Amanda M. Eudy

Progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus: a systematic literature review:

Objective To determine risk factors for progressive multifocal leukoencephalopathy (PML) in systemic lupus erythematosus (SLE) patients, and understand how underlying disease or treatment for SLE may be associated with PML in this population. Methods Studies published in English between January 1, 1984 and October 31, 2014 that reported PML in adult SLE patients were included. Immunosuppression was defined as exposure to ≥1 immunosuppressant drug of interest at PML diagnosis: belimumab, rituximab, mycophenolate mofetil, azathioprine, cyclophosphamide, methotrexate and high-dose corticosteroids (>15 mg/day). Minimal immunosuppression was defined as low-dose corticosteroids (≤15 mg/day) and/or anti-malarials. Results Thirty-five publications met our inclusion criteria: four observational studies, two large case series, and 29 case reports that described 35 cases. Reported PML incidence rates among SLE patients based on observational studies ranged from 1.0 to 2.4 cases/100,000 person-years. Of the 35 case reports, three cases were exposed to no immunosuppressant drugs at PML diagnosis, five cases had minimal immunosuppression, 23 cases had immunosuppression, and four cases were indeterminate. Conclusions The evidence from this literature review suggests that, while PML is a very rare disease in SLE patients, there does appear to be an increased risk of PML associated with SLE compared to the general population, potentially due to immunosuppression, other contributing factors in their underlying disease, treatments prescribed to manage disease, or some combination of these factors. Additional large observational studies, designed to assess exposure to drugs of interest and complicated treatment histories, are needed to provide further evidence about potential mechanisms contributing to the onset of PML in SLE patients.

Elevated C-reactive protein and self-reported disease activity in systemic lupus erythematosus.

C-reactive protein (CRP), a biomarker of inflammation, has been associated with increased disease activity in rheumatoid arthritis. However, the association in systemic lupus erythematosus (SLE) remains unclear. We examined the association of CRP with self-reported disease activity in the Carolina Lupus Study and described differences by sociodemographic characteristics. The study included baseline and three-year follow-up data on 107 African-American and 69 Caucasian SLE patients enrolled at a median 13 months since diagnosis. Models estimated prevalence differences in the association of baseline CRP with self-reported flares, adjusting for age, sex, race and education. Active disease or flare was reported by 59% at baseline and 58% at follow-up. Higher CRP (>10 µg/ml vs. <3 µg/ml) was associated with a 17% (95% confidence interval (CI): −20, 53%) higher prevalence of flare at baseline and a 26% (95% CI: −9, 62%) higher prevalence of flare at follow-up. These CRP–flare associations were notably stronger in patients with lower education at baseline and in African-Americans at follow-up. These findings suggest that CRP may be a useful marker in studies of SLE health disparities.

Effect of pregnancy on disease flares in patients with systemic lupus erythematosus

Objective Prior studies found conflicting results about whether lupus is likely to flare during or after pregnancy. Using a large cohort of pregnant and non-pregnant women with lupus, we estimated the effect of pregnancy on disease flares in systemic lupus erythematosus. Methods Data were collected in the Hopkins Lupus Cohort 1987–2015. Women aged 14–45 years with >1 measurement of disease activity were included. The time-varying exposures were classified as pregnancy, postpartum or non-pregnant/non-postpartum periods. Flares were defined as: (1) change in Physician Global Assessment (PGA)≥1 from previous visit and (2) change in Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI)≥4 from previous visit. A stratified Cox model estimated HRs with bootstrap 95% CIs. Results There were 1349 patients, including 398 pregnancies in 304 patients. There was an increased rate of flare defined by PGA during pregnancy (HR: 1.59; 95% CI 1.27 to 1.96); however, this effect was modified by hydroxychloroquine (HCQ) use, with the HR of flares in pregnancy compared with non-pregnant/non-postpartum periods estimated to be 1.83 (95% CI 1.34 to 2.45) for patients with no HCQ use and 1.26 (95% CI 0.88 to 1.69) for patients with HCQ use. The risk of flare was similarly elevated among non-HCQ users in the 3 months postpartum, but not for women taking HCQ after delivery. Conclusions Our study supports and extends previous findings that the incidence of flare is increased during pregnancy and within the 3 months postpartum. Continuing HCQ, however, appeared to mitigate the risk of flare during and after pregnancy.

Reasons for cesarean and medically indicated deliveries in pregnancies in women with systemic lupus erythematosus

Objective To determine reasons for cesarean and medically indicated deliveries in a registry of pregnant women with SLE compared to RA. Methods Pregnant women with SLE or RA were prospectively followed, and pregnancy outcomes were collected, including whether labor was spontaneous or medically indicated and delivery was vaginal or cesarean. Preterm birth was defined as a birth <37 weeks gestation. Differences in reasons for cesarean delivery and indication of delivery between term and preterm births were determined by Fisher’s exact test. Results Compared to RA pregnancies, SLE pregnancies had modestly higher rates of preterm birth (24% SLE vs 14% RA), pre-eclampsia (15% SLE vs 7% RA), and cesarean delivery (48% SLE vs 30% RA). The majority of preterm births among women with SLE were indicated (70%), most commonly for pre-eclampsia or the health of the infant or mother. The majority of preterm births among women with RA, however, were spontaneous, primarily due to premature rupture of membranes. Conclusion Pre-eclampsia and maternal SLE activity appear to be the key drivers for the high rate of preterm birth and medically indicated delivery in SLE. This contrasts with RA, where preterm labor is most often due to spontaneous onset of labor.

The prevention, screening and treatment of congenital heart block from neonatal lupus: a survey of provider practices

Objective To survey an international sample of providers to determine their current practices for the prevention, screening, and treatment of congenital heart block (CHB) due to maternal Ro/SSA antibodies. Methods A survey was designed by the organizing committee of the 9th International Conference of Reproduction, Pregnancy and Rheumatic Diseases. It was sent to attendants of the conference and authors of recent publications or abstracts at ACR 2012, 2013 or 2014 on rheumatic diseases and pregnancy. Results In anti-Ro/SSA positive women, 80% of 49 respondents recommended screening by serial fetal echocardiogram (ECHO), with most starting at week 16 (59%) and stopping at week 28 (25%), although the time to stop varied widely. For women without a prior infant with neonatal lupus, respondents recommend every other week (44%) or weekly (28%) fetal ECHOs. For women with a prior infant with neonatal lupus, 80% recommend weekly fetal ECHOs. To prevent CHB, HCQ was recommended by 67% of respondents and most would start pre-pregnancy (62%). Respondents were asked about medications to treat varying degrees of CHB in a 20-week pregnant, anti-Ro and La positive SLE patient. For first degree, respondents recommended starting dexamethasone (53%) or HCQ (43%). For second degree, respondents recommended starting dexamethasone (88%). For third degree, respondents recommended starting dexamethasone (55%) or IVIg (33%), although 27% would not start treatment. Conclusion Despite the absence of official guidelines, many physicians with a focus on pregnancy and rheumatic disease have developed similar patterns in the screening, prevention and treatment of CHB.

Preconceptional Cardiovascular Health and Pregnancy Outcomes in Women with Systemic Lupus Erythematosus

Objective. To estimate the effects of preconceptional cardiovascular (CV) health, measured by American Heart Association (AHA) guidelines, on pregnancy outcomes in women with systemic lupus erythematosus (SLE). Methods. The study included patients in the Hopkins Lupus Pregnancy Cohort. Body mass index (BMI), total cholesterol, and blood pressure (BP) in the most recent clinic visit prior to conception or first trimester were used to determine CV health (ideal, intermediate, or poor health) based on AHA definitions. Outcomes included preterm birth, gestational age at birth, and small for gestational age (SGA). Multivariable linear and logistic regression models with generalized estimating equations estimated the association of each CV health factor and outcome. Results. The analysis included 309 live births. There were 95 preterm births (31%), and of the 293 pregnancies with birth weights, 18% were SGA. Ideal BMI, total cholesterol, and BP were reported in 56%, 85%, and 51% of pregnancies, respectively. Intermediate BMI was associated with decreased odds of SGA (OR 0.26, 95% CI 0.11–0.63), adjusted for race and prednisone use. Intermediate/poor total cholesterol was associated with increased odds of preterm birth (OR 2.21, 95% CI 1.06–4.62). Intermediate/poor BP was associated with decreased gestational age at birth (β −0.96, 95% CI −1.62 to −0.29). Conclusion. Poor/intermediate preconception CV health affects pregnancy outcomes of preterm birth and SGA infants among women with SLE. Efforts to maintain BMI, total cholesterol, and BP within the recommended ideal range prior to pregnancy is important to improve pregnancy outcomes in women with SLE.

Hydroxychloroquine Levels throughout Pregnancies Complicated by Rheumatic Disease: Implications for Maternal and Neonatal Outcomes

Objective. Pregnancies in women with active rheumatic disease often result in poor neonatal outcomes. Hydroxychloroquine (HCQ) reduces disease activity and flares; however, pregnancy causes significant physiologic changes that may alter HCQ levels and lead to therapeutic failure. Therefore, our objective was to evaluate HCQ concentrations during pregnancy and relate levels to outcomes. Methods. We performed an observational study of pregnant patients with rheumatic disease who were taking HCQ from a single center during 2013–2016. Serum samples were analyzed using high-performance liquid chromatography/mass spectrometry. Primary HCQ exposure was categorized as nontherapeutic (≤ 100 ng/ml) or therapeutic (> 100 ng/ml). Categorical outcomes were analyzed using Fisher’s exact test and continuous outcomes using linear regression models, Wilcoxon signed-rank test, Kruskal-Wallis test, t test, and ANOVA. Results. We analyzed 145 samples from 50 patients with rheumatic disease, 56% of whom had systemic lupus erythematosus (SLE). HCQ concentration varied widely among individuals at each trimester. Mean physician’s global assessment scores in patients with SLE were significantly higher in those with average drug levels ≤ 100 ng/ml compared to > 100 ng/ml (0.93 vs 0.32, p = 0.01). Of patients with SLE, 83% with average drug levels ≤ 100 ng/ml delivered prematurely (n = 6), compared to only 21% with average levels > 100 ng/ml (n = 19; p = 0.01). HCQ levels were not associated with prematurity or disease activity in non-SLE patients. Conclusion. With both high and low HCQ levels associated with preterm birth and disease activity in SLE, further study is necessary to understand HCQ disposition throughout pregnancy and to clarify the relationship between drug levels and outcomes.

PS4:80 Hydroxychloroquine in lupus pregnancy: a meta-analysis of individual participant data

Purpose Our current knowledge about how to treat lupus in pregnancy derives from small prospective or retrospective cohorts. The goal of this individual participant meta-analysis was to pool data from multiple prospective cohorts to answer the clinical question of whether hydroxychloroquine (HCQ) treatment affects pregnancy outcomes Methods The literature was searched for prospective cohorts of pregnancies among women with lupus. HCQ use was defined as use any time during pregnancy. Outcomes of interest included fetal loss, preterm birth, high disease, and preeclampsia. Data from each cohort were collected and analysed individually. Pooled ORs were calculated by random-effect models in Review Manager. Due to multiple pregnancies per patient, one pregnancy was randomly selected per patient. Primary analysis included only women with first trimester visits (6 cohorts). Subgroup analyses were stratified by a history of nephritis, APS, and disease activity at first clinic visit. Results The current analysis included 591 pregnancies from six cohorts, of which 73% were exposed to HCQ during pregnancy. Fetal loss: Overall, there was a 51% decrease in the risk of fetal loss among patients taking HCQ during pregnancy (OR: 0.49; 95% CI: 0.24 to 1.00). Among patients with a history of lupus nephritis, taking HCQ during pregnancy reduced the risk of fetal loss by 76% (OR: 0.24; 95% CI: 0.07 to 0.83; table 1). Preterm birth: There was no evidence that HCQ decreased the risk of preterm birth. Disease activity: Although not significant, among patients with a history of lupus nephritis, HCQ use during pregnancy may reduce the risk of having high disease activity during pregnancy (OR: 0.47; 95% CI: 0.21 to 1.09). Preeclampsia: Overall, there was no evidence that HCQ decreased the risk of. Among patients with APS, there may be a protective effect of HCQ, but the precision of the estimate was limited (OR: 0.55; 95% CI: 0.12 to 2.45). Conclusion Our results suggest that among patients with lupus nephritis, HCQ use may decrease the risk of fetal loss and decrease high disease activity during pregnancy. The heterogeneity of data collection suggests the need for a unified approach to identify larger cohorts of lupus pregnancies.Abstract PS4:80 Table 1 Pooled odds ratios for the association of hydroxychloroquine use and pregnancy outcomes

LL-06 Provider perceptions on the management of lupus during pregnancy: barriers to improved care

Background More than half of pregnancies in women with systemic lupus erythematosus (lupus) result in adverse outcomes for both mother and fetus. As demonstrated in the PROMISSE study, pregnancies managed by experts can have outcomes similar to the general population. However, many women with lupus do not receive this level of care and suffer complications at higher rates. We sought to identify aspects of current community rheumatologic care that could be improved to decrease the frequency of poor outcomes. Methods Focus groups with clinical rheumatologists were held at state rheumatology conferences in North Carolina, South Carolina, Virginia, and Northern California. The interview guide was based on the PRECEDE/PROCEED framework, seeking factors that predisposed, reinforced, and enabled physician practice patterns. Focus groups were recorded, transcribed, and coded to identify the elements of this framework. A group of women with lupus on their reproductive journey contributed to our understanding of the dilemmas and care provided. Results Medically ill-timed pregnancies and medication non-adherence during pregnancy were identified by the rheumatologists as the 2 key dilemmas in care. We identified several communication gaps as a key modifiable barrier to optimal management: 1) the approach to physician/patient communication was often ill-suited to the sensitive discussion about pregnancy planning; 2) the communication of treatment plans was often hampered by gaps in knowledge and confidence in data, encouraging non-adherence among nervous patients; and 3) local rheumatologists and OB/GYN frequently did not communicate, leading to varying treatment plans and confusion for patients. The key predisposing factors that impaired care included gaps in knowledge and skills in discussing pregnancy planning and management, as well as clinic time for repeated discussions. Reinforcing factors that influenced care included local treatment factors and concerns over legal consequences. Factors that could enable improved care included access to an expert or guidelines, clinical reminders, and patient handouts.Abstract LL-06 Figure 1 The PRECEDE/PROCEED model underlying the HOP-STEP program Conclusions Our goal is to ensure that all women with lupus across the country receive expert-level care for pregnancy planning and management by elevating the care received from community rheumatologists. This study demonstrated the importance of communication skills, knowledge, and cohesive plans between community physicians in reaching this goal. We are currently developing HOP-STEP (Healthy Outcomes for Pregnancies in SLE Through Educating Providers and Patients), a multifaceted implementation project to enable women with lupus and their rheumatologists to have honest and accurate conversations about pregnancy planning and management. Acknowledgements The Duke Autoimmunity in Pregnancy Patient Advisors and Collaborators contributed to this abstract.

Pregnancy in rheumatoid arthritis: a retrospective study

Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting women. Previous research has found that women with RA have an increased risk of cesarean delivery, preterm birth, and longer hospitalization after birth compared to women without RA [1–3]. Little is known, however, about changes in pregnancy outcomes after the diagnosis of RA. Information has been published about RA in pregnancy dating back to the 1930s, when it was noted that many women with RA entered Bremission^ during pregnancy and flared postpartum [4]. More recent studies, however, do not show the dramatic shifts in RA activity seen in the earlier studies, perhaps now mediated by the immunosuppressants that control the disease [5]. The difference in perceived disease activity shifts may be due to improved therapy outside of pregnancy and more precise measures of arthritis activity. The primary objective of this study was to determine the pregnancy outcomes for women with RA compared to healthy controls and the effect of RA diagnosis on pregnancy outcomes. Secondary objectives included charting changes in arthritis during and following pregnancy, as well as identifying patterns of medication use.