) was a negative predictor of surgery: RR=0.43, 95%CI 0.21-0.90.Figure 1Conclusion: The use of IV CSA resulted in colonic preservation in half of CC patients with severe disease, the majority of whom previously failed anti-TNFs and thiopurines. A randomized clinical trial to further explore IV CSA use in Crohn's colitis is needed.

BACKGROUND:Even in the biologic era, corticosteroid dependency in IBD patients is common and causes a lot of morbidity, but methods of withdrawal are not well described.AIM:To assess the effectiveness of a corticosteroid withdrawal method.METHODS:Twelve patients (10 men, 2 women; 6 ulcerative colitis, 6 Crohn's disease), median age 53.5 years (range 29-75) were included. IBD patients with quiescent disease refractory to conventional weaning were transitioned to oral dexamethasone, educated about symptoms of the corticosteroid withdrawal syndrome (CWS) and weaned under the supervision of an endocrinologist. When patients failed to wean despite a slow weaning pace and their IBD remaining quiescent, low dose synthetic ACTH stimulation testing was performed to assess for adrenal insufficiency. Multivariate analysis was performed to assess predictors of a slow wean.RESULTS:Median durations for disease and corticosteroid dependency were 21 (range 3-45) and 14 (range 2-45) years respectively. Ten patients (83%) were successfully weaned after a median follow-up from final wean of 38 months (range 5-73). Disease flares occurred in two patients, CWS in five and ACTH testing was performed in 10. Multivariate analysis showed that longer duration of corticosteroid use appeared to be associated with a slower wean (P = 0.056).CONCLUSIONS:Corticosteroid withdrawal using this protocol had a high success rate and durable effect and was effective in patients with long-standing (up to 45 years) dependency. As symptoms of CWS mimic symptoms of IBD disease flares, gastroenterologists may have difficulty distinguishing them, which may be a contributory factor to the frequency of corticosteroid dependency in IBD patients.

BACKGROUND & AIMS:The efficacy of infliximab for treating patients with ulcerative colitis has been established.METHODS:The Active Ulcerative Colitis Trial (ACT)-1 and ACT-2 randomized, double-blind, placebo-controlled studies evaluated infliximab induction and maintenance therapy in moderately to severely active ulcerative colitis. Overall, 728 patients received placebo or infliximab (5 or 10 mg/kg) intravenously at weeks 0, 2, and 6, then every 8 weeks through week 46 (ACT-1) or 22 (ACT-2). Colectomy, hospitalization, and surgery/procedure data through 54 weeks after the first infusion were obtained from ACT-1, ACT-2, and associated data sources. In the prespecified analysis, all data were combined to ascertain time to colectomy. Kaplan-Meier product-limit method was used to estimate the cumulative incidence of colectomy, and log-rank test was used to compare the combined infliximab group and placebo.RESULTS:Eighty-seven percent (630 of 728) of patients had complete colectomy follow-up; 13% (98 of 728) of patients had a median follow-up of 6.2 months. The cumulative incidence of colectomy through 54 weeks was 10% for infliximab and 17% for placebo (P = .02), yielding an absolute risk reduction of 7%. Compared with placebo, fewer ulcerative colitis-related hospitalizations and surgeries/procedures per 100 patient-years of treatment occurred with infliximab therapy: 40 vs 20 (P = .003) and 34 vs 21 (P = .03), respectively. Serious adverse events occurring in infliximab-treated patients included serious infections, tuberculosis, histoplasmosis, listeriosis, and malignancy.CONCLUSIONS:Patients with moderately to severely active ulcerative colitis treated with infliximab were less likely to undergo colectomy through 54 weeks than those receiving placebo.

Ulcerative colitis (UC) is a chronic disease of the bowel, characterized by inflammation of the colonic mucosa. Symptoms include rectal bleeding, diarrhea, and abdominal cramping. Approximately 250,000–500,000 individuals in the United States suffer from UC, and its annual incidence ranges from 2–7 per 100,000 people.1 Although the pathophysiology of UC is not fully understood, an abnormal immune response causes chronic inflammation, which is believed to be triggered by both environmental and genetic factors (Figure 1). Figure 1 Etiology and pathogenesis of ulcerative colitis. UC is categorized according to the severity of symptoms and extent of disease (Figure 2). Disease severity is defined as mild, moderate, severe, or fulminant depending on symptom severity, the number of stools per day, changes in erythrocyte sedimentation rate, and signs of toxicity.1,2 Ulcerative proctitis is defined as inflammation that is limited to the rectum, whereas proctosigmoiditis extends into the rectosigmoid colon. Together, proctitis and proctosigmoiditis affect approximately 46% of patients with UC.3 Distal UC, often referred to as “left-sided disease,” involves inflammation of the colon up to the splenic flexure and affects 17% of UC patients.3 In extensive UC, inflammation extends beyond the splenic flexure and may include the entire colon (pancolitis). Pancolitis accounts for approximately 37% of patients with UC.3 Symptoms are often correlated with the location of inflammation and can range from intermittent rectal bleeding in patients with mild proctitis, to increased urgency, tenesmus, cramps, weight loss, and colon perforation in patients with more extensive, severe disease. Figure 2 The ulcerative colitis continuum: endoscopic extent of disease. Treatment guidelines recommend endoscopy and symptom assessment to confirm the diagnosis of UC and determine the extent and severity of the disease.2 Biopsy of the colonic mucosa may show distortion of the architecture of the mucosal crypts and the presence of increased numbers of inflammatory cells within the mucosa. Mesalamine, or 5-aminosalycylate (5-ASA), has emerged as the first-line choice in treating mild-to-moderate UC. Oral agents are available, but most formulations require a high number of pills per day and may fail to deliver the active agent to the area of inflammation (Figure 3). Topical agents (in the form of enemas or suppositories) are considered to be more effective than oral agents in inducing remission in disease manifesting below the splenic flexure, and the combination of oral and topical agents is considered to be more effective than either alone.4 Corticosteroids are considered second-line therapy for induction of remission in distal disease that is refractory to 5-ASA but steroids are associated with high toxicity, particularly when used for longer than 3 months. The immunomodulators 6-mercaptopurine (6-MP) and azathioprine are recommended for patients with extensive disease, who fail to improve on 5-ASAs or steroids. Figure 3 Topical action of 5-ASA: extent of disease impacts formulation choice. Both oral and rectal 5-ASA formulations are used in the maintenance of remission. Steroids are not recommended for maintenance because of both lack of long-term efficacy and the risk of side effects, whereas azathioprine or 6-MP may be used in patients for whom 5-ASA therapy is not sufficient. Patients with moderate or severe refractory disease usually require hospitalization for treatment with intravenous steroids, cyclosporine or surgical resection of the colon. Some patients may be treated successfully as outpatients with anti-TNF biologic therapies or may receive this therapy with variable results as inpatients. The following roundtable discussion was convened to discuss the latest issues in diagnosis, treatment, and induction and maintenance of remission in patients with UC and proctitis.