Séverine Vermeire

Publications of Séverine Vermeire

• Management of inflammatory bowel disease in pregnancy.

  Authors: Séverine Vermeire, Franck Carbonnel, Pierre G Coulie, Vincent Geenen, Johanna M W Hazes, Pierre L Masson, Filip De Keyser, Edouard Louis

  Journal of Crohn's & colitis. 05/2012;

  BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic disease affecting mainly young people in their reproductive years. IBD therefore has a major impact on patients' family planningBACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic disease affecting mainly young people in their reproductive years. IBD therefore has a major impact on patients' family planning decisions. Management of IBD in pregnancy requires a challenging balance between optimal disease control and drug safety considerations. This article aims to provide a framework for clinical decision making in IBD based on review of the literature on pregnancy-related topics. METHODS: Medline searches with search terms 'IBD', 'Crohn's disease' or 'ulcerative colitis' in combination with keywords for the topics fertility, pregnancy, congenital abnormalities and drugs names of drugs used for treatment of IBD. RESULTS: IBD patients have normal fertility, except for women after ileal pouch-anal anastomosis (IPAA) and men under sulfasalazine treatment. Achieving and maintaining disease remission is a key factor for successful pregnancy outcomes in this population, as active disease at conception carries an increased risk of preterm delivery and low birth weight. Clinicians should discuss the need for drug therapy to maintain remission with their patients in order to ensure therapy compliance. Most IBD drugs are compatible with pregnancy, except for methotrexate and thalidomide. If possible, anti-TNF therapy should be stopped by the end of the second trimester and the choice of delivery route should be discussed with the patient. CONCLUSIONS: Disease control prior to conception and throughout pregnancy is the cornerstone of successful pregnancy management in IBD patients.

• Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol.

  Authors: Xavier Hébuterne, Marc Lémann, Yoram Bouhnik, Olivier Dewit, Jean-Louis Dupas, Michael Mross, Geert D'Haens, Krassimir Mitchev, Etienne Ernault, Séverine Vermeire, Hedia Brixi-Benmansour, Tom G Moreels, Jean-Yves Mary, Philippe Marteau, Jean-Frédéric Colombel

  Gut. 04/2012;

  ObjectiveTo evaluate the efficacy of certolizumab pegol (CZP) in improving endoscopic lesions in patients with active ileocolonic Crohn's disease (CD).MethodsThis phase IIIB multicentre open-labelObjectiveTo evaluate the efficacy of certolizumab pegol (CZP) in improving endoscopic lesions in patients with active ileocolonic Crohn's disease (CD).MethodsThis phase IIIB multicentre open-label clinical trial enrolled 89 adult patients with active endoscopic disease (ulceration in ≥2 intestinal segments with a Crohn's Disease Endoscopic Index of Severity (CDEIS) score ≥8 points). Patients received subcutaneous CZP 400 mg at weeks 0, 2 and 4 and every 4 weeks up to week 52. Endoscopic evaluations were performed at weeks 0, 10 and 54. The primary outcome was mean change in CDEIS score at week 10; secondary outcome measures included endoscopic response (decrease in CDEIS score >5 points), remission (CDEIS score <6), complete remission (CDEIS score <3) and mucosal healing (no ulcer) at weeks 10 and 54.ResultsIn the intention-to-treat population (n=89) the mean±SD CDEIS score was 14.5±5.3 at baseline; the mean decrease in CDEIS score at week 10 was 5.7 (95% CI 4.6 to 6.8, p<0.0001). Rates of endoscopic response, endoscopic remission, complete endoscopic remission and mucosal healing at week 10 were 54%, 37%, 10% and 4%, respectively. At week 54 the corresponding rates were 49%, 27%, 14% and 8%, respectively. The safety profile was consistent with that of previous CZP trials.ConclusionsFollowing CZP treatment in patients with active CD, endoscopic lesions were improved as shown by the decrease in mean CDEIS score and by endoscopic response and remission rates. These benefits were achieved as early as week 10 and were generally maintained through week 54.Clinical Trial Registration NumberNCT00297648.

• Recommendations for the treatment of ulcerative colitis with infliximab: a gastroenterology expert group consensus.

  Authors: Walter Reinisch, Gert Van Assche, Ragnar Befrits, William Connell, Geert D'Haens, Subrata Ghosh, Pierre Michetti, Thomas Ochsenkühn, Remo Panaccione, Stefan Schreiber, Mark S Silverberg, Dario Sorrentino, C Janneke van der Woude, Séverine Vermeire, Julian Panes

  Journal of Crohn's & colitis. 03/2012; 6(2):248-58.

  Infliximab is currently the only biologic approved for treatment of adults with moderate to severe, active ulcerative colitis (UC) unresponsive to conventional therapies. It rapidly controlsInfliximab is currently the only biologic approved for treatment of adults with moderate to severe, active ulcerative colitis (UC) unresponsive to conventional therapies. It rapidly controls symptoms, induces and sustains steroid-free remission, stimulates mucosal healing, and reduces serious complications. Although infliximab tends to be reserved for patients with severe disease, it may be even more beneficial for moderate disease earlier in the disease course. Therefore, it is important to identify which patients are candidates for infliximab therapy. A collaborative Delphi survey was used to obtain consensus on use of biologic therapy in patients with UC from an expert panel of 12 gastroenterologists with substantial experience using infliximab in clinical practice and clinical trials. The panel also addressed issues that influence the use of infliximab in UC, including its potential as an alternative to surgery. The panel agreed that: (1) it is necessary to adopt additional treatment goals beyond symptom control, i.e., complete mucosal healing, steroid-free remission, improved QoL, and reduced long-term complications; (2) it may be possible to achieve these treatment goals with infliximab, especially if it is used earlier in the course of UC; and (3) infliximab should be offered as an alternative to surgery in patients being considered for colectomy. The panel also agreed on factors for identifying candidates for infliximab therapy (e.g., persistently active UC, steroid-dependent/refractory disease, and high C-reactive protein). This consensus statement provides useful and practical information on how to achieve evolving treatment goals with infliximab in moderate to severe UC.

• Genetic variants in autophagy-related genes and granuloma formation in a cohort of surgically treated Crohn's disease patients.

  Authors: Marko Brinar, Séverine Vermeire, Isabelle Cleynen, Bart Lemmens, Xavier Sagaert, Liesbet Henckaerts, Gert Van Assche, Karel Geboes, Paul Rutgeerts, Gert De Hertogh

  Journal of Crohn's & colitis. 02/2012; 6(1):43-50.

  Granulomas are a characteristic microscopic finding in Crohn's disease. Their clinical significance is controversial and their pathogenesis is unknown, but impaired processing of bacterial componentsGranulomas are a characteristic microscopic finding in Crohn's disease. Their clinical significance is controversial and their pathogenesis is unknown, but impaired processing of bacterial components has been suggested. Autophagy is a fundamental process involved in the elimination of intracellular bacteria. Genetic variants in autophagy genes IRGM and ATG16L1 have been associated with susceptibility to Crohn's disease. We therefore investigated whether variants in autophagy genes contribute to granuloma formation. Surgical specimens from 464 clinically well-documented Crohn's patients were reviewed and scored for the presence and distribution of granulomas. All patients were genotyped for the CD-associated SNPs in ATG16L1 and IRGM as well as for 77 haplotype tagging SNPs in 13 additional autophagy genes. Granulomas were found in 75% of the patients. Their frequency increased with more distal involvement of the GI tract. Granuloma positive patients were significantly younger at the time of diagnosis and surgery, and were more likely to smoke. We identified associations between granulomas and autophagy gene variants ATG4A (rs5973822), FNBP1L (rs17109951) and ATG4D (rs7248026; rs2304165; rs10439163). These findings suggest that granuloma formation is a marker of a more aggressive disease course, and that variants in autophagy genes ATG4A, ATG2A, FNBP1L and ATG4D, may contribute to granuloma formation.

• Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease.

  Authors: Maureen J Koslowski, Zora Teltschik, Julia Beisner, Elke Schaeffeler, Guoxing Wang, Irmgard Kübler, Michael Gersemann, Rachel Cooney, Derek Jewell, Walter Reinisch, Séverine Vermeire, Paul Rutgeerts, Matthias Schwab, Eduard F Stange, Jan Wehkamp

  PLoS genetics. 02/2012; 8(2):e1002523.

  Ileal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensinsIleal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensins are exclusively produced in Paneth cells (PCs) at small intestinal crypt bases. Different ileal CD-associated genes including NOD2, ATG16L1, and recently the β-catenin-dependant Wnt transcription factor TCF7L2 have been linked to impaired PC antimicrobial function. The Wnt pathway influences gut mucosal homeostasis and PC maturation, besides directly controlling HD-5/6 gene expression. The herein reported candidate gene study focuses on another crucial Wnt factor, the co-receptor low density lipoprotein receptor-related protein 6 (LRP6). We analysed exonic single nucleotide polymorphisms (SNPs) in a large cohort (Oxford: n = 1,893) and prospectively tested 2 additional European sample sets (Leuven: n = 688, Vienna: n = 1,628). We revealed an association of a non-synonymous SNP (rs2302685; Ile1062Val) with early onset ileal CD (OR 1.8; p = 0.00034; for homozygous carriers: OR 4.1; p = 0.00004) and additionally with penetrating ileal CD behaviour (OR 1.3; p = 0.00917). In contrast, it was not linked to adult onset ileal CD, colonic CD, or ulcerative colitis. Since the rare variant is known to impair LRP6 activity, we investigated its role in patient mucosa. Overall, LRP6 mRNA was diminished in patients independently from the genotype. Analysing the mRNA levels of PC product in biopsies from genotyped individuals (15 controls, 32 ileal, and 12 exclusively colonic CD), we found particularly low defensin levels in ileal CD patients who were carrying the variant. In addition, we confirmed a direct relationship between LRP6 activity and the transcriptional expression of HD-5 using transient transfection. Taken together, we identified LRP6 as a new candidate gene in ileal CD. Impairments in Wnt signalling and Paneth cell biology seem to represent pathophysiological hallmarks in small intestinal inflammation and should therefore be considered as interesting targets for new therapeutic approaches.

• Intestinal expression of SHIP in inflammatory bowel diseases.

  Authors: Ingrid Arijs, Gert De Hertogh, Bart Lemmens, Jan Van der Goten, Séverine Vermeire, Frans Schuit, Paul Rutgeerts

  Gut. 11/2011;

• Immune reactivity to β-tubulin isotype 5 and vesicular integral-membrane protein 36 in patients with autoimmune gastrointestinal disorders.

  Authors: Katrijn Op De Beéck, Karolien Van den Bergh, Séverine Vermeire, Sofie Decock, Rita Derua, Etienne Waelkens, Paul Rutgeerts, Frederik Nevens, Xavier Bossuyt

  Gut. 11/2011; 60(11):1601-2.

• Switch to adalimumab in patients with Crohn's disease controlled by maintenance infliximab: prospective randomised SWITCH trial.

  Authors: Gert Van Assche, Séverine Vermeire, Vera Ballet, Frederik Gabriels, Maja Noman, Geert D'Haens, Christophe Claessens, Evelien Humblet, Niels Vande Casteele, Ann Gils, Paul Rutgeerts

  Gut. 09/2011; 61(2):229-34.

  Elective switching between anti-tumour necrosis factor (TNF) agents not necessarily dictated by efficacy or tolerability occurs in clinical practice. A study was undertaken to evaluate prospectivelyElective switching between anti-tumour necrosis factor (TNF) agents not necessarily dictated by efficacy or tolerability occurs in clinical practice. A study was undertaken to evaluate prospectively the impact of elective switching of patients with Crohn's disease well controlled with intravenous infliximab to subcutaneous adalimumab in a controlled trial. An open-label randomised single-centre trial recruited 73 patients with ongoing response to at least 6 months of scheduled maintenance infliximab. Patients were randomised to continue intravenous 5 mg/kg infliximab or to switch to subcutaneous adalimumab 80 mg at baseline followed by 40 mg every other week for 1 year. Dose optimisation was allowed for intermittent flares, and patients with loss of response or intolerance could cross over to the alternative treatment group. Tolerability, patient preference and efficacy of both treatment options were the primary outcomes. Dose optimisation or interruption of treatment occurred in 17/36 patients (47%) in the adalimumab group and in 6/37 patients (16%) in the infliximab group (p=0.006). One patient interrupted infliximab treatment and 10 patients interrupted adalimumab treatment (p=0.003), mostly for loss of tolerance. Overall, patients preferred adalimumab treatment. All five serious adverse events were related to complicated Crohn's disease and occurred in patients randomised to adalimumab. Injection site reactions were more frequent than infusion reactions (8 vs 1, p=0.01), but only the latter caused cessation of further dosing. Anti-TNF serum levels were stable throughout the 1-year period in both groups. Elective switching from infliximab to adalimumab is associated with loss of tolerance and loss of efficacy within 1 year. Adherence to the first anti-TNF agent is recommended.

• Octreotide for the treatment of diarrhoea in patients with ileal pouch anal anastomosis: a placebo-controlled crossover study.

  Authors: G Van Assche, M Ferrante, S Vermeire, M Noman, K Rans, L Van der Biest, F Penninckx, A Wolthuis, P Rutgeerts, A D'Hoore

  Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 09/2011; 14(4):e181-6.

  Aim  Diarrhoea with urgency is a debilitating long-term complication of ileal pouch anal anastomosis (IPAA) after a proctocolectomy. Somatostatin analogues are used to control diarrhoea andAim  Diarrhoea with urgency is a debilitating long-term complication of ileal pouch anal anastomosis (IPAA) after a proctocolectomy. Somatostatin analogues are used to control diarrhoea and high-output ostomies. Hence, we designed a prospective, double-blind, crossover trial to explore the efficacy and tolerability of octreotide to reduce diarrhoea in adult patients with IPAA. Method  Patients were randomized to octreotide subcutaneously (SC), 500 μg three times daily (t.i.d.), or matching placebo SC for 7 days. Responders (a reduction in stool frequency of three or more stools per 24-h period and with a reduction in stool frequency of at least 30% after 7 days of treatment compared with baseline; the primary end-point) remained in the same group and nonresponders could cross over to the alternative treatment for 7 days. Open-label octeotide LAR 30 mg was offered to all responders on day 14. Flexible pouchoscopy with biopsies was performed at baseline in all patients and was repeated on days 7 and 14 in patients with pouchitis. Results  Fifteen patients (11 men, median age 52 years), all with ulcerative colitis, were randomized. Three patients were withdrawn for side effects during the blinded phase. Response was achieved by two of 12 and two of 11 patients treated with octreotide or placebo, respectively (including crossover, P = 0.9). The median stool frequency remained stable in both groups [Δoctreotide: 0 (IQR, -4 to 0), Δplacebo: -1 (IQR, -1 to 1), P = 0.45]. Octreotide had no effect on the modified pouch disease activity index (mPDAI), and pouchitis persisted in five of six subjects with pouchitis at onset. One subject received open-label octreotide LAR. Conclusion  Octreotide has no clear beneficial effect on the stool pattern or on pouchitis severity in patients with high stool frequency after IPAA.

• Regulatory macrophages induced by infliximab are involved in healing in vivo and in vitro.

  Authors: Anne Christine W Vos, Manon E Wildenberg, Ingrid Arijs, Marjolijn Duijvestein, Auke P Verhaar, Gert de Hertogh, Séverine Vermeire, Paul Rutgeerts, Gijs R van den Brink, Daniel W Hommes

  Inflammatory bowel diseases. 09/2011; 18(3):401-8.

  Regulatory macrophages play an important role in wound healing and gut homeostasis and have antiinflammatory properties. Induction of this cell type (Mψ(ind) ) by the anti-tumor necrosis factor (TNF)Regulatory macrophages play an important role in wound healing and gut homeostasis and have antiinflammatory properties. Induction of this cell type (Mψ(ind) ) by the anti-tumor necrosis factor (TNF) antibodies, infliximab and adalimumab, has recently been shown in vitro. Also, the superiority of infliximab/azathioprine combination therapy over infliximab or azathioprine monotherapy has recently been established, but the mechanism behind this remains unclear. The aim of this study was to examine the induction of regulatory macrophages in patients with and without mucosal healing in response to infliximab. In addition, we studied the effect of infliximab/azathioprine combination treatment on the differentiation and function of regulatory macrophages. Inflammatory bowel disease (IBD) patients (n = 10) underwent endoscopy before and after first infliximab treatment. Immunohistochemical staining of CD68 and CD206 was performed in all patients. Mixed lymphocyte reactions (MLRs) were treated with infliximab, azathioprine, or both. Macrophage phenotype was evaluated by flow cytometry and inhibition of T-cell proliferation was measured in a secondary MLR containing macrophages and third-party lymphocytes. A significant induction of regulatory macrophages was observed in patients with mucosal healing after treatment with infliximab; this induction was absent in patients without mucosal healing. In addition, Mψ(ind) have the ability to induce wound healing in an in vitro model, further suggesting a key role for infliximab-induced macrophages in mucosal healing. Upon infliximab/azathioprine combination treatment, an increased number of regulatory macrophages was observed. These macrophages also displayed stronger immunosuppressive properties than macrophages induced by infliximab monotherapy. These data show that regulatory macrophages may be involved in mucosal healing and provide a rationale for the superiority of infliximab/azathioprine combination treatment observed in the clinic. (Inflamm Bowel Dis 2012;).

• Rheumatoid arthritis and pregnancy: evolution of disease activity and pathophysiological considerations for drug use.

  Authors: Johanna M W Hazes, Pierre G Coulie, Vincent Geenen, Séverine Vermeire, Franck Carbonnel, Edouard Louis, Pierre Masson, Filip De Keyser

  Rheumatology (Oxford, England). 09/2011; 50(11):1955-68.

  It has long been known that pregnancy and childbirth have a profound effect on the disease activity of rheumatic diseases. For clinicians, the management of patients with RA wishing to becomeIt has long been known that pregnancy and childbirth have a profound effect on the disease activity of rheumatic diseases. For clinicians, the management of patients with RA wishing to become pregnant involves the challenge of keeping disease activity under control and adequately adapting drug therapy during pregnancy and post-partum. This article aims to summarize the current evidence on the evolution of RA disease activity during and after pregnancy and the use of anti-rheumatic drugs around this period. Of recent interest is the potential use of anti-TNF compounds in the preconception period and during pregnancy. Accumulating experience with anti-TNF therapy in other immune-mediated inflammatory diseases, such as Crohn's disease, provides useful insights for the use of TNF blockade in pregnant women with RA, or RA patients wishing to become pregnant.

• Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy.

  Authors: Fabian Schnitzler, Herma Fidder, Marc Ferrante, Vera Ballet, Maja Noman, Gert Van Assche, Bernard Spitz, Ilse Hoffman, Kristel Van Steen, Séverine Vermeire, Paul Rutgeerts

  Inflammatory bowel diseases. 09/2011; 17(9):1846-54.

  Infliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit/riskInfliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit/risk profile of IFX and ADA during pregnancy. This observational study assessed pregnancy outcomes in 212 women with IBD under antitumor necrosis factor alpha (TNF) treatment at our IBD unit. Pregnancy outcomes in 42 pregnancies with direct exposure to anti-TNF treatment (35 IFX, 7 ADA) were compared with that in 23 pregnancies prior to IBD diagnosis, 78 pregnancies before start of IFX, 53 pregnancies with indirect exposure to IFX, and 56 matched pregnancies in healthy women. Thirty-two of the 42 pregnancies ended in live births with a median gestational age of 38 weeks (interquartile range [IQR] 37-39). There were seven premature deliveries, six children had low birth weight, and there was one stillbirth. One boy weighed 1640 g delivered at week 33, died at age of 13 days because of necrotizing enterocolitis. A total of eight abortions (one patient wish) occurred in seven women. Trisomy 18 was diagnosed in one fetus of a mother with CD at age 37 under ADA treatment (40 mg weekly) and pregnancy was terminated. Pregnancy outcomes after direct exposure to anti-TNF treatment were not different from those in pregnancies before anti-TNF treatment or with indirect exposure to anti-TNF treatment but outcomes were worse than in pregnancies before IBD diagnosis. Direct exposure to anti-TNF treatment during pregnancy was not related to a higher incidence of adverse pregnancy outcomes than IBD overall.

• Malignancies and mortality in 200 patients with primary sclerosering cholangitis: a long-term single-centre study.

  Authors: Johan Fevery, Liesbet Henckaerts, Robin Van Oirbeek, Séverine Vermeire, Paul Rutgeerts, Frederik Nevens, Werner Van Steenbergen

  Liver international : official journal of the International Association for the Study of the Liver. 07/2011; 32(2):214-22.

  The outcome of primary sclerosing cholangitis (PSC) has improved by liver transplantation (LT), but patients often develop malignancies. We analysed morbidity and mortality patterns to defineThe outcome of primary sclerosing cholangitis (PSC) has improved by liver transplantation (LT), but patients often develop malignancies. We analysed morbidity and mortality patterns to define strategies to prevent complications. Two hundred consecutive patients diagnosed before October 2005 were studied. Malignancies developed in 40 (20%) and led to death in 28 patients (45.9% of the 61 mortalities). Cholangiocarcinoma (CCa) developed in 13 patients, and was detected shortly after the diagnosis of PSC in 31%. Colorectal carcinomas were documented in 10 and dysplastic adenomas in four patients; eight had ulcerative colitis, two Crohn's colitis, one unclassified inflammatory bowel disease (IBDu), three had no IBD. Five died of colorectal cancer. Three carcinomas and two adenomas were localized in the caecum or ascending colon, but most (n=10) in the recto-sigmoidal region. Hepatocellular carcinoma developed in three patients with advanced fibrosis/cirrhosis, and pancreatic cancer in five. LT has been carried out in 42 patients, 6.1 years (median, 0.5-25) after the diagnosis of PSC. Mortality was due to hepatic complications in 13 patients. Within 5 years of the diagnosis, deaths were because of malignancy in 12 patients and to hepatobiliary decompensation in only three, whereas 18 had been transplanted. Since the use of transplantation, malignancies are the major cause of death. CCa has to be searched for in any new symptomatic patient. Colorectal malignancy occurs frequently. Colonoscopy at the diagnosis of PSC is obligatory and should be repeated at 1-2 years interval in the patients with IBD and every 5 years in those without IBD.

• Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease.

  Authors: Liesbet Henckaerts, Isabelle Cleynen, Marko Brinar, Jestinah Mahachie John, Kristel Van Steen, Paul Rutgeerts, Séverine Vermeire

  Inflammatory bowel diseases. 06/2011; 17(6):1392-7.

  The autophagy pathway has been linked with Crohn's disease (CD) through association of the ATG16L1 and IRGM genes with susceptibility for CD, and also to the Nod2 pathway, involved in CD. Our aim wasThe autophagy pathway has been linked with Crohn's disease (CD) through association of the ATG16L1 and IRGM genes with susceptibility for CD, and also to the Nod2 pathway, involved in CD. Our aim was to investigate polymorphisms in selected autophagy genes for their association with susceptibility to CD. We prioritized all known human homologs of yeast autophagy (Atg) genes according to their location in a known inflammatory bowel disease (IBD) locus or in a genomic region detected in a genome-wide association study (GWAS) or GWAS-meta-analysis. A total of 70 haplotype tagging single nucleotide polymorphisms (tSNPs) in 12 genes were genotyped in a cohort of CD patients (n = 947) and controls (n = 548). Transmission disequilibrium testing (TDT) was performed in an independent cohort of 335 parent-child CD-trios. The frequency of the T-allele of tSNP rs12303764 in ULK1 was significantly higher in CD (64%) versus controls (57%, corrected P-value 0.002). TDT demonstrated overtransmission of this allele to affected offspring (P = 0.02). Model-based multifactor dimensionality reduction (MB-MDR) interaction analysis confirmed a strong main effect for rs12303764. No interaction was found between ULK1 and CARD15, or between ULK1 genotypes and CD phenotypes. We report a genetic association with a tSNP in ULK1, an interesting candidate gene for IBD, given the role of ULK1 in autophagy initiation, and the interaction between Nod2 and autophagy pathways. To further clarify the role of ULK1 in CD, an in-depth investigation of the variation in the region and possible role for copy number variation in this region should be evaluated.

• To what extent are genetics clinically useful?

  Authors: Séverine Vermeire

  Best practice & research. Clinical gastroenterology. 04/2011; 25 Suppl 1:S8-14.

  The volume of research undertaken on the genetic susceptibility of inflammatory bowel diseases has been tremendous. International collaborative efforts which initiated in 1997 and have not stoppedThe volume of research undertaken on the genetic susceptibility of inflammatory bowel diseases has been tremendous. International collaborative efforts which initiated in 1997 and have not stopped since, led to the identification at present of more than 100 IBD risk loci. Yet, only 25% of the genetic variance is explained. It is hypothesized that rare variants, other forms of genetic variation (copy number variation), as well as gene-gene and geneenvironment interactions, explain the missing heritability. From all genes identified, the pattern recognition receptor NOD2/CARD15 is still the most understood at present. The field of IBD genetics has translated itself so far in identifying pathways important for disease pathogenesis (autophagy, Th17/IL23, pattern recognition receptors and innate immunity, barrier integrity), some of which have promising therapeutic consequences. Second, although genetic testing will most likely have no or a very limited role in diagnosing patients, it is anticipated that genetic markers will be implemented in an integrated prognostic approach. Efforts to predict disease course and response to therapy have shown interesting results.

• Dilate or wait for effective anti-inflammatory treatment for stenotic lesions associated with active inflammatory signs in Crohn's disease - The authors' response.

  Authors: Clara Thienpont, Séverine Vermeire, Paul Rutgeerts, Gert Van Assche

  Gut. 03/2011;

• Tolerability of shortened infliximab infusion times in patients with inflammatory bowel diseases: a single-center cohort study.

  Authors: Christine Breynaert, Marc Ferrante, Herma Fidder, Kristel Van Steen, Maja Noman, Vera Ballet, Séverine Vermeire, Paul Rutgeerts, Gert Van Assche

  The American journal of gastroenterology. 03/2011; 106(4):778-85.

  Scheduled maintenance therapy with infliximab decreases the risk of infusion reactions. Many centers have accelerated infusion times to 1 h in selected patients who tolerate 5 mg/kg infliximabScheduled maintenance therapy with infliximab decreases the risk of infusion reactions. Many centers have accelerated infusion times to 1 h in selected patients who tolerate 5 mg/kg infliximab infusions. The aim of this study was to compare the tolerability of 1-h and 2-h infliximab infusions in patients with inflammatory bowel disease (IBD) in a large single-center cohort. The primary end point was the incidence of infusion reactions in both groups. A retrospective chart analysis of all IBD patients treated with infliximab was performed. Infusions in scheduled maintenance for at least 6 months from December 1994 until March 2009 were included. All patients were treated at the infusion unit or during hospitalization under standard operating procedures. Infusion parameters were prospectively recorded. From 2004, in patients tolerating at least four 2-h infusions, infusions were given over 1 h. As of March 2009, 953 patients with IBD (77.6% Crohn's disease, 22.4% ulcerative colitis) had been treated with infliximab. A total of 474 patients met the criteria of scheduled maintenance therapy. In total, 9,155 maintenance infusions were administered (4,307 over 1 h). No severe infusion reactions were documented. Mild acute reactions occurred in 0.6% (27/4,307) of the 1-h-infusion group and in 1.7% (80/4848) of the 2-h infusion group (P=0.0034). Delayed infusion reactions occurred in 0.2% of 1-h and 0.5% of 2-h infusion group patients (P=0.277). Loss of tolerability due to infusion reactions (1-h group 2.9% versus 2-h group 4.1%) was evenly distributed (P=0.34). None of the prespecified variables were predictive of infusion reactions in a multivariate analysis. In patients with IBD tolerating 2-h infusions of infliximab scheduled maintenance therapy, the infusion time can be shortened to 1 h with good tolerability. No severe reactions were observed and no predictors of infusion reactions were identified.

• High-throughput method for comparative analysis of denaturing gradient gel electrophoresis profiles from human fecal samples reveals significant increases in two bifidobacterial species after inulin-type prebiotic intake.

  Authors: Marie Joossens, Geert Huys, Kristel Van Steen, Margo Cnockaert, Séverine Vermeire, Paul Rutgeerts, Kristin Verbeke, Peter Vandamme, Vicky De Preter

  FEMS microbiology ecology. 02/2011; 75(2):343-9.

  Denaturing gradient gel electrophoresis (DGGE) is one of the most commonly used molecular tools to study complex microbial communities. Despite its widespread use, meaningful interpretative analysisDenaturing gradient gel electrophoresis (DGGE) is one of the most commonly used molecular tools to study complex microbial communities. Despite its widespread use, meaningful interpretative analysis remains a major drawback of this method. We evaluated the combination of computer-assisted band-matching with nonparametric statistics for comparative analysis of DGGE banding patterns. Fecal samples from 17 healthy volunteers who consumed 20 g of the prebiotic compound oligofructose-enriched inulin (OF-IN) for 4 weeks were analyzed before and after treatment. DGGE fingerprinting profiles were analyzed using bionumerics software version 4.6., which resulted in a data matrix that was used for statistical analysis. When comparing DGGE profiles before and after OF-IN intake with a Wilcoxon nonparametric test for paired data, two band-classes increased significantly after OF-IN intake (P<0.003 and <0.02). These two band-classes could be assigned to the species Bifidobacterium longum and Bifidobacterium adolescentis by band-sequencing analysis, and their significant increase was quantitatively confirmed with real-time PCR using species-specific primers (respectively P<0.012 and <0.010). Therefore, the nonparametric analysis of a data matrix obtained by computer-assisted band-matching of complex profiles facilitated the interpretative analysis of these profiles and provided an objective and high-throughput method for the detection of significant taxonomic differences in larger numbers of complex profiles.

• Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

  Authors: Carl A Anderson, Gabrielle Boucher, Charlie W Lees, Andre Franke, Mauro D'Amato, Kent D Taylor, James C Lee, Philippe Goyette, Marcin Imielinski, Anna Latiano [......] Mark J Daly, Jeffrey C Barrett, Miles Parkes, Vito Annese, Hakon Hakonarson, Graham Radford-Smith, Richard H Duerr, Séverine Vermeire, Rinse K Weersma, John D Rioux

  Nature genetics. 02/2011; 43(3):246-52.

  Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide associationGenome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

• The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study.

  Authors: Séverine Vermeire, Subrata Ghosh, Julian Panes, Jens F Dahlerup, Andreas Luegering, Jana Sirotiakova, Ulrike Strauch, Gary Burgess, Jacqueline Spanton, Steven W Martin, Wojciech Niezychowski

  Gut. 02/2011; 60(8):1068-75.

  Leucocyte migration to gut mucosa, mediated by integrin binding to mucosal addressin cell adhesion molecule (MAdCAM), is a promising target for therapeutic intervention in inflammatory bowel disease.Leucocyte migration to gut mucosa, mediated by integrin binding to mucosal addressin cell adhesion molecule (MAdCAM), is a promising target for therapeutic intervention in inflammatory bowel disease. This first-in-human study of a monoclonal antibody to MAdCAM, PF-00547,659, aimed to explore the safety and preliminary efficacy of this gut-specific mechanism in ulcerative colitis. In this randomised, double-blind placebo-controlled study, 80 patients with active ulcerative colitis received single or multiple (three doses, 4-week intervals) doses of PF-00547,659 0.03-10 mg/kg IV/SC, or placebo. Safety was assessed by adverse events, laboratory tests, and immunogenicity. Exploratory efficacy analyses were based on Mayo score and endoscopic responder rates at weeks 4 and 12. Faecal calprotectin was quantified as a measure of disease activity, and the number of α₄β₇⁺ lymphocytes was measured to demonstrate drug activity. No obvious drug-related side effects were observed in the PF-00547,659 group, while patient numbers, especially those fully exposed, were small. Overall responder/remission rates at 4 and 12 weeks were 52%/13% and 42%/22%, respectively with combined PF-00547,659 doses compared with 32%/11% and 21%/0%, respectively with placebo. Equivalent endoscopic responder rates were 50% and 42% versus 26% and 29%, respectively. Faecal calprotectin levels decreased to a greater extent with PF-00547,659 than placebo (week 4: 63% vs 18%). Despite variability, there was a trend for an increase in α₄β₇⁺ lymphocytes in patients receiving PF-00547,659. The favourable short-term safety profile and preliminary efficacy findings for PF-00547,659 in this first-in-human study pave the way for further investigation in larger trials, to establish the role of PF-00547,659 in ulcerative colitis treatment. Trial Register No: NCT00928681.