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A Woman with Rheumatoid Arthritis Who Successfully Delivered a Healthy Child with Continuous Administration of Sarilumab Throughout Pregnancy
Abstract
We herein report a patient with rheumatoid arthritis (RA) who successfully delivered a healthy child with continuous administration of sarilumab throughout pregnancy. She delivered her first child, a healthy boy, following in vitro fertilization-embryo transfer (IVF-ET) while using etanercept and low-dose prednisolone. Disease activity persisted after delivery, so etanercept was switched to sarilumab. She became pregnant by IVF-ET again. Because RA was still active, sarilumab was continued during pregnancy. She delivered a healthy girl at the 38th week of gestation by Caesarean section. No abnormalities were detected at or within 6 months after birth. Sarilumab was safe and effective in this pregnant woman with RA.
Introduction
Patients with rheumatoid arthritis (RA) who are planning to become pregnant have limited treatment options. Methotrexate (MTX), which is the first-line treatment for RA, cannot be used during pregnancy due to teratogenicity (1). In pregnant RA patients, some anti-tumor necrosis factor (TNF) therapies are considered safe, such as etanercept (ETN) and certolizumab-pegol (CZP), the structures of which do not favor crossing the placenta (2). In contrast, use of anti-interleukin-6 (IL-6) agents is controversial because the existing data are not compelling (3,4).
We herein report a woman with RA who was treated with sarilumab (SAR) throughout her second pregnancy because ETN, which had been used in her first pregnancy, lost efficacy, and the disease activity was high during the second pregnancy. We discuss the antepartum course, fetal growth, and disease activity from conception to six months postpartum, during which she was treated continuously with SAR for RA.
Case Report
The patient developed RA at 25 years old. Prednisone [(PSL); 5 mg/day], MTX (8 mg/week), and ETN (50 mg/week) were used in combination to stabilize her symptoms. At 29 years old, MTX was discontinued during pre-conception planning. At 35 years old, she became pregnant for the first time by in vitro fertilization-embryo transfer (IVF-ET). Her joint symptoms worsened during the antepartum period, so she was referred to our hospital. Tacrolimus [(TAC), 1.5 mg/day] was started and increased to 3 mg/day after safety was confirmed. Administration of TAC was slightly effective, but her joint symptoms remained active. Therefore, PSL was increased to 10 mg/day and shortly thereafter increased to 15 mg/day. ETN was continued until 39 weeks' gestation, at which time she delivered a healthy boy by Caesarean section.
Because the RA activity continued to be high, ETN was switched to an anti-IL-6 agent [SAR (200 mg biweekly)] at 36 years old. At the time SAR treatment was initiated, she was not contemplating another pregnancy, but we explained to her that the data on SAR safety during pregnancy were insufficient. SAR was effective in ameliorating her symptoms, and the PSL dose was decreased.
At 38 years old, she became pregnant for the second time following IVF-ET. This pregnancy treatment was given without informing the rheumatologist in charge of her treatment. At her first visit after her conception was discovered, we explained to her concerns about the effects of the drug on the immune system of her fetus and suggested discontinuing or spacing SAR. However, the patient herself desired to continue SAR, as she feared that stopping would worsen her arthritis disease activity. Figure shows the antepartum course, fetal growth, and disease activity from conception to six months postpartum. The RA disease activity, as assessed by the clinical disease activity index (CDAI), was 6.1 while she was being treated with PSL (10 mg/day), TAC (3 mg/day), and SAR (200 mg biweekly). At this point, we asked the patient whether she would prefer to discontinue SAR or take SAR intermittently; however, because the joint symptoms remained active and other drugs were being taken in relatively large doses, she decided to continue SAR continuously.
Fetal development and disease activity of RA during pregnancy and the postpartum period. The pregnancy and puerperal course during sarilumab administration, showing disease activity, changes in estimated fetal weight, and changes in treatment content, is shown. The Japanese fetal growth curve shows the average estimated fetal weight ±2.0 standard deviations. SAR: sarilumab, TAC: tacrolimus, PSL: prednisone, CDAI: clinical disease activity index, SD: standard deviations
Fetal growth was appropriate for gestational age; specifically, the estimated fetal weight was within 94.5% (±2 standard deviations) of the Japanese fetal growth curve (5). At 19 weeks gestation, however, the maternal RA disease activity worsened (CDAI=7.4). Therefore, SAR was continued until 37 weeks+1 day of gestation, TAC was continued until 37 weeks+6 days of gestation, and PSL (10 mg/day) was continued until delivery. At 38 weeks+3 days of gestation, she delivered a healthy girl by Caesarean section. The newborn weighed 3,054 g and had an Apgar score of 8 points at 1 minute and 9 points at 5 minutes. The newborn was transferred from labor and delivery to the regular nursery for routine care.
The patient desired to breastfeed during the newborn period, so TAC (3 mg/day) was resumed 7 days postpartum, and SAR (200 mg biweekly) was resumed 28 days postpartum. The patient continued to breastfeed while receiving SAR. This second child was vaccinated with multiple live vaccines after reaching six months old, including the Bacille-Calmette-Guerin vaccine, with no adverse effects.
Discussion
We encountered a woman with RA who was treated with SAR throughout pregnancy and the postpartum period. She delivered a healthy child and breastfed while being treated with SAR.
Prior to the availability of biologics, it was a challenge to treat RA patients during pregnancy and the postpartum period, including patients who desired to breastfeed, as safe and effective drugs were limited (1,6,7). The introduction of biologic DMARDs has significantly improved treatment for RA patients, as well as for RA women who plan to become pregnant. Currently, the use of some anti-TNF therapies for RA patients during pregnancy has been shown to be safe and effective, such as ETN, which is a fusion protein composed of extracellular TNF receptor domains and immunoglobulin G (IgG) Fc fragments (8), and CZP, which is a pegylated anti-TNF-α that has minimal placenta transfer because it has no Fc region and no affinity for fetal Fc receptor (9,10). An alternative treatment strategy for pregnant RA patients who are refractory to anti-TNF therapy has not yet been established. There are no reports that tocilizumab (TCZ), an IL-6 receptor antagonist, increases the risk of congenital anomalies when used during pregnancies complicated by RA (3). Human IgG is known to transfer to the placenta and breast milk, but TCZ, a humanized IgG1 monoclonal antibody, has been reported to have lower concentrations in umbilical cord blood and milk than in maternal serum (11). SAR, which is also an IL-6 receptor antagonist, is a human IgG1 monoclonal antibody and is assumed to have the same pharmacologic effect and drug action as TCZ.
High serum IL-6 levels in the mother have been suggested to correlate with fetal brain developmental disorders and postnatal mental developmental disorders (12,13). In particular, it has been suggested that high maternal IL-6 and CRP levels in the third trimester may adversely affect the fetal heart rate and cognitive function in early childhood (12). In RA patients with pregnancy, high maternal serum IL-6 levels in the first trimester were also reported to reduce birth weight (14). IL-6 inhibition improved the risk of preterm birth in artificially induced chorioamnionitis and did not significantly affect the fetus (15). Based on these reports, inhibiting of high level of IL-6 should be desirable for both patients with inflammatory disorders such as RA and their babies. However, there was a report that IL-6 knockout mice showed a decrease in the immune response to multiple viruses, such as influenza, in animal experiments, as IL-6 is an important cytokine in the immune system against viral infections (16). Thus, further discussion is needed to determine at what dose and for how long IL-6 inhibitors should be continued in order to obtain optimal effects in patients exposed to high levels of IL-6, including collecting data on the outcomes of pregnancy involving SAR treatment.
There have been no reported cases involving treatment with SAR prior to and throughout pregnancy until delivery or during breastfeeding. Indeed, our case is the first report of a patient with RA who was treated throughout pregnancy. Notably, a healthy girl was delivered, breastfed, and vaccinated after reaching six months old with no side effects, despite continued maternal treatment with SAR during the postpartum period.
In general, it is known that RA disease activity improves when RA patients become pregnant (17). This finding may be due to pregnancy-related progesterone and estrogen levels and the suppression of Th1- and Th17-type T cells (18). In contrast, it has been reported that some pregnant RA patients do not improve, and disease activity is exacerbated after childbirth (17). In addition, high RA disease activity during pregnancy increases the risk of endometrial dysgenesis and pregnancy complications (19). In our patient, RA disease activity worsened during pregnancy; however, fetal growth was not affected, and pregnancy complications did not affect the newborn.
In conclusion, there is growing experience with the use of TNF inhibitors during pregnancy, but data on IL-6 inhibitors are still insufficient. We hope that this case will serve as a model of a woman safely treated with an IL-6 inhibitor (SAR) throughout pregnancy and the postpartum period.
We obtained written informed consent from this patient for the publication of her case prior to submission of this manuscript.
No additional ethical approval was needed according to the Institutional Ethical Board of Mie University because no interventional procedure was performed involving this patient.
The authors state that they have no Conflict of Interest (COI).