IBD RISKS
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:
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 | 1. Discuss the challenges in evaluating drug safety.
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| 2. Review the safety of available biologic agents for mortality, infection, autoimmunity, neurologic conditions, and malignancy.
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| 3. Describe the effect of IBD on body image and sexuality, menstrual cycle, osteoporosis, and pregnancy and fertility.
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| 4. Review the Food and Drug Administration categories of drugs in pregnancy.
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| 5. Prescribe drugs that are safe to use in pregnancy.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee 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. Devlin is
a consultant for and on the Speakers’ Bureau of Schering-Plough and Abbott Laboratories and on the Advisory Board of
UCB. Dr. Mahadevan is a consultant for Centocor, Abbott Laboratories, UCB, and Procter & Gamble.
Acknowledgements
Dr. Devlin was recorded at IBD Hot Topics 2008, held March 29, 2008, in Los Angeles, CA, and sponsored by the Cedars-Sinai
Medical Center and the Crohn’s and Colitis Foundation of America, Greater Los Angeles and Orange
County Chapter. Dr. Mahadevan was recorded at the 8th Annual Update in Gastroenterology, held October 26-28, 2007,
in La Quinta, CA, and sponsored by the Cedars-Sinai Medical Center, Division of Gastroenterology. The Audio-Digest
Foundation thanks Drs. Devlin and Mahadevan and the sponsors for their cooperation in the production of this
program.
| PUTTING THERAPEUTIC RISKS INTO PERSPECTIVE —Shane Devlin, MD, Clinical Assistant Professor, Inflammatory
Bowel Disease Clinic, Division of Gastroenterology, University of Calgary Faculty of Medicine, Calgary, AB
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| Evaluation of drug safety: challenges in pharmacoepidemiology—underlying condition systemic, with multiorgan
involvement and morbidity; use of concomitant and preexistent medications; rare events; all applicable to inflammatory
bowel disease (IBD); safety of available biologic agents—determined in clinical trials, postmarketing surveillance registries,
case reports, and personal patients; clinical trials involved >6000 patients with Crohn’s disease (CD) and ulcerative
colitis (UC) with study periods of 1 yr or ≤18 mo; from postmarketing surveillance, infliximab patient exposures close to
1 million (3 million patient-years), with majority in rheumatoid arthritis and significant percentage in CD
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| Mortality associated with infliximab: mortality ultimate complication; meta-analysis shows slight increase in mortality
associated with CD, but unknown whether related to biologic agents; in Mayo Clinic paper, 1% mortality associated
with use of infliximab; death associated with inappropriate use of drug in elderly, patient with multisystem disease, or unrecog
nized infection; from postmarketing surveillance and Crohn’s Therapy, Resource, Evaluation, and Assessment Tool
(TREAT) Registry, infliximab not independently associated with mortality (not true for corticosteroids)
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| Infection: most common adverse event; across clinical trials, approximately one-third of participants develop clinical infection;
opportunistic infections (OIs) occur; minority of infections occurred in patients with CD; looking at ≈3000 patients
in registry treated with infliximab (unadjusted), increased risk found; when adjusted for concomitant use of
steroids, immunosuppressants, and severity of disease, infliximab not independently associated; corticosteroids and severe
disease main predictors of complications; complications avoided, to some extent, by vigilance and common sense
and minimizing exposure to corticosteroids; suppressing immune response only way to treat IBD, so any effective therapy
immunosuppressive and associated with increased risk for OIs; combination of drugs increases risk; know which OIs
endemic in local area
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| Immunologic phenomena: infliximab and adalimumab induce apoptosis; over time, antinuclear antibody (ANA) positivity
increases; at 2 yr, >50% of patients develop positive ANA (tends to occur early with infliximab); ANA positivity
associated more with women and with skin manifestations
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| Neurologic complications: tumor necrosis factor (TNF) inhibitors associated with exacerbation of underlying multiple
sclerosis (MS) or de novo demyelination; progressive multifocal leukoencephalopathy (PML)—OI possibly associated
with natalizumab; demyelinating brain disorder associated with John Cunningham (JC) virus, which most individuals
previously exposed to and have antibodies against; risk ≈1 in 1000
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| Malignancies: theoretically, any immunosuppressive agent associated with malignancy; with anti-TNF antibody, majority
of lymphomas described non-Hodgkin’s; from postmarketing reports, rate 0.03/100 patient-years; from cancer database
in United States, rate 0.07/100 patient-years for those ≥65 yr; across all clinical trials for infliximab, including
patients with rheumatoid arthritis (RA), increase above general population estimates seen; RA associated with independent
risk for lymphoma; same shown with adalimumab; meta-analysis—9 controlled trials in RA; 29 malignancies in
anti-TNF treated patients and 3 malignancies in control group; dose response seen; in anti-TNF group, largest proportion
lymphomas; rate of malignancy in control group 8 times less than expected in general population; tendency for underreporting
in placebo group; risk and benefit of infliximab in CD—mathematical model simulating clinical trial comparing
infliximab to standard therapy; patient model 35 yr of age with moderate to severe CD; 5 lymphomas reported in 1711
patients (converted to rate of 0.2%/yr); assumed that CD itself not associated with increased baseline risk for lymphoma
and 3-fold increased risk for lymphoma with thiopurines; by treating 100,000 patients with infliximab, cause 201 more
lymphomas and 250 more deaths; benefits include 12,000 more remissions, 4200 fewer surgeries, and 33 fewer deaths
from CD; quality-adjusted life-years (QALY) for infliximab 0.77 and for standard therapy 0.75; 1 in 500 chance/yr of developing
lymphoma on infliximab; summary of risk—conflicting signals; serious infections uncommon but risk worthy
of vigilance; mortality not associated with infliximab; risk for PML with natalizumab requires further study; association
of anti-TNF therapy with lymphoma not definite, but likely true phenomenon, although magnitude of risk uncertain; CD
associated with diminished quality of life; direct costs related to therapy and surgery associated with indirect costs on personal
and societal level; patients willing to accept ≈1% annual risk for lymphoma to go from severe CD to remission, and
0.4% annual risk to go from moderate to mild disease
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| MANAGEMENT OF IBD IN WOMEN —Uma Mahadevan, MD, Associate Professor of Medicine, University of California,
San Francisco, School of Medicine, Center for Colitis and Crohn’s Disease, San Francisco, CA
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| Patient concerns in IBD: include energy level, medication side effects, surgery, ostomy, and being burden; issues particular
to women include feelings about body, attractiveness, feeling alone, having children, intimacy, and sexual performance;
depression not uncommon; problem of noncompliance with medications in adolescents and young patients due to
denial and concerns about these issues
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| Menstrual cycle: symptoms worsen immediately before menses; most frequently reported symptoms include pelvic pain,
low back pain, diarrhea, irritability, and headache; incidence of any menstrual symptoms significantly higher in IBD than in
healthy controls; in some patients, symptoms severe and debilitating, and use of oral contraceptives (OCs) helpful; no data to
support hypothesis that OCs worsen disease, although some soft data suggest increased incidence of IBD in patients using
OCs; OCs have no influence on course of disease, but patients must not smoke (increased risk for thromboembolism)
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| Osteopenia and osteoporosis: IBD-related risk factors include medications, persistence of disease activity, vitamin-D
deficiency, and calcium malabsorption; overall prevalence of osteoporosis in patients with IBD 15%; similar risk profiles
for men and women; corticosteroid use most strongly associated with osteoporosis; overall incidence of fractures
in population-based study 1 in 100 patient-years, but rate affected by age (more common in individuals >60 yr of age);
overall relative risk for fractures 40% greater than that in general population
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| Screening: National Osteoporosis Foundation—advocates testing all women ≥65 yr of age, and younger postmenopausal
women with previous fractures or >1 risk factor; American College of Gastroenterology (ACG) 2002 guidelines—dual
energy x-ray absorptiometry (DEXA) recommended for patients with IBD who use steroids for >3 mo or recurrently;
consider DEXA in IBD patients >60 yr of age because of increased risk for fracture and in patients who have had no or
low-trauma fractures
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| Treatment: lifestyle modification (exercise; smoking cessation); minimizing corticosteroid use; nutritional supplementation;
bisphosphonates (half-life 10 yr; cross placenta); consider hormone replacement therapy (HRT) in postmenopausal
women; study by Kane—incidence of abnormal Papanicolaou (Pap) test 14% among control group, 33% in
women with IBD not exposed to immunosuppressants, and 63% in those exposed; increased incidence of high-grade
lesions in IBD group vs controls; incidence of >1 abnormal Pap test almost double in those exposed to azathioprine/6-
mercaptopurine (AZA/6-MP), compared to those not exposed (similar results with infliximab); concluded that women
with IBD carry higher risk for clinically important cervical lesions, particularly if on immunosuppressants; correspond
with American College of Obstetricians and Gynecologists (ACOG) guidelines for annual Pap test screening (rather
than every 3 yr); if patient <25 yr of age, consider human papillomavirus (HPV) vaccine
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| Pregnancy and fertility: Oxford study—similar rate of fertility in participants with UC, compared to controls; study by
Olsen—80% reduction in ability to conceive (without help) after ileal pouch-anal anastomosis (IPAA); most likely due to
surgery in pelvis, with adhesions and damage to reproductive organs; Hudson study—in CD, those who had surgery had
higher rates of infertility than general population
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| Pregnancy outcomes: studies show that patients with IBD, UC, and CD have higher rates of preterm birth; patients with
CD have higher rates of low birth weight (LBW) and small for gestational age (SGA) infants; no data that patients with
CD have higher rates of congenital malformations (data from UC); meta-analysis—confirmed that patients with IBD
had higher rates of prematurity, LBW, and cesarean delivery; also higher rate of congenital abnormalities (in UC patients);
Dominitz study—rate of congenital malformations 7.9% in patients with UC, 3.4% in CD, and 1.7% in controls;
did not control for medication use or disease activity; Norgard—found 0.3% rate of anomalies among patients with UC;
when controlled for parity, age, and medication use, odds ratio 1.3 (not significant); when looked at individual anomalies,
significant increased risk found, compared to general population; reason for increased risk in UC and not in CD unknown;
Northern California Kaiser study—found increased risk for adverse conception outcomes (spontaneous
abortion or abortion undefined) among patients with IBD; higher rate of adverse pregnancy outcomes (defined as SGA
infants, preterm births, and stillbirths), compared to general population; also higher rate of pregnancy complications (eg,
preeclampsia, abruptio placentae) and maternal mortality; newborn abnormalities (ie, neonatal seizures, neonatal intensive
care unit [NICU] stay) and neonatal mortality not statistically significant but had highest odds ratio; in this study,
medication use and disease severity not predictors of poor outcome; no increased rate of birth defects seen; for best outcome,
maintain patient in remission throughout pregnancy
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Medical Therapy in Pregnancy
| Food and Drug Administration (FDA) categories: category A, controlled studies show no risk in humans; category
B, no evidence of risk in humans; category C, animal studies show adverse effect, but benefits possibly acceptable; category D,
positive evidence of risk; category X, contraindicated in pregnancy
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| Fish oil: supplement (not rated); essential fatty acids and docosahexaenoic acid (DHA) have potential antithrombotic effect
and prolong gestation; no evidence of preventing preeclampsia; mild benefit in CD; contains no mercury
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| Aminosalicylates: category B, except for olsalazine (Dipentum; category C); no increased risk with use during pregnancy
and breast-feeding; controlled trial showed no increase in teratogenicity; initially, case reports of adverse events
seen with sulfasalazine (not seen in larger case series); reduces folic acid (important for neural tube defects); during pregnancy,
patient should have 2 mg of folic acid daily if continuing to use sulfasalazine; placental and breast transfer occurs;
infant may develop watery diarrhea if breast-feeding
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| Corticosteroids: category C, including budesonide; case-control studies show that use in first trimester associated with
very small risk for oral clefts; overall, risk for malformation low; in transplant setting, adrenal suppression in newborn
and premature rupture of membranes reported; compatible with breast-feeding; no adverse events reported for patients on
budesonide during pregnancy
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| Antibiotics: metronidazole category B; ciprofloxacin category C; low risk for teratogenicity; shown that use of metronidazole
in first trimester associated with cleft lip and palate; prospective study showed ciprofloxacin associated with low risk
for defects (however, use not advised due to affinity for bones and possible arthropathy in offspring); breast-feeding not advised
with metronidazole, but probably compatible with ciprofloxacin; caveat—studies with antibiotics from obstetrics/
gynecology literature, so involve short courses of antibiotics, not weeks to months of use as in IBD; rifaximin—pregnancy
category C; insufficient data in humans; overall, benefit in IBD minimal in long term (limit use in pregnancy; avoid in first
trimester)
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| 6MP/AZA: category D; teratogenic in animals given supratherapeutic doses intravenously; low oral bioavailability in humans
(47% for AZA; 16% for 6MP); fetal liver in early pregnancy lacks ability to convert AZA to active metabolites (may account
for protection during organogenesis); in transplantation studies, frequency of anomalies 0% to 12%, with no recurrent pattern;
no increase in anomalies in rheumatic disease and lupus studies; Norgard study—cohort of 900 children born to women with
CD; found 6.5% rate of preterm births in control group (25% in AZA group [statistically significant]; 12% in steroid group);
for congenital anomalies, 5.7% in control group and 15.4% in AZA group (not statistically significant); Goldstein study—no
difference in rate of major malformations in pregnant women on AZA, compared to those on nonteratogenic treatments; more
prematurity and LBW in AZA group (expected in IBD); speaker continues AZA if only drug pregnant woman taking; if
woman on infliximab and on AZA for immunogenicity, speaker considers stopping AZA; breast-feeding—no breast-feeding
on AZA (American Academy of Pediatrics recommendation); 3 small studies show that AZA crosses placenta and 6-thioguanine
nucleotide (TGN) found in infant at slightly lower levels than in mother; very low levels detected in breast milk, and metabolite
levels not detectable in infant; elevated levels expected for 1 to 2 mo after birth due to placental transfer
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| Cyclosporine and tacrolimus: both category C; meta-analysis showed odds ratio of malformations 3.83 for cyclosporine;
benefit of tacrolimus over cyclosporine due to lower hypertension and hyperlipidemia in mother, but higher incidence
of diabetes in newborn; 5.6% rate of malformations, with no specific pattern; prematurity common; breast-feeding not recommended
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| Infliximab: category B; Katz study showed rates of live births, miscarriages, and therapeutic termination similar with infliximab
as in general population; study of 10 patients with CD intentionally exposed to infliximab during pregnancy showed no
birth defects but some preterm births and LBW infants (expected); infliximab and adalimumab IgG1 antibodies (do not cross
placenta in first trimester); IgG1 antibodies transferred in third trimester, accounting for high levels detected in infant at birth
(takes 2-7 mo for levels to disappear in infant); unable to monitor adalimumab (category B) levels in infants
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| Use with caution: diphenoxylate (category C) teratogenic in animals; loperamide associated with increased cardiovascular
defects; bisphosphonates category C; alendronate (Fosamax) half-life 10 yr; study of 24 pregnancies showed no increased
teratogenic risk; methotrexate (category X) known abortifacient, and causes teratogenic defects; thalidomide
category X
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| Special circumstances: perianal CD—study found that in patients with no perianal disease at delivery, 1 in 39 developed
perianal disease after pregnancy, but 4 in 4 with active perianal disease worsened after vaginal delivery; speaker recommends
cesarean delivery for patient with active perianal disease (obstetrician’s discretion if perianal disease inactive or
absent); fulminant UC—indications for surgery in pregnant patient same as for nonpregnant; case series in 1970s and
1980s showed high fetal mortality (40%-50%); series from Haq (2005) and Mayo Clinic showed 0% infant and maternal
mortality; recommendation to perform colonic decompression and ileal diversion in first trimester; later in pregnancy,
synchronous delivery and colectomy possibly best option; if possible, attempt medical therapy first and work closely with
experienced colorectal surgeon; IPAA—reversible deterioration of pouch function during pregnancy; cesarean delivery
recommended to preserve anal sphincter
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Suggested Reading
Bebb JR et al: Immunosuppression, IBD, and risk of lymphoma. Gut 51:296, 2002; Cendan JC et al: Associated neoplastic
disease in inflammatory bowel disease. Surg Clin North Am 87:659, 2007; Coburn LA et al: The successful use of
adalimumab to treat active Crohn's disease of an ileoanal pouch during pregnancy. Dig Dis Sci 51:2045, 2006; Deshpande
AR et al: Combination therapy with infliximab and immunomodulators: is the glass half empty? Gastroenterology
134:2161, 2008; Dorsey ER et al: Quantifying the risks and benefits of natalizumab in relapsing multiple sclerosis. Neurology
68:1524, 2007; Farrell RJ et al: Increased incidence of non-Hodgkin's lymphoma in inflammatory bowel disease
patients on immunosuppressive therapy but overall risk is low. Gut 47:514, 2000; Ferguson CB et al: Inflammatory
bowel disease in pregnancy. BMJ 337:a427, 2008; Hanauer SB: Risks and benefits of combining immunosuppressives
and biological agents in inflammatory bowel disease: is the synergy worth the risk? Gut 56:1181, 2007; Johnson FR et
al: Crohn's disease patients' risk-benefit preferences: serious adverse event risks versus treatment efficacy. Gastroenterology
133:769, 2007; Rudolph SJ et al: Long-term durability of Crohn's disease treatment with infliximab. Dig Dis Sci
53:1033, 2008; Rutgeerts P et al: Optimizing anti-TNF treatment in inflammatory bowel disease. Gastroenterology
126:1593, 2004; Tilg H et al: Gut, inflammation and osteoporosis: basic and clinical concepts. Gut 57:684, 2008; van
Staa TP et al: Inflammatory bowel disease and the risk of fracture. Gastroenterology 125:1591, 2003; Viget N et al:
Opportunistic infections in patients with inflammatory bowel disease: prevention and diagnosis. Gut 57:549, 2008.
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