Meb Clowse

The impact of cyclophosphamide on menstruation and pregnancy in women with rheumatologic disease.

Background While cyclophosphamide (CYC) can save the life of a young woman with severe rheumatologic disease, it may lead to the long-term side-effects of infertility and premature menopause. We compared the reproductive health histories of young women with rheumatologic disease with and without prior CYC exposure to identify the impact of this medication on this important component of health. Methods This research includes a case-series study of women diagnosed with SLE, vasculitis, and scleroderma prior to age 35. Each patient completed a questionnaire about desired childbearing, menstrual regularity, infertility, and pregnancy history. Women with prior CYC therapy were queried about the use of gonadotropin-releasing hormone agonists (GnRH-a) for fertility preservation. The responses to this questionnaire were compared for women with and without CYC exposure. Results Of the 43 participants, 23 had prior CYC exposure and 20 were CYC naïve. The current age of these groups was similar (average age 32), but women with prior CYC were four years younger at diagnosis than women without CYC. More women with prior CYC had cessation of menses in the year prior to the study (30.4% vs 0%, p < 0.05). Of the women with prior CYC exposure, those with loss of menses were older at study enrollment, older at CYC treatment, and had a higher cumulative CYC dose than those with preserved menstruation. While more women with GnRH-a co-therapy during CYC had maintained menses, this difference did not reach statistical significance. Women with prior CYC without GnRH-a co-therapy had a higher frequency of nulliparity and had greater trouble conceiving than women with GnRH-a co-therapy. Few pregnancies were conceived following CYC exposure and all resulted in elective termination, miscarriage, or preterm birth. Conclusion In this cohort of young women with rheumatologic disease, more women with prior CYC than without had amenorrhea, nulliparity, and infertility. GnRH-a co-therapy may prevent these adverse effects of CYC.

The management of rheumatic diseases in pregnancy

Pregnancy can create a challenge for physicians caring for women with rheumatic diseases. For many women with rheumatoid arthritis (RA), pregnancy can provide a reprieve from long-term joint pain and inflammation, but others will not experience remission and will continue to need medication. Systemic lupus erythematosus (SLE) may remain quiet in some women, but in others may become more aggressive during pregnancy, putting both mother and foetus at risk. Women with limited scleroderma can do remarkably well, but scleroderma renal crises can be difficult to manage. A third of pregnancies in women with antiphospholipid syndrome (APS) may be refractory to our best therapy. In general, active inflammation from rheumatic diseases poses a stronger threat to the well-being of both mother and foetus than many immunosuppressant medications. Therefore, continued immunosuppression with the least risky medications will allow for the most optimal pregnancy outcomes.

FRI0179 Minimal to no transfer of certolizumab pegol into breast milk: results from cradle, a prospective, postmarketing, multicenter, pharmacokinetic study

Background Women with active chronic rheumatic inflammatory conditions (RA, PsA, AxSpA) often face uncertainty regarding the safety of the use of biologics during breastfeeding.1 Limited and non-validated data exist on the potential transfer of anti-TNFs into breast milk.2 CRADLE (NCT02154425) was the first sponsored study to evaluate certolizumab pegol (CZP) concentrations in breast milk, and to estimate the Average Daily Infant Dose (ADID) of maternal CZP. Objectives To determine the concentration of CZP in breast milk and calculate the ADID of maternal CZP. Methods CRADLE was a pharmacokinetic study of lactating mothers (≥6 weeks postpartum) receiving commercial CZP. Decision to treat with CZP and breastfeed was independent of study participation. At steady state (≥3 CZP doses), breast milk samples were collected on Days 0, 2, 4, 6, 8, 10, 12, 14 (±28) from each mother across 1 dosing period. CZP was detected using a highly sensitive, CZP-specific electrochemiluminescence immunoassay validated in milk (lower limit of quantification [LLOQ]=0.032 μg/mL; 10-fold lower than previous assays). CZP stability in milk was confirmed. Results 18 CZP-treated mothers were screened: 17 entered the sampling period; 16 on CZP 200 mg Q2W; 1 on CZP 400 mg Q4W (7 RA; 5 SpA; 5 CD; Table A). Samples from 4/17 mothers had no measurable CZP in breast milk; 13/17 had quantifiable levels for at least 1 time point (highest concentration: 0.076 μg/mL; Table B). Estimated ADID ranged 0–0.0104 mg/kg/day; median Relative Infant Dose (RID; calculated post hoc3): 0.15%. Infants of CZP-exposed mothers had a safety profile consisting of events occurring in unexposed infants of similar age. Conclusions CZP was below the lower limit of quantification in 56% of the milk samples. When detectable, CZP concentrations were less than 3x LLOQ (<1% of expected plasma concentration of a therapeutic dose4), indicating no to minimal transfer of CZP from plasma to breast milk. RID was below 0.5% of maternal dose; <10% is unlikely to be of clinical concern.3 CZP absorption via breast milk is unlikely, due to low bioavailability and its Fc-free molecular structure. These findings support continuation of CZP treatment during breastfeeding. References Götestam Skorpen C. Ann Rheum Dis 2016;75:795–810. Ben-Horin S. J Crohns Colitis 2011;5:555–8. Hale TW. Textbook of Human Lactation. Amarillo, TX: Hale Publishing, 2007. Lacroix BD. Gastroenterology 2010;138:S163–4. Acknowledgements This study was funded by UCB Pharma. We are indebted to the mothers and their infants for their altruistic participation. We thank the nurses, investigator teams and Nicole Hurst, PPD, and acknowledge Amanda Golembesky and Gerry Parker, UCB Pharma. Editorial services were provided by Costello Medical Consulting. Disclosure of Interest M. Clowse Grant/research support from: Pfizer, Janssen, Consultant for: UCB Pharma, F. Förger Grant/research support from: UCB Pharma, Speakers bureau: Mepha, Roche, UCB Pharma, C. Hwang Grant/research support from: AbbVie, UCB Pharma, Consultant for: Janssen, J. Thorp Grant/research support from: UCB Pharma, Consultant for: Genentech/Roche, UCB Pharma, R. Dolhain Grant/research support from: UCB Pharma, A. van Tubergen Grant/research support from: Pfizer, AbbVie, UCB Pharma, Janssen-Cilag, Celgene, Novartis, MSD, Consultant for: AbbVie, Novartis, Janssen-Cilag, Pfizer, Speakers bureau: MSD, Janssen-Cilag, Pfizer, L. Shaughnessy Employee of: UCB Pharma, J. Simpson Employee of: UCB Pharma, M. Teil Employee of: UCB Pharma, N. Toublanc Employee of: UCB Pharma, M. Wang Employee of: UCB Pharma, T. Hale Consultant for: UCB Pharma

THU0242 Pregnancy outcomes and disease activity in women with axial spondyloarthritis: a systematic literature review

Background Women with axial spondyloarthritis (axSpA) are often affected by the disease during their reproductive years,1 but reports on disease activity and pregnancy outcomes in these patients (pts) are sparse. In women with ankylosing spondylitis (AS), also currently termed as radiographic axSpA, a higher risk of disease activity flares and prevalence of adverse pregnancy outcomes have been reported vs healthy controls; however, in non-radiographic (nr)-axSpA pts, such data are virtually non-existent.2,3 Objectives To review the available evidence on the relationship between axSpA disease activity and pregnancy, including foetal outcomes. Methods A systematic literature review was conducted in October 2017 by searching EMBASE, MEDLINE®, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effects. Publications were systematically screened for English language articles on observational studies of axSpA pts reporting pregnancy outcomes or disease activity during pregnancy. Studies utilising agents contraindicated in pregnancy were excluded. Supplementary searches of selected, 2016–17 conference proceedings and bibliographies of relevant review articles were also conducted. Results 2216 publications were reviewed, with 20 publications on 15 unique studies meeting the inclusion criteria. When utilising the verified disease activity measurement instruments, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) or Ankylosing Spondylitis Disease Activity Score C-Reactive Protein (ASDAS-CRP), 5 studies (3 prospective, 2 retrospective) reported active disease (as described by individual studies; table 1) both during pregnancy and postpartum in most pts. Pregnancy outcomes in axSpA pts were compared with healthy controls in 6 studies (3 retrospective, 2 prospective, 1 case-control), the 3 largest of which (including 1 prospective) revealed higher risk or odds of preterm births in axSpA pts. Higher rates or risk of low birth weight/small-for-gestational-age neonates were shown in pts vs controls in 2/5 studies reporting such outcomes. Stillbirths, miscarriages or foetal loss/abortion were found to occur at similar rates in both populations. Conclusions Robust, prospective data on disease activity during pregnancies of women with axSpA are limited. Within the samples reported here, available data suggest that there may be a small increase in pre-term births; no signal for increased pregnancy loss was detected. Further research is needed to investigate relationships between maternal disease activity and pregnancy outcomes in axSpA.Abstract THU0242 – Table 1 Maternal disease activity and pregnancy outcomes in axSpA patients References [1] van den Brandt S. Arthritis Res Ther2017;19(1):64. [2] Jethwa H. Arthritis Rheumatol2016;68(suppl 10). [3] Jakobsson GL. Ann Rheum Dis2016;75(10):1838–42. Acknowledgements This study was funded by UCB Pharma. Editorial services were provided by Costello Medical. Disclosure of Interest A. Moltó Grant/research support from: MSD, AbbVie, Pfizer, UCB Pharma, Consultant for: MSD, AbbVie, Pfizer, UCB Pharma, L. Gensler Grant/research support from: UCB Pharma, M. Clowse Grant/research support from: AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, Consultant for: Pfizer, Janssen, UCB Pharma, H. Marzo-Ortega Grant/research support from: Janssen, Speakers bureau: Abbvie, Celgene, Janssen, MSD, Novartis, Pfizer, UCB Pharma, A. Artignan Employee of: Costello Medical, D. Goff-Leggett Employee of: Costello Medical, S. Leonard Employee of: Costello Medical, H. Resemann Employee of: Costello Medical, E. Thurtle Employee of: Costello Medical, N. de Peyrecave Employee of: UCB Pharma, C. Ecoffet Employee of: UCB Pharma, F. Förger Grant/research support from: UCB Pharma, Speakers bureau: Mepha, Roche, UCB Pharma

SAT0466 Pregnancy in women with psoriatic arthritis: pregnancy outcomes and changes in disease activity

Background Very little has been published about psoriatic arthritis (PsA) in pregnancy, and it remains unknown whether pregnancy outcomes are impacted by this disease or whether disease activity is changed by pregnancy or delivery. Objectives To discover the rate of pregnancy complications for women with psoriatic arthritis, and to determine whether psoriasis and the associated arthritis change during and following pregnancy. Methods A retrospective survey was completed by 40 women aged 20–50 years with psoriatic arthritis managed at a university center. Each survey collected information about infertility, pregnancy outcomes and complications, as well as patient-reported assessments of changes in both skin and joint disease activity at the onset of pregnancy, over the course of the pregnancy, and in the months following pregnancy. Simple statistics were used to compare outcomes before and after the diagnosis of PsA. Results The survey was completed by 40 women with PsA. The majority (93%) were white, non-Hispanic with a high level of education (40% completed college and another 30% either started or finished a graduate degree); 62.5% were married. The average age at the time of the study was 37.4 (SD 7.9) years and age at PsA diagnosis was 30.9 (8.4) years. Twenty-five women reported they had ever tried to become pregnant, and of those, 9 had been unable to become pregnant after 12 months of trying or had been diagnosed with infertility by a physician (36%). The reasons for infertility or inability to become pregnant included polycystic ovarian syndrome (44%), problem with ovulation (11%), problem with uterus (11%), elevated prolactin (11%), infection in pelvic area (11%), and/or cervical problems (30%). Infertility was unexplained in 33%. There were 70 pregnancies to 26 patients, with 37 pregnancies occurring after the diagnosis of PsA (see table). Pregnancy outcomes following PsA diagnosis were worse than those prior to PsA diagnosis, particularly the rate of pregnancy loss (32% compared to 12%; p=0.05) and preterm birth (48% compared to 21%; p=0.02). Only 24% of patients took psoriasis or arthritis medications during pregnancy. The most commonly used medications during pregnancy were TNF inhibitors (16%), corticosteroids (8%), and DMARDs (5%). The large majority of patients had minimal arthritis and psoriasis during pregnancy. Only 12% had moderate and 6% had severe arthritis. Similarly, only 10% had moderate and 7% had severe psoriasis. During and following pregnancy, about half of all patients reported no change in either joint or skin activity during and follow pregnancy, with fairly equal numbers reporting improved and worsened arthritis. On the other hand, 42% had improved psoriasis during pregnancy compared to 6% with worsened. There did not appear to be a significant postpartum flare. Conclusions Our analysis found that among women with PsA who have tried to become pregnant, 36% experienced infertility, primarily due to PCOS. Compared to pregnancies occurring before the diagnosis of PsA, pregnancies after PsA diagnosis had a lower frequency of live births and a higher frequency of preterm births. Overall, in this cohort of women with mostly mild disease during pregnancy, arthritis pain and psoriasis activity did not appear to substantially worsen during pregnancy. Acknowledgements This study was funded by Janssen. Disclosure of Interest None declared

FRI0157 Fertility in women with rheumatoid arthritis compared to healthy controls

Background Data suggest infertility is increased in women with rheumatoid arthritis (RA) compared to healthy women. Therefore, it is possible that diminished ovarian reserve and ovulatory dysfunction may be more common among women with RA. Objectives To compare differences in ovarian reserve and ovulatory frequency, as well as in self-reported infertility, between women with and without RA. Methods Women with RA aged 20–40 seen in a university clinic without a history of ovarian surgery or prior exposure to possible ovary-toxic medications were invited to participate in a cross-sectional survey. Healthy controls were women aged 20–40 without an autoimmune disease, matched for age and current use of hormonal contraceptives. Infertility was defined as a patient reporting physician-diagnosed infertility or being unable to get pregnant after 12 months of trying. Ovarian reserve was assessed by measuring anti-Müllerian hormone (AMH). In women who were not taking hormonal contraceptives, progesterone level was measured from a serum sample drawn between days 21 and 23 of the menstrual cycle. Anovulation was defined as a progesterone level <3 ng/mL. In descriptive comparisons, differences in proportions were determined by Fishers exact test, and ANOVA determined differences in means for continuous variables. Multivariate linear models estimated the effect of RA on AMH. In women with RA, the effect of RA medication use on AMH and anovulation was explored. Results There were 75 RA patients (83% Caucasian, 4% Hispanic, 77% with at least a college education) and 75 controls (64% Caucasian, 5% Hispanic, 88% with at least a college education). The majority of RA patients were married (60%), compared to 31% of controls. The mean age of both RA patients and controls was 32 years. Mean AMH in RA patients was 3.0 (SD: 2.6) compared to 3.9 (SD: 3.9) in controls (p-value: 0.1). In linear regression models adjusted for age, hormonal contraceptives and race (nonwhite vs. white), RA patients had a lower AMH than healthy controls (β: -1.05; 95% CI: -2.09, -0.005; p=0.05). There was no observed difference in the proportion of RA patients and controls with anovulation (19% in RA and 21% in controls). Infertility was reported by 12% of RA patients and 7% of controls (p=0.4). Among RA patients, 81% reported having ever used methotrexate (MTX). The mean AMH for MTX users was 2.8 (SD: 2.4) compared to 4.0 (SD: 3.1) in never users (p=0.1). In linear regression models adjusted for age, hormonal contraceptives and race, RA patients who had ever taken MTX had a lower AMH than those who had never taken MTX (β: -1.49; 95% CI: -2.83, -0.15; p=0.03). However, when the cumulative dose of MTX was analyzed, there was no effect of cumulative MTX and AMH. Ever use of prednisone or NSAIDs did not appear to affect AMH levels in RA patients. Methotrexate, prednisone, and NSAIDs use did not have an observed effect on anovulation. Conclusions In this cross-sectional study, women with RA appeared to have a lower AMH level than healthy controls, suggesting ovarian reserve may be lower in these patients. In RA patients, previous use of methotrexate was associated with lower AMH, although no dose response of cumulative methotrexate exposure was observed. We did not observe a difference in anovulation between RA patients and controls. This suggests women with RA may have reduced fertility for reasons other than anovulation. Acknowledgements This study was funded by Pfizer. Disclosure of Interest M. Clowse Grant/research support from: Pfizer, Janssen, Consultant for: UCB, G. McDaniel: None declared, A. Eudy: None declared

FRI0387 Association of Pre-Pregnancy Body Mass Index with Preterm Birth and Birthweight Percentiles in Systemic Lupus Erythematosus

Background Women with systemic lupus erythematosus (SLE) have an increased risk of delivering preterm and low birthweight infants. In the general population, maternal obesity is associated with an increased risk of preterm birth and lower risk for small for gestational age (SGA) infants. The effect of maternal obesity on birth outcomes among SLE patients is unknown. Objectives To estimate the association of pre-pregnancy body mass index (BMI) among women with SLE on preterm birth and birthweight for gestational age percentiles in live born infants. Methods We used data prospectively collected in the Hopkins Lupus Pregnancy Cohort from 1987-2011 (n=450 pregnancies). Our analysis sample was restricted to SLE patients with a maternal weight measurement within one year prior to pregnancy or during the first trimester (n=216). Outcomes of interest were preterm birth (<37 weeks gestation), infants born small for gestational age (SGA; birthweight <10th percentile for gestational age), and birthweight for gestational age percentiles. BMI was categorized as underweight or normal weight (<25 kg/m2), overweight (25-29.9 kg/m2) and obese (≥30 kg/m2). Data were analyzed by ANOVA and logistic regression models. Race and prednisone use ever during pregnancy were included as a covariates in all models. Results Of the 216 eligible pregnancies who had a pre-pregnancy weight available in the eligible time frame, patients were 59% white, 32% black, had a median age of 29.2 years, a median disease duration of 5.1 years and a median highest physician global assessment of disease activity (PGA) score during pregnancy of 1.0 (range: 0-2.5). There were 68 preterm births (32%), and the median birthweight percentile was 31.5 (19% SGA of 202 live births). The majority of women were underweight or normal weight (56%), 24% were overweight and 20% were obese. The frequency of preterm birth was 32% for underweight/normal weight women, 41% for overweight women and 18% for obese women. The exact odds ratio (OR) for preterm birth for overweight and obese women compared to underweight and normal weight women was 1.1 (95% CI: 0.6-2.2), adjusted for race and prednisone use. Adjustment for disease activity did not affect the results. The frequency of SGA was 23% for underweight/normal weight women, 11% for overweight women and 19% for obese women. The exact OR for SGA for overweight and obese women compared to underweight and normal weight women was 0.6 (95% CI: 0.3-1.4), adjusted for race and prednisone use during pregnancy. Adjustment for disease activity did not affect the results. The mean birthweight for gestational age percentile was lower for women classified as underweight/normal weight (31.0±23.6 vs. 44.4±27.0 in overweight and 37.6±29.9 in obese). Conclusions While pre-pregnancy BMI was not significantly associated with preterm birth or SGA, our results suggest that, although the precision of the estimate is limited due to the small sample, being overweight and obese may potentially be protective against SGA, which is similar to what is seen in the general population. Disclosure of Interest None declared