Walter Reinisch

Publications of Walter Reinisch

• Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial.

  Authors: Wolfgang Hueber, Bruce E Sands, Steve Lewitzky, Marc Vandemeulebroecke, Walter Reinisch, Peter D R Higgins, Jan Wehkamp, Brian G Feagan, Michael D Yao, Marek Karczewski, Jacek Karczewski, Nicole Pezous, Stephan Bek, Gerard Bruin, Bjoern Mellgard, Claudia Berger, Marco Londei, Arthur P Bertolino, Gervais Tougas, Simon P L Travis

  Gut. 05/2012;

  ObjectiveThe authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease.DesignIn a double-blind,ObjectiveThe authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease.DesignIn a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response.Results59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (CDAI (SD) =33.9 (19.7), 95% credible interval -4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4-10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (-1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected).ConclusionsBlockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo.Clinical trial registrationThis trial was registered at ClinicalTrial.gov with the number NCT01009281.

• Extracorporeal photopheresis (ECP) in patients with steroid-dependent Crohn's disease: An open-label, multicenter, prospective trial.

  Authors: Walter Reinisch, Robert Knobler, Paul J Rutgeerts, Thomas Ochsenkühn, Frank Anderson, Christian von Tirpitz, Martin Kaatz, C Janneke van der Woude, Dennis Parenti, Peter J Mannon

  Inflammatory bowel diseases. 05/2012;

  BACKGROUND: Extracorporeal photopheresis (ECP) involves ex vivo leukocyte treatment with methoxsalen and UVA light to generate a tolerogenic response. A previous trial demonstrated that ECP permitsBACKGROUND: Extracorporeal photopheresis (ECP) involves ex vivo leukocyte treatment with methoxsalen and UVA light to generate a tolerogenic response. A previous trial demonstrated that ECP permits corticosteroid withdrawal in steroid-dependent Crohn's disease (CD) patients who were in clinical remission. We studied the effect of ECP on steroid withdrawal in steroid-dependent CD. METHODS: Patients with CD for ≥6 months, in remission at baseline while on steroids, but who had failed at ≥1 steroid withdrawal were included. Patients received two ECP treatments every 2 weeks for the 24-week steroid tapering period and underwent steroid-tapering. Patients completing steroid tapering could receive maintenance ECP (two treatments/week) every month for 24 weeks. RESULTS: Thirty-one patients (Crohn's Disease Activity Index [CDAI] score 91; Inflammatory Bowel Disease Questionnaire [IBDQ] 172.5) were enrolled (baseline corticosteroid dose, 20 mg/day); 65% were refractory to/intolerant of anti-tumor necrosis factor (TNF) agents or immunosuppressants. After 24 weeks of ECP, 7 of 31 (22.6%) patients discontinued steroids while maintaining a CDAI of <150. At week 24, the steroid dose for the remaining patients on corticosteroids was 10 mg (P < 0.003 vs. baseline) with a CDAI of 110 and an IBDQ of 179. Following maintenance treatment, three patients remained in steroid-free remission. The 10 patients in the study and receiving ECP at week 48 had a steroid dose of 3.5 mg with a CDAI of 40 and an IBDQ of 188. CONCLUSIONS: ECP permitted discontinuation or reduction of steroids in a population of refractory steroid-dependent CD patients. ECP may be useful in permitting steroid withdrawal in selected steroid-dependent CD patients. Ideally, these results need to be confirmed in a "sham-controlled" clinical trial. (Inflamm Bowel Dis 2012;).

• High Risk of Transfusion-induced Alloimmunization of Patients with Inflammatory Bowel Disease.

  Authors: Pavol Papay, Klaus Hackner, Harald Vogelsang, Gottfried Novacek, Christian Primas, Walter Reinisch, Alexander Eser, Andrea Mikulits, Wolfgang R Mayr, Günther F Körmöczi

  The American journal of medicine. 05/2012;

  BACKGROUND: Anemia is highly prevalent in inflammatory bowel disease patients, and red blood cell transfusion is often indicated already at reproductive age. Both transfusion and pregnancy may induceBACKGROUND: Anemia is highly prevalent in inflammatory bowel disease patients, and red blood cell transfusion is often indicated already at reproductive age. Both transfusion and pregnancy may induce red cell alloantibodies, potentially complicating further transfusions and pregnancies. As recent evidence suggests that inflammation may promote red cell antibody induction, the alloimmunization risk of these patients after allogenic erythrocyte exposure was investigated. METHODS: Red cell alloantibody status and clinical data were analyzed in 193 inflammatory bowel disease patients with a history of transfusion or pregnancy, and compared with transfused controls with noninflammatory diseases (n=357). RESULTS: In transfused patients with inflammatory bowel disease, a 2.5-fold-increased red cell antibody prevalence was found (10/119, 8.4%), compared with transfused sex-matched controls with noninflammatory diseases (12/357, 3.4%; P=.023). Patients with inflammatory bowel disease had fewer transfusions (mean 3.0 vs 4.2, P=.003) but higher C-reactive protein levels during transfusion than controls (mean 8.4 vs 5.4 mg/dL, P <.001). The red cell antibodies of inflammatory bowel disease patients were clinically significant, directed against different Rh, Kell, Duffy, or Lutheran blood group antigens, and associated with higher number of transfusions (odds ratio 1.57; 95% confidence interval, 1.03-2.39). Conversely, immunomodulatory therapy during transfusion showed negative association (odds ratio 0.12; 95% confidence interval, 0.02-0.61). Only 1.4% of inflammatory bowel disease patients with pregnancy alone had antibodies. CONCLUSIONS: Patients with inflammatory bowel disease exhibited a very high risk of transfusion-induced red cell alloimmunization, possibly potentiated by inflammation. Aside from a restrictive transfusion strategy, the implementation of prophylactic blood group phenotype matching of red cell concentrates (not only for ABO and RhD but also RhCcEe, Kell, Kidd, Duffy) could prevent antibody induction and associated complications in these patients.

• Adalimumab improves patient-reported outcomes and reduces indirect costs in patients with moderate to severe Crohn's disease: Results from the CARE trial.

  Authors: Edouard Louis, Robert Löfberg, Walter Reinisch, Anne Camez, Mei Yang, Paul F Pollack, Naijun Chen, Jingdong Chao, Parvez M Mulani

  Journal of Crohn's & colitis. 04/2012;

  BACKGROUND AND AIMS: Crohn's disease negatively affects patients' quality of life and ability to work. We investigated the impact of adalimumab on work productivity, daily activities, and quality ofBACKGROUND AND AIMS: Crohn's disease negatively affects patients' quality of life and ability to work. We investigated the impact of adalimumab on work productivity, daily activities, and quality of life in an open-label trial (N=945). The population comprised both infliximab-naïve and -exposed patients, including infliximab primary non-responders. METHODS: Patients received adalimumab induction therapy (160mg/80mg at Weeks 0/2), followed by adalimumab 40mg every other week for up to 20weeks (patients with flares/non-response could receive 40mg weekly at/after Week 12). The Work Productivity and Activity Impairment Questionnaire and Short Inflammatory Bowel Disease Questionnaire were assessed. Indirect cost savings were estimated based on the average work productivity improvements at Week 20. RESULTS: Mean baseline scores indicated severe productivity impairment and poor quality of life. At Week 20, 60% of infliximab-naïve and 47% of infliximab primary non-responders achieved clinically important improvements (≥9 points) on the Short Inflammatory Bowel Disease Questionnaire, and 51% and 43%, respectively, achieved the minimum clinically important difference (improvement ≥7 percentage points) for total work productivity impairment (non-responder imputation). At Week 20, 64% of infliximab-naïve and 55% of infliximab primary non-responders achieved clinically important improvements in total activity impairment. Estimated 20-week total indirect productivity-related cost savings were €3070 per infliximab-naïve patient and €2059 per infliximab-exposed patient. CONCLUSIONS: Adalimumab therapy significantly improved work productivity and disease-specific quality of life for patients with moderate to severe Crohn's disease. Patients who failed prior infliximab therapy and patients naïve to infliximab benefited from adalimumab, with potentially greater benefits for infliximab-naïve patients (NCT00409617).

• Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS).

  Authors: Simon P L Travis, Dan Schnell, Piotr Krzeski, Maria T Abreu, Douglas G Altman, Jean-Frédéric Colombel, Brian G Feagan, Stephen B Hanauer, Marc Lémann, Gary R Lichtenstein, Phillippe R Marteau, Walter Reinisch, Bruce E Sands, Bruce R Yacyshyn, Christian A Bernhardt, Jean-Yves Mary, William J Sandborn

  Gut. 04/2012; 61(4):535-42.

  Background Variability in endoscopic assessment necessitates rigorous investigation of descriptors for scoring severity of ulcerative colitis (UC). Objective To evaluate variation in the overallBackground Variability in endoscopic assessment necessitates rigorous investigation of descriptors for scoring severity of ulcerative colitis (UC). Objective To evaluate variation in the overall endoscopic assessment of severity, the intra- and interindividual variation of descriptive terms and to create an Ulcerative Colitis Endoscopic Index of Severity which could be validated. Design A two-phase study used a library of 670 video sigmoidoscopies from patients with Mayo Clinic scores 0-11, supplemented by 10 videos from five people without UC and five hospitalised patients with acute severe UC. In phase 1, each of 10 investigators viewed 16/24 videos to assess agreement on the Baron score with a central reader and agreed definitions of 10 endoscopic descriptors. In phase 2, each of 30 different investigators rated 25/60 different videos for the descriptors and assessed overall severity on a 0-100 visual analogue scale. κ Statistics tested inter- and intraobserver variability for each descriptor. A general linear mixed regression model based on logit link and β distribution of variance was used to predict overall endoscopic severity from descriptors. Results There was 76% agreement for 'severe', but 27% agreement for 'normal' appearances between phase I investigators and the central reader. In phase 2, weighted κ values ranged from 0.34 to 0.65 and 0.30 to 0.45 within and between observers for the 10 descriptors. The final model incorporated vascular pattern, (normal/patchy/complete obliteration) bleeding (none/mucosal/luminal mild/luminal moderate or severe), erosions and ulcers (none/erosions/superficial/deep), each with precise definitions, which explained 90% of the variance (pR(2), Akaike Information Criterion) in the overall assessment of endoscopic severity, predictions varying from 4 to 93 on a 100-point scale (from normal to worst endoscopic severity). Conclusion The Ulcerative Colitis Endoscopic Index of Severity accurately predicts overall assessment of endoscopic severity of UC. Validity and responsiveness need further testing before it can be applied as an outcome measure in clinical trials or clinical practice.

• Results of the 2nd scientific workshop of the ECCO (IV): Therapeutic strategies to enhance intestinal healing in inflammatory bowel disease.

  Authors: Alessandro Armuzzi, Gert Van Assche, Walter Reinisch, Guillaume Pineton de Chambrun, Anne Griffiths, Malgorzata Sladek, Jan C Preiss, Milan Lukas, Geert D'Haens

  Journal of Crohn's & colitis. 03/2012;

  Evidence supporting the importance of assessment of mucosal healing in inflammatory bowel disease has increased in the last years. Mucosal healing has been integrated in the assessment of treatmentEvidence supporting the importance of assessment of mucosal healing in inflammatory bowel disease has increased in the last years. Mucosal healing has been integrated in the assessment of treatment efficacy in ulcerative colitis, but in Crohn's disease this thought has arised after biological agents have been evaluated in clinical trials. Although a validated definition of mucosal healing still does not exist, its use is also assuming an increasingly important role in the follow-up of individual patients in clinical practice. Corticosteroids induce mucosal healing in a small proportion of patients with Crohn's disease and are of no benefit to maintain it. By contrast, mucosal healing in Crohn's disease can be achieved and maintained, with varying degrees of evidence and success, with thiopurines and biological agents. In ulcerative colitis, the ability of corticosteroids to induce mucosal healing is well recognized. 5-aminosalicylates, thiopurines and biological agents are also able to induce mucosal healing and, additionally, to maintain it. Mucosal healing assessment should be considered in clinical practice when symptoms persist despite therapy or when treatment discontinuation is being considered. Conversely, in patients whose clinical remission is not associated with mucosal healing, intensification of treatment is not currently recommended because of lack of evidence.

• 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.

• Adalimumab Induces and Maintains Mucosal Healing in Patients With Crohn's Disease: Data From the EXTEND Trial.

  Authors: Paul Rutgeerts, Gert Van Assche, William J Sandborn, Douglas C Wolf, Karel Geboes, Jean-Frédéric Colombel, Walter Reinisch, Ashish Kumar, Andreas Lazar, Anne Camez, Kathleen G Lomax, Paul F Pollack, Geert D'haens

  Gastroenterology. 02/2012;

  BACKGROUND & AIMS: We investigated the efficacy of adalimumab for inducing and maintaining mucosal healing in patients with Crohn's disease (CD). METHODS: A randomized, double-blind,BACKGROUND & AIMS: We investigated the efficacy of adalimumab for inducing and maintaining mucosal healing in patients with Crohn's disease (CD). METHODS: A randomized, double-blind, placebo-controlled trial (extend the safety and efficacy of adalimumab through endoscopic healing [EXTEND]) evaluated adalimumab for induction and maintenance of mucosal healing in 135 adults with moderate to severe ileocolonic CD. The baseline degree of mucosal ulceration was documented by ileocolonoscopy. All patients received induction therapy (subcutaneous adalimumab 160/80 mg at weeks 0/2). At week 4, patients were randomly assigned to groups given 40 mg adalimumab or placebo every other week through week 52. Open-label adalimumab was given to patients with flares or no response, starting at week 8. Mucosal healing was reassessed by ileocolonoscopy at weeks 12 and 52. RESULTS: Twenty-seven percent of patients receiving adalimumab had mucosal healing at week 12 (the primary end point) versus 13% given placebo (P = .056). At week 52, rates of mucosal healing were 24% and 0, respectively (P < .001). Remission rates, based on the Crohn's Disease Endoscopic Index of Severity, were 52% for adalimumab and 28% for placebo at week 12 (P = .006) and 28% and 3%, respectively, at week 52 (P < .001). Rates of clinical remission based on the Crohn's Disease Activity Index were greater among patients given continuous adalimumab therapy versus placebo at weeks 12 (47% vs 28%; P = .021) and 52 (33% vs 9%; P = .001). Five serious (1 during induction and 4 during open-label therapy) and 3 opportunistic infections (1 in each group during double-blind therapy and 1 during open-label therapy) were reported (n = 135). CONCLUSIONS: Following induction therapy with adalimumab, patients with moderately to severely active CD who continue to receive adalimumab are more likely to achieve mucosal healing than those given placebo.

• Simultaneous quantification of eleven thiopurine nucleotides by liquid chromatography-tandem mass spectrometry.

  Authors: Ute Hofmann, Georg Heinkele, Sieglinde Angelberger, Elke Schaeffeler, Cornelia Lichtenberger, Simon Jaeger, Walter Reinisch, Matthias Schwab

  Analytical chemistry. 02/2012; 84(3):1294-301.

  The prodrugs azathioprine and 6-mercaptopurine, which are well-established anticancer and immunosuppressive agents, are extensively metabolized by activating and inactivating enzymes. Whereas theThe prodrugs azathioprine and 6-mercaptopurine, which are well-established anticancer and immunosuppressive agents, are extensively metabolized by activating and inactivating enzymes. Whereas the 6-thioguanine nucleotides (TGN) are currently being considered as major active metabolites, methylthioinosine nucleotides seem to contribute to the cytotoxic effect as well. Thiopurine-related adverse drug reactions and thiopurine failure are frequent. Thus, therapeutic monitoring of TGN and methylthioinosine derivatives has been suggested to improve thiopurine therapy, however with limited success. To elucidate systematically underlying molecular mechanisms as potential explanation for interindividual variability of thiopurine response, we developed a novel highly specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantitation of eleven mono-, di-, and triphosphates of thioguanosine, methylthioinosine, methylthioguanosine, and thioinosine. Using stable isotope-labeled analogues as internal standards obtained by chemical synthesis, an intra- and interassay variability below 8% and an accuracy of 92% to 107% were achieved in spiked quality control samples with known standards. All eleven metabolites could be determined in red blood cells from patients with inflammatory bowel diseases and long-term azathioprine therapy. Thus, our novel method opens a new avenue for the understanding of the thiopurine metabolism by quantitation of all important thiopurine nucleotide metabolites in one run.

• Physician perspectives on unresolved issues in the use of conventional therapy in Crohn's disease: results from an international survey and discussion programme.

  Authors: Marc Ferrante, Konstantinos Karmiris, Evan Newnham, Jesse Siffledeen, Zuzana Zelinkova, Gert van Assche, Peter L Lakatos, Julian Panés, Andreas Sturm, Simon Travis, C Janneke van der Woude, Walter Reinisch, Jean-Frédéric Colombel, Remo Panaccione

  Journal of Crohn's & colitis. 02/2012; 6(1):116-31.

  Data on the optimal use of conventional therapies in Crohn's disease are lacking in guidelines. An educational programme was established to explore questions raised in clinical practice and toData on the optimal use of conventional therapies in Crohn's disease are lacking in guidelines. An educational programme was established to explore questions raised in clinical practice and to provide practical answers. Telephone interviews with 96 gastroenterologists and a web survey of 1370 gastroenterologists identified 26 key questions. Ten questions were taken forward to the next stage based on the opinion of an International Steering Committee. Draft answers to the questions were prepared from available evidence following a literature search. The draft answers were debated in national meetings of participating countries (n=36) and voted on using a standard scoring system. Revised answers went forward to an international meeting and were debated and voted on using the same methodology. Final answers were developed, based on evidence and clinical experience of the participants. Evidence on corticosteroid and immunomodulator use such as dosage, timing and duration, choice of drug or regimen, and safety is scarce. Key points of the answers included the importance of: identifying patients with poor prognosis; early intervention with optimal doses of immunomodulators; avoiding prolonged or repetitive corticosteroid therapy; achieving corticosteroid-free remission; achieving a balance between clinical benefit and safety when intensifying or prolonging therapy or combining different agents; re-evaluating therapy at appropriate time points; and considering the role of biomarkers and mucosal healing. The answers to 10 key questions were based on available evidence and clinical experience of programme participants. It is hoped they will be of practical use in everyday gastroenterology practice.

• 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.

• Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.

  Authors: William J Sandborn, Gert van Assche, Walter Reinisch, Jean-Frederic Colombel, Geert D'Haens, Douglas C Wolf, Martina Kron, Mary Beth Tighe, Andreas Lazar, Roopal B Thakkar

  Gastroenterology. 11/2011; 142(2):257-65.e1-3.

  Adalimumab is a fully human monoclonal antibody that binds tumor necrosis factor (TNF)-α. Its efficacy as maintenance therapy for patients with ulcerative colitis has not been studied in aAdalimumab is a fully human monoclonal antibody that binds tumor necrosis factor (TNF)-α. Its efficacy as maintenance therapy for patients with ulcerative colitis has not been studied in a controlled, double-blind trial. Ulcerative colitis long-term remission and maintenance with adalimumab 2 (ULTRA 2) was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of adalimumab in induction and maintenance of clinical remission in 494 patients with moderate-to-severe ulcerative colitis who received concurrent treatment with oral corticosteroids or immunosuppressants. Patients were stratified based on prior exposure to TNF-α antagonists (either had or had not been previously treated with anti-TNF-α) and randomly assigned to groups given adalimumab 160 mg at week 0, 80 mg at week 2, and then 40 mg every other week or placebo. Primary end points were remission at weeks 8 and 52. Overall rates of clinical remission at week 8 were 16.5% on adalimumab and 9.3% on placebo (P = .019); corresponding values for week 52 were 17.3% and 8.5% (P = .004). Among anti-TNF-α naïve patients, rates of remission at week 8 were 21.3% on adalimumab and 11% on placebo (P = .017); corresponding values for week 52 were 22% and 12.4% (P = .029). Among patients who had previously received anti-TNF agents, rates of remission at week 8 were 9.2% on adalimumab and 6.9% on placebo (P = .559); corresponding values for week 52 were 10.2% and 3% (P = .039). Serious adverse events occurred in 12% of patients given adalimumab or placebo. Serious infections developed in 1.6% of patients given adalimumab and 1.9% given placebo. In the group given adalimumab, 1 patient developed squamous cell carcinoma and 1 developed gastric cancer. Adalimumab was safe and more effective than placebo in inducing and maintaining clinical remission in patients with moderate-to-severe ulcerative colitis who did not have an adequate response to conventional therapy with steroids or immunosuppressants.

• Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis.

  Authors: Jean Frédéric Colombel, Paul Rutgeerts, Walter Reinisch, Dirk Esser, Yanxin Wang, Yinghua Lang, Colleen W Marano, Richard Strauss, Björn J Oddens, Brian G Feagan, Stephen B Hanauer, Gary R Lichtenstein, Daniel Present, Bruce E Sands, William J Sandborn

  Gastroenterology. 06/2011; 141(4):1194-201.

  In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergoIn the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergo remission, and have mucosal healing. We investigated the association between early improvement (based on endoscopy) and subsequent clinical outcome. Patients underwent endoscopic evaluations at weeks 0, 8, 30, and 54 (ACT-1 only), and were categorized into 4 subgroups by week 8 (Mayo endoscopy subscore, 0-3). The association of week 8 endoscopy subscores, subsequent colectomy risk, symptoms and corticosteroid use outcomes were analyzed. Mucosal healing was defined as a Mayo endoscopy subscore of 0 (normal) or 1 (mild). Infliximab-treated patients with lower week 8 endoscopy subscores were less likely to progress to colectomy through 54 weeks of follow-up evaluation (P=.0004). This trend was not observed among patients given placebo (P=.47). Patients with lower endoscopy subscores achieved better symptomatic and corticosteroid use outcomes at weeks 30 and 54 (P<.0001, infliximab; P<.01, placebo). Among patients who achieved clinical response at week 8, trends in subsequent clinical outcomes by week 8 endoscopy subscores were generally consistent with that for the overall patient population; no trends were observed among patients who achieved clinical remission. The degree of mucosal healing after 8 weeks of infliximab was correlated with improved clinical outcomes including colectomy. Similar trends were observed for all outcomes except colectomy among the subgroup with clinical response at week 8. The degree of mucosal healing at week 8 among those in clinical remission did not predict subsequent disease course.

• IL-10RA truncation mutations and Semite populations.

  Authors: Christoph Gasche, Walter Reinisch, Wolf-Dietrich Huber, Esther Leshinsky-Silver, Arie Levine, Heitham Abdul-Baki, Ala I Sharara, Yousef Ajlouni, Abdelaziz Sefiani

  Inflammatory bowel diseases. 06/2011; 17(6):1438.

• Development of the Crohn's disease digestive damage score, the Lémann score.

  Authors: Benjamin Pariente, Jacques Cosnes, Silvio Danese, William J Sandborn, Maïté Lewin, Joel G Fletcher, Yehuda Chowers, Geert D'Haens, Brian G Feagan, Toshifumi Hibi [......] Bruce E Sands, Juergen Schoelmerich, Stefan Schreiber, Herbert Tilg, Simon Travis, Gert van Assche, Maurizio Vecchi, Jean-Yves Mary, Jean-Frédéric Colombel, Marc Lémann

  Inflammatory bowel diseases. 06/2011; 17(6):1415-22.

  Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structuralCrohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage.

• Long-term infliximab maintenance therapy for ulcerative colitis: the ACT-1 and -2 extension studies.

  Authors: Walter Reinisch, William J Sandborn, Paul Rutgeerts, Brian G Feagan, Daniel Rachmilewitz, Stephen B Hanauer, Gary R Lichtenstein, Willem J S de Villiers, Marion Blank, Yinghua Lang, Jewel Johanns, Jean Frédéric Colombel, Daniel Present, Bruce E Sands

  Inflammatory bowel diseases. 04/2011; 18(2):201-11.

  The aim was to evaluate long-term efficacy, quality of life, and safety in ulcerative colitis patients who received infliximab during the ACT-1 and -2 extension studies. Adults withThe aim was to evaluate long-term efficacy, quality of life, and safety in ulcerative colitis patients who received infliximab during the ACT-1 and -2 extension studies. Adults with moderate-to-severely active ulcerative colitis in the 54-week ACT-1 and 30-week ACT-2 studies who achieved benefit from infliximab were eligible to participate in extension studies and receive up to 3 additional years of therapy. Patients received randomized study medication until all sites were unblinded; placebo-treated patients were discontinued. Patients receiving 5 or 10 mg/kg infliximab continued to receive open-label infliximab every 8 weeks. Patients receiving infliximab 10 mg/kg could decrease to 5 mg/kg; patients receiving infliximab 5 mg/kg could increase to 10 mg/kg if response was lost. A total of 229 of 484 infliximab-treated patients from the ACT-1 and ACT-2 main studies entered the long-term extensions. Overall, 70 (30.6%) patients discontinued infliximab infusions for adverse events (24 [10.5%]), lack of efficacy (11 [4.8%]), required a colectomy (1 [0.4%]), or for other reasons (34 [14.8%]). Proportions of patients whose Physician's Global Assessment scores were indicative of no or mild disease (score = 0 or 1) were maintained during the extension studies; 76.5% at Extension week 0 and ranged between 90.0% and 94.3% through Extension week 152. Improvement in Inflammatory Bowel Disease Questionnaire scores observed in the main studies was maintained. During the long-term extension, the infliximab safety profile was consistent with that of the main studies; no new or unexpected safety signals were observed. Long-term treatment with infliximab for up to 3 additional years was effective and well tolerated.

• Long-term follow-up of babies exposed to azathioprine in utero and via breastfeeding.

  Authors: Sieglinde Angelberger, Walter Reinisch, Agnes Messerschmidt, Wolfgang Miehsler, Gottfried Novacek, Harald Vogelsang, Clemens Dejaco

  Journal of Crohn's & colitis. 04/2011; 5(2):95-100.

  Recommendations on breastfeeding under thiopurines are inconsistent due to limited data. To assess the risk of infections in offspring breastfed by mothers receiving azathioprine (AZA) forRecommendations on breastfeeding under thiopurines are inconsistent due to limited data. To assess the risk of infections in offspring breastfed by mothers receiving azathioprine (AZA) for inflammatory bowel disease (IBD). Babies, who were breastfed from their mothers treated either with or without AZA were included from a local pregnancy-registry. Women were asked by structured personal interview on general development, infections, hospitalisations and vaccinations of their offspring. A group of 11 mothers taking AZA (median 150 mg/d) during pregnancy and lactation and another of 12 patients without using any immunosuppressive therapy breastfed 15 babies each for median 6 months and 8 months, respectively. Median age of children at time of interview was 3.3 and 4.7 years, respectively. All offspring showed age-appropriate mental and physical development. Infections were commonly seen childhood diseases. Similar rates were observed for most of the various infections between offspring with and without azathioprine exposure during breastfeeding. However, common cold more than two episodes/year and conjunctivitis were numerically more often reported in the group without AZA exposure. In an exploratory analysis no difference in the rate of hospitalisations was seen between exposed (0.06 hospitalisations/patient year) versus non-exposed children (0.12 hospitalisations/patient year, p=0.8) Our study which reports the largest number of babies breastfed with exposure to AZA suggests that breastfeeding does not increase the risk of infections.

• Efficacy of azathioprine versus mesalazine in postoperative Crohn's disease-the authors' response.

  Authors: Walter Reinisch, Eduard F Stange

  Gut. 03/2011; 60(5):739-40.

• Predictors of indeterminate IFN-γ release assay in screening for latent TB in inflammatory bowel diseases.

  Authors: Pavol Papay, Alexander Eser, Stefan Winkler, Sophie Frantal, Christian Primas, Wolfgang Miehsler, Sieglinde Angelberger, Gottfried Novacek, Andrea Mikulits, Harald Vogelsang, Walter Reinisch

  European journal of clinical investigation. 03/2011; 41(10):1071-6.

  IFN-γ release assays (IGRA), widely used for latent tuberculosis screening prior to anti-TNF-α treatment, are limited by indeterminate results in patients under immunomodulatory (IM) therapy. The aimIFN-γ release assays (IGRA), widely used for latent tuberculosis screening prior to anti-TNF-α treatment, are limited by indeterminate results in patients under immunomodulatory (IM) therapy. The aim of our observational study was to delineate factors associated with indeterminate IGRA results. A total of 190 patients with inflammatory bowel disease were included. IGRA was indeterminate if the result of IFN-γ concentration was < 0·35 IU mL(-1) for tuberculosis-specific antigens and < 0·5 IU mL(-1) for the positive control. Predictors for indeterminate results were delineated from multivariate logistic regression. IFN-γ release assays was indeterminate in 26/190 (13·7%) patients. Indeterminate IGRA were associated with lower serum albumin levels (odds ratio [OR] 0·88, 95% confidence interval [CI] 0·79-0·96), lower absolute lymphocyte count (OR 0·39, 95% CI 0·18-0·75) and double IM therapy (OR 2·98, 95% CI 0·95-8·90). Sub-analysis of IM therapy revealed an association of steroid therapy with indeterminate IGRA (OR 3·19, 95% CI 1·35-7·70). Hypoalbuminaemia increased the risk of indeterminate IGRA by (OR 2·97, 95% CI 1·03-8·61) and lymphopaenia by (OR 3·28, 95% CI 1·41-7·65). After a mean of 18·5 ± 14·4 days, retesting of IGRA in 18 patients with indeterminate results yielded 9 negative vs. 9 indeterminate results. Our results reveal associations of indeterminate IGRA with low serum albumin levels and absolute lymphocyte count and double IM therapy. IGRA testing appears best to be performed prior to initiation of IM therapy in patients with inflammatory bowel disease.

• Infliximab or cyclosporine as rescue therapy in hospitalized patients with steroid-refractory ulcerative colitis: a retrospective observational study.

  Authors: Mats Sjöberg, Andrea Walch, Mina Meshkat, Anders Gustavsson, Gunnar Järnerot, Harald Vogelsang, Erik Hertervig, Gottfried Novacek, Ingalill Friis-Liby, Lars Blomquist [......] Christer Grännö, Mogens Vilien, Magnus Ström, Hans Verbaan, Per M Hellström, Clemens Dejaco, Anders Magnuson, Jonas Halfvarson, Walter Reinisch, Curt Tysk

  Inflammatory bowel diseases. 03/2011; 18(2):212-8.

  Cyclosporine (CsA) or infliximab (IFX) are used as rescue therapies in steroid-refractory, severe attacks of ulcerative colitis (UC). There are no data comparing the efficacy of these twoCyclosporine (CsA) or infliximab (IFX) are used as rescue therapies in steroid-refractory, severe attacks of ulcerative colitis (UC). There are no data comparing the efficacy of these two alternatives. Outcome of rescue therapy was retrospectively studied in two cohorts of patients hospitalized due to steroid-refractory moderate to severe UC: 1) a Swedish-Danish cohort (n = 49) treated with a single infusion of IFX; 2) an Austrian cohort (n = 43) treated with intravenous CsA. After successful rescue therapy, maintenance immunomodulator treatment was given to 27/33 (82%) of IFX patients and to 31/40 (78%) of CsA patients. Endpoints were colectomy-free survival at 3 and 12 months. Kaplan-Meier and Cox regression models were used to evaluate the association between treatment groups and colectomy. At 15 days, colectomy-free survival in the IFX cohort was 36/49 (73%) versus 41/43 (95%) in the CsA cohort (P = 0.005), at 3 months 33/49 (67%) versus 40/43 (93%) (P = 0.002), and at 12 months 28/49 (57%) versus 33/43 (77%) (P = 0.034). After adjusting for potential confounding factors, Cox regression analysis yielded adjusted hazard ratios for risk of colectomy in IFX-treated patients of 11.2 (95% confidence interval [CI] 2.4-53.1, P = 0.002) at 3 months and of 3.0 (95% CI 1.1-8.2, P = 0.030) at 12 months in comparison with CsA-treated patients. There were no opportunistic infections or mortality. Colectomy frequencies were significantly lower after rescue therapy with CsA than with a single infusion of IFX both at 3 and 12 months' follow-up. The superiority of CsA was seen principally during the first 15 days.