Pregnancy and the Autoimmune Patient.

PURPOSE OF REVIEW: This article will review the current understanding of the immunologic changes that occur during pregnancy. It will discuss the impact of pregnancy on the disease activity of autoimmune or inflammatory rheumatic diseases (AIRD). Lastly, it will highlight the most recent data on pre-conception and pregnancy management practices that can improve pregnancy outcomes in autoimmune patients. RECENT FINDINGS: Pregnancy is an immunologically complex and dynamic state that may affect the activity of AIRDs, with more patients having active disease during pregnancy than previously thought. Uncontrolled inflammatory diseases are associated with poor pregnancy outcomes such as preeclampsia, small for gestational age infants, and prematurity. Pre-conception counseling and early pregnancy planning discussions can help ensure optimal disease control and medication management prior to attempting conception. Adequate control of AIRDs on pregnancy-compatible medications during the pre-conception, pregnancy, and postpartum periods is required for optimal pregnancy outcomes.

Safety of biologic agents for the management of rheumatic diseases during pregnancy.

PURPOSE OF REVIEW: To discuss the current understanding regarding the use of biologic therapeutics in pregnancy. RECENT FINDINGS: Our understanding of the mechanisms underlying the potential fetal and infant exposure to biologics as well as a growing body of empirical evidence from real world use of biologics in pregnancy have demonstrated that biologics are generally compatible preconception and during pregnancy. Long-term effects of exposure to biologic agents in utero are not known, but will be uncovered in time. Biosimilars, which are becoming more popular, may not always share the same safety profiles as their originators. SUMMARY: Biologics have revolutionized the management of rheumatologic disease and ushered in a new era of clinical remission among patients. These agents, developed and introduced into clinical use at the beginning of the new millennium, are very potent, yet their efficacy in treating disease often in reproductive aged women, raises questions regarding their safety during pregnancy. These therapeutics can cause immunosuppression and can inhibit immunologic circuits that are not only involved in disease pathophysiology but hypothetically could impact the development of the fetal immune system. Reassuringly, biologics, typically antibodies or antibody-based proteins, are introduced to the fetus via the typical route of transplacental antibody transfer, and thus only begin to be transferred in appreciable amounts in the second trimester (after organogenesis). From theoretic and empirical standpoints, biologic use during pregnancy appears well tolerated for fetal development and to not substantially affect infant immune development.

Expert Perspective on a Clinical Challenge: Lupus and Pregnancy.

Systemic lupus erythematosus (SLE), a multiorgan systemic inflammatory disorder, predominantly affects women during their reproductive years. In this review, we summarize the state of knowledge about preconception planning and management of SLE during pregnancy. Achieving remission or low disease activity for several months on medications compatible with pregnancy prior to conception is essential to decreasing the risk of disease flare and improving pregnancy outcomes, including pre-eclampsia, preterm birth, and intrauterine growth restriction. With close management and well-controlled disease before and during pregnancy, <10% of patients flare. All patients with SLE should remain on hydroxychloroquine unless contraindicated. Expectant mothers with a history of antiphospholipid syndrome should be treated with anticoagulant therapy during pregnancy. Women with anti-Ro/SSA or anti-La/SSB antibodies require additional monitoring because their offspring are at increased risk for congenital heart block. Patients with SLE should be offered low-dose aspirin starting at the end of the first trimester to reduce the risk of pre-eclampsia. Flares of SLE during pregnancy require escalation of therapy. The immunosuppressives azathioprine, tacrolimus, and cyclosporine are compatible with pregnancy, and biologic agents can also be considered. Glucocorticoid use in pregnancy should be limited to the lowest effective dose. Mycophenolate mofetil/mycophenolic acid, methotrexate, leflunomide, and cyclophosphamide are known to be teratogenic and are contraindicated in pregnancy. Distinguishing a flare of lupus nephritis during pregnancy from pre-eclampsia can be particularly challenging. Overall, outcomes in pregnancy for women with lupus are improving, but gaps in knowledge about optimal management strategies persist.

Patients with autoimmune skin diseases are at increased risk of adverse pregnancy outcomes.

BACKGROUND: Increased rates of adverse pregnancy outcomes have been reported in association with rheumatologic diseases such as systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis. However, little is known about pregnancy outcomes in patients with autoimmune skin diseases. OBJECTIVE: This study aimed to determine the frequency of adverse pregnancy outcomes in patients with autoimmune skin diseases. We hypothesized that similar to rheumatic diseases, the rate of adverse pregnancy outcomes in patients with autoimmune skin diseases would be higher than the general population. STUDY DESIGN: This is a case control study using the TriNetX US Collaborative Network, which is a database of electronic medical records of >95 million patients seen at 57 healthcare organizations in the United States. All pregnant women between the ages of 15 and 44 years who were seen at a healthcare organization between January 1, 2016 and December 31, 2021 were included. Participants with autoimmune skin disease were matched to healthy controls and controls with systemic rheumatologic conditions (systemic lupus erythematosus or rheumatoid arthritis). For both the autoimmune skin disease and healthy control groups, those with systemic rheumatologic condition or hidradenitis suppurativa were excluded. The primary outcomes were adverse pregnancy outcomes defined as spontaneous abortion, gestational hypertension, preeclampsia or eclampsia, gestational diabetes mellitus, intrauterine growth restriction, preterm premature rupture of membranes, preterm birth, and stillbirth. Patients with autoimmune skin diseases and controls were 1:1 propensity score-matched by age, race, ethnicity, comorbidities, obesity, and substance use. For each outcome, odds ratio with a 95% confidence interval was calculated. RESULTS: A total of 2788 patients with autoimmune skin diseases were matched to 2788 healthy controls. Patients with autoimmune skin diseases were at a higher risk of spontaneous abortions than controls (odds ratio, 1.54; 95% confidence interval, 1.36-1.75; P<.001). Compared with patients with systemic lupus erythematosus, patients with autoimmune skin diseases were at lower risk of having infants with intrauterine growth restriction (odds ratio, 0.59; 95% confidence interval, 0.4-0.87; P=.01), preterm birth (odds ratio, 0.68; 95% confidence interval, 0.47-0.98; P=.04), and stillbirth (odds ratio, 0.50; 95% confidence interval, 0.25-0.97; P=.04). The differences in adverse pregnancy outcomes between patients with autoimmune skin diseases and those with rheumatoid arthritis were not statistically significant. CONCLUSION: Patients with autoimmune skin diseases are at a higher risk of spontaneous abortions than patients without autoimmune skin diseases. When analyzed by each autoimmune skin disease, patients with cutaneous lupus erythematosus or vitiligo remained at increased risk of spontaneous abortions compared with patients without autoimmune skin diseases. Patients with autoimmune skin diseases have similar risks of adverse pregnancy outcomes as patients with rheumatoid arthritis, but lower risks than patients with systemic lupus erythematosus.

The pathogenesis of obstetric APS: a 2023 update.

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the persistent presence of antibodies directed against phospholipids and phospholipid-binding proteins that are associated with thrombosis and pregnancy-related morbidity. The latter includes fetal deaths, premature birth and maternal complications. In the early 1990s, a distinct set of autoantibodies, termed collectively antiphospholipid antibodies (aPL), were identified as the causative agents of this disorder. Subsequently histological analyses of the placenta from APS pregnancies revealed various abnormalities, including inflammation at maternal-fetal interface and poor placentation manifested by reduced trophoblast invasion and limited uterine spiral artery remodeling. Further preclinical investigations identified the molecular targets of aPL and the downstream intracellular pathways of key placental cell types. While these discoveries suggest potential therapeutics for this disorder, definitive clinical trials have not been completed. This concise review focuses on the recent developments in the field of basic and translational research pursuing novel mechanisms underlying obstetric APS.

Vasculitis and Pregnancy: Disease State and Management.

Family planning in women with vasculitis requires an interdisciplinary approach. This article summarizes recommendations and guidance for each phase of family planning in persons with vasculitis including preconception counseling, birth control, pregnancy, and breastfeeding. Pregnancy complications are presented by category of vasculitis with accompanying diagnostic and therapeutic recommendations. Birth control and assisted reproductive technology options are reviewed with special considerations for women who are high risk or have a history of blood clots. This article can be used as a clinical reference for reproductive discussions in all patients with vasculitis.

Development of American College of Rheumatology Quality Measures for Systemic Lupus Erythematosus: A Modified Delphi Process With Rheumatology Informatics System for Effectiveness (RISE) Registry Data Review.

OBJECTIVE: We aimed to develop readily measurable digital quality measure statements for clinical care in systemic lupus erythematosus (SLE) using a multistep process guided by consensus methods. METHODS: Using a modified Delphi process, an American College of Rheumatology (ACR) workgroup of SLE experts reviewed all North American and European guidelines from 2000 to 2020 on treatment, monitoring, and phenotyping of patients with lupus. Workgroup members extracted quality constructs from guidelines, rated these by importance and feasibility, and generated evidence-based quality measure statements. The ACR Rheumatology Informatics System for Effectiveness (RISE) Registry was queried for measurement data availability. In 3 consecutive Delphi sessions, a multidisciplinary Delphi panel voted on the importance and feasibility of each statement. Proposed measures with consensus on feasibility and importance were ranked to identify the top 3 measures. RESULTS: Review of guidelines and distillation of 57 quality constructs resulted in 15 quality measure statements. Among these, 5 met high consensus for importance and feasibility, including 2 on treatment and 3 on laboratory monitoring measures. The 3 highest-ranked statements were recommended for further measure specification as SLE digital quality measures: 1) hydroxychloroquine use, 2) limiting glucocorticoid use >7.5 mg/day to <6 months, and 3) end-organ monitoring of kidney function and urine protein excretion at least every 6 months. CONCLUSION: The Delphi process selected 3 quality measures for SLE care on hydroxychloroquine, glucocorticoid reduction, and kidney monitoring. Next, measures will undergo specification and validity testing in RISE and US rheumatology practices as the foundation for national implementation and use in quality improvement programs.

Prevalence of Antiphospholipid Antibodies and Association With Incident Cardiovascular Events.

Importance: The prevalence of antiphospholipid antibodies (aPL) and their association with future atherosclerotic cardiovascular disease (ASCVD) risk has yet to be thoroughly investigated. Objective: To determine the association between measurements of aPL at a single time point and ASCVD risk in a diverse population. Design, Setting, and Participants: This cohort study measured 8 aPL (anticardiolipin [aCL] IgG/IgM/IgA, anti-beta-2 glycoprotein I [aß2GPI] IgG/IgM/IgA, and antiphosphatidylserine/prothrombin [aPS/PT] IgG/IgM) by solid-phase assays in plasma from participants of the Dallas Heart Study (DHS) phase 2, a multiethnic, population-based cohort study. Blood samples were collected between 2007 and 2009. The median follow-up was 8 years. Statistical analysis was performed from April 2022 to January 2023. Main Outcomes and Measures: Associations of aPL with future ASCVD events (defined as first nonfatal myocardial infarction, first nonfatal stroke, coronary revascularization, or death from cardiovascular cause) were assessed by Cox proportional hazards models, adjusting for known risk factors, medications, and multiple comparisons. Results: Among the 2427 participants (mean [SD] age, 50.6 [10.3] years; 1399 [57.6%] female; 1244 [51.3%] Black, 339 [14.0%] Hispanic, and 796 [32.8%] White), the prevalence of any positive aPL tested at a single time point was 14.5% (353 of 2427), with approximately one-third of those detected at a moderate or high titer; aCL IgM had the highest prevalence (156 individuals [6.4%]), followed by aPS/PT IgM (88 [3.4%]), aß2GPI IgM (63 [2.6%]), and aß2GPI IgA (62 [2.5%]). The IgA of aCL (adjusted hazard ratio [HR], 4.92; 95% CI, 1.52-15.98) and aß2GPI (HR, 2.91; 95% CI, 1.32-6.41) were independently associated with future ASCVD events. The risk further increased when applying a positivity threshold of at least 40 units (aCL IgA: HR, 9.01 [95% CI, 2.73-29.72]; aß2GPI IgA: HR, 4.09 [95% CI, 1.45-11.54]). Levels of aß2GPI IgA negatively correlated with cholesterol efflux capacity (r = -0.055; P = .009) and positively correlated with circulating oxidized LDL (r = 0.055; P = .007). aß2GPI IgA-positive plasma was associated with an activated endothelial cell phenotype as evidenced by increased surface expression of surface E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Conclusions and Relevance: In this population-based cohort study, aPL detectable by solid-phase assays were present in a substantial proportion of adults; positive aCL IgA and aß2GPI IgA at a single time point were independently associated with future ASCVD events. Longitudinal studies with serial aPL measurements are needed to further explore these findings.

Rheumatologic immune checkpoint inhibitor-related adverse events.

PURPOSE OF REVIEW: Immune check point inhibitors (ICIs) are a unique class of cancer treatments that harness the body's innate antitumor response. Although these medications have transformed oncology care, they also lead to generalized immune activation that can result in toxicities across a spectrum of organ systems called immune-related adverse events. This article reviews the most common rheumatologic immune-related adverse events and their management. RECENT FINDINGS: Inflammatory arthritis, polymyalgia rheumatic, sicca symptoms, systemic sclerosis, myositis, and vasculitis have all been reported as ICI adverse events. Treatment includes nonsteroidal anti-inflammatory drugs, glucocorticoids, traditional DMARDs, and biologics. SUMMARY: Rheumatologists have an important role in the management of patients with rheumatologic immune-related adverse events. Working with our oncology colleagues, we can help manage rheumatologic immune-related adverse events while optimally preserving ICI's antitumor effects.

Low Rates of Reproductive Counseling Documentation in Women With Interstitial Pneumonia With Autoimmune Features.

BACKGROUND/OBJECTIVE: Women with interstitial pneumonia with autoimmune features (IPAFs), a subset of interstitial lung disease (ILD), are at risk for pregnancy complications. Family planning discussions improve pregnancy outcomes in women with ILD. The objective of this study was to evaluate the documentation of reproductive counseling in IPAF female patients of childbearing age by pulmonary and rheumatology providers at an academic medical center. METHODS: We conducted a medical record review study of pulmonary and rheumatology encounters in reproductive-aged women with IPAF to evaluate documentation of family planning discussions and contraceptive use. We used nonparametric measures of association and logistic regression to evaluate the relationship between patient characteristics and the presence of reproductive counseling documentation by providers. RESULTS: Thirty-one women met IPAF classification and were ≤50 years at initial ILD clinic visit. Twenty-five (81%) of these women had risk factors for adverse pregnancy outcomes. Ten women (32%) had a record of reproductive counseling during any visit with their pulmonary provider. Of the 21 patients who also saw a rheumatology provider, 12 (57%) women had a record of reproductive counseling during any visit with their rheumatology provider. No baseline characteristics were associated with odds of reproductive counseling documentation. CONCLUSIONS: Neither pulmonary nor rheumatology providers consistently discussed family planning/contraceptive use with reproductive-aged women with IPAF. There was a trend for rheumatology providers to discuss reproductive issues with IPAF patients more frequently than pulmonary providers. Efforts should focus on educating providers about the need for reproductive counseling in women with IPAF of childbearing age.

Obstetric outcomes in women with rheumatic disease and COVID-19 in the context of vaccination status.

OBJECTIVE: To describe obstetric outcomes based on COVID-19 vaccination status, in women with rheumatic and musculoskeletal diseases (RMDs) who developed COVID-19 during pregnancy. METHODS: Data regarding pregnant women entered into the COVID-19 Global Rheumatology Alliance registry from 24 March 2020-25 February 2022 were analysed. Obstetric outcomes were stratified by number of COVID-19 vaccine doses received prior to COVID-19 infection in pregnancy. Descriptive differences between groups were tested using the chi-squared or Fisher's exact test. RESULTS: There were 73 pregnancies in 73 women with RMD and COVID-19. Overall, 24.7% (18) of pregnancies were ongoing, while of the 55 completed pregnancies, 90.9% (50) of pregnancies resulted in livebirths. At the time of COVID-19 diagnosis, 60.3% (n = 44) of women were unvaccinated, 4.1% (n = 3) had received one vaccine dose while 35.6% (n = 26) had two or more doses. Although 83.6% (n = 61) of women required no treatment for COVID-19, 20.5% (n = 15) required hospital admission. COVID-19 resulted in delivery in 6.8% (n = 3) of unvaccinated women and 3.8% (n = 1) of fully vaccinated women. There was a greater number of preterm births (PTB) in unvaccinated women compared with fully vaccinated 29.5% (n = 13) vs 18.2% (n = 2). CONCLUSIONS: In this descriptive study, unvaccinated pregnant women with RMD and COVID-19 had a greater number of PTB compared with those fully vaccinated against COVID-19. Additionally, the need for COVID-19 pharmacological treatment was uncommon in pregnant women with RMD regardless of vaccination status. These results support active promotion of COVID-19 vaccination in women with RMD who are pregnant or planning a pregnancy.

Implementing a Nurse-Driven Protocol for Pneumococcal Vaccination in an Academic Rheumatology Clinic.

OBJECTIVE: Rheumatology patients are at high risk for complications from pneumococcal infections. The goal of this study was to assess the feasibility of implementing a nurse-driven pneumococcal vaccination protocol based on the 2012 Advisory Committee on Immunization Practices (ACIP) guidelines within an academic rheumatology clinic. Our aims were to increase (1) pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23) monthly vaccination rates in immunosuppressed patients aged 19 to 64 years, and (2) the overall proportion of immunosuppressed patients aged 19 to 64 years who have received both PCV13 and PPSV23 vaccinations by ≥ 10% over a 2-year period. METHODS: We identified eligible adults in the electronic medical record using a search protocol based on preset medication group. We obtained baseline pneumococcal vaccination rates in 2019, calculating the proportion of patients who were unvaccinated, partially vaccinated (received either PCV13 or PPSV23), or fully vaccinated. We created a pneumococcal vaccination protocol based on 2012 ACIP guidelines and converted it into a standing medical order to be implemented by the nursing staff. Postintervention vaccination rates were calculated monthly and at the end of the study period. Multiple comparison testing was performed to assess for significant postintervention changes. RESULTS: The average rate of monthly vaccination with either PCV13 or PPSV23 increased from 4.3% in 2019 to 12.6% in 2021. The proportion of patients who were fully vaccinated increased from 14.6% in 2019 to 26.2% in 2021. Both changes were statistically significant. CONCLUSION: It is feasible to employ a nurse-driven protocol for improving pneumococcal vaccination rates in immunosuppressed patients, despite difficulties posed by coronavirus disease 2019 (COVID-19) pandemic disruptions.

Immunology of pregnancy and reproductive health in autoimmune rheumatic diseases. Update from the 11th International Conference on Reproduction, Pregnancy and Rheumatic Diseases.

Autoimmune rheumatic diseases (ARD) can affect women and men during fertile age, therefore reproductive health is a priority issue in rheumatology. Many topics need to be considered during preconception counselling: fertility, the impact of disease-related factors on pregnancy outcomes, the influence of pregnancy on disease activity, the compatibility of medications with pregnancy and breastfeeding. Risk stratification and individualized treatment approach elaborated by a multidisciplinary team minimize the risk of adverse pregnancy outcomes (APO). Research has been focused on identifying biomarkers that can be predictive of APO. Specifically, preeclampsia and hypertensive disorders of pregnancy tend to develop more frequently in women with ARD. Placental insufficiency can lead to intrauterine growth restriction and small-for-gestational age newborns. Such APO have been shown to be associated with maternal disease activity in different ARD. Therefore, a key message to be addressed to the woman wishing for a pregnancy and to her family is that treatment with compatible drugs is the best way to ensure maternal and fetal wellbeing. An increasing number of medications have entered the management of ARD, but data about their use in pregnancy and lactation are scarce. More information is needed for most biologic drugs and their biosimilars, and for the so-called small molecules, while there is sufficient evidence to recommend the use of TNF inhibitors if needed for keeping maternal disease under control. Other issues related to the reproductive journey have emerged as "unmet needs", such as sexual dysfunction, contraception, medically assisted reproduction techniques, long-term outcome of children, and they will be addressed in this review paper. Collaborative research has been instrumental to reach current knowledge and the future will bring novel insights thanks to pregnancy registries and prospective studies that have been established in several Countries and to their joint efforts in merging data.