UEG Week 2019 Oral Presentations
2019; Wiley; Volume: 7; Issue: S8 Linguagem: Inglês
10.1177/2050640619854670
ISSN2050-6414
Tópico(s)Helicobacter pylori-related gastroenterology studies
ResumoUnited European Gastroenterology JournalVolume 7, Issue S8 p. 10-188 UEG Week 2019 Oral PresentationsOpen Access UEG Week 2019 Oral Presentations First published: 01 October 2019 https://doi.org/10.1177/2050640619854670Citations: 6AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat OP001 Top-Down Infliximab Superior to Step-Up in Children with Moderate-To-Severe Crohn's Disease - a Multicenter Randomized Controlled Trial M.M.E. Jongsma1, M. Cozijnsen1, M. van Pieterson1, T. de Meij2, O. Norbuis3, M. Groeneweg4, V. Wolters5, H. Wering6, I. Hojsak7, K.-L. Kolho8, T. Hummel9, J. Stapelbroek1, C. van der Feen1, P. Van Rheenen1, 2, M. Wijk2, S. Teklenburg-Roord3, J.C. Escher1, J. Samsom1, 3, L. de Ridder1 1 Erasmus MC Sophia Children's Hospital, Dept. of Paediatric Gastroenterology, Rotterdam, Netherlands 2 Amsterdam UMC - Locatie VUmc, Paediatric Gastroenterology, Amsterdam, Netherlands 3 Isala Hospital, Paediatric Gastroenterology, Zwolle, Netherlands 4 Maasstad Hospital, Paediatric Gastroenterology, Rotterdam, Netherlands 5 University Medical Center Utrecht - Wilhelmina Children's hospital, Paediatric Gastroenterology, Utrecht, Netherlands 6 Amphia Hosptial, Breda, Netherlands 7 Catharina Hospital, Referral Center for Pediatric Gastroenterology and Nutrition, Zagreb, Croatia 8 Tampere University Hospital and University of Tampere, Helsinki, Finland 9 Medisch Spectrum Twente, Pediatric Gastroenterology, Enschede, Netherlands 10 Catharina Hospital, Paediatric Gastroenterology, Eindhoven, Netherlands 11 Jeroen Bosch Hospital, den Bosch, Netherlands 12 University Medical Center Groningen, Pediatric Gastroenterology, Groningen, Netherlands 13 Erasmus MC Sophia Children's Hospital, Laboratory of Pediatrics, Rotterdam, Netherlands l.deridder@erasmusmc.nl Introduction In newly diagnosed paediatric Crohn's Disease (CD) patients current guidelines instruct to start exclusive enteral nutrition (EEN) or oral prednisolone in combination with immunomodulators to achieve remission. Infliximab (IFX) is proven to be highly effective in paediatric CD patients, but only used once patients are refractory, the so called step-up (SU) treatment strategy. However, evidence is emerging IFX is more effective the sooner it is initiated. We hypothesize that initiation of IFX directly, i.e. top-down (TD) after diagnosis of moderate-to-severe CD, results in higher long term remission rate. Aims & Methods: Aim To compare efficacy of TD and SU treatment in newly diagnosed moderate-to-severe paediatric CD Methods For this international randomized controlled trial (RCT) 100 patients aged 3-17 years, with new-onset, untreated CD with weighted paediatric CD activity index (wPCDAI) > 40 were included in 12 centres. All patients were randomly assigned to TD or SU treatment. TD treatment consisted of 5 IFX (CT-P13) infusions of 5 mg/kg (0, 2, 6, 14, 22 weeks) combined with azathioprine (AZA). After 5 infusions, IFX was stopped while continuing AZA. SU treatment consisted of induction therapy with EEN or oral prednisolone (at physician and patient/parents discretion) combined with AZA as maintenance treatment. In both groups, IFX could be (re)started on predefined conditions. Primary endpoint of this study was sustained clinical remission (wPCDAI < 12.5) at week 52 without need for additional therapy or surgery. Secondary endpoints included patient rate using IFX at week 52, as well as clinical remission, endoscopic detection of mucosal healing (SES-CD < 3) and low fecal calprotectin levels (< 250 ug/g) at week 10. Results Three out of 100 patients didn't start with the study after randomization (n=97; TD:50 vs SU:47). There were no significant differences within the two groups at baseline. Median age was 15.0 years [IQR 11.7-16.6] in TD, and 14.2 years [IQR 12.0-16.3] in the SU group. 54% and 57% were males, and median wPCDAI was 55 [IQR 45-65] and 57.5 [IQR 47.5-67.5]) in the TD vs SU group, respectively. For preliminary analysis of the primary endpoint data of 75/97 patients were available. At week 52, TD treatment resulted in sustained clinical remission for 18/37 [49%] of the patients compared to 5/38 [13%] of SU patients (p=0.001). After induction therapy IFX was (re)started in 13/37 [35%] TD patients compared to 27/38 [70%] SU patients within 52 weeks (p=0.001). Two patients underwent surgical resection (ileocecal resection), one in each treatment group. At week 10, TD resulted in significant more patients in clinical remission (TD: 24/41 [59%] vs SU: 15/42 [36%], p=0.037) as well as endoscopic remission (47/97 consented to repeated endoscopy; TD: 17/28 [61%]; median SES-CD 0 [IQR 0-5] vs SU: 5/29 [17%]; median SES-CD 6 [IQR 3-15.5], p=0.001). Lastly, significantly more TD patients had a low fecal calprotectin level (n=44; TD: 9/23 [39%] vs SU: 4/21 [19%], p=0.005). Conclusion We are the first to compare TD IFX to SU treatment in an RCT of paediatric CD patients. Although this analysis is preliminary, TD treatment was superior to SU in achieving sustained clinical remission (wPCDAI < 12.5) without the need for additional therapy or surgery at week 52. Moreover, at week 10, significantly more TD patients were in clinical and endo-scopic remission and had low calprotectin levels compared to SU patients. Disclosure Nothing to disclose OP002 Defining the Clonal Origin, Expansion Rate and Clonal Diversity of Intestinal Metaplasia in the Helicobacter-Infected Human Stomach W. Waddingham1, 2, W. Cross3, K. Curtius3, G. Metcalf3, B. Mohammadi4, A. Jenkinson4, K. Dawas4, D. Graham2, M. Banks2, S. Sekine5, M. Jansen6 1 UCL Cancer Institute, Research Department of Pathology, London, United Kingdom 2 University College London Hospitals NHS Foundation Trust, Endoscopy, London, United Kingdom 3 Barts Cancer Institute, Tumour Biology, London, United Kingdom 4 University College London Hospital NHS Trust (UCLH), Surgery, London, United Kingdom 5 National Cancer Center Japan, Pathology, Tokyo, Japan 6 University College London, UCL Cancer Institute, London, United Kingdom w.waddingham@ucl.ac.uk Introduction Over half the world's population is chronically infected with Helicobacter pylori, the main risk factor for gastric cancer (GC). Chronic infection provokes a mutagenic cascade involving extensive metaplastic remodelling of the gastric mucosa. Although gastric intestinal metaplasia (GIM) is an accepted pre-cursor lesion to GC, its origins, evolution and neoplastic potential remain unclear. An understanding of the stem cell dynamics and clonal diversity of GIM may allow targeted endoscopic surveillance to patients at greatest risk of progression to GC. Aims & Methods Our objective was to develop a quantitative understanding of the initiation, expansion, and clonal diversity of GIM in the chronically inflamed stomach. We developed a unique workflow to visualise and trace the clonal initiation and expansion of GIM in patients' tissues. Analysis of en face embedded gastric mucosa from cancer patients (n=12) who underwent gastrectomy reveals a mosaic patchwork of islands of GIM. Using patch size dynamics, 3D modelling, and whole exome sequencing (WES) we quantified the clonal expansion and genetic diversity of GIM. Comparison was made with normal gastric mucosa from patients undergoing sleeve gastrectomy for weight loss (n=12). Results Tracing the cellular origin of GIM in 3D, we demonstrate for the first time that GIM originates from a single stem cell within a single gastric gland. These metaplastic lineages expand within the gastric gland, display all cellular lines of intestinal epithelial differentiation (enterocyte, goblet cells, etc) and rapidly colonise singular glandular units. Direct quantification of the competitive advantage of these metaplastic lineages at single cell resolution shows that metaplastic stem cell lineages display biased drift. Patch size dynamics of neutral clonal markers in chronically inflamed gastric mucosa reveals a tenfold increased clonal expansion rate when compared to non-inflamed mucosa. Analysis of the patch size dynamics of GIM reveal that its clonal expansion rate is increased further by another order of magnitude. Finally, we have carried out whole exome sequencing (WES) to reconstruct the clonal phylogeny of patches of GIM and assess the mutation burden within metaplastic patches. Our analysis shows that the mutation burden of GIM is comparable to mature gastric cancer with some patches showing arm level copy number variation. Together, these data show that H. pylori provokes a massive adaptive radiation of metaplastic cellular clones, greatly accelerating the selection and expansion of mutant lineages. Conclusion This work reveals that the metaplastic phenotype confers a fitness advantage at the level of the individual stem cell. The markedly exaggerated expansion rate of GIM explains the time-dependent transformation of the gastric mucosa into a competitive field of cancer precursor lineages. Clonal genetic diversity may be a potential marker for GC progression risk in chronic gastritis patients. Disclosure Nothing to disclose OP003 The Neuropeptide Receptor Activity Modifying Protein (RAMP)1 Promotes Liver Regeneration by Regulating Yes-Associated Protein (YAP) Activity During Acute Or Chronic Liver Injury Y. Wang1, M. Laschinger1, G. Holzmann1, B. Wang2, C. Stöß3, M. Lu1, M. Brugger4, P. Knolle4, S. Schulze2, K. Steiger5, F. Altmayr1, H. Friess6, D. Hartmann2, N. Hüser1, B. Holzmann1 1 Technical University of Munich, Department of Surgery, Munich, Germany 2 Klinikum rechts der Isar, Technical University of Munich, Department of Surgery, Munich, Germany 3 Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, München, Germany 4 Technical University of Munich, Institute of Molecular Immunology & Experimental Oncology, Munich, Germany 5 Technical University of Munich, Department of Pathology, Munich, Germany 6 Klinikum rechts der Isar, Department of Surgery, Munich, Germany wangyangtum@163.com Introduction The adult liver has a high capacity to regenerate after acute injury. In addition, chronic liver damage in patients with liver fibrosis triggers proliferation of residual hepatocytes and, thus, prevents liver failure. The liver is innervated by sensory nerves containing the neuropeptide calcitonin gene-related peptide (CGRP) that binds to the receptor activity-modifying protein (RAMP)1. Aims & Methods We aim to investigate whether the neuropeptide CGRP is able to modulate liver regeneration upon partial hepatectomy and during hepatic fibrosis. Wild type and RAMP1 deficient mice were subjected either to 70% partial hepatectomy (PH) or were injected with carbon tetrachloride (CCl4) for four weeks to induce chronic liver fibrosis. The de novo synthesis of CGRP receptor components in liver tissues of both models was determined by quantitative RT-PCR. Hepatocyte proliferation was quantified using Ki67- and BrdU-specific immunohistochemistry, and cell cycle regulatory components were analyzed by western blot and quantitative RT-PCR. Sirius Red staining was performed in order to assess collagen fibers deposition within hepatic parenchyma. Protein expression of fibrotic markers, such as α-SMA and collagen, was evaluated by western blot. Involvement of CGRP/RAMP1 in the Hippo pathway was tested by the presence of global or active YAP, as well as global and active YAP-regulators LATS1/2 and MOB1 using western blot analysis. To investigate the direct effect of CGRP signaling on hepatocytes or intact liver tissue in vitro, we stimulated primary hepatocytes or precision-cut liver slices with CGRP and analyzed YAP signaling components by detecting global and phosphory-lated YAP protein by western Blot analysis. Results Liver injury induced through partial hepatectomy or CCl4-injection caused a sustained upregulation of hepatic CGRP mRNA and a late increase of RAMP1 expression. During liver fibrosis absence of RAMP1 impairs collagen fibers deposition as well as expression of α-SMA and Collagen Type 1 proteins. RAMP1 deficiency severely delayed recovery of organ mass upon PH, and inhibited hepatocyte proliferation and cell cycle progression in both liver injury models. Mechanistically, expression of the Hippo pathway-regulated transcriptional coactivator YAP was decreased in livers of RAMP1-deficient mice following either partial hepatectomy or 4-weeks' CCl4 injection. RAMP1 deficiency impaired nuclear localization of YAP protein in hepatocytes and upregulation of YAP target genes in regenerating livers. Phosphorylation of YAP on Ser127 and Ser397, which promote YAP cytoplastic retention and extranuclear degradation, was found to be elevated in RAMP1-deficient livers in both models. Consistently, phosphorylation of the YAP kinases LATS1/2 as well as MOB1 was upregulated. Stimulation of primary hepatocytes or precision-cut liver slices with the neuropeptide CGRP corroborated our in vivo results in an in vitro setting and demonstrates that CGRP/RAMP1 signaling positively regulates YAP activity. Conclusion Our study identifies the neuropeptide CGRP signaling via its receptor RAMP1 as a previously unrecognized inducer of YAP activity in liver regeneration upon acute and chronic injury. Disclosure Nothing to disclose OP004 Effects of Faecal Microbiota Transplantation in Patients with Irritable Bowel Syndrome (IBS): A Randomised, Double-Blind Placebo-Controlled Study M. El-Salhy1, J.G. Hatlebakk2, O.H. Gilja3, A. Kristoffersen4, T. Hausken5 1 Stord Hospital Medical Clinic, University of Bergen, Gastroenterology, Stord, Norway 2 Haukeland University Hospital Dept. of Medicine, Bergen, Norway 3 University of Bergen, Medical Dept. A, Bergen, Norway 4 Genetic Analysis AS, Oslo, Norway 5 Institute of Clinical Medicine, University of Bergen, Medical Dept., Bergen, Norway magdy.elsalhy@sklbb.no Introduction The intestinal bacterial profile in IBS patients differs from that of the healthy subjects with a low diversity (dysbiosis) (1,2,3). Mi-crobiota dysbiosis in IBS patients is believed to play an important role in the pathophysiology of this disorder (3). Faecal microbiota transplantation (FMT) has been tried in two double-blind placebo-controlled studies (4,5). While the first study showed improvement of the IBS symptoms, the other study did not show any effect at all. The present study was conducted to study the effect of FMT using a single donor with a favourable microbiota profile. Aims & Methods A randomised, double-blind placebo-controlled study was conducted, where 164 IBS patients were randomised to either placebo, 30 g transplant or 60 g transplant in ratio 1:1:1. The primary outcome was a reduction in the IBS-symptoms defined as a decrease in the IBS-SSS total score with ≥50 points 3 months after FMT. The secondary outcome was a reduction in the Dysbiosis index (DI) and a change in the intestinal bacterial profile 3 months following FMT. Abdominal symptoms, fatigue and quality of life were assessed by the IBS-SSS and Birmingham IBS symptom, fatigue Assessment Scale, IBS-Quality of Life and the Short-Form Dyspepsia index Questionnaires. Gut bacterial analysis was done using a commercially available test, GA-map Dysbiosis Test® (Genetic Analysis AS, Oslo, Norway). Results The response to FMT occurred in 23.6, 75.9 and 87.3% of patients received placebo, 30 g and 60 g transplant, respectively. This was accompanied by a significant improvement in fatigue and quality of life in these patients. Symptom remission (SSS≥175 points) occurred in 5.5, 35.2 and 47.3% in placebo, FMT 30 g and FMT 60 g groups, respectively. Similarly, a significant clinical improvement in fatigue (FAS≥4 points) was found in 21.8, 53.7 and 52.7% of patients received placebo, FMT30 g and FMT 60 g, respectively. The corresponding figures for the quality of life (IBS-QoL≥14 points) were 7.3, 61.1 and 58.2%. DI did not decrease significantly in patients received FMT or placebo. The intestinal bacterial profiles changed in both groups received 30 and 60 g transplant, but not in the placebo group. Conclusion FMT is an effective treatment for patients with IBS. A well-de-fined donor with normal DI and favourable specific microbial signature is essential for the success of FMT. Response to FMT increases with increased dose. There was a significant difference in the intestinal bacterial profile between responders and non-responders, which might be used to identify candidates for FMT. Disclosure Nothing to disclose References 1El-Salhy M., Mazzawi T.: Fecal microbiota transplantation for managing irritable bowel syndrome. Expert Rev Gastroenterol Hepatol 12: 439– 445, 2018. 2Casen C., Vebo H.C., Sekelja M. et al.: Deviations in human gut microbiota: a novel diagnostic test for determining dysbiosis in patients with IBS or IBD. Aliment Pharmacol Ther 42: 71– 83, 2015. 3Enck P., Mazurak N.: Dysbiosis in Functional Bowel Disorders. Annals of nutrition & metabolism 72: 296– 306, 2018. 4Johnsen P.H., Hilpusch F., Cavanagh J.P. et al.: Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. The lancet. Gastroenterology & hepatology 3: 17– 24, 2018. 5Halkjaer S.I., Christensen A.H., Lo B.Z.S. et al.: Faecal microbiota transplantation alters gut microbiota in patients with irritable bowel syndrome: results from a randomised, double-blind placebo-controlled study. Gut 67: 2107– 2115, 2018. OP005 Real-World Safety of Vedolizumab and Anti-Tnf Therapies in Biologic-Naïve Ulcerative Colitis and Crohn's Disease Patients: Results from the Evolve Study A. Yarur1, G.J. Mantzaris2, U. Kopylov3, M. Bassel4, N. Brett4, T. Lissoos5, C. Lopez5, A. Natsios6, C. Kifnidi6, S. Saha7, D. Demuth8, H. Patel9, B. Bressler10 1 Medical College of Wisconsin, Milwaukee, United States 2 Evangelismos Hospital, Athens, Greece 3 Chaim Sheba Medical Center, Ramat Gan, Israel 4 Evidera, Montreal, Canada 5 Takeda Pharmaceuticals USA Inc, Deerfield, United States 6 Takeda Hellas S.A., Athens, Greece 7 Takeda Canada Inc, Oakville, Canada 8 Takeda Pharmaceuticals International, Singapore, Singapore 9 Takeda Pharmaceuticals International, Deerfield, United States 10 University of British Columbia, Vancouver, Canada ayarur@mcw.edu Introduction The GEMINI phase III clinical trials showed a favourable safety profile for vedolizumab (VDZ) in treating patients (pts) with moderate-to-severely active ulcerative colitis (UC) and Crohn's disease (CD), however real-world studies are needed comparing the safety of VDZ to anti-tumour necrosis factors (anti-TNF) agents. Aims & Methods The objective was to compare the safety of VDZ and anti-TNF agents in a real-world cohort of biologic (bio)-naïve pts with UC or CD. This was a multi-country (Canada, Greece and the United States), retrospective chart review study of bio-naïve pts (≥18 years old) with ≥ 6 months follow-up, initiating treatment (Tx) with VDZ or an anti-TNF [adalimumab, infliximab, golimumab, certolizumab pegol] between May 2014 and March 2018. Data were collected from Tx initiation to earliest of death, chart abstraction date or 6 months post-Tx discontinuation (Canada only). Serious adverse events (SAEs) and serious infections (SIs) (defined as either life threatening, requiring hospital admission, resulting in significant disability/incapacity, or recorded in the chart as an important medical event) occurring from Tx initiation up to five half-lives post-Tx discontinuation were assessed. Incidence rates (per 100 person-years [PYs]) of SAEs and SIs were estimated. A Cox proportional hazards model adjusted for baseline characteristics was used to compare incidence rates between Tx cohorts. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) are reported. Results This study included 1,095 pts (VDZ: 598 [UC: 380; CD: 218]; anti-TNF: 497 [UC: 224; CD: 273]) from 42 sites. Compared to anti-TNF pts, the VDZ cohort were older (mean [SD] age [years]: VDZ, 47.9 [17.4]; anti-TNF, 39.6 [15.2] [p< 0.01]), were proportionately more male (male: VDZ, 56.9%; anti-TNF, 49.9% [p=0.02]) and had a longer disease duration (median [range: min-max] disease duration [years]: VDZ, 5.0 [0.04- 54.0]; anti-TNF, 2.0 [< 0.1 - 49.0] [p< 0.01]). Median (range: min-max) follow-up (months) was: VDZ, 15.3 (3.0-47.0); anti-TNF, 16.3 (3.5-51.0). Incidence rates of first occurrence (per 100 PY [95% CI]) of SAEs (VDZ: 4.6 [3.5-6.8]; anti-TNF: 10.3 [9.5-14.9]) and SIs (VDZ: 2.6 [1.9-4.4]; anti-TNF: 7.0 [5.9-10.2]) were significantly lower in VDZ versus anti-TNF pts (adjusted HR: SAE, 0.42 [0.27-0.66]; SI, 0.33 [0.18-0.58]). Similar trends were shown when data were stratified by UC and CD, separately (Table 1). Table 1. [Safety Profile of Vedolizumab and Anti-TNF Therapies in Real-World Biologic-Naïve Ulcerative Colitis and Crohn's Disease Patients] Ulcerative Colitis Crohn's Disease Outcome Vedolizumab IR (95% CI) N=380 Anti-TNF IR (95% CI) N=224 Adjusted Hazard Ratio (95% CI) Vedolizumab IR (95% CI) N=218 Anti-TNF IR (95% CI) N=273 Adjusted Hazard Ratio (95% CI) Serious Adverse Events 3.8 (2.6-6.2) 11.3 (8.9-17.5) 0.34 (0.19-0.63)* 3.0 (1.8-5.0) 5.7 (3.5-9.4) 0.47 (0.22-1.02) Serious infections 6.1 (4.1-10.5) 9.5 (7.7-14.5) 0.45 (0.23-0.89)* 1.9 (0.8-4.5) 7.9 (5.5-11.3) 0.18 (0.06-0.50)* Data are incidence rates (95% CI) and hazard ratios (95% CI). Incidence rates are unadjusted and are per 100 person-years; hazard ratios are from adjusted Cox proportional hazards models (adjusted for baseline confounders: age, sex, disease duration, albumin, C-reactive protein, UC/CD-related hospitalisations [prior 12 months] and disease severity). Indication (UC/CD) was a covariate for the overall analysis and was not included for disease specific models. CD: Crohn's Disease; UC: Ulcerative colitis, IR: Incidence rate. Half-lives for treatments: VDZ: 125 days (18 weeks), Infliximab: 47.5 days (6.8 weeks), Infliximab-dyyb: 47.5 days (6.8 weeks), Infliximab-abda: 47.5 days (6.8 weeks), Adalimumab: 70 days (10 weeks), Adalimumab-atto: 70 days (10 weeks), Golimumab: 70 days (10 weeks), Certolizumab pegol: 70 days (10 weeks). * Significant difference between VDZ and Anti-TNF cohorts based on adjusted HRs. Lastly, the proportion of pts who experienced gastrointestinal (GI) infections was significantly higher among anti-TNF versus VDZ pts (4.4% versus 1.5%, respectively, p< 0.01). Conclusion Bio-naïve pts treated with VDZ had a significantly lower likelihood of experiencing SAEs and SIs, including GI infections, than those treated with anti-TNF therapies. These data support a favourable safety profile of VDZ versus anti-TNF in bio-naïve inflammatory bowel disease pts in real-world clinical practice. Disclosure The study was funded by Takeda Pharmaceuticals Company Ltd. BB, AY, UK and GM received honoraria from Takeda Pharmaceuticals Company Ltd; MB and NB are employees of Evidera which received funding from Takeda Pharmaceuticals Company Ltd. TL, CL, AN, CK, SS, DD and HP are employees of Takeda Pharmaceuticals Company Ltd. OP006 An Update on the Analysis of Non-Melanoma Skin Cancer in the Tofacitinib Ulcerative Colitis Programme B.E. Sands1, M.D. Long2, L. Baidoo3, W. Reinisch4, J. Panés5, A. Soonasra6, R.D. Pedersen6, N. Lawendy6, G. Chan6 1 Icahn School of Medicine at Mount Sinai, New York, United States 2 University of North Carolina, Center for Gastrointestinal Biology and Disease, Chapel Hill, United States 3 Northwestern University School of Medicine, Chicago, United States 4 Medical University of Vienna, Vienna, Austria 5 Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain 6 Pfizer Inc, Collegeville, United States bruce.sands@mssm.edu Introduction Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present an update on the integrated analysis of non-melanoma skin cancer (NMSC) events in the tofacitinib UC clinical programme, as of Sep 2018. Aims & Methods The safety of tofacitinib for the treatment of moderate to severe UC was evaluated in a randomised, placebo (PBO)-controlled induction Phase (P) 2 study (NCT00787202),1 two induction P3 studies (NCT01465763; NCT01458951), one maintenance P3 study (NCT01458574),2 and an ongoing open-label, long-term extension (OLE) study (NCT01470612).3 Patients (pts) were analysed as three cohorts: Induction (P2/P3 induction studies); Maintenance (P3 maintenance study); Overall (pts receiving ≥1 dose of tofacitinib 5 or 10 mg twice daily [BID] in P2, P3 or ongoing OLE studies). For P3 studies, a blinded independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis. Overall Cohort data are as of Sep 2018. Results 1124 pts were evaluated for NMSC (P3 studies only), with 2399 PY of tofacitinib exposure and up to 6.1 years of treatment. NMSC occurred in two Induction pts receiving tofacitinib 10 mg BID. In the Maintenance Cohort, the NMSC IR for pts receiving PBO was 0.97 (one pt) and was 1.91 for tofacitinib 10 mg BID (three pts) (Table). In the Overall Cohort, the NMSC IR for tofacitinib-treated pts was 0.78 (19 pts): 0.82 for pts receiving a predominant dose (PD) of 10 mg BID (defined as an average daily dose ≥15 mg; 15 pts) and 0.67 for pts receiving a PD of 5 mg BID (an average daily dose < 15 mg; four pts). Ten pts had squamous cell carcinoma (SCC) and 12 pts had basal cell carcinoma (BCC); three pts had both SCC and BCC. No NMSC was metastatic or led to study discontinuation. Of all tofacitinib-treated pts with NMSC, seven had prior NMSC history, 18 had prior use of thiopurines and 15 had prior tumour necrosis factor inhibitor (TNFi) exposure. The Overall Cohort showed higher IRs for subgroups of pts aged ≥50 years (1.93 [95% confidence interval (CI) 1.08, 3.19]) vs 40 to < 50 years (0.74 [95% CI 0.20, 1.89]), 30 to < 40 years (0.00 [95% CI 0.00, 0.58]) and < 30 years (0.00 [95% CI 0.00, 0.77]), and for pts with prior TNFi treatment (1.23 [95% CI 0.69, 2.04]) vs those without (0.33 [95% CI 0.09, 0.84]), or prior immunosuppressant use (0.99 [95% CI 0.59, 1.57]) vs those without (0.16 [95% CI 0.00, 0.90]). Cox regression selected prior NMSC (hazard ratio [HR] 10.95; 95% CI 3.72, 32.24; p< 0.0001) and age (HR per 10-year increase 2.10; 95% CI 1.41, 3.13; p=0.0003) as significant risk factors for NMSC. [Demographics, and proportions and IRs for all NMSC events, for the Induction, Maintenance and Overall Cohorts] All NMSC Induction Cohort (8 weeks) Maintenance Cohort (52 weeks) Overall Cohort (≤6.1 years) Placebo (N=282) Tofacitinib 10 mg BID (N=938) Placebo (N=198) Tofacitinib 5 mg BID (N=198) Tofacitinib 10 mg BID (N=196) Tofacitinib All (N=1157) Age (years), mean (SD) 41.4 (14.4) 41.3 (13.8) 43.4 (14.0) 41.9 (13.7) 43.0 (14.4) 41.3 (13.9) Exposure, PYa 40.39 158.37 103.20 148.77 156.80 2398.6 Pts with events, n (%)a 0 (0.0) 2 (0.2) 1 (0.5) 0 (0.0) 3 (1.5) 19 (1.7)b IR (95% CI)a 0.00 (0.00, 9.13) 1.26 (0.15, 4.56) 0.97 (0.02, 5.40) 0.00 (0.00, 2.48) 1.91 (0.39, 5.59) 0.7 8 (0.47, 1.22) Data are as of Sep 2018 for the Overall Cohort (OLE study database not locked) a Adjudicated data do not include data from the P2 Study (A3921063; NCT00787202); b Including five pts from the P3 Induction and Maintenance Cohorts BID, twice daily; CI, confidence interval; IR, incidence rate (unique patients with events per 100 PY of exposure); N, number of patients randomised and treated; N/A, not applicable; NMSC, non-melanoma skin cancer; OLE, open-label, long-term extension; P, Phase; pts, patients; PY, patient-years Conclusion NMSC events were infrequent in the tofacitinib UC programme, and were more likely to occur in pts with prior NMSC and with increasing age, known risk factors for the development of NMSC.4 NMSC IRs were similar to those reported for tofacitinib in other indications, including for tofacitinib in rheumatoid arthritis,5 and for biologic UC treatments.6 Disclosure BE Sands has received consultancy fees from 4D Pharma, AbbVie, Allergan Sales, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Capella Biosciences, Eli Lilly, enGene, Ferring, Gilead, Janssen, Lyndra, MedImmune, Oppilan Pharma, Otsuka, Palatin Technologies, Pfizer Inc, Progenity, Rheos, Seres Therapeutics, Synergy Pharmaceuticals, Takeda, TARGET PharmaSolutions, Theravance Biopharma R&D, TiGenix and Vivelix Pharmaceuticals; and other fees from WebMD (honoria for speaking in a CME program). MD Long has received consultancy fees and research support from Takeda, and consultancy fees from AbbVie, Pfizer Inc and TARGET PharmaSolutions. L Baidoo has received research support and advisory board fees from Pfizer Inc, and speaker's bureau fees from Takeda. W Reinisch has received research support, consultancy fees, advisory board fees a
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