Dig Liver Dis. 2015 Oct 27.
Long-term infliximab therapy is needed for sustained steroid-free remission in patients with ulcerative colitis.
Le Roy F, Siproudhis L, Bretagne JF, et al.

No abstract available.

J Crohns Colitis. 2015 Nov 17. [Epub ahead of print]
The Ulcerative Colitis Endoscopic Index of Severity more accurately reflects clinical outcomes and long-term prognosis than the Mayo Endoscopic Score.
Ikeya K, Hanai H, Sugimoto K, et al.

BACKGROUND AND AIMS: The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and the Mayo Endoscopic score (Mayo ES) are applied to evaluate ulcerative colitis (UC) severity. This study was to compare UCEIS and the Mayo ES for evaluating UC severity and outcomes in patients undergoing remission induction during routine clinical practice with interest to predict medium to long-term prognosis.
METHODS: Forty-one UC patients who received colonoscopy before and after tacrolimus remission induction therapy were included. UC clinical activity index and endoscopic findings scored by both the UCEIS and the Mayo ES were determined. The changes in the UCEIS and the Mayo ES before and after induction therapy were compared.
RESULTS: The mean UCEIS improved from 6.2±0.9 to 3.4±2.1 (P<0.001). Based on the UCEIS, a significant level was reached in both the response and the remission groups. In contrast, the Mayo ES did not reflect significant change in the response group. The discrepancy appeared to be due to ulcers becoming smaller and shallower during the early stages of mucosal healing; Mayo ES seems to miss these early changes. In other words, whereas, the UCEIS indicates improvements when ulcers shrink, the Mayo ES does not distinguish deep ulcers from shallow ulcers, remains 3 (severe UC). Additionally, better UCEIS strata after induction therapy were associated with lower incidence of colectomy (P=0.0001) or relapse (P=0.0008).
CONCLUSIONS: The UCEIS accurately reflects clinical outcomes and predicts medium to long-term prognosis in UC patients undergoing induction therapy. These findings should support decision making in clinical practice settings.

J Pediatr Gastroenterol Nutr. 2015 Nov 17.]
Durability of infliximab is associated with disease extent in children with inflammatory bowel disease.
Shapiro JM, Subedi S, Machan JT, et al.

OBJECTIVES: To evaluate infliximab (IFX) dosing and treatment durability relative to luminal disease burden in patients with inflammatory bowel disease.
METHODS: Records from 98 pediatric patients treated with IFX between 2012 and 2014 were reviewed. Disease extent was classified as "limited", "moderate" or "extensive" based on cumulative assessment of mucosal involvement. Patients started on standard 5 mg/kg dosing were compared to those initiated on 10 mg/kg with regard to treatment durability.
RESULTS: Overall, 26.4%, 58.3% and 70% with limited, moderate or extensive disease, respectively, started on a standard IFX dose of 5 mg/kg required therapy escalation. Patients with moderate and extensive disease, started on the 5 mg/kg/dose, showed statistically significant shorter times to escalation than those with limited disease. The percentage of patients remaining on their initial 5 mg/kg/dose at 12 months was 80.1%, 56.9%, and 40.0% for limited, moderate, and extensive disease, respectively. Among patients started on 10 mg/kg, 100% remained on this dose. All patients with limited disease who required dose escalation continued on the higher dose at the time of analysis, however among those with the most extensive disease, 43% failed escalation due to non-response or infusion reaction.
CONCLUSIONS: Patients with extensive disease started on 5 mg/kg of IFX were more likely to require dose escalation compared to those with limited or moderate disease. All patients with moderate and extensive disease started on 10 mg/kg of IFX remained on this dose. These results suggest that patients with more extensive disease may benefit from higher initial IFX dosing as it relates to durability of treatment.

J Pediatr Gastroenterol Nutr. 2015 Nov 5.
Practical use of infliximab concentration monitoring in pediatric Crohn's disease.
Minar P, Saeed SA, Afreen M, et al.

OBJECTIVE: Therapeutic drug monitoring (TDM) that guides infliximab (IFX) intensification strategies has been shown to improve IFX efficacy. We conducted a review to evaluate the utility of TDM in the assessment and subsequent management of IFX loss of response in our pediatric Crohn's disease (CD) population.
METHODS: Single-center retrospective study of CD patients receiving IFX that had TDM from 12/2009-9/2013. We defined subtherapeutic trough as a drug level below the detection limit of the Prometheus® ELISA and ANSER reference values (1.4 μg/ml and 1 μg/ml, respectively) or a mid-interval level <12 g="" ml="" br=""> RESULTS: 191 IFX concentration tests were performed on 72 CD patients with loss of response to therapy as the primary indication (72%). 34% of all TDM were subtherapeutic. Following initial TDM, 25/72 patients received regimen intensification with 72% in clinical remission at six months Including all TDM that resulted in IFX dose intensification, we found a significant improvement in six month remission rates whether intensification followed mid-interval (88% remission) or trough (56% remission) testing (p = 0.026). Antibody to infliximab (ATI) was found in 14 patients with five occurring in the first year of therapy. Further, 71% of patients with ATI that were switched to an alternative anti-TNF achieved clinical remission at six months. In multivariable regression analysis, we found IFX dose (mg/kg), IFX dosing frequency (weeks) and the ESR at the previous infusion were significantly associated with the IFX concentration.
CONCLUSIONS: TDM in our pediatric CD population led to informed clinical decisions and improved rates of clinical remission.

J Pediatr Gastroenterol Nutr. 2015 Nov 3.
Use of placebo in pediatric inflammatory bowel diseases: a position paper from ESPGHAN, ECCO, PIBDnet and the Canadian Children IBD Network.
Turner D, Koletzko S, Griffiths AM, et al.

Performing well designed and ethical trials in pediatric inflammatory bowel diseases (IBD) is a priority to support optimal therapy and to reduce the unacceptable long lag between adult and pediatric drug approval. Recently, clinical trials in children have been incorporating placebo arms into their protocols under conditions that created controversy. Therefore, four organizations (ESPGHAN, ECCO, the Canadian Children IBD Network and the global pediatric IBD network (PIBDnet)) jointly provide a statement on the role of placebo in pediatric IBD trials. Consensus was achieved by 94/100 (94%) voting committees' members that placebo should only be used if there is genuine equipoise between the active treatment and placebo. For example, this may be considered in trials of drugs with new mechanisms of action without existing adult data, especially when proven effective alternatives do not exist outside the trial. Placebo may also be used in situations where it is an 'add-on" to an effective therapy or to evaluate exit-strategies of maintenance therapy after long-term deep remission. However, it has been agreed that no child enrolled in a trial should receive a known inferior treatment both within and outside the trial. This also includes withholding therapy in children who show clinical response after a short induction therapy. Given the similarity between pediatric and adult IBD in regards to pathophysiology and response to treatments, drugs generally cannot be considered being in genuine equipoise with placebo if it has proven efficacy in adults. Continued collaboration of all stakeholders is needed to facilitate drug development and evaluation in pediatric IBD.

J Crohns Colitis. 2015 Nov 27.
The first European evidence-based consensus on extra-intestinal manifestations in inflammatory bowel disease.
Harbord M, Annese V, Vavricka SR, et al.

No abstract available.

Inflamm Bowel Dis. 2015 Nov 20.
Immunogenicity of influenza vaccine for patients with inflammatory bowel disease on maintenance infliximab therapy: a randomized trial.
deBruyn J, Fonseca K, Ghosh S, et al.

BACKGROUND: In patients with inflammatory bowel disease (IBD) on infliximab, data are limited on immune response to influenza vaccine and the impact of vaccine timing. The study aims were to evaluate immune responses to the influenza vaccine in IBD patients on infliximab and the impact of vaccine timing on immune responses.
METHODS: In this randomized study, 137 subjects with IBD on maintenance infliximab therapy were allocated to receive the 2012/2013 inactivated influenza vaccine at the time of infliximab infusion (n= 69) or midway between infusions (n = 68). Serum was collected before and after vaccination for hemagglutination inhibition titers. Serologic protection was defined by postvaccine titer of ≥1:40.
RESULTS: Comparing subjects vaccinated at the time of infliximab with those vaccinated midway, serologic protection was achieved in 67% versus 66% to H1N1 (P = 0.8), in 43% versus 49% to H3N2 (P = 0.5), and in 69% versus 79% to influenza B (P = 0.2). Although solicited adverse events were common (60%), no subject experienced a serious adverse event requiring additional medical attention. Only 6% of subjects had a clinically significant increase in disease activity score, not impacted by vaccine timing.
CONCLUSIONS: Serologic protection to influenza vaccine is achieved in only approximately 45% to 80% of IBD patients on maintenance infliximab therapy varying by antigen. Yet, importantly, vaccine timing relative to infliximab infusion does not affect the achievement of serologic protection, and the influenza vaccine is well tolerated. Therefore, influenza vaccination at any point during infliximab scheduling is recommended for patients with IBD and opportunities to broaden the availability and convenience of influenza vaccine to optimize coverage should be explored.

Clin Chem Lab Med. 2015 Nov 20.
Therapeutic drug monitoring of infliximab: performance evaluation of three commercial ELISA kits.
Schmitz EM, van de Kerkhof D, Hamann D, et al.

BACKGROUND: Therapeutic drug monitoring (TDM) of infliximab (IFX, Remicade®) can aid to optimize therapy efficacy. Many assays are available for this purpose. However, a reference standard is lacking. Therefore, we evaluated the analytical performance, agreement and clinically relevant differences of three commercially available IFX ELISA kits on an automated processing system.
METHODS: The kits of Theradiag (Lisa Tracker Infliximab), Progenika (Promonitor IFX) and apDia (Infliximab ELISA) were implemented on an automated processing system. Imprecision was determined by triplicate measurements of patient samples on five days. Agreement was evaluated by analysis of 30 patient samples and four spiked samples by the selected ELISA kits and the in-house IFX ELISA of Sanquin Diagnostics (Amsterdam, The Netherlands). Therapeutic consequences were evaluated by dividing patients into four treatment groups using cut-off levels of 1, 3 and 7 μg/mL and determining assay concordance.
RESULTS: Within-run and between-run imprecision were acceptable (≤12% and ≤17%, respectively) within the quantification range of the selected ELISA kits. The apDia assay had the best precision and agreement to target values. Statistically significant differences were found between all assays except between Sanquin Diagnostics and the Lisa Tracker assay. The Promonitor assay measured the lowest IFX concentrations, the apDia assay the highest. When patients were classified in four treatment categories, 70% concordance was achieved.
CONCLUSIONS: Although all assays are suitable for TDM, significant differences were observed in both imprecision and agreement. Therapeutic consequences were acceptable when patients were divided in treatment categories, but this could be improved by assay standardization.

Gastroenterology. 2015 Nov 26.
Methotrexate is not superior to placebo for inducing steroid-free remission, but induces steroid-free clinical remission in a larger proportion of patients with ulcerative colitis.
Carbonnel F, Carbonne JF, Filippi J, et al.

BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC.
METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24.
RESULTS: Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)-a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group-a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006).
CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC.

J Pediatr Surg. 2015 Nov 6.
Colonic disease site and perioperative complications predict need for later intestinal interventions following intestinal resection in pediatric Crohn's disease.
Abdelaal K, Jaffray B.

INTRODUCTION: We studied variables associated with outcomes following intestinal resection for Crohn's disease.
METHODS: A retrospective review of a prospectively maintained single surgeon database was performed. Outcomes evaluated included disease recurrence, need for further resection/dilatation, and complications. Explanatory variables included: anatomical region of resection, open or laparoscopic approach, surgical procedure, technique of anastomosis, number of anastomoses, use of biological therapy, resection margin disease, age at resection, and period (quartile) in series.
RESULTS: 81 children had 100 resections at a median age 14.5years with a median follow-up of 7.7years. Overall complication rate was 22%. Of the 77 children with no prior resection, 40 (52%) had disease recurrence, and 24 (31%) underwent further resection or dilatation. None of the explanatory variables predicted complications. Disease recurrence was significantly associated with younger age at first resection but not duration of follow-up. The probability of further intestinal intervention was strongly associated with disease site and complications. Odds ratio for further surgery for colonic disease site compared to ileocecal disease site was 7 (95% CI 1.8-26; P=0.004). Odds ratio for further intestinal resection following surgery where a complication had occurred compared to no complication was 3.4 (95% CI 1.1-10.3; P=0.02. Both disease site and complication status also significantly affected the interval to further surgery.
CONCLUSIONS: The probability of requiring a second intestinal intervention for pediatric Crohn's disease is related to the disease site and the complication status.

J Pediatr Surg. 2015 Nov 6.
Colectomy in pediatric ulcerative colitis: A single center experience of indications, outcomes, and complications.
Ashton JJ, Versteegh HP, Batra A, et al.

BACKGROUND/PURPOSE: There is a paucity of data on outcomes and complications of colectomy for pediatric ulcerative colitis (UC). This study reports the experience of a regional center for 18 years.
METHODS: Patients were identified from a prospective database and data obtained by note review. Median height/weight-SDS were calculated preoperatively and postoperatively. Data are expressed as median values (range).
RESULTS: 220 patients with UC (diagnosed <17years) were identified, and 19 (9%) had undergone colectomy. Age at diagnosis was 11.6years (1.3-16.5), and 42% of patients were male. Time from diagnosis to surgery was 2.2years (0.1-13.1). All patients had failed maximal medical therapy. Fifteen patients had urgent scheduled operation, and 4 had emergency procedures, with 2 for (11%) acute-severe colitis (1 Clostridium difficile colitis) and 2 for acute-severe colitis with toxic dilatation. All initial procedures were subtotal-colectomy with ileostomy. Nine patients (47%) had early complications (during initial admission), 7 (37%) requiring reoperation. Six (32%) had late complications, with 5 requiring laparotomy. No patients had both early and late complications. Height-SDS was -0.27 before surgery and -0.23 (maximal follow-up). Weight-SDS was 0.32 and 0.05 (maximal follow-up).
CONCLUSION: Approximately 1/11 children with UC required colectomy during childhood. Half of patients had acute complications, and 1/3 of patients required another operation during their first admission. 1/3 of patients developed late complications.

Clin Gastroenterol Hepatol. 2015 Dec 2.
Increased postoperative mortality and complications among elderly patients with inflammatory bowel diseases: an analysis of the national surgical quality improvement program cohort.
Bollegala N, Jackson TD, Nguyen GC.

BACKGROUND & AIMS: Elderly patients may be at increased risk for poor outcomes after surgery for inflammatory bowel disease (IBD). We investigated postoperative mortality and the incidence of complications in elderly patients with IBD.
METHODS: We identified patients who underwent major IBD-related abdominal surgery using the American College of Surgeons National Surgical Quality Improvement Program Participant Use Files, from 2005 through 2012. We compared mortality and postoperative complications between elderly patients (≥65 years old) and nonelderly patients (<65 years="" old="" br=""> RESULTS: We identified 15,495 IBD patients who underwent surgery; of these, 1707 (11%) were elderly. Postoperative 30-day mortality was higher among elderly patients with Crohn's disease (CD) (4.2% vs 0.3% in nonelderly patients; P < .001) or ulcerative colitis (UC) (6.1% vs 0.7%; P < .001). After accounting for potential confounders, the adjusted odds ratio (aOR) of postoperative mortality in patients with CD was 11.67 (95% confidence interval [CI], 5.99-22.74), and in patients with UC was 4.39 (95% CI, 2.49-7.72). Postoperative complications were more common among elderly patients with CD (28.0% vs 19.4% in nonelderly patients; P < .001) or UC (39.3% vs 23.6% in elderly patients; P < .001). The aOR for any postoperative complication (excluding death) was 1.40 (95% CI, 1.16-1.69) in patients with CD and 1.74 for patients with UC (95% CI, 1.49-2.05). Elderly patients with UC were at increased risk for infectious complications, compared with nonelderly patients (aOR, 1.52; 95% CI, 1.27-1.82). The risk of postoperative venous thromboembolism was higher in elderly patients with CD (aOR, 1.68; 95% CI, 1.04-2.73). A higher proportion of elderly patients was still in the hospital more than 30 days after surgery (5.0% vs 1.8% for nonelderly patients; P < .001).
CONCLUSIONS: Elderly patients with IBD have substantially higher postoperative mortality and more complications than nonelderly patients with IBD. These increased risks should be considered when comparing risks of surgical vs medical therapy in this population.

Inflamm Bowel Dis. 2015 Dec 8.
Postoperative use of anti-TNF-α agents in patients with Crohn's disease and risk of reoperation-A nationwide cohort study.
Kjeldsen J, Nielsen J, Larsen MD, et al.

BACKGROUND: Approximately 80% of patients with Crohn's disease will require surgery. Surgery for Crohn's disease is not curative, and recurrence is typical. In this cohort study, based on nationwide Danish registries, we examined the association between postoperative treatment with anti-tumor necrosis factor α (anti-TNF-α) agents and reoperation.
METHODS: The association was examined in cohort 1 = patients not treated with anti-TNF-α agents within 6 months before operation, cohort 2 = patients treated with anti-TNF-α agents within 6 months before operation. Within both cohorts, we defined postoperative exposure to anti-TNF-α agents as at least 1 treatment within 6 months after the first operation and the reference cohorts were those not treated. Patients were followed from 6 months after operation and until 5 years. We used Cox proportional-hazards regression to compute adjusted hazard ratios with 95% confidence intervals.
RESULTS: In cohort 1, 31 (1.3%) were treated with anti-TNF-α agents within 6 months after operation and compared with those not treated, the adjusted hazard ratio of reoperation among those treated with anti-TNF-α agents was 3.53 (95% confidence interval: 1.61-7.72). In cohort 2, 63 (16.3%) were treated with anti-TNF-α agents within 6 months after operation, and the corresponding adjusted hazard ratio of reoperation was 2.16 (95% confidence interval: 1.11-4.18).
CONCLUSIONS: Our data suggest that anti-TNF-α treatment within 6 months after the first operation is not associated with a reduction in the need for subsequent operation. Uncontrolled confounding might have influenced our results, and, furthermore, future studies are warranted to clarify whether our study population is different from populations most often associated with postoperative anti-TNF-α treatment.

Clin Chim Acta. 2015 Dec 12;453:147-153.
Clinical laboratory application of a reporter-gene assay for measurement of functional activity and neutralizing antibody response to infliximab.
Pavlov IY, Carper J, Lázár-Molnár E, et al.

BACKGROUND: TNF-α antagonists such as infliximab are effective for the treatment of inflammatory bowel disease and other inflammatory and autoimmune diseases. Development of an immune response and subsequent neutralizing antibodies against these protein-based drugs is a major impediment that contributes to therapeutic failure, or adverse effects such as hypersensitivity reactions. As opposed to empirical dose-escalation strategies, rational and cost-effective evaluation of clinical non-responsiveness includes measurement of serum drug levels, and detection of drug-specific antibodies. We present the validation and 2-y experience using a functional, cell-based reporter gene assay (RGA) developed for measuring the biological activity and antibody response to serum infliximab.
METHODS: The RGA was used to test 4699 clinical specimens from patients suspected of therapeutic failure. In contrast to binding assays, which detect an overall antibody response, the RGA specifically detects those antibodies that have drug-neutralizing function, and thus, poses higher risk for therapeutic failure.
RESULTS: The RGA presented here is currently the only functional clinical test available to measure serum infliximab activity and neutralizing antibodies.
CONCLUSIONS: Due to its accuracy and precision, and suitability for high-throughput testing, this robust platform can be applied to any TNF-α antagonist, providing an invaluable tool for the clinical management of patients with treatment failure.