Publicações Recentes | 2015

Artigos completos disponíveis no PUBMED | Acesse pelo ano: 2016

  • Dezembro
  • Novembro
  • Outubro
  • Setembro
  • Agosto
  • Julho
  • Junho
  • Maio
  • Abril
  • Março
  • Fevereiro
  • Janeiro

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.

 

Saiba mais

Lancet. 2015 Sep 2.
Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial.
Khanna R, Bressler B, Levesque BG, et al.

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.


Lancet. 2015 Sep 3.
Crohn's disease: REACT to save the gut.
Singh S, Loftus EV Jr.

Cochrane Database Syst Rev. 2015 Oct 30;10:CD000067.
Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease.
Chande N, Patton PH, Tsoulis DJ, et al.

BACKGROUND: The therapeutic role of 6-mercaptopurine (6-MP) and azathioprine (AZA) remains controversial due to their perceived relatively slowacting effect and adverse effects. An updated meta-analysis was performed to evaluate the efficacy of these agents for the maintenance of remission in quiescent Crohn's disease.
OBJECTIVES : To assess the efficacy of AZA and 6-MP for maintenance of remission in quiescent Crohn's disease.
SEARCH METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library from inception to June 30, 2015.
SELECTION CRITERIA: Randomized controlled trials of oral azathioprine or 6-mercaptopurine compared to placebo or active therapy involving adult patients (> 18 years) with quiescent Crohn's disease were considered for inclusion. Patients with surgically-induced remission were excluded.
DATA COLLECTION AND ANALYSIS: At least two authors independently extracted data and assessed study quality using the Cochrane risk of bias tool. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (CI). The primary outcomes was maintenance of remission. Secondary outcomes included steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. All data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria.
MAIN RESULTS: Eleven studies (881 participants) were included. Comparisons included AZA versus placebo (7 studies, 532 participants), AZA or 6-MP versus mesalazine or sulfasalazine (2 studies, 166 participants), AZA versus budesonide (1 study, 77 participants), AZA and infliximab versus infliximab (1 study, 36 patients), 6-MP versus methotrexate (1 study, 31 patients), and early AZA versus conventional management (1 study, 147 participants). Two studies were rated as low risk of bias. Three studies were rated as high risk of bias for being non-blinded. Six studies were rated as unclear risk of bias. A pooled analysis of six studies (489 participants) showed that AZA (1.0 to 2.5 mg/kg/day) was significantly superior to placebo for maintenance of remission over a 6 to 18 month period. Seventy-three per cent of patients in the AZA group maintained remission compared to 62% of placebo patients (RR 1.19, 95% CI 1.05 to 1.34). The number needed to treat for an additional beneficial outcome was nine. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (327 events) and unclear risk of bias. A pooled analysis of two studies (166 participants) showed no statistically significant difference in the proportion of patients who maintained remission between AZA (1.0 to 2.5 mg/kg/day) or 6-MP (1.0 mg/day) and mesalazine (3 g/day) sulphasalazine (0.5 g/15 kg) therapy. Sixty-nine per cent of patients in the AZA/6-MP group maintained remission compared to 67% of mesalazine/sulphasalazine patients (RR 1.09, 95% CI 0.88 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (113 events) and high or unclear risk of bias. One small study found AZA (2.0 to 2.5 mg/kg/day) to be superior to budesonide (6 to 9 mg/day) for maintenance of remission at one year. Seventy-six per cent (29/38) of AZA patients maintained remission compared to 46% (18/39) of budesonide patients (RR 1.65, 95% CI 1.13 to 2.42). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (47 events) and high risk of bias. One small study found no difference in maintenance of remission rates at one year between combination therapy with AZA (2.5 mg/kg) and infliximab (5 mg/kg every 8 weeks) compared to infliximab monotherapy. Eighty-one per cent (13/16) of patients in the combination therapy group maintained remission compared to 80% (16/20) of patients in the infliximab group (RR 1.02, 95% CI 0.74 to 1.40). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (29 events) and unclear risk of bias. One small study found no difference in maintenance of remission rates at one year between 6-MP (1 mg/day) and methotrexate (10 mg/week). Fifty per cent (8/16) of 6- MP patients maintained remission at one year compared to 53% (8/15) of methotrexate patients (RR 0.94, 95% CI 0.47 to 1.85). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (16 events) and high risk of bias. One study (147 participants) failed to show any significant benefit for early azathioprine treatment over a conventional management strategy. In the early azathioprine treatment group 67% (11-85%) of the trimesters were spent in remission compared to 56% (29-73%) in the conventional management group. AZA when compared to placebo had significantly increased risk of adverse events (RR 1.29, 95% CI 1.02 to 1.64), withdrawal due to adverse events (3.12, 95% CI 1.59 to 6.09) and serious adverse events (RR 2.45, 95% CI 1.22 to 4.90). AZA/6-MP also demonstrated a significantly higher risk of serious adverse events when compared to mesalazine or sulphasalazine (RR 9.37, 95% CI 1.84 to 47.7). AZA/6-MP did not differ significantly from other active therapies with respect to adverse event data. Common adverse events included pancreatitis, leukopenia, nausea, allergic reaction and infection.
AUTHORS' CONCLUSIONS: Low quality evidence suggests that AZA is more effective than placebo for maintenance of remission in Crohn's disease. Although AZA may be effective for maintenance of remission its use is limited by adverse effects. Low quality evidence suggests that AZA may be superior to budesonide for maintenance of remission but because of small study size and high risk of bias, this result should be interpreted with caution. No conclusions can be drawn from the other active comparator studies because of low and very low quality evidence. Adequately powered trials are needed to determine the comparative efficacy and safety of AZA and 6-MP compared to other active maintenance therapies. Further research is needed to assess the efficacy and safety of the use of AZA with infliximab and other biologics and to determine the optimal management strategy for patients quiescent Crohn's disease.


Ann Pharmacother. 2015 Oct 27.
Methotrexate for the management of Crohn's disease in children.
Scherkenbach LA, Stumpf JL.

OBJECTIVE: To review the literature evaluating methotrexate as a treatment option for Crohn's disease (CD) in pediatric patients.
DATA SOURCES: A search of PubMed electronic database (1966 to August 2015) and secondary resources was performed using the terms methotrexate, Crohn's, and inflammatory bowel disease. Other relevant articles cited within identified articles were also utilized.
STUDY SELECTION AND DATA EXTRACTION: Data sources were limited to English-language studies that included children less than 18 years of age. In total, 10 clinical studies met the criteria.
DATA SYNTHESIS: Awareness of the risk of hepatosplenic T-cell lymphoma associated with anti-tumor necrosis factor and thiopurine therapies has renewed interest in methotrexate to treat CD in children. According to data from 10 predominantly retrospective studies, children treated with oral or subcutaneous methotrexate once weekly had remission rates of 25% to 53% at 1 year. Adverse effects most often included nausea and vomiting, elevated liver function tests, headache, and hematological toxicity. The evidence to support methotrexate is limited by inconsistent study design and poorly described dosage regimens. It has been most frequently evaluated in patients with prior thiopurine exposure and has not been thoroughly evaluated as first-line therapy.
CONCLUSIONS: Based on results of retrospective studies, methotrexate is useful in the treatment of pediatric CD in those who fail thiopurine therapy. Remission rates with methotrexate are similar to those for thiopurine therapy, although no studies directly compare these agents. Although preliminary results are promising, prospective studies are needed to assess the use of methotrexate as initial first-line therapy in the pediatric CD population.

J Crohns Colitis. 2015 Oct 27.
The Swedish Crohn Trial: a prematurely terminated randomized controlled trial of thiopurines or open surgery for primary treatment of ileocaecal Crohn's disease.
Gerdin L, Eriksson AS, Olaison G, et al.

BACKGROUND AND AIMS: The importance of efficient and safe treatment of Crohn's disease is highlighted by its chronicity. Both medical and surgical treatments have shown good results in the symptomatic control of limited ileocaecal Crohn's disease. The aim of this study was to compare medical treatment with surgical treatment of ileocaecal Crohn's disease.
METHODS: Thirty-six patients from seven hospitals with primary ileocaecal Crohn's disease were randomized to either medical or surgical treatment. The medical treatment was induction of remission with budesonide and thereafter maintenance treatment with azathioprine. The surgical treatment was open ileocaecal resection. Crohn's disease activity index over time, expressed as area under the curve at 1, 3 and 5 years, was the primary endpoint. Subjective health measured with the 36-item Short Form Survey Instrument (SF36) and a visual analogue scale (VAS) were secondary endpoints.
RESULTS: There were no differences between the treatment groups in Crohn's disease activity index over time. General health, measured as SF36 score, was higher in patients receiving surgical treatment than in those receiving medical treatment at 1 year, but there was no corresponding difference in VAS. Due to the slow inclusion rate and changes in clinical practice, the study was terminated prematurely. CONCLUSION: The study ended up being underpowered and should be interpreted with caution, but there was no clinically significant difference between the two treatment arms. Further studies are needed to address this important clinical question.


Clin Biochem. 2015 Oct 24.
Comparison of the Liaison® Calprotectin kit with a well-established point of care test (Quantum Blue - Bühlmann-Alere®) in terms of analytical performances and ability to detect relapses amongst a Crohn population in follow-up.
Delefortrie Q, Schatt P, Grimmelprez A, et al.

BACKGROUND: Although colonoscopy associated with histopathological sampling remains the gold standard in the diagnostic and follow-up of inflammatory bowel disease (IBD), calprotectin is becoming an essential biomarker in gastroenterology. The aim of this work is to compare a newly developed kit (Liaison® Calprotectin - Diasorin®) and its two distinct extraction protocols (weighing and extraction device protocol) with a well-established point of care test (Quantum Blue® - Bühlmann-Alere®) in terms of analytical performances and ability to detect relapses amongst a Crohn's population in follow-up.
METHODS: Stool specimens were collected over a six month period and were composed of control and Crohn's patients. Amongst the Crohn's population disease activity (active vs quiescent) was evaluated by gastroenterologists.
RESULTS: A significant difference was found between all three procedures in terms of calprotectin measurements (weighing protocol=30.3μg/g (median); stool extraction device protocol=36.9μg/g (median); Quantum Blue® (median)=63; Friedman test, P value=0.05). However, a good correlation was found between both extraction methods coupled with the Liaison® analyzer and between the Quantum Blue® (weighing protocol/extraction device protocol Rs=0.844, P=0.01; Quantum Blue®/extraction device protocol Rs=0.708, P=0.01; Quantum Blue®/weighing protocol, Rs=0.808, P=0.01). Finally, optimal cut-offs (and associated negative predictive values - NPV) for detecting relapses were in accordance with above results (Quantum Blue® 183.5μg/g and NPV of 100%>extraction device protocol+Liaison® analyzer 124.5μg/g and NPV of 93.5%>weighing protocol+Liaison® analyzer 106.5μg/g and NPV of 95%).
CONCLUSIONS: Although all three methods correlated well and had relatively good NPV in terms of detecting relapses amongst a Crohn's population in follow-up, the lack of any international standard is the origin of different optimal cut-offs between the three procedures.

Lancet. 2015 Oct 18.
Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.
Cleynen I, Boucher G, Jostins L, et al.

BACKGROUND: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.
METHODS: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile.
FINDINGS: After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10•5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1•65 × 10-78), even after exclusion of NOD2, MHC, and 3p21 (p=9•23 × 10-18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6•8 × 10-4).
INTERPRETATION: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time.


Cochrane Database Syst Rev. 2015 Oct 26;10:CD007698.
Oral budesonide for induction of remission in ulcerative colitis.
Sherlock ME, MacDonald JK, Griffiths AM, et al.

BACKGROUND: Corticosteroids are first-line therapy for induction of remission in ulcerative colitis. Although corticosteroids may improve symptoms, they have significant adverse effects. Steroids which act topically, with less systemic side-effects may be more desirable. Budesonide is a topically acting corticosteroid with extensive first pass hepatic metabolism. There are currently three formulations of budesonide: two standard formulations including a controlled-ileal release capsule and a pH-dependent capsule both designed to release the drug in the distal small intestine and right colon; and the newer Budesonide-MMX® capsule designed to release the drug throughout the entire colon.
OBJECTIVES: The primary objective was to evaluate the efficacy and safety of oral budesonide for the induction of remission in ulcerative colitis.
SEARCH METHODS: We searched MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD Group Specialised Register from inception to April 2015. We also searched reference lists of articles, conference proceedings and ClinicalTrials.gov.
SELECTION CRITERIA: Randomised controlled trials comparing oral budesonide to placebo or another active therapy for induction of remission in ulcerative colitis were considered eligible. There were no exclusions based on patient age or the type, dose, duration or formulation of budesonide therapy.
DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed studies for eligibility, extracted data and assessed study quality. Methodological quality was assessed using the Cochrane risk of bias tool. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. The primary outcome was induction of remission (as defined by the primary studies) at week eight. Secondary outcomes included clinical, endoscopic and histologic improvement, adverse events and early withdrawal. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome and the mean difference (MD) and corresponding 95% CI for each continuous outcome. Data were analysed on an intention-to-treat basis.
MAIN RESULTS: Six studies (1808 participants) were included. Four studies compared budesonide-MMX® with placebo, one small pilot study looked at clinical remission at week four, and was subsequently followed by three large, studies that assessed combined clinical and endoscopic remission at week eight. Although two placebo-controlled studies had mesalamine and Entocort (standard budesonide) treatment arms, these studies were not sufficiently powered to compare Budesonide-MMX® with these active comparators. One small study compared standard budesonide with prednisolone and one study compared standard budesonide to mesalamine. Four studies were rated as low risk of bias and two studies had an unclear risk of bias. A pooled analysis of three studies (900 participants) showed that budesonide-MMX® 9 mg was significantly superior to placebo for inducing remission (combined clinical and endoscopic remission) at 8 weeks. Fifteen per cent (71/462) of budesonide-MMX® 9 mg patients achieved remission compared to 7% (30/438) of placebo patients (RR 2.25, 95% CI 1.50 to 3.39). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (101 events). A subgroup analysis by concurrent mesalamine use suggests higher efficacy in the 442 patients who were not considered to be mesalamine-refractory (RR 2.89, 95% CI 1.59 to 5.25). A subgroup analysis by disease location suggests budesonide is most effective in patients with left-sided disease (RR 2.98, 95% CI 1.56 to 5.67; 289 patients). A small pilot study reported no statistically significant difference in endoscopic remission between budesonide and prednisolone (RR 0.75, 95% CI 0.23 to 2.42; 72 patients). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to unclear risk of bias and very sparse data (10 events). Standard oral budesonide was significantly less likely to induce clinical remission than oral mesalamine after 8 weeks of therapy (RR 0.72, 95% CI 0.57 to 0.91; 1 study, 343 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (161 events). Another study found no difference in remission rates between budesonide-MMX® 9 mg and mesalamine (RR 1.48, 95% CI 0.81 to 2.71; 247 patients). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (37 events). One study found no difference in remission rates between budesonide-MMX® 9 mg and standard budesonide 9 mg (RR 1.38, 95% CI 0.72 to 2.65; 212 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (32 events). Suppression of plasma cortisol was more common in prednisolone-treated patients (RR 0.02, 95% CI 0.0 to 0.33). While budesonide does appear to suppress morning cortisol to some extent, mean morning cortisol values remained within the normal range in 2 large studies (n = 899) and there was no difference in glucocorticoid-related side-effects across different treatment groups. Further, study withdrawal due to adverse events was not more common in budesonide compared with placebo treated patients (RR 0.85, 95% CI 0.53 to 1.38). Common adverse events included worsening ulcerative colitis, headache, pyrexia, insomnia, back pain, nausea, abdominal pain, diarrhoea, flatulence and nasopharyngitis.
AUTHORS' CONCLUSIONS: Moderate quality evidence to supports the use of oral budesonide-MMX® at a 9 mg daily dose for induction of remission in active ulcerative colitis, particularly in patients with left-sided colitis. Budesonide-MMX® 9 mg daily is effective for induction of remission in the presence or absence of concurrent 5-ASA therapy. Further, budesonide-MMX® appears to be safe, and does not lead to significant impairment of adrenocorticoid function compared to placebo. Moderate quality evidence from a single study suggests that mesalamine may be superior to standard budesonide for the treatment of active ulcerative colitis. Low quality evidence from one study found no difference in remission rates between budesonide MMX® and mesalamine. Very low quality evidence from one small study showed no difference in endoscopic remission rates between standard budesonide and prednisolone. Low quality evidence from one study showed no difference in remission rates between budesonide-MMX® and standard budesonide. Adequately powered studies are needed to allow conclusions regarding the comparative efficacy and safety of budesonide versus prednisolone, budesonide-MMX® versus standard budesonide and budesonide versus mesalamine.

 


J Crohns Colitis. 2015 Oct 29.
Donor species richness determines fecal microbiota transplantation success in inflammatory bowel disease.
Vermeire S, Joossens M, Verbeke K, et al.

 

BACKGROUND AND AIMS: Fecal microbiota transplantation is a successful therapy for patients with refractory Clostridium difficile infections. It has also been suggested as a treatment option for inflammatory bowel disease, given the role of the intestinal microbiota in this disease. We assessed the impact of fecal microbiota transplantation in patients with inflammatory bowel disease and studied predictors of clinical (non)response in microbial profiles of donors and patients.
METHODS: Fourteen refractory patients (8 ulcerative colitis and 6 Crohn's disease) underwent ileocolonoscopy with fecal microbiota transplantation through naso-jejunal (n=9) or rectal tube (n=5). Efficacy was assessed by endoscopic healing at week 8, clinical activity scores and C-reactive protein measurement. Fecal microbiota was analyzed by 16S rDNA pyrosequencing.
RESULTS: There was no significant improvement among the 6 patients with Crohn's disease at week 8 following fecal microbiota transplantation. One patient experienced temporary clinical remission for 6 weeks. In contrast, 2/8 patients with ulcerative colitis had endoscopic remission at week 8 and of the 6 remaining patients with ulcerative colitis, one reported temporary remission for 6 weeks. The donor microbiota richness and the number of transferred phylotypes were associated with treatment success. Persistent increased C-reactive protein two weeks after transplantation was predictive for failure of response.
CONCLUSION: Fecal microbiota transplantation led to endoscopic and long-term (> 2 years) remission in 2 out of 8 ulcerative colitis patients. Higher donor richness was associated with successful transplant. Therefore, fecal microbiota transplantation with donor pre-screening could be a treatment option for selected refractory ulcerative colitis patients.


Am J Gastroenterol. 2015 Oct 20.
Inflammatory bowel disease patients' willingness to accept medication risk to avoid future disease relapse.
Bewtra M, Fairchild AO, Gilroy E, et al.

OBJECTIVES: Biomarkers, endoscopy and imaging tests can identify patients at increased risk for early recurrence of symptomatic inflammatory bowel disease (IBD). However, patients may be unwilling to accept additional medical therapy risks related to therapy escalation to avoid a future disease relapse. We sought to quantify IBD patients' willingness to accept medication risk to avoid future disease relapse.
METHODS: We conducted a discrete-choice experiment among 202 patients with IBD who were offered choices of therapies with varying risks of lymphoma and infection, and varying time to next IBD relapse. Random parameters logit was used to estimate patients' willingness to accept tradeoffs among treatment features in selecting medication therapy to avoid future disease relapse.
RESULTS: To avoid a disease relapse over the next 5 years, IBD patients were willing to accept an average of a 28% chance of a serious infection; and an average of 1.8% chance of developing lymphoma. These results did not significantly change when patients were offered 10 years until their next disease relapse, but were lower (11 and 0.7%, respectively) when offered 1.5 years until the next disease relapse. Patients with active disease symptoms were significantly less willing to accept medication risk for time in remission.
CONCLUSIONS: IBD patients are willing to accept high levels of lymphoma and serious infection risk to maintain disease remission. These preferences are congruent with the treatment paradigms emphasizing mucosal healing and early aggressive therapy and highlight patients' strong preferences for therapies resulting in durable remission of at least 5 years.


J Crohns Colitis. 2015 Oct 31.
Impact of new treatments on hospitalisation, surgery, infection, and mortality in IBD: a focus paper by the Epidemiology Committee of ECCO.
Vito A, Dana D, Corinne GR, et al.

The medical management of inflammatory bowel disease has changed considerably over time with wider use of immunosuppressant therapy and the introduction of biologic therapy. To which extent this change of medical paradigms has influenced and modified the disease course is incompletely known. To address this issue an extensive review of the literature has been carried out on time trends of hospitalization, surgery, infections, cancer, and mortality rates in IBD patients. Preference was given to population-based studies, but when data from these sources were limited, large cohort studies and randomized controlled trials were also considered. In general, data on hospitalization rates are strikingly heterogeneous and conflicting. In contrast, the consistent drop in surgery/colectomy rates suggests that the growing use of immunosuppressants and biologic agents has had a positive impact on the course of IBD. Most clinical trial data indicate that the risk of serious infections is not increased in patients treated with anti-TNFα agents, but a different picture emerges from cohort studies. The use of thiopurines increases the risk for non-melanoma skin cancers and to a lesser extent for lymphoma and cervical cancer (absolute risk: low), whereas no clear increase in the cancer risk has been reported for anti-TNF agents. Finally, the majority of studies reported in the literature did not reveal any increase in mortality with immunosuppressant therapy or biologics/anti-TNF agent.


J Crohns Colitis. 2015 Oct 31.
Timing of thiopurine or anti-TNF initiation is associated with the risk of major abdominal surgery in Crohn's disease: a retrospective cohort study.
González-Lama Y, Suárez C, González-Partida I, et al.

INTRODUCTION: Early stages of Crohn's disease [CD] are predominantly inflammatory and early treatment could be useful to change the natural history of CD. We aimed to evaluate the impact of early treatment in our cohort of CD patients. METHODS: We retrospectively reviewed clinical records of all CD patients at our centre who have received immunomodulators. Time from diagnosis to first CD-related major abdominal surgery or end of follow-up was considered. Dates of diagnosis, of starting immunomodulators (thiopurines / anti-tumour necrosis factor [TNF]), and of the first CD-related surgery when appropriate were collected. RESULTS: Of 422 patients who received thiopurines, 189 operated patients started thiopurines after a median of 117 months (interquartile range [IQR] 44-196) since diagnosis; non-operated patients, after a median of 30 months [IQR 6-128], p < 0,005. Odds ratio [OR] for surgery was 1.006 (95% confidence interval [CI]1.004-1008) for each month of delay in starting thiopurines. Among 272 patients who received anti-TNFs, 137 operated patients started anti-TNFs after a median of 166 months [IQR 90-233] since diagnosis; non-operated patients after a median of 59 months [IQR 14-162]; p < 0,005. OR for surgery was 1.008 [95% CI 1.005-1.010] for each month of delay in starting anti-TNFs. Among 467 patients who received thiopurines and/or anti-TNF, 210 operated patients started any immunomodulator after a median of 120 months [IQR 48-197] since diagnosis and non-operated patients after a median of 30 months [IQR 6-126], p < 0,005. OR for surgery was 1.008 [95% CI 1.005-1.010] for each month of delay in starting immunomodulators. CONCLUSIONS: In our experience, time between diagnosis and thiopurine or anti-TNF initiation was associated with the risk of major abdominal surgery in Crohn's disease.


Clin Gastroenterol Hepatol. 2015 Oct 29.
Optimizing anti-TNFα therapy: serum levels of infliximab and adalimumab associate with mucosal healing in patients with inflammatory bowel diseases.
Ungar B, Levy I, Yavne Y, et al.

BACKGROUND & AIMS: It is not clear what serum levels of anti-tumor necrosis factor (anti-TNF) are associated with reduced intestinal inflammation in patients with inflammatory bowel diseases (IBD). We aimed to identify serum levels of infliximab and adalimumab associated with mucosal healing in patients with IBD and to evaluate the putative gain in control of inflammation by incremental increases in drug levels. METHODS: We performed a retrospective cross-sectional study of 145 patients with IBD treated with infliximab (n=78) or adalimumab (n=67) at a medical center in Israel from 2009 through 2014. We collected data from colonoscopy examinations; mucosal healing was defined as simple endoscopic score of <3 or="" a="" mayo="" score="" 1="" these="" data="" were="" compared="" with="" serum="" levels="" of="" anti-tnf="" agents="" clinical="" scores="" and="" c-reactive="" protein="" results:="" median="" infliximab="" adalimumab="" significantly="" higher="" in="" patients="" mucosal="" healing="" than="" active="" disease="" based="" on="" endoscopy="" for="" 4="" 3="" vs="" 7="" g="" ml="" p=".004)" 6="" 2="" above="" 5="" area="" under="" the="" curve="0.7," 0001="" identified="" 85="" specificity="" increasing="" beyond="" 8="" produced="" only="" minimal="" increases="" rate="" whereas="" association="" between="" level="" increased="" reached="" plateau="" at="" 12="" measurable="">3 μg/ml, the presence of antibodies to infliximab, was associated with a lower rate of mucosal healing compared to patients with similar drug level without antibodies (16% versus 50%, respectively, P=.003). CONCLUSIONS: In a retrospective study, we found significant association between serum levels of anti-TNF agents and level of mucosal healing. We propose that serum levels of 6-10 μg/ml for infliximab and 8-12 μg/ml for adalimumab are required to achieve mucosal healing in 80%-90% of patients with IBD, and that this could be considered as a "therapeutic window". Exceeding these levels produces only a negligible gain in proportion of patients with mucosal healing.


Inflamm Bowel Dis. 2015 Nov 3.
Calprotectin measured by patients at home using smartphones-a new clinical tool in monitoring patients with inflammatory bowel disease.
Vinding KK, Elsberg H, Thorkilgaard T, et al.

BACKGROUND: Fecal calprotectin is a reliable noninvasive marker for intestinal inflammation usable for monitoring patients with inflammatory bowel disease. Tests are usually performed by enzyme-linked immunosorbent assay (ELISA), which is time consuming and delays results, thus limiting its use in clinical practice. Our aim was to evaluate CalproSmart, a new rapid test for fecal calprotectin performed by patients themselves at home, and compare it to gold standard ELISA. METHODS: A total of 221 patients with inflammatory bowel disease (115 ulcerative colitis and 106 Crohn's disease) were included. The CalproSmart test involves extraction of feces, application to the lateral flow device, and taking a picture with a smartphone after 10 minutes of incubation. Results appear on the screen within seconds. Patients were instructed at inclusion and had a video guide of the procedure as support. When using CalproSmart at home, patients also sent in 2 fecal samples to be analyzed by ELISA. RESULTS: Totally, 894 fecal calprotectin results were obtained by ELISA, and 632 of them from CalproSmart. The correlation coefficient was 0.685, higher for academics than nonacademics (0.768 versus 0.637; P = 0.0037). The intra-assay and interassay coefficients of variation of the CalproSmart test were 4.42% and 12.49%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value were 82%, 85%, 47%, and 97%, respectively, with an optimal cutoff at 150 μg/g. CONCLUSIONS: The CalproSmart test performed by patients with inflammatory bowel disease for fast assessment of gut inflammation seems a reliable alternative to ELISA and presents a new way of monitoring patients by eHealth.


J Crohns Colitis. 2015 Nov 6.
De-escalation of infliximab maintenance therapy from 8- to 10-week dosing interval based on fecal calprotectin in patients with Crohn's disease.
Papamichael K, Karatzas P, Mantzaris GJ.

No abstract available.

Arch Dis Child. 2015 Nov 9.
Management of ulcerative colitis.
Fell JM, Muhammed R, Spray C, et al.

Ulcerative colitis (UC) in children is increasing. The range of treatments available has also increased too but around 1 in 4 children still require surgery to control their disease. An up-to-date understanding of treatments is essential for all clinicians involved in the care of UC patients to ensure appropriate and timely treatment while minimising the risk of complications and side effects. Ann Rheum Dis. 2015 Dec;74(12):2107-16. Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Winthrop KL, Novosad SA, Baddley JW, et al. No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.

 

Saiba mais

Digestion. 2015;91(2):158-63.
Disease duration did not influence the rates of loss of efficacy of the anti-TNF therapy in Latin American Crohn's disease patients.
Kotze PG, Ludvig JC, Teixeira FV, et al.

BACKGROUND/AIMS: The efficacy of both Infliximab (IFX) and Adalimumab (ADA) can be reduced over time. The aim of this study was to analyze the incidence of loss of efficacy (LOE) of both IFX and ADA, and outline the influence of disease duration on its occurrence.
METHODS: Retrospective, multicenter, observational cohort study, with CD patients treated with anti-TNF therapy. LOE was defined as the need for steroids, occurrence of major abdominal surgery during treatment, dose increase, interval shortening or switching of the anti- TNF agent. Patients were allocated in three subgroups based on disease duration (DD): '24 months, between 24 and 60 months and '60 months.
RESULTS: 175 patients were included in the study (117 under IFX and 58 under ADA therapy). LOE occurred in 32% of patients with DD <24 months="" in="" 33="" 3="" with="" dd="" between="" 24="" and="" 60="" 31="" of="" subjects="" over="" p="0.975)." br=""> CONCLUSIONS: Disease duration (DD) did not influence LOE rates. These results suggest that in real-world observational practice, patients with early CD might have the same rates of LOE than patients with a disease prolonging for a longer duration.


Inflamm Bowel Dis. 2015 Sep 29.
Anti-tumor necrosis factor-α antibody therapy management before and after intestinal surgery for inflammatory bowel disease: a CCFA position paper.
Holubar SD, Holder-Murray J, Flasar M, et al.

Biologic therapy with anti-tumor necrosis factor (TNF)-α antibody medications has become part of the standard of care for medical therapy for patients with inflammatory bowel disease and may help to avoid surgery in some. However, many of these patients will still require surgical intervention in the form of bowel resection and anastomosis or ostomy formation for the treatment of their disease. Postsurgical studies suggest up to 30% of patients with inflammatory bowel disease may be on or have used anti-TNF-α antibody medications for disease management preoperatively. Significant controversy exists regarding the potential deleterious impact of these medications on the outcomes of surgery, specifically overall and/or infectious complications. In this position statement, we systematically reviewed the literature regarding the potential risk of anti-TNF-α antibody use in the perioperative period, offer recommendations based both on the best-available evidence and expert opinion on the use and timing of anti-TNF-α antibody therapy in the perioperative period, and discuss whether or not the presence of these medications should lead to an alteration in surgical technique such as temporary stoma formation.


J Crohns Colitis. 2015 Oct 4.
Mucosal healing in ulcerative colitis - when zero is better.
Boal Carvalho P, Dias de Castro F, Rosa B, et al.

BACKGROUND AND AIMS: Extensive evidence has underlined the importance of mucosal healing as a treatment aim for ulcerative colitis (UC). We aimed to assess differences in the incidence of clinical relapse at 12 months between UC patients with Mayo endoscopic scores (MES) 0 and 1.
METHODS: Retrospective study, including consecutive patients in corticosteroid-free remission between 2008 and 2013 and follow-up of at least one year, with MES 0 or 1 in complete colonoscopy. Clinical relapse was defined as need for induction treatment, treatment escalation, hospitalization or surgery. A p value < 0,05 was considered statistically significant.
RESULTS: Included 138 patients, 72 (52,2%) female, with mean age 49 (±14) years. Inflammatory activity was classified as MES 0 in 61 (44,2%) patients and MES 1 in 77 (55,8%) patients. Clinical relapse during follow-up was significantly more frequent in patients with MES 1 than MES 0 (27,3 versus 11,5%; p=0,022), and in the multivariate analysis, MES 1 was the only factor significantly associated with an increased risk of relapse (OR=2,89 CI 95% 1,14-7,36; p=0,026). This association was encountered in the subgroup of patients with left-sided/extensive colitis (29,7 versus 11,1%; p=0,049), but not proctitis (25,0% versus 12,0%, p=0,202).
CONCLUSIONS: In patients with ulcerative colitis in corticosteroid-free remission, particularly those with left sided colitis or extensive colitis, MES 1 was significantly associated with a threefold increased risk of relapse compared to endoscopic MES 0. Our results support the use of endoscopic MES 0 as the most suitable treatment endpoint to define mucosal healing in patients with UC.


J Crohns Colitis. 2015 Sep 20.
Efficacy and safety of adalimumab in ulcerative colitis refractory to conventional therapy in routine clinical practice.
Bálint A, Farkas K, Palatka K, et al.

BACKGROUND AND AIM: Adalimumab [ADA] was approved for the treatment of ulcerative colitis [UC] refractory to conventional therapy in 2012 in Europe. Due to the observed discrepancies between clinical trials and practice, data on the outcome of ADA therapy are really needed from the real life. The aim of this study was to estimate the short- and long-term efficacy and safety of ADA in UC patients from each Hungarian biological centre.
PATIENTS AND METHODS: This prospective study consisted of UC patients treated with ADA in 10 Hungarian inflammatory bowel disease centres. The primary endpoints of the study were rates of continuous clinical response, remission, non-response and loss of response at Weeks 12, 30, and 52.The secondary endpoints included mucosal healing at Week 52 and the comparison of the efficacy of ADA between biological naive and infliximab [IFX]-treated groups. Colonoscopy was performed before starting the therapy and at Week 52.
RESULTS: In all, 73 active UC patients were enrolled in the study: 67.1% of the patients received previous IFX therapy; 75.3% of the patients showed short-term clinical response at Week 12. The probability of maintaining ADA was 48.6% at Week 52 with a continuous clinical response in 92% of these remaining patients. Mucosal healing was achieved in 48.1% of the patients at Week 52. Escalation of ADA was performed in 17.6%, and minor side effects developed in 4% of the patients; 5.4% of the patients underwent colectomy during the 1-year treatment period.
CONCLUSION: UC is a progressive disease that may need early aggressive therapy to prevent structural and functional complications. The results of our study demonstrated the favourable efficacy of short- and long-term ADA treatment for patients with UC.


World J Gastroenterol. 2015 Oct 7;21(37):10654-61.
Histological healing after infliximab induction therapy in children with ulcerative colitis.
Wiernicka A, Szymanska S, Cielecka-Kuszyk J, et al.

AIM: To verify the impact of induction therapy with infliximab (IFX) on mucosal healing in children with ulcerative colitis (UC).
METHODS: The study included all UC pediatric patients treated with IFX at our center over the last 10 years. The data were collected from patients' medical charts and analyzed retrospectively. A total of 16 patients with UC underwent colonoscopy with sample collection before and after three IFX injections. Pediatric Ulcerative Colitis Activity Index (PUCAI) was used to assess the clinical condition; endoscopic features were classified according to the Baron scale; and histological changes were evaluated according to the protocol of The British Society of Gastroenterology and Geboes Index. Clinical response was defined as a ≥ 20-point reduction in PUCAI index, and clinical remission as PUCAI index < 10 points. Endoscopic mucosal remission was defined as completely normal (score 0) on the Baron scale. Histological remission was defined as grade 0 in the Geboes Index. To assess correlation between variables, Spearman's rank correlation coefficient was used.
RESULTS: Clinical remission (PUCAI < 10) at week 8 was achieved in 68.75% of investigated subjects. Endoscopic mucosal remission at week 8 (Baron 0) was observed in 12.5% of patients. Histological remission (Geboes 0) after induction therapy with IFX was noticed in 18.75% cases. A general histological improvement, expressed by normal surface and crypt architecture, number of crypts, and lamina propria cellularity, was observed in six (37.5%) patients; there was no improvement in nine (56.25%) individuals, and worsening was observed in one (3.75%) case. Changes were not related to UC location. A reduction of inflammatory process was observed in 10 (62.5%) patients; there were no changes in four (25%) individuals, and the inflammation became more severe in two (12.5 %) cases. Simultaneous clinical, endoscopic and histological improvement of parameters assessing disease activity at week 8 was noticed in six (37.5%) patients. 55.5% of investigated patients with normal mucosa seen on endoscopy showed no inflammation on histology. A Baron score of 2 and 3 showed a good correlation with histology results (78.2% of patients with a Geboes Index ≥ 3).
CONCLUSION: IFX has a positive histological effect in more than one-third of UC patients. IFX reduces intestinal inflammation and improves clinical condition.


Gut. 2015 Oct 16.
Development and validation of a histological index for UC.
Mosli MH, Feagan BG, Zou G, et al.

OBJECTIVE: Although the Geboes score (GS) and modified Riley score (MRS) are commonly used to evaluate histological disease activity in UC, their operating properties are unknown. Accordingly, we developed an alternative instrument.
DESIGN: Four pathologists scored 48 UC colon biopsies using the GS, MRS and a visual analogue scale global rating. Intra-rater and inter-rater reliability for each index and individual index items were measured using intraclass correlation coefficients (ICCs). Items with high reliability were used to develop the Robarts histopathology index (RHI). The responsiveness/validity of the RHI and multiple histological, endoscopic and clinical outcome measures were evaluated by analyses of change scores, standardised effect size (SES) and Guyatt's responsiveness statistic (GRS) using data from a clinical trial of an effective therapy.
RESULTS: Inter-rater ICCs (95% CIs) for the total GS and MRS scores were 0.79 (0.63 to 0.87) and 0.80 (0.69 to 0.87). The correlation estimates between change scores in RHI and change score in GS and MRS were 0.75 (0.67 to 0.82) and 0.84 (0.79 to 0.88), respectively. The SES and GRS estimates for GS, MRS and RHI were: 1.87 (1.54 to 2.20) and 1.23 (0.97 to 1.50), 1.29 (1.02 to 1.56) and 0.88 (0.65 to 1.12), and 1.05 (0.79 to 1.30) and 0.88 (0.64 to 1.12), respectively.
CONCLUSIONS: The RHI is a new histopathological index with favourable operating properties


Gut. 2015 Oct 13.
Development and validation of the Nancy histological index for UC.
Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, et al.

OBJECTIVE: We developed a validated index for assessing histological disease activity in UC and established its responsiveness.
METHODS: Two hundred biopsies were scored. The outcome was the Global Visual Evaluation (GVE). Eight histological features were tested. The Nancy index was developed by multiple linear regression and bootstrap process to create an index that best matched the GVE. Goodness of fit was assessed by the adjusted R squared (adjusted R2). The second step was the validation of the index: 100 biopsies were scored for the Nancy index by three pathologists from different centres. Inter-reader reliability was evaluated for each reader. The relationship between the change of the Nancy index and the Geboes index was assessed to assess the responsiveness.
RESULTS: After backward selection with bootstrap validation, 3/8 items were selected: ulceration (adjusted R2=0.55), acute inflammatory infiltrate (adjusted R2=0.88) and chronic inflammatory infiltrate (adjusted R2=0.79). The Nancy index is defined by a 5-level classification ranging from grade 0 (absence of significant histological disease activity) to grade 4 (severely active disease). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.88 (95% CI 0.82 to 0.92) and the index had good inter-reader reliability (ICC=0.86 (0.81 to 0.99)). The correlation between the Nancy index and the Geboes score or the GVE was very good. The index had a good responsiveness with a high correlation between changes in the Geboes score and changes in the Nancy index (0.910 (0.813 to 0.955)).
CONCLUSIONS: A three descriptor histological index has been validated for use in clinical practice and clinical trials.


Rheumatology (Oxford). 2015 Nov;54(11):1941-3.
Measurement of anti-drug antibodies to biologic drugs.
Felis-Giemza A, Moots RJ.

No abstract available.


 

Saiba mais

Inflamm Bowel Dis. 2015 Aug 12.
New insights into the mechanisms of action of anti-tumor necrosis factor-α monoclonal antibodies in inflammatory bowel disease.
Slevin SM, Egan LJ.

Tumor necrosis factor alpha (TNF-α) has been widely accepted as a therapeutic target for inflammatory disorders including inflammatory bowel disease. Anti-TNF-α monoclonal antibodies (mAbs) including infliximab, adalimumab, golimumab, and certolizumab pegol have revolutionized therapy for these chronic inflammatory disorders. These agents are potent inhibitors of TNF-α, but significant evidence points to the fact that their actions extend beyond simple neutralization of the cytokine. Recent advances in understanding the mechanism of action of anti-TNF-α mAbs has discovered a number of previously unrecognized actions that are likely to be relevant in mediating their anti-inflammatory effects. Many of those actions are mediated by the binding of the antibodies to transmembrane TNF-α (tmTNF-α) and involve complex interactions with other molecular factors and cells. In this review, we have highlighted new information on the mechanism of actions of anti-TNF-α mAbs, from in vitro and in vivo studies. Despite obvious benefits in many patients, the clinical use of these antibodies are hampered by the fact that some patients do not respond to them, and among patients who do respond, many will develop recurrent disease despite continued dosing. Although pharmacokinetic factors explain some of the observed cases of partial or complete resistance to the effects of anti-TNF-α mAbs, other nonresponder patients may be resistant to those agents mechanism of action. A more thorough understanding of the mechanism of action of anti-TNF-α mAbs may allow the development of strategies to individualize therapy and to overcome resistance.

 


Rev Esp Enferm Dig. 2015 Sep;107(9):527-533.
Frequency, predictors, and consequences of maintenance infliximab therapy intensification in ulcerative colitis.
Fernández-Salazar L, Barrio J, Muñoz F, et al.

INTRODUCTION: Infliximab (IFX) therapy intensification in ulcerative colitis (UC) is more common than established in pivotal studies.
OBJECTIVES: To establish the frequency and form of intensification for UC in clinical practice, as well as predictors, and to compare outcomes between intensified and non-intensified treatment.
METHODS: A retrospective study of 10 hospitals and 144 patients with response to infliximab (IFX) induction. Predictive variables for intensification were analyzed using a Cox regression analysis. Outcome, loss of response to IFX, and colectomy were compared between intensified and non-intensified therapy.
RESULTS: Follow-up time from induction to data collection: 38 months [interquartile range (IQR), 20-62]. Time on IFX therapy: 24 months (IQR, 10-44). In all, 37% of patients required intensification. Interval was shortened for 36 patients, dose was increased for 7, and 10 subjects received both. Concurrent thiopurine immunosuppressants (IMM) and IFX initiation was an independent predictor of intensification [Hazard ratio, 0.034; p, 0.006; CI, 0.003-0.371]. In patients on intensified therapy IFX discontinuation for loss of response (30.4% vs. 10.2%; p, 0.002), steroid reintroduction (35% vs. 18%; p, 0.018), and colectomy (22% vs. 6.4%; p, 0.011) were more common. Of patients on intensification, 17% returned to receiving 5 mg/kg every 8 weeks.
CONCLUSIONS: Intensification is common and occasionally reversible. IMM initiation at the time of induction with IFX predicts non-intensification. Intensification, while effective, is associated with poorer outcome.


Inflamm Bowel Dis. 2015 Oct;21(10):E25.
Is diffusion-weighted magnetic resonance imaging for assessing Crohn's disease ready for prime time? Experience with the Nancy score.
Peyrin-Biroulet L, Laurent V.
No abstract available.


Gastroenterology. 2015 Sep 14.
Systematic review of effects of withdrawal of immunomodulators or biologic agents from patients with inflammatory bowel disease.
Torres J, Boyapati RK, Kennedy N, et al.

Little is known about the optimal duration of therapy with an anti-tumor necrosis factor (TNF) agent and/or an immunomodulator for patients with inflammatory bowel disease (IBD). We performed a systematic search of the literature to identify studies reporting after de-escalation (drug cessation or dose reduction) of anti-TNF agents and/or immunomodulators in patients in remission from IBD. Studies were reviewed according to the type of IBD and drug. Rates of relapse, factors associated with relapse, and response to re-treatment were determined. Our search yielded 6315 unique citations; we analyzed findings from 69 studies (18 on de-escalation (drug cessation or dose reduction) of immunomodulator monotherapy, 8 on immunomodulator de-escalation from combination therapy, and 43 on de-escalation of anti-TNF agents, including 3 during pregnancy) comprising 4672 patients. Stopping immunomodulator monotherapy after a period of remission was associated with high rates of relapse in patients with Crohn's disease or ulcerative colitis (around 75% relapse by 5 years after therapy was stopped). Most studies of patients with Crohn's disease who discontinued the immunomodulator after combination therapy found that rates of relapse did not differ from those of patients who continued taking the drug (55%-60% had disease relapse 24 months after they stopped taking the immunomodulator). The only study in patients with ulcerative colitis supported continued immunomodulator use. Approximately 50% of patients who discontinued anti-TNF agents after combination therapy maintained remission 24 months later, but the proportion in remission decreased with time. Markers of disease activity, poor prognostic factors, and complicated or relapsing disease course were associated with future relapse. In conclusion, based on a systematic review, 50% or more of patients with IBD who cease therapy have a disease relapse. Further studies are required to accurately identify subgroups of patients who are good candidates for discontinuation of treatment. The decision to withdraw a drug should be made for each individual based on patient preference, disease markers, consequences of relapse, safety, and cost.


Dig Dis. 2015 Sep 14;33 Suppl 1:95-104.
Targeting leukocyte trafficking in inflammatory bowel disease: what is the clinical evidence?
Khanna R, Mosli MH, Feagan BG.

Since the cause of inflammatory bowel disease (IBD) is unknown, therapy has traditionally been based on the empiric use of anti-inflammatory drugs. However, the recent identification of specific mechanisms that regulate cellular migration into inflamed intestinal tissue has provided novel targets for drug development. In this article, we discuss these mechanisms and review emerging safety and efficacy data regarding use of selective inhibitors of leukocyte trafficking for the treatment of IBD.


Gut. 2015 Sep 9.
IOIBD technical review on endoscopic indices for Crohn's disease clinical trials.
Vuitton L, Marteau P, Sandborn WJ, et al.

BACKGROUND: Crohn's disease (CD) is a chronic disabling and progressive IBD. Only strategies looking beyond symptoms and based on tight monitoring of objective signs of inflammation such as mucosal lesions may have the potential for disease modification. Endoscopic evaluation is currently the gold standard to assess mucosal lesions and has become a major therapeutic endpoint in clinical trials. Several endoscopic indices have been proposed to evaluate disease activity; unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response and endoscopic remission in CD.

METHODS: In these recommendations from the International Organization for the Study of Inflammatory Bowel Disease, we first reviewed all technical aspects of available endoscopic scoring systems in the literature. Second, in order to achieve consensus on endoscopic definitions of remission and response in trials, a two-round vote based on a Delphi method was performed among 14 specialists in the field of IBDs.

RESULTS: At the end of the voting process, the investigators ranked first a >50% decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) or Crohn's Disease Endoscopic Index of Severity for the definition of endoscopic response, and an SES-CD 0-2 for the definition of endoscopic remission in CD. All experts agreed on a Rutgeerts' score i0-i1 for the definition of endoscopic remission after surgery. J Crohns Colitis. 2015 Sep 7.]


A matrix-based model predicts primary response to infliximab in Crohn's disease.
Billiet T, Papamichael K, de Bruyn M, et al.

BACKGROUND: Prediction of primary non-response [PNR] to anti-tumour necrosis factors [TNFs] in inflammatory bowel disease [IBD] is direly needed to select the optimal therapeutic class for a given patient. We developed a matrix-based prediction tool to predict response to infliximab [IFX] in Crohn's disease [CD] patients.

METHODS: This retrospective single-centre study included 201 anti-TNF naïve CD patients who started with IFX induction therapy. PNR occurred in 16 [8%] patients. Clinical, biological [including serum TNF and the IBD serology 6 panel and genetic [the 163 validated IBD risk loci] markers were collected before start. Based on the best fitted regression model, probabilities of primary response to IFX were calculated and arranged in a prediction matrix tool.

RESULTS: Multiple logistic regression withheld three final independent predictors [p < 0.05] for PNR: age at first IFX, {odds ratio (OR) (95% confidence interval [CI] of 1.1 (1.0-1.1)}, body mass index [BMI] (0.86 [0.7-1.0]), and previous surgery (4.4 [1.2-16.5]). The accuracy of this prediction model did not improve when the genetic markers were added (area under the curve [AUC] from 0.80 [0.67-0.93] to 0.78 [0.65-0.91]). The predicted probabilities for PNR to IFX increased from 1% to 53% depending on the combination of final predictors.

CONCLUSIONS: Readily available clinical factors [age at first IFX, BMI, and previous surgery] outperform serological and IBD risk loci in prediction of primary response to infliximab in this real-life cohort of CD patients. This matrix tool could be useful for guiding physicians and may avoid unnecessary or inappropriate exposure to IFX in IBD patients unlikely to benefit.


Aliment Pharmacol Ther. 2015 Sep 3.
Randomised clinical study: discrepancies between patient-reported outcomes and endoscopic appearance in moderate to severe ulcerative colitis.
Jharap B, Sandborn WJ, Reinisch W, et al.

BACKGROUND: Associations between patient-reported outcomes and mucosal healing have not been established in ulcerative colitis (UC).

AIM: To evaluate relationships of rectal bleeding and stool frequency with mucosal healing and quality of life (QoL) in patients with UC in two Phase 3 studies (ULTRA 1 and 2).

METHODS: Associations of patient-reported rectal bleeding and stool frequency subscores with mucosal healing (Mayo endoscopy subscore = 0 or 0/1) and QoL [inflammatory bowel disease questionnaire (IBDQ)] were assessed in adalimumab-randomised patients (160/80 mg at Weeks 0/2 followed by 40 mg biweekly or weekly) at Weeks 8 (n = 433) and 52 (n = 299), and in patients with mucosal healing [endoscopy subscore = 0 (n = 17); 0/1 (n = 52)] at Weeks 8 and 52.

RESULTS: At Week 8, the positive predictive values (PPVs) of rectal bleeding subscore = 0, stool frequency subscore = 0 or both scores = 0 for endoscopy subscore = 0/1 were 69%, 84% and 90% respectively; all proportions increased at Week 52. Equivalent PPVs for these subscores in patients with endoscopy subscore = 0 were 26%, 37% and 46% respectively. Among patients with endoscopy subscore = 0 at Week 8, 87% reported no rectal bleeding, while only 29% reported normal stool frequency; these proportions had increased to 94% and 41% respectively, at Week 52. Among patients with mucosal healing, IBDQ scores trended highest for patients with both rectal bleeding and stool frequency subscores = 0.

CONCLUSIONS: Absence of rectal bleeding and normal stool frequency are often predictive of mucosal healing and QoL, but complete normalisation of stool frequency is encountered rarely in patients with mucosal healing.


Aliment Pharmacol Ther. 2015 Sep 10. [Epub ahead of print]
The outcome of infliximab dose doubling in 157 patients with ulcerative colitis after loss of response to infliximab.
Dumitrescu G, Amiot A, Seksik P, et al.

BACKGROUND: Optimising infliximab therapy is recommended in inflammatory bowel disease (IBD) patients who lose response to infliximab; however, there are no data on the outcome of ulcerative colitis (UC) patients after doubling the dose.

AIM: To determine the efficacy and safety of infliximab dose doubling in UC patients with a loss of response to infliximab.

METHODS: From January 2006 to May 2013, we retrospectively reviewed the outcome of the consecutive UC patients who were treated with infliximab dose doubling (10 mg/kg) for loss of response in four French academic centres. The clinical response and remission were assessed. A composite event-free survival analysis was performed using the log-rank test and the Cox model.

RESULTS: One hundred and fifty-seven patients [84 males; median age 37. 6 (IQR 28.2-49.4) years] were included. The median follow-up after infliximab dose doubling was 1.8 (1.0-3.1) years. At weeks 8 and 24, 55% and 43% of the patients achieved a clinical response respectively. The probabilities of the event-free survival were 71%, 61% and 55% at 6 months, 1 year and 2 years respectively. In the multivariate analysis, the predictors of infliximab dose doubling failure were the absence of the introduction of an immunomodulator concomitantly to dose doubling, a partial Ulcerative Colitis Disease Activity Index >6, a C-reactive protein level >10 mg/L, a leucocyte count >8000/mm3 and a haemoglobin level <12.5 g="" dl="" adverse="" events="" were="" reported="" in="" 12="" patients="" 8="" p="">

CONCLUSIONS: Infliximab dose doubling led to short- and long-term event-free survival in UC patients, who had a loss of response to infliximab, in greater than 50% of the cases. The benefits of such a strategy were significantly improved by adding a concomitant immunomodulator.


J Crohns Colitis. 2015 Sep 7.
Evaluation of the risk of relapse in ulcerative colitis according to the degree of mucosal healing (Mayo 0 vs 1): a longitudinal cohort study.
Barreiro-de Acosta M, Vallejo N, de la Iglesia D, et al.

BACKGROUND AND AIMS: Mucosal healing in ulcerative colitis (UC) has become a common endpoint in most clinical trials and a relevant therapeutic goal in clinical practice. Despite important differences between endoscopic Mayo scores 0 and 1, both scores are considered as mucosal healing in most important trials. The aim of the present study was to evaluate the risk of relapse in UC patients according to the degree of mucosal healing (endoscopic Mayo scores of 0 and 1).

METHODS: A prospective longitudinal cohort study was designed. All UC patients who presented with mucosal healing at colonoscopy were consecutively included. Mucosal healing was defined as an endoscopic Mayo score of 0 or 1. Clinical relapse was defined as the need for therapy to induce remission, any treatment escalation, hospitalization or colectomy. All clinical relapses were evaluated at months 6 and 12 after study entry. Results were subjected to unconditional stepwise logistic and Kaplan-Meier regression analysis. RESULTS: One hundred and eighty-seven consecutive UC patients (126 [67.3%] with Mayo score 0 and 61 [32.7%] with Mayo score 1) were included. Of patients with Mayo scores 0 and 1, 9.4 and 36.6% respectively presented a relapse during the first 6 months of follow-up (p < 0.001). The only factor independently associated with UC relapses in the multivariate analysis was an endoscopic Mayo score of 1 (odds ratio6.27, 95% confidence interval 2.73-14.40, p < 0.001).

CONCLUSIONS: Patients with an endoscopic Mayo score of 1 have a higher risk of relapse than those with a score of 0. The concept of mucosal healing should be limited to patients with an endoscopic Mayo score of 0.


Ann Rheum Dis. 2015 Sep 22.
Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance.
Winthrop KL, Novosad SA, Baddley JW, et al.

No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.


Inflamm Bowel Dis. 2015 Sep 9.
Mortality and causes of death in ulcerative colitis: results from 20 years of follow-up in the IBSEN study.
Hovde Ø, Småstuen MC, Høivik ML, et al.

BACKGROUND: The best way to obtain knowledge about the natural history, including mortality, of ulcerative colitis (UC) is to conduct a longitudinal, population-based, prospective study. The aims of this study were to calculate the mortality rates and causes of death in patients with UC. METHODS: A prospective, population-based, longitudinal cohort study was conducted in South-Eastern Norway. A total of 519 patients (51.4% men) with UC were included over a 4-year period. A gastroenterologist from a university hospital reviewed the clinical information of all of the patients. Mortality data were retrieved from the Cause of Death Registry and from Statistics Norway. RESULTS: No statistically significant increases in total mortality or cause-specific mortality between the patients with UC and the controls were found. CONCLUSIONS: The present 20-year population-based cohort study revealed a good prognosis regarding the mortality, which partially might be explained by the patients' coverage by a generally well-functioning health care system.


Aliment Pharmacol Ther. 2015 Sep 13. [Epub ahead of print]
Review article: pharmacological aspects of anti-TNF biosimilars in inflammatory bowel diseases.
Papamichael K, Van Stappen T, Jairath V, et al.

BACKGROUND: Anti-tumour necrosis factor (anti-TNF) monoclonal antibodies have shown efficacy in inflammatory bowel diseases (IBD). As these therapies lose patent protection, biosimilar versions of the originator products are being developed, such as the infliximab biosimilar CT-P13; however, some uncertainty exists regarding their pharmacology in IBD.

AIM: To review the literature on anti-TNF biosimilars focusing on pharmacokinetics, pharmacodynamic properties and comparative effectiveness, related to their use in IBD.

METHODS: A PubMed literature search was performed using the following terms individually or in combination: 'biosimilars,' 'CT-P13,' 'Crohn's disease,' 'inflammatory bowel disease,' 'ulcerative colitis,' 'anti-TNFα therapy,' 'infliximab,' 'adalimumab,' 'pharmacokinetics,' 'immunogenicity.'

RESULTS: Bioequivalence of CT-P13 and infliximab was shown in ankylosing spondylitis (AS) and therapeutic equivalence in rheumatoid arthritis (RA). Preliminary results of CT-P13 in IBD come from small post-marketing registries and case series with a relatively short-term follow-up period and suggest comparable efficacy and safety to infliximab. Inter- and intra-individual differences in exposure and response are well known for the original molecules but dosing regimens and concomitant medications are different for RA compared to IBD, limiting the ability to translate some of the pharmacology data in RA to IBD. Uncertainty exists about cross-reactivity of anti-drug antibodies and whether similar exposure-response relationships will be observed for biosimilars and efficacy thresholds for therapeutic drug monitoring can be used interchangeably.

CONCLUSIONS: It is likely that biosimilars will be widely used for the treatment of IBD due to their cost savings and comparable efficacy. Nevertheless, robust post-marketing studies and pharmacovigilance are warranted in the coming years.

 

Saiba mais

J Autoimmun. 2015 Aug 6.
Understanding inflammatory bowel disease via immunogenetics.
de Lange KM, Barrett JC.

The major inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are both debilitating disorders of the gastrointestinal tract, characterized by a dysregulated immune response to unknown environmental triggers. Both disorders have an important and overlapping genetic component, and much progress has been made in the last 20 years at elucidating some of the specific factors contributing to disease pathogenesis. Here we review our growing understanding of the immunogenetics of inflammatory bowel disease, from the twin studies that first implicated a role for the genome in disease susceptibility to the latest genome-wide association studies that have identified hundreds of associated loci. We consider the insight this offers into the biological mechanisms of the inflammatory bowel diseases, such as autophagy, barrier defence and T-cell differentiation signalling. We reflect on these findings in the context of other immune-related disorders, both common and rare. These observations include links both obvious, such as to pediatric colitis, and more surprising, such as to leprosy. As a changing picture of the underlying genetic architecture emerges, we turn to future directions for the study of complex human diseases such as these, including the use of next generation sequencing technologies for the identification of rarer risk alleles, and potential approaches for narrowing down associated loci to casual variants. We consider the implications of this work for translation into clinical practice, for example via early therapeutic hypotheses arising from our improved understanding of the biology of inflammatory bowel disease. Finally, we present potential opportunities to better understand environmental risk factors, such as the human microbiota in the context of immunogenetics.


J Crohns Colitis. 2015 Jul 29. [Epub ahead of print]
Benefit for earlier anti-TNF treatment on IBD disease complications?
Nuij VJ, Fuhler GM, Edel MJ, et al.

BACKGROUND: Anti-Tumor Necrosis Factor (anti-TNF) treatment was demonstrated to have disease modifying abilities in IBD. With this study, we aimed to determine the effect of anti-TNF timing on IBD-disease complications and mucosal healing (MH).

METHODS: The following IBD-related complications were tested in relation to timing of anti-TNF therapy start in newly diagnosed IBD patients (n=413): fistula formation, abscess formation, EIM, surgery, referral to academic center and MH. RESULTS: Eighty-five patients (21%) received anti-TNF (66 CD, 16 UC, 3 IBDU) of whom 57% (48 pts) < 16 months after diagnosis. Patients receiving anti-TNF early (<16 months="" did="" not="" differ="" from="" patients="" receiving="" anti-tnf="" late="">16 months) regarding gender, age, smoking status and familial IBD. More importantly, patients receiving anti-TNF early did not suffer less IBD-related complications during follow-up as compared to patients started on anti-TNF late, nor was more MH observed. Similar results were obtained when anti-TNF treated patient were stratified more stringently, i.e. <12 months="" 40="" pts="" vs="">24 months (24 pts). Cox-regression analysis showed no beneficial correlations between anti-TNF timing and IBD-related complications. Anti-TNF treated patients achieving MH were 11 times less likely to develop EIMs compared to patients who did not achieved MH while on anti-TNF.

CONCLUSION: This study was unable to confirm a benefit for earlier anti-TNF treatment on IBD-disease complications. This could be explained by more aggressive treatment earlier in disease, resulting in fewer IBD complications. However, it seems more likely that inappropriate selection of patients for therapy leads to suboptimal treatment and subsequently outcome.


Am J Gastroenterol. 2015 Jul 28. [Epub ahead of print]
Detection of small bowel mucosal healing and deep remission in patients with known small bowel Crohn's disease using biomarkers, capsule endoscopy, and imaging.
Kopylov U, Yablecovitch D, Lahat A, et al.

OBJECTIVES: Mucosal healing (MH) and deep remission (DR) are associated with improved outcomes in Crohn's disease (CD). However, most of the current data pertain to colonic MH and DR, whereas the evidence regarding the prevalence and impact of small bowel (SB) MH is scarce. The aim of this study was to to evaluate the prevalence of SBMH and DR in quiescent SBCD.

METHODS: Patients with known SBCD in clinical remission (CDAI<150) or with mild symptoms (CDAI<220) were prospectively recruited and underwent video capsule endoscopy after verification of SB patency. Inflammation was quantified using the Lewis score (LS). SBMH was defined as LS<135, whereas a significant inflammation was defined as LS>790. Clinico-biomarker remission was defined as a combination of clinical remission and normal biomarkers. DR was defined as a combination of clinico-biomarker remission and MH. RESULTS: Fifty-six patients with proven SB patency were enrolled; 52 (92.9%) patients were in clinical remission and 21 (40.4%) in clinico-biomarker remission. SBMH was demonstrated in 8/52 (15.4%) of patients in clinical remission. Moderate-to-severe SB inflammation was demonstrated in 11/52 (21.1%) of patients in clinical remission and in 1/21 (4.7%) of patients in clinical and biomarker remission. Only 7/52 (13.5%) patients were in DR.

CONCLUSIONS: SB inflammation is detected in the majority of CD patients in clinical and biomarker remission. SBMH and DR were rare and were independent of treatment modality. Our findings represent the true inflammatory burden in quiescent patients with SBCD.


Gastroenterology. 2015 Jun;148(7):1474-5. Epub 2015 Apr 30.
The POCER Trial: Bet on Active Care.
Vuitton L, Peyrin-Biroulet L.

No abstract available.


Scand J Gastroenterol. 2015 Jul 22:1-10. [Epub ahead of print]
Infliximab in ulcerative colitis: real-life analysis of factors predicting treatment discontinuation due to lack of response or colectomy: ECIA (ACAD Colitis and Infliximab Study).
Fernández-Salazar L, Muñoz F, Barrio J, et al.

OBJECTIVE: To describe clinical practice with infliximab (IFX) in ulcerative colitis (UC); identification of predictive factors for IFX treatment discontinuation due to insufficient response and for colectomy.

MATERIAL AND METHODS: Retrospective, multicentric and observational study including every UC IFX-treated patient in 10 Spanish hospitals. Variables analyzed: epidemiological data; variables for poor prognosis; IFX prior treatments; characteristics of the IFX treatment; time from the UC diagnosis to induction with IFX; time from induction to colectomy or until data collection. Predictive and protective factors for IFX discontinuation due to lack of response and for colectomy were analyzed with binary logistic regression and Cox analysis.

RESULTS: Follow-up time from induction with IFX to the collection of data or colectomy: 36.7 ± 25.7 months. Prior treatment with immunomodulator medications (IMM): 79%; IFX + immunosuppressant therapy: 77%; discontinuation of IFX: 26%, colectomy 16%. Independent predictive or protective factors for IFX discontinuation: IMM resistance (OR: 2.9, p = 0.022, 95%CI: 1.2-7.2), prior use of leukocytapheresis (OR: 3.3, p = 0.024, 95%CI: 1.1-9.4), IFX + IMM therapy (OR: 0.3, p = 0.022, 95%CI: 0.1-0.9, and HR: 0.4, p = 0.006, 95%CI: 0.2-0.8) and corticosteroid use in induction (HR: 1.9, p = 0.049, 95%CI: 1.0-3.8). Independent predictive or protective factors for colectomy: Use of leukocytapheresis (OR: 3.0, p = 0.036, 95%CI: 1.1-8.4), IFX + IMM therapy (OR: 0.3, p = 0.022, 95%CI: 0.1-0.8, and HR: 0.3, p = 0.011, 95%CI: 0.1-0.8) and severe cortico-resistant flare-up (HR: 2.5, p = 0.032, 95%CI: 1.1-5.9).

CONCLUSIONS: Prior use of IMM and leukocytapheresis, the use of corticosteroids in induction and a severe cortico-resistant flare predict a worse response to IFX and the need for colectomy. Combination therapy is a protective factor for both.


J Gastroenterol Hepatol. 2015 Jul 25. [Epub ahead of print]
Fecal calprotectin is a clinically relevant biomarker of mucosal healing in patients with quiescent ulcerative colitis.
Yamaguchi S, Takeuchi Y, Arai K, et al.

BACKGROUND AND AIM: Calprotectin is an abundant protein in neutrophils, which infiltrate the mucosa during inflammation. Fecal calprotectin (FC) level has shown correlation with disease activity in ulcerative colitis (UC) patients. Additionally, FC level is expected to indicate mucosal healing (MH). This study was to see the significance of FC for predicting MH in patients with quiescent UC.

METHODS: A total of 112 patients with quiescent UC were included. After taking blood and stool samples, patients underwent total colonoscopy and the Mayo endoscopic subscore was recorded. FC was measured by fluorescence enzyme immunoassay. C-reactive protein, hemoglobin, erythrocyte sedimentation rate, and serum albumin were measured as conventional biomarkers. MH was defined as Mayo 0 or 0&1, and receiver operator characteristic (ROC) analyses were undertaken to determine the significance levels of measurements.

RESULTS: Data from 105 patients were available. Eleven patients showed Mayo ≥2. The median (interquartile range) of FC level of all patients was 115 μg/g (45.4-420). The area under the curve (AUC) in ROC analysis of FC to predict Mayo 0&1 was 0.869 with a cut-off value of 200 μg/g yielding 67% sensitivity and 91% specificity, which were the best among all biomarkers. However, the power of FC to predict Mayo 0 was modest; the AUC was 0.639, cut-off value 194 μg/g with 71% sensitivity and 58% specificity.

CONCLUSIONS: Based on the findings of this study, we believe that FC is a clinically relevant biomarker of MH in patients with quiescent UC. Other favorable features of FC test include feasibility and non-invasiveness.


Aliment Pharmacol Ther. 2015 Aug 24. [Epub ahead of print]
Review article: the histological assessment of disease activity in ulcerative colitis.
Marchal Bressenot A, Riddell RH, Boulagnon-Rombi C, et al.

BACKGOUND: In patients with ulcerative colitis (UC), mucosal healing has emerged as a major therapeutic goal, and is usually assessed endoscopically. Histological healing does not correlate very well with endoscopic mucosal healing in UC and persistent histological inflammation might be a better predictor of future clinical relapse than the endoscopic appearance alone. AIM: To define how histological assessment of disease activity should be best done in UC.

METHODS: Electronic (PubMed/Embase) and manual search.

RESULTS: At least 18 histological indices to assess disease activity in UC have been described, though none are fully validated. However, histological assessment is increasingly used as a secondary endpoint in clinical trials in UC. After reviewing and discussing existing histological scoring systems for UC activity, we describe features of histological response and define three grades of activity: (i) histological healing - complete resolution of abnormalities; (ii) quiescent disease, - lack of mucosal neutrophils but chronic inflammation may remain; (iii) active disease - presence of neutrophils plus possible epithelial damage. It is recommended that two biopsies are taken from each colonic segment which should include always biopsy of the rectum and the most affected segments. There is to date no agreed preferable scoring system but the Geboes Index is the best validated (kappa for interobserver variation 0.59-0.70).

CONCLUSION: Histological assessment of disease activity in UC is increasingly used, but needs to be carefully defined.


Scandinavian Journal of Gastroenterology. 2015;
The epidemiology of inflammatory bowel disease
JOHAN BURISCH1,2 & PIA MUNKHOLM2

Abstract

Background and aims. The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are chronic relapsing disorders of unknown aetiology. The aim of this review is to present the latest epidemiology data on occurrence, disease course, risk for surgery, as well as mortality and cancer risks. Material and methods. Gold standard epidemiology data on the disease course and prognosis of patients with inflammatory bowel disease (IBD) are based on unselected population-based cohort studies.

Results. The incidence of ulcerative colitis (UC) and Crohn’s disease (CD) has increased overall in Europe from 6.0 per 100,000 person-years in UC and 1.0 per 100,000 person-years in CD in 1962 to 9.8 per 100,000 person-years and 6.3 per 100,000 person-years in 2010, respectively. The highest incidence of IBD is found on the Faroe Islands. Overall, surgery rates have been declining over the last decades, partly due to aggressive medical therapy. Among IBD patients, mortality risk is increased by up to 50% in CD when compared to the background population, but this is not the case for UC. In CD, 25 – 50% deaths are disease-specific deaths, e.g. malnutrition, postoperative complications and intestinal cancer. In UC, disease-specific causes of deaths include colorectal cancer (CRC), and surgical and postoperative complications. The risk of CRC and small bowel cancer is increased two- to eightfold among IBD patients. Various subgroups carry increased risk of malignancy, e.g. those with persistent inflammation, long-standing disease, extensive disease, young age at diagnosis, family history of CRC and co-existing primary sclerosing cholangitis. The risk of extra-intestinal cancers, including lymphoproliferative disorders (LD) and intra- and extrahepatic cholangio carcinoma, is significantly higher among IBD patients.

Conclusion. In recent years, self-management and patient empowerment, combined with evolving eHealth solutions, has utilized epidemiological knowledge on disease patterns and has been improving compliance and the timing of adjusting therapies, thus optimizing efficacy by individualizing medication in the community setting.


Inflamm Bowel Dis. 2015 Sep;21(9):2172-7.
An optimized anti-infliximab bridging enzyme-linked immunosorbent assay for harmonization of anti-infliximab antibody titers in patients with inflammatory bowel diseases.
Van Stappen T, Billiet T, Vande Casteele N, et al.

BACKGROUND: The formation of anti-infliximab antibodies (ATI) is associated with loss of response and adverse events in patients with inflammatory bowel diseases, leading to the introduction of ATI monitoring for guiding treatment adjustments. However, a lack of standardization among current available assays exists, hampering comparison of results from different studies. This study aimed to improve the harmonization of clinically validated ATI enzyme-linked immunosorbent assays (ELISAs) by introducing a monoclonal anti-infliximab antibody (MA-IFX).

METHODS: A panel of MA-IFX was evaluated as calibrator in the first generation ATI ELISA. After selection of 1 MA-IFX, assay conditions were optimized and biotin-streptavidin-enhanced detection of bound infliximab was introduced. The novel second generation ELISA was used for reanalysis of 127 serum samples from a cohort of 12 patients with inflammatory bowel disease, previously identified as ATI positive.

RESULTS: Of 55 MA-IFX, MA-IFX10F9 was selected as calibrator in the ATI ELISA. After optimization of the assay conditions, a 4-fold improvement in sensitivity was obtained. Reanalysis of 127 serum samples revealed that in 5 of 12 patients (46%), ATI were detected at least 1 time point earlier with the second generation ELISA compared with the first generation ELISA. In 1 patient, the second generation ELISA allowed to detect ATI before the reinitiation of IFX after a drug holiday.

CONCLUSIONS: In addition to the improved sensitivity and specificity of the second generation ATI ELISA, MA-IFX10F9 can serve as a universal calibrator to achieve assay harmonization. Moreover, the superiority of the second generation assay in analyzing serum of restarters was demonstrated.


J Crohns Colitis. 2015 Aug 20. [Epub ahead of print]
European evidence-based consensus: inflammatory bowel disease and malignancies.
Annese V, Beaugerie L, Egan L, et al.

No abstract available.

Saiba mais

Clin Res Hepatol Gastroenterol. 2015 Jun 29. [Epub ahead of print]
Therapeutic drug monitoring is predictive of loss of response after de-escalation of infliximab therapy in patients with inflammatory bowel disease in clinical remission.
Amiot A, Hulin A, Belhassan M, et al.

BACKGROUND: There is no evidence that therapeutic drug monitoring is helpful in patients with inflammatory bowel disease patients in clinical remission with infliximab therapy.

METHODS: Eighty consecutive inflammatory bowel disease patients in clinical remission on infliximab maintenance therapy were included and followed-up for at least one year. Infliximab trough level and antibody to infliximab concentration were measured prior to enrollment. At the time of enrollment, physicians in charge were free to alleviate infliximab therapy. Discrepancies between blind and therapeutic drug monitoring-based adjustments were assessed at the end of the follow-up period. Relapse-free survival was analyzed using univariate and multivariate analyses.

RESULTS: The mean infliximab trough level was 3.1μg/mL. Antibody to infliximab was found in 15 (19%) patients. At the end of the follow-up period, 18 (22.5%) patients experienced a relapse. The 3, 6, 9 and 12-month relapse-free rates were 98%, 87%, 86% and 80%, respectively. In our multivariate analysis, relapse-free survival was negatively associated with discrepancies between therapeutic drug monitoring-based and blind adjustments of infliximab therapy, absence of concomitant immunomodulator, the absence of mucosal healing, prior use of infliximab, infliximab therapy duration>2years and C-reactive protein levels>5mg/L at the time of enrollment.

CONCLUSION: In patients with inflammatory bowel disease in clinical remission on infliximab therapy, de-escalation of infliximab therapy should be considered based on therapeutic drug monitoring rather than according to symptoms and CRP


Aliment Pharmacol Ther. 2015 Jun 26. [Epub ahead of print]
Population pharmacokinetics of infliximab in patients with inflammatory bowel disease: potential implications for dosing in clinical practice.
Buurman DJ, Maurer JM, Keizer RJ, et al.

BACKGROUND: Infliximab (IFX) is effective in the treatment of inflammatory bowel diseases (IBD). Currently, IFX is administered at fixed doses and intervals; however, costs are high and optimisation is necessary. Several publications indicate that IFX should be dosed on trough levels ≥3.0 mg/L. For optimising IFX dosing, the use of a pharmacokinetic model is important. Population pharmacokinetics of IFX have been described earlier; however, these models were not used for dose optimising.

AIMS: To develop a pharmacokinetic model for IFX in IBD patients that can be used for dose-optimisation of IFX and to predict serum trough levels in this population.

METHODS: An observational retrospective study was performed in 42 IFX-treated IBD patients. Serum samples were drawn before infusion at T = 0, 2, 6, 14, 22 and 54 weeks and analysed for IFX and antibodies against IFX (ATI). Relevant covariates were recorded and a population pharmacokinetic model was developed.

RESULTS: Individual plots created using the final model showed good correspondence between observed and model predicted values. Serum levels were influenced by ATI, disease activity, sex and albumin. Our results show that in patients without ATI target trough levels ≥3.0 mg/L can be achieved by increasing dosing intervals from 8 to 12 weeks combined with a dose increase. This results in a reduction of 33% in concomitant costs.

CONCLUSIONS: In IBD patients without ATI, trough level dosing based on longer intervals can reduce IFX therapy-related visits to the hospital with one-third. Trough level based dose intensification should always be justified by disease activity parameters.


J Crohns Colitis. 2015 Jun 26. [Epub ahead of print]
Serum concentration of anti-TNF antibodies, adverse effects and quality of life in patients with inflammatory bowel disease in remission on maintenance treatment.
Brandse JF, Vos LM, Jansen J, et al.

BACKGROUND AND AIMS: High serum concentrations of Infliximab (IFX) and Adalimumab (ADA) may be associated with adverse effects in patients with inflammatory bowel disease (IBD). We aimed to investigate whether high anti-TNF trough levels (TLs) were associated with toxicity and impaired quality of life (QoL).

METHODS: We conducted a prospective cohort study in IBD patients in clinical and biochemical remission on IFX or ADA maintenance therapy. Trough serum concentrations and antidrug antibodies were measured in addition to biochemical markers of inflammation in serum and stool to confirm quiescent disease. QoL was assessed using IBDQ and SF-36. Side effects such as fatigue and arthralgia were measured with a visual analogue score. Skin toxicity was reported with an EORTC derived score.

RESULTS: 252 IBD patients on maintenance anti-TNF therapy were screened, of whom 95 (73 CD, 22 UC; 72 IFX, 23 ADA) were in clinical and biochemical remission and included. Median TLs were 5.5ug/ml and 6.6 ug/ml for IFX and ADA, respectively. Patients with anti-TNF TLs above median had lower IBDQ scores than patients with lower TLs (IBDQ 176 vs. 187, P=0.02), particularly regarding systemic symptoms and emotional status. A trend towards lower SF-36 and higher fatigue scores was observed in the higher anti-TNF TL group. Skin and arthralgia scores were not significantly different between both groups.

CONCLUSIONS: IBD patients with higher anti-TNF serum concentrations had significantly lower disease-specific QoL. Fatigue, arthralgia and skin lesions do not occur more often in these patients. This data is reassuring that high serum concentrations of anti-TNF antibodies are not toxic.


Aliment Pharmacol Ther. 2015 Jun 24. [Epub ahead of print]
Efficacy and safety of anti-TNF therapy in elderly patients with inflammatory bowel disease.
Lobatón T, Ferrante M, Rutgeerts P, et al.

BACKGROUND: The general increased life expectancy is reflected in the age of patients with inflammatory bowel disease (IBD). The knowledge about efficacy and safety of anti-tumour necrosis factor (TNF) therapy in elderly is scarce and conflicting.

AIM: To assess the efficacy and safety of anti-TNF therapy in elderly patients taking into account eventual comorbidity.

METHODS: Observational and retrospective single-centred study where 66 IBD patients initiating anti-TNF treatment at age >= 65 years (cases: >= 65 anti-TNF) were compared with 112 IBD patients initiating anti-TNF < 65 years (controls < 65 anti-TNF) and 61 anti-TNF naïve IBD patients treated with immunosuppressants (IMS) and/or corticosteroids (CS) >= 65 years (controls >= 65 IMS/CS). Controls were matched to cases for IBD type, follow-up, disease duration and anti-TNF type. Comorbidity was assessed by using the Charlson Comorbidity Index (CCI). Both efficacy and safety of treatment were adjusted for comorbidity.

RESULTS: The short-term clinical response to anti-TNF at 10 weeks was significantly lower in cases: >= 65 anti-TNF (68% vs. 89%; P < 0.001), whereas at >= 6 months, differences were not significant (79.5% vs. 82.8%; P = 0.639). The risk for any severe adverse events was higher in cases: >= 65 anti-TNF than in controls < 65 anti-TNF (RR = 4.7; P < 0.001) or controls >= 65 IMS/CS (RR = 3.09; P = 0.0008). Age older than 65 and CCI > 0 were independent risk factors for malignancy and mortality regardless of the medication.

CONCLUSION: Elderly patients treated with anti-TNF have a lower rate of short-term clinical response and a higher rate of severe adverse events than the younger patients under the same treatment.


Dermatol Clin. 2015 Jul;33(3):417-31.
Cutaneous manifestations of Crohn disease.
Hagen JW, Swoger JM, Grandinetti LM.

Awareness of the extraintestinal manifestations of Crohn disease is increasing in dermatology and gastroenterology, with enhanced identification of entities that range from granulomatous diseases recapitulating the underlying inflammatory bowel disease to reactive conditions and associated dermatoses. In this review, the underlying etiopathology of Crohn disease is discussed, and how this mirrors certain skin manifestations that present in a subset of patients is explored. The array of extraintestinal manifestations that do not share a similar pathology, but which are often seen in association with inflammatory bowel disease, is also discussed. Treatment and pathogenetic mechanisms, where available, are discussed.


Clin Gastroenterol Hepatol. 2015 Jun 30. [Epub ahead of print]
Effects of concomitant immunomodulator therapy on efficacy and safety of anti-TNF therapy for Crohn's disease: a meta-analysis of placebo-controlled trials.
Jones JL, Kaplan GG, Peyrin-Biroulet L, et al.

BACKGROUND & AIMS: There is debate over whether patients with Crohn's disease who start anti-tumor necrosis factor (TNF) therapy after failed immunomodulator therapy should continue to receive concomitant immunomodulators. We conducted a meta-analysis of subgroups from randomized controlled trials (RCTs) of anti-TNF agents to compare the efficacy and safety of concomitant immunomodulator therapy vs anti-TNF monotherapy.

METHODS: We performed a systematic review of literature published from 1980 through 2008, and identified 11 RCTs of anti-TNF agents in patients with luminal or fistulizing Crohn's disease. We excluded RCTs of patients who were naïve to anti-TNF and immunomodulator therapy. The primary endpoints were clinical response at weeks 4-14 and 24-30, and remission at weeks 24-30. Secondary endpoints included infusion- or injection-site reactions and selected adverse events. A priori subgroup analyses were performed to evaluate fistula closure and the efficacy and safety of combination therapy with different anti-TNF agents.

RESULTS: Overall, combination therapy was no more effective than monotherapy in inducing 6 months remission (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.80-1.31), inducing a response (OR, 1.08; 95% CI 0.79-1.48), maintaining a response (OR, 1.53; 95% CI 0.67-3.49), or inducing partial (OR, 1.25; 95% CI, 0.84-1.88) or complete fistula closure (OR, 1.10; 95% CI, 0.68-1.78). In subgroup analyses of individual anti-TNF agents, combination therapy was not more effective than monotherapy in inducing 6-month remission in those treated with infliximab (OR, 1.73; 95% CI, 0.97-3.07), adalimumab (OR, 0.88; 95% CI, 0.58-1.35), or certolizumab (OR, 0.93; 95% CI, 0.65-1.34). Overall, combination therapy was not associated with an increase in adverse events, but inclusion of infliximab was associated with fewer injection site reactions (OR, 0.46; 95% CI, 0.26-0.79.)

CONCLUSIONS: Based on a meta-analysis, continued use of immunomodulator therapy after starting anti-TNF therapy is no more effective than anti-TNF monotherapy in inducing or maintaining response or remission. RCTs are needed to adequately assess the efficacy of continued immunomodulator therapy after anti-TNF therapy is initiated.


Therap Adv Gastroenterol. 2015 Jul;8(4):168-75.
Specialized enteral nutrition therapy in Crohn's disease patients on maintenance infliximab therapy: a meta-analysis.
Nguyen DL, Palmer LB, Nguyen ET, et al.

OBJECTIVES: Many patients with Crohn's disease on infliximab maintenance therapy have recurrent symptoms despite an initial clinical response. Therefore, concomitant therapies have been studied. We conducted a meta-analysis to assess the effect of specialized enteral nutrition therapy with infliximab versus infliximab monotherapy in patients with Crohn's disease.

METHODS: A comprehensive search of multiple databases was performed. All studies of adult patients with Crohn's disease comparing specialized enteral nutrition therapy (elemental or polymeric diet with low-fat or regular diet) with infliximab versus infliximab monotherapy without dietary restrictions were included. Meta-analysis was performed using the Mantel-Haenszel (fixed effect) model with odds ratio (OR) to assess for clinical remission.

RESULTS: Four studies (n = 342) met inclusion criteria. Specialized enteral nutrition therapy with infliximab resulted in 109 of 157 (69.4%) patients reaching clinical remission compared with 84 of 185 (45.4%) with infliximab monotherapy [OR 2.73; 95% confidence interval (CI): 1.73-4.31, p < 0.01]. Similarly, 79 of 106 (74.5%) patients receiving enteral nutrition therapy and infliximab remained in clinical remission after one year compared with 62 of 126 (49.2%) patients receiving infliximab monotherapy (OR 2.93; 95% CI: 1.66-5.17, p < 0.01). No publication bias or heterogeneity was noted for either outcome.

CONCLUSIONS: The use of specialized enteral nutrition therapy in combination with infliximab appears to be more effective at inducing and maintaining clinical remission among patients with Crohn's disease than infliximab monotherapy.


Intest Res. 2015 Jul;13(3):259-65.
Conventional versus biological therapy for prevention of postoperative endoscopic recurrence in patients with Crohn's disease: an international, multicenter, and observational study.
Kotze PG, Spinelli A, da Silva RN, et al.

BACKGROUND/AIMS: Postoperative endoscopic recurrence (PER) occurs in nearly 80% of patients 1 year after ileocecal resection in patients with Crohn's disease (CD). Biological agents were more effective in reducing the rates of PER in comparison with conventional therapy, in prospective trials. The aim of this study was to compare the PER rates of biological versus conventional therapy after ileocecal resections in patients with CD in real-world practice.

METHODS: The MULTIPER (Multicenter International Postoperative Endoscopic Recurrence) database is a retrospective analysis of PER rates in CD patients after ileocecal resection, from 7 referral centers in 3 different countries. All consecutive patients who underwent ileocecal resections between 2008 and 2012 and in whom colonoscopies had been performed up to 12 months after surgery, were included. Recurrence was defined as Rutgeerts' score ≥i2. The patients were allocated to either biological or conventional therapy after surgery, and PER rates were compared between the groups.

RESULTS: Initially, 231 patients were evaluated, and 63 were excluded. Of the 168 patients in the database, 96 received anti-tumor necrosis factor agents and 72 were treated with conventional therapy after resection. The groups were comparable regarding age, gender, and perianal disease. There was longer disease duration, more previous resections, and more open surgical procedures in patients on biologicals postoperatively. PER was identified in 25/96 (26%) patients on biological therapy and in 24/72 (33.3%) patients on conventional therapy (P=0.310).

CONCLUSIONS: In this retrospective observational analysis from an international database, no difference was observed between biological and conventional therapy in preventing PER after ileocecal resections in CD patients.


J Crohns Colitis. 2015 Jun 26. [Epub ahead of print]
Higher rates of dose optimization for infliximab responders in ulcerative colitis than in Crohn's disease.
O'Donnell S, Stempak JM, Steinhart HA, et al.

BACKGROUND: Studies have demonstrated the benefit of dose optimization in the setting of secondary loss of response to infliximab in inflammatory bowel disease.

AIM: The aim of our study was to retrospectively investigate the rates of dose optimization in an inflammatory bowel disease cohort receiving maintenance infliximab therapy to determine if there are different rates of dose optimization between CD and UC cases and what impact this has on the durability of treatment effect.

METHODS: Cases receiving infliximab for treatment of IBD between January 2008 and February 2014 were identified from an infusion center database. Cases receiving ≥ 4 infusions were included in the study. Details of infusion dosing and timing were obtained. A dose increase from 5 mg/kg to 10 mg/kg or a reduction in the dosing interval were considered a dose optimization.

RESULTS: 412 cases were included in the study. 52.7% required at least one dose optimization. Dose optimization was more common in UC than in CD cases (67.2% vs 46.3%, p=0.00006). The median time to dose optimization was 7 months (95% CI 4.8-9.2) for UC cases and 27 months (95% CI 7.3-46.7) for CD cases, p=0.00003.

CONCLUSION: Here we have shown that dose optimization is required more frequently in UC than in CD with a significantly shorter time to dose optimization for UC cases than CD cases. While the majority of cases responding to induction therapy with infliximab will have a sustained response to therapy, over 50% will require a dose optimization during their treatment.

 


J Crohns Colitis. 2015 Jun 26. [Epub ahead of print]
The Modified Mayo Endoscopic Score (MMES): a new index for the assessment of extension and severity of endoscopic activity in ulcerative colitis patients.
Lobatón T, Bessissow T, De Hertogh G, et al.

INTRODUCTION: Current endoscopic activity scores for ulcerative colitis (UC) do not take into account the extent of mucosal inflammation. We have developed a simple endoscopic index for UC that takes into account the severity and the distribution of mucosal inflammation.

METHODS: In this multicenter trial, UC patients undergoing colonoscopy were prospectively enrolled. For the Modified Score (MS), the sum of the Mayo endoscopic subscore (MES) for five colon segments (ascending, transverse, descending, sigmoid and rectum) was calculated. The Extended Modified Score (EMS) was obtained by multiplying the MS by the maximal extent of inflammation. The Modified Mayo Endoscopic Score (MMES) was obtained by dividing the EMS with the number of segments with active inflammation. Colon biopsies were standardly obtained from rectum and sigmoid, as well as from all inflamed segments. Clinical activity was scored according to the Partial Mayo score (PMS). Biological activity was scored according to C-reactive protein (CRP) and fecal calprotectin (FC) levels. Histological activity was scored according to the Geboes' score (GS).

RESULTS: 171 UC patients (38% female, median age 47 years, median disease duration 13 years) were included. The MMES correlated significantly with the PMS (r=0.535), CRP (r=0.238), FC (r=0.730) and GS (r=0.615) (all P<0.001). Median MMES scores were significantly higher in patients with clinical, biological or histological activity (all P ≤0.001)

CONCLUSIONS: The MMES is an easy to use endoscopic index for UC that combines the severity analysis of the MES with the disease extent, and correlates very well with clinical, biological and histological disease activity.


Scand J Gastroenterol. 2015 Jul 3:1-7.
Risk matrix model for prediction of colectomy in a population-based study of ulcerative colitis patients (the IBSEN study).
Solberg IC, Høivik ML, Cvancarova M, et al.

OBJECTIVES: Identifying ulcerative colitis (UC) patients with increased risk of colectomy is essential for appropriate treatment. We aimed to develop a prediction model assessing the risk of having colectomy within the first 10 years after diagnosis.

MATERIAL AND METHODS: A population-based inception cohort of UC patients diagnosed in south-eastern Norway between 1990 and 1994 has been followed for 10 years. Altogether 519 patients were recruited including 49 patients who were colectomized. Based on the best-fitted multivariate model, the probabilities of colectomy were computed for selected levels of baseline covariates, and the results arranged in a prediction matrix. The following risk factors at diagnosis were analyzed: age, smoking, sex, disease extent, weight loss and fever and need for systemic steroids. Biochemical markers included C-reactive protein (CRP, < 30 or >=30 mg/l); erythrocyte sedimentation rate (ESR, <30 or >=30 mm/h) and hemoglobin (Hgb, <10.5 or >=10.5 g/dL).

RESULTS: Extent of disease, age (<40 years, >=40 years), need for systemic steroids and CRP or ESR (< 30 or > 30) at diagnosis were independently associated with colectomy and were combined in a prediction matrix. The probabilities of colectomy during the follow-up period ranged from 2.6% to 40.1% depending on the combination of predictors at diagnosis.

CONCLUSIONS: Our prediction model revealed significant differences in the probability of undergoing colectomy during a 10-years course of disease, which supports an early individualized treatment approach in UC.


J Rheumatol. 2015 Jul;42(7):1105-11.
Incidence and management of infusion reactions to infliximab in a prospective real-world community registry.
Choquette D, Faraawi R, Chow A, et al.

OBJECTIVE: Infliximab (IFX) is a therapeutic monoclonal antibody targeting tumor necrosis factor-α indicated in the treatment of chronic inflammatory diseases. IFX is administered by intravenous infusion and may be associated with different types of infusion reactions.

METHODS: RemiTRAC Infusion (NCT00723905) is a Canadian observational registry in which patients receiving IFX are followed prospectively to document premedication use, adverse events, infusion reactions, and the management of infusion reactions. The primary endpoint was to assess factors associated with infusion reactions.

RESULTS: There were 1632 patients enrolled and 24,852 infusions recorded. Most patients (63.1%) were treated for rheumatologic conditions such as rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis. Of the 1632 patients, 201 (12.3%) reported at least 1 infusion reaction. Three hundred twenty-two infusions were associated with an infusion reaction (1.3%), and most were mild to moderate in severity (95%). The most common infusion reactions were pruritus (19.9%), flushing (9.9%), or dyspnea (6.2%). Multivariate analysis showed that antihistamines premedication, number of previous infusion reactions, and female sex were significantly associated with an increased incidence of infusion reactions (p < 0.0011). The use of any concomitant immunosuppressant or corticosteroids did not influence the incidence of infusion reactions. Antihistamine premedication was associated with an increased incidence of infusion reactions (OR 1.58, p = 0.0007).

CONCLUSION: This registry shows that in community-based infusion clinics, infusion reactions to IFX are uncommon and mild to moderate in nature. Antihistamines, intravenous steroids, and acetaminophen are widely used as preventative premedication, although this study showed an absence of benefit with their use.


Expert Opin Biol Ther. 2015 Jul 20:1-3. [Epub ahead of print]
Could therapeutic drug monitoring of anti-TNF-α be useful to consider a de-escalation of treatment?
Flamant M, Roblin X.

In recent years, many retrospective studies have demonstrated the interest of therapeutic anti-TNF drug monitoring in inflammatory bowel disease. This could be especially helpful in two different situations: a secondary loss of anti-TNF response where a re-elevation of drug levels by treatment optimization is predictive of better clinical outcome; a therapeutic de-escalation or discontinuation for Crohn's disease patients in long-standing remission where an undetectable anti-TNF drug level could be predictive of clinical remission.


Gastroenterology. 2015 Jul 10. [Epub ahead of print]
Proteolytic cleavage and loss of function of biologic agents that neutralize tumor necrosis factor in the mucosa of patients with inflammatory bowel disease.
Biancheri P, Brezski RJ, Di Sabatino A, et al.

BACKGROUND & AIMS: Many patients with inflammatory bowel disease (IBD) fail to respond to anti-tumor necrosis factor (TNF) agents such as infliximab and adalimumab, and etanercept is not effective in treatment of Crohn's disease. Activated matrix metalloproteinase 3 (MMP3) and MMP12, which are increased in inflamed mucosa of patients with IBD, have a wide range of substrates, including immunoglobulin (Ig)G1. TNF neutralizing agents act in inflamed tissues; we investigated the effects of MMP3, MMP12, and mucosal proteins from IBD patients on these drugs.

METHODS: Biopsies from inflamed colon of 8 patients with Crohn's disease and 8 with ulcerative colitis, and from normal colon of 8 healthy individuals (controls), were analyzed histologically, or homogenized and proteins were extracted. We also analyzed sera from 29 patients with active Crohn's disease and 33 with active ulcerative colitis who were candidates to receive infliximab treatment. Infliximab, adalimumab, and etanercept were incubated with mucosal homogenates from patients with IBD or activated recombinant human MMP3 or MMP12 and analyzed on immunoblots or in luciferase reporter assays designed to measure TNF activity. IgG cleaved by MMP3 or MMP12 and anti-hinge autoantibodies against neo-epitopes on cleaved IgG were measured in sera from IBD patients who subsequently responded (clinical remission and complete mucosal healing) or did not respond to infliximab. RESULTS: MMP3 and MMP12 cleaved infliximab, adalimumab, and etanercept, releasing a 32 kDa Fc monomer. After MMP degradation, infliximab and adalimumab functioned as F(ab')2 fragments, whereas cleaved etanercept lost its ability to neutralize TNF. Proteins from the mucosa of patients with IBD reduced the integrity and function of infliximab, adalimumab, and etanercept. TNF-neutralizing function was restored following incubation of the drugs with MMP inhibitors. Serum levels of endogenous IgG cleaved by MMP3 and MMP12, and anti-hinge autoantibodies against neo-epitopes of cleaved IgG, were higher in patients that did not respond to treatment vs responders.

CONCLUSIONS: Proteolytic degradation may contribute to non-responsiveness of patients with IBD to anti-TNF agents.


Crohns Colitis. 2015 Jul 17. [Epub ahead of print]
Disease outcome of ulcerative colitis in an era of changing treatment strategies - Results from the Dutch population-based IBDSL cohort.
Jeuring SF, Bours PH, Zeegers MP, et al.

BACKGROUND AND AIMS: In the last decades, treatment options and strategies for ulcerative colitis (UC) have radically changed. Whether these developments have altered the disease outcome at population level is yet unknown. Therefore, we evaluated the disease outcome of UC over the last two decades in the South-Limburg area of the Netherlands.

METHODS: In the Dutch population-based IBDSL cohort, three time cohorts were defined: cohort 1991-1997 (cohort A), cohort 1998-2005 (cohort B), and cohort 2006-2010 (cohort C). The colectomy and hospitalisation rates were compared between cohorts by Kaplan-Meier survival analyses. Hazard ratios (HR) for early colectomy (within six months after diagnosis), late colectomy (beyond six months after diagnosis), and hospitalisation were calculated using Cox regression models.

RESULTS: In total, 476 UC patients were included in cohort A, 587 patients in cohort B, and 598 patients in cohort C. Over time, an increase in the use of immunomodulators (8.1% to 22.8% to 21.7%, p<0.01) and biological agents (0% to 4.3% to 10.6%, p<0.01) was observed. The early colectomy rate decreased from 1.5% in cohort A to 0.5% in cohort B (HR 0.14; 95%CI 0.04-0.47), with no further decrease in cohort C (0.3%, HR 0.98; 95%CI 0.20-4.85). Late colectomy rate remained unchanged over time: 4.0% vs. 5.2% vs. 3.6% (p=0.54), respectively. Hospitalisation rate was also similar among cohorts (22.3% vs. 19.5% vs. 18.3%, p=0.10).

CONCLUSION: Over the last two decades, a reduction in early colectomy rate was observed, with no further reduction in the most recent era. Late colectomy rate and hospitalisation rate remained unchanged over time.


J Gastroenterol. 2015 Jul 11. [Epub ahead of print]
First trough level of infliximab at week 2 predicts future outcomes of induction therapy in ulcerative colitis-results from a multicenter prospective randomized controlled trial and its post hoc analysis.
Kobayashi T, Suzuki Y, Motoya S, et al.

BACKGROUND: Infliximab (IFX) is one of the treatments of choice for corticosteroid-refractory and corticosteroid-dependent ulcerative colitis (UC). A high serum trough level of IFX (TL) is reported to be associated with sustained efficacy during maintenance treatment. As part of a phase 3 randomized controlled trial of IFX in UC, we assessed the predictive value of the first TL at week 2 for short- and long-term response.

METHODS: Patients received intravenous IFX 5 mg/kg or placebo at weeks 0, 2, and 6. Patients with evidence of a response by week 8 continued treatment at weeks 14 and 22. TL was measured by enzyme-linked immunosorbent assay. Post hoc analysis was then performed for TL and clinical outcomes.

RESULTS: Clinical response rate at week 8, the primary end point, was significantly higher in the IFX group than placebo (p = 0.005). The incidence of adverse events between groups was similar. Week 2 TL was significantly associated with a 14-week clinical activity index (CAI) remission. In multiple logistic regression analysis, the week 2 TL-to-CAI ratio (TL/CAI, odds ratio 8.07; 95 % confidence interval 2.84-27.07, p < 0.001) was an independent factor correlating with 14-week CAI remission. The week 2 TL and TL/CAI were also significantly associated with 30-week mucosal healing.

CONCLUSIONS: IFX was confirmed to be effective and safe in this population. Our results suggest that the first TL at week 2, in combination with clinical evaluation, is useful for predicting both short- and long-term outcomes, allowing an earlier decision between continuing IFX or switching to other options.

 

 

 

 

Saiba mais

World J Gastroenterol. 2015 May 21;21(19):6044-51.
Infliximab is superior to other biological agents for treatment of active ulcerative colitis: A meta-analysis.
Mei WQ, Hu HZ, Liu Y, et al.

AIM: To compare the efficacy and safety of biological agents for the treatment of active ulcerative colitis (UC).

METHODS: PubMed, MEDLINE, EMBASE and the Cochrane library were searched to screen relevant articles from January 1996 to August 2014. The mixed treatment comparison meta-analysis within a Bayesian framework was performed using WinBUGS14 software. The proportions of patients reaching clinical response, clinical remission and mucosal healing in induction and maintenance phases were analyzed as efficacy indicators. Serious adverse events in maintenance phase were analyzed as safety indicators.

RESULTS: The meta-analysis results showed that biological agents achieved better clinical response, clinical remission and mucosal healing than placebo. Indirect comparison indicated that in induction phase, infliximab was more effective than adalimumab in inducing clinical response (OR = 0.41, 95%CI: 0.29-0.57), clinical remission (OR = 0.33, 95%CI: 0.19-0.56) and mucosal healing (OR = 0.33, 95%CI: 0.19-0.56), and golimumab in inducing clinical response (OR = 0.66, 95%CI: 0.39-2.33) and mucosal healing (OR = 2.15, 95%CI: 1.18-4.22). No significant difference was found between placebo and biological agents regarding their safety.

CONCLUSION: All biological agents were superior to placebo for UC treatment in both induction and maintenance phases with a similar safety profile, and infliximab had a better clinical effect than the other biological agents.

 


Inflamm Bowel Dis. 2015 Jun 19. [Epub ahead of print]
Extent of early clinical response to infliximab predicts long-term treatment success in active ulcerative colitis.
Murthy SK, Greenberg GR, Croitoru K, et al.

 

BACKGROUND: The long-term effectiveness of infliximab (IFX) in ulcerative colitis (UC) and predictors of treatment response remain poorly characterized.

METHODS: A retrospective cohort study was conducted in 213 consecutive patients with active steroid-refractory or steroid-dependent UC treated with induction and scheduled maintenance IFX at an inflammatory bowel disease referral center. Outcomes included annual steroid-free remission (SFR), IFX failure with discontinuation, colectomy, and serious adverse events.

RESULTS: The 1- and 5-year cumulative probabilities for SFR were 39% and 14%, for IFX failure were 31.7% and 55.6%, and for colectomy were 19.2% and 37.4%, respectively. A sensitivity analysis considering the last clinical observation in patients with incomplete follow-up demonstrated a long-term SFR rate of 36%. Among responders to IFX induction therapy, achieving clinical remission before maintenance IFX therapy predicted SFR at 1 year (adjusted odds ratio = 4.50; 95% CI, 1.75-11.53), whereas the need for IFX dose intensification during the first year of therapy predicted a lower odds of SFR at 1 year (adjusted odds ratio = 0.28; 95% CI, 0.11-0.67) and a greater hazard of IFX failure beyond 1 year (adjusted hazard ratio = 2.57; 95% CI, 1.14-5.81). Older age and shorter UC duration at IFX initiation predicted poorer long-term outcomes.

CONCLUSIONS: In patients with moderate-to-severe UC treated with scheduled IFX at an inflammatory bowel disease center, close to half of the patients are still on IFX at 5 years, although a smaller proportion of patients achieve long-term SFR. The magnitude and stability of early response to IFX is associated with long-term therapeutic benefit to this agent.

 


ClinGastroenterolHepatol. 2015 Jun 10.pii: S1542-3565(15)00787-9.
Defining disease severity in inflammatory bowel diseases: current and future directions.
Peyrin-Biroulet L, Panés J, Sandborn WJ, et al.

 

No abstract available.

 


Systematic review: factors associated with relapse of inflammatory bowel disease after discontinuation of anti-TNF therapy.
Gisbert JP, Marín AC, Chaparro M.

 

BACKGROUND: The discontinuation of anti-tumour necrosis factor (anti-TNF) treatment in inflammatory bowel disease (IBD) patients in remission could be considered.

AIM: To evaluate the factors associated with relapse of IBD after discontinuation of anti-TNF therapy.

METHODS: Electronic (PubMed/Embase) and manual search up to January 2015.

RESULTS: The overall risk of relapse after discontinuation of anti-TNFs (27 studies) was 44% for Crohn's disease (CD; follow-up range: 6-125 months) and 38% for ulcerative colitis (follow-up range: 6-24 months). Several factors were investigated to identify patients who are more likely to achieve long-lasting remission after anti-TNF discontinuation. The factors associated with a higher risk of relapse are younger age, smoking, longer disease duration, and fistulising perianal CD. Laboratory markers such as low haemoglobin levels, high C-reactive protein levels and high faecalcalprotectin seem to increase the risk of relapse. On the other hand, low serum anti-TNF levels seem to be associated with a lower risk of flare-up. Mucosal healing seems to decrease the risk of relapse after anti-TNF discontinuation (overall, this risk is 26% at 1 year with mucosal healing and 42% without), although this observation has not been confirmed by some authors. In patients receiving escalated anti-TNF doses or receiving anti-TNFs for the prevention of post-operative CD recurrence, the risk of relapse after discontinuation is high (>75%). Re-administration of the drug in those who relapsed after stopping treatment is effective and safe.

CONCLUSIONS: A high proportion of patients with IBD relapse after discontinuation of anti-TNF treatment. As available data are insufficient to make strong recommendations on when anti-TNF therapy could be stopped, decisions should be taken on an individual basis.

 


J Rheumatol.2015 Jun 15.pii: jrheum.140538. [Epub ahead of print]
Incidence and management of infusion reactions to infliximab in a prospective real-world community registry.
Choquette D, Faraawi R, Chow A, et al.

 

OBJECTIVE: Infliximab (IFX) is a therapeutic monoclonal antibody targeting tumor necrosis factor-α indicated in the treatment of chronic inflammatory diseases. IFX is administered by intravenous infusion and may be associated with different types of infusion reactions.

METHODS: RemiTRAC Infusion (NCT00723905) is a Canadian observational registry in which patients receiving IFX are followed prospectively to document premedication use, adverse events, infusion reactions, and the management of infusion reactions. The primary endpoint was to assess factors associated with infusion reactions.

RESULTS: There were 1632 patients enrolled and 24,852 infusions recorded. Most patients (63.1%) were treated for rheumatologic conditions such as rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis. Of the 1632 patients, 201 (12.3%) reported at least 1 infusion reaction. Three hundred twenty-two infusions were associated with an infusion reaction (1.3%), and most were mild to moderate in severity (95%). The most common infusion reactions were pruritus (19.9%), flushing (9.9%), or dyspnea (6.2%). Multivariate analysis showed that antihistamines premedication, number of previous infusion reactions, and female sex were significantly associated with an increased incidence of infusion reactions (p < 0.0011). The use of any concomitant immunosuppressant or corticosteroids did not influence the incidence of infusion reactions. Antihistamine premedication was associated with an increased incidence of infusion reactions (OR 1.58, p = 0.0007).

CONCLUSION: This registry shows that in community-based infusion clinics, infusion reactions to IFX are uncommon and mild to moderate in nature. Antihistamines, intravenous steroids, and acetaminophen are widely used as preventative premedication, although this study showed an absence of benefit with their use.

 


J Crohns Colitis.2015 Jun 7.pii: jjv099. [Epub ahead of print]
Treatment steps, surgery and hospitalization rates during the first year of follow-up in patients with inflammatory bowel diseases from the 2011 ECCO-EpiCom inception cohort.
Vegh Z, Burisch J, Pedersen N, et al.

 

BACKGROUND AND AIMS: The ECCO-EpiCom study investigates the differences in the incidence and therapeutic management of inflammatory bowel diseases (IBD) between Eastern and Western Europe. The aim of this study was to analyze the differences in the disease phenotype, medical therapy, surgery and hospitalization rates in the ECCO-EpiCom 2011 inception cohort during the first year after diagnosis.

METHODS: Nine Western, five Eastern European centers and one Australian center with 258 Crohn's disease (CD), 380 ulcerative colitis (UC) and 71 IBD unclassified (IBDU) patients (female/male: 326/383; mean age at diagnosis: 40.9 years, SD: 17.3 years) participated. Patients' data were registered and entered in the web-based ECCO-EpiCom database (www.epicom-ecco.eu).

RESULTS: In CD, 36 (19%) Western Europe/Australian and 6 (9%) Eastern European patients received biological therapy (p=0.04), but the immunosuppressive (IS) use was equal and high in these regions (Eastern Europe vs. Western Europe/Australia: 53% vs. 45%; p=0.27). Surgery was performed in 17 (24%) CD patients in Eastern Europe and 13 (7%) in Western Europe/Australia (p<0.001, pLogRank=0.001). Twenty-four (34%) CD patients from Eastern Europe and 39 (21%) from Western Europe/Australia were hospitalized (p=0.02, pLogRank=0.01). In UC, exposure to biologics and colectomy rates were low and hospitalization rates did not differ between these regions during the one-year follow-up period (16% vs. 16%; p=0.93).

CONCLUSIONS: During the first year after diagnosis, surgery and hospitalization rates were significantly higher in CD patients in Eastern Europe compared to Western Europe/Australia, while significantly more CD patients were treated with biologicals in the Western Europe/Australian centers.

 


Dig Dis Sci. 2015 Jun 5. [Epub ahead of print]
Infliximab dose escalation as an effective strategy for managing secondary loss of response in ulcerative colitis.
Taxonera C, Barreiro-de Acosta M, Calvo M, et al.

 

BACKGROUND: The outcomes of infliximab dose escalation in ulcerative colitis (UC) have not been well evaluated.

AIMS: To assess the short- and long-term outcomes of infliximab dose escalation in a cohort of patients with UC.

METHODS: This was a multicenter, retrospective, cohort study. All consecutive UC patients who had lost response to infliximab maintenance infusions and who underwent infliximab dose escalation were included. Post-escalation short-term clinical response and remission were evaluated. In the long term, the cumulative probabilities of infliximab failure-free survival and colectomy-free survival were calculated. Predictors of short-term response and event-free survival were estimated using logistic regression analysis and Cox proportional hazard regression analysis.

RESULTS: Seventy-nine patients were included. Fifty-four patients (68.4 %) achieved short-term clinical response and 41 patients (51.9 %) entered in clinical remission. After a median follow-up of 15 months [interquartile range (IQR) 8-26], 33 patients (41.8 %) had infliximab failure. Patients with short-term response had a significantly lower adjusted rate of infliximab failure [hazard ratio (HR) 0.24, 95 % confidence interval (CI) 0.12-0.49; p < 0.001]. During a median follow-up of 24 months (IQR 13-34), 9 patients (11.4 %) needed colectomy. Short-term response was identified as a predictor of colectomy avoidance (HR 0.14; 95 % CI 0.03-0.69; p < 0.007).

CONCLUSIONS: In UC patients who lost response to infliximab during maintenance, infliximab dose escalation enabled recovery of short-term response in nearly 70 % of patients. In the long term, 58 % of patients maintained sustained clinical benefit, and 9 of 10 avoided colectomy. Short-term response was associated with an 86 % reduction in the relative risk of colectomy.

 


J GastroenterolHepatol.2015 Jun 5. [Epub ahead of print]
Magnetic resonance enterography findings as predictors of clinical outcome following antitumor necrosis factor treatment in small bowel Crohn's disease.
Gibson DJ, Murphy DJ, Smyth AE, et al.

 

AIMS: To determine whether specific magnetic resonance enterography (MRE) findings can predict outcome following commencement of antitumor necrosis factor (aTNF) in small bowel Crohn's disease (CD).

PATIENTS AND METHODS: This was a single-centre retrospective study of patients with CD who commenced aTNF (infliximab or adalimumab) between 2007 and 2013. Patients who had an MRE within 6 months before commencing aTNF were included. The primary end-point was the need for CD-related surgery. The secondary end-points were time to surgery and time to treatment failure. The relationship between these end-points, clinical variables and specific MRE findings were studied.

RESULTS: Four hundred and eighteen patients commenced aTNF for CD during the study period. Seventy-five patients had an MRE within 6 months before commencing aTNF (30 infliximab; 45 adalimumab). The median time from MRE to commencing aTNF was 43 days (IQR 19.5-87 days). Eighteen of 75 (24%) had surgery during a median follow-up of 16.7 months (IQR 9.0-30.1 months). Patients with small bowel stenosis (SBS) on MRE were at a significantly higher risk of requiring surgery: 12/18 (66.7%) versus 6/57 (10.5%) (P<0.001). Time to surgery was significantly shorter in patients with SBS on MRE (P<0.001). In a multivariate analysis, SBS (P<0.0001, hazard ratio 26.45, 95% confidence interval 5.45-128.49) and presence of penetrating complications (P=0.003, hazard ratio 36.53, 95% confidence interval 3.40-393.19) were associated independently with time to surgery.

CONCLUSION: SBS and penetrating complications on MRE are associated independently with a need for early surgery and treatment failure in patients commencing aTNF.

 


BMJ. 2015 Jun 5;350:h2809.
Association between tumour necrosis factor-α inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study.
Nyboe Andersen N, Pasternak B, Friis-Møller N, et al.

 

OBJECTIVE: To investigate whether people with inflammatory bowel disease treated with tumour necrosis factor-α (TNF-α) inhibitors are at increased risk of serious infections.

DESIGN: Nationwide register based propensity score matched cohort study.

SETTING: Denmark, 2002-12.

PARTICIPANTS: The background cohort eligible for matching comprised 52 392 people with inflammatory bowel disease, aged 15 to 75 years, of whom 4300 were treated with TNF-α inhibitors.To limit confounding, a two stage matching method was applied; firstly matching on age, sex, disease duration, and inflammatory bowel disease subtype, and secondly matching on propensity scores (1:1 ratio); this yielded 1543 people treated with TNF-α inhibitors and 1543 untreated to be included in the analyses. MAIN OUTCOME MEASURES: The main outcome was any serious infection, defined as a diagnosis of infection associated with hospital admission. Cox regression was used to estimate hazard ratios for two risk periods (90 and 365 days after the start of TNF-α inhibitor treatment). Hazard ratios of site specific serious infections were obtained solely for the 365 days risk period.

RESULTS: Within the 90 days risk period, 51 cases of infection were observed in users of TNF-α inhibitors (incidence rate 14/100 person years), compared with 33 cases in non-users (9/100 person years), yielding a hazard ratio of 1.63 (95% confidence interval 1.01 to 2.63). Within the risk period of 365 days, the hazard ratio was 1.27 (0.92 to 1.75). In analyses of site specific infections, the hazard ratio was above 2 for several of the subgroups but only reached statistical significance for skin and soft tissue infections (2.51, 1.23 to 5.12).

CONCLUSIONS: This nationwide propensity score matched cohort study suggests an increased risk of serious infections associated with use of TNF-α inhibitors within the first 90 days of starting treatment and a subsequent decline in risk. This calls for increased clinical awareness of potential infectious complications among people with inflammatory bowel disease using these drugs, especially early in the course of treatment.

 


ArqGastroenterol. 2015 Jan-Mar;52(1):76-80.
Biosimilars in inflammatory bowel diseases: an important moment for Brazilian gastroenterologists.
Teixeira FV, Kotze PG, Damião AO, et al.

 

Biosimilars are not generic drugs. These are more complex medications than small molecules, with identical chemical structures of monoclonal antibodies that lost their patency over time. Besides identical to the original product at the end, the process of achieving its final forms differs from the one used in the reference products. These differences in the formulation process can alter final outcomes such as safety and efficacy of the drugs. Recently, a biosimilar of Infliximab was approved in some countries, even to the management of inflammatory bowel diseases. However, this decision was based on studies performed in rheumatologic conditions such as rheumatoid arthritis and ankylosing spondylitis. Extrapolation of the indications from rheumatologic conditions was done for Crohn's disease and ulcerative colitis based on these studies. In this article, the authors explain possible different mechanisms in the pathogenesis between rheumatologic conditions and inflammatory bowel diseases, that can lead to different actions of the medications in different diseases. The authors also alert the gastroenterological community for the problem of extrapolation of indications, and explain in full details the reasons for being care with the use of biosimilars in inflammatory bowel diseases without specific data from trials performed in this scenario.

Saiba mais

Gut. 2015 May 2. pii: gutjnl-2014-308973.
Reliability among central readers in the evaluation of endoscopic findings from patients with Crohn's disease.
Khanna R, Zou G, D'Haens G, et al.

OBJECTIVE: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however, neither instrument has been fully validated. We assessed intra-rater and inter-rater reliability of these indices.

DESIGN: Video recordings of colonoscopies obtained from 50 patients with CD who participated in an induction trial of a biological therapy were triplicated and reviewed in random order by four central readers. Data were used to assess intra-rater and inter-rater reliability for CDEIS, SES-CD and a global evaluation of lesion severity (GELS). Subsequently, readers participated in a consensus process that identified common sources of disagreement.

RESULTS: Intraclass correlation coefficients (ICCs) for intra-rater reliability for CDEIS, SES-CD and GELS (95% CIs) were 0.89 (0.86 to 0.93), 0.91 (0.89 to 0.95) and 0.81 (0.77 to 0.89), respectively, with standard error of measurement (SEM) of 2.10, 2.42 and 1.15. The corresponding ICCs for inter-rater reliability were 0.71 (0.63 to 0.76), 0.83 (0.75 to 0.88) and 0.62 (0.52 to 0.70), with SEM of 3.42, 3.07 and 1.63, respectively. Correlation between CDEIS and GELS was 0.75, between SES-CD and GELS was 0.74 and between CDEIS and SES-CD was 0.92. The most common sources of disagreement were interpretation of superficial ulceration, definition of disease site at the ileocolonic anastomosis, assessment of anorectal lesions and grading severity of stenosis.

CONCLUSIONS: Central reading of CDEIS and SES-CD had 'substantial' to 'almost perfect' intra-rater and inter-rater reliability; however, the responsiveness of these instruments is yet to be determined.

 


Am J Gastroenterol. 2015 May 12.
C-reactive protein, fecal calprotectin, and stool lactoferrin for detection of endoscopic activity in symptomatic inflammatory bowel disease patients: a systematic review and meta-analysis.
Mosli MH, Zou G, Garg SK, et al.

 

OBJECTIVES: Persistent disease activity is associated with a poor prognosis in inflammatory bowel disease (IBD). Therefore, monitoring of patients with intent to suppress subclinical inflammation has emerged as a treatment concept. As endoscopic monitoring is invasive and resource intensive, identification of valid markers of disease activity is a priority. The objective was to evaluate thediagnostic accuracy of C-reactive protein (CRP), fecal calprotectin (FC), and stool lactoferrin (SL) for assessment of endoscopically defined disease activity in IBD.

METHODS: Databases were searched from inception to November 6, 2014 for relevant cohort and case-control studies that evaluated the diagnostic accuracy of CRP, FC, or SL and used endoscopy as a gold standard in patients with symptoms consistent with active IBD. Sensitivities and specificities were pooled to generate operating property estimates for each test using a bivariate diagnostic meta-analysis.

RESULTS: Nineteen studies (n=2499 patients) were eligible. The pooled sensitivity and specificity estimates for CRP, FC, and SL were 0.49 (95% confidence interval (CI) 0.34-0.64) and 0.92 (95% CI 0.72-0.96), 0.88 (95% CI 0.84-0.90) and 0.73 (95% CI 0.66-0.79), and 0.82 (95% CI 0.73-0.88) and 0.79 (95% CI 0.62-0.89), respectively. FC was more sensitive than CRP in both diseases and was more sensitive in ulcerative colitis than Crohn's disease.

CONCLUSIONS: Although CRP, FC, and SL are useful biomarkers, their value in managing individual patients must be considered in specific clinical contexts.

 


Crohns Colitis. 2015 May 9. pii: jjv080.
Bowel damage as assessed by the Lémann Index is reversible on anti-TNF therapy for Crohn's disease.
Fiorino G, Bonifacio C, Allocca M, et al.

 

BACKGROUND AND AIMS: Bowel damage (BD) will develop in about 50% of Crohn's disease (CD) patients. Recently, the Lémann Index (LI) was developed to measure BD.

METHODS: This was a prospective single-center cohort study. All included patients underwent full evaluation for bowel damage before starting anti-TNF therapy and every year thereafter. BD at baseline and during follow-up was measured using the LI. We assessed the impact of anti-TNF therapy on BD. We also assessed the sensitivity to change of the LI and the relationship between BD progression and disease outcomes, including the need for surgery.

RESULTS: Thirty CD patients were enrolled (13 on infliximab, 17 on adalimumab). Median baseline LI was 9.1 (range, 1.6-34.1). Median follow up was 32.5 months (range, 10-64). By a ROC curve analysis, a LI >4.8 defined CD subjects with BD. Any change >0.3 in the LI was related to BD change (AUC 0.98). During follow-up, 83% of subjects had BD regression and 17% had BD progression. Anti-TNF therapy significantly reduced LI at 12 months (p=0.007). Subjects with BD progression were more likely to undergo major abdominal surgery through the follow-up period (HR 0.19, p=0.005).

CONCLUSION: The LI has good sensitivity to change. Anti-TNFs agents are able to reverse BD in some CD patients. BD progression as measured by the LI may be predictive of major abdominal surgery in these patients

 


Inflamm Bowel Dis. 2015 May 5. [Epub ahead of print]
Previous cancer in a patient with Crohn's disease: is it appropriate to use biologics and immunosuppressants for IBD treatment?
Le PN, Greer JB, Oikonomou I, et al.

 

No abstract available

 


Eur J ClinPharmacol. 2015 May 27. [Epub ahead of print]
Review article: The pharmacokinetics and pharmacodynamics of drugs used in inflammatory bowel disease treatment.
Quetglas EG, Armuzzi A, Wigge S, et al.

 

BACKGROUND: The following review is a compilation of the recent advances and knowledge on the behaviour of the most frequently used compounds to treat inflammatory bowel disease in an organism.

RESULTS: It considers clinical aspects of each entity and the pharmacokinetic/pharmacodynamic relationship supported by the use of plasma monitoring, tissue concentrations, and certain aspects derived from pharmacogenetics.

 


J ClinGastroenterol. 2015 May 6. [Epub ahead of print]
Experience with anti-TNF-α biologic agents in succession in patients with Crohn's disease: a retrospective analysis of a single center.
Ferges W, Rampertab SD, Shafqet M, et al.

 

GOALS: Our aim was to identify and compare the effectiveness of antitumor necrosis factor biologics when used as initial agents and when used in succession for the treatment of moderate to severe Crohn's disease (CD).

BACKGROUND: Studies directly comparing the efficacy of biologics are lacking. When one biologic loses efficacy, patients are often treated with an alternate biologic. The effectiveness of this strategy has not been thoroughly investigated.

STUDY: This is a retrospective cohort study from a database of 153 patients with CD treated with infliximab, adalimumab, or certolizumabpegol. Response rates determined by physician global assessment were compared between biologics when given as initial agents and after failure of 1 or 2 prior biologics.

RESULTS: There were no significant differences in response between infliximab (64.5%), adalimumab (60.0%), and certolizumabpegol (66.7%) when given as initial biologics. As second-line or third-line agents after prior biologic failure, there was a trend toward increased response with infliximab (83.3%) versus adalimumab (52.7%) and certolizumabpegol (59.4%); however, this did not meet statistical significance. After failure or loss of response of 2 previous biologics, use of a third biologic was still effective with a response rate of 54.2%.CONCLUSIONS: All 3 biologics have similar efficacy in the treatment of CD when given as initial agents. Infliximab has a trend toward increased response after prior biologic failure; however, this did not meet statistical significance. Even after loss of response or failure of 2 previous biologics, trial of a third alternate biologic is an effective strategy

 


Inflamm Bowel Dis. 2015 May 12. [Epub ahead of print]
Comparative effectiveness of nutritional and biological therapy in North American children with active Crohn's disease.
Lee D, Baldassano RN, Otley AR, et al.

 

BACKGROUND: Therapeutic targets in pediatric Crohn's disease include symptoms, quality of life (QOL), and mucosal healing. Although partial enteral nutrition (PEN), exclusive enteral nutritional(EEN), and anti-tumor necrosis factor alpha (anti-TNF) therapy all improve symptoms, the comparative effectiveness of these approaches to improve QOL and achieve mucosal healing has not been assessed prospectively.

METHODS: In a prospective study of children initiating PEN, EEN, or anti-TNF therapy for Crohn's disease, we compared clinical outcomes using the Pediatric Crohn's Disease Activity Index (PCDAI), QOL (IMPACT score), and mucosal healing as estimated by fecal calprotectin (FCP). PCDAI, IMPACT, FCP, and diet (prompted 24-h recall) were measured at baseline and after 8 weeks of therapy.

RESULTS: We enrolled 90 children with active Crohn's disease (PCDAI, 33.7 ±13.7; and FCP, 976 ±754), of whom 52 were treated with anti-TNF, 22 with EEN, and 16 with PEN plus ad lib diet. Clinical response (PCDAI reduction ≥15 or final PCDAI ≤10) was achieved by 64% on PEN, 88% EEN, and 84% anti-TNF (test for trend P = 0.08). FCP ≤250 μg/g was achieved with PEN in 14%, EEN 45%, and anti-TNF 62% (test for trend P = 0.001). Improvement in overall QOL was not statistically significantly different between the 3 groups (P = 0.86). However, QOL improvement was the greatest with EEN in the body image (P = 0.03) domain and with anti-TNF in the emotional domain (P = 0.04).

CONCLUSIONS: Although PEN improved clinical symptoms, EEN and anti-TNF were more effective for decreasing mucosal inflammation and improving specific aspects of QOL.

 


Arch Med Sci. 2015 Apr 25;11(2):353-61. Epub 2015 Apr 23.
Is faecalcalprotectin equally useful in all Crohn's disease locations? A prospective, comparative study. Stawczyk-Eder K, Eder P, Lykowska-Szuber L, et al.

 

INTRODUCTION: There are data suggesting that the diagnostic usefulness of faecalcalprotectin (FC) may vary depending on the Crohn's disease (CD) location. The aim of the study was to compare the diagnostic usefulness of FC in CD patients with different disease locations.

MATERIAL AND METHODS: We prospectively enrolled 120 CD patients in the study. Disease activity was assessed by using Crohn's Disease Activity Index (CDAI), biochemical markers, and endoscopic and radiographic methods. Faecalcalprotectin concentration was assessed in single stool samples by using the ELISA method.

RESULTS: Among all patients, 54 (45%) had ileocolonic CD location, 44 (36.5%) had isolated small bowel location, and 22 (18.5%) had colonic CD location. FC correlated significantly with C-reactive protein concentration and endoscopic and radiographic activity among patients with isolated small bowel CD (p = 0.03, r = 0.32; p < 0.0001, r = 0.78; p = 0.03, r = 0.35; respectively) and with C-reactive protein and endoscopic activity in isolated colonic CD (p = 0.0009, r = 0.7; p = 0.0002, r = 0.78; respectively). CDAI and inflammatory biochemical markers did not correlate with endoscopic and radiographic assessment in small bowel CD. In patients with ileocolonic CD, FC correlated significantly with endoscopy (p = 0.006, r = 0.5), radiographic assessment (p = 0.04, r = 0.3), CDAI (p = 0.0006, r = 0.5) and the majority of biochemical markers.

CONCLUSIONS: Faecalcalprotectin is a useful diagnostic marker in all CD patients. Although its usefulness in small bowel CD seems to be the lowest, it should be utilized particularly in this disease location because of the lack of other reliable, non-invasive diagnostic methods.

 


Gut. 2015 May 18. pii: gutjnl-2015-309598. [Epub ahead of print]
Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up.
Bryant RV, Burger DC, Delo J, et al.

 

BACKGROUND: Endoscopic mucosal healing is an established treatment target for UC, yet the value of achieving histological remission remains unclear.

AIMS: To evaluate histological remission compared to endoscopic mucosal healing for predicting patient outcomes in UC.

METHODS: Blinded assessment of endoscopic and histological measures of disease activity was performed on patients with established UC at baseline. Concordance and prognostic values of endoscopic mucosal healing (defined by Baron score ≤1) and histological remission (defined by Truelove and Richards' index) for predicting outcomes of corticosteroid use, hospitalisation and colectomy were determined over a median 6 years follow-up, including κ statistics and Cox regression multivariate analysis.

RESULTS: 91 patients with UC were followed up for a median 72 months (IQR 54-75 months). Overall, concordance between endoscopic and histological remission was moderate (κ=0.56, 95% CI 0.36 to 0.77); 24% patients had persistent inflammation despite endoscopic remission. Histological remission predicted corticosteroid use and acute severe colitis requiring hospitalisation over the follow-up period (HR 0.42 (0.2 to 0.9), p=0.02; HR 0.21 (0.1 to 0.7), p=0.02; respectively), whereas endoscopic mucosal healing did not (HR 0.86, 95% CI 0.5 to 1.7, p0.65; HR 0.83 95% CI 0.3 to 2.4, p0.74; respectively).

CONCLUSIONS: Histological remission is a target distinct from endoscopic mucosal healing in UC and better predicts lower rates of corticosteroid use and acute severe colitis requiring hospitalisation, over a median of 6 years of follow-up. Our findings support the inclusion of histological indices in both UC clinical trials and practice, towards a target of 'complete remission

 


Mayo Clin Proc. 2015 May 8. pii: S0025-6196(15)00299-2. [Epub ahead of print]
Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
Yadav S, Singh S, Harmsen WS, et al.

 

OBJECTIVES: To estimate the overall risk of cancer in a population-based cohort of patients with inflammatory bowel disease (IBD) and how IBD-related medications modify this risk.

METHODS: We identified all incident cancers (excluding nonmelanoma skin cancer) after IBD diagnosis in a cohort of 839 patients diagnosed as having IBD from January 1, 1940, through December 31, 2004, in Olmsted County, Minnesota, and followed up for a median 18 years through December 31, 2011 (122 patients taking biologic agents at last follow-up). We calculated standardized incidence ratios (SIRs) with 95% CIs of all cancers and compared cancer risk in patients treated with immunomodulators (IMMs) and biologics with that of patients not exposed to these medications, using an incidence rate ratio (IRR).

RESULTS: One hundred nine patients developed 135 cancers. The 10-year cumulative probability of cancer was 3.8%. Patients with Crohn disease (SIR, 1.6; 95% CI, 1.2-2.1) but not ulcerative colitis (SIR, 1.1; 95% CI, 0.8-1.4) had an increased overall risk of cancer compared with the general population. Patients treated with IMMs (relative to IMM-naive patients) had an increased risk of melanoma (IRR, 5.3; 95% CI, 1.1-24.8) (and a numerically higher risk of hematologic malignant tumors [IRR, 4.2; 95% CI, 0.9-19.2]), although this risk returned to baseline on discontinuation of IMM treatment. Patients treated with biologics (relative to biologic-naive patients) had a numerically higher risk of hematologic malignant tumors (IRR, 5.3; 95% CI, 0.7-40.5). There was no significant increase in the risk of gastrointestinal malignancies in patients with IBD compared with the general population.

CONCLUSIONS: We observed an increased risk of melanoma in IMM-treated patients with IBD, and this risk returned to baseline after discontinued use of the medications

 


Inflamm Bowel Dis. 2015 May 19. [Epub ahead of print]
Risk of lymphoma, colorectal and skin cancer in patients with IBD treated with immunomodulators and biologics: a Quebec claims database study.
Kopylov U, Vutcovici M, Kezouh A, et al.

 

BACKGROUND: Immunomodulatory medications in patients with inflammatory bowel disease (IBD) have been associated with an increased risk of developing certain malignancies. The aim of this study was to evaluate the risk of melanoma, nonmelanoma skin cancer, colorectal cancer and lymphoma associated with immunomodulators and biologics in patients with IBD.

METHODS: A nested case-control study was carried out using the provincial health insurance database of Québec, Canada (RAMQ/MedECHO).RESULTS: A total of 41,176 patients with IBD were identified of whom 19,582 patients were eligible for inclusion in the study. Treatment with thiopurine for more than 5 years was associated with a significantly increased risk of nonmelanoma skin cancer (odds ratio: 1.78; 95% confidence interval, 1.25-2.54). Immunomodulator treatment was not associated with an increased risk of non-Hodgkin's lymphoma (odds ratio: 0.87; 95% confidence interval, 0.53-1.41). Neither immunomodulators nor anti-TNF-α agents were associated with an increased risk of melanoma or colorectal cancer.

CONCLUSIONS: In a large provincial IBD cohort, treatment with immunomodulators for more than 5 years was associated with an increased risk of non-melanoma skin cancer, whereas the risk of lymphoma, melanoma, and colorectal cancer was not increased. No association was found between the risk of the evaluated malignancies and anti-TNF-α medications.

 


SAFETY

 

Bowel Dis. 2015 May 15. [Epub ahead of print]
Combined immunosuppression impairs immunogenicity to tetanus and pertussis vaccination among patients with inflammatory bowel disease.
Dezfoli S, Horton HA, Thepyasuwan N, et al.

BACKGROUND: Pertussis epidemics have recently emerged across the United States, prompting broad public health recommendations for adult Tdap vaccination (tetanus, diphtheria, acellular pertussis). The impact of immunosuppressive regimens for inflammatory bowel disease (IBD) on vaccine responses to the Tdap vaccine is not known.

METHODS: We performed a prospective controlled trial between April 2011 and March 2012. Adults with IBD were consecutively stratified based on therapeutic regimen into one of 5 groups: A: no IBD therapy or 5-aminosalicylates alone; B: maintenance biologic monotherapy; C: maintenance immunomodulator monotherapy; D: combined biologic and immunomodulator therapy; and E: healthy age-matched controls. Subjects received Tdap, and serum antibody levels against tetanus toxoid, pertussis toxoid, and filamentous hemagglutinin (FHA) were drawn just before and approximately 4 weeks after vaccination. The primary outcome was the booster response rate to each antigen. Secondary outcomes included the differences in pregeometric and postgeometric mean titers.

RESULTS: A total of 98 subjects enrolled, and 84 completed the study. Tetanus response rates were 55%, 56%, 40%, 27%, and 63% across groups A to E, respectively. Group D rates were lower than those of group B (P = 0.02). Postvaccination pertussis toxoid responses were 59%, 72%, 47%, 45%, and 75%, while FHA responses were 86%, 72%, 80%, 64%, and 75% across groups A to E, respectively. Prevaccination and postvaccination geometric mean titer differences for FHA were lower in group D than those in group A (P = 0.05).

CONCLUSIONS: Antibody responses to tetanus and pertussis vaccination may be affected by therapeutic drug regimen. Patients with IBD should optimally receive Tdap before starting immunomodulators, particularly when used in combination with anti-tumor necrosis factor alpha agents.

 


J GastroenterolHepatol. 2015 May 13. [Epub ahead of print]
Treatment with infliximab or azathioprine negatively impact the efficacy of hepatitis B vaccine in inflammatory bowel disease patient's.
Andrade P, Santos-Antunes J, Rodrigues S, et al.

 

BACKGROUND: Immunization against Hepatitis B virus (HBV) infection is recommended in patients with Inflammatory Bowel Disease (IBD), particularly in those under immunosuppressive therapy. Limited data are available about IBD patient's response to HBV vaccination.

AIM: We assessed the response rate to HBV vaccination in IBD patient's and evaluated the impact of different factors on the efficacy of HBV vaccination.

METHODS: Anti-HBs titers were measured in a cohort of IBD patients under treatment with infliximab and/or azathioprine. Vaccination was considered efficient when anti-HBs titers were higher than 10 UI/L.

RESULTS: We have identified 217 patients with IBD under infliximab who were vaccinated for Hepatitis B, 172 (79%) with Crohn's Disease and the remaining with Ulcerative Colitis; 114 patients (53%) were male and mean age was 33 ± 11 years. Overall, HBV vaccine was successful in 164 (76%) patients. Only 14 patients were vaccinated after infliximab was initiated and only 2 of them had antibodies levels above 10 IU/L. Among the patients that received vaccination before the beginning of infliximab, 88% of those who were vaccinated before starting azathioprine, developed antibodies, in contrast to 55% who already were under azathioprine. In multivariable analysis, treatment with infliximab [adjusted OR (95% CI): 17.642 (8.514-33.937)] and with azathioprine [adjusted OR (95% CI): 3.344 (1.653-9.145)] were the only factors associated with weaker response to HBV vaccination.

CONCLUSIONS: The response rate to the standard HBV vaccination in IBD patients is low mainly in those treated with infliximab and/or azathioprine.

Saiba mais

Inflamm Bowel Dis. 2015 Apr 1. [Epub ahead of print]
Systematic review: sequential rescue therapy in severe ulcerative colitis: do the benefits outweigh the risks?
Narula N, Fine M, Colombel JF, et al.

BACKGROUND: The options for medical management of acute severe steroid-refractory ulcerative colitis (UC) are limited. Recent guidelines recommend against use of sequential rescue therapy in the setting of failed medical management with initial salvage therapy. A systematic review was conducted to assess outcomes of sequential rescue therapy with infliximab (IFX) and calcineurin inhibitors like cyclosporine (CsA) or tacrolimus (Tac) in patients with steroid-refractory UC.

METHODS: A literature search identified studies that investigated treatment with IFX and CsA or Tac in acute severe UC. Outcomes of interest included short-term symptomatic response to treatment, rates of remission, adverse drug reactions, serious infections, mortality, and colectomy at 3 and 12 months.

RESULTS: Overall, ten studies with 314 participants were eligible for inclusion. After sequential treatment, patients achieved short-term treatment response in 62.4% (95% confidence interval [CI], 57.0%-67.8%) of cases and remission in 38.9% (95% CI, 33.5%-44.3%). Colectomy rates were 28.3% (95% CI, 21.7%-34.5%) at 3 months and 42.3% (95% CI, 36.0%-48.6%) at 12 months. Adverse events were encountered by 23.0% (95% CI, 17.7%-28.3%) of patients, including serious infections in 6.7% (95% CI, 3.6%-9.8%) and mortality in 1% (95% CI, 0%-2.1%).

CONCLUSIONS: The risk of sequential therapy in steroid-refractory UC seems lower than initially reported. Caution must be exercised however because of very low-quality evidence. In contrast to recent guidelines, the current analysis does not support a decision for or against use of sequential rescue therapy, which should only be performed at specialized referral centers familiar with the use of calcineurin inhibition.

 


Gastroenterology.2015 Apr 6.pii: S0016-5085(15)00451-5.
Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized, controlled trial.
Moayyedi P, Surette MG, Kim PT, et al.

BACKGROUND & AIMS: Ulcerative colitis (UC) is difficult to treat and standard therapy does not always induce remission. Fecal microbial transplantation (FMT) is an alternative approach that induced remission in in small series of patients with active UC. We investigated its safety and efficacy in a placebo-controlled, randomized trial.

METHODS: We performed a parallel study of patients with active UC without infectious diarrhea. Participants were examined by flexible sigmoidoscopy when the study began and then were randomly assigned to groups that received FMT (50 ml, via enema, from healthy anonymous donors; n=38) or placebo (50 ml water enema; n=37) once weekly for 6 weeks. Patients, clinicians, and investigators were blinded to the groups. The primary outcome was remission of UC, defined as a Mayo score ≤ 2 with an endoscopic Mayo score of 0, at week 7. Patients provided stool samples when the study began and during each week of FMT for microbiome analysis. The trial was stopped early for futility by the data monitoring and safety committee, but all patients already enrolled in the trial were allowed to complete the study.

RESULTS: Seventy patients completed the trial (3 dropped out from the placebo group and 2 from the FMT group). Nine patients who received FMT (24%) and 2 who received placebo (5%) were in remission at 7 weeks (a statistically significant difference in risk of 17%; 95% confidence interval, 2%-33%). There was no significant difference in adverse events between groups. Seven of the 9 patients in remission after FMT received fecal material from a single donor. Three of the 4 patients with UC ≤1 year entered remission, compared to 6/34 of those with UC > 1 year (P=.04 Fisher's exact test). Stool from patients receiving FMT had greater microbial diversity, compared with baseline, than that of patients given the placebo (P=.02, Mann Whitney U test).

CONCLUSIONS: FMT induces remission in a significantly greater percentage of patients with active UC than placebo, with no difference in adverse events. Fecal donor and time of UC appear to affect outcomes.

 


Scand J Gastroenterol. 2015 Apr 11:1-8. [Epub ahead of print]
The association of infliximab trough levels with disease activity in pediatric inflammatory bowel disease.
Hoekman DR, Brandse JF, de Meij TG, et al.

 

OBJECTIVE: Low serum trough levels (TLs) of infliximab (IFX) and antibodies to IFX (ATIs) are associated with the loss of therapeutic response in adults with inflammatory bowel disease (IBD) receiving IFX. Until now, pediatric data are scarce. Therefore, we aimed to cross-sectionally investigate the association between ATIs and IFX TLs, and clinical and biochemical disease activity in children receiving IFX for IBD.

MATERIAL AND METHODS: Children aged <18 years="" receiving="" ifx="" maintenance="" treatment="" for="" crohn="" s="" disease="" cd="" or="" ulcerative="" colitis="" uc="" at="" three="" dutch="" hospitals="" were="" included="" prior="" to="" two="" consecutive="" infusions="" tls="" and="" ati="" levels="" measured="" clinical="" activity="" was="" determined="" by="" pediatric="" index="" pcdai="" pucai="" respectively="" biochemical="" assessed="" serum="" c-reactive="" protein="" crp="" fecal="" calprotectin="" fc="" remission="" defined="" as="" a="" score="" of="" 10="" therapeutic="" range="" considered="" 3-7="" g="" ml="" p="">

RESULTS: Thirty-nine patients were included (31 CD; 16 females). Median age was 15 years. Median IFX TL was 3.5 μg/ml [IQR 2-7]. Subtherapeutic and supratherapeutic TLs were found in 38% and 23% of children, respectively. ATIs were detected in four patients. A correlation was found between IFX TL and CRP [rs = -0.51; p < 0.01] and FC [rs = -0.49; p < 0.01]. However, when only clinical disease activity was considered, no difference in median TL was found between remission and active disease (resp. 3.5 μg/ml [IQR 2-5] and 2.3 μg/ml [IQR 0.3-4.6]; p = 0.2).

CONCLUSIONS: IFX TLs are related to biochemical markers of disease activity. This could provide a rationale for monitoring TLs in children receiving IFX for IBD.

 


Br J Clin Pharmacol. 2015 Mar 25.
Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective multicentre cohort study.
Weber-Schoendorfer C, Oppermann M, Wacker E, et al.

 

AIMS: TNF-α inhibitors are considered relatively safe in pregnancy but experience is still limited. The aim of this study was to evaluate the risk of major birth defects, spontaneous abortion, preterm birth, and reduced birth weight after first trimester exposure to TNF-α inhibitors.

METHODS: Pregnancy outcomes of women on adalimumab, infliximab, etanercept, certolizumabpegol, or golimumab were evaluated in a prospective observational cohort study and compared to outcomes of a non-exposed random sample. The samples were drawn from pregnancies identified by institutes collaborating in the European Network of Teratology Information Services.

RESULTS: In total, 495 exposed and 1532 comparison pregnancies were contributed from 9 countries. The risk of major birth defects was increased in the exposed (5.0%) compared to the non-exposed group (1.5%; ORadj 2.2; 95% CI 1.0-4.8). The risk of preterm birth was increased (17.6%; ORadj 1.69; 95% CI 1.1-2.5), but not the risk of spontaneous abortion (16.2%; HRadj 1.06; 95% CI 0.7-1.7). Birth weights adjusted for gestational age and sex were significantly lower in the exposed group compared to the non-exposed cohort (p = 0.02). As a diseased comparison group was not possible to ascertain, the influence of disease and treatment on birth weight and preterm birth could not be differentiated.

CONCLUSIONS: TNF-α inhibitors may carry a risk of adverse pregnancy outcome of moderate clinical relevance. Considering the impact of insufficiently controlled autoimmune disease on the mother and the unborn child, TNF-α inhibitors may nevertheless be a treatment option in women with severe disease refractory to established immunomodulatory drugs.

 


J Crohns Colitis. 2015 Apr 25. pii: jjv074. [Epub ahead of print]
Clinical trials in ulcerative colitis: a historical perspective.
Hindryckx P, Baert F, Hart A, et al. /

 

The clinical trial landscape in ulcerative colitis has significantly evolved over the last decades. Study endpoints have been shifting from mere clinical response to mucosal healing. It has become clear that the choice for combined clinical and endoscopic outcome criteria leads to a reduction of placebo responses, especially when central reading of the endoscopic images is performed. Accumulating evidence suggests that histological remission yields better long term outcomes for ulcerative colitis patients than mucosal healing alone and clinical trials with prolonged follow-up will have to address whether histological remission should be the ultimate treatment goal in ulcerative colitis. In recent years, there has also been increasing interest for the implementation of patient-reported outcomes (PROs) in clinical practice and research and the regulatory authorities have set up guidelines for the development of such PROs. This papers aims to provide a comprehensive review on historical aspects of clinical trials in ulcerative colitis and to discuss challenges and perspectives for clinical trials in the near future. A thorough analysis of all available "landmark" literature (both original papers and reviews) on clinical trials in UC was performed.

 


Scand J Gastroenterol. 2015 Apr 16:1-9. [Epub ahead of print]
Global mucosal and serum cytokine profile in patients with ulcerative colitis undergoing anti-TNF therapy.
Dahlén R, Magnusson MK, Bajor A, et al.

 

BACKGROUND AND OBJECTIVE: The knowledge of the effects of anti-tumour necrosis factor (TNF) treatment on the global cytokine profile in patients with ulcerative colitis (UC) is limited. A better understanding of these mechanisms could improve the ability to select patients that should undergo the therapy. Therefore, the aim was to determine the global mucosal and serum cytokine profile before and during induction therapy with anti-TNF in UC patients.

MATERIALS AND METHODS: In total, mucosal biopsies (n = 28) and serum samples (n = 42) were collected from UC patients (total n = 48) before anti-TNF therapy. At week 14 response to the therapy was evaluated and again mucosal biopsies (n = 14) and serum samples (n = 42) were collected. Quantitative real-time PCR was used to determine mucosal cytokine mRNA expression and the MSD MULTI-ARRAY assay system platform was used for analysis of cytokines in serum. The global cytokine profile was evaluated by multivariate factor analysis.

RESULTS: At baseline, the global profile of mucosal cytokine mRNA expression and serum cytokines discriminated therapy responders from non-responders. Responders had lower mucosal mRNA expression of interleukin 1β (IL-1β), IL-17A, IL-6 and interferon γ (IFN-γ) than non-responders. Fourteen weeks after therapy start mucosal IL-1β and IL-6 were down-regulated in therapy responders but not in non-responders. At week 14, serum levels of IL-6 were decreased in therapy responders whereas IFN-γ and IL-12p70 were increased in non-responders.

CONCLUSIONS: Our data suggest that patients with a therapy failure have a more severe pro-inflammatory cytokine profile before start of anti-TNF treatment, which is less well suppressed by the treatment as compared to therapy responders.

 


Eur J Gastroenterol Hepatol. 2015 Apr;27(4):436-41.
Azathioprine discontinuation earlier than 6 months in Crohn's disease patients started on anti-TNF therapy is associated with loss of response and the need for anti-TNF dose escalation.
Viazis N, Koukouratos T, Anastasiou J, et al.

 

OBJECTIVES: A high proportion of Crohn's disease (CD) patients lose response to antitumor necrosis factor (anti-TNF) and therapy needs to be intensified. We aimed to prospectively determine the predictors and frequency of anti-TNF loss of response and therefore the need for dose escalation and de-escalation in CD patients treated with infliximab or adalimumab.

METHODS: All patients were anti-TNF naive while concomitant azathioprine was administered for 6 months. In patients initially responding to anti-TNF and subsequently losing clinical response after the first 14 weeks of therapy, dose escalation was scheduled. During the follow-up period and after 1 year of intensified administration, anti-TNF was de-escalated in patients in remission.

RESULTS: A total of 161 patients were started on infliximab (n=96) or adalimumab (n=65); however, 29 patients (18.0%) did not respond to therapy and were excluded from further analysis. From the remaining 132 patients (infliximab=77, adalimumab=55), 31 (23.5%) needed a dose escalation for maintenance of remission during a median 28-month follow-up period. Factors associated with loss of response and therefore the need for anti-TNF dose escalation were azathioprine discontinuation earlier than 6 months and smoking. Most patients achieved clinical remission (n=25, 80.6%) without other interventions and among these, 16 patients (64%) were successfully de-escalated to the standard maintenance infliximab or adalimumab dose schedule after 1 year of intensified anti-TNF administration.

CONCLUSION: Azathioprine discontinuation earlier than 6 months and smoking in CD patients started on anti-TNF therapy is associated with loss of response and the need for anti-TNF dose escalation

 


J Crohns Colitis. 2015 Apr 19. pii: jjv061. [Epub ahead of print]
Combination of C-reactive protein, infliximab trough levels and stable but not transient antibodies to infliximab are associated with loss of response to infliximab in inflammatory bowel disease.
Roblin X, Marotte H, Leclerc M, et al.

 

Background Antibodies to infliximab (ATI) and trough levels to infliximab (TRI) are associated with loss of response in inflammatory bowel diseases (IBD). The best way to predict loss of response (LOR) to infliximab (IFX) is unknown. Methods We conducted a prospective observational cohort study enrolling all IBD patients who were in clinical remission at week 14 after IFX treatment initiation. TRI, ATI and C-reactive protein (CRP) level were measured at week 22 (T1) and thereafter at every other IFX infusion. Loss of clinical response was defined by a flare requiring therapeutic change (IFX dose intensification, initiation of another drug class and/or surgery). Results 93 patients (59 Crohn's disease, mean duration of follow up 17.2 months) were included. 32 patients (34.4%) lost clinical response during follow-up. Cumulative probability of LOR was 50% at 20 months. Mean TRI at T1 was significantly lower in IBD patients with stable ATI as compared to those with transient ATI or without ATI (0.052, 3.34 and 4.29 μg/mL, respectively; p=0.001 between no ATI vs. stable ATI, and p=0.005 between stable and transient ATI) (p=0.0001). Three independent factors were predictive of LOR after Cox proportional hazards modelling: TRI > 5.5 μg/mL (HR: 0.21; 95% CI: 0.05-0.89: p=0.034) at T1, CRP > 5mg/L (HR: 2.5; 95% CI: 1.16-5.26; p=0.019) at T1, and stable ATI defined by two consecutive ATI > 20ng/ml (HR: 3.77; 95% CI: 1.45-10.0: p= 0.007). Transient ATI did not influence LOR. Conclusions LOR can be predicted based on a combination of CRP, TRI and stable ATI with a high degree of accuracy.

 

 

Saiba mais

Aliment Pharmacol Ther. 2015 Mar 1.
Randomised clinical trial: deep remission in biologic and immunomodulator naïve patients with Crohn's disease - a SONIC post hoc analysis.
Colombel JF, Reinisch W, Mantzaris GJ, et al.

BACKGROUND: As treatment goals in Crohn's disease (CD) evolve, targets now include clinical remission (CR), mucosal healing (MH) and biological remission [C-reactive protein normalisation (CRPnorm )]. AIMS: To evaluate the association of baseline factors and treatment with the achievement of different composite remission parameters at week 26.

METHODS: This post hoc analysis of the SONIC trial evaluated different composite remission measures at week 26 in a subgroup of patients with Crohn's disease activity index (CDAI) scores, CRP, and endoscopic data available at baseline and week 26 (N = 188). Assessed composite remission measures were: CR (CDAI < 150) and MH (absence of any mucosal ulcerations), previously referred to as 'deep remission;' and alternative composite endpoints: CR + CRPnorm (CRP < 0.8 mg/dL); CRPnorm + MH; and CR + CRPnorm + MH.

RESULTS: Among analysed patients, 136/188 (72.3%) achieved CR and 90/188 (47.9%) achieved MH at week 26. All composite outcomes were significantly greater (Bonferroni significance level, P ≤ 0.016) with combination therapy (i.e. infliximab and azathioprine; 52.3-63.6%) vs. azathioprine monotherapy (12.9-29.0%; p ≤ 0.005 for all comparisons). Composite remission rates including MH were significantly greater with combination therapy (52.3-56.9%) vs. infliximab (25.6-32.3%; P ≤ 0.015 for all comparisons except CRPnorm + MH, P = 0.017) and vs. azathioprine monotherapy (12.9-20.4%; P ≤ 0.002 for all comparisons). Median serum trough infliximab concentrations among patients who achieved MH or CR + MH were greater when compared with those among patients who did not achieve MH (P = 0.018) or CR + MH (P = 0.053). Among the subgroup of patients with early Crohn's disease, MH alone or in combination with composite remission criteria significantly improved clinical outcomes of patients who received combination therapy.

CONCLUSIONS: Combination therapy was more effective in achieving various composite remission measures vs. azathioprine or infliximab monotherapy. These data illustrate that 'deep remission' is achievable with combination therapy in a high percentage of patients with early Crohn's disease.


Gastroenterology. 2015 Feb 24. pii: S0016-5085(15)00253-X.
Trough Concentrations of Infliximab Guide Dosing for Patients with Inflammatory Bowel Disease.
Vande Casteele N, Ferrante M, Van Assche G, et al.

BACKGROUND & AIMS: Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC.

METHODS: We performed a 1 y, randomized, controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3-7 μg/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n=123) or continued dosing based on TCs (n=128) (maintenance phase). The primary endpoint was clinical and biochemical remission at 1 y after the optimization phase. RESULTS: At screening, 115/263 patients had a TC of infliximab of 3-7 μg/mL (43.7%). Of 76 patients with TCs <3 g="" ml="" 69="" patients="" 91="" achieved="" tcs="" of="" 3-7="" after="" dose="" escalation="" this="" resulted="" in="" a="" higher="" proportion="" cd="" remission="" than="" before="" 88="" vs="" 65="" p="" and="" decrease="" the="" median="" concentration="" c-reactive="" protein="" compared="" to="" increase="" 3="" 2="" 4="" mg="" l="" 001="" these="" changes="" were="" not="" observed="" with="" uc="" 72="">7 μg/mL, 67 patients (93%) achieved TCs of 3-7 μg/mL after dose reduction. This resulted in a 28% reduction in drug cost than before dose reduction (P<.001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary endpoint (P=.686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) (P=.018).

CONCLUSIONS: Targeting patients' infliximab TCs to 3-7 μg/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 y, but was associated with fewer flares during the course of treatment. Dig Liver Dis. 2015 Feb 4. pii: S1590-8658(15)00179-6.


Dig Liver Dis. 2015 Feb 4. pii: S1590-8658(15)00179-6.
Managing pediatric acute severe ulcerative colitis according to the 2011 ECCO-ESPGHAN guidelines: Efficacy of infliximab as a rescue therapy.
Aloi M, D'Arcangelo G, Capponi M, et al.

BACKGROUND: The effectiveness of medical therapy in paediatric acute severe colitis is scarcely described. We aimed to assess the efficacy of infliximab in children prospectively enrolled at Sapienza University of Rome between May 2010 and 2012.

METHODS: Clinical assessment and laboratory data were recorded at admission and at day 3 and 5. All patients received corticosteroids; infliximab was administered in refractory patients. Colectomy rate was assessed at 2-year follow-up.

RESULTS: Thirty-one patients (mean age 10.6±4.9 years, 52% females) were included: 21 responded to corticosteroids (68%), 10 were refractory and received infliximab (32%). Among the latter, 2 required urgent colectomy (20%); 80% responded, however 50% of these required elective colectomy during follow-up. Patients refractory to corticosteroids showed a significantly shorter interval from ulcerative colitis diagnosis to acute severe colitis compared to responders (7.4±9.6 vs. 23.1±21.6 months, respectively; p=0.01), and a higher rate of colectomy at follow-up (50% vs. 14%, respectively; p=0.007). More than 2 courses of corticosteroids before acute severe colitis were predictive of surgical need (OR 4.4).

CONCLUSION: Despite its short-term efficacy, infliximab did not modify the long-term surgical rate of paediatric acute severe colitis in our cohort. Children with an early severe colitis commonly need a second-line therapy, whilst frequent courses of corticosteroids are predictive of a poor outcome. Inflamm Bowel Dis. 2015 Feb 26. [Epub ahead of print]


Inflamm Bowel Dis. 2015 Feb 26.
Benefits and risks of combining anti-tumor necrosis factor with immunomodulator therapy in pediatric inflammatory bowel disease.
Cozijnsen MA, Escher JC, Griffiths A, et al.

Since the introduction of anti-tumor necrosis factor (TNF) therapy as treatment of inflammatory bowel disease (IBD), care of pediatric and adult patients with IBD has significantly improved. To further improve treatment efficacy and durability, multiple trials have compared the efficacy of combination therapy, using anti-TNF therapy combined with an immunomodulator (a thiopurine or methotrexate), with that of anti-TNF monotherapy with contradicting results. The safety of combined therapy has been questioned after several reported cases of hepatosplenic T-cell lymphoma in young patients with IBD so treated. Physicians prescribing anti-TNF therapy to patients with IBD are required to weigh the benefits of combined therapy with its risks. To inform physicians treating children with IBD of these benefits and risks, we reviewed studies in pediatric and adult patients with IBD comparing efficacy, durability, and/or safety of combined therapy with anti-TNF monotherapy.


Clin Gastroenterology Hepatol. 2015 Feb 24.
Effectiveness and safety of immunomodulators with anti-TNF therapy in Crohn's disease.
Osterman MT, Haynes K, Delzell E, et al.

BACKGROUND & AIMS: The benefit of continuing immunomodulators when "stepping up" to anti-tumor necrosis factor (anti-TNF) therapy for Crohn's disease (CD) is uncertain. This study assessed the effectiveness and safety of immunomodulators with anti-TNF therapy in CD.

METHODS: We conducted a retrospective cohort study of new users of anti-TNF therapy for CD in Medicare. Users of anti-TNF combination therapy with immunomodulators were matched to up to 3 users of anti-TNF monotherapy via propensity score and compared using 3 metrics of effectiveness - surgery, hospitalization, and discontinuation of anti-TNF therapy or surgery - and 2 metrics of safety - serious infection and non-Candida opportunistic infection. Cox regression was used for all analyses.

RESULTS: Among new users of infliximab, we matched 381 users of combination therapy to 912 users of monotherapy; among new users of adalimumab, we matched 196 users of combination therapy to 505 users of monotherapy. Combination therapy occurred predominantly as "step up" after thiopurine therapy. The rates of surgery (hazard ratio [HR] 1.20, 95% CI 0.73-1.96), hospitalization (HR 0.82 [0.57-1.19]), discontinuation of anti-TNF therapy or surgery (HR 1.09, [0.88-1.34]), and serious infection (HR 0.93 [0.88-1.34]) did not differ between users of anti-TNF combination therapy and monotherapy. However, the risk of opportunistic infection (HR 2.64 [1.21-5.73]) and herpes zoster (HR 3.16 [1.25-7.97]) were increased with combination therapy.

CONCLUSIONS: We found that continuation of immunomodulators after "stepping up" to anti-TNF therapy did not improve outcomes but was associated with an increased risk of opportunistic infection.


J Gastroenterol Hepatol. 2015 Mar 25.
The Asia Pacific consensus statements on Crohn's disease part 1: definition, diagnosis and epidemiology.
Ooi CJ, Hilmi I, Makharia GK, et al.

Inflammatory bowel disease (IBD) was previously thought to be rare in Asia, but emerging data indicate rising incidence and prevalence of IBD in the region. The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology (APAGE) with the goal of developing best management practices, coordinating research and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis (UC) with specific relevance to the Asia-Pacific region.1 The present consensus statements were developed following a similar process to address the epidemiology, diagnosis and management of Crohn's disease (CD). The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses and treatment availability. It does not intend to be all-comprehensive and future revisions are likely to be required in this ever-changing field.
J Gastroenterol Hepatol. 2015 Mar 25.


Clin Gastroenterol Hepatol. 2015 Mar 9. pii: S1542-3565(15)00246-3.
Changes in the Lemann index values during the first years of Crohn's disease.
Gilletta C, Lewin M, Bourrier A, et al.

BACKGROUND & AIMS: Stricturing or penetrating lesions develop over time in most patients with Crohn's disease. The Lémann Index indicates the degree of digestive damage at a given time in 1 individual. We tracked changes in Lémann Index scores in an inception cohort of patients and looked for factors associated with digestive damage. METHODS: We studied 221 patients diagnosed with Crohn's disease from 2004 through 2011 who received 2 or 3 serial morphological evaluations over a period of 2-10 y. We collected cross-sectional images and had them reviewed by a gastroenterologist and a radiologist; Lémann index scores were calculated. A value of 2 was chosen as the cut-off for substantial transparietal damage. Factors associated with score >2 at last evaluation and progression of index scores were identified using univariate analysis and logistic regression analyses.

RESULTS: Median index Lémann Index scores were 2.3 (intra-quartile range [IQR], 1.2-3.9) at first evaluation, 3.5 (IQR, 1.2-8.6) 2-5 y after diagnosis, and 8.3 (IQR, 1.2-12.1) 5-10 y after diagnosis. Index scores increased significantly at each stage compared with initial or previous values (P<.0001). After 73 months (IQR, 51-96) of follow up, 138 patients had a Lémann Index score >2.0. The only early factor that predicted later damage was first index value. Intestinal resection, time, and percentage of time elapsed with a clinically active disease were associated with progressing damage.

CONCLUSIONS: Based on an analysis of patients with Crohn's disease using the Lémann Index, nearly two thirds have substantial mucosal damage 2-10 y after diagnosis. High Lémann index scores at first evaluation, time, persistent clinical activity, and intestinal resection are associated with damage.


Digestion. 2015 Mar 24;91(3):233-238.
Combination therapy with infliximab and thiopurine compared to infliximab monotherapy in maintaining remission of postoperative Crohn's disease.
Sakuraba A, Okamoto S, Matsuoka K, et al.

BACKGROUND AND AIMS: Infliximab is an efficacious agent used for the induction and maintenance of remission in Crohn's disease (CD), and recent studies suggested that it may also prevent the recurrence of this disease after surgery. The present study was performed to assess the efficacy and safety of infliximab in the postoperative setting, and to identify whether combination treatment with thiopurines had any additional beneficial effect as compared to mono-therapy.

METHODS: We performed a retrospective cohort study to compare the efficacy of infliximab mono-therapy and combination treatment with a thiopurine in preventing recurrence after surgery.

RESULTS: Forty-one patients who received infliximab as maintenance treatment following surgery from May 2002 to April 2010 were identified. Twenty-four were naive to infliximab, and 17 who underwent surgery during infliximab treatment were continued on it following surgery. The median follow-up period was 27 months (range 12-66 months). All patients continued infliximab as maintenance treatment, but 10 required dose intensification due to clinical recurrence. Kaplan-Meier analysis demonstrated that the use of concomitant thiopurine was correlated with the continuation of infliximab treatment at an 8-week interval (log-rank test p = 0.018). The rate of adverse event was 9.8% with no patient experiencing severe adverse reactions.

CONCLUSION: Infliximab appears to be safe and it prevented clinical recurrence after surgery. Concomitant thiopurine use predicted response toward continuation of therapy at an 8-week interval. Prospective controlled studies to assess the efficacy of combination treatment in the postoperative setting are warranted.


Gastroenterology. 2015 Feb;148(2):344-54.e5; quiz e14-5.
Comparative effectiveness of immunosuppressants and biologics for inducing and maintaining remission in Crohn's disease: a network meta-analysis.
Hazlewood GS, Rezaie A, Borman M, et al.

BACKGROUND & AIMS: There is controversy regarding the best treatment for patients with Crohn's disease because of the lack of direct comparative trials. We compared therapies for induction and maintenance of remission in patients with Crohn's disease, based on direct and indirect evidence.

METHODS: We performed systematic reviews of MEDLINE, EMBASE, and Cochrane Central databases, through June 2014. We identified randomized controlled trials (N = 39) comparing methotrexate, azathioprine/6-mercaptopurine, infliximab, adalimumab, certolizumab, vedolizumab, or combined therapies with placebo or an active agent for induction and maintenance of remission in adult patients with Crohn's disease. Pairwise treatment effects were estimated through a Bayesian random-effects network meta-analysis and reported as odds ratios (OR) with a 95% credible interval (CrI).

RESULTS: Infliximab, the combination of infliximab and azathioprine (infliximab + azathioprine), adalimumab, and vedolizumab were superior to placebo for induction of remission. In pair-wise comparisons of anti-tumor necrosis factor agents, infliximab + azathioprine (OR, 3.1; 95% CrI, 1.4-7.7) and adalimumab (OR, 2.1; 95% CrI, 1.0-4.6) were superior to certolizumab for induction of remission. All treatments were superior to placebo for maintaining remission, except for the combination of infliximab and methotrexate. Adalimumab, infliximab, and infliximab + azathioprine were superior to azathioprine/6-mercaptopurine: adalimumab (OR, 2.9; 95% CrI, 1.6-5.1), infliximab (OR, 1.6; 95% CrI, 1.0-2.5), infliximab + azathioprine (OR, 3.0; 95% CrI, 1.7-5.5) for maintenance of remission. Adalimumab and infliximab + azathioprine were superior to certolizumab: adalimumab (OR, 2.5; 95% CrI, 1.4-4.6) and infliximab + azathioprine (OR, 2.6; 95% CrI, 1.3-6.0). Adalimumab was superior to vedolizumab (OR, 2.4; 95% CrI, 1.2-4.6).

CONCLUSIONS: Based on a network meta-analysis, adalimumab and infliximab + azathioprine are the most effective therapies for induction and maintenance of remission of Crohn's disease


Gastroenterology. 2015 Mar 21. pii: S0016-5085(15)00381-9.
The Toronto consensus guidelines for nonhospitalized ulcerative colitis: a welcome update but not the end of the story.
Ananthakrishnan AN, Kane SV.
No abstract available.


Gastroenterology. 2015 Mar 4. pii: S0016-5085(15)00303-0.
Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus.
Bressler B, Marshall JK, Bernstein CN, et al.


Dig Dis Sci. 2015 Mar 22. [Epub ahead of print]
Effect of immunosuppressive therapies for the treatment of inflammatory bowel disease on response to routine vaccinations: a meta-analysis.
Nguyen DL, Nguyen ET, Bechtold ML.

BACKGROUND: Several studies have evaluated the effect of immunosuppressive therapy for the treatment of inflammatory bowel disease (IBD) on response to routine vaccinations. The overall effect of specific classes of medications (i.e., immunomodulator vs. biologics) on vaccine response remains undefined. The aim of this study was to determine the effect of each class of immunosuppressive therapy in IBD patients on response to routine vaccinations.

METHODS: A comprehensive search of PubMed/MEDLINE, Scopus, CINAHL, and Cochrane databases was performed (December 2014). All studies on adults comparing vaccine response among IBD patients on immunosuppression with non-immunosuppressed patients were included. Meta-analysis was performed using the Mantel-Haenszel (fixed effects) model with odds ratio (OR) to assess for adequate vaccine response.

RESULTS: In the pooled analysis of nine studies (N = 1474), we found that there was nearly a 60 % lower chance of achieving adequate seroprotection in the group that received immunosuppressive therapy compared to the group that was not on any immunosuppressive therapies (OR 0.41 95 % CI 0.30, 0.55, p < 0.001). Specifically, we also demonstrated that patients on immunomodulator monotherapy had a twofold higher probability of achieving adequate immune response to vaccination, compared to patients on anti-tumor necrosis factor (anti-TNF) monotherapy (OR 1.92 95 % CI 1.30, 2.84).

CONCLUSION: In conclusion, IBD patients on immunosuppressive therapy have a significantly lower response to routine vaccinations. The greatest effect is seen among patients on anti-TNF and combination immunosuppressive therapy. Routine monitoring of vaccine titers post-vaccination is important to ensure that adequate immunologic response has been achieved among IBD patients.

Saiba mais

Liver Dis. 2015 Jan 22. pii: S1590-8658(15)00171-1.
Efficacy of tumour necrosis factor antagonists on remission, colectomy and hospitalisations in ulcerative colitis: Meta-analysis of placebo-controlled trials.
Lopez A, Ford AC, Colombel JF, et al.

BACKGROUND: The potential for disease modification of tumour necrosis factor antagonists in ulcerative colitis remains debated. METHODS: We searched MEDLINE, the Cochrane Library and EMBASE. Clinical response/remission, mucosal healing, colectomy, disease-related hospitalisations, and adverse events were analysed by the methods of Peto and Der Simonian and Laird.

RESULTS: Five trials enrolled 3654 patients (anti-tumour necrosis factor=2338). Anti-tumour necrosis factor therapy was more effective than placebo to induce and maintain clinical remission, with a number needed to treat of 12 (95% confidence interval [CI], 7-35) and 6 (95% CI, 4-12) for adalimumab and infliximab, respectively. Anti-tumour necrosis factor therapy was more effective than placebo to induce and maintain mucosal healing, with number needed to treat of 9 (95% CI, 5-48), 7 (95% CI, 5-17), 4 (95% CI, 3-6) for adalimumab, golimumab and infliximab, respectively. Only infliximab was associated with a reduced need for colectomy. Both infliximab and adalimumab were associated with less hospitalisations. Anti-tumour necrosis factor therapy did not increase the risk of adverse events.

CONCLUSIONS: Anti-tumour necrosis factor therapy is more effective than placebo to induce and maintain clinical remission and mucosal healing. Both infliximab and adalimumab are associated with less hospitalisations. Infliximab reduces the need for colectomy. Anti-tumour necrosis factor therapy does not increase the risk of adverse events.

 


Scand J Gastroenterol. 2015 Jan 30:1-8. [Epub ahead of print]
Use of a third anti-TNF after failure of two previous anti-TNFs in patients with inflammatory bowel disease: is it worth it?
Gisbert JP, Chaparro M.

 

Background. Some patients with inflammatory bowel disease (IBD) never respond or lose their response to a second anti-TNF. Aim. To review the efficacy and safety of a third anti-TNF after failure of two previous anti-TNFs. Methods. Bibliographical searches in PubMed for studies evaluating infliximab, adalimumab, or certolizumab as the third anti-TNF in IBD patients whose two previous anti-TNF treatments had failed. Results. Two retrospective studies with a small sample size and limited follow up evaluated the effectiveness of a third anti-TNF patients whose two previous anti-TNFs had failed. The arguments for this switching strategy are as follows: a)favorable-albeit limited-efficacy (in the study by Allez et al., clinical response was observed in 51% of patients at week 20; and in the study by de Silva et al., over 50% of patients remained on the third anti-TNF at 1 year); b)the eventual response to the third anti-TNF is relatively quick; c) no other medical options have been approved for IBD treatment; d)the only alternative options are surgery, compassionate use with non-anti-TNFs, and clinical trials. However, there are also arguments against the prescription of a third anti-TNF: a)lack of experience, since the few available studies are limited by their small sample size; b)the relatively low response in the long term (mainly due to loss of response); c) and finally, and most importantly, the risk of severe adverse events. Conclusion. The delicate balance between pros and cons means the use of a third anti-TNF after failure of two previous agents should be considered only in patients with no other therapeutic options. Decisions should be taken on an individual basis.

 


Aliment Pharmacol Ther. 2015 Feb 4.
Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed.
Gisbert JP, Marín AC, McNicholl AG, et al.

 

BACKGROUND: One-third of patients with Crohn's disease (CD) or ulcerative colitis (UC) receiving anti-TNFs do not respond to treatment, and a relevant proportion experience loss of response or intolerance.

AIM: To investigate the efficacy and safety of a second anti-TNF agent after primary/secondary failure or intolerance to a first drug.

METHODS: Inclusion criteria: studies evaluating the efficacy of infliximab (IFX), adalimumab (ADA) and certolizumab-pegol (CZP) as the second anti-TNF in CD or UC. Search strategy: Bibliographical searches (PubMed/Embase). Data synthesis: percentage of response/remission; the meta-analysis was performed using the inverse variance method.

RESULTS: We included 46 studies (37 CD, 8 UC, 1 pouchitis). The CD studies comprised 32 switching IFX→ADA, 4 IFX→CZP and 1 ADA→IFX. Overall, the second anti-TNF after the failure of IFX in CD induced remission in 43% and response in 63% of patients. The remission rate was higher when the reason to withdraw the first anti-TNF was intolerance (61%) than after secondary (45%) or primary failure (30%); response rates were, respectively, 72%, 62% and 53%. All UC studies switched IFX→ADA, six of them reporting remission rates ranging from 0% to 50%. Adverse events rate ranged from 0% to 81% in CD, most of them mild (serious adverse event 0-21%, discontinuation rate <20%).

CONCLUSIONS: The efficacy of a second anti-TNF in CD patients largely depends on the cause for switching. The remission rate is higher when the reason to withdraw the first anti-TNF is intolerance (61%), compared with secondary (45%) or primary failure (30%). Further studies of switch ADA→IFX are needed to evaluate this strategy.

 


J Crohns Colitis. 2015 Feb 5. pii: jjv031. [Epub ahead of print]
Methotrexate for maintaining remission in pediatric Crohn's patients with prior failure or intolerance to thiopurines: a multicenter cohort study.
Haisma SM, Lijftogt T, Kindermann A, et al.

 

BACKGROUND AND AIMS: Methotrexate (MTX) is an immunomodulating drug that can be used to maintain remission in patients with Crohn's disease (CD), but data on efficacy and tolerability in children and teenagers are scarce. We evaluated the long-term efficacy and tolerability of MTX monotherapy after thiopurine therapy in pediatric CD patients.

METHODS: A multicentre cohort of pediatric MTX users who stopped thiopurines due to ineffectiveness or intolerance between 2002 and 2012 were included and followed for at least 12 months. Relapse-free use was defined as steroid and biologic-free clinical remission after the introduction of MTX, and included intentional discontinuation of successful therapy before the end of the observation period.

RESULTS: One hundred thirteen patients with CD in remission were followed while on MTX monotherapy, of which 75 (66%) had failed on thiopurines and 38 (34%) had stopped thiopurines due to side effects. Median age at the introduction of MTX was 14 years (range 7 to 17), and 93% used the subcutaneous route. Kaplan-Meier analysis showed that 52% of the study cohort was still in steroid and biologic-free remission after 12 months of MTX monotherapy, with a difference that did not reach significance between thiopurine intolerant and thiopurine failing patients (P=0.21, log-rank test).

CONCLUSIONS: The findings of this cohort study suggest that MTX is an effective immunomodulator to maintain remission after stopping thiopurines. MTX maintenance should be considered before stepping up to anti-TNF-alpha therapy. It is probably somewhat more effective in patients who stopped thiopurines due to side effects than in those who failed on thiopurines.

 


United European Gastroenterol J. 2015 Feb;3(1):5-10.
The clinical value of faecal calprotectin and lactoferrin measurement in postoperative Crohn's disease.
Yamamoto T.

 

Most patients with Crohn's disease (CD) ultimately require one or more operations over their lifetime. Nevertheless, surgery is not a cure and postoperative CD recurrence is common. Ileocolonoscopy has been considered to be the gold standard in the diagnosis and monitoring of postoperative recurrence in patients with CD. However, endoscopy is a time-consuming and invasive procedure. Simple and non-invasive methods for the detection of postoperative recurrence are desirable. Faecal inflammatory biomarkers such as calprotectin and lactoferrin provide an accurate and non-invasive diagnostic and monitoring modality for inflammatory bowel disease. However, there have been limited data on the role of faecal biomarkers in the postoperative setting. Recently, several studies evaluated the value of faecal calprotectin and lactoferrin measurement after surgery for CD. This review was conducted to assess the role of faecal calprotectin and lactoferrin measurements in patients with postoperative CD.

Saiba mais

VClin Gastroenterol Hepatol. 2015 Jan 3. pii: S1542-3565(14)01839-4.
Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy.
Yarur AJ, Kubiliun MJ, Czul F, et al.

BACKGROUND & AIMS: In patients with inflammatory bowel diseases (IBD), the combination of infliximab and thiopurines (such as 6-thioguanine) is more effective than monotherapy. We assessed the correlation between serum levels of 6-thioguanine (6-TGN) and infliximab levels or antibodies to infliximab (ATI). METHODS: We performed a cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for IBD at the Crohn's and Colitis Center of the University of Miami, FL. We collected clinical, endoscopic, biochemical data, and levels of thiopurine metabolites. The primary outcomes were trough level of infliximab and the presence of ATI. RESULTS: Levels of 6-thioguanine correlated with those of infliximab (ρ=0.53; P<0.0001). The cut point of 6-TGN that best predicted a higher level of infliximab was 125 pmol/8x108 red blood cells (RBC) (area under receiver operating characteristic=0.86; P<0.001). Patients in the lowest quartile of 6-TGN had infliximab levels that were similar to patients on no thiopurines (4.3 vs. 4.8 mcg/ml respectively [p=0.8]). A level of infliximab ≥ 8.3 mcg/mL was associated with mucosal healing. Only 8 patients (11%) had detectable ATI. Patients with levels of 6-thioguanine <125 pmol="" 8x108="" rbc="" were="" significantly="" more="" likely="" to="" have="" ati="" odds="" ratio="" 1="" 3="" 95="" ci="" 2="" 3-72="" 5="" p="" 0="" 01="">

CONCLUSIONS: Whereas 6-thioguanine levels of >230 pmol/8x108 RBC have been associated with improved outcomes in patients on monotherapy, a level of 6-thioguanine ≥125 pmol/8x108 RBC may be adequate to achieve therapeutic levels of infliximab. In the long term, this may minimize the toxicity for patients on combination therapy.


Eur J Gastroenterol Hepatol. 2015 Jan 7. [Epub ahead of print]
Therapeutic drug monitoring of infliximab in inflammatory bowel disease patients in a teaching hospital setting: results of a prospective cohort study.
Warman A, Straathof JW, Derijks LJ.

OBJECTIVE: Therapeutic drug monitoring (TDM) of infliximab (IFX) is not routinely implemented in our clinical practice. We therefore carried out a prospective cohort study measuring IFX trough levels in our total inflammatory bowel disease (IBD) population in relation to remission. METHODS: Patient demographics, and medication and clinical history were collected from the electronic hospital information system. Blood was drawn at one time point for the determination of IFX trough levels and antibodies to IFX (ATI). Disease activity indices [Crohn's disease activity index (CDAI) and the Truelove-Witts disease activity index (TWDAI) for Crohn's disease and ulcerative colitis, respectively] and quality-of-life scores (Visual Analog Scale) were obtained. RESULTS: We included 107 patients. IFX levels varied from less than 0.02 to 21.9 μg/ml. The median IFX level was 2.8 μg/ml [interquartile range (IQR) 1.37-5.13]. The IFX level was associated significantly with remission (P=0.007). The median IFX level was 3.9 μg/ml (IQR 1.9-6.53) in patients in remission and 2.1 μg/ml in patients with active disease (IQR 0.77-4.38) (P=0.074). Receiver operating charecteristic curve analysis indicated a cutoff value of 2.18 μg/ml for CD and 6.26 μg/ml for UC. Eleven patients (10.3%) had developed ATI. The appearance of ATI was associated with the disappearance of IFX [relative risk: 2.2 (95% confidence interval: 1.368-3.610) P<0.0001], but not with relapse. The presence of ATI induced more infusion reactions [relative risk: 11.7 (95% confidence interval: 2.74-49.60) P<0.001].

CONCLUSION: TDM of IFX in IBD outpatients in a teaching hospital setting showed large interindividual differences in IFX trough levels. Despite this, we still found a significant association between remission and IFX trough levels. We determined cutoff values for both IBD modalities. IFX trough levels were not detectable in a significant proportion of IBD patients; TDM is indicated to identify this group of patients.


Inflamm Bowel Dis. 2015 Jan 7. [Epub ahead of print]
Fecal calprotectin for evaluating postoperative recurrence of Crohn's disease: a meta-analysis of prospective studies.
Qiu Y, Mao R, Chen BL, et al.

 

BACKGROUND: Fecal calprotectin (FC) levels have been extensively reported to correlate with clinical and endoscopic activities in Crohn's disease (CD); however, the utility of FC levels in the postoperative setting remains to be determined. Using meta-analysis, we aimed to evaluate the utility of FC as a noninvasive marker of recurrence in patients with CD who had undergone previous surgical resection.

METHODS: An electronic search using keywords related to CD and FC was performed in multiple electronic resources from 1966 to March 2014. The extracted data were pooled using a hierarchical summary receiver operating curve model. RESULTS: Ten articles met the inclusion criteria, and methodological quality was determined in detail for each study. The 10 studies presented FC levels in 613 postoperative CD patients. The pooled sensitivity and specificity values for assessing suspected endoscopic recurrence were 0.82 (95% confidence interval (CI), 0.73-0.89, 8 studies, n = 391) and 0.61 (95% CI, 0.51-0.71), respectively. The overall positive and negative likelihood ratios were 2.11 (95% CI, 1.68-2.66) and 0.29 (95% CI, 0.197-0.44), respectively. The pooled sensitivity and specificity values for evaluating clinical relapse were 0.59 (95% CI, 0.47-0.71; 3 studies, n = 183) and 0.88 (95% CI, 0.80-0.93), respectively. The overall positive and negative likelihood ratios were 5.10 and 0.47, respectively.

CONCLUSIONS: As a simple and noninvasive marker, FC is useful in evaluating recurrence of postoperative patients with CD.


Inflamm Bowel Dis. 2015 Jan 9. [Epub ahead of print]
Change in erythrocyte mean corpuscular volume during combination therapy with azathioprine and infliximab is associated with mucosal healing: a post hoc analysis from SONIC.
Bouguen G, Sninsky C, Tang KL, et al.

BACKGROUND: The adequacy of exposure of purine analogs as measured by 6-thioguanine nucleotides concentrations in the setting of combination therapy remains poorly understood. The aim of this study was to investigate the relationship between the mean corpuscular volume (MCV) value (as a surrogate marker of 6-thioguanine nucleotides concentration) and Crohn's disease outcomes in the setting of combination therapy with infliximab.

METHODS: The SONIC trial was a randomized controlled trial comparing infliximab to azathioprine and to infliximab plus azathioprine in 508 Crohn's disease patients. An increase of at least 7 femtoliter (fL) of the MCV (ΔMCV) was used for statistical analysis. RESULTS: At week 26, the mean increase of MCV was similar among patients treated with azathioprine alone (mean of 7.9 fL) or in combination with infliximab (mean of 8.5 fL). In the azathioprine group, 63.6% of patients with ΔMCV >7 were in steroid-free clinical remission at week 26 as compared with 33.3% of patients without ΔMCV >7 (P = 0.0046). In the combination therapy group, ΔMCV above 7 was associated with mucosal healing (75.0% for ΔMCV >7 versus 47.1% for ΔMCV <7, P = 0.0172) but not with steroid-free clinical remission. Patients with a ΔMCV above 7 were more likely to have infliximab trough level above 3 μg/mL at week 30 (68.4% versus 38.8% for ΔMCV <7, P = 0.0032).

CONCLUSIONS: These results suggest that ΔMCV above 7 (which is a surrogate for a higher 6-thioguanine nucleotides concentration) leads to improved Crohn's disease outcomes, even when combined with infliximab. It also suggests the possibility that a lower azathioprine exposure might be less effective in combination therapy.


J Crohns Colitis. 2015 Jan 9. pii: jjv004. [Epub ahead of print]
Changes in serum trough levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn's disease.
Steenholdt C, Bendtzen K, Brynskov J, et al.

BACKGROUND: It is recommended to intensify the infliximab (IFX) regimen in case of inadequate treatment effect. However, the rationale is not well defined as underlying mechanisms varies. AIM: To explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes. METHODS: Post hoc analysis of randomized clinical trial including 42 Crohn's disease patients with IFX treatment failure all treated by an intensified IFX regimen (5 mg/kg every 4 week) throughout 12 weeks. Trough serum IFX and anti-IFX Abs were measured by homogeneous mobility shift binding assay (HMSA) and functional cell-based reporter gene assay (RGA) at treatment failure and end of trial.

RESULTS: 21 patients (50%) regained clinical response on intensified IFX regimen. The increase in serum trough levels of IFX during treatment intensification was higher among responders than non-responders (RGA: 8.8 μg/ml vs. 3.0, p=0.035; HMSA: 9.9 μg/ml vs. 4.7, p=0.040), and differentiated patients by clinical outcome (AUCROC RGA 0.75 [0.53-0.97], p=0.035; AUCROC HMSA 0.74 [0.53-0.95], p=0.042). All responders exhibited IFX increase ≥2.6 μg/ml (sensitivity 100%, specificity 50%). Anti-IFX Abs detected by HMSA in 13 patients (32%) were often non-functional and became undetectable during IFX intensification. However, even functional anti-IFX Abs detected by RGA in 6 patients (15%) became undetectable.

CONCLUSION: Increase in IFX levels following treatment intensification associates with improved clinical outcomes indicating insufficient drug levels in a subgroup of patients. Anti-IFX Abs may become undetectable during treatment intensification suggesting lowered production or formation of immune complexes.


J Pediatr Gastroenterol Nutr. 2015 Jan 5. [Epub ahead of print]
Monotherapy with infliximab vs. combo therapy in the maintenance of clinical remission in children with moderate to severe Crohn's disease - a randomized study.
Kierkuś J, Iwańczak B, Wegner A, et al.

OBJECTIVES: To compare the efficacy and safety of two various protocols of maintenance therapy with infliximab (IFX) and immunomodulatory agent in pediatric Crohn's disease (CD) patients: withdrawal of immunomodulators vs. continuation of immunosupressants.

METHODS: This multicenter randomized open label trial included 99 CD patients (aged 14.5±2.6 years) who were administered IFX (5 mg/kg body weight, b.w.) along with immunomodulatory agent (azathioprine 1.5-3 mg/kg b.w. per day, methotrexate 10-25 mg per week). After 10 weeks of the induction therapy, 84 responders were centrally randomized into one of the following groups: group I (n=45) in which IFX and immunomodulatory agent were continued until week 54, and group II (n=39) in which immunomodulatory agent was discontinued after 26 weeks.

RESULTS: The induction therapy was reflected by significant decrease in Pediatric Crohn's Disease Activity Index (PCDAI) and Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD) values. After the maintenance phase, the analyzed groups did not differ significantly in terms of the clinical response loss rates and final PCDAI and SES-CD scores. Furthermore, no significant intragroup differences were documented between mean PCDAI scores determined at the end of induction and maintenance phases. Intensification/modification of the treatment was required in 13/45 (29%) and 11/39 (28%) patients of group I and II, respectively. A total of 9 serious adverse events were documented; none of the patients died during the trial.

CONCLUSION: 26 weeks likely represent the safe duration of combined IFX/immunomodulatory therapy in our sample of pediatric CD patients.


Gut. 2015 Jan 7. pii: gutjnl-2014-308337.
Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study.
Reinisch W, Panés J, Khurana S, et al.

OBJECTIVE: Interleukin 13 (IL-13) is thought to play a key role as an effector cytokine in UC. Anrukinzumab, a humanised antibody that inhibits human IL-13, was evaluated for the treatment of UC.

DESIGN: In a multicentre, randomised, double-blind, placebo-controlled study, patients with active UC (Mayo score ≥4 and <10) were randomised to anrukinzumab 200, 400 or 600 mg or placebo. Patients received five intravenous administrations over 14 weeks. The primary endpoint was fold change from baseline in faecal calprotectin (FC) at Week 14. Secondary endpoints included safety, pharmacokinetics and IL-13 levels.

RESULTS: The modified intention-to-treat population included 84 patients (21 patients/arm). Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo. The study had a high dropout rate, in part, related to lack of efficacy. The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score, clinical response, clinical remission and proportion of subjects with mucosal healing. An increase in serum total IL-13 (free and bound to anrukinzumab) was observed for all anrukinzumab groups but not with placebo. This suggests significant binding of anrukinzumab to IL-13. The safety profile was not different between the anrukinzumab and placebo groups. CONCLUSIONS: A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number NCT01284062.


Clin Epidemiol. 2014 Dec 23;7:29-35.
Incorporating alternative design clinical trials in network meta-analyses.
Thorlund K, Druyts E, Toor K, et al.

INTRODUCTION: Network meta-analysis (NMA) is an extension of conventional pairwise meta-analysis that allows for simultaneous comparison of multiple interventions. Well-established drug class efficacies have become commonplace in many disease areas. Thus, for reasons of ethics and equipoise, it is not practical to randomize patients to placebo or older drug classes. Unique randomized clinical trial designs are an attempt to navigate these obstacles. These alternative designs, however, pose challenges when attempting to incorporate data into NMAs. Using ulcerative colitis as an example, we illustrate an example of a method where data provided by these trials are used to populate treatment networks.

METHODS: We present the methods used to convert data from the PURSUIT trial into a typical parallel design for inclusion in our NMA. Data were required for three arms: golimumab 100 mg; golimumab 50 mg; and placebo. Golimumab 100 mg induction data were available; however, data regarding those individuals who were nonresponders at induction and those who were responders at maintenance were not reported, and as such, had to be imputed using data from the rerandomization phase. Golimumab 50 mg data regarding responses at week 6 were not available. Existing relationships between the available components were used to impute the expected proportions in this missing subpopulation. Data for placebo maintenance response were incomplete, as all induction nonresponders were assigned to golimumab 100 mg. Data from the PURSUIT trial were combined with ACT-1 and ULTRA-2 trial data to impute missing information.

DISCUSSION: We have demonstrated methods for converting results from alternative study designs to more conventional parallel randomized clinical trials. These conversions allow for indirect treatment comparisons that are informed by a wider array of evidence, adding to the precision of estimates.


Gut. 2014 Dec 30. pii: gutjnl-2014-308839.
An endoscopic Mayo score of 0 is associated with a lower risk of colectomy than a score of 1 in ulcerative colitis.
Manginot C, Baumann C, Peyrin-Biroulet L.

No abstract available.

 

 

Saiba mais

Entre em contato

 

  (11) 3436-9335

  contato@gamedii.com.br

 

GAMEDII no Facebook

Apoio

  • Sociedade Brasileira de Coloproctologia
  • Federação
  • Grupo de Estudos da Doença Inflamatória do Brasil
  • SOBEST
  • 1

Newsletter

Cadastre-se para receber nossas notícias!