Gary R. Lichtenstein

Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial

BACKGROUND We did a randomised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohns disease who respond to a single infusion of infliximab. METHODS 573 patients with a score of at least 220 on the Crohns disease activity index (CDAI) received a 5 mg/kg intravenous infusion of infliximab at week 0. After assessment of response at week 2, patients were randomly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group I), repeat infusions of 5 mg/kg infliximab at the same timepoints (group II), or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg (group III). The prespecified co-primary endpoints were the proportion of patients who responded at week 2 and were in remission (CDAI <150) at week 30 and the time to loss of response up to week 54 in patients who responded. Analyses of the co-primary endpoints were by intention to treat. FINDINGS 335 (58%) patients responded to a single infusion of infliximab within 2 weeks. At week 30, 23 of 110 (21%) group I patients were in remission, compared with 44 of 113 (39%) group II (p=0.003) and 50 of 112 (45%) group III (p=0.0002) patients. Thus, patients in groups II and III combined were more likely to sustain clinical remission than patients in group I (odds ratio 2.7, 95% CI 1.6-4.6). Throughout the 54-week trial, the median time to loss of response was 38 weeks (IQR 15 to >54) and more than 54 weeks (21 to >54) for groups II and III, respectively, compared with 19 weeks (10-45) for group I (p=0.002 and p=0.0002, respectively). Infliximab safety was consistent with that seen in other trials of infliximab in Crohns disease and rheumatoid arthritis. In particular, the incidence of serious infections was similar across treatment groups. INTERPRETATION Patients with Crohns disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if infliximab treatment is maintained every 8 weeks.

Early Mucosal Healing With Infliximab Is Associated With Improved Long-term Clinical Outcomes in Ulcerative Colitis

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.

Serious Infection and Mortality in Patients With Crohn ' s Disease: More Than 5 Years of Follow-Up in the TREAT ™ Registry

OBJECTIVES:The objective of this study was to contribute long-term safety data for infliximab and other therapies in Crohns disease (CD).METHODS:We prospectively evaluated CD patients enrolled in the large, observational Crohns Therapy, Resource, Evaluation, and Assessment Tool registry, established to compare infliximab safety with conventional nonbiological medications in CD.RESULTS:A total of 6,273 patients were enrolled and evaluated on or before 23 February 2010; 3,420 received infliximab (17,712 patient-years; 89.9% received ≥2 infusions) and 2,853 received other-treatments-only (13,251 patient-years). Mean length of patient follow-up was 5.2 years. More infliximab- than other-treatments-only-treated patients had moderate-to-severe (30.6% vs. 10.7%) or severe-to-fulminant (2.5% vs. 0.6%) disease severity (P<0.001). In the year before enrollment, more infliximab- than other-treatments-only-treated patients required surgical intervention (17.4% vs. 13.6%), medical hospitalization (14.2% vs. 8.8%), prednisone (47.8% vs. 31.4%), immunomodulators (52.0% vs. 32.1%), and narcotic analgesics (17.3% vs. 9.1%). Patient mortality was similar for infliximab- and other-treatments-only-treated patients (0.58 vs. 0.59/100 patient-years). In multivariate logistic regression analyses, treatment with prednisone (hazard ratio (HR)=2.14, 95% confidence interval (CI)=1.55, 2.95; P<0.001) or narcotic analgesics (HR=1.79, 95% CI=1.29, 2.48; P<0.001) and age (HR=1.08, 95% CI=1.07, 1.09; P<0.001) were associated with increased mortality risk. Neither infliximab nor immunomodulator treatment was associated with increased mortality risk. Factors independently associated with serious infections included moderate-to-severe disease activity (HR=2.24, 95% CI=1.57, 3.19; P<0.001), narcotic analgesic treatment (HR=1.98, 95% CI=1.44, 2.73; P<0.001), prednisone therapy (HR=1.57, 95% CI=1.17, 2.10; P=0.002), and infliximab treatment (HR=1.43, 95% CI=1.11, 1.84; P=0.006).CONCLUSIONS:Mortality was similar between infliximab- and other-treatments-only-treated CD patients. An increased risk of serious infection with infliximab was observed, although CD severity and use of prednisone or narcotic analgesics carried higher risks.

Colectomy Rate Comparison After Treatment of Ulcerative Colitis With Placebo or Infliximab

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.

A Systematic Review of Factors That Contribute to Hepatosplenic T-Cell Lymphoma in Patients With Inflammatory Bowel Disease

BACKGROUND & AIMS Hepatosplenic T-cell lymphoma (HSTCL) is a rare and usually fatal lymphoma that primarily affects men younger than 35 years old. Treatment of patients with inflammatory bowel disease (IBD) using antibodies to tumor necrosis factor (anti-TNFs) and thiopurines has been associated with HSTCL. We investigated the medications, duration of therapy, and ages of patients associated with HSTCL. METHODS We collected and analyzed data on the association between HSTCL, and anti-TNF and thiopurine therapies in patients with IBD from published reports and the MedWatch reporting system of the US Food and Drug Administration. RESULTS Of 36 patients with HSTCL, 20 received therapy with infliximab and a thiopurine and 16 received a thiopurine as monotherapy for IBD. Four patients who had been treated with infliximab and a thiopurine also received adalimumab. One of these patients had been given infliximab, adalimumab, and natalizumab. Of 31 patients of known gender, only 2 were female. Twenty-seven of the 30 patients of known age were younger than 35 years old. CONCLUSIONS Most patients with HSTCL who received long-term therapy (at least 2 y) with thiopurines for IBD were men younger than 35 years old. There were no reported cases of HSTCL in patients with IBD who received only anti-TNF therapy. Physicians should consider giving thiopurines and anti-TNF agents to young male patients with IBD only in cases in which a clear benefit is expected, such as in early stage disease in untreated patients or possibly in very severe cases.

Extraintestinal manifestations of inflammatory bowel disease

Numerous extraintestinal diseases have been associated with IBD. The role of the gastrointestinal tract in host response to the foreign antigens present in the gut makes the enteric immune system highly susceptible to any external perturbation to the system. Dysregulation of the enteric immune response results in pathology in various organs outside of the gut. The site-specific manifestations of this immune response are not understood fully. Better understanding of the pathogenesis of IBD and the complex interactions between the gut immune system and the extraintestinal systems would provide insights into the development of many of these extraintestinal manifestations. Much is unknown about the presence of cardiac, pulmonary, and hematologic diseases in patients with IBD. True association or coincidental presence of the diseases in these organ systems with IBD requires better delineation. An important consideration in all patients with IBD presenting with extraintestinal manifestations should be a careful search for medication-related complications.

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 patients 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 patients 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.

Azathioprine for maintenance of remission in Crohn's disease : Benefits outweigh the risk of lymphoma

BACKGROUND & AIMS Azathioprine is a commonly used and effective treatment for maintenance of remission for patients with steroid-dependent Crohns disease (CD). However, azathioprine therapy is associated with an increased risk of non-Hodgkins lymphoma. The objective of this analysis was to determine the impact of azathioprine therapy on survival and quality-adjusted life expectancy after accounting for both the benefits of therapy and potential increased risk of lymphoma. METHODS A decision analysis using a Markov model depicting the natural history of alternative management strategies for maintenance of remission in patients with CD was performed. RESULTS In the base-case analysis, treatment of CD patients with a steroid-induced remission with azathioprine resulted in an average increase in life expectancy of 0.04 years and 0.05 quality-adjusted years. The incremental gain in life expectancy decreased with increasing patient age and increasing risk of lymphoma. CONCLUSIONS Therapy with azathioprine to preserve remission in patients with CD results in increased quality-adjusted life expectancy. This increase was greatest in young patients who have the lowest baseline risk of non-Hodgkins lymphoma and who have the greatest life expectancy in the absence of a CD-related death.

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.

Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS)

Background Variability in endoscopic assessment necessitates rigorous investigation of descriptors for scoring severity of ulcerative colitis (UC). Objective To evaluate variation in the overall endoscopic assessment of severity, the intra- and interindividual variation of descriptive terms and to create an Ulcerative Colitis Endoscopic Index of Severity which could be validated. Design A two-phase study used a library of 670 video sigmoidoscopies from patients with Mayo Clinic scores 0–11, supplemented by 10 videos from five people without UC and five hospitalised patients with acute severe UC. In phase 1, each of 10 investigators viewed 16/24 videos to assess agreement on the Baron score with a central reader and agreed definitions of 10 endoscopic descriptors. In phase 2, each of 30 different investigators rated 25/60 different videos for the descriptors and assessed overall severity on a 0–100 visual analogue scale. κ Statistics tested inter- and intraobserver variability for each descriptor. A general linear mixed regression model based on logit link and β distribution of variance was used to predict overall endoscopic severity from descriptors. Results There was 76% agreement for ‘severe’, but 27% agreement for ‘normal’ appearances between phase I investigators and the central reader. In phase 2, weighted κ values ranged from 0.34 to 0.65 and 0.30 to 0.45 within and between observers for the 10 descriptors. The final model incorporated vascular pattern, (normal/patchy/complete obliteration) bleeding (none/mucosal/luminal mild/luminal moderate or severe), erosions and ulcers (none/erosions/superficial/deep), each with precise definitions, which explained 90% of the variance (pR2, Akaike Information Criterion) in the overall assessment of endoscopic severity, predictions varying from 4 to 93 on a 100-point scale (from normal to worst endoscopic severity). Conclusion The Ulcerative Colitis Endoscopic Index of Severity accurately predicts overall assessment of endoscopic severity of UC. Validity and responsiveness need further testing before it can be applied as an outcome measure in clinical trials or clinical practice.