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Hydroxychloroquine and pregnancy on lupus flares in Korean patients with systemic lupus erythematosus J H Koh, H S Ko, S-K Kwok, J H Ju and S-H Park Lupus published online 10 October 2014 DOI: 10.1177/0961203314555352 The online version of this article can be found at: http://lup.sagepub.com/content/early/2014/10/10/0961203314555352

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Hydroxychloroquine and pregnancy on lupus flares in Korean patients with systemic lupus erythematosus JH Koh1, HS Ko2, S-K Kwok1, JH Ju1 and S-H Park1 1

Division of Rheumatology, Department of Internal Medicine, School of Medicine; and 2Department of Obstetrics and Gynecology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea

We investigated the clinical and laboratory characteristics of pregnancies with systemic lupus erythematosus (SLE) and identified lupus flare predictors during pregnancy. Additionally, we examined lupus activity and pregnancy outcomes in SLE patients who continued, discontinued or underwent no hydroxychloroquine (HCQ) treatment during pregnancy. We retrospectively analyzed 179 pregnancies in 128 SLE patients at Seoul St. Mary’s Hospital, Korea, between 1998 and 2012 and then assessed the clinical profiles and maternal and fetal outcomes. Overall, 90.5% of pregnancies resulted in a successful delivery and were divided into two groups: those who experienced lupus flares (80 pregnancies, 44.7%) and those who did not (99 pregnancies, 55.3%). Increased preeclampsia, preterm births, low birth weight, intrauterine growth restriction (IUGR), and low 1-minute Apgar scores occurred in pregnancies with lupus flares compared to pregnancies in quiescent disease. Lupus flares were predicted by HCQ discontinuation, a history of lupus nephritis, high pre-pregnancy serum uric acid and low C4 levels. Our study indicates that achieving pre-pregnancy remission and continuing HCQ treatment during pregnancy are important for preventing lupus flares. Lupus (2014) 0, 1–8. Key words: Systemic lupus erythematosus; hydroxychloroquine; pregnancy

Introduction Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease that affects women of childbearing age.1 Patients with SLE have more maternal and fetal complications than the general population, such as increased rates of preeclampsia, fetal loss, preterm delivery, intrauterine growth restriction (IUGR) and infants with low birth weight.1–3Active SLE within four months prior to conception, a history of lupus nephritis, and discontinuation of hydroxychloroquine (HCQ) treatment are considered to increase the risk of flares.2–6 Recent studies have reported improved outcomes and a live birth rate in 85–90% of pregnancies.1,4

Correspondence to: Sung-Hwan Park, Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, 222 Banpo-Daero, Seocho-Gu, Seoul 137701, South Korea. Email: [email protected] J.H.K. and H.S.K. contributed equally to this manuscript. Received 13 April 2014; revised: 8 July 2014; 23 August 2014; 12 September 2014; accepted 18 September 2014

Although many expert reviews have recommended taking HCQ during pregnancy, physicians in Korea often encounter patients who do not want to take HCQ during pregnancy, even though a prospective cohort study established the preventive effects of HCQ on lupus flares in pregnant women,6 and several studies have documented the safety of HCQ during pregnancy.7 However, HCQ was categorized as C by the United States Food and Drug Administration (US FDA)8 and was classified as category D by the Australian Drug Evaluation Committee (ADEC).9,10 Actually, the rationale for the C category classification by the US FDA and D category classification by ADEC is that HCQ is classified as a chloroquine used at higher doses for the treatment of malaria.9 This higher category might be causing many Korean mothers to be reluctant to use HCQ during pregnancy. In the present study, we described the clinical and laboratory manifestations during pregnancy in patients with SLE and identified the predictors for lupus flares. Additionally, to assess the protective effect of HCQ on lupus flares during

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10.1177/0961203314555352

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pregnancy, the history of medication changes was reviewed carefully.

Patients and methods Patient selection We retrospectively reviewed the medical records of pregnant patients with SLE who were managed at the rheumatology center and obstetrics and gynecology department at Seoul St. Mary’s Hospital, a tertiary care university hospital and referral center, between January 1, 1998 and December 31, 2012. All patients who fulfilled the American College of Rheumatology (ACR) SLE criteria, which were revised in 1997,11 were followed up with disease monitoring up to 12 months after delivery. Patients who were diagnosed with SLE after pregnancy were also excluded. The present study was approved by the institutional review board of Seoul St. Mary’s Hospital (KC13RISI0357). Clinical and laboratory data Demographic data, clinical features, and laboratory findings at the time of preconception were extracted from medical charts. The medications received before and during pregnancy and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores12 that were assessed at that time were also collected. Our institutes have measured the SLEDAI score on admission to evaluate the disease activity of all SLE patients since 1993. Thus, the SLEDAI score was used as an index of disease activity. Autoantibodies such as antinuclear antibodies (ANA), anti-Ro/SSA, antiLa/SSB, anti-ribonucleoprotein P (RNP) and antiphospholipid (aPL) were retrieved from records within one year of pregnancy. Clinical and laboratory data were assessed before conception, during pregnancy, one month after pregnancy or whenever a flare-up was suspected. These data included a complete blood count assessment, urinalysis, anti-double-stranded DNA (anti-dsDNA) or anti-DNA positivity, C3 and C4 levels, creatinine levels, uric acid levels, 24-hour proteinuria or urine protein-to-creatinine ratio assessment, and urinary sediment microscopy. Of the laboratory tests, anti-dsDNA positivity was evaluated using an enzyme-linked immunosorbent assay (ELISA) (anti-dsDNA ELISA kit; GENESIS, Leicester, UK), and anti-DNA positivity was determined by the Farr assay. Because of the two distinct reference ranges obtained from the

latter tests, anti-dsDNA positivity was classified as positive when the level was above the normal range. The pre-pregnancy glomerular filtration rate (GFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKDequation: GFR ¼ 141  min (Scr/ EPI)13 k,1)a  max (Scr/k,1)1.209  0.993Age  1.018 (if female)  1.159 (if black) and was expressed in ml/min/1.73 m2 of body surface area. Definitions The criteria for an SLE flare included a change in the SLEDAI score greater than three points.14 Active disease at conception indicated a high SLEDAI score (4) and a steroid requirement of greater than 15 mg/day within four months before conception.5 The duration of a lupus flare during pregnancy was defined as the period from conception to one month after delivery. The Sydney criteria15 were applied for diagnosis of antiphospholipid syndrome (APS). Hypertension was considered if systolic blood pressure was >140 mmHg and/or diastolic blood pressure was >90 mmHg in the sitting position in three consecutive measurements, or if antihypertensive drugs were used. Preeclampsia was defined as a new onset of hypertension and proteinuria >0.3 g/ day after 20 weeks’ gestation in women without baseline hypertension and proteinuria 0.3 g/day at baseline, the diagnosis of superimposed preeclampsia required both worsening hypertension and doubling of proteinuria. If there were red blood cell casts, a lupus nephritis flare-up was considered. A renal flare was defined as a new onset of proteinuria >0.5 g/day or urinalysis with cellular casts or a confirmed case by renal biopsy after delivery. The elimination half-life of HCQ is estimated to be 50 days,16 and the impact of cessation of the drug on SLE activity can take several months.6 Therefore, the HCQ cessation group was defined as those who underwent cessation of HCQ treatment within the three months prior to pregnancy. If the patient discontinued HCQ more than three months prior to pregnancy, she was considered as not having used HCQ. Spontaneous abortion was defined as fetal loss before 24 weeks of gestation, stillbirth as an intrauterine fetal death after 24 weeks of gestation, neonatal death as a live infant who died within 28 days after delivery, preterm delivery as a live birth before the 37th week and very preterm delivery as a live birth before the 34th week. IUGR was estimated

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when the growth index was below the 10th percentile of the Korean population according to gestational week measured by obstetric ultrasound. The generic birth weight centiles were calculated with Generic birthweight centile calculator17 v1.0 (National Health Service (NHS) Perinatal Institute, UK) on the basis of Korean average birth weight at 40 weeks.18 Low birth weight was defined as a live birth weighing

Hydroxychloroquine and pregnancy on lupus flares in Korean patients with systemic lupus erythematosus.

We investigated the clinical and laboratory characteristics of pregnancies with systemic lupus erythematosus (SLE) and identified lupus flare predicto...
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