Literature Review

1. Literature Review Peter R. McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045

2. Bolin TD, Wong S, Ult GC, Crouch R, Engelman JL and Riordan SM. Gastrointestinal and Liver Unit, Department of Medicine, The Prince Wales Hospital, New South Wales, Australia; Department of Surgery, the Prince of Wales Hospital, Sydney, New South Wales, Australia; faculty of Medicine, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia; Department of Anatomical Pathology the prince Wales Hospital, Sydney, New South Wales, Australia; St George Private Hospital, Sydney, New South Wales, Australia. Appendectomy as a Therapy for Ulcerative Proctitis. Am J Gastroenterol. 2009;104:2476-2482.

3. Introduction • The etiology of ulcerative colitis (UC) is multi-factorial: • Genetic susceptibility • Environmental triggers Radford-Smith GL et al. Gut. 2002;51:808-13. Naganuma M, et al. Am J Gastroenterol. 2001;96:1123-6. Rutgeert P, et al. Gastro. 1994;106:1251-82. Irvine EJ, et a. Scan J Gastenterol 2001;36:2-15. Gent AE, et al. Lancet. 1994;343:766-7.

4. Introduction • The epidemiology of ulcerative colitis: • Two large national cohort studies in Denmark and Sweden have suggested a reduced relative risk for subsequent development of UC among persons that have undergone appendectomy. • The reduction in relative risk to develop UC is particularly striking when appendectomy is performed before 20 yrs of age. Andersson RE, et al. N Engl J Med. 2001;334:808-14. Frisch M, et al. Surgery. 2001;130:36-43. Peyrin-Biroulet L. Am J Gastroenterol. 2008;103:491-2.

5. Introduction • The Immunology of Appendix & UC: • The appendix is often considered a vestigial organ with no current functional importance. • Careful immunologic studies of the appendix indicate that it may serve as a sanctuary site for gut T- lymphocytes and a reservoir for commensal bacteria important in the re-population of gut microbiotica after severe gastroenteritis or broad spectrum antibiotic therapy. • The appendix may have an important role in priming and or perpetuating gut mucosal responses in UC. Matsushita M, et al. World J Gastroenterol. 2005;11:4869-74. Mizoguchi A, et al. J Exp Med. 1996;184:707-15. Andersson RE, et al. N Engl J Med. 2001;344:808-14.

6. Introduction • Modulation of UC Activity by Appendectomy • Okazaki, et al, reported a single case of remarkable 3 yr symptomatic remission for severe, refractory Ulcerative Proctitis after appendectomy. • Shelby, et al, reported improvement in a group UC patients after appendectomy (18%) compared to a small group of patients that did not undergo appendectomy (12%), but statistical significance was not achieved. • Anderson, et al, retrospectively showed appendectomy in UC favored better clinical course. Okazaki K, et al. Gastroenterology. 2000;119:502-6. Selby WS, et al. Am J Gastroenterol. 2002;97:2834-8. Andersson RE, et al. N Engl J Med. 2001;334:808-14.

7. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Aim The authors sought to prospectively determine: 1. Does elective, asymptomatic appendectomy in non-smoking patients with active Ulcerative Proctitis, impact the clinical course of disease? 2. Examine histological findings of appendectomy specimens and demographic variables for possible associations with UP disease activity and response to appendectomy.

8. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Study Design: Methods • Prospective study of patients with active Ulcerative Proctitis. The study was approved by Institutional Review Board. • All patients exhibited active Ulcerative Proctitis (n=30), unresponsive to ongoing medical treatment. • Each patient gave written, informed consent for asymptomatic appendectomy. • Study Time Interval July 2006 to July 2008.

9. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Study Design: Methods Measurement of UP Clinical Activity • “Simple Clinical Colitis Activity Index” • Bowel frequency AM score 0-3 pts • Bowel frequency PM score 0-2 pts • Urgency of defecation score 1-3 pts • Blood in stool score 1-3 pts • Gen well-being score 0-4 pts • Extra-colonic features • Walmsley RS, et al. Gut. 1998;43:29-32.

10. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Study Design: Methods Criteria for Diagnosis of Ulcerative Proctitis • All patients underwent colonoscopy and biopsy with 3 months of appendectomy. • Endoscopic criteria for Ulcerative Proctitis by established criteria. All had clear transition “cut-off”. Appendiceal orifice inflammation (AOI) was identified in 3 of 30 patients (10%). • Powell-Tuck, et al. Scand J Gastroenterol. 1978;13:833-7. • All met established pathologic criteria for ulcerative proctitis.

11. Ulcerative Proctitis

12. Normal Appendiceal Orifice

13. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Study Design: Methods Assessment of Post Appendectomy Outcome • “Simple Clinical Colitis Activity Index” used to assess UP activity after appendectomy. All patients interviewed monthly. • Pre-operative medical therapies for Ulcerative Proctitis were decreased or discontinued in accordance with each patient’s clinical course. • A Simple Clinical Colitis Activity Index score of “0” required absence of clinical symptoms and removal of all existing pharmacologic therapies.

14. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Study Design: Methods Statistics: • Fisher ‘s exact test • Wilcoxon test • Mann-Whitney rank sum test. • Sytat 5.02 for Windows, Sytat, Evanston, Il. • A p-value < 0.05 was set for statistical significance.

15. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Results: • 30 non-smoking, UP pts unresponsive to Medical therapy (Topical & oral Mesalamine, corticosteroids, immunomodulators &/or biological). • Mean Duration of UP: 5 yr (8 mo - 30 yr) • Mean Age: 35 yrs (17 - 70 yrs) • Gender: 19 ♀ and 11 ♂

16. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Results: • Surgical Results • 29 of 30 (97%) appendices removed macroscopically normal. • 1 appendix had appearance of a mucocele. • Pathologic Results • 29 of 30 (97%) appendices had histological identification of “ulcerative appendicitis,” defined as mucosal abnormalities resembling ulcerative proctitis. • 1 appendix confirmed mucinous cystadenoma.

17. Baseline Characteristics of Patients with Ulcerative Proctitis Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482.

18. Comparison of UP Patients Pre- and Post Appendectomy Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482.

19. Proportion of UP Patients with Ongoing Symptoms After Appendectomy Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482.

20. Comparison of Pts after Appendectomyby Disease Remission or Activity Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482.

21. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Study Conclusions • Investigators found that 40% of non-smoking UP patients with medically refractory disease exhibited COMPLETE remission of disease for up to 25 months after appendectomy. • Additional 50% of patients exhibited clinical improvement after appendectomy. • Only 10% of patients with refractory UP did not show any clinical improvement.

22. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Study Summary • Response of refractory UC patients was not limited to patients < 20 yoa. • Appendectomy histology was not predictive of clinical outcome. • Duration of symptoms did not appear to predict response to appendectomy. • AOI was present in too small a number to determine if this finding predicts outcome of appendectomy.

23. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Reviewer Comments Bolin, et al, are congratulated on the insight and fortitude to prospectively examine the impact of elective appendectomy on patients with active and refractory Ulcerative Proctitis. • There findings of 90% overall improvement rate and 40% remission rate of UP are important and compelling results.

24. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Reviewer Comments • However, larger studies are needed to further determine the long term efficacy and possible consequences of appendectomy for UP refractory to medical therapy? • The authors were careful to note that their patients were not cigarette smokers and the results of this is study would not necessarily apply to cohort of cigarette smoking UP patients.

25. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482. Reviewer Conclusions • Striking results that indicate that in 90% of patients in this small cohort of non-smoking patients with UP refractory to medical therapy can be expected to have significant clinical improvement as measured by the SCCAI and more strikingly that 40% of non-smoking patients with UP, complete remission and elimination of all medical therapy • Larger studies with long term follow up are necessary to truly determine the benefit of this therapy for patients with medically refractory UP. • These study results are specific to non-smoking patients with UP and should NOT be expected to be effective in patients with extensive ulcerative colitis or those that smoke cigarettes.

26. Reviewer Conclusions 4. The authors do identify an association with the appendix and UP. However, the authors do not tell us the precise pathophysiology involved between the appendix and UP interaction. Could it be that the appendix is a sanctuary site for immunocytes that promote auto inflammation of the colon, specifically rectum or that the appendix is a reservoir of bacterial that influence gut microbiotica – intestinal interactions? 5. More sophisticated research design is necessary to carefully look beyond the histology of the removed appendix in the patients. Perhaps B- and T-cell sub-population studies, surrogate serologic markers (Prometheus 7) or even detailed characterization of the intrinsic bacterial microbiotica of the appendix will unravel this mystery. Bolin, et al. Am J Gastroenterol. 2009;104;2476-2482.

27. Normal Appendix Ulcerative Proctitis