Inflammatory Bowel Disease in “Special Situations” David T. Rubin, MD Professor of Medicine, Interim Chief Co-Director, Inflammatory Bowel Disease Center The University of Chicago Medicine Outline     Pregnancy and the IBD Patient Approach to the IBD patient with a personal or family history of malignancy Approach to the IBD patient who develops a malignancy while on therapy Considerations for EBV testing in our patients Relationships and Fertility in IBD  Peak incidence of IBD overlaps the prime child bearing years  Fertility and pregnancy outcome is of great concern to the IBD patient  Addressing these issues is part of our goals of management Before Pregnancy • • Stable disease control Healthcare maintenance up to date    • • Vaccinations (live virus if not on immune suppression) Pap smears, vitamin levels (Vitamin D) Colon cancer surveillance Find the right Obstetrician! Counseling regarding use of IBD medications during pregnancy and lactation   What will happen if you are off all meds? The reality of the timing of this approach… IBD and Pregnancy: Overlapping Immune Pathways  Preterm birth (>37 wks gestation)    Leading cause of mortality in newborns Higher rates CP, sensory deficits, learning disabilities, respiratory illness Animal models: During pregnancy, shift Th1:Th2 balance by placenta which produces Th2 cytokines (IL4) and progesterone. Nasef. Translational Research 2012;160:65-83 Cytokine Spectrum in Pregnancy  Early: dominant proinflammatory profile   Middle:   Embryo invades and damages maternal uterus to implant Decrease in proinflammatory cytokines. Mother, fetus, placenta in synchrony Late:  Increase in proinflammatory cytokines to activate parturition Effect of Pregnancy on CD: Disease Activity at Conception 73% N = 186 N = 93 33% 27% No Relapse Relapse Inactive 34% 32% Worsened Continued Decreased Activity Activity Activity Active Miller JP. J R Soc Med. 1986;79(4):221. 7 Risk of Infertility in UC Increases Threefold After Ileal Pouch-Anal Anastomosis (IPAA)* Relative Risk (95% CI) Study % Weight Wikland 1.93 (0.92, 4.03) 9.9 Oresland 14.40 (0.98, 211.94) 1.2 Counihan 3.60 (1.39, 9.35) 9.1 Sjogren 1.00 (0.32, 3.10) 9.1 Hudson 3.38 (1.66, 6.89) 5.8 Olsen 3.62 (2.42, 5.41) 44.1 2.89 (1.47, 5.68) 20.9 Johnson Heterogeneity P value = 0.273 Overall (95% CI) 3.17 (2.41, 4.18) 0.1 1 10 Relative Risk Waljee A, et al. Gut. 2006;55:1575. *Compared to medical management 8 Meta-Analysis of Pregnancy Outcomes in IBD 12 studies N= 3,907 (CD 1,952; UC 1,113) versus 320,531 Controls Prematurity: OR = 1.87 (1.52-2.31) P<0.001 Low birth weight: OR = 2.10 (1.38-3.19) P<0.001 Caesarean section: OR = 1.50 (1.26-1.79) P<0.001 Cornish J, et al. Gut. 2007;56(6):830. 9 Pregnancy-Risk Categories A. Controlled human studies do not show risk to fetus; chance of risk remote B. No evidence of risk to fetus in human studies; chance of risk remote but possible C. Inadequate studies in humans; risk cannot be ruled out, but benefits may outweigh risks D. Positive evidence of fetal risk; benefits might outweigh risks in life-threatening situations when safer drugs are ineffective X. Contraindicated in pregnancy Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998. 10 Medications During Pregnancy: FDA Categories Category B Category C Loperamide Mesalamine [all but Asacol (C), olsalazine (C)] Balsalazide Corticosteriods Sulfasalazine Anti-TNF Agents Metronidazole* Category X Ciprofloxacin Category D Azathioprine† Cyclosporine 6-Mercaptopurine† Thalidomide Methotrexate Diphenoxylate Olsalazine Tacrolimus Natalizumab Asacol *Safe for use after first trimester. †Increasing use in pregnancy. Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998. Physician’s Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003. 11 Azathioprine Does Not increase Congenital Malformation Risk Rate of Major Malformations Did Not Differ with Six Neonates Each Azathioprine (n=6) Controls (n=6) Percent 3.5% 3.0% OR P Value P Value CI 1.17 P=.775 0.37, 3.69 Goldstein LH, et al. Birth Defects Res A Clin Mol Teratol. 2007;79(10):696. 12 Placental Transfer of IgG Ab • • INF and ADA are IgG1 antibodies Fc portion of IgG actively transported across placenta by specific neonatal FcR Highly efficient transfer in 3rd T leads to elevated levels of drug in newborn 20 B: Fetal 15 IgG (g/L) • r2=0.87, p<0.04 10 5 0 0 10 20 30 40 Gestational age (weeks) Wiley-Blackwell Publishing Ltd. Malek A, Evolution of maternofetal transport of immunoglobulins During human pregnancy. Am J Reprod Immunol 1996; 36(5):248-55. Image Courtesy of Sunanda Kane MD 50 Placental Transfer of Anti-TNF Therapy Infliximab Study of 10 mothers on infliximab In all cases, infant and cord infliximab levels were greater than the mother; 6 months to clear Adalimumab Study of 10 mothers on adalimumab In all cases, infant and cord adalimumab levels were greater than the mother; up to 4 months to clear ¾ patients who stopped adalimumab 35 days prior to delivery had a flare Certolizumab Study of 10 mothers In all cases, infant and cord levels were less than 2 mcg/ml even if mom dosed during the week of delivery Clin Gastroenterol Hepatol. 2013 Mar;11(3):286-92 14 PIANO: A 1,000 Patient Prospective Registry of Pregnancy Outcomes in Women with IBD Exposed to Immunomodulators/ Biologic Therapy PIANO, Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes Unexposed (Steroids/5-ASA/ABX) Group A 1,115 Pregnant IBD Patients 896 Delivered AZA/6-MP Group B Biologics (IFX/ADA/CZP/NAT) Pregnancy outcomes, maternal disease course, newborn complications, and developmental milestones are recorded for 1 year from birth Group AB Combo AZA/Biologic ABX, antibiotics; ADA, adalimumab; AZA, azathioprine; CZP, certolixumab pegol; 6-MP, 6-mercaptopurine; NAT, natalizumab Mahadevan U, et al. Presented at DDW; May 21, 2012. Abstract 865. PIANO: Adverse Pregnancy Outcomes Group A (IMM only) RR (CI) Group B (Biologic Only) RR (CI) Group AB (IMM + Biologics) RR (CI) Any Complication 0.98(0.69-1.40) 1.09 (0.80-1.48) 1.28 (0.82-1.98) Spontaneous Abortion 2.03 (0.74-5.55) 2.56 (1.07-6.12)* 1.29 (0.79-2.11) Preterm Birth 1.06 (0.62-1.81) 0.89 (0.54-1.47) 1.83 (1.01-3.31)* Low Birth Weight 0.69 (0.32-1.48) 1.17 (0.66-2.09) 1.05 (0.41-2.68) IUGR 0.96 (0.28-3.27) 1.01 (0.35-2.98) 1.25 (0.26-5.88) Cesarean section 1.07 (0.86-1.33) 1.23 (1.02-1.48)* 1.14 (0.86-1.53) NICU 1.09 (0.66-1.81) 1.20 (0.77-1.88) 1.71 (0.96-3.07) Congenital Anomalies 1.05 (0.50-2.21) 1.07 (0.55-2.08) 1.36 (0.52-3.56) Adjusted for: none/mild vs. moderate-to-severe disease activity Mahadevan U, et al. Presented at DDW; May 21, 2012. Abstract 865. *P<0.05 IUGR, intrauterine growth restriction; NICU, neonatal intensive care unit 16 Timing of Biological Therapies in Pregnancy     Elective switching of therapies is not recommended Outcomes of moms on biological therapies not different than moms who are off these therapies (recognizing differences in disease severity) Trying to time dosing based on third trimester is an unproven strategy, and not based on known pharmacokinetics No live virus vaccine for first 6 months for infants exposed to IFX or ADA during pregnancy  Focus on newborn- consider testing for immune conversion with vaccinations Management of Flares in the Pregnant IBD Patient  Medication choices are similar    Imaging   MRI preferred to CT, but NO gadolinium in T1 Endoscopy   Avoid new aza/6mp in pregnancy Avoid metronidazole, corticosteroids in T1 Unsedated flexible sigmoidoscopy preferred Surgery   Indications similar to non-pregnant patient T2 best time to operate Special Circumstances: Perianal Crohn’s Disease  Episiotomy may predispose to perineal disease (17.9%) without prior disease   103 Vaginal delivery(87% episiotomy)1 Active perianal disease: Caesarean section   No history(1/39) or inactive (0/11) perianal disease at birth, risk of relapse very low 4/4 with active perianal disease worsened post-vaginal delivery2 1 Brandt LJ. Am J Gastroenterol. 1995;90(11):1918-22. 2 Ilnyckyji A. Am J Gastroenterol. 1999;94(11):3274-8. Key Points: Pregnancy and IBD Disease control at conception improves pregnancy outcomes Thiopurines and anti-TNF therapies are safe during pregnancy Infliximab and adalimumab do cross the placenta in the third trimester; certolizumab pegol crosses the placenta at very low levels Most IBD medications can be continued during breastfeeding 20 Safety of IBD Medications in Breast-Feeding Low Risk to Use When Warranted Oral Mesalamine Topical Mesalamine Sulfasalazine Corticosteroids 6-MP/AZA* Anti-TNF Limited Data Available Tacrolimus Natalizumab Vedolizumab Physicians’ Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003. de Boer NK, et al. Am J Gastroenterol. 2006;101(6):1390. Sau A, et al. BJOG. 2007;114(4):498. Moretti ME, et al. Ann Pharmacother. 2006;40(12):2269. Gardiner SJ, et al. Br J Clin Pharmacol. 2006;62(4):453. Contraindicated Methotrexate Cyclosporine Metronidazole Ciprofloxacin *New evidence suggests safe AZA, azathioprine; 6-MP, 6-mercaptopurine 21 What about the patient with a personal or family history of malignancy? Personal History of Cancer and IBD Therapy    No evidence that personal history of cancer should prohibit use of immune suppressives or biologics Timing is important: “history of” means how long since diagnosis, treatment and NED? All cancers are not the same  solid tumors    Infection-associated (HPV- cervical) Non-infectious (2011): breast, colon, etc Lymphoma  Role of EBV Family History of Cancer and IBD Therapy   No evidence that family history of cancer should prohibit use of immune suppressives or biologics? Patients often don’t know their family history What do we know about family history of cancer in IBD?    Do you obtain one when you interview a patient? FH of colorectal cancer is a risk for dysplasia and colorectal cancer in IBD1,2 A family history (first degree) of hematopoietic malignancy does increase the risk of NHL, HL or B cell lymphoma in patients (not just IBD) (OR = 1.8, 95% CI = 1.2 to 2.5)3 1Askling et al. Gastroenterology. 2001. 2Rubin et al. Clin Gastroenterol Hep. 2006. 3Chang, et al. J Natl Cancer Inst 2005;97:1466 – 74. The Patient with Acute EBV Infection         EBV negative patients who receive thiopurines and become infected Particularly risky group Stop immunesuppression Monitor for acuity and severity with EBV titers Involve infectious disease May look like post-transplant lymphoproliferative disorder Role of pre-testing for EBV in patients unclear Increasing discussion about avoidance of thiopurines in some patients Practical Matters: Your Patient with a Known Malignancy   There is no evidence that a family history of malignancy or a personal history of malignancy, whether hematopoietic or solid, should result in avoidance of existing immunosuppressive or biologic therapies in IBD. Timing of immunosuppressive therapy in a patient with a known malignancy is important to avoid complications of immune suppression if cytotoxic therapies are used to treat the malignancy.    When in doubt, obtain additional opinions from oncology (but remember they don’t know IBD!). Screening and prevention: cervix, skin, colorectum, HPV vaccine Must weigh the known and unknown risks of therapeutic exposures with the available treatment options and patient wishes!