First, Do No Harm

Fully 75 percent of Americans with autoimmune diseases are women, according to the American Autoimmune Related Diseases Association, Inc., and many of these women are of child-bearing age. Autoimmune conditions may improve, stay the same, or worsen during pregnancy. Psoriasis, for example, flares in about one third of women during pregnancy.

Active inflammatory disease during pregnancy can have serious consequences for both mother and baby, so extreme caution must be exercised when prescribing medication to pregnant women.

Cimzia (Certolizumab pegol) is FDA-approved for psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), Crohn’s disease, and ankylosing spondylitis. Cimzia is an Fc-free, PEGylated to the Fab portion monoclonal antibody that binds tumor necrosis factor. Because there is no Fc component, Cimzia does not bind the neonatal Fc receptor (FcRn) for immunoglobulin G (IgG) and is not expected to undergo FcRn-mediated transfer across the placenta.

How Well Does Cimzia Work?

Cimzia’s FDA-approved dose for psoriasis for patients who weigh more than 90kg is 400mg at week 0,2, and 4. For those weighing less than 90kg or for the patient who is pregnant or lactating, the dose is cut to 200mg every other week.

In a study¹ designed to assess the safety and efficacy of Cimzia in adults with moderate to severe chronic plaque psoriasis, Lebwohl et al. report that at week 16, Psoriasis Area and Severity Index (PASI) 75 and PASI 90 response were 75 percent and 50 percent, respectively. Maintenance of PASI 75 response was 98 percent through week 48.

During the first 12 weeks of the trial, there were no malignancies, herpes zoster activations, cases of tuberculosis, or deaths in the Cimzia cohort. One cutaneous Candida infection and one serious infection (pneumonia) occurred during the study period. This tells us that Cimzia’s safety and efficacy are comparable to, if not better than that for Humira (adalimumab), Stelara (ustekinumab), and Enbrel (etanercept).

Cimzia in Pregnancy: Weighing the Evidence

This brings us to the data regarding Cimzia’s safety during pregnancy and lactation, and there is a growing body of reassuring data suggesting that it is safe for mother and baby. The FDA approved a label update that includes pharmacokinetic data showing negligible to low transfer of Cimzia through placenta and minimal transfer to breast milk from mother to infant.

Current studies via the Organization of Teratology Specialists suggest that therapeutic monoclonal antibodies do not increase clinical risk of congenital anomalies during conception or early pregnancy. However, placental transfer of drug can occur during the third trimester. Therefore many advise discontinuing biologic therapy during the third trimester.

Porter et al.² explored the in vitro and ex vivo transfer of Cimzia and showed that binding to the Fc-Rn was strongest with Remicade (infliximab), Humira (adalimumab), and Enbrel (etanercept), respectively. There was no binding with Cimzia or a matched control. The amount of Cimzia that transfused through the placenta was less than one percent of the other biologics and less than the control in this study.

Mariette et al.³ note that active transport of IgG from mother to neonate is mediated by FcRn and occurs during the second and third trimester. They evaluated 16 women >30 weeks pregnant receiving Cimzia during pregnancy. The last dose was administered less than 35 days prior to delivery. Blood samples were collected, and Cimzia levels were measured from mothers, umbilical cords, and infants at delivery and four and eight weeks post partum. Blood levels of Cimzia in mothers was 25ug/ml. Only three cord samples had detectable Cimzia of 0.04ug.ml (i.e., 0.16%). At birth, two children had Cimzia levels, one was thought to be false positive, and the other had 0.42 (i.e., 0.09%) of the mother’s blood level. Importantly, no infants had Cimzia blood levels at weeks four and eight. Nine women continued Cimzia post partum and breastfed their infants with no detectable levels of Cimzia found in infant’s blood.

Mahadevan et al.⁴ evaluated 31 pregnant women including 11 taking Remicade, 10 taking Humira, and 10 taking Cimzia. At birth, concentrations of Cimzia were negligible.

Clouse et al.⁵ evaluated pregnancy outcomes in women exposed to Cimzia. Of 625 reported pregnancies, the most frequent indications were Crohn’s disease and RA. The study authors concluded that there was no harmful effect seen with maternal Cimzia exposure on pregnancy outcomes. The median cord level of Remicade, Humira, and Cimzia relative to mother’s blood was 160 percent, 153 percent, and 3.9 percent, respectively. By contrast, Remicade and Humira could be detected in infants blood for up to six months.

Cimzia During Lactation: Weighing the Evidence

Clouse et al.⁶ evaluated transfer of Cimzia during lactation and found that breast milk contained no measurable Cimzia. Biologics have a low oral bioavailability due to their size and proteolytic cleavage in the digestive system, but the neonate Fc receptors in human intestinal epithelial cells promote uptake of undigested IgG’s. Since Cimzia has no Fc portion, it is less likely to be absorbed via the lactation route. Cimzia was undetectable in 56 percent of breast milk samples. In the remaining samples, there was less than one percent of the concentration in the mother’s blood, indicating no-to-minimal transfer from plasma to breast milk. The researchers concluded that Cimzia ingestion by suckling is minimal, and Cimzia treatment is compatible with breast feeding

The immune system of the neonate is immature. It depends on innate immunity as well as factors such as IgGs received through lactation. The concept of adding “anti-immunoglobulins” theoretically may interfere in the development of the immune system, especially during the third trimester and lactation. Hence, it would seem prudent to utilize a therapy that does not pass the placenta or get passed via lactation. Cimzia seems to have an advantage over other biologics in these areas.

A New Era?

Until now, avoidance of biologics during the third trimester and lactation seemed prudent, but the Cimzia data tells us that we may have entered a new era and can now control psoriasis in the pregnant and lactating female without fear of harming the neonate.

1. Lebwohl, et al. “Certolizumab pegol for the treatment of chronic plaque psoriasis: Results through 48 weeks of a phase 3, multicenter, randomized, double-blind, etanercept- and placebo-controlled study (CIMPACT).” J Am Acad Dermatol. 2018; 266-276.

2. Porter C, et al. “Certolizumab pegol does not bind the neonatal Fc receptor (FcRn): Consequences for FcRn-mediated in vitro transcytosis and ex vivo human placental transfer.” Journal of Reproductive Immunology 2016;1167-12.

3. Mariette X, et al. “Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study.” Ann Rheum Dis. 2018;77:228–233.

4. Mahadevan U, et al. “Placental Transfer of Anti–Tumor Necrosis Factor Agents in Pregnant Patients With Inflammatory Bowel Disease.” 2013;11: 286–292.

5. Clouse MEB, et al. “Pregnancy Outcomes in Subjects Exposed to Certolizumab Pegol.” Journal of Rheumatology. 2015;42 (12) 2270-2278.

6. Clouse MEB, et al. “Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study.” Ann Rheum Dis. 2017;76:1890–1896.