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

Sunanda Kane, MD,1 Bahar Khatibi B Sc2 & Deepa Reddy, MD1 Higher Incidence of Abnormal Pap Smears in Women With Inflammatory Bowel Disease. AM J Gastroenterol. 2008;103:631-636 1Mayo Clinic, Rochester, Minnesota, and 2University of Chicago, Chicago, Illinois

Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Introduction Cervical cancer is one of the leading causes of cancer death among women world wide. 1 Human Papilloma Virus (HPV) infection has been linked to cervical cancer. 2 American College of Obstetricians and Gynecologists (ACOG) recommend yearly Pap smears for women younger than 30 yrs and screenings every 2-3 yrs for older women who have has three consecutive negative Pap smears.3 immunosuppression 1. Wright TC, et al. AJOG. 2007; 346-355. 2. Ellerbrock, et al. JAMA 2000;283:1031-7. 3. ACOG. Obstet Gynecol 2003;102:845-54.

Introduction Risk Factors for evolution of Cervical cancer4,5 Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Introduction Risk Factors for evolution of Cervical cancer4,5 HPV (Human Papilloma Virus) infection of cervix HIV Immune suppression Smoking Serial Pap smear has been show to effectively detect HPV infection and dysplastic changes of the cervix. A Meta-Analysis of the Yield of Capsule Endoscopy Compared to Other Diagnostic Modalities in Patients with Non-Stricturing Small Bowel Crohn's Disease. Triester S, Leighton JA, Leontiadis GI, et al. Am J Gastroenterol 2006;101:954-64 4. Edelman M, et al. Cancer. 1999;87;184-9. 5. Bernatsky S, et al. Rheumatol. 2004;43:1386-9

Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Aim To determine if there is increased risk for abnormal Pap among patients with IBD compared to a like control population. To determine if immune suppression medication among IBD patients increased the risk for abnormal Pap.

Study Design: Study Population Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Study Design: Study Population Prospectively enrolled IBD patients over a 2 yr period of January 2004 through December 2005. Demographics N=40 (8 UC and 32 CD) Baseline normal Pap smear prior to diagnosis of IBD & at least 2 Pap smears after Dx IBD All had at least 3 Pap smears available for review Exclusion Criteria Pap smears unavailable for review History of total hysterectomy

Study Design: Control Population Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Study Design: Control Population Women receiving routine Pap smears in the University of Chicago Gynecology Clinic All women without diagnosis of IBD or history of immune suppressant use Each IBD patient was control matched to 3 ♀ Age within 2 yrs Race Parity Smoking

Study Evaluations Definition of Immune Suppressant Rx (I-Rx) Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Study Evaluations Definition of Immune Suppressant Rx (I-Rx) Azathioprine/6MP for 3 months Prednisone > 15 mg/day for > 8 consecutive weeks Methotrexate > 100 mg Infliximab within 8 wk of Pap smear

Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Study Evaluations Pap Smears were conducted at University of Chicago Gynecology Clinics Cytopapthology using Bethesda Criteria All Pap smears tested using Digent Hybrid Capture II HPV-DNA test.

Study Evaluations Definition of Pap Smear Abnormalities Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Study Evaluations Definition of Pap Smear Abnormalities ASC: atypical squamous cells of unknown significance ASC-US: atypical squamous cells cannot r/o high grade lesion ASG-H: atypical glandular cells AGC: atypical glandular cells unknown significance AGS-US: glandular or squamous carcinoma SILs: atypical squamous cells with high grade intra- epithelial cells

Study Evaluations Bethesda Criteria for Pap Smear Classification Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Study Evaluations Bethesda Criteria for Pap Smear Classification Pap Smear “High Grade” ASG-H SILs (low and high grade) Pap Smear “Low Grade” ASC ASC-US AGC AGC-US

Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Normal squamous cells Illustrations Courtesy of: Mattu Rubina, MD, AFIP, Washington, DC

Normal endocervical cells Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Normal endocervical cells Illustrations Courtesy of: Mattu Rubina, MD, AFIP, Washington, DC

Low grade squamous intraepithelial lesion (LSIL) with koilocytes Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Low grade squamous intraepithelial lesion (LSIL) with koilocytes Illustrations Courtesy of: Mattu Rubina, MD, AFIP, Washington, DC

High Grade Squamous Intraepithelial lesion (HSIL) Kane S, et al. AM J Gastroenterol. 2008;103;631-636 High Grade Squamous Intraepithelial lesion (HSIL) Illustrations Courtesy of: Mattu Rubina, MD, AFIP, Washington, DC

High Grade Squamous Intraepithelial lesion (HSIL)

Demographics: IBD vs. Controls Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Demographics: IBD vs. Controls Variable IBD N=40 Controls N=120 P value (+) I-Rx 23 NA Age 1st abn Pap 24 +/- 4 yr 25+/- 3 yr NS Oral contraceptive 58% 70% P=0.04 Sexually Active 97% 96% Smoking 37% 34%

Results: No. of women with history of abn Pap smear. Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Results: No. of women with history of abn Pap smear. Variable IBD (+) I-Rx (-) I-Rx Control Total 40 23 17 120 Normal Pap 11 12 112 Low Risk Pap 7 9 4 6 High Risk Pap 10 3 1 2 OR 4.3(2.2-10.5) 4.5 (1.5-12.3 1.9 (1.1-12.1 NA

Results: No abnormal Pap smears among all pts for 2 yr. Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Results: No abnormal Pap smears among all pts for 2 yr. Variable IBD (+) I-Rx IBD (-) Controls P value Normal Pap 47 35 298 Low Risk Pap 20 15 <0.001 High Risk Pap 2 7

Results: IBD (+) I-Rx, IBD (-) I-Rx, vs. Controls Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Results: IBD (+) I-Rx, IBD (-) I-Rx, vs. Controls 50% 30% 7% IBD (+) I-Rx IBD (-) I-Rx Control Percentage of women with any history of abnormal Pap smear.

Results: HPV-DNA testing Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Results: HPV-DNA testing All “high risk” Pap smears were positive for HPV-DNA Either serotype 16 or 18 50% of “low risk” Pap smears were (+) for HPV-DNA Percentage of women with any history of abnormal Pap smear.

Results: Influence of I-Rx on Pap Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Results: Influence of I-Rx on Pap ♀ on multiple I-Rx more likely to have abnormal Pap smear (p < 0.04) ♀ on I-Rx > 6 mo had a trend for abnormal pap (p=0.048) ♀ with “low grade” pap on I-Rx, lesions regressed with 6 mo of stopping I-Rx

Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Conclusions: Abnormal Pap smears were more common among IBD pts (17/40) vs. matched controls (8/120) 42% vs. 7%, respectively, p < 0.001. Both “low risk” and “high risk” Pap smears were more common in IBD group, P < 0.001 for both Pap smear groups. Stratification by IBD (+) I-Rx further increased risk over IBD (-) I-Rx for abnormal Pap smear, p < 0.001.

Reviewer Comments Kane, et al, have clearly shown the following: Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Reviewer Comments Kane, et al, have clearly shown the following: IBD pts have greater risk for abnormal Pap smear than matched controls, p < 0.001. IBD pts on I-Rx have greater risk for abnormal Pap smears that IBD pts not on I-Rx, p < 0.001. All ♀ with IBD and more importantly those on I-Rx should be considered for inclusion among the ACOG guidelines for more frequent cancer screening for immune compromised pts.

Reviewer Comments Kane, et al, do not answer the following questions? Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Reviewer Comments Kane, et al, do not answer the following questions? What is the efficacy of quadrivalent HPV vaccine (Gardasil, Merck) among IBD pts? Is vaccine protection of Gardasil (Merck) against HPV 16, 18 and 6, 11 as effective in IBD patients, especially those on I-Rx? Should IBD pts still be undergo Pap smears after Gardasil (Merck) vaccination and how often?

Kane S, et al. AM J Gastroenterol. 2008;103;631-636 Reviewer Comments Dr. Kane and colleagues are commended for demonstrating that IBD patients clearly have an increased risk for abnormal Pap smears in the decade prior to Gardasil vaccination against HPV 16 & 18. We, as gastroenterologists should actively recommend Gardasil to ALL of our sexually active ♀ IBD pts. and caution that the vaccine is only 70% protective against cervical cancer. Hence, periodic gynecologic evaluation IS still advisable even after Gardasil in this high risk group.