Janneke van der Woude

Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial

BACKGROUND Most patients who have active Crohns disease are treated initially with corticosteroids. Although this approach usually controls symptoms, many patients become resistant to or dependent on corticosteroids, and long exposure is associated with an increased risk of mortality. We aimed to compare the effectiveness of early use of combined immunosuppression with conventional management in patients with active Crohns disease who had not previously received glucocorticoids, antimetabolites, or infliximab. METHODS We did a 2-year open-label randomised trial at 18 centres in Belgium, Holland, and Germany between May, 2001, and January, 2004. We randomly assigned 133 patients to either early combined immunosuppression or conventional treatment. The 67 patients assigned to combined immunosuppression received three infusions of infliximab (5 mg/kg of bodyweight) at weeks 0, 2, and 6, with azathioprine. We gave additional treatment with infliximab and, if necessary, corticosteroids, to control disease activity. 66 patients assigned to conventional management received corticosteroids, followed, in sequence, by azathioprine and infliximab. The primary outcome measures were remission without corticosteroids and without bowel resection at weeks 26 and 52. Analysis was by modified intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00554710. FINDINGS Four patients (two in each group) did not receive treatment as per protocol. At week 26, 39 (60.0%) of 65 patients in the combined immunosuppression group were in remission without corticosteroids and without surgical resection, compared with 23 (35.9%) of 64 controls, for an absolute difference of 24.1% (95% CI 7.3-40.8, p=0.0062). Corresponding rates at week 52 were 40/65 (61.5%) and 27/64 (42.2%) (absolute difference 19.3%, 95% CI 2.4-36.3, p=0.0278). 20 of the 65 patients (30.8%) in the early combined immunosuppression group had serious adverse events, compared with 19 of 64 (25.3%) controls (p=1.0). INTERPRETATION Combined immunosuppression was more effective than conventional management for induction of remission and reduction of corticosteroid use in patients who had been recently diagnosed with Crohns disease. Initiation of more intensive treatment early in the course of the disease could result in better outcomes.

Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: Definitions, frequency and pharmacological aspects

The first ECCO pathogenesis workshop focused on anti-TNF therapy failures in inflammatory bowel diseases (IBDs). The overall objective was to better understand and explore primary non response and loss of response to anti-TNF agents in IBD. The outcome of this workshop is presented into two parts. This first section addresses definitions, frequency and pharmacological aspects of anti-TNF therapy failure, including pharmacokinetics of anti-TNF monoclonal antibodies and immune and non-immune mediated clearance of anti-TNF mAbs. The second section concerns the biological roles of TNF and TNF antagonists, including mechanisms of action of anti-TNF agents, and discuss hypothesis regarding their failures and phenomenon of paradoxical inflammation, including the potential role of TNF independent inflammatory pathways.

The metabolic activity of fecal microbiota from healthy individuals and patients with inflammatory bowel disease.

The hypothesis was studied that intestinal microbial metabolites play a role in the pathogenesis of inflammatory bowel disease. For that purpose, an in vitro model of the colon was inoculated with fresh feces of six healthy individuals and eight inflammatory bowel disease patients. Samples were taken from the model over time to analyze metabolites from both saccharolytic and proteolytic fermentation. Microbiotas from inflammatory bowel disease patients produced significantly more short-chain fatty acids and ammonia than microbiotas from healthy individuals. Furthermore, the branched-chain fatty acid production was 25% higher after inoculation with microbiotas from patients than after inoculation with microbiotas from healthy individuals. Phenolic compounds were produced by all microbiotas, with large interindividual variation. The production of (potentially toxic) metabolites may play a role in the onset or chronicity of inflammatory bowel disease, because they were produced in higher amounts by microbiotas from these patients than by microbiotas from healthy individuals.

ECCO Position Statement on the Use of Biosimilars for Inflammatory Bowel Disease—An Update

Biosimilars of infliximab were first approved by the European Medicine Agency in 2013,1 , 2 based on pre-clinical studies on biosimilarity and on clinical data coming from two randomised controlled trials conducted in rheumatoid arthritis [RA] and ankylosing spondylitis [AS].3 , 4 Initially the European Crohn’s Colitis Organisation [ECCO] raised some caution on the use of biosimilars.5 This cautious approach was also supported by several national inflammatory bowel disease [IBD] societies5–12 [Table 1]. An insufficient understanding of the characteristics and use of biosimilars became evident in a web survey among ECCO members in the same period.13 View this table: Table 1. Available society guidelines. Since biosimilars were introduced in the EU market in early 2015, more data from IBD patients14–19 have supported the biosimilarity of biosimilar infliximab CT-P13 and the reference product, with no significant differences in terms of efficacy or safety, in either naive or switched patients in cohort studies. Importantly, a study showed clear cross-reactivity between the infliximab originator and CT-P13.20 Recently, a large nationwide Norwegian randomised controlled trial [NOR-SWITCH] on patients with immune-mediated diseases [Crohn’s disease; ulcerative colitis; psoriasis; psoriatic arthritis; RA and AS] found no differences in terms of clinical response, maintenance of remission, or adverse events in patients receiving CT-P13 compared with those receiving originator infliximab.21 Consideration of these findings22 together with a better understanding of the process of biosimilar development and regulatory approval, have contributed to a change in the perception of IBD experts, who now prescribe biosimilars with significantly more confidence.23 A task-force including Governing Board representatives and one representative from pertinent ECCO Committees performed a literature search and made relevant statements to summarise their shared position. The proposed statements were then discussed, agreed and approved in a Consensus meeting. The licensing of any biosimilar medication …

Non-colorectal intestinal tract carcinomas in inflammatory bowel disease: results of the 3rd ECCO Pathogenesis Scientific Workshop (II)

Patients with inflammatory bowel diseases (IBD) have an excess risk of certain gastrointestinal cancers. Much work has focused on colon cancer in IBD patients, but comparatively less is known about other more rare cancers. The European Crohns and Colitis Organization established a pathogenesis workshop to review what is known about these cancers and formulate proposals for future studies to address the most important knowledge gaps. This article reviews the current state of knowledge about small bowel adenocarcinoma, ileo-anal pouch and rectal cuff cancer, and anal/perianal fistula cancers in IBD patients.

Genetic analysis in a dutch study sample identifies more ulcerative colitis susceptibility loci and shows their additive role in disease risk

OBJECTIVES:Genetic susceptibility is known to make a major contribution to the pathogenesis of ulcerative colitis (UC). Recently, three studies, including a genome-wide association study (GWAS), reported novel UC risk loci.METHODS:The top-20 single-nucleotide polymorphisms (SNPs) from the first UC-GWAS were genotyped, as part of the studys replication phase, in 561 UC cases and 728 controls from our Dutch UC study sample. We genotyped eight SNPs identified in two more studies, in these individuals, and replicated all significantly associated SNPs in an additional 894 UC cases and 1,174 controls from our Dutch UC study sample. A combined analysis for all patients (n=1,455) and controls (n=1,902) was performed. Dose–response models were constructed with the associated risk alleles.RESULTS:We found 12 SNPs tagging ten loci, including HLA-DRA, IL10, IL23R, JAK2, S100Z, ARPC2, and ECM1, to be associated with UC. We identified 10q26, flagged by the UC-GWAS but not confirmed in its replication phase, as a UC locus and found a trend toward association for GAS7. No association with disease localization or severity was found. The dose–response models show that individuals carrying 11 or more risk alleles have an odds ratio of 8.2 (confidence interval 3.0–22.8) for UC susceptibility.CONCLUSIONS:We confirmed the association of multiple loci with UC in the Dutch population and found evidence for association of 10q26 and a trend suggesting association for GAS7. Genetic models show that multiple risk loci in an individual increase the risk for developing UC.

Change in Erythrocyte Mean Corpuscular Volume During Combination Therapy with Azathioprine and Infliximab Is Associated with Mucosal Healing: A Post hoc Analysis from SONIC

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 Crohns 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 Crohns disease patients. An increase of at least 7 femtoliter (fL) of the MCV (&Dgr;MCV) 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 &Dgr;MCV >7 were in steroid-free clinical remission at week 26 as compared with 33.3% of patients without &Dgr;MCV >7 (P = 0.0046). In the combination therapy group, &Dgr;MCV above 7 was associated with mucosal healing (75.0% for &Dgr;MCV >7 versus 47.1% for &Dgr;MCV <7, P = 0.0172) but not with steroid-free clinical remission. Patients with a &Dgr;MCV above 7 were more likely to have infliximab trough level above 3 &mgr;g/mL at week 30 (68.4% versus 38.8% for &Dgr;MCV <7, P = 0.0032). Conclusions:These results suggest that &Dgr;MCV above 7 (which is a surrogate for a higher 6-thioguanine nucleotides concentration) leads to improved Crohns disease outcomes, even when combined with infliximab. It also suggests the possibility that a lower azathioprine exposure might be less effective in combination therapy.

Linking risk conferring mutations in NCF4 to functional consequences in Crohn's disease

We read with interest the paper from Muise et al in which they describe a rare variant in the NCF2 gene, which demonstrates a diminished RAC2 binding capacity.1 The NCF2 encoded protein p67phox is one of the components of the NADPH oxidase complex which drives the production of reactive oxygen species (ROS) during the bactericidal response of innate immune cells. Output of disturbed granulocytic ROS as a result of impaired functioning of this enzyme complex has been shown in a number of diseases, including myelodysplasia (MDS) and chronic granulomatous disease.2 3 As Muise and colleagues point out, these diseases have been linked to development of a colitis resembling that seen in Crohns disease (CD), suggesting a potential role for impaired ROS production in CD pathology. Genome-wide association studies (GWAS) are a promising tool to identify genetic variants …

How can we improve models of care in inflammatory bowel disease? An international survey of IBD health professionals

BACKGROUND AND AIMS Few studies have specifically examined models of care in IBD. This survey was designed to help gather information from health professionals working in IBD services on current care models, and their views on how to best reshape existing models for IBD care worldwide. METHODS An online mixed-methods survey was conducted with health professionals caring for IBD patients. Recruitment was conducted using the snowballing technique, where members of professional networks of the investigators were invited to participate. Results of the survey were summarised using descriptive statistics. RESULTS Of the 135 included respondents, 76 (56%) were female, with a median age of 44 (range: 23-69) years, 50% were GI physicians, 34% nurses, 8% psychologists, 4% dieticians, 2% surgeons, 1% psychiatrists, and 1% physiotherapists. Overall, 73 (54%) respondents considered their IBD service to apply the integrated model of care, and only 5% reported that they worked exclusively using the biomedical care (no recognition of psychosocial factors). The majority of respondents reported including mental health assessment in their standard IBD care (65%), 51% believed that an ideal IBD service should be managed in specialist led clinics, and 64% wanted the service to be publicly funded. Respondents pictured an ideal IBD service as easy-access fully multi-disciplinary, with a significant role for IBD nurses and routine psychological and nutritional assessment and care. CONCLUSIONS Health care professionals believe that an ideal IBD service should: be fully integrated, involve significant roles of nurses, psychologists and dieticians, run in specialist clinics, be easily accessible to patients and publicly funded.

Determinants of fatigue in Crohn's disease patients

Objective Crohn’s disease (CD) is often associated with severe fatigue. Little is known about patients who may be at the highest risk for fatigue. Therefore, we assessed the disease phenotype and factors related to fatigue in the presence of CD in two different populations. Methods Patients presenting at the clinic of a referral hospital and a general hospital were included in the study. They completed questionnaires including the Checklist Individual Strength, the Hospital Anxiety and Depression Scale, a questionnaire on disease activity, and one on medication use. The Montreal classification and sociodemographics were obtained from medical records. Hemoglobin and C-reactive protein levels were measured at baseline. Results In total, 425 patients were included (276 women, mean age: 42 years). Compared with patients from the general hospital, patients at the referral hospital had worse disease activity, worse disease behavior, more bowel resections, and a higher percentage of side-effects to medication and use of anti-tumor necrosis factor (TNF). The prevalence of fatigue was significantly higher in the referral patients compared with the general patients (65.7 vs. 52.5%, respectively; P=0.01). Similar results were found in patients in remission (53.3 vs. 40.5%; P=0.061). Factors related to fatigue were the use of anti-TNF at baseline, side-effects to 5-aminosalicylic acid, disease activity, female sex, and shorter disease duration. Furthermore, we found improvement in fatigue and a trend toward lower disease activity after 1 year of anti-TNF use. Conclusion A high percentage of CD patients suffer from fatigue. As a more aggressive phenotype seems to be associated with more severe fatigue and patients in remission still suffer from fatigue, a multidimensional approach for fatigue is warranted in these patients.