Leflunomide exposure through second trimester of pregnancy: A case report

Leflunomide is a commonly used disease modifying antirheumatic agent. However, its use is contraindicated in pregnancy. The American College of Rheumatology (ACR) guidelines recommend discontinuing Leflunomide at least 24 months before conception. If a woman is found to be pregnant while on Leflunomide, ACR suggests close monitoring and cholestyramine washout. We describe a case of a patient with a history of juvenile idiopathic arthritis who was on Leflunomide throughout the first and second trimester of her pregnancy. A cholestyramine washout regimen was started but not completed. The patient was induced at 37 weeks of gestation due to non‐reassuring fetal heart rate. She ultimately delivered a healthy baby via emergency cesarian section.


| INTRODUCTION
Juvenile Idiopathic Arthritis (JIA) is a rheumatologic disease, affecting children and adolescence with an estimated prevalence of 1 per 1000 pediatric population (Ringold et al., 2019).The current American College of Rheumatology (ACR) guidelines for the treatment of active JIA suggest the use of nonbiologic diseasemodifying antirheumatic drugs (DMARDs), such as Methotrexate and Leflunomide, not responding to nonsteroidal anti-inflammatory medications (NSAIDs) or intraarticular steroid injections (Onel et al., 2022).Leflunomide is a non-biologic DMARD that acts to reduce the de novo synthesis of ribonucleotide uridine monophosphate pyrimidine (rUMP) by inhibiting the activity of dihydro-orotate dehydrogenase.A reduction in the levels of rUMP causes activation of P53 that causes arrest of the cell cycle.These biological actions prevent lymphocyte activation and promote the anti-inflammatory and immune-modulating effects of Leflunomide (Padda & Goyal, 2022).
The 2020 ACR and 2022 British Society for Rheumatology guidelines classify Leflunomide as "incompatible" with pregnancy and recommend discontinuing it at least 24 months before attempting to conceive (Russell et al., 2023;Sammaritano et al., 2020).Most of the information on the teratogenic effects of Leflunomide comes from animal models where exposure to a high dose during conception reduced fetal viability and increased the risk of fetal malformations (Fukushima et al., 2007).
Despite the recommendations about avoiding the use of Leflunomide in pregnancy, the actual data to support this are sparse.On the contrary, there is mounting evidence that suggests exposure to Leflunomide during any trimester may not cause adverse maternal or fetal outcomes (Bérard et al., 2018;Chambers et al., 2010;Pfaller et al., 2020).We present a case of a young female who was treated with Leflunomide for JIA.The patient discovered she is pregnant at 26 weeks of gestation.

| CASE
We present a case of a 27-year-old female with a history of juvenile idiopathic arthritis diagnosed at age of 2.5 years involving elbows and knees.She had initial treatment with NSAIDs and intra-articular medications.Due to persistence of her symptoms, she was then treated with Sulfasalazine and subsequently Methotrexate.Due to ongoing symptoms and gastrointestinal side effects with Methotrexate, she was started on Leflunomide 20 mg daily at the age of 21 which was successful in achieving full disease control along with Sulfasalazine.
Past medical history was notable for polycystic ovarian syndrome, asthma, and iron-deficiency anemia.Her prepregnancy body max index was 39.She had an allergy to Nystatin.Family history was significant for hypertension in her father, and diabetes in her mother.She was not using any form of contraception for 4 years as she was previously told she "could not conceive spontaneously" due to her underlying diagnosis of Polycystic ovary syndrome (PCOS).She noticed rapid weight gain and took a home pregnancy test which was positive.She discontinued Leflunomide and Sulfasalazine immediately following the positive home pregnancy test (around 26 weeks of gestation).She contacted her primary rheumatologist who recommended initiation of cholestyramine wash out.It was also recommended she continues Sulfasalazine to prevent further disease flare up.Initially, the patient wanted to pursue a therapeutic abortion before realizing how far along in her pregnancy she is.For that reason, a cholestyramine washout was not started immediately.A subsequent fetal ultrasound confirmed that she was approximately 26 + 4 weeks pregnant, therefore the patient decided to keep the pregnancy.At around 28 weeks of gestation, she had a phone follow-up with her primary Rheumatologist, who recommended initiation of cholestyramine wash out.Seven days of cholestyramine 8 g three times a day were completed.However, she could not complete the full 11 days of wash out therapy due to side effects of constipation.
Leflunomide metabolite level was <0.5 μg/mL, measured 20 days following the completion of 7 days of the cholestyramine washout.Only a single Leflunomide level was obtained due to lack of access to drug levels and long delays in result turn around.
Subsequently, she was assessed in the Pregnancy and Rheumatic Diseases Clinic at 31 + 5 weeks of gestation.She was on Sulfasalazine 1000 mg twice a day.By this time, she had started folic acid and supplemental iron.At the time of assessment, she was noted to be hypertensive (left arm 156/112 mmHg, right arm 143/100 mmHg).Her knees were tender on palpation, but she did not have any swollen joints.Initiation of hydroxychloroquine was recommended to prevent worsening joint symptoms.Her laboratory investigations showed anemia (hemoglobin 94 g/L), positive antinuclear antibody (ANA) level of 1:80 (nuclear homogenous pattern), along with negative rheumatoid factor, anti-cyclic citrullinated peptide (CCP), extractable nuclear antigen (ENA), double-stranded DNA.Her C-Reactive Protein (CRP) level was elevated at 17 mg/L.Protein to creatinine ratio was elevated at 34 mg/mmol (normal range <30 mg/mmol).Creatinine, liver enzymes, lactate dehydrogenase (LDH) and platelets were normal.
At 32 weeks of gestation, she was seen urgently by Maternal Fetal Medicine and was diagnosed with preeclampsia based on hypertension, elevated protein to creatinine ratio and symptoms of headache.She was admitted to the hospital briefly for fetal as well as maternal surveillance and to ensure adequate blood pressure control.Labetalol 200 mg three times a day and Nifedipine XL 30 mg twice a day were started.As her nonstress test (NST) and fetal ultrasound was normal, she was discharged from the hospital and managed as an outpatient with close follow-up.
Her serial ultrasounds that occurred every 2 weeks showed normal fetal growth measurements for gestational age, as well as normal amniotic fluid volume and umbilical cord Dopplers.On repeated assessments, there was no evidence of intrauterine growth restriction or slowing of fetal growth.The fetal abdominal circumference (AC) measurement progressed as expected throughout the pregnancy.Her last ultrasound was at 36 weeks gestational age and the fetal AC measurement was within normal limit at the 54th percentile.Estimated fetal weight was normal at the 45th percentile.
The patient was induced at 37 weeks of gestation.However, she was noted to have abnormal fetal heart rate on reassessment.Therefore, the decision was made to proceed with an emergency cesarian section.The child weighed 2325 g at birth with Apgar scores of 9 and 10 at 1 and 5 min, respectively.No malformations were noted at delivery.She was discharged home on Day 3 along with her infant.Postpartum, Nifedipine was discontinued.She initially required Labetalol due to hypertension.However, this, too, was discontinued after approximately 4 weeks.Sulfasalazine and hydroxychloroquine were continued postpartum with no evidence of postpartum flare at 6 months.

| CASE DISCUSSION AND REVIEW OF LITERATURE
Leflunomide is a pyrimidine synthesis inhibitor and helps control symptoms of active disease and prevents disease progression (Padda & Goyal, 2022).Animal studies have evaluated the teratogenic and fetotoxic effects of Leflunomide.In one study, pregnant mice were given variable doses of Leflunomide (10, 30, or 70 mg/kg/day) from Day 6 to Day 15 of their pregnancy.A high dose of 70 mg/kg/day led to the resorption of fetuses in all the test group mice and no live fetuses were detected.At 30 mg/kg/day, Leflunomide led to a variety of fetotoxic effects such as reduced fetal viability, neural tube defects, tail deformities, cleft palate, persistent truncus arteriosus, ventricular septal defect, and multiple skeletal abnormalities (Fukushima et al., 2007).A Leflunomide blood level of 0.03 μg/mL has been deemed safe in humans.This "threshold" number has been extrapolated from animal data (Chambers et al., 2010).
Due to the prolonged half-life of its active metabolite and results from animal data, the current ACR reproductive guidelines deem Leflunomide incompatible with pregnancy and recommend women of childbearing age to use contraceptives while using Leflunomide (Sammaritano et al., 2020).The literature also suggests avoiding conception while on Leflunomide (Sanofi-Aventis Arava prescribing information, n.d.).If on Leflunomide, pregnant patients should discontinue it as soon as the pregnancy occurs and immediate cessation of medication is recommended along with testing for drug level.The concentration considered to have minimal teratogenic and fetotoxic effects is less than 0.02 mg/L (0.02 μg/mL) in humans (Sanofi-Aventis Arava prescribing information, n.d.; Sammaritano et al., 2020).For levels higher than this, accelerated washout of the active metabolite with cholestyramine 8 mg orally three times daily for 11 days or activated charcoal 50 g every 12 h for 11 days is recommended.A plasma level of less than 0.02 mg/L (0.02 μg/mL) should be verified by two blood tests at least 14 days apart.If the levels are found to be high, the washout procedure should be repeated (Sanofi-Aventis Arava prescribing information, n.d.).
However, in "real-world" settings, obtaining Leflunomide levels can be difficult and delayed as seen in our case.Therefore, cholestyramine wash out was started without testing for drug levels given patient was on Leflunomide when she conceived.
Clinical data studying the effects of Leflunomide in human pregnancies are sparse.Chambers et al. compared the birth outcomes in females with rheumatoid arthritis who were exposed to at least one dose of Leflunomide on or after their estimated date of conception (females who were earlier than 21 weeks pregnant were enrolled in this study).This group was compared to disease-matched comparison groups of females who were not exposed to Leflunomide and healthy controls.The rates of congenital malformations (5.4% in the Leflunomide group vs. 4.2% in either two groups) were comparable in all the groups (Chambers et al., 2010).
Bérard et al. studied a cohort of 72 pregnancies where the females were exposed to Leflunomide during the first trimester (n = 51) or second/third trimester (n = 21).Results showed that regardless of the time of exposure to Leflunomide, there was no statistically significant increase in the risk of major congenital malformations, abortions, low birth weight, and prematurity (Bérard et al., 2018).
Pfaller et al. did a critical review of 13 publications with 169 live births in females exposed to Leflunomide preconception and/or during pregnancy.Eight cases of congenital malformations were reported without a consistent pattern and a statistically significant difference between exposed and unexposed groups (Pfaller et al., 2020).
Henson et al. reviewed 1167 reported pregnancies from clinical trials and the post marketing settings.Out of the reported pregnancies reviewed, 587 cases had known outcomes, out of which had 15 sets of twin births.The reported cases were divided into 333 live births, 285 full-term and 48 preterm births.Results showed that birth defects were reported in 44 fetuses/embryos which is comparable to rates of birth defects in the general population.Overall concluding that there is no significant fetal toxicity reported in pregnancies exposed to Leflunomide from preconception or during pregnancy (Henson et al., 2020).
Our case was interesting as the patient realized she was pregnant almost at the third trimester of her pregnancy while she had been continuously taking Leflunomide.She underwent the cholestyramine washout procedure as per the recommended guidelines but could not tolerate the full duration due to side effects.
Prior to initiation of Leflunomide, the patient's rheumatologist had a detailed discussion about use of effective contraception while on Leflunomide with the patient.However, the patient had not followed through with this as she thought that she was "unable to conceive" due to her underlying diagnosis of PCOS.Furthermore, due to her underlying PCOS, and irregular menstrual cycles, there was a delay in diagnosis of her pregnancy.
Lastly, the patient was diagnosed with preeclampsia around 32 weeks of gestation in the context of hypertension, elevated protein to creatinine ratio and headaches.Although Leflunomide may also be associated with hypertension, we suspect her newfound hypertension was due to preeclampsia rather than medication side effects, as she previously had no history of hypertension and her symptoms resolved following the birth of her child.
Leflunomide is an effective therapy for the treatment of a variety of rheumatological disorders.Its use becomes challenging in females of reproductive age.The current guidelines suggest avoiding the use of Leflunomide in women who are planning a pregnancy.In case of an unintended pregnancy, the patient should undergo a cholestyramine washout procedure.However, most of the information regarding the safety of the use of Leflunomide preconception or during pregnancy is extrapolated from animal data.The limited human data have not been associated with an increased risk of miscarriage or congenital malformations.
We have also described a case where a female delivered a structurally normal infant despite being exposed to Leflunomide during the first two trimesters.Leflunomide safety in pregnancy needs further evaluation.