Long-term Considerations With Advanced Therapies
Long-term Follow-up
Hematologic and liver function need to be closely monitored during initiation and escalation of thiopurines but less frequently monitored after a stable dose has been reached. Although published guidelines and clinical practices vary considerably, a reasonable approach is to perform a complete blood count and liver function tests every 2 weeks for 6 weeks and then every 4 to 12 weeks after that period. Testing for 6-thioguanine nucleotide and 6-methylmercaptopurine metabolites can help guide dosage adjustments over the long-term. Methotrexate monitoring should involve liver function tests every 1 to 3 months and periodic complete blood count testing.
Biologic therapy does not require absolute monitoring. If a patient's clinical picture suggests worsening disease, analysis of trough level and antibodies (for infliximab and adalimumab) can help determine whether the drug is still effective. These laboratory tests are not available commercially for certolizumab pegol. Patients should have yearly tuberculous skin testing or serum interferon-gamma release assay testing.
Pregnancy and Family Planning
Many patients with IBD are affected during their peak reproductive years. Thiopurines are classified as Federal Drug Administration (FDA) pregnancy category D, but this classification is based on teratogenicity in animals. The preponderance of human data suggests that thiopurines are not associated with a significant increase in the rates of prematurity, spontaneous abortion, congenital defects, neonatal infections, or neoplasia. Given the known correlation of active IBD with adverse neonatal outcomes, the risks of discontinuing thiopurines in a patient with IBD before (or during) pregnancy generally outweigh the benefits. Although thiopurine can be transferred through the placenta, the transfer of the drug via lactation is minimal, particularly after the first 4 hours of drug intake. Therefore, breastfeeding is generally considered safe if performed 4 to 6 hours after ingestion of azathioprine or 6-MP.
Methotrexate is a well-established teratogen and cannot be used in women considering pregnancy. It is FDA pregnancy category X. Methotrexate embryopathy occurs during the critical period of organogenesis (6–8 weeks after conception) but can occur during the second and third trimester, too. Intrauterine growth retardation, decreased ossification of the calvarium, low-set ears, micrognathia, limb deformities, and mental retardation occur. Because of its penetration into tissue, women of childbearing age who are taking methotrexate should use 2 forms of birth control and wait 6 months after stopping the drug before trying to conceive. Breastfeeding while taking methotrexate is also contraindicated.
Infliximab, adalimumab, and certolizumab pegol are FDA pregnancy category B drugs and are generally considered safe for use during pregnancy. Despite their overall safety during pregnancy, infliximab and adalimumab cross the placenta in the second and third trimester and are detectable in infants for up to 7 months after birth. Although low concentrations of infliximab and adalimumab are generally considered safe for infants, caution should be exercised when considering the rotavirus vaccine in these infants. For this reason, some experts recommend that infliximab and adalimumab be stopped at gestational week 30. However, this should be an individualized decision with input from the patient, primary care physician, gastroenterologist, and obstetrician. Certolizumab pegol is a fragment of an antibody and therefore can be used throughout pregnancy without significant placental transfer. Certolizumab, as well as infliximab and adalimumab, are considered safe to use while breastfeeding.
Thiopurines and biologic therapies do not affect male fertility, and pregnancy outcomes are not adversely affected if the father is taking these medications. However, men taking sulfasalazine or methotrexate should be warned of reversible oligospermia when trying to conceive. Fertility should be restored in men who stop taking methotrexate or sulfasalazine 3 months before trying to conceive.
Health Maintenance Measures
Primary care physicians and gastroenterologists need to work in tandem to cover the health maintenance needs of patients with IBD. Issues surrounding appropriate vaccinations should be addressed at the time of diagnosis. Live vaccines, including measles-mumps-rubella, varicella, and varicella zoster, are safe to use 4 to 12 weeks before immunosuppression. Inactivated vaccines can be given during immunosuppression but have a greater serologic response before immunosuppression. Tetanus/diphtheria, human papillomavirus, pneumococcal, hepatitis A, hepatitis B, meningococcal, and annual influenza vaccines should be considered as appropriate. Female patients with IBD, particularly those taking immunosuppressants, have an increased risk of cervical neoplasia; they are considered high risk and should undergo screening for cervical cancer per the American College of Gynecology guidelines.
Approximate Costs
Both patients and primary care providers should be aware of the relatively high costs of advanced IBD therapies (Table 2). Fortunately, the manufacturers of these drugs have patient-assistance programs, which offer discounted or free therapies to eligible patients. Furthermore, it is important to consider the long-term cost-effectiveness of these expensive medicines, particularly biologic therapies. Achieving and maintaining remission can decrease the need for major surgery and inpatient hospitalizations, thus increasing patients' productivity in the workplace. As these therapies become more prevalent, further analyses will better delineate their cost-effectiveness.