Complications of IBD

Educational Objectives

The goal of this program is to improve the management of inflammatory bowel disease (IBD). After hearing and as­similating this program, the clinician will be better able to:

1.   Discuss the factors that predispose to infection in IBD.

2.   Recognize which drugs used to treat IBD result in increased risk for infections.

3.   Apply guidelines for vaccination in patients with IBD.

4.   Review the factors that affect fertility in patients with IBD.

5.   Describe the effects of pregnancy on IBD and effects of IBD on pregnancy.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committe to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Rubin receives grant support from Procter & Gamble, Salix, and Prometheus, is a consultant for Procter & Gamble, Prometheus, Abbott Immunology, UCB Pharma, Given Imaging, Shire, and Millenium Pharma, and is on the Speakers’ Bureaus of Abbott Im­munology and UCB Pharma. Dr. Isaacs has received grant support from Abbott, Elan, UCB Pharma, Centocor, Otsuka, and Millenium Pharma.  The planning committee reported nothing to disclose. In her lecture, Dr. Isaacs presents information that is related to off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Rubin was recorded at New Advances in Inflammatory Bowel Disease, held September 13, 2008, in San Diego, CA, and sponsored by the Scripps Clinic. Dr. Isaacs was recorded at Update in Gastroenterology and Hepatology: Applying Sound Principles in Daily Practice, held April 17-19, 2009, in Chapel Hill, NC, and sponsored by the University of North Carolina at Chapel Hill School of Medicine. The Audio-Digest Foundation thanks Drs. Rubin and Isaacs and the sponsors for their cooperation in the production of this program

Managing Infectious Disease andCancer Complications of IBD

David T. Rubin, MD, Associate Professor of Medicine, University of Chicago Medical Center, Chicago, IL

Infectious complications of inflammatory bowel disease (IBD): disease-related infections; hospital-acquired infec­tions; therapy-related infections; vaccine-preventable infections; factors that predispose to infection  —  IBD type and location; malnutrition; ability to heal after surgery; use of medications and perioperative exposure to medica­tions

Disease-related infections: intra-abdominal abscess and fistula; perianal disease; Clostridium difficile infection

Hospital-acquired infections: C difficile  —  in speaker’s hospital, 50% of patients admitted for flare of IBD positive for C difficile; in those negative initially, 30% subsequently become positive; alcohol-based sanitizers ineffective in eradicating spores; emergence of resistant or more virulent strain of C difficile seen; should test for toxins A and B (virulent strain produces more toxin B); worse course seen in IBD patients with C difficile; disease course worse in patients with IBD; aggressive treatment with double therapy and longer length of treatment suggested (not evi­dence-based)

Opportunistic infections: related to treatment; many described and reported in older traditional therapies; concern about progressive multifocal leukoencephalopathy (PML) with use of immunosuppressive therapies (eg, steroids, azathioprine [AZA], mycophenolate mofetil [MMF; black box warning for PML]); invasive fungal infections  —  specifically, histoplasmosis, associated with antitumor necrosis factor (TNF) therapy, including etanercept; warn­ing issued by Food and Drug Administration (FDA) these infections being missed by clinicians; most due to inflix­imab (in use longer); consider in patients who develop new pulmonary symptoms or fever of unknown origin (FUO); cytomegalovirus (CMV)  —  consider in patient admitted for flare of ulcerative colitis (UC); flexible sig­moidoscopy to investigate; also those on immunosuppressive therapy (especially steroids) before admission to hos­pital; unclear whether CMV cause of colitis flare or “innocent bystander”; limited data as to whether treatment with ganciclovir changes outcome; varicella zoster virus (VZV) infection  —  retrospective cohort study of patients with Crohn’s disease (CD) or UC and controls demonstrated increased risk of »1.5 for developing VZV infection; ques­tion of whether patients require vaccination for VZV before treatment of IBD; increased risk also seen in patients with rheumatoid arthritis (RA); risk factors include immunosuppression; Pneumocystis  —  deaths due to Pneumo­cystis seen with use of cyclosporine for severe UC; routine prophylaxis standard of care (double-strength trime­thoprim-sulfamethoxazole [TMP-SMZ; eg, Bactrim] 3 times weekly); tuberculosis (TB)  — retrospective cohort study in preinfliximab era showed increased risk; also dependent on country of residence (increasing incidence of IBD in India and China); most cases of TB associated with anti-TNF therapy seen in Europe, especially in RA and older populations; data from Periodic Safety Update Report on infliximab in 2007 showed 157 cases of TB in »350,000 exposed IBD patients; challenge seen in some patients with negative purified protein derivative and chest x-ray; QuantiFERON-TB test  —  serum-based assay that helps diagnose latent TB, especially in patients with an­ergy or previously vaccinated with bacillus Calmette-Guerin (BCG); however, negative predictive value poor

Crohn’s Therapy Resource, Evaluation, and Assessment Tool (TREAT) registry: prospectively collected data­base of patients with CD exposed to variety of therapies, with »50% on infliximab; 80% community-based patients and 20% in academic centers; treatment at discretion of patient’s physician; publication in 2006 showed tendency for more severe and fulminant disease and more surgery in 50% of patients on infliximab, compared to other thera­pies; increase in serious infections marginal; after multivariate regression analysis, risk factors for serious infec­tions included disease severity, exposure to steroids, and narcotics (not infliximab, 6-mercaptopurine [6-MP] or AZA); European registry looking at serious infections found risk factors disease severity, older age, and exposure to steroids; study by Mayo Clinic  —  looked at predictive risk factors for opportunistic infections; found that being on any medication that affects immune system significant risk factor; also steroids, 6-MP, and AZA alone (not seen with methotrexate and infliximab); using >1 medication increases risk (substantially in some cases); odds ratio for developing opportunistic infection »3 with one immunomodulator, increasing to 14.5 with 2 or 3 medications

Risk for infections: corticosteroids  —  data from 71 controlled clinical trials show increased risk for infections; 6-MP and AZA  —  study of 396 IBD patients followed for 60 mo over 18 yr found 2% rate of serious infections; British study of 739 IBD participants over 27 yr for median of »1 yr found leukopenia, with no specific increased risk for infections reported; anti-TNF therapy in CD  —  meta-analysis of 21 randomized controlled trials (RCTs), evaluating 6 anti-TNF agents found 2% risk for serious infections but not significantly different from control group; unable to extract effect of infliximab or other anti-TNF agents as monotherapy because most patients on combined therapy; anti-TNF therapy in RA  —  meta-analysis of 9 RCTs evaluating infliximab and adalimumab found 2-fold increase in pooled odds ratio for serious infections; number needed to harm (NNH) 59 patients; cyclosporine  —  increased risk for serious infection present; data on cyclosporine for severe cases of UC based on slightly different population; risk for opportunistic infections serious and important to consider; natalizumab  —  JC polyomavirus possibly lethal and reported in other therapies; crosses blood-brain barrier; 3 cases reported; estimated risk 1 in 1000 for PML; used as monotherapy for patients with lost response or failed treatment with anti-TNF therapy; risk for PML still present with monotherapy

Vaccinations in IBD: study showed that many patients with IBD not receiving influenza and pneumococcal vac­cines; efficacy of vaccinations in immunosuppressed patients poor due to inability to mount appropriate immune response; in transplant population and in children with IBD, rates of effective conversion to immunoprotective ef­fect of vaccination low; study compared pneumococcal vaccination in IBD patients to controls found that patients on immunosuppressives much less likely to mount appropriate response (measured in titers); guidelines  —  should vaccinate before starting immunosuppressive therapy; general adherence to all standard immunizations, but should avoid live vaccines in patients on immunosuppressive therapy; live vaccines include measles, mumps, and rubella (MMR), oral polio, oral cholera, BCG live, smallpox, oral typhoid, yellow fever, and rotavirus

Risk for cancer and dysplasia in UC: inflammation leads to increased risk for dysplasia and cancer; evidence sug­gests that early effective therapy modulates risk and affects long-term outcomes (eg, cancer) and short-term out­comes (disease control and avoiding hospitalization and colectomy); study from United Kingdom shows that as degree of inflammation (specifically histologic) increased, likelihood for dysplasia or cancer increased; similar re­sults seen in other studies; previously thought that dysplasia and IBD developed through different biologic path­ways and “invisible”; actually, different biologic pathways exist, supported by biologic and molecular markers, but not invisible; inflammatory activity modifies follow-up and surveillance

Detection of neoplasia in IBD with chromoendoscopy: in retrospective review of patients with colonoscopies and sigmoidoscopies, most of time dysplastic lesions or cancer visible to endoscopist; old approach of systematically performing random biopsies throughout colon not recommended; should perform chromoendoscopy, although not yet standard of care; 2 types include dye spraying and electronic filtering; indigo carmine dye not absorbed but en­hances surface architecture; methylene blue best approach, but possibly associated with upregulating some inflam­mation in cells; more dysplasia found with chromoendoscopy, but unknown whether this leads to better outcomes; summary of guidelines  —  identify individuals at risk; understand that degree of inflammation is risk; proctocolec­tomy performed when dysplasia confirmed; chemoprevention with ursodiol for primary sclerosing cholangitis and UC; 5-aminosalicylic acid (5-ASA) chemopreventive, but not necessarily in patients with UC

Pregnancy in IBD

Kim L. Isaacs, MD, PhD, Professor of Medicine, University of North Carolina, School of Medicine, Chapel Hill

Fertility issues: studies show that, in general, fertility rates in patients with UC (precolectomy) same as that of gen­eral population (»92%); mixed results in patients with CD; well-controlled studies show fairly comparable fertility rates (similar to general population), looking at voluntary infertility and advice of physicians against pregnancy; high rate of voluntary infertility due to illness; clear difference in fertility rate in patients with pelvic pouch; factors that affect fertility  —  disease activity; advice against pregnancy; reluctance to conceive due to fear of reactivating disease; abstinence; reduced sexual activity due to fear of incontinence and diarrhea; standard surgery for UC total abdominal colectomy with ileal pouch; infertility rates in patients with UC managed nonoperatively »13.3% (after pouch procedure, close to 40%); rate of becoming pregnant before surgery 95% (after surgery, 56%); with nonoper­ative management, pregnancy rate 96% before diagnosis, 97% after diagnosis; surgery in pelvis, especially creation of pelvic pouch, leads to increase in infertility (likely due to anatomic effects on fallopian tubes); in patient with acute fulminant colitis, need for colectomy outweighs fertility issues; work-up for infertility (primary or secondary)  —  in normal healthy female patient, initiated if no conception occurs after 1 yr of unprotected sex; ear­lier work-up performed in those with history of surgery, particularly after pouch procedure or complicated ileal re­section; start with hysterosalpingography to check patency and alignment of fallopian tubes; with infertility in men, check for drugs; male infertility seen with sulfasalazine, but not with other 5-ASAs; effect on sperm motility seen with infliximab and methotrexate

Pregnancy and medications: patient with condition under control, on immunosuppressant or other medication, and with complicated disease course, should not be off medication; healthy mother necessary for healthy pregnancy; if patient started on AZA at first presentation during childhood and now 10 yr later, no evidence of recurrent disease present, possibly able to discontinue AZA; individualize decision; consider disease status of patient, risk if patient discontinues medication, risks from medications patient taking, and whether any adjustments in medication possi­ble to improve safety for mother and infant

Categories of drugs in pregnancy: category A  —  controlled studies performed during pregnancy (rare); category B  —animal studies show no risk or human data reassuring; category C  —  human data lacking; animal studies posi­tive or none available (most drugs in this category); category D  —human data show risk; benefits possibly out­weigh risk; category X  —  animal or human data positive; no benefit; contraindicated; most IBD drugs category B, including 5-ASA, steroids, and biologics (proteins; do not cross placenta during early pregnancy); category C drugs include cyclosporine and tacrolimus; AZA and 6-MP category D; methotrexate and thalidomide category X

6-MP and AZA: study  —  looked at patients on 6-MP who discontinued before attempting pregnancy, on 6-MP at conception, on 6-MP throughout pregnancy, and before starting 6-MP; slight increase in spontaneous abortions in those who discontinued drug before pregnancy and those on drug at time of conception and throughout pregnancy (not markedly different from general population); congenital abnormalities fairly common and comparable across board; slight increase in first trimester miscarriage rate; difficult to determine whether due to drug or fact that pa­tient more ill than healthy person on no medications during pregnancy

Infliximab: antibody (protein); does not cross placenta in first trimester of pregnancy, but efficiently crosses in third trimester; detectable levels in infant at birth; possible strategy to give last dose early in third trimester and if patient remains in remission, next dose given after delivery; if patient on infliximab, especially during third trimester of pregnancy, avoid giving live vaccines (rotavirus) to infant in first 6 mo; earlier studies looking at intentional inflix­imab during pregnancy (maintenance infusions) found no congenital abnormalities, no intrauterine growth retarda­tion, no small-for-gestational age infants, 3 preterm deliveries, and 1 low-birth-weight (LBW) infant; in IBD population overall, LBW and early deliveries more common; larger study looking at patients on infliximab found rates for live birth, miscarriage, and therapeutic termination fairly comparable to that in general population; not seen in breast milk (breastfeeding safe)

Effects of pregnancy on disease and effects of disease on pregnancy: UC  —  in patients with inactive disease at be­ginning of pregnancy, >60% stay inactive and >30% develop flares; in patients with active disease at beginning of pregnancy, >40% become worse, some stay same, and some improve; CD  —  in patients with inactive CD who be­come pregnant, >70% stay inactive; in those with active CD, one-third improve, one-third stay same, and one-third worsen; flares of disease after pregnancy  —  study looking at 580 pregnancies (403 before diagnosis and 177 after diagnosis) found number of flares decreased after pregnancy; birth outcomes  —  in normal population, prematurity and birth defects seen in £24%; in IBD population, tendency for slightly smaller infants and slightly earlier deliver­ies; pregnancy outcomes  —  if flare occurs during pregnancy, chances of preterm delivery and LBW much higher; birth outcome dependent on disease activity; delivery method  —  ideally, patient with IBD delivered per obstetric in­dications; 2 exceptions, ie, cesarean delivery performed in patient with active perineal disease during delivery (doc­umented worsening); patient with ileal pouch-anal anastomosis (IPAA) usually safely delivered vaginally; in patient with IPAA, borderline continence, and large infant, consider cesarean delivery (if tear sustained, continent patient may convert to incontinent patient); dilemma seen in patient with quiescent perineal disease (avoid tear and episiotomy, so as not to reactivate disease); in those with inactive disease at time of vaginal delivery, most stayed inactive, with no relapse; breastfeeding  —  mesalamine safe; concern about sulfasalazine and kernicterus (due to sulfur content); study looking at 31 breast milk samples of patients on 6-MP and AZA found only 2 had exceed­ingly low levels of 6-MP in breast milk, with no neonatal immunosuppression (probably safe to breastfeed)

Suggested Reading

Bourikas LA et al: Disseminated tuberculosis in a Crohn's disease patient on anti-TNF alpha therapy despite chemoprophylaxis. Gut 57:425, 2008;.Bronner MP et al: Genomic biomarkers to improve ulcerative colitis neoplasia surveillance. Am J Pathol 173:1853, 2008; Ferguson CB et al: Inflammatory bowel disease in pregnancy. BMJ 337:a427, 2008; Gupta RB et al: Histologic inflamma­tion is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology 133:1099, 2007; Hus­sein K et al: Acute cytomegalovirus infection associated with the onset of inflammatory bowel disease. Am J Med Sci 331:40, 2006; Kaur N et al: Pneumocystis jiroveci (carinii) pneumonia after infliximab therapy: a review of 84 cases. Dig Dis Sci 52:1481, 2007; Lepistö A et al: Female fertility and childbirth after ileal pouch-anal anastomosis for ulcerative colitis. Br J Surg 94:478, 2007; Mar­tin SI et al: Primary infection with cytomegalovirus in ulcerative colitis. Dig Dis Sci 51:2184, 2006; Prescott K et al: Tumor necrosis factor-alpha inhibitor associated ulcerative colitis. Am J Med Sci 333:137, 2007; Samarasena J et al: Development of hepatocellular carcinoma in a patient with Crohn's disease treated with azathioprine. Dig Dis Sci 52:2748, 2007; Toruner M et al: Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 134:929, 2008; Van Assche G et al: Progres­sive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 353:362, 2005; van Staa TP et al: 5-Aminosalicylate use and colorectal cancer risk in inflammatory bowel disease: a large epidemiological study. Gut 54:1573, 2005; Vesga L et al: Adalimumab use in pregnancy. Gut 54:890, 2005.