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.

 

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