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The Role of Biologics in the Treatment of Ulcerative Colitis

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The Role of Biologics in the Treatment of Ulcerative Colitis The role of biologics in the treatment of ulcerative colitis A Thesis Submitted to the Faculty of Drexel University by Andrew James Klink in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2014 ® Copyright 2014 Andrew J. Klink. All Rights Reserved. ii Dedication I dedicate this work to Samson, who sat on my lap for two years while I wrote this, imparting his own form of wisdom and offering much needed distraction and calming energy. iii Acknowledgments There are numerous individuals who generously gave their time, effort, and expertise to make this work possible. Without them, I would still be struggling through my 65th draft of manuscript number 1. Somehow I had been lucky enough to be surrounded with the following individuals and countless more to help me along the way. Brevity is not my strong suit, so bare with me, and forgive the lack of page space necessary to include everyone who make a lasting contribution to my development. I first want to thank members of my thesis committee. Thanks to Lucy Robinson for always providing a fresh perspective and a new angle on all of my papers. Lindsey Albenberg was invaluable at combing through my manuscripts to make them clinically meaningful. Thank you, Bob Baldassano, for not only your clinical expertise and professional guidance, but also for generously offering valuable resources to complete this project. I am grateful for the critical appraisal of my work by Alison Evans, who made this project leagues stronger; I still cannot believe you agreed to be my on my doctoral committee even after graciously serving as my master’s thesis advisor; thank you! I am indebted to Judith Kelsen, who provided me with the necessary clinical guidance throughout this project. I especially appreciate that you entrusted me with your own research so that I could lend a hand (I hope) where I could. Of course, I would not have made it without the support, counsel, and guidance offered by my advisor, Brian Lee. You truly pushed me to think outside the chi-square box and try more challenging and exciting methods. I would be remised if I did not acknowledge the many friends, colleagues, professors, and classmates who offered support and encouragement, while patiently iv holding my hand at times: Anna Wallace, Zee Mohamad, Alex Kecojevic, Dorothy Miller, Betsy Brooks, Nicole Cossrow, Pam Weiss, Seth Welles, Loni Philip Tabb, Marcy Polansky, Amy Auchincloss, Yvonne Michael, and Craig Newschaffer. Arguably deserving greatest credit to my success in this project is my partner, Frank Calabrese. Thank you for putting up with me, particularly after the 927th time I used the excuse that I was “busy writing my dissertation.” You can finally cease your refrain, “hurry up and finish your paper!” Oh, and your weekend care packages you made for me in the fridge certainly made long weekends more enjoyable. Special gratitude is due to my parents, Jim and Cindy Klink, whose love and encouragement were always a needed boost. Lastly, I want to give thanks to my family in Wisconsin, Minnesota, Connecticut/Florida/North Carolina, and New Jersey. Thank you all! v Table of Contents 1! LIST OF TABLES ................................................................................................... IX! 2! LIST OF FIGURES ................................................................................................... X! 3! ABSTRACT .............................................................................................................. XI! 4! INTRODUCTION ..................................................................................................... 13! 5! BACKGROUND ....................................................................................................... 16! 5.1! INCIDENCE, PREVALENCE, & MORBIDITY ............................................................ 16! 5.1.1! Burden of IBD .............................................................................................. 16! 5.1.2! Burden of disease secondary to IBD ............................................................ 18! 5.1.3! Burden of severe and fulminant UC ............................................................. 18! 5.2! TREATMENT OF SEVERE UC ................................................................................ 20! 5.2.1! Lack of established standards of care for inpatient pediatric UC ............... 21! 5.3! COMPARATIVE EFFECTIVENESS RESEARCH ......................................................... 22! 5.3.1! Limitations of current disease severity scores for UC ................................. 24! 5.3.2! Data source .................................................................................................. 25! 5.4! STATISTICAL ANALYSES ...................................................................................... 26! 5.4.1! Disease risk scores ....................................................................................... 27! 5.5! SUMMARY ............................................................................................................ 34! 5.6! TABLES ................................................................................................................. 36! 6! TRENDS IN INPATIENT MANAGEMENT OF PEDIATRIC SEVERE ULCERATIVE COLITIS: A RETROSPECTIVE US COHORT FROM 2003 TO 2012 .... 39! 6.1! ABSTRACT ........................................................................................................ 40! 6.2! INTRODUCTION ............................................................................................... 41! 6.3! MATERIALS & METHODS .............................................................................. 43! vi 6.3.1! Data source .................................................................................................. 43! 6.3.2! Study cohort .................................................................................................. 43! 6.3.3! Statistical analysis ........................................................................................ 44! 6.4! ETHICAL CONSIDERATIONS ......................................................................... 45! 6.5! RESULTS ............................................................................................................ 45! 6.5.1! Study cohort .................................................................................................. 45! 6.5.2! Participating hospitals ................................................................................. 45! 6.5.3! Length of stay ............................................................................................... 46! 6.5.4! Medications .................................................................................................. 46! 6.5.5! Diagnostic procedures and labs ................................................................... 48! 6.5.6! Surgical procedures ..................................................................................... 49! 6.6! DISCUSSION ...................................................................................................... 50! 6.7! REFERENCES .................................................................................................... 56! 6.8! TABLES & FIGURES ......................................................................................... 59! 7! DEVELOPING AND IMPLEMENTING A DISEASE RISK SCORE TO CONTROL FOR CONFOUNDING BY INDICATION IN PHARMACOEPIDEMIOLOGIC STUDIES ............................................................................ 68! 7.1! ABSTRACT ........................................................................................................ 69! 7.2! INTRODUCTION ............................................................................................... 70! 7.3! METHODS .......................................................................................................... 71! 7.3.1! Variable selection ......................................................................................... 72! 7.3.2! Fitting the model .......................................................................................... 72! 7.3.3! Model assessment and diagnostics ............................................................... 73! 7.3.4! Implementation in the final model ................................................................ 76! 7.3.5! Case study .................................................................................................... 77! vii 7.4! RESULTS ............................................................................................................ 80! 7.5! DISCUSSION ...................................................................................................... 83! 7.6! TABLES & FIGURES ......................................................................................... 87! 7.7! REFERENCES .................................................................................................... 92! 7.8! APPENDIX. R CODE FOR DRS DEVELOPMENT BY BOOSTED CART AND IMPLEMENTATION IN FINAL MODELS. ........................................................................................ 95! 8! INFLIXIMAB REDUCES RISK OF COLECTOMY AMONG HIGH-RISK PEDIATRIC PATIENTS WITH ULCERATIVE COLITIS ................................................... 97! 8.1! ABSTRACT ........................................................................................................ 98! 8.2! INTRODUCTION ..............................................................................................
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