Successful use of infliximab for perianal Crohn's disease in pregnancy.

To the Editor: Over the last decade the medical treatment of fistulizing Crohn’s disease (CD) has improved dramatically with the introduction of antitumor necrosis factor-alpha antibodies such as infliximab, adalimumab, and certolizumab. However, there are few data about its use during pregnancy. We report a successful outcome of an adalimumabresistant perianal CD treated with infliximab during pregnancy. A 30-year-old woman with longstanding ileocolonic CD diagnosed in 1997 presented to our outpatient clinic in 2008 reporting for the first time discharge from two perianal fistulas. We performed a colonoscopy and luminal activity was eliminated. The magnetic resonance imaging (MRI) showed two high transsphinteric fistulous tracts without perianal abscesses. Azathioprine and antibiotics were started. Four months later the patient did not have any improvement and adalimumab was started (induction doses with 160 mg/80 mg, and then 40 mg every other week), with a good clinical response initially. However, over time she required an increase in her dosage and a shortened administration interval to every week. After adalimumab dose escalation, the discharge disappeared, but she quickly lost response to the drug. The sigmoidoscopy was normal and the MRI showed two transsphinteric fistulous tracts, as previously described. There was no inflammatory activity in the rectal mucosa assessed by endoscopy. The surgeons evaluated the patient and they placed two setons in the two fistulous tracts. Subsequently, infliximab was started (5 mg/kg at 0, 2, and 6 weeks and thereafter every 8 weeks). After the second infusion the patient had a complete response with no further fistula drainage with gentle pressure. Two months after starting on infliximab she became pregnant. After discussions with the patient, a decision was made to continue infliximab throughout her pregnancy. The patient received the last dose of infliximab before delivery at 30 weeks gestation and the baby was born at 38 weeks gestation by a planned cesarean section. The baby is now 4 weeks old with normal growth and development. Infliximab has been shown to be efficacious in the treatment of CD fistula in multicenter randomized, double-blind, placebo-controlled trials. Domenech et al performed a study in CD patients who were in remission and discontinued treatment after being on infliximab therapy for at least 1 year. They reported that the cumulative probability of being free from relapse after discontinuing infliximab treatment for perianal disease was only 45% at 6 months and as low as 34% at 12 months. Consistent with their results, the authors concluded that infliximab discontinuation would not be recommended in perianal CD because of a high rate of early relapse. On the other hand, diagnosis of inflammatory bowel disease (IBD) is often made early in life and 50% of patients are diagnosed before 35 years of age. Women with this disease may wish to stop taking their drugs during pregnancy because of the perceived risk of harm to the fetus. However, it is crucial that the disease is controlled, and fears of adverse drugs events should be allayed. Taking this into account, the main issue concerning treatment with antiTNF therapy during pregnancy should be safety. Embryo-fetal perinatal developmental toxicity studies performed in cynomolgus monkeys using doses several hundred times the recommended human dose of anti-TNF revealed no evidence of teratogenic or other deleterious effect. The three TNF antagonists are rated category B by the FDA, meaning they are presumed to be safe based on animal studies. It is generally believed that the chimeric structure of the infliximab molecule containing a human IgG1 constant region limits placental transfer during the first trimester. However, the safety of infliximab beyond the first trimester is unknown because IgG subclasses are readily passed to the fetus during the second and third trimester. These findings suggest that pregnant patients should avoid therapeutic antibody treatments after 30 weeks gestation if possible. As pregnancy is an exclusion criterion in all drugs trials, data about the safety of anti-TNF are provided by registries such as the TREAT (Crohn’s Therapy Resource Evaluation and Assessment Tool) registry and the Infliximab Safety Database. Data from these registries support the safety of intentional or inadvertent use of infliximab in pregnancy. Our patient had an especially refractory complex perianal disease, which had failed to immunomodulators and a previous anti-TNF agent. Taking into account the involvement of the anal sphincters in this patient and the high risk of relapse after the discontinuation the anti-TNF therapy, after discussing the benefits and potential risks with the patient we decided to maintain infliximab up to the end of pregnancy, with a good outcome for both the mother and newborn. In summary, the limited clinical results available suggest that the benefits of infliximab in attaining a response and maintaining remission in pregnant IBD patients, particularly with complex perianal disease, might outweigh the (theoretical) risks of drug exposure to the fetus. However, physicians should be aware that the fetus might be exposed to therapeutic Copyright VC 2010 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.21368 Published online 17 June 2010 inWiley Online Library (wileyonlinelibrary.com).