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ObjectiveSLE is associated with increased risks of maternal cardiovascular events (CVEs) as well as adverse pregnancy outcomes. The influence of maternal CVEs on pregnancy complications in lupus is not clearly known. Our primary aim was to assess the risks of adverse pregnancy outcomes in individuals with SLE, specifically examining the influence of CVEs.MethodsUsing a California population-based birth cohort from 2005 to 2020, pregnant individuals with SLE were identified via International Classification of Diseases codes on maternal discharge records and further subdivided based on whether they had lupus nephritis (LN) or antiphospholipid syndrome (APS). We analysed adjusted relative risks (aRRs) of adverse pregnancy outcomes in SLE subgroups, comparing those with and without CVEs, to the reference group of pregnant individuals without autoimmune rheumatic diseases or APS and CVEs. CVEs were broadly defined to encompass thromboembolic and cardiovascular conditions associated with SLE.ResultsCVEs complicated 17 130/7004 334 (0.2%) of pregnancies in individuals without autoimmune rheumatic diseases or APS, and 176/8422 (2.1%) with SLE, including 52/903 (5.8%) with LN and 40/513 (7.8%) with APS. Compared with the reference group, the aRRs for maternal complications were higher in SLE subgroups: non-cardiac severe maternal morbidity (3.2-fold to 31.5-fold), intensive care admission (2.0-fold to 12.2-fold), 1 year re-admission (2.4-fold to 6.0-fold) and death (7.0-fold to 7.9-fold). Similarly, adverse infant outcomes were higher: preterm birth (2.3-fold to 6.8-fold), small-for-gestational-age infant (1.8-fold to 3.4-fold), neonatal intensive care admission (2.1-fold to 7.9-fold) and infant death (1.6-fold to 3.7-fold), with highest risk estimates for SLE with LN or APS, particularly when complicated by CVEs.ConclusionsLN and APS in SLE contributed to incremental risks for adverse outcomes, with the combination of LN or APS with CVEs yielding the highest point estimates. This underscores the importance of disease severity but also the impact of CVEs, helping to individualise the risks of pregnancy complications for various SLE subpopulations.

ObjectiveSLE is prevalent among women of reproductive age, increasing the risk of adverse pregnancy outcomes (APOs). However, the correlation between the onset time of SLE and APOs remains unclear. This study aimed to analyse and compare pregnancy outcomes and clinical characteristics among three groups of patients with SLE: those with childhood onset, onset in adulthood before pregnancy and onset in adulthood during pregnancy.MethodsA retrospective analysis was conducted on pregnant women with SLE admitted to Nanfang Hospital of Southern Medical University from 2010 to 2024. Patients were categorised based on the onset time of SLE. Clinical features, laboratory characteristics, medication and pregnancy outcomes were compared among three groups. Logistic regression analyses were used to explore the relationship between the onset time of SLE and APOs.ResultsThe study included a total of 251 pregnancies from 223 women. Pregnant women with SLE onset in adulthood during pregnancy had more pronounced multisystem disorders, higher disease activity and an increased incidence of APOs. SLE onset in adulthood during pregnancy was associated with a higher risk of fetal loss (OR=5.342, 95% CI 1.629 to 17.520, p=0.006) and premature birth (OR=6.390, 95% CI 1.244 to 32.828, p=0.026).ConclusionsPatients with SLE onset in adulthood during pregnancy exhibit more aggressive disease manifestations and higher rates of APOs, while women with childhood-onset or pre-pregnancy-onset SLE had a lower risk. The incidence of APOs does not correlate with disease duration if maternal disease is quiescent in the period before conception. Closer monitoring and tailored management strategies are needed for these patients.

ObjectiveIt is still a matter of debate whether low-dose acetylsalicylic acid (LDASA) should be prescribed to all patients with SLE during pregnancy. This study aimed at investigating the impact of LDASA on pregnancy outcomes in patients with SLE without history of renal involvement and without antiphospholipid antibodies (aPL).MethodsThis is a retrospective analysis of prospectively monitored pregnancies at seven rheumatology centres. Previous/current renal involvement and aPL positivity were the exclusion criteria. Adverse pregnancy outcome (APO) is the composite outcome of the study and included proteinuric pre-eclampsia, preterm delivery <37 weeks, small-for-gestational age infant, low birth weight <2500 g, intrauterine growth restriction and intrauterine fetal death after 12 weeks of gestation of a morphologically normal fetus.Results216 pregnancies in 187 patients were included; 82 pregnancies (38.0%) were exposed to LDASA treatment. No differences in terms of age at conception, disease duration, clinical manifestations, comorbidities and disease flare during pregnancy were observed between patients taking LDASA and those who did not take LDASA during pregnancy. APO was observed in 65 cases (30.1%), including 13 cases (6.1%) of pre-eclampsia. The incidence of all complications was similar in the two groups. However, it is interesting to note that pre-eclampsia had lower frequency in patients taking LDASA versus those not taking LDASA (2.4% vs 8.3%, p=0.14).ConclusionsIn pregnant patients with SLE without renal involvement and were aPL-negative, there is a low risk of severe obstetric complications, such as early pre-eclampsia. LDASA treatment does not provide a statistically significant advantage over these complications. However, a careful individual risk–benefit balance is warranted.

IntroductionSLE is an autoimmune disease with an increased risk for poor outcomes in pregnancy. In 2020, ACR specified several recommendations to assist clinicians in preparing patients with SLE and other rheumatic diseases for pregnancy management, with the intention of risk reduction for both the mother and developing fetus.1 Two recommendations that are of particular importance in managing SLE pregnancies are to initiate low dose aspirin (LDA) and continuation of hydroxychloroquine (HCQ) therapy. We investigated whether the rate of adherence to these guidelines increased after their release at a single healthcare site.MethodsWe identified all patients at Northwestern Medicine (NM) with 4 or more encounters billed for SLE, with at least one SLE encounter billed by a rheumatologist. Using diagnosis and procedure codes, we ascertained the approximate start and end dates of pregnancies that occurred following the first SLE diagnosis among these patients from 2012 to 2022. Next, we identified the presence of LDA if a medication order for low dose or baby aspirin occurred from 6 months prior to the beginning of pregnancy up to the end of the first trimester. The presence of HCQ therapy was determined by medication orders for HCQ occurring either 6 months before or during the pregnancy. The presence of antiphospholipid (APL) antibodies was determined if anti-cardiolipin, anti-beta-2-glycoprotein, or lupus anticoagulant were positive on two separate occasions 12 or more weeks apart. Finally, the number of pregnancies during which patients received specific ACR guidelines over the study period were summarized over time, before and after the start of 2020, and further delineated by patient APL status at the time of pregnancy.ResultsWe identified 529 pregnancies among people with SLE that occurred over the study period from 3,312 total female patients meeting our SLE identification algorithm. Overall, there was a general upward trend in the rates of patients receiving HCQ, LDA, or both over the study period (figure 1). The rates of pregnancies during which both LDA and HCQ were administered were 34% and 39% (p = 0.30) before 2020 and following the start of 2020, respectively (table 2). A larger, although non-significant, increase was also observed among patients with two different positive APLs, where the rate increased from 37% to 50% (p = 0.55) (table 1).DiscussionOur results suggest that there was only a modest, non-significant increase in implementing ACR guidelines for SLE in pregnancy in our health system following their release. Limitations include the single-center nature of the study and short follow-up period after implementation of the guidelines. It is anticipated that the recommended care will continue to increase as the guidelines are disseminated more widely. To obtain a sample with adequate size to study changes in prescribing patterns for pregnancy among patients with SLE in a broader context, future work will focus on implementation of our SLE and pregnancy identification strategies in a larger data network derived from multiple healthcare sites.ReferenceSammaritano LR, Bermas BL, Chakravarty EE, Chambers C, Clowse MEB, Lockshin MD, et al. 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases. Arthritis Care & Research. 2020;72(4):461–88.Abstract 604 Table 1Cohort summary statistics over the study period N Patients 505 ICD Coded SLE Encounters Mean (SD) 44.8 (46.9) Median [Min, Max] 28.0 [4, 282] Rheumatology SLE Encounters Mean (SD) 20.7 (23.6) Median [Min, Max] 12 [1, 141] Race: N (%) White 243 (48) Black or African American 140 (27) Asian 30 (5) Other or Unknown 92 (18) Age at First SLE Encounter Mean (SD) 31.1 (7.22) Median [Min, Max] 30.9 [15.8, 58.1] Age at First SLE Pregnancy Mean (SD) 31.7 (5.8) Median [Min, Max] 31.8 [18, 45] Abstract 604 Figure 1Use of ACR recommendations over timeAbstract 604 Table 2Implementation of ACR Recommendations before and after the start of 2020 Pre 2020 2020–2022 All Pregnancies p = 0.30 N Pregnancies 357 172 0 Guidelines 51 (14) 26 (15) LDA or HCQ 185 (52) 79 (46) LDA & HCQ 121 (34) 67 (39) 0 Positive APL Tests P = 0.64 N Pregnancies 282 141 0 Guidelines 39 (14) 24 (17) LDA or HCQ 145 (51) 64 (45) LDA & HCQ 98 (35) 53 (38) 1 Positive APL Test P = 0.81 N Pregnancies 48 11 0 Guidelines 9 (19) 2 (18) LDA or HCQ 26 (54) 5 (45) LDA & HCQ 13 (27) 4 (36) 2 Positive APL Tests p = 0.55 N Pregnancies 25 20 0 Guidelines 3 (11) 0 (0) LDA or HCQ 14 (52) 10 (50) LDA & HCQ 10 (37) 10 (50)

Background>36,000 Veterans have been diagnosed with systemic lupus erythematosus (SLE). With the SLE and cutaneous lupus (CLE) cases and unaffected controls in MVP, we performed a genome-wide association study (GWAS).MethodsCases with two SLE (phe_695_42) or CLE (phe_695_41) (S/CLE) qualifying diagnoses were compared to controls with none of 44 idiopathic inflammatory, autoimmune, and laboratory concept codes. We used OHDSI Atas and Gen3 GWAS. The 104 and 11 published non-Hispanic white (European (EU) and black (admixed African (AA)) SLE risk loci were queried in the MVP at - log_pc>3.3 and -log_pc>2.3, respectively.ResultsMVP S/CLE has 2,629 cases, containing 1,575 males, 1,054 females with 1,396 EU and 982 AA; 489,637 controls qualify.GWAS for 1,396 EU Veterans with S/CLE compared to 352,354 controls has χ2 inflation of 1.041. Of 6,419 genetic markers in 7 loci at -log_p>7.3, HLA has 6,310 (98.3%) with C4B being most associated at -log_p=24.4. Also, IRF5 (Ch-7), -log p=12.6; ITGAM (Ch-16), -log_p=11.9; NCF2 (Ch- 1), -log_p=10.1; STAT4 (third intron) (Ch-2), -log_p=10.1; TNFAIP3 (Ch-6), -log_p=7.4; and IKZF1 (Ch-7), -log_p=7.3 (figure 1).The GWAS for the 982 AA MVP Veterans in S/CLE compared to 91,062 controls has 1.029 inflation. With HLA-DQA1, -log_p=14.6; ITGAM (Ch-16), -log_p=14.5; and POTEA (Ch-8), -log_p=8.1. POTEA has 12 variants exceeding -log_p>7.3, representing a probable convincing locus (figure 1).Of the 106 EU and 11 AA SLE risk loci now known at -log_p>7.3, at least, 26 of 106 (25%) at - log_p>3.3 and 5 of 11 (45%) at -log_p>2.3 are in the EU SLE and 19 of 106 and 5 of 11 in AA SLE are found in these MVP data.ConclusionWhile the MVP GWAS of S/CLE in MVP reproduces many known SLE risk loci in EU and AA, findings also highlight genetic divergence between these ancestries, such as the differences in and near ITGAM and the novel AA locus at POTEA.Abstract 701 Figure 1Comparative MVPGW/l5 Analysis of Lupus (SLE or CLE) for the non-Hispanic Black andnon-Hispanic White VeteransGWASof non-Hispanic Slack lupuscases(n=982) vs controls• {n=91,062} on left, withGWASof non-Hispanic lupus cases(n=1396) vs controls• (n=3S2,3S4}on right.• Controls exduded 44 conce-pu for autoimmune or immune mediated conditions, as wellaspositive relevant tab results.

DisclosuresAME, JLR, MEBC: Exagen, ImmunovantFundingDuke CTSA grant ( UL1TR002553 )BackgroundThe Type 1 & 2 SLE Model encompass symptoms classically attributed to inflammation, including arthritis, rash, serositis and nephritis (Type 1 SLE), and symptoms of fatigue, widespread pain, mood disturbance, and brain fog (Type 2 SLE). Our preliminary data suggest there are at least two distinct sub-types of Type 2 SLE, one related to active inflammation and another that exists regardless of inflammation. The objective of this study was to use longitudinal measures of Type 1 and Type 2 SLE activity to identify subgroups of Type 2 SLE.MethodsSLE patients meeting Systemic Lupus Collaborating Clinics (SLICC) criteria with ≥2 visits at a university rheumatology clinic over a 36-month period between February 2018 and August 2022 were included. At each visit, rheumatologists scored Type 1 and 2 SLE activity separately by Physician’s Global Assessments (PGA), visual analog scales of 0–3 (0=no activity, 3=severe activity). Growth mixture models derived classes of patients based on their Type 1 and Type 2 PGA trajectories, and posterior probabilities assigned patients to the class with the highest probability. Patients were then classified according to their classes of Type 1 and Type 2 PGA trajectories into different ‘groups’. Clinical and demographic characteristics were compared across groups.ResultsWe included 297 patients with 2,011 visits. The best model fit of trajectories for both the Type 1 and Type 2 PGA included three classes. When patients were grouped according to their Type 1 and Type 2 PGA classes, the majority (73%) fell into one of four groups: 29% had low Type 1 and Type 2 activity (Minimal); 19% had constant high Type 2 but low Type 1 activity (Type 2); 7% had constant high Type 1 but low Type 2 activity (Type 1); and 18% had constant high Type 1 and Type 2 activity (Mixed). The remaining 27% of patients had variable Type 1 and Type 2 changes over time that did not fit into a distinct group (figure 1).Patients in the Type 2 SLE group were older and more likely to be on disability (table 1). While the SLEDAI and Type 1 PGA scores were similar between the Type 1 and Mixed groups, the disease manifestations were somewhat different, with more nephritis in the Type 1 group and higher LFA-REAL Musculoskeletal PGA scores in the Mixed group. While overall Type 2 PGA scores were similar for those in the Type 2 and Mixed groups, there was more depression, pain, and symptom severity among those in the Mixed group.In a descriptive analysis to determine if Type 1 and Type 2 PGA changed concordantly, 39% of patients had Type 1 and Type 2 SLE PGAs that consistently changed together.ConclusionWe identified four main longitudinal subgroups of patient trajectories. Supporting our prior qualitative work, we found changes in Type 1 and Type 2 occurred together in almost 40% of patients. Future work is needed to understand the underlying etiology of each subgroup, allowing us to target these groups with appropriate medical and non-medical treatments.Abstract 605 Figure 1Spaghetti plots showing the individual trajectories of Type 1 and 2 PGAs for patients in each group.Abstract 605 Table 1Cohort characteristics Minimal Type 2 SLE Type 1 SLE Mixed SLE Not classified p- value n=87 n=55 n=21 n=56 n=78 Age 45.8 (13.9) 48.0 (12.8) 37.8 (13.3) 40.1 (13.4) 40.3 (12.2) 0.0005 Female 78 (89.7%) 54 (98.2%) 18 (85.7%) 53 (94.6%) 72 (92.3%) 0.2486 Black 49 (56.3%) 27 (49.1%) 13 (61.9%) 34 (60.7%) 44 (57.1%) 0.1820 Hispanic Ethnicity 1/87 (1.1%) 3/54 (5.6%) 4/21 (19.0%) 1/56 (1.8%) 4/76 (5.3%) 0.0071 Disability 13/84 (15.5%) 23/51 (45.1%) 3/19 (15.8%) 20/50 (40.0%) 22/71 (31.0%) 0.0010 Medicare/Medicaid 30/83 (36.1%) 29/51 (56.9%) 7/19 (36.8%) 29/53 (54.7%) 28/72 (38.9%) 0.0583 Depression 12/76 (15.8%) 18/46 (39.1%) 4/18 (22.2%) 28/45 (62.2%) 29/61 (47.5%) <.0001 Total areas of widespread pain across visits 1.6 (1.7) 4.4 (3.1) 1.7 (1.7) 6.0 (3.6) 3.8 (3.1) <.0001 Symptom severity score across visits 2.5 (1.7) 6.4 (2.2) 2.6 (1.7) 7.3 (2.2) 5.7 (3.0) <.0001 Total FSS (also known as PSD) across visits 4.3 (3.1) 11.2 (4.7) 4.5 (2.9) 14.5 (5.4) 10.2 (6.0) <.0001 Active lupus nephritis during study period 8/87 (9.2%) 10/55 (18.2%) 13/21 (61.9%) 19/56 (33.9%) 29/78 (37.2%) <.0001 Clinical SLEDAI across visits 0.3 (0.8) 0.5 (1.1) 1.5 (2.2) 2.3 (2.4) 3.5 (2.8) <.0001 SELENA-SLEDAI across visits 1.2 (1.4) 1.4 (1.6) 4.7 (2.1) 4.7 (2.8) 3.6 (2.5) <.0001 Musculoskeletal PGA across visits 0.0 (0.1) 0.2 (0.2) 0.2 (0.3) 0.6 (0.4) 0.3 (0.3) <.0001 Mucocutaneous PGA across visits 0.1 (0.1) 0.1 (0.1) 0.5 (0.5) 0.4 (0.5) 0.3 (0.4) <.0001 Type 1 PGA across visits 0.1 (0.1) 0.3 (0.2) 0.9 (0.3) 1.0 (0.4) 0.8 (0.3) <.0001 Type 2 PGA across visits 0.2 (0.2) 1.1 (0.4) 0.3 (0.2) 1.2 (0.4) 0.9 (0.5) <.0001 Numbers are presented as n (%) or mean (SD)

ObjectiveTo achieve consensus on a definition of remission in SLE (DORIS).BackgroundRemission is the stated goal for both patient and caregiver, but consensus on a definition of remission has been lacking. Previously, an international task force consisting of patient representatives and medical specialists published a framework for such a definition, without reaching a final recommendation.MethodsSeveral systematic literature reviews were performed and specific research questions examined in suitably chosen data sets. The findings were discussed, reformulated as recommendations and voted on.ResultsBased on data from the literature and several SLE-specific data sets, a set of recommendations was endorsed. Ultimately, the DORIS Task Force recommended a single definition of remission in SLE, based on clinical systemic lupus erythematosus disease activitiy index (SLEDAI)=0, Evaluator’s Global Assessment <0.5 (0–3), prednisolone 5 mg/day or less, and stable antimalarials, immunosuppressives, and biologics.ConclusionThe 2021 DORIS definition of remission in SLE is recommended for use in clinical care, education, and research including clinical trials and observational studies.

Acute kidney injury (AKI), previously termed acute renal failure, is associated with increased mortality, prolonged hospital stay, and accelerated chronic kidney disease (CKD). Over the past 2 decades, dramatic rises in the incidences of AKI have been reported, particularly within the United States. The question arises as to whether these changes reflect actual increases in disease incidence, or are potentially explained by the introduction of consensus definitions that rely on small standardized changes in serum creatinine, changes in coding and reimbursement, or increasingly available and more liberal use of dialysis. In this review, we explore the secular trends in AKI incidence in North America and Western Europe and its potential contributors.

The magnitude of the suspected increase in risk of acute interstitial nephritis among proton pump inhibitor users is uncertain. Here, we conducted a nested case-control study using routinely collected national health and drug dispensing data in New Zealand to estimate the relative and absolute risks of acute interstitial nephritis resulting in hospitalization or death in users of proton pump inhibitors. The cohort included 572,661 patients without a history of interstitial nephritis or other renal diseases who started a new episode of proton pump inhibitor use between 2005 and 2009. Cases had a first diagnosis after cohort entry of acute interstitial nephritis confirmed by hospital discharge letter or death record, and renal histology (definite, 46 patients), or discharge letter or death record only (probable, 26 patients). Ten controls, matched by birth year and sex, were randomly selected for each case. In the case-control analysis based on definite cases and their controls, the unadjusted matched odds ratio (95% confidence interval) for current versus past use of proton pump inhibitors was 5.16 (2.21–12.05). The estimate was similar when all cases (definite and probable) and their corresponding controls were analyzed, and when potential confounders were added to the models. The crude incidence rates and confidence intervals per 100,000 person-years were 11.98 (9.11–15.47) and 1.68 (0.91–2.86) for current and past use, respectively. Thus, current use of a proton pump inhibitor was associated with a significantly increased risk of acute interstitial nephritis, relative to past use.

BackgroundStrong evidence supports Epstein-Barr virus (EBV) being an original cause for most cases of both systemic lupus erythematosus (SLE) and multiple sclerosis (MS). The Million Veteran Program (MVP) data reduces artifacts from technical processing and Veteran life experience providing a basis for disease comparisons. We compared SLE to MS to find define the similar and different genetic variants that alter risk for these disorders.MethodsCases had the relevant concept code twice. Cutaneous and systemic lupus (C/SLE) cases were combined. After removing 44 concept codes (inflammatory conditions, labs), controls were tested against: I. MS, II. S/CLE, conditioned on age and sex. Additional case and control GWAS analyses: III. C/SLE versus MS (C/SLEvsMS), IV. C/SLE or MS versus controls (C/SLEorMS); and V. Men versus women from C/SLEvsMS. The 106 and 11 known SLE loci in non-Hispanic whites and blacks (European (EA) and admixed African (AA) ancestries), respectively, were evaluated in S/CLE, MS, C/SLEvsMS, and C/SLE&MS.ResultsOnly European ancestry provided pertinent results at -log_p>7.3 (figure 1). S/CLE had 1,396 and MS had 2,815 cases (20 shared) with 352,354 controls. The S/CLE and MS GWASs confirm known MS loci at HLA-DRB5 and for S/CLE at NCF2, STAT4, C4B, IKZF1, IRF5, ITGAM. We find three kinds of results: 1. Disease specific (separate genetic mechanisms): NCF2, HLA-DRB5, C4B, IRF5, ITGAM; 2. Neutral (a similar contribution from both disorders): STAT4, TNFAIP3; and 3.Accentuated (opposing risk alleles in S/CLE and MS): R3HDM1 (-log_p=9.1), overlapping an established SLE locus (-log_p>7.3).ConclusionsThis novel approach has the potential to identify the similarities and differences in genetic mechanisms between phenotypes. Power to establish MS associations at -log_p>7.3 outside of HLA is inadequate in the available MVP data release. Some S/CLE loci appear to be disease specific and may not be involved in MS pathogenesis. Opposing alleles increase risk of S/CLE and MS at R3HDM1, perhaps involving lactase expression and the microbiome in pathogenesis. These data are consistent with R3HDM1, STAT4 and TNFAIP3 being involved in genetic mechanisms responsible for both S/CLE and MS.Abstract 702 Figure 1Comparative GWAS Analysis Between Lupus (SLE or CLE) and Multiple Sclerosis (MS), non-Hispanic White (European Ancestry (EU)) in the Million Veteran Program (MVP). lA. Lupus cases (n=1396) on left, MS cases (n=2815) on right, with both GWAS conducted with matching controls (n=352,354) excluding 44 concepts for autoimmune or immune mediated conditions, as well as positive relevant lab results. 1B. On the left, GWAS of Lupus as cases using MS as controls. On right, GWAS of those with either Lupus or MS combined (n=4191), compared to controls excluding the 44 concepts used in lA.