Rates and Predictors of Endoscopic and Clinical Recurrence After Primary Ileocolic Resection for Crohn's Disease.

BACKGROUND AND AIMS: The utility of postoperative medical prophylaxis (POMP) and the treatment of mild endoscopic recurrence remain controversial. METHODS: This study is a retrospective review of patients undergoing a primary ileocolic resection for CD at a single academic center. Endoscopic recurrence (ER) was defined using the Rutgeerts score (RS), and clinical recurrence (CR) was defined as symptoms of CD with endoscopic or radiologic evidence of neo-terminal ileal disease. RESULTS: There were 171 patients who met inclusion criteria. The cumulative probability of ER (RS ≥ i-1) at 1, 2, and 5 years was 29, 51, and 77 %, respectively. The only independent predictors of ER were the absence of POMP (HR 1.50; P = 0.03) and penetrating disease behavior (HR 1.50; P = 0.05). The cumulative probability of CR at 1, 2, and 5 years was 8, 13, and 27 %, respectively. There was a higher rate of clinical recurrence in patients with RS-2 compared to RS-1 on the initial postoperative endoscopy (HR 2.50; P = 0.02). In 11 patients not exposed to POMP with i-1 on initial endoscopy, only 2 patients (18 %) progressed endoscopically during the study period while 5 patients (45 %) regressed to i-0 on subsequent endoscopy without treatment. CONCLUSIONS: Postoperative medical prophylaxis decreased the likelihood of ER while certain phenotypes of CD appear to increase the risk of developing ER and CR. There may be a role for watchful waiting in patients with mild endoscopic recurrence on the initial postoperative endoscopy.

Preoperative Anti-tumor Necrosis Factor Therapy in Patients with Ulcerative Colitis Is Not Associated with an Increased Risk of Infectious and Noninfectious Complications After Ileal Pouch-anal Anastomosis.

BACKGROUND: There are conflicting data regarding the effect of previous exposure to anti-tumor necrosis factor (anti-TNF) therapy on complication rates after pelvic pouch surgery for patients with ulcerative colitis (UC). In particular, there is concern surrounding the rates of pouch leaks and infectious complications, including pelvic abscesses, in anti-TNF-treated subjects who require ileal pouch-anal anastomosis (IPAA) surgery. METHODS: A retrospective study was performed in UC subjects who underwent IPAA between 2002 and 2013. Demographic data, clinical data, use of anti-TNF therapy, steroids, immunosuppressants, and surgical outcomes were assessed. RESULTS: Seven hundred seventy-three patients with UC/IPAA were reviewed. Fifteen patients were excluded from the analysis because of missing data. There were 196 patients who were exposed to anti-TNF therapy and 562 patients who were not exposed to anti-TNF therapy preoperatively. There were no significant differences in the postoperative IPAA leak rate between those exposed to anti-TNF therapy and the control group (n = 26 [13.2%] versus 66 [11.7%], respectively, P = 0.44). In addition, there were no significant differences in the postoperative 2-stage IPAA leak rate in those who had been operated on within 15 days from the last anti-TNF dose (n = 10), within 15 to 30 days (n = 17), or 31 to 180 days (n = 54) (10%, 5.9%, and 14.8% respectively, P = 0.43) nor were there differences based on the presence of detectable infliximab serum levels. CONCLUSIONS: Preoperative anti-TNF therapy in patients with UC is not associated with an increased risk of infectious and noninfectious complications after IPAA including pelvic abscesses, leaks, and wound infections.

Infliximab to Treat Refractory Inflammation After Pelvic Pouch Surgery for Ulcerative Colitis.

BACKGROUND: Inflammatory pouch complications refractory to first-line therapies remain problematic following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC). We evaluated infliximab efficacy and associations with therapeutic response. METHODS: Data from individuals who underwent colectomy and IPAA for UC (2000-2014) were reviewed. Patients with chronic refractory pouchitis (CP) and Crohn's disease (CD)-like outcomes treated with infliximab were included. Pre-treatment parameters and response at median 8 (initial) and 48 weeks (sustained) were measured. Complete response was defined as symptomatic and endoscopic resolution with modified Pouchitis Disease Activity Index (mPDAI) <5. Partial response included mPDAI improvement >2. Serum was analysed for Anti-Saccharomyces cerevisiae antibodies (ASCA), anti-OmpC, anti-CBir1 and perinuclear Anti-Neutrophil Cytoplasmic Antibodies (pANCA). RESULTS: One hundred and fifty-two patients with CP or a CD-like phenotype were identified. Forty-two were treated with infliximab (33% male; age 32.6±2.6 years, 28.5% CD-like). Post-induction response was achieved in 74% (48% complete) and sustained response in 62.6% (29.6% complete). Mean mPDAI and C-reactive protein declined from 8.5±0.3 to 2±3.4 (p < 0.002) and from 29.48±6.2 to 5.76±1.6mg/L (p < 0.001), respectively. Female gender, smoking and presence of anti-CBir1 were associated with infliximab use (p < 0.01) but not response. Pre-treatment mPDAI <10 (p < 0.01), resolution of rectal bleeding (p < 0.001 ) and week 8 endoscopic activity were associated with sustained response (p = 0.04; odds ratio [OR] 2.2; 95% confidence interval [CI] 1.1-16.5]). More than 2 positive antimicrobial antibody titres were associated with non-response (p < 0.05), but did not retain significance in multivariate analysis (p = 0.197; OR 0.632; 95% CI 0.31-1.2). CONCLUSIONS: Infliximab can effectively treat inflammatory pouch complications. Pre-treatment mPDAI <10 and early endoscopy may identify responders.

Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial.

BACKGROUND: Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease. METHODS: In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809. FINDINGS: This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events. INTERPRETATION: Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality. FUNDING: AbbVie Pharmaceuticals.

Predictors of Outcome in Ulcerative Colitis.

BACKGROUND: Approximately 80% of patients with ulcerative colitis (UC) have intermittently active disease and up to 20% will require a colectomy, but little data available on predictors of poor disease course. The aim of this study was to identify clinical and genetic markers that can predict prognosis. METHODS: Medical records of patients with UC with ≥5 years of follow-up and available DNA and serum were retrospectively assessed. Immunochip was used to genotype loci associated with immune mediated inflammatory disorders (IMIDs), inflammatory bowel diseases, and other single nucleotide polypmorphisms previously associated with disease severity. Serum levels of pANCA, ASCA, CBir1, and OmpC were also evaluated. Requirement for colectomy, medication, and hospitalization were used to group patients into 3 prognostic groups. RESULTS: Six hundred one patients with UC were classified as mild (n = 78), moderate (n = 273), or severe disease (n = 250). Proximal disease location frequencies at diagnosis were 13%, 21%, and 30% for mild, moderate, and severe UC, respectively (P = 0.001). Disease severity was associated with greater proximal extension rates on follow-up (P < 0.0001) and with shorter time to extension (P = 0.03) and to prednisone initiation (P = 0.0004). When comparing severe UC with mild and moderate UC together, diagnosis age >40 and proximal disease location were associated with severe UC (odds ratios = 1.94 and 2.12, respectively). None of the single nucleotide polypmorphisms or serum markers tested was associated with severe UC, proximal disease extension or colectomy. CONCLUSIONS: Older age and proximal disease location at diagnosis, but not genetic and serum markers, were associated with a more severe course. Further work is required to identify biomarkers that will predict outcomes in UC.

The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease.

OBJECTIVE: Although low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohn's disease (CD), the clinical relevance of ATI in patients with adequate infliximab concentrations is uncertain. We evaluated this question using an assay sensitive for identification of ATI in the presence of infliximab. DESIGN: In an observational study, 1487 trough serum samples from 483 patients with CD who participated in four clinical studies of maintenance infliximab therapy were analysed using a fluid phase mobility shift assay. Infliximab and ATI concentrations most discriminant for remission, defined as a C-reactive protein concentration of ≤ 5 mg/L, were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission. RESULTS: Based upon analysis of 1487 samples, 77.1% of patients had detectable and 22.9% had undetectable infliximab concentrations, of which 9.5% and 71.8%, respectively, were positive for ATI. An infliximab concentration of > 2.79 µg/mL (area under the curve (AUC) = 0.681; 95% CI 0.632 to 0.731) and ATI concentration of < 3.15 U/mL (AUC = 0.632; 95% CI 0.589 to 0.676) were associated with remission. Multivariable analysis showed that concentrations of both infliximab trough (OR 1.8; 95% CI 1.3 to 2.5; p < 0.001) and ATI (OR 0.57; 95% CI 0.39 to 0.81; p = 0.002) were independent predictors of remission. CONCLUSIONS: The development of ATI increases the probability of active disease even at low concentrations and in the presence of a therapeutic concentration of drug during infliximab maintenance therapy. Evaluation of strategies to prevent ATI formation, including therapeutic drug monitoring with selective infliximab dose intensification, is needed.

Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease.

BACKGROUND & AIMS: Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone. METHODS: In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50. RESULTS: Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62-2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated. CONCLUSIONS: The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. ClincialTrials.gov number, NCT00132899.

Ileal pouch symptoms do not correlate with inflammation of the pouch.

BACKGROUND & AIMS: Pouchitis is the most common complication after ileal pouch-anal anastomosis (IPAA). However, symptoms are not specific. The Pouchitis Disease Activity Index (PDAI) and the Pouchitis Activity Score (PAS) have been used to diagnose pouchitis. We evaluated the correlation between the clinical components of these scores and endoscopic and histologic findings. METHODS: We performed a cross-sectional study, analyzing data from 278 patients from Mount Sinai Hospital (Toronto, Canada) who had an IPAA. Patients underwent pouchoscopy with a biopsy, and data were collected on patients' clinical status. The PDAI and PAS were calculated for each subject. The Spearman rank correlation (ρ) statistical test was used to evaluate correlations between the PDAI scores and PAS, and between total scores and subscores. RESULTS: The total PDAI scores and PAS scores were correlated; the clinical components of each correlated with the total score (ρ = 0.59 and ρ = 0.71, respectively). However, we observed a low level of correlation between clinical and endoscopic or histologic subscores, with ρ of 0.20 and 0.10, respectively, by PDAI, and ρ of 0.19 and 0.04, respectively, by PAS. CONCLUSIONS: There is a low level of correlation between clinical and endoscopic and histologic subscores of patients with IPAA; clinical symptoms therefore might not reflect objective evidence of inflammation. These findings, along with evidence of correlation between total scores and clinical symptoms, indicate that these indices do not accurately identify patients with pouch inflammation. Further research is required to understand additional factors that contribute to clinical symptoms in the absence of objective signs of pouch inflammation.

Preoperative biological therapy and short-term outcomes of abdominal surgery in patients with inflammatory bowel disease.

OBJECTIVE: Previous investigations of short-term outcomes after preoperative exposure to biological therapy in inflammatory bowel disease (IBD) were conflicting. The authors aimed to assess postoperative outcomes in patients who underwent abdominal surgery with recent exposure to anti-tumour necrosis factor therapy. DESIGN: A retrospective case-control study with detailed matching was performed for subjects with IBD with and without exposure to biologics within 180 days of abdominal surgery. Postoperative outcomes were compared between the groups. RESULTS: 473 procedures were reviewed consisting of 195 patients with exposure to biologics and 278 matched controls. There were no significant differences in most postoperative outcomes such as: length of stay, fever (≥ 38.5°C), urinary tract infection, pneumonia, bacteraemia, readmission, reoperations and mortality. On univariate analysis, procedures on biologics had more wound infections compared with controls (19% vs 11%; p=0.008), but this was not significant in multivariate analysis. Concomitant therapy with biologics and thiopurines was associated with increased frequencies of urinary tract infections (p=0.0007) and wound infections (p=0.0045). Operations performed ≤ 14 days from last biologic dose had similar rates of infections and other outcomes when compared with those performed within 15-30 days or 31-180 days. Patients with detectable preoperative infliximab levels had similar rates of wound infection compared with those with undetectable levels (3/10 vs 0/9; p=0.21). CONCLUSION: Preoperative treatment with TNF-α antagonists in patients with IBD is not associated with most early postoperative complications. A shorter time interval from last biological dose is not associated with increased postoperative complications. In most cases, surgery should not be delayed, and appropriate biological therapy may be continued perioperatively.

Ustekinumab induction and maintenance therapy in refractory Crohn's disease.

BACKGROUND: In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown. METHODS: We evaluated ustekinumab in adults with moderate-to-severe Crohn's disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks. RESULTS: The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P=0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P=0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab. CONCLUSIONS: Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov number, NCT00771667.).

Antimicrobial antibodies are associated with a Crohn's disease-like phenotype after ileal pouch-anal anastomosis.

BACKGROUND & AIMS: Pouchitis and Crohn's disease (CD)-like (CDL) complications of the pouch occur at rates near 50% and 20%, respectively, after colectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC). We investigated whether antimicrobial antibodies are associated with pouch outcome after IPAA. METHODS: We studied clinical and endoscopic data from 399 individuals with UC who underwent colectomy with IPAA at Mount Sinai Hospital in Toronto, Canada; patients were classified as no pouchitis (NP), chronic pouchitis (CP), or CDL. Serum samples were analyzed from 341 patients for antibodies against Saccharomyces cerevisiae (ASCA), OmpC, CBir1, and perinuclear antineutrophil cytoplasmic antibody (pANCA). RESULTS: Of the subjects, 70.7% had NP, 16.8% developed CP, and 12.5% developed CDL. Smoking was associated with CDL (P = .003). Ashkenazi Jewish individuals more commonly had CP (P = .008). Of patients with CDL, 53.5% and 14.0% had positive test results for anti-CBir1 and ASCA (immunoglobulin G), respectively, compared with 21.4% and 3.8% of those with NP and 28.3% and 5.0% of those with CP (P < .0001 and P = .03). Anti-CBir1 was associated with CDL, compared with NP (P = 2.8 × 10(-5); odds ratio [OR], 4.2; 95% confidence interval [CI], 2.2-8.3) or CP (P = .011; OR, 2.9; 95% CI, 1.3-6.6). ASCA immunoglobulin G was associated with CDL, compared with patients with NP (P = .01; OR, 4.1; 95% CI, 1.4-12.3). In a combined model, pANCA and the antimicrobial antibodies were associated with CP (P = .029) and CDL (P = 4.7 × 10(-4)). CONCLUSIONS: Antimicrobial antibodies and pANCA are associated with inflammatory complications of the pouch. The CDL phenotype is associated with factors that characterize Crohn's disease, including smoking, anti-CBir1, and ASCA.

Distinct and overlapping genetic loci in Crohn's disease and ulcerative colitis: correlations with pathogenesis.

BACKGROUND: A common genotypic basis for ulcerative colitis (UC) and Crohn's disease (CD) is implied by overlapping clinical characteristics, epidemiological studies, and association of genes with both UC and CD. We evaluated the overlap between CD and UC genetic loci stratified by pathogenetic pathways and by disease location. METHODS: The allele frequencies of six UC-associated and 34 CD-associated single nucleotide polymorphisms (SNPs) were determined in a Canadian IBD cohort (n = 2374). Differences between CD, UC, colon-only CD, ileal CD, and controls were analyzed controlling for ethnicity, age of diagnosis, and gender. RESULTS: In all, 21 of 34 CD-associated SNPs had similar allele frequencies in UC (n = 1230) and CD (n = 1144). Three of six UC-associated SNPs had significantly different frequencies in CD (n = 1144). Most of the divergence in allele frequency among CD and UC was noted in NOD2/autophagy pathway SNPs, while most SNPs with similar frequencies were in IL-22/23 Th17, adaptive immunity, and barrier pathways. Colon-only CD (n = 228) was compared with healthy controls: three of six UC SNPs (in MST1, HLA-DRA, and IL-23R) and 11 of 34 CD SNPs: in IRGM, NOD2 (rs2066845), CCNY, MST1, IL23R, PTPN22, C11orf30, ZNF365, PTPN2, PSMG1, and rs1456893 were significantly associated. In all, 29 of 34 CD SNPs had similar allele frequencies in colonic CD compared with ileal CD (n = 366). All UC SNPs had similar frequencies in UC and colonic CD. CONCLUSIONS: Our results suggest that CD and UC share common genetic associations related to impaired adaptive immunity and diverge in pathways of foreign antigen processing. Colon-only CD overlaps extensively with UC and considerably with ileal CD.

Novel anti-glycan antibodies related to inflammatory bowel disease diagnosis and phenotype.

OBJECTIVES: We sought to evaluate whether two novel immunoglobulin A (IgA) cell wall polysaccharide antibodies, anti-laminarin (anti-L) and anti-chitin (anti-C), aid in the diagnosis and phenotype differentiation of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A cohort of 818 individuals with inflammatory bowel disease (IBD; 517 CD and 301 UC) from two IBD tertiary referral centers, with median ages of 33 and 39 years, respectively, and disease duration of 8.9 years, were phenotyped using the Montreal classification, and analyzed for seven anti-glycan antibodies (gASCA (anti-Saccharomyces cerevisiae) IgG, gASCA IgA, anti-chitobioside (GlcNAc(beta1,4)GlcNAc(beta)), anti-laminaribioside (Glc(beta1,3)Glb(beta)), anti-mannobioside (Man(alpha1,3)Man(alpha)), anti-L, and anti-C) and perinuclear atypical neutrophil cytoplasmic antibodies (pANCA). RESULTS: In the CD patient population, 73% were positive for >/=1 anti-glycan antibody. All glycan markers were specific for CD (85.4-97.7%) and more prevalent in CD vs. UC (P<0.0015). gASCA IgG and IgA best differentiated CD from UC followed by anti-L (area under the curve 0.818, 0.815, and 0.702, respectively). The addition of anti-L and anti-C to gASCA IgG and pANCA improved discrimination between CD and UC (P<0.001). Adding anti-L to gASCA and pANCA differentiated colonic CD and UC (P=0.02). An increasing number of positive antibodies was associated with early CD onset, penetrating phenotype, perianal disease, and the need for surgery (P<0.001). Anti-L was associated with ileocolonic CD (odds ratio (OR) 2.28, 95% confidence interval (CI) 1.40-3.69; P=0.001), and anti-C with penetrating (OR 2.75, 95% CI 1.50-5.04; P=0.001) and perianal disease (OR 1.95, 95% CI 1.06-3.59; P=0.03). CONCLUSIONS: Anti-L and anti-C improve differentiation between CD and UC. Anti-L may also differentiate between isolated colonic CD and UC. Both anti-L and anti-C are independently associated with a more aggressive CD phenotype.

Treatment of active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 integrin.

BACKGROUND & AIMS: Selective blockade of lymphocyte-vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the alpha4beta7 integrin, in patients with active Crohn's disease. METHODS: Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (>or=70-point decrement in the Crohn's Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score or=100-point decrement in CDAI). Human anti-human antibody levels were measured. RESULTS: Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively (P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohn's disease. CONCLUSIONS: This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohn's disease.

Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease.

BACKGROUND & AIMS: The effect of infliximab infused at scheduled intervals on antibody formation, preinfusion trough serum concentrations of infliximab, and their clinical significance was evaluated in patients with Crohn's disease. METHODS: Antibodies to infliximab and trough serum infliximab were measured in 105 patients with Crohn's disease treated with 5 mg/kg infliximab for induction followed by maintenance episodic re-treatment (n = 23) or scheduled therapy at 6- to 8-week intervals (n = 82). RESULTS: After a median of 14 infusions (range, 2-45), 21% of patients had detectable antibodies, 25% were antibody negative, and 54% were antibody inconclusive. Antibody formation was higher after episodic compared with scheduled treatment (39% vs 16%; P = .036) and was associated with a higher rate of infusion reactions (50% vs 21%; P = .018). Ninety patients continued maintenance scheduled therapy beyond 12 months including 12 converted episodic patients, with a median follow-up of 23 months (range, 16-68 months). The rate of clinical remission was higher for patients with a detectable trough serum infliximab compared with patients in whom serum infliximab was undetectable, including those without antibodies (82% vs 6%; P < .001). A detectable trough serum infliximab was also associated with a lower C-reactive protein (2.0 vs 11.8 mug/L; P < .001) and a higher rate of endoscopic improvement (88% vs 33%; P < .001). Concurrent immunomodulators did not alter outcomes. CONCLUSIONS: For Crohn's disease patients treated with scheduled maintenance infusions of infliximab, the trough serum concentration of infliximab predicts clinical outcome. Factors in addition to antibody formation, likely pharmacokinetic, modulate serum infliximab and thus the response to infliximab therapy.

Maintenance infliximab treatment is associated with improved bone mineral density in Crohn's disease.

OBJECTIVES: Diminished bone mineral density (BMD) is a recognized complication of Crohn's disease (CD). The mechanisms underlying bone loss are unclear but may include a direct effect of inflammatory cytokines related to disease activity. Because tumor necrosis factor alpha (TNF-alpha) plays a central role in the pathogenesis of CD inflammation, we evaluated the effect on BMD of maintenance treatment with infliximab in patients with CD. METHODS: BMD of the lumbar spine (L2-L4) and proximal left femur (neck and trochanter) were measured at baseline and 1 yr in 46 CD patients treated with infliximab (5 mg/kg) at 6-8 wk intervals for 1 yr. Thirteen patients received concurrent prednisone at a mean dose of 10 mg/day (range: 5-15). RESULTS: At baseline, reduced BMD (T-score

Budesonide for maintenance of remission in patients with Crohn's disease in medically induced remission: a predetermined pooled analysis of four randomized, double-blind, placebo-controlled trials.

OBJECTIVES: To evaluate the efficacy and safety of oral budesonide for maintenance of remission in patients with mild to moderately active Crohn's disease (CD) of the ileum and/or ascending colon. METHODS: Four double-blind, placebo-controlled trials with identical protocols were combined according to a predetermined analysis plan. Three hundred eighty patients with CD in medically induced remission (CD activity index [CDAI]< or =150) were randomized to receive oral budesonide 3 mg, 6 mg, or placebo daily for 12 months. The primary outcome measure was time to relapse (increase in CDAI of 60 points above baseline and >150). RESULTS: The median time to relapse was 268, 170, and 154 days for budesonide 6 mg, budesonide 3 mg, and placebo groups, respectively (p= 0.0072). The frequency of adverse events and glucocorticosteroid side effects were similar in all groups. CONCLUSION: Budesonide 6 mg/day is effective for prolonging time to relapse and for significantly reducing rates of relapse at 3 and 6 months but not 12 months in patients with CD in medically induced remission.

Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn's disease.

BACKGROUND & AIMS: Crohn's disease causes an increase in osteopenia and osteoporosis. This study assessed the efficacy of adding etidronate to calcium and vitamin D supplementation for treatment of low bone mineral density in Crohn's disease. METHODS: One hundred fifty-four patients with Crohn's disease with decreased bone mineral density, determined by using dual-energy x-ray absorptiometry, were randomly assigned to receive etidronate (400 mg orally) or not for 14 days; both groups were then given daily calcium (500 mg) and vitamin D (400 IU) supplementation for 76 days. This cycle was repeated 8 times during a period of 24 months. Biochemical characteristics and bone mineral densities were assessed at 6, 12, and 24 months. RESULTS: After 24 months bone mineral density significantly increased from baseline in both the etidronate- and the non-etidronate-treated groups (both groups receiving calcium and vitamin D supplementation) at the lumbar spine (P < .001), ultradistal radius (P < .001), and trochanter (P = .004) sites, but not at the total hip. The increase in bone mineral density was similar in each treatment group. No bone mineral density differences were found when groups were analyzed according to gender, corticosteroid use, bone mineral density at baseline, or age. CONCLUSIONS: Low bone mineral density is frequently associated with Crohn's disease. Supplementation with daily calcium and vitamin D is associated with increases in bone mineral density. The addition of oral etidronate does not further enhance bone mineral density.

High-level serum antibodies to bacterial antigens are associated with antibiotic-induced clinical remission in Crohn's disease: a pilot study.

In Crohn's disease, antibiotics are used with variable efficacy, suggesting that some patients are more likely to respond. The aim of this study was to determine whether Crohn's patients with predominant serum antibody reactivity toward bacterial antigens OmpC and/or I2 were more likely to achieve remission with antibiotics. Patients with ileal or ileal with right-sided colonic Crohn's disease were studied in a double-blind trial of budesonide alone or budesonide plus metronidazole and ciprofloxacin. In the budesonide plus metronidazole and ciprofloxacin group, patients with OmpC/I2 predominant profiles had the highest remission rate, whereas the group with no antibody predominant profiles had the lowest rate. In the budesonide group, patients with the OmpC/I2 predominant profile had the lowest remission rate, and the no-antibody group rate was higher. Although not statistically significant, these results support further testing to determine whether predominant serum reactivity to certain bacterial antigens may be a marker for efficacious use of antibiotics.