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Abstract: Autoimmune rheumatic diseases (ARDs) often affect women during their reproductive years, and early studies of pregnancy in these patients reported high rates of adverse outcomes. Continuation or initiation of safe and effective medications in the preconception period is beneficial for maintaining or achieving disease quiescence throughout pregnancy thereby improving both maternal and pregnancy outcomes. The European Alliance of Associations for Rheumatology, the American College of Rheumatology, and the British Society for Rheumatology have published recommendations and guidelines regarding management of ARDs during pregnancy. The American College of Obstetricians and Gynecologists and the American Gastroenterological Association have also provided guidance statements with relevant recommendations. This review provides an overview of available recommendations for medication use in ARD pregnancy, with discussion of safety considerations for maternal and fetal well-being. Medications considered compatible with pregnancy include hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine, tacrolimus, and TNF inhibitors. Methotrexate, mycophenolate, leflunomide, and cyclophosphamide should be avoided before and during pregnancy. Other medications, most of them newer, are largely discouraged for use in pregnancy due to inadequate data or concerns for neonatal immunosuppression, including non-TNF biologics and small molecule therapies. Further investigation is needed regarding effects of non-TNF biologics, biosimilars, and small molecules in pregnancy. Important efforts for the future will include improved methodologies to gather critical safety data, with consideration of inclusion of pregnant women in clinical trials, a complex and controversial issue. Long-term information on outcomes in offspring of treated women is lacking for many of these medications., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by inflammation and immune-mediated injury to multiple organ systems, including the mucocutaneous, musculoskeletal, hematologic, and kidney systems. Approximately 3.4 million people worldwide have received a diagnosis of SLE., Observations: Approximately 90% of people with SLE are female. Although there are no uniformly accepted diagnostic criteria for SLE, the 2019 European Alliance of Associations for Rheumatology (formerly the European League Against Rheumatism)/American College of Rheumatology classification criteria developed for scientific study are an estimated 96.1% sensitive and 93.4% specific for SLE. These classification criteria include both clinical factors, such as fever, cytopenia, rash, arthritis, and proteinuria, which may be indicative of lupus nephritis; and immunologic measures, such as SLE-specific autoantibodies and low complement levels. Approximately 40% of people with SLE develop lupus nephritis, and an estimated 10% of people with lupus nephritis develop end-stage kidney disease after 10 years. The primary goal of treatment is to achieve disease remission or quiescence, defined by minimal symptoms, low levels of autoimmune inflammatory markers, and minimal systemic glucocorticoid requirement while the patient is treated with maintenance doses of immunomodulatory or immunosuppressive medications. Treatment goals include reducing disease exacerbations, hospitalizations, and organ damage due to the disease or treatment toxicity. Hydroxychloroquine is standard of care for SLE and has been associated with a significant reduction in mortality. Treatments in addition to hydroxychloroquine are individualized, with immunosuppressive agents, such as azathioprine, mycophenolate mofetil, and cyclophosphamide, typically used for treating moderate to severe disease. Three SLE medications were recently approved by the Food and Drug Administration: belimumab (for active SLE in 2011 and for lupus nephritis in 2020), voclosporin (for lupus nephritis), and anifrolumab (for active SLE)., Conclusions and Relevance: Systemic lupus erythematosus is associated with immune-mediated damage to multiple organs and increased mortality. Hydroxychloroquine is first-line therapy and reduces disease activity, morbidity, and mortality. When needed, additional immunosuppressive and biologic therapies include azathioprine, mycophenolate mofetil, cyclophosphamide, belimumab, voclosporin, and anifrolumab.

Objective: To evaluate and quantify the indicators of fetal and maternal morbidity in deliveries for patients with systemic lupus erythematosus (SLE) compared with deliveries in patients without SLE., Methods: We used retrospective data from the National Inpatient Sample (NIS) to identify all delivery related hospital admissions of patients with and without SLE from 2008 to 2017 using ICD-9/10 codes. Fetal morbidity indicators included pre-term delivery and intrauterine growth restriction (IUGR). 21 indicators of severe maternal morbidity were identified using standard Centers for Disease Control and Prevention (CDC) definitions. Descriptive statistics, including 95% confidence intervals, were calculated using sample weights from the NIS dataset., Results: Among the 40 million delivery-related admissions, 51 161 patients were reported to have SLE. Patients with SLE had a higher risk of fetal morbidity, including IUGR (8.0% vs 2.7%) and pre-term delivery (14.5% vs 7.3%), than patients without SLE. During delivery, mothers with SLE were nearly four times as likely to require a blood transfusion or develop a cerebrovascular disorder, and 15 times as likely to develop acute renal failure than those without SLE., Conclusion: Our study demonstrates that fetal morbidity and severe maternal morbidity occur at a higher rate in patients with SLE compared with those without. This quantitative work can help inform and counsel patients with SLE during pregnancy and planning., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Methods: We identified 20 adult patients with UCTD enrolled in the UCTD and Overlap Registry at our tertiary care level hospital. A licensed clinical social worker administered a 30-minute semistructured interview by telephone. The standardized questionnaire consisted of 14 open-ended questions on UCTD. A team of physicians, research coordinators, and a social worker used grounded theory to analyze the qualitative data and identify themes., Results: Among 14/20 study participants (100% female; mean age, 53.6 ± 13.2 years [range, 27-74 years]), all had at least an associate's/bachelor's degree; 9 (64%) were White. The mean disease duration was 14.5 ± 13.5 years (range, 0.5-44 years). Nine study participants (64%) were engaged in counseling or mindfulness training. Ten specific psychosocial themes and categories emerged, including the need for professional guidance and peer and family support to increase awareness, reduce isolation, and promote self-efficacy., Conclusions: Emerging themes from semistructured interviews of women with UCTD at a major academic center suggest the need for psychosocial interventions (e.g., patient support groups, educational materials, peer counselors) to help UCTD patients manage and cope with their illness. Future studies evaluating the psychosocial impact of UCTD diagnosis on diverse cohorts are needed., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Frailty is associated with mortality in systemic lupus erythematosus (SLE), but how best to measure frailty is unclear. We aimed to compare 2 frailty metrics, the self-reported Fatigue, Resistance, Ambulation, Illnesses, and Loss of weight (FRAIL) scale (FS) and the Fried phenotype (FP), in SLE to evaluate differences between frail and nonfrail women and whether frailty is associated with self-reported disability., Methods: Adult women aged < 70 years with validated SLE and mild/moderate disease enrolled in this cross-sectional study between August 2018 and October 2019. Correlation and agreement between the FS and the FP were determined. Differences in sociodemographic and disease characteristics, patient-reported outcome measures (PROMs), and biomarkers between frail and nonfrail participants were evaluated, as well as the association of frailty with Valued Life Activities disability., Results: Of 67 participants, 27% and 18% were frail according to the FS and the FP, respectively. Correlation ( r = 0.51; P < 0.0001) and agreement (κ = 0.46; P = 0.0004) between the FS and the FP were significant. Frail women had greater disease damage, high-sensitivity C-reactive protein, and interleukin 6, and worse PROMs according to both frailty definitions. Both frailty measures were associated with self-reported disability after adjustment for age, comorbidity, and disease activity and damage; this relationship was attenuated for the FP., Conclusion: Frailty prevalence was high in this cohort of women with SLE using both frailty definitions, suggesting that frailty may be accelerated in women with SLE, particularly when based exclusively on self-report. Frailty remained associated with self-reported disability in adjusted analyses. The FS may be an informative point-of-care tool to identify frail women with SLE., (© 2022 The Journal of Rheumatology.)

Purpose of Review: Use of exogenous estrogen carries significant risk for patients with prothrombotic disorders including those with antiphospholipid antibody (aPL) and antiphospholipid syndrome (APS). This review summarizes current knowledge of contraceptive and other hormone therapies for aPL-positive and APS women and highlights knowledge gaps to guide future research., Recent Findings: Studies support very low risk for most progestin-only contraceptives in patients with increased thrombotic risk, but suggest increased VTE risk with depot-medroxyprogesterone acetate. Highest efficacy contraceptives are intrauterine devices and subdermal implants, and these are recommended for women with aPL/APS. Progestin-only pills are effective and low risk. Perimenopausal symptoms may be treated with nonhormone therapies in aPL/APS patients: vasomotor symptoms can improve with nonhormonal medications and cognitive behavioral therapy, and genitourinary symptoms often improve with intravaginal estrogen that has limited systemic absorption.

Objective: To evaluate the longitudinal responsiveness (sensitivity to change) of the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Short Form (PROMIS10) in outpatients with systemic lupus erythematosus (SLE)., Methods: Outpatients with SLE who were receiving care at an academic medical center completed the PROMIS10 at 2 visits that were a minimum of 1 month apart. Responsiveness of the PROMIS10 global physical and mental health domains to Patient-Reported improvement or deterioration of health status was evaluated, as measured by standard validated instruments. Effect sizes of changes in PROMIS10 scores between visits were evaluated using Kruskal-Wallis testing., Results: A total of 223 SLE patients enrolled and completed baseline surveys, with 186 (83.4%) completing a second set of questionnaires. The PROMIS10 demonstrated mild-to-moderate responsiveness to Patient-Reported improvement (effect size 0.29) and worsening (effect sizes -0.27 and -0.54) of health status for both global physical health and global mental health. Changes in the PROMIS10 correlated poorly with changes in physician-reported measures of disease activity., Conclusion: The PROMIS10 showed responsiveness over time to Patient-Reported changes in SLE health status, but not physician-assessed changes. These data suggest that the PROMIS10 can be used to efficiently measure and monitor important aspects of the SLE patient experience that are not captured by standard physician-derived metrics. Further studies are needed to evaluate the role of the PROMIS10 in optimizing longitudinal disease management in SLE and to determine its responsiveness in other chronic health conditions., (© 2019, American College of Rheumatology.)

Objective: To develop an evidence-based guideline on contraception, assisted reproductive technologies (ART), fertility preservation with gonadotoxic therapy, use of menopausal hormone replacement therapy (HRT), pregnancy assessment and management, and medication use in patients with rheumatic and musculoskeletal disease (RMD)., Methods: We conducted a systematic review of evidence relating to contraception, ART, fertility preservation, HRT, pregnancy and lactation, and medication use in RMD populations, using Grading of Recommendations Assessment, Development and Evaluation methodology to rate the quality of evidence and a group consensus process to determine final recommendations and grade their strength (conditional or strong). Good practice statements were agreed upon when indirect evidence was sufficiently compelling that a formal vote was unnecessary., Results: This American College of Rheumatology guideline provides 12 ungraded good practice statements and 131 graded recommendations for reproductive health care in RMD patients. These recommendations are intended to guide care for all patients with RMD, except where indicated as being specific for patients with systemic lupus erythematosus, those positive for antiphospholipid antibody, and/or those positive for anti-Ro/SSA and/or anti-La/SSB antibodies. Recommendations and good practice statements support several guiding principles: use of safe and effective contraception to prevent unplanned pregnancy, pre-pregnancy counseling to encourage conception during periods of disease quiescence and while receiving pregnancy-compatible medications, and ongoing physician-patient discussion with obstetrics/gynecology collaboration for all reproductive health issues, given the overall low level of available evidence that relates specifically to RMD., Conclusion: This guideline provides evidence-based recommendations developed and reviewed by panels of experts and RMD patients. Many recommendations are conditional, reflecting a lack of data or low-level data. We intend that this guideline be used to inform a shared decision-making process between patients and their physicians on issues related to reproductive health that incorporates patients' values, preferences, and comorbidities., (© 2020, American College of Rheumatology.)

Appropriate contraception and preconception counseling are critical for women of reproductive age with systemic autoimmune diseases (AIDs) because clinical diagnosis, rheumatology medications, and disease activity may impact the safety or efficacy of certain contraceptives as well as the risk of adverse pregnancy outcomes. The presence of antiphospholipid (aPL) antibodies (anticardiolipin, anti-β2 glycoprotein I, and lupus anticoagulant) is the most important determinant of contraception choice, as women with these antibodies should not receive estrogen-containing contraceptives because of the increased risk of thrombosis. Prepregnancy counseling generally includes the assessment of preexisting disease-related organ damage, current disease activity, aPL antibodies, anti-Ro/SS-A and anti-La/SS-B antibodies, and medication safety in pregnancy. Quiescent AID for six months on pregnancy-compatible medications optimizes maternal and fetal/neonatal outcomes for most patients., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Lupus patients are at risk for pregnancy loss, and it has been generally accepted that women with SLE should have low disease activity prior to conception. However, there are conflicting results regarding the effect of pregnancy on SLE flares. This study aims to identify predictors of flares during and after pregnancy in SLE patients with inactive or stable disease activity during the first trimester and to characterize and estimate the frequency of post-partum flares in these patients., Methods: SLE patients in the multicenter, prospective PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study were evaluated for flares during and after pregnancy using the SELENA-SLEDAI Flare Index. Flares during pregnancy were assessed in all 384 patients and post-partum flares in 234 patients with study visits 2-6 months post-partum. Logistic regression models were fit to the data to identify independent risk factors for flare., Results: During pregnancy, 20.8% of patients had mild/moderate flares and 6.25% had severe. Post-partum, 27.7% of patients had mild/moderate flares and 1.7% had severe. The mild flares rarely required treatment. Younger age, low C4 and higher PGA at baseline were independently associated with higher risk of having at least one mild/moderate or severe flare during pregnancy. Older patients were at decreased risk of flare, as well as those with quiescent disease at baseline. No variables evaluated at baseline or the visit most proximal to delivery was significantly associated with risk of flare post-partum. Medications were not associated with flare during or after pregnancy., Conclusion: In patients with inactive or stable mild disease activity at the time of conception, lupus disease flares during and after pregnancy are typically mild and occur at similar rates. Flares during pregnancy are predicted by the patients' age and clinical and serological activity at baseline.

Antiphospholipid syndrome is an autoimmune systemic disorder characterized by arterial, venous, or small vessel thrombosis and/or recurrent early pregnancy loss, fetal loss, or pregnancy morbidity in the setting of documented persistent antiphospholipid antibodies that include the lupus anticoagulant, or moderate-high titer anticardiolipin, or anti-β2Glycoprotein I antibodies. Associated clinical manifestations include livedo reticularis, cutaneous ulcerations, thrombocytopenia, hemolytic anemia, valvular heart disease, and nephropathy. The degree of risk associated with antiphospholipid antibody depends on the characteristics of the antiphospholipid antibody profile and on the presence of additional thrombotic risk factors. Current standard treatment for unprovoked thrombosis is long-term warfarin or other vitamin K antagonist therapy. Treatment to prevent recurrent obstetric complications is low-dose aspirin and prophylactic heparin, usually low-molecular-weight heparin. Optimal treatment for standard therapy failures or for certain nonthrombotic manifestations is uncertain, although nonanticoagulation therapies that address multiple demonstrated mechanisms of disease are being explored., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019. Published by Elsevier Ltd.)

Systemic lupus erythematosus carries an increased risk of pregnancy complications, including preeclampsia and fetal adverse outcomes. To identify the underlying molecular mechanisms, we longitudinally profiled the blood transcriptome of 92 lupus patients and 43 healthy women during pregnancy and postpartum and performed multicolor flow cytometry in a subset of them. We also profiled 25 healthy women undergoing assisted reproductive technology to monitor transcriptional changes around embryo implantation. Sustained down-regulation of multiple immune signatures, including interferon and plasma cells, was observed during healthy pregnancy. These changes appeared early after embryo implantation and were mirrored in uncomplicated lupus pregnancies. Patients with preeclampsia displayed early up-regulation of neutrophil signatures that correlated with expansion of immature neutrophils. Lupus pregnancies with fetal complications carried the highest interferon and plasma cell signatures as well as activated CD4 + T cell counts. Thus, blood immunomonitoring reveals that both healthy and uncomplicated lupus pregnancies exhibit early and sustained transcriptional modulation of lupus-related signatures, and a lack thereof associates with adverse outcomes., (© 2019 Hong et al.)

Management of pregnancy in patients with rheumatic and musculoskeletal disorders is both challenging and rewarding. Most patients with rheumatic disease can have a successful pregnancy. Pregnancy outcome is improved when maternal autoimmune disease is stable or quiescent. Prepregnancy evaluation and counseling is important to identify risk factors for adverse maternal and pregnancy outcomes and to guide therapy and monitoring. Severe disease-related damage, disease activity, and the presence of antiphospholipid and anti-Ro/SS-A and La/SS-B antibodies may all impact prognosis. Knowledge of the safety of certain medications during pregnancy and lactation is still incomplete, but an increasing number of effective rheumatic disease medications can be used during these periods with low risk to maintain stable disease and to improve outcomes for mother and child., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose The purpose of this study was to evaluate the safety of antithrombotic treatments prescribed during pregnancy in patients with antiphospholipid syndrome (APS). Methods This international, multicenter study included two cohorts of patients: a retrospective French cohort and a prospective US cohort (PROMISSE study). Inclusion criteria were (1) APS (Sydney criteria), (2) live pregnancy at 12 weeks of gestation (WG) with (3) follow-up data until six weeks post-partum. According to APS standard of care, patients were treated with aspirin and/or low-molecular weight heparin (LMWH) at prophylactic (pure obstetric APS) or therapeutic doses (history of thrombosis). Major bleeding was defined as abnormal blood loss during the pregnancy and/or post-partum period requiring intervention for hemostasis or transfusion, or during the peripartum period greater than 500 mL and/or requiring surgery or transfusion. Other bleeding events were classified as minor. Results Two hundred and sixty-four pregnancies (87 prospectively collected) in 204 patients were included (46% with history of thrombosis, 23% with associated systemic lupus). During pregnancy, treatment included LMWH ( n = 253; 96%) or low-dose aspirin ( n = 223; 84%), and 215 (81%) patients received both therapies. The live birth rate was 89% and 82% in the retrospective and prospective cohorts, respectively. Adverse pregnancy outcomes occurred in 28% of the retrospective cohort and in 40% of the prospective cohort. No maternal death was observed in either cohort. A combined total of 45 hemorrhagic events (25%) occurred in the retrospective cohort, but major bleeding was reported in only six pregnancies (3%). Neither heparin nor aspirin alone nor combined therapy increased the risk of hemorrhage. We also did not observe an increased rate of bleeding in the case of a short interval between last LMWH (less than 24 hours) or aspirin (less than five days) doses and delivery. Only emergency Caesarean section was significantly associated with an increased risk of bleeding (odds ratio (OR) 5.03 (1.41-17.96); p=.016). In the prospective cohort, only one minor bleeding event was reported (vaginal bleeding). Conclusion Our findings support the safety of antithrombotic therapy with aspirin and/or LMWH during pregnancy in high-risk women with APS, and highlight the need for better treatments to improve pregnancy outcomes in APS. PROMISSE Study ClinicalTrials.gov identifier: NCT00198068.

Objective The aims of this study were to assess the feasibility of administering Patient-Reported Outcomes Measurement Information System (PROMIS®) computerized adaptive tests (CATs) to outpatients with systemic lupus erythematosus (SLE). Methods Adults with SLE were recruited during routine outpatient visits at an SLE Center of Excellence. Participants completed 14 PROMIS CATs and provided feedback on their experience. Differences in socio-demographic and clinical characteristics between participants and non-participants were evaluated. Results A total of 204 (86%) of 238 socioeconomically and racially diverse SLE patients completed PROMIS CATs. There were no significant differences between participants and non-participants. Time constraints were cited most frequently as reasons for non-participation. More than 75% of individuals submitted positive comments, including approval of the content and format of questions, and the survey's promotion of self-reflection. A minority of participants cited challenges, most often related to question phrasing (8%) and technical difficulties (6%). Conclusions The administration of PROMIS CATs was feasible and positively received in a diverse cohort of SLE outpatients. Neither socio-demographic nor disease characteristics were significant barriers to successful completion of PROMIS CATs. PROMIS CATs have great potential for efficiently measuring important patient-centered outcomes in routine clinical care of a wide range of SLE patients.

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.

Objective: Studies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies., Methods: The PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at <12 weeks gestation and evaluated them monthly. APOs were: fetal/neonatal death, preterm delivery <36 weeks because of placental insufficiency or preeclampsia and/or growth restriction <5th percentile. Complement activation products were measured on serial blood samples obtained at each monthly visit., Results: APO occurred in 20.5% of SLE and/or aPL pregnancies. As early as 12-15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with APOs and remained elevated through 31 weeks compared with those with normal outcomes. Moreover, Bb and sC5b-9 were significantly higher in patients with SLE and/or aPL without APOs compared with healthy controls. In logistic regression analyses, Bb and sC5b-9 at 12-15 weeks remained significantly associated with APO (OR adj =1.41 per SD increase; 95% CI 1.06 to 1.89; P=0.019 and OR adj =1.37 per SD increase; 95% CI 1.05 to 1.80; P=0.022, respectively) after controlling for demographic and clinical risk factors for APOs in PROMISSE. When analyses were restricted to patients with aPL (n=161), associations between Bb at 12-15 weeks and APOs became stronger (OR adj =2.01 per SD increase; 95% CI 1.16 to 3.49; P=0.013)., Conclusion: In pregnant patients with SLE and/or aPL, increased Bb and sC5b-9 detectable early in pregnancy are strongly predictive of APOs and support activation of complement, particularly the alternative pathway, as a contributor to APOs., Competing Interests: Competing interests: DWB reports serving on the UCB Pharmaceuticals Advisory Board; JES has received an investigator-initiated grant from UCB Pharmaceuticals and consulting fees from Alnylam and Alexion., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To assess the feasibility, validity, and reliability of the Patient Reported Outcomes Measurement Information System Global Health Short Form (PROMIS10) in outpatients with systemic lupus erythematosus (SLE)., Methods: SLE outpatients completed PROMIS10, Medical Outcomes Study Short Form-36 (SF-36), LupusQoL-US, and selected PROMIS computerized adaptive tests (CAT) at routine visits at an SLE Center of Excellence. Construct validity was evaluated by correlating PROMIS10 physical and mental health scores with PROMIS CAT, legacy instruments, and physician-derived measures of disease activity and damage. Test-retest reliability was determined among subjects reporting stable SLE activity at 2 assessments 1 week apart using intraclass correlation coefficients (ICC)., Results: A diverse cohort of 204 out of 238 patients with SLE (86%) completed survey instruments. PROMIS10 physical health scores strongly correlated with physical function, pain, and social health domains in PROMIS CAT, SF-36, and LupusQoL, while mental health scores strongly correlated with PROMIS depression CAT, SF-36, and LupusQoL mental health domains (Spearman correlations ≥ 0.70). Active arthritis, comorbid fibromyalgia (FM), and anxiety were associated with worse PROMIS10 scores, but sociodemographic factors and physician-assessed flare status were not. Test-retest reliability for PROMIS10 physical and mental health scores was high (ICC ≥ 0.85). PROMIS10 required < 2 minutes to complete., Conclusion: PROMIS10 is valid and reliable, and can efficiently screen for impaired physical function, pain, and emotional distress in outpatients with SLE. With strong correlations to LupusQoL and SF-36 but significantly reduced responder burden, PROMIS10 is a promising tool for measuring patient-reported outcomes in routine SLE clinical care and value-based healthcare initiatives.

Objective: We examined rates of adverse pregnancy outcomes (APO) by race/ethnicity among women with systemic lupus erythematosus (SLE), with and without antiphospholipid antibodies (aPL), and whether socioeconomic status (SES) accounted for differences., Methods: Data were from the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study, a multicenter study that enrolled 346 patients with SLE and 62 patients with SLE and aPL (50% white, 20% African American, 17% Hispanic, 12% Asian/Pacific Islander). Measures of SES were educational attainment, median community income, and community education. Logistic regression analyses were conducted to determine odds of APO for each racial/ethnic group, controlling first for age and clinical variables, and then for SES., Results: The frequency of APO in white women with SLE, with and without aPL, was 29% and 11%, respectively. For African American and Hispanic women it was approximately 2-fold greater. In African American women with SLE alone, adjustment for clinical variables attenuated the odds ratio (OR) from 2.7 (95% confidence interval [95% CI] 1.3-5.5) to 2.3 (95% CI 1.1-5.1), and after additional adjustment for SES, there were no longer significant differences in APO compared to whites. In contrast, in SLE patients with aPL, whites, African Americans, and Hispanics had markedly higher risks of APO compared to white SLE patients without aPL (OR 3.5 [95% CI 1.4-7.7], OR 12.4 [95% CI 1.9-79.8], and OR 10.4 [95% CI 2.5-42.4], respectively), which were not accounted for by clinical or SES covariates., Conclusion: This finding suggests that for African American women with SLE without aPL, SES factors are key contributors to disparities in APO, despite monthly care from experts, whereas other factors contribute to disparities in SLE with aPL., (© 2017, American College of Rheumatology.)

Objective: The aims of this study were to assess the construct validity and the test-retest reliability of Patient Reported Outcomes Measurement Information System (PROMIS) computerized adaptive tests (CAT) in patients with systemic lupus erythematosus (SLE)., Methods: Adults with SLE completed the Medical Outcomes Study Short Form-36, LupusQoL-US version ("legacy instruments"), and 14 selected PROMIS CAT. Using Spearman correlations, PROMIS CAT were compared with similar domains measured with legacy instruments. CAT were also correlated with the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) disease activity and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) scores. Test-retest reliability was evaluated using ICC., Results: There were 204 outpatients with SLE enrolled in the study and 162 completed a retest. PROMIS CAT showed good performance characteristics and moderate to strong correlations with similar domains in the 2 legacy instruments (r = -0.49 to 0.86, p < 0.001). However, correlations between PROMIS CAT and the SELENA-SLEDAI disease activity and SDI were generally weak and statistically insignificant. PROMIS CAT test-retest ICC were good to excellent, ranging from 0.72 to 0.88., Conclusion: To our knowledge, these data are the first to show that PROMIS CAT are valid and reliable for many SLE-relevant domains. Importantly, PROMIS scores did not correlate well with physician-derived measures. This disconnect between objective signs and symptoms and the subjective patient disease experience underscores the crucial need to integrate patient-reported outcomes into clinical care to ensure optimal disease management.

Background and Objectives: Kidney disease is a critical concern in counseling patients with lupus considering pregnancy. This study sought to assess the risk of renal flares during pregnancy in women with previous lupus nephritis in partial or complete remission, particularly in those with antidouble-stranded DNA antibodies and low complement levels, and the risk of new-onset nephritis in patients with stable/mildly active SLE., Design, Setting, Participants, & Measurements: We assessed active nephritis (renal flares and de novo kidney disease) and associated predictors during pregnancy in patients with lupus with urine protein ≤1000 mg and serum creatinine <1.2 mg/dl at baseline; 373 patients (52% ethnic/racial minorities) enrolled between 2003 and 2012 were prospectively followed in the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus Study. Active nephritis was defined by proteinuria increase of >500 mg and/or red blood cell casts., Results: Of 118 patients with previous kidney disease, 13 renal flares (11%) occurred (seven of 89 in complete remission and six of 29 in partial remission) compared with four with de novo kidney involvement (2%) in 255 patients without past kidney disease ( P <0.001). Active nephritis was not associated with ethnicity, race, age, creatinine, BP, or antihypertensive and other medications. In multivariable logistic regression analyses, patients with past kidney disease in complete or partial remission more often experienced active nephritis (adjusted odds ratio, 6.88; 95% confidence interval, 1.84 to 25.71; P =0.004 and adjusted odds ratio, 20.98; 95% confidence interval, 4.69 to 93.98; P <0.001, respectively) than those without past kidney disease. Low C4 was associated with renal flares/ de novo disease (adjusted odds ratio, 5.59; 95% confidence interval, 1.64 to 19.13; P <0.01) but not low C3 or positive anti-dsDNA alone., Conclusions: De novo kidney involvement in SLE, even in ethnic/racial minorities, is uncommon during pregnancy. Past kidney disease and low C4 at baseline independently associate with higher risk of developing active nephritis. Antibodies to dsDNA alone should not raise concern, even in patients with past kidney disease, if in remission., (Copyright © 2017 by the American Society of Nephrology.)

Contraception represents an important area of reproductive health for patients with rheumatic diseases given the potential pregnancy risks associated with active disease, teratogenic medications, and severe disease-related damage. A high proportion of patients with rheumatic disease do not use effective contraception. Long-acting contraceptives are most effective. Antiphospholipid-negative patients with stable systemic lupus erythematosus may use oral combined contraceptives. Antiphospholipid-positive patients, or patients with rheumatic disease with other risk factors for thrombosis, should avoid estrogen-containing contraceptives. Contraceptive methods should be addressed by both the rheumatologist and gynecologist to determine the safest, most effective, and most convenient form for each patient., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Reproductive issues including contraception, fertility, and pregnancy are important components of the comprehensive care of women with systemic lupus erythematosus (SLE). SLE pregnancies are complicated due to risk for maternal disease exacerbation and potential for fetal and neonatal complications. Pre-pregnancy assessment is important to identify patients with severe disease-related damage who should avoid pregnancy, counsel patients to conceive when disease has been stable and inactive on appropriate medications, and assess relevant risk factors including renal disease, antiphospholipid antibody, and anti-Ro/SS-A and anti-La/SS-B antibodies. With careful planning, monitoring, and care, most women with SLE can anticipate a successful pregnancy.

Objective: To measure variance in antiphospholipid antibody (aPL) levels during pregnancy and to determine if variation affects pregnancy outcomes., Methods: We used data from the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study, a multicenter prospective study of pregnant women with aPL and/or systemic lupus erythematosus (SLE). Antiphospholipid antibodies were considered present if any of the following were positive: anticardiolipin (aCL), anti-β2 -glycoprotein I (anti-β2 GPI) titers ≥40 IgG phospholipid (GPL) or IgM phospholipid (MPL) units, and/or lupus anticoagulant (LAC). Antiphospholipid antibodies were measured every trimester and postpartum. Adverse pregnancy outcomes were defined as fetal/neonatal death, preterm delivery (<36 weeks) due to preeclampsia or placental insufficiency, or growth restriction., Results: One hundred fifty-two aPL-positive patients were studied. Fifty-seven percent had clinical antiphospholipid syndrome (APS) and 36% had SLE. IgG aPL levels were significantly lower during the second and third trimesters compared to initial screening, but IgG aCL and anti-β2 GPI remained high-positive through pregnancy in 93% of patients during the second trimester, and in 85% of patients during the third trimester. IgM aPL titers were negative in the majority of patients and decreased modestly during pregnancy among patients who were positive. LAC frequency also decreased, but 75% of patients remained positive through the second trimester. Only 4% of patients with aPL at baseline did not have aPL in either the second or third trimesters. Changes in aPL levels or aPL status were not associated with adverse pregnancy outcomes. LAC was the only aPL associated with adverse pregnancy outcomes., Conclusion: The aPL in the cohort decreased marginally during pregnancy, and changes were not associated with pregnancy outcomes. Our results suggest that, among women with aPL and/or SLE, measuring aPL early in pregnancy is sufficient to assess risk. Repeat aPL testing through pregnancy is unnecessary., (© 2016, American College of Rheumatology.)

Corticosteroids are the mainstay of treatment of systemic lupus erythematosus, with most patients receiving them at some point in the course of their disease. Corticosteroid use is associated with significant side effects, including infections, hypertension, hyperglycemia, osteoporosis, avascular necrosis, myopathy, cataracts, and glaucoma. Dosing regimens are based on limited data, with the goal of adequately controlling inflammatory symptoms while minimizing steroid exposure in order to reduce adverse effects., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: We previously reported that lupus anticoagulant (LAC) is the main predictor of poor pregnancy outcome in antiphospholipid antibody (aPL)-positive patients. We sought to confirm this finding in an independent group of patients who were subsequently recruited into the PROMISSE study., Methods: The PROMISSE study is a multicentre, prospective, observational study of pregnancy outcomes in women with aPL and/or systemic lupus erythematosus (SLE) that enrolled patients from 2003 to 2015. All consecutive, aPL-positive patients from the PROMISSE study who completed their pregnancy between April 2011 and January 2015 (after the previous PROMISSE report) are included in the current report. Patients were followed monthly until delivery, and aPL was tested at first, second and third trimesters of pregnancy and at 12 weeks post partum. Adverse pregnancy outcomes (APOs) were defined as fetal death after 12 weeks of gestation, neonatal death, delivery prior to 36 weeks of gestation due to pre-eclampsia or placental insufficiency or small-for-gestational age (birth weight <5th percentile)., Results: Forty-four aPL-positive patients are included in this paper. Thirteen patients had APOs, which occurred in 80% of cases during the second trimester of pregnancy. LAC was present in 69% of patients with APOs compared with 27% of patients without APOs (p=0.01). No association was found between anticardiolipin antibodies (aCL) or anti-β2 glycoprotein I antibodies (aβ2GPI) IgG or IgM positivity and APOs. Definite antiphospholipid syndrome (history of thrombosis and/or pregnancy morbidity and aPL) was found in 92% of patients with any APOs compared with 45% of patients without APOs (p=0.004). Conversely, the frequency of SLE was not statistically different between those with and without APOs (30% vs 39%)., Conclusions: Our findings, in an independent group of aPL-positive patients from the PROMISSE study, confirm that LAC, but not aCL and aβ2GPI, is predictive of poor pregnancy outcomes after 12 weeks of pregnancy., Trial Registration Number: NCT00198068.

Background: Over 20% of pregnancies in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL) result in an adverse pregnancy outcome (APO) related to abnormal placentation. The ability to identify, early in pregnancy, patients who are destined for poor outcomes would significantly impact care of this high-risk population. In nonautoimmune patients, circulating angiogenic factors are dysregulated in disorders of placentation, such as preeclampsia (PE) and fetal growth restriction., Objective: We sought to determine whether early dysregulation of circulating angiogenic factors can predict APO in high-risk SLE and/or APL pregnancies., Study Design: We used data and samples from the Predictors of Pregnancy Outcome: Biomarkers in APL Syndrome and SLE (PROMISSE), a multicenter prospective study that enrolled 492 pregnant women with SLE and/or APL from September 2003 through August 2013. Patients were followed through pregnancy from <12 weeks gestation. Circulating levels of soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin were measured monthly and subjects followed up for APO, classified as severe (PE <34 weeks, fetal/neonatal death, indicated preterm delivery <30 weeks) or moderate (PE ≥34 weeks, indicated preterm delivery 30-36 weeks, growth restriction without PE)., Results: Severe APOs occurred in 12% and moderate APOs in 10% of patients. By 12-15 weeks, sFlt1, PlGF, and soluble endoglin levels were markedly altered in women who developed severe APO. After adjusting for clinical risk factors, sFlt1 was the strongest predictor of severe APO among 12-15 week measures (odds ratio, 17.3 comparing highest and lowest quartiles; 95% confidence interval [CI], 3.5-84.8; positive predictive value [PPV], 61%; negative predictive value [NPV], 93%). At 16-19 weeks, the combination of sFlt1 and PlGF was most predictive of severe APO, with risk greatest for subjects with both PlGF in lowest quartile (<70.3 pg/mL) and sFlt1 in highest quartile (>1872 pg/mL; odds ratio, 31.1; 95% CI, 8.0-121.9; PPV, 58%; NPV, 95%). Severe APO rate in this high-risk subgroup was 94% (95% CI, 70-99.8%), if lupus anticoagulant or history of high blood pressure was additionally present. In contrast, among patients with both sFlt1 <1872 pg/mL and PlGF >70.3 pg/mL, rate of severe APO was only 4.6% (95% CI, 2.1-8.6%)., Conclusion: Circulating angiogenic factors measured during early gestation have a high NPV in ruling out the development of severe adverse outcomes among patients with SLE and/or APL syndrome. Timely risk stratification of patients is important for effective clinical care and optimal allocation of health care resources., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are disorders that commonly impact reproductive aged women., Findings: Both women with RA and SLE have smaller sized families than do controls. In the case of RA factors other than fertility contribute, while in women with SLE there may be diminished ovarian reserve due to cyclophosphamide therapy and advanced maternal age. RA pregnancies can be complicated by preterm birth and small-for-gestational aged infants. SLE pregnancies have higher rates of fetal loss, in particular in those patients with co-existing antiphospholipid syndrome. SLE pregnancies are also more likely to be complicated by pre-eclampsia and hypertension and to result in preterm birth and small-for-gestational aged infants., Conclusion: Appropriate fertility evaluation and careful pregnancy planning with coordinated obstetrical care help ensure better outcomes in these patient populations.

The major manifestations of antiphospholipid syndrome (APS) are caused by thrombosis within the venous or arterial vasculature, whereas the vascular lesions in systemic vasculitis result from an inflammatory infiltrate in the vessel wall. There is an association between vascular thrombosis and inflammation, however, as vasculitis can occur in APS and thromboembolic complications are seen in systemic vasculitis. Although differentiating between vasculitis and antiphospholipid-associated thrombosis can be difficult, it may be crucial to do so given the different therapeutic implications for immunosuppression or anticoagulation. This article explores the relationship between thrombosis and inflammation as it relates to APS and systemic vasculitis.

Purpose of Review: In contrast to the disease remission enjoyed by a majority of rheumatoid arthritis (RA) patients during pregnancy, the immediate postpartum period is generally characterized by flare. Managing symptoms during this time is challenging because the potential transfer of medication into the breast milk of nursing mothers may limit which antirheumatic drugs can be safely used. The benefits of breastfeeding are significant, however, so an understanding of how to adjust medications to permit lactation and nursing is important for rheumatologists., Recent Findings: Although nonsteroidal antiinflammatory drugs (NSAIDs) in general are passed into milk in low doses, shorter acting NSAIDs are preferred, with caution for premature infants. Prednisone can be taken by nursing mothers, although when used at doses higher than 20 mg/day an interval of 4 h after dosing and prior to breastfeeding is recommended. Hydroxychloroquine and sulfasalazine are compatible with nursing. Cyclosporine is generally allowed in lactating women, although a single infant was reported to develop therapeutic drug levels. Azathioprine (AZA) and tissue necrosis factor-α-inhibitors have little to no transfer into breast milk, with negligible levels measured in infant sera, and thus may be considered for use in lactating mothers. Methotrexate and leflunomide should not be used. Other biological RA medications have not been evaluated, and are, therefore, best avoided by breastfeeding patients., Summary: Many but not all RA medications may be used during lactation with low risk to the nursing infant; this review summarizes the available data for commonly used medications in order to help guide therapy during the postpartum period.

Menopause represents a time of significant clinical and hormonal change. Given the incompletely understood interrelationship between gonadal hormones and the immune system, it is possible that menopause may affect, or be affected by, the presence of autoimmune disease. Menopause has significant effects on a number of organ systems including the cardiovascular, skeletal, central nervous and genitourinary systems. Premature ovarian failure is related to autoimmune factors in a proportion of cases, but is not generally associated with systemic autoimmune disorders unless secondary to treatment with alkylating agents such as cyclophosphamide. Gonadal hormones have been suggested to relate to both onset and activity in certain autoimmune diseases. For patients with systemic lupus erythematosus, disease activity is lower, and damage accrual higher, in the postmenopausal years, but the mechanisms responsible may relate to age, duration of disease, menopause changes, long-term effects of therapy, or some combination of these factors. Early menopause is a risk factor for rheumatoid arthritis, and post-menopausal status in RA is associated with greater damage and disability. Systemic sclerosis and giant cell arteritis may also be adversely affected by onset of menopause. Importantly, autoimmune disease and menopause may have an additive effect on risk for common comorbidities such as cardiovascular disease and osteoporosis., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Pregnancy, whether normal or complicated, induces change in nearly every system of the body. Because most rheumatologic disorders are multisystemic and often affect young women, it may be difficult to differentiate pregnancy-related change from new onset or exacerbation of rheumatic disease. Familiarity with common manifestations of pregnancy is important in evaluating young women of childbearing age,whether or not they have known rheumatologic disease. Presentation of new connective tissue disease during pregnancy is often associated with poorer prognosis, so it is especially important to distinguish between pregnancy-induced change and true autoimmune inflammation requiring prompt and aggressive therapy., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Use of contraceptives by women with rheumatic diseases, especially those with systemic lupus erythematosus, has long been thought to carry risks, such as disease exacerbation, thrombosis and other adverse effects. The use of effective contraception has, therefore, been avoided, despite many affected women being of reproductive age. Knowledge of risks and benefits of contraceptive methods in the general population has improved, as have the safety and effectiveness of hormonal contraceptives. Methods of administration have evolved and now include transdermal and intravaginal routes, a progesterone-releasing intrauterine device, and an extended-cycle oral contraceptive. Birth control pills are not all alike; the risk of adverse effects varies depending on the amount of estrogen and type of progestin used. Data show that patients with stable systemic lupus erythematosus are not at increased risk of disease flare while taking standard oral contraceptives. Despite a lack of randomized studies, evidence strongly suggests that the elevated risk of thrombosis makes estrogen-containing contraceptives unsuitable for patients with antiphospholipid antibody. Other important issues include potential interactions between hormonal contraceptives and other medications and possible risk of infection if an intrauterine device is used. Rheumatologists are increasingly working with gynecologists and patients to make choices about which contraceptive methods to use. Decisions should be individualized according to the patient's medical status, personal preference, and stage of reproductive life.

Antiphospholipid syndrome spans many medical disciplines. Classic criteria include the presence of anticardiolipin antibody or lupus anticoagulant with typical complications of thrombosis or pregnancy loss. Other common associated manifestations include livedo reticularis, thrombocytopenia, valvular heart disease, and nephropathy with renal insufficiency, hypertension, and proteinuria. Treatment of serious complications with anticoagulation is standard; generally warfarin for thrombosis and aspirin/heparin for pregnancy prophylaxis. Detailed recommendations regarding precise intensity and duration of anticoagulation are still a subject of debate.

Pregnancy markedly alters a normal woman's physiology and immune response mechanisms. The effect of pregnancy changes on the course of systemic lupus erythematosus (SLE) remains, however, speculative. Pregnant lupus patients are susceptible to pre-eclampsia, especially if they suffer lupus nephritis, and to steroid-induced hypertension and hyperglycemia. Fetuses are susceptible to placental insufficiency if antiphospholipid antibody or other procoagulant states are present, and to neonatal lupus if anti-Ro/La antibodies are present. Artificial reproductive technologies ("in vitro fertilization") can be safely used in SLE patients. Study of the physiology of pregnancy, for instance complement kinetics, may inform our understanding of SLE, and vice versa.