Hydroxychloroquine and Preeclampsia in a Diverse Cohort of Women with SLE.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) are at risk for pregnancy complications such as preeclampsia and eclampsia. These clinically important complications are associated with maternal morbidity, mortality and postpartum cardiovascular disease. Some studies suggest that hydroxychloroquine (HCQ) may reduce preeclampsia risk in lupus pregnancy. Using a cohort of pregnancies in prevalent SLE patients at Kaiser Permanente Northern California (KPNC), we investigated whether HCQ use in early pregnancy reduced the risk of preeclampsia/eclampsia. METHODS: Among SLE pregnancies from 2011-2020, we assessed HCQ use from three months before pregnancy through the first trimester. HCQ exposure was defined multiple ways to account for adherence and duration of use. Propensity scores accounted for multiple confounders and modified Poisson models estimated risk ratios (RR) and 95% confidence intervals of the association between HCQ and preeclampsia/eclampsia. Effect modification by pregestational hypertension, history of nephritis, and antiphospholipid antibody status was investigated through stratified analysis. RESULTS: There were 399 pregnancies among 324 patients with SLE at KPNC between 2011 and 2020. Considering multiple exposure definitions, we consistently found a null association between HCQ and preeclampsia/eclampsia. The RRs were consistently lower among the nullipara pregnancies, and RRs were consistently protective but not statistically significant among the high-risk subgroup of those with history of nephritis, aPL positivity, or pregestational hypertension (both nullipara and multipara). DISCUSSION: Although this study found no reduced risk of HCQ on preeclampsia/eclampsia, residual confounding may be attenuating the effect despite an integrated health care delivery system setting with detailed clinical data.

Neutrophils isolated from systemic lupus erythematosus patients exhibit a distinct functional phenotype.

Neutrophil dysregulation, particularly of a low-density subset, is associated with systemic lupus erythematosus (SLE); however, the exact role of normal-density neutrophils in SLE remains unknown. This study compares activation and functional phenotypes of neutrophils from SLE patients and healthy controls to determine potential contributions to SLE pathogenesis. Surface activation markers and release of neutrophil extracellular traps (NETs), granule proteins, and cytokines/chemokines were measured in resting and stimulated neutrophils from SLE patients (n=19) and healthy controls (n=10). Select miRNA and mRNA involved in neutrophil development and function were also measured. Resting SLE neutrophils exhibited fewer activation markers compared to control neutrophils, and activation markers were associated with different plasma cytokines/chemokines in SLE patients compared to healthy controls. However, activation markers increased similarly in SLE and control neutrophils following stimulation with a TLR7/8 agonist, neutrophil growth factors, and bacterial mimic. At the resting state, SLE neutrophils produced significantly more CXCL10 (IP-10), with trends toward other increased cytokines/chemokines. Following stimulation, SLE neutrophils produced fewer NETs and proinflammatory cytokines compared to control neutrophils but more MMP-8. In addition, SLE neutrophils expressed less miR130a, miR132, miR27a, and miR223. In conclusion, SLE neutrophils exhibit distinct functional responses compared to control neutrophils. These functional differences may result from differential gene expression via miRNAs. Furthermore, the differences in functional phenotype of SLE neutrophils suggest that they may contribute to SLE differently dependent on the inflammatory milieu.

Mycophenolate mofetil withdrawal in patients with systemic lupus erythematosus: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Mycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy. METHODS: This multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed. FINDINGS: Between Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%]). INTERPRETATIONS: Mycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE. FUNDING: The National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Hydroxychloroquine in Lupus Pregnancy and Risk of Preeclampsia.

OBJECTIVE: Systemic lupus erythematosus (SLE) disproportionately affects women during childbearing years, and hydroxychloroquine (HCQ) is the standard first-line treatment. Preeclampsia complicates up to one-third of pregnancies in lupus patients, although reports vary by parity and multifetal gestation. We investigated whether taking HCQ early in pregnancy may reduce the risk of preeclampsia. METHODS: We studied 1,068 live birth singleton pregnancies among 1,020 privately insured patients with SLE (2007-2016). HCQ treatment was defined as three months preconception through the first trimester, and prescription fills were a proxy for taking HCQ. Modified Poisson regression estimated risk ratios (RRs) and 95% confidence intervals (CIs), stratified by parity. Propensity scores accounted for confounders, and stratified analyses examined effect modification. RESULTS: Approximately 15% of pregnant patients were diagnosed with preeclampsia. In 52% of pregnancies, patients had one or more HCQ fills. Pregnant patients exposed to HCQ had more comorbidities, SLE activity, and azathioprine treatment. We found no evidence of a statistical association between HCQ and preeclampsia among nulliparous (RR 1.26 [95% CI 0.82-1.93]) and multiparous pregnancies (RR 1.20 [95% CI 0.80-1.70]). Additional controls for confounding decreased the RRs toward the null (nulliparous pregnancy, propensity score-adjusted [PS-adj] RR 1.09 [95% CI 0.68-1.76]; multiparous pregnancy, PS-adj RR 1.01 [95% CI 0.66-1.53]). CONCLUSION: Using a large insurance-based database, we did not observe a decreased risk of preeclampsia associated with HCQ treatment in pregnancy, although we cannot rule out residual and unmeasured confounding and misclassification. Further studies leveraging large population-based data and prospective collection could characterize how HCQ influences preeclampsia risk in pregnant patients with SLE and among persons at greater risk of hypertensive disorders of pregnancy.

Pregnancy Outcomes in a Diverse US Lupus Cohort.

OBJECTIVE: Although the population of patients with systemic lupus erythematosus (SLE) is racially and ethnically diverse, many study populations are homogeneous. Further, data are often lacking on critical factors, such as antiphospholipid antibodies (aPLs). We investigated live birth rates in patients with SLE at Kaiser Permanente Northern California, including race and ethnicity and aPL data. METHODS: Electronic health records of pregnancies with outcomes observed from 2011 to 2020 were identified among patients with SLE. Prevalent SLE was defined as two or more International Classification of Diseases-coded visits seven or more days apart before the last menstrual period. We summarized patient characteristics, medication orders, health care use, and medication use. Pregnancy outcomes (live birth, stillbirth, spontaneous abortion, ectopic pregnancy, and molar pregnancy) were presented overall and stratified by race and ethnicity, aPL status, and nephritis history. RESULTS: We identified 657 pregnancies among 453 patients with SLE. The cohort was diverse, reflecting the Northern California population (27% Asian, 26% Hispanic, 26% Non-Hispanic White, 13% Non-Hispanic Black, 5% multiracial, and approximately 2% Pacific Islander and Native American). Approximately 74% of observed pregnancies ended in live birth, 23% resulted in spontaneous abortion, 2% were ectopic or molar pregnancies, and <1% were stillbirths. There was limited variability in live births by race and ethnic group (72%-79%), aPL status (69.5%-77%), and nephritis history (71%-75%). CONCLUSION: Our findings are consistent with previous studies; however, some methodologic differences may yield a range of live birth rates. We found that approximately 74% of pregnancies in patients with SLE ended in live birth, with modest variability in spontaneous abortion by race and ethnicity, nephritis history, and aPL status.

Ancestry-based differences in the immune phenotype are associated with lupus activity.

Systemic lupus erythematosus (SLE) affects 1 in 537 Black women, which is >2-fold more than White women. Black patients develop the disease at a younger age, have more severe symptoms, and have a greater chance of early mortality. We used a multiomics approach to uncover ancestry-associated immune alterations in patients with SLE and healthy controls that may contribute biologically to disease disparities. Cell composition, signaling, epigenetics, and proteomics were evaluated by mass cytometry; droplet-based single-cell transcriptomics and proteomics; and bead-based multiplex soluble mediator levels in plasma. We observed altered whole blood frequencies and enhanced activity in CD8+ T cells, B cells, monocytes, and DCs in Black patients with more active disease. Epigenetic modifications in CD8+ T cells (H3K27ac) could distinguish disease activity level in Black patients and differentiate Black from White patient samples. TLR3/4/7/8/9-related gene expression was elevated in immune cells from Black patients with SLE, and TLR7/8/9 and IFN-α phospho-signaling and cytokine responses were heightened even in immune cells from healthy Black control patients compared with White individuals. TLR stimulation of healthy immune cells recapitulated the ancestry-associated SLE immunophenotypes. This multiomic resource defines ancestry-associated immune phenotypes that differ between Black and White patients with SLE, which may influence the course and severity of SLE and other diseases.

2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases.

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. RESULTS: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. CONCLUSION: Application of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases.

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. RESULTS: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. CONCLUSION: Application of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

A Flare Risk Index Informed by Select Immune Mediators in Systemic Lupus Erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is marked by immune dysregulation linked to varied clinical disease activity. Using a unique longitudinal cohort of SLE patients, this study sought to identify optimal immune mediators informing an empirically refined flare risk index (FRI) reflecting altered immunity prior to clinical disease flare. METHODS: Thirty-seven SLE-associated plasma mediators were evaluated by microfluidic immunoassay in 46 samples obtained in SLE patients with an imminent clinical disease flare (preflare) and 53 samples obtained in SLE patients without a flare over a corresponding period (pre-nonflare). SLE patients were selected from a unique longitudinal cohort of 106 patients with classified SLE (meeting the American College of Rheumatology 1997 revised criteria for SLE or the Systemic Lupus International Collaborating Clinics 2012 revised criteria for SLE). Autoantibody specificities, hybrid SLE Disease Activity Index (hSLEDAI) scores, clinical features, and medication usage were also compared at preflare (mean ± SD 111 ± 47 days prior to flare) versus pre-nonflare (99 ± 21 days prior to nonflare) time points. Variable importance was determined by random forest analysis with logistic regression subsequently applied to determine the optimal number and type of analytes informing a refined FRI. RESULTS: Preflare versus pre-nonflare differences were not associated with demographics, autoantibody specificities, hSLEDAI scores, clinical features, nor medication usage. Forward selection and backward elimination of mediators ranked by variable importance resulted in 17 plasma mediator candidates differentiating preflare from pre-nonflare visits. A final combination of 11 mediators best informed a newly refined FRI, which achieved a maximum sensitivity of 97% and maximum specificity of 98% after applying decision curve analysis to define low, medium, and high FRI scores. CONCLUSION: We verified altered immune mediators associated with imminent disease flare, and a subset of these mediators improved the FRI to identify SLE patients at risk of imminent flare. This molecularly informed, proactive management approach could be critical in prospective clinical trials and the clinical management of lupus.

Reconciling Between Medication Orders and Medication Fills for Lupus in Pregnancy.

OBJECTIVE: Most studies consider either medications ordered or filled, but not both. Medication underuse based on filling data cannot necessarily be ascribed to patient nonadherence. Using both data sources, we quantified primary medication adherence in a cohort of prevalent systemic lupus erythematosus (SLE) pregnancies. METHODS: We identified 419 pregnancies in Kaiser Permanente Northern California in patients with prevalent SLE from 2011 to 2020. We calculated the number of physician-initiated orders or pharmacy-initiated reorders during pregnancy and a comparable 9-month window the year before (prepregnancy) and the proportion of orders ever filled and filled within 30 days for hydroxychloroquine (HCQ), azathioprine, and corticosteroids. For pregnancies without an order or reorder, we identified the proportion with previous prescription fills overlapping into the respective study period. RESULTS: New orders for lupus medications were usually filled. HCQ was prescribed most often (45.8% pregnancies) and usually filled (89.7% in prepregnancy, 93.2% during pregnancy). The majority filled within 30 days (80.5% prepregnancy, 83.3% pregnancy). Some pregnancies without new HCQ orders had continuous refills from prior orders; 53% of 2011-2015 pregnancies either had a new order or fill coverage from a previous period, compared to 63.2% of pregnancies delivering in 2016-2019. Corticosteroid fill frequencies were 90.6% in prepregnancy and 83.6% during pregnancy. Fewer patients used azathioprine; however, most new orders were filled (94.3% prepregnancy, 91.7% pregnancy). For azathioprine and corticosteroids, fill rates were modestly higher in prepregnancy compared to pregnancy. CONCLUSION: We observed that patients have high adherence to filling new orders for lupus medications, such as HCQ and azathioprine, in pregnancy.

Management of Pregnancy in Lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that primarily affects women of childbearing age. Pregnancy-related morbidity and mortality are well described in SLE; however, better management of disease activity throughout the disease course have minimized periods of disease activity and damage accrual, making pregnancy more feasible and desirable. A growing body of literature has defined risk factors for adverse pregnancy outcomes in patients with SLE, and coordinated medical and obstetric management has allowed most patients with SLE to safely achieve full-term pregnancies by timing pregnancy to maximal disease quiescence and use of pregnancy-compatible medications from preconception through lactation.

Development of a Set of Lupus-Specific, Ambulatory Care-Sensitive, Potentially Preventable Adverse Conditions: A Delphi Consensus Study.

OBJECTIVE: Individuals with systemic lupus erythematosus (SLE) are at high risk for infections and SLE- and medication-related complications. The present study was undertaken to define a set of SLE-specific adverse outcomes that could be prevented, or their complications minimized, if timely, effective ambulatory care had been received. METHODS: We used a modified Delphi process beginning with a literature review and key informant interviews to select initial SLE-specific potentially preventable conditions. We assembled a panel of 16 nationally recognized US-based experts from 8 subspecialties. Guided by the RAND-UCLA Appropriateness Method, we held 2 survey rounds with controlled feedback and an interactive webinar to reach consensus regarding preventability and importance on a population level for a set of SLE-specific adverse conditions. In a final round, the panelists endorsed the potentially preventable conditions. RESULTS: Thirty-five potential conditions were initially proposed; 62 conditions were ultimately considered during the Delphi process. The response rate was 100% for both survey rounds, 88% for the webinar, and 94% for final approval. The 25 SLE-specific conditions meeting consensus as potentially preventable and important on a population level fell into 4 categories: vaccine-preventable illnesses (6 conditions), medication-related complications (8 conditions), reproductive health-related complications (6 conditions), and SLE-related complications (5 conditions). CONCLUSION: We reached consensus on a diverse set of adverse outcomes relevant to SLE patients that may be preventable if patients receive high-quality ambulatory care. This set of outcomes may be studied at the health system level to determine how to best allocate resources and improve quality to reduce avoidable outcomes and disparities among those at highest risk.

Serologic markers of Epstein-Barr virus reactivation are associated with increased disease activity, inflammation, and interferon pathway activation in patients with systemic lupus erythematosus.

SLE is a clinically heterogeneous disease characterized by an unpredictable relapsing-remitting disease course. Although the etiology and mechanisms of SLE flares remain elusive, Epstein-Barr virus (EBV) reactivation is implicated in SLE pathogenesis. This study examined the relationships between serological measures of EBV reactivation, disease activity, and interferon (IFN)-associated immune pathways in SLE patients. Sera from adult SLE patients (n = 175) and matched unaffected controls (n = 47) were collected and tested for antibodies against EBV-viral capsid antigen (EBV-VCA; IgG and IgA), EBV-early antigen (EBV-EA; IgG), cytomegalovirus (CMV; IgG), and herpes simplex virus (HSV-1; IgG). Serological evidence of EBV reactivation was more common in SLE patients compared to controls as demonstrated by seropositivity to EBV-EA IgG (39% vs 13%; p = 0.0011) and EBV-VCA IgA (37% vs 17%; p = 0.018). EBV-VCA, CMV1, and HSV-1 IgG seropositivity rates did not differ between SLE patients and controls. Furthermore, concentrations of EBV-VCA (IgG and IgA) and EBV-EA (IgG) were higher in SLE patients. SLE patients with high disease activity had increased concentrations of EBV-VCA IgA (mean ISR 1.34 vs. 0.97; p = 0.041) and EBV-EA IgG levels (mean ISR 1.38 vs. 0.90; p = 0.007) compared with those with lower disease activity. EBV reactivation was associated with enhanced levels of the IFN-associated molecule IP-10 (p < 0.001) and the soluble mediators BLyS (p < 0.001) and IL-10 (p = 0.0011). In addition, EBV-EA IgG responses were enriched in two previously defined patient clusters with robust expression of IFN and inflammatory or lymphoid and monocyte responses. Patients in these clusters were also more likely to have major organ involvement, such as renal disease. This study supports a possible role for EBV reactivation in SLE disease activity.

Ovarian antibodies among SLE women with premature menopause after cyclophosphamide.

BACKGROUND: Women with systemic lupus erythematosus (SLE) are at risk of premature ovarian failure when treated with cyclophosphamide. This risk is increased when autoimmune thyroid disease is present. We undertook this study to determine whether the presence of ovarian autoimmunity also increased the risk of early ovarian failure among women receiving cyclophosphamide. METHODS: We examined the records of women enrolled in the Lupus Family Registry and Repository, a cross-sectional study of ~3300 SLE subjects, for treatment with cyclophosphamide as well as menopausal status. We defined premature menopause as permanent, spontaneous cessation of menstruation before age 45. We measured anti-ovarian antibodies by enzyme-linked immunosorbent assay using stored sera. RESULTS: There were 258 women treated with cyclophosphamide in whom presence of absence or premature menopause could by defined. A total of 169 (65.6%) had premature ovarian failure, while 89 (34.6%) did not. While anti-ovarian antibodies were present in a small percentage of patients, there was no association of premature menopause to either level of these antibodies (16.2 ± 20.3 units vs 17.4 ± 21.7 units, P = NS by Fisher's exact test), or positivity on this testing (11 of 169 [6.5%] positive vs 8 of 89 [8.9%], χ2  = 0.53, P = .46, 95% CI 0.95-1.1). Neither renal disease nor hypothyroidism increased the risk of premature ovarian failure in these women receiving cyclophosphamide. CONCLUSION: Anti-ovarian antibodies among women with SLE are not associated with premature ovarian failure after treatment with cyclophosphamide.

Autoantibody-positive healthy individuals with lower lupus risk display a unique immune endotype.

BACKGROUND: Autoimmune diseases comprise a spectrum of illnesses and are on the rise worldwide. Although antinuclear antibodies (ANAs) are detected in many autoimmune diseases, up to 20% of healthy women are ANA-positive (ANA+) and most will never develop clinical symptoms. Furthermore, disease transition is higher among ANA+ African Americans compared with ANA+ European Americans. OBJECTIVE: We sought to determine the immune features that might define and prevent transition to clinical autoimmunity in ANA+ healthy individuals. METHODS: We comprehensively phenotyped immune profiles of African Americans and European Americans who are ANA-negative (ANA-) healthy, ANA+ healthy, or have SLE using single cell mass cytometry, next-generation RNA-sequencing, multiplex cytokine profiling, and phospho-signaling analyses. RESULTS: We found that, compared with both ANA- and ANA+ healthy individuals, patients with SLE of both races displayed T-cell expansion and elevated expression of type I and II interferon pathways. We discovered a unique immune signature that suggests a suppressive immune phenotype and reduced CD11C+ autoimmunity-associated B cells in healthy ANA+ European Americans that is absent in their SLE or even healthy ANA- counterparts, or among African American cohorts. In contrast, ANA+ healthy African Americans exhibited elevated expression of T-cell activation markers and higher plasma levels of IL-6 than did healthy ANA+ European Americans. CONCLUSIONS: We propose that this novel immune signature identified in ANA+ healthy European Americans may protect them from T-cell expansion, heightened activation of interferon pathways, and disease transition.

2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases

To develop an evidence-based guideline on contraception, assisted reproductive technologies (ART), fertility preservation with gonadotoxic therapy, use of menopausal hormone replacement therapy (HRT), pregnancyassessment and management, and medication use in patients with rheumatic and musculoskeletal disease (RMD). 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 todetermine final recommendations and grade their strength (conditional or strong). Good practice statements wereagreed upon when indirect evidence was sufficiently compelling that a formal vote was unnecessary.. This American College of Rheumatology guideline provides 12 ungraded good practice statements and131 graded recommendations for reproductive health care in RMD patients. These recommendations are intended toguide 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/SSBantibodies. Recommendations and good practice statements support several guiding principles: use of safe andeffective contraception to prevent unplanned pregnancy, pre-pregnancy counseling to encourage conception during periods of disease quiescence and while receiving pregnancy-compatible medications, and ongoing physicianpatient discussion with obstetrics/gynecology collaboration for all reproductive health issues, given the overall low level of available evidence that relates specifically to RMD. Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to the recommendations within this guideline to be voluntary, with the ultimate determination regarding their application to be made by the clinician in light of each patient's individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes, but cannot guarantee any specific outcome. Guidelines and recommendations developed and endorsed by the ACR are subject to periodic revision, as warranted by the evolution of medical knowledge, technology, and practice. ACR recommendations are not intended to dictate payment or insurance decisions. These recommendations cannot adequately convey all uncertainties and nuances of patient care. The American College of Rheumatology is an independent, professional, medical and scientific society that does not guarantee, warrant, or endorse any commercial product or service. 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.

Lupus patient decisions about clinical trial participation: a qualitative evaluation of perceptions, facilitators and barriers.

Objective: Although SLE disproportionately affects minority racial groups, they are significantly under-represented in clinical trials in the USA. This may lead to misleading conclusions in race-based subgroup analyses. We conducted focus groups to evaluate the perceptions of diverse patients with lupus about clinical trial participation. Methods: A qualitative research design employed three 90 min focus groups led by a trained moderator and guided by the Theory of Planned Behaviour. Open-ended questions about trial participation included advantages and disadvantages (behavioural beliefs), approving and disapproving significant others (normative beliefs), and participation enhancers and barriers (control beliefs). Discussions were recorded, transcribed and analysed to identify emerging themes. Results: Patients with SLE (n=23) aged 21-72, with increased proportion of minority groups (65%), participated. Reported advantages of trial participation included altruism and personal benefit. Disadvantages included uncertainties, disappointment, information burden, and life-health balance. Although some patients had discussed research participation with approving or disapproving family or friends, self-approval superseded external approval. Barriers included logistics and time, and facilitators included flexibility in scheduling, advance notice of studies, streamlined forms, and hope for SLE improvement. Conclusions: Knowledge about potential benefits of clinical trial participation was high. Minority patients demonstrated confidence in making their own informed decisions, but major barriers for all participants included burdensome forms, travel, childcare, and work. These suggest a major impact on minority and all recruitment from behavioural and control aspects, which should be considered in the logistics of trial design. This does not minimise the potential importance of improved access and education about clinical research.

Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study.

BACKGROUND: The clinical and pathologic diversity of systemic lupus erythematosus (SLE) hinders diagnosis, management, and treatment development. This study addresses heterogeneity in SLE through comprehensive molecular phenotyping and machine learning clustering. METHODS: Adult SLE patients (n = 198) provided plasma, serum, and RNA. Disease activity was scored by modified SELENA-SLEDAI. Twenty-nine co-expression module scores were calculated from microarray gene-expression data. Plasma soluble mediators (n = 23) and autoantibodies (n = 13) were assessed by multiplex bead-based assays and ELISAs. Patient clusters were identified by machine learning combining K-means clustering and random forest analysis of co-expression module scores and soluble mediators. FINDINGS: SLEDAI scores correlated with interferon, plasma cell, and select cell cycle modules, and with circulating IFN-α, IP10, and IL-1α levels. Co-expression modules and soluble mediators differentiated seven clusters of SLE patients with unique molecular phenotypes. Inflammation and interferon modules were elevated in Clusters 1 (moderately) and 4 (strongly), with decreased T cell modules in Cluster 4. Monocyte, neutrophil, plasmablast, B cell, and T cell modules distinguished the remaining clusters. Active clinical features were similar across clusters. Clinical SLEDAI trended highest in Clusters 3 and 4, though Cluster 3 lacked strong interferon and inflammation signatures. Renal activity was more frequent in Cluster 4, and rare in Clusters 2, 5, and 7. Serology findings were lowest in Clusters 2 and 5. Musculoskeletal and mucocutaneous activity were common in all clusters. INTERPRETATION: Molecular profiles distinguish SLE subsets that are not apparent from clinical information. Prospective longitudinal studies of these profiles may help improve prognostic evaluation, clinical trial design, and precision medicine approaches. FUNDING: US National Institutes of Health.

2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases.

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 Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases.

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.