Managing risks of TNF inhibitors: An update for the internist
ABSTRACTTumor necrosis factor (TNF) inhibitors have many beneficial effects, but they also pose infrequent but significant risks, including serious infection and malignancy. These risks can be minimized by judicious patient selection, appropriate screening, careful monitoring during treatment, and close communication between primary care physicians and subspecialists.
KEY POINTS
- Over the past 10 years, TNF inhibitors have substantially altered the management of autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.
- Safety concerns include risks of infection, reactivation of latent infection (eg, fungal infection, granulomatous infection), malignancy, and autoimmune and neurologic effects.
- Before treating, take a complete history, including exposure to latent infections and geographic considerations, and bring patients’ immunizations up to date.
- Regular clinical and laboratory monitoring during treatment helps optimize therapy and minimize the risk of adverse effects.
- Physicians must be aware of atypical presentations of infection and understand how their treatment may differ in patients on biologic therapy.
PREGNANCY
Physicians caring for patients with rheumatoid arthritis and inflammatory bowel disease must be aware of how these diseases affect fecundity and fertility and how the medications can affect conception and pregnancy. Many patients have difficulty conceiving while their autoimmune disease is active, and better disease control may improve fecundity and result in unanticipated pregnancy. Patients should be advised of the need for contraception if pregnancy is ill-advised or undesired.
Many patients seek advice about teratogenicity before conceiving, or seek guidance about rheumatoid arthritis and inflammatory bowel disease treatment while pregnant.
Several studies have reported a higher risk of adverse pregnancy outcomes in patients with rheumatoid arthritis and inflammatory bowel disease than in the general population.99–105 In inflammatory bowel disease, the odds of a premature delivery or having a low-birth-weight child are twice as high as in the normal population.100,103 Higher rates of cesarean delivery and stillbirth have also been reported. The main predisposing factor appears to be the disease activity at the time of conception, as active disease seems to be linked to adverse pregnancy outcomes.
Treatment with anti-TNF agents may rapidly achieve and maintain remission, raising the question of the safety of continued anti-TNF use during pregnancy. The FDA classifies anti-TNF agents as category B drugs, as animal studies have not demonstrated fetal risk, and no well-controlled prospective study has yet been conducted with pregnant women.
In an observational study, Schnitzler et al105 assessed the outcomes of 42 pregnancies in 35 patients with inflammatory bowel disease receiving either infliximab or adalimumab during pregnancy, compared with 56 pregnancies in 45 healthy patients without inflammatory bowel disease. There was no statistical difference in abortion rates between patients receiving anti-TNF agents and healthy women without inflammatory bowel disease (21% vs 14%, P = .4234). There was also no significant difference observed in birth weight, birth length, or cranial circumference of the children between the two groups. However, pregnancies with direct exposure to anti-TNF agents resulted in a higher frequency of premature delivery (25% vs 6%, P = .023).
Similar results were noted from the Crohn’s Therapy, Resource, Evaluation, and Assessment Tool, or TREAT, registry, as well as from a large systematic review by Vinet et al106 and case reports of rheumatoid arthritis and inflammatory bowel disease in women exposed to anti-TNF agents during pregnancy.
In addition, results from a recent systematic review of 38 studies of anti-TNF use and fetal risk, with a total of 437 women (189 on infliximab, 230 on adalimumab, 18 on certolizumab pegol), showed similar results.107 In pregnancies exposed to anti-TNF agents, the rates of congenital abnormalities (3.4%), fetal deaths (8.5%), and preterm births (2.7%) were similar to those in the general population.
For patients in disease remission on TNF inhibitors, it is reasonable to continue these agents during pregnancy after careful discussion with the patient. Fetal safety and infant immunization response after delivery are the primary concerns in these cases.
Both infliximab and adalimumab cross the placenta and remain detectable in the baby’s circulation 4 months (for adalimumab) to 6 months (for infliximab) after delivery. It is currently recommended that infliximab be stopped at 32 weeks of gestation for the remainder of the pregnancy and that adalimumab be stopped at 34 to 36 weeks, given a planned 40-week gestation.
Certolizumab does not cross the placenta in significant amounts and should be continued throughout pregnancy; drug levels in infants were shown to be less than 2 μg/mL, even when dosed the week of delivery.108–112
TAKE-HOME POINTS
- All health care providers of patients with rheumatoid arthritis and inflammatory bowel disease should be familiar with anti-TNF agents used in treating these diseases.
- The benefits of controlling the disease far outweigh the risks of therapy when used appropriately.
- Care of these patients should be multidisciplinary, with clear communication between primary care physician and specialist.
- Patient education and monitoring combined with prompt communication between primary care physician and specialist are key.
